Comprehensive Pediatric Hospital Medicine [2 ed.] 9780071829298

Table of contents :
Cover Page
Title Page
Copyright Page
Dedication Page
Contents
Section Editors
Contributors
Foreword
Preface
Part I Inpatient Pediatric Medicine
1 Understanding the Value of Pediatric Hospitalists: Studies of Efficiency, Education, Care Processes, and Quality of Care
2 Variation in Healthcare
3 Evidence-Based Medicine
4 Overview: Quality of Care
5 Infection Control for Pediatric Hospitalists
6 Electronic Health Records and Clinical Decision Support
7 Family-Centered Care
8 Medical Comanagement and Consultation
9 Child Development: Implications for Inpatient Medicine
10 Palliative Care
11 Communication and Discharge Planning
12 Ethical Issues in Pediatric Hospital Practice
13 Medicolegal Issues in Pediatric Hospital Medicine
14 Hospitalist Professional Organizations and Models of Care
15 Careers in Hospital Medicine
Part II Common Presenting Signs and Symptoms
16 Abdominal Mass
17 Abdominal Pain
18 Acidosis
19 Altered Mental Status
20 Chest Pain
21 Cyanosis
22 Diarrhea
23 Failure to Thrive
24 Fever
25 Gastrointestinal Bleeding
26 Hypertension
27 Hypoglycemia
28 Hypoxemia
29 Irritability and Intractable Crying
30 Limp
31 Lymphadenitis
32 Oral Lesions and Oral Health
33 Neck Pain
34 Petechiae and Purpura
35 Respiratory Distress
36 Shock
37 Syncope
38 Vomiting
Part III Systems Approach
Section A: Abuse and Neglect
39 Cutaneous Injuries of Concern for Nonaccidental Trauma
40 Abusive Head Trauma
41 Imaging of Child Abuse
42 Medical Child Abuse: Münchausen Syndrome by Proxy and Other Manifestations
43 Legal Issues
Section B: Adolescent Medicine
44 Eating Disorders
45 Sexually Transmitted Infections in Adolescents and Young Adults
46 Abnormal Uterine Bleeding
Section C: Allergy and Immunology
47 Anaphylaxis
48 Drug Allergy
49 Primary Immunodeficiency Diseases
50 Immunoglobulin
Section D: Cardiology
51 The Cardiac Examination
52 Electrocardiogram Interpretation
53 Congenital Heart Disease
54 Infective Endocarditis
55 Myocarditis and Cardiomyopathy
56 Pericarditis
57 Acute Rheumatic Fever
Section E: Dermatology
58 Purpura
59 Vesicles and Bullae
60 Vascular Anomalies
61 Atopic Dermatitis
62 Ecthyma Gangrenosum
63 Drug-Associated Rashes
64 Erythema Multiforme
65 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
66 Skin Disease in Immunosuppressed Hosts
67 Epidermolysis Bullosa
Section F: Endocrinology
68 Diabetes Mellitus and Hyperglycemia
69 Disorders of Thyroid Hormone
70 Disorders of Pituitary Function
71 Disorders of Calcium Metabolism
72 Disorders of the Adrenal Gland
Section G: Fluids and Electrolytes
73 Dehydration
74 Fluid and Electrolyte Therapy
Section H: Gastroenterology and Nutrition
75 Biliary Disease
76 Constipation
77 Dyspepsia
78 Disorders of Gastric Emptying
79 Liver Failure
80 Inflammatory Bowel Disease
81 Malnutrition
82 Pancreatitis
83 Feeding Issues
Section I: Genetics and Metabolism
84 Genetic Syndromes Caused by Chromosomal Abnormalities
85 Hyperammonemia
86 Hypoglycemia
87 Metabolic Acidosis
Section J: Hematology
88 Anemia
89 Management of Sickle Cell Disease
90 Neutropenia and Bone Marrow Failure
91 Thrombocytopenia
92 Disorders of Coagulation and Thrombosis
93 Transfusion Medicine
Section K: Infectious Diseases
94 Empirical Treatment of Bacterial Infections
95 Fever
96 Prolonged Fever and Fever of Unknown Origin
97 Fever and Rash
98 Central Nervous System Infections
99 Complications of Acute Otitis Media and Sinusitis
100 Neck and Oral Cavity Infections
101 Middle Respiratory Tract Infections and Bronchiolitis
102 Lower Respiratory Tract Infections
103 Gastrointestinal Infections
104 Urinary Tract Infections in Childhood
105 Bone and Joint Infections
106 Skin and Soft Tissue Infections
107 Device-Related Infections
108 Human Immunodeficiency Virus
109 Infections in Special Hosts
Section L: Nephrology
110 Acute Renal Failure
111 Chronic Renal Failure
112 Glomerulonephritis
113 Hemolytic Uremic Syndrome
114 Interstitial Nephritis
115 Nephrotic Syndrome
116 Renal Tubular Acidosis
117 Renal Venous Thrombosis
Section M: Neurology
118 Seizures
119 Headache
120 Hypotonia and Weakness
121 Stroke, Arteriopathy, and Vascular Malformations
122 Demyelinating Disease
Section N: Newborn Medicine
123 Delivery Room Medicine
124 The Well Newborn
125 Birth Injury
126 Congenital Anomalies
127 Transient Tachypnea of the Newborn and Persistent Pulmonary Hypertension
128 Congenital and Perinatal Infections
129 Hypoglycemia and Infants of Diabetic Mothers
130 Neonatal Hyperbilirubinemia
131 Neonatal Abstinence Syndrome
Section O: Oncology
132 Childhood Cancer
133 Oncologic Emergencies
134 Hematopoietic Stem Cell Transplant
Section P: Psychiatry
135 Depression and Physical Illness
136 Assessment and Management of the Suicidal Patient
137 Conversion and Pain Disorders
138 Agitation
139 New-Onset Psychosis
Section Q: Pulmonology
140 Apparent Life-Threatening Event, Infant Apnea, and Pediatric Obstructive Sleep Apnea Syndrome
141 Asthma
142 Aspiration
143 Bronchopulmonary Dysplasia and Chronic Lung Disease of Infancy
144 Cystic Fibrosis
145 Choking and Foreign Body Aspiration
146 Pulmonary Function Testing
Section R: Rheumatology
147 Kawasaki Disease
148 Henoch-Schönlein Purpura
149 Juvenile Dermatomyositis
150 Juvenile Idiopathic Arthritis
151 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome
152 Infection-Associated Arthritis
153 Systemic Lupus Erythematosus
Section S: Surgical Issues
154 Gastrointestinal Obstruction: Pyloric Stenosis, Malrotation and Volvulus, and Intussusception
155 Appendicitis
156 Hernias
157 General Trauma
158 Ear, Nose, and Throat
159 Neurosurgical Issues
160 Ophthalmology
161 Orthopedics
162 Burns and Other Skin Injuries
163 Pneumothorax and Pneumomediastinum
164 Urology
Section T: Toxins, Substance Abuse, and Environmental Exposures
165 Stabilization and Hospitalization of the Poisoned Child
166 Toxicity of Over-the-Counter Medications and Oral Hypoglycemic Agents
167 Hazardous Household Chemicals: Hydrocarbons, Alcohols, and Caustics
168 Lead, Other Metals, and Chelation Therapy
169 Drugs of Abuse
170 Withdrawal Syndromes
171 Fire-Related Inhalational Injury
172 Heat Disorders
173 Hypothermia and Cold-Related Injuries
174 Drowning
175 Human and Animal Bites
176 Envenomation
177 Infant Botulism
178 Anticoagulants and Antithrombotics
Section U: Care of the Child with Medical Complexity
179 Introduction to the Child with Medical Complexity
180 Acute Care of the Child with Medical Complexity
181 Managing Comorbidities in Children with Severe Neurologic Impairment
182 Technologic Devices in the Child with Medical Complexity
183 Do-Not-Attempt-Resuscitation Orders
Part IV Procedures
184 Procedural Sedation
185 Radiology for the Pediatric Hospitalist
186 Ultrasonography for the Pediatric Hospitalist
187 Lumbar Puncture
188 Cerebrospinal Fluid Shunt Assessment
189 Bladder Catheterization
190 Arterial Blood Gas
191 Vascular Access
192 Intraosseous Catheters
193 Umbilical Artery and Vein Catheterization
194 Phlebotomy
195 Noninvasive Positive-Pressure Ventilation
196 Emergent Airway Management
197 Replacing a Tracheostomy Tube
198 Thoracentesis
199 Arthrocentesis
Index

Citation preview

Comprehensive Pediatric Hospital Medicine

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Comprehensive Pediatric Hospital Medicine Second Edition Editors

Lisa B. Zaoutis, MD Associate Professor of Clinical Pediatrics Department of Pediatrics Perelman School of Medicine of the University of Pennsylvania Director, Pediatrics Residency Program The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Vincent W. Chiang, MD Chief, Inpatient Services Boston Children’s Hospital Associate Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Associate Editors

Brian Alverson, MD Director, Division of Hospital Medicine Hasbro Children’s Hospital Professor of Pediatrics Alpert Medical School Brown University Providence, Rhode Island

Sanjay Mahant, MD, FRCPC, MSc Staff Paediatrician, Division of Paediatric Medicine Associate Professor Department of Paediatrics University of Toronto Hospital for Sick Children Toronto, Canada

Samir S. Shah, MD, MSCE Director, Division of Hospital Medicine James M. Ewell Endowed Chair Attending Physician in Hospital Medicine & Infectious Diseases Cincinnati Children’s Hospital Medical Center Professor, Department of Pediatrics University of Cincinnati College of Medicine Cincinnati, Ohio

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COMPREHENSIVE PEDIATRIC HOSPITAL MEDICINE, Second Edition Copyright © 2018 by McGraw-Hill Education. All rights reserved. Printed in the China. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. 1 2 3 4 5 6 7 8 9 DSS 22 21 20 19 18 17 ISBN 978-0-07-182928-1 MHID 0-07-182928-8 e-ISBN 978-0-07-182929-8 e-MHID 0-07-182929-6 This book was set in Minion Pro by Cenveo® Publisher Services The editors were Andrew Moyer and Christie Naglieri The production supervisor was Richard Ruzycka Project management was provided by Neha Bhargava The cover designer was Randomatrix The index was prepared by Susan Hunter RR Donnelley Shenzhen was the printer and binder This book is printed on acid-free paper.

Library of Congress Cataloging-in-Publication Data Names: Zaoutis, Lisa B., editor. | Chiang, Vincent W., editor. | Shah, Samir S., editor. | Alverson, Brian, editor. | Mahant, Sanjay, editor. Title: Comprehensive pediatric hospital medicine / editors, Lisa B. Zaoutis, Vincent W. Chiang ; associate editors, Samir S. Shah, Brian Alverson, Sanjay Mahant. Description: Second edition. | New York : McGraw-Hill Education, [2017] | Includes bibliographical references and index. Identifiers: LCCN 2016051100| ISBN 9780071829281 (hardcover : alk. paper) | ISBN 0071829288 (hardcover : alk. paper)

Subjects: | MESH: Pediatrics | Hospitalists | Child, Hospitalized Classification: LCC RJ45 | NLM WS 100 | DDC 618.92—dc23 LC record available at https:// na01.safelinks.protection.outlook.com/?url=https%3A%2F%2Flccn.loc.gov%2F2016051100&data= 01%7C01%7Cjessica.gonzalez%40mheducation.com%7C1ccf4ef0dd404ca9704808d40cb7ecf2%7Cf919b1efc0c3473 JfsZWGscM78%2FO2e5Qoykzt9XpKHflhC5XPRn%2BYcsqQ8%3D&reserved=0 McGraw-Hill Education books are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative, please visit the Contact Us pages at www.mhprofessional.com.

I am grateful for the wisdom and support of my mentors, colleagues, learners, friends, and family. LBZ

Deepest thanks to all of the hospitalists with whom I have had the privilege to work on CHIPS—I am forever in your debt. I am most appreciative of Drs Fleisher, Schuster, Bachur, and Churchwell for letting me do what I do. And finally, thanks and love to my family who both support me and put up with me; especially Susanne without whom none of this would work. I am eternally grateful. VWC

Contents Section Editors Contributors Foreword Preface

PART I

Inpatient Pediatric Medicine

1 Understanding the Value of Pediatric Hospitalists: Studies of Efficiency, Education, Care Processes, and Quality of Care Rajendu Srivastava and Christopher P. Landrigan 2 Variation in Healthcare Lisa McLeod and Ron Keren 3 Evidence-Based Medicine Jonathan M. Mansbach 4 Overview: Quality of Care Jeffrey Simmons, Paul Hain, and Michele Saysana 5 Infection Control for Pediatric Hospitalists Julia S. Sammons and Susan E. Coffin 6 Electronic Health Records and Clinical Decision Support Levon Utidjian, Eric Shelov, Bimal R. Desai, and Christopher P. Bonafide 7 Family-Centered Care Vineeta Mittal and Michael T. Vossmeyer

8 Medical Comanagement and Consultation Erin Stucky Fisher 9 Child Development: Implications for Inpatient Medicine Deirdre A.L. Caplin 10 Palliative Care Tammy Kang, Lindsay Burns Ragsdale, Daniel J. Licht, Oscar H. Mayer, Gina Santucci, Malinda Ann Hill, Jennifer Hwang, and Chris Feudtner 11 Communication and Discharge Planning Daniel A. Rauch and David Zipes 12 Ethical Issues in Pediatric Hospital Practice Jennifer K. Walter, Sarah Hoehn, and Chris Feudtner 13 Medicolegal Issues in Pediatric Hospital Medicine Steven M. Selbst and Joel B. Korin 14 Hospitalist Professional Organizations and Models of Care Daniel A. Rauch and David Zipes 15 Careers in Hospital Medicine Karen Smith and Mary C. Ottolini

PART II

Common Presenting Signs and

Symptoms 16 Abdominal Mass Daniel A. Rauch 17 Abdominal Pain Timothy Gibson 18 Acidosis Chén Kenyon 19 Altered Mental Status Fabienne C. Bourgeois 20 Chest Pain David A. Kane 21 Cyanosis

Jonathan D. Hron 22 Diarrhea Amy Fleming and Carrie B. Lind 23 Failure to Thrive Stephen D. Wilson 24 Fever Sarah E.S. Parker and Kris P. Rehm 25 Gastrointestinal Bleeding April Buchanan 26 Hypertension Avram Z. Traum and Michael J.G. Somers 27 Hypoglycemia Erica Chung 28 Hypoxemia Bryan L. Stone 29 Irritability and Intractable Crying Karen E. Schetzina 30 Limp Robert Sundel 31 Lymphadenitis Amanda S. Growdon 32 Oral Lesions and Oral Health Suzanne Swanson Mendez 33 Neck Pain Matthew T. Lister and Nicole E. St Clair 34 Petechiae and Purpura Susan H. Frangiskakis 35 Respiratory Distress Juliann Lipps Kim 36 Shock Raina Paul and Andrew M. Fine 37 Syncope Sarah C. McBride

38 Vomiting Anne K. Beasley

PART III

Systems Approach

Section A: Abuse and Neglect 39 Cutaneous Injuries of Concern for Nonaccidental Trauma Celeste R. Wilson 40 Abusive Head Trauma Alice W. Newton 41 Imaging of Child Abuse Jeannette M. Pérez-Rosselló and Paul K. Kleinman 42 Medical Child Abuse: Münchausen Syndrome by Proxy and Other Manifestations Genevieve Preer 43 Legal Issues Lisa Santos Spector

Section B: Adolescent Medicine 44 Eating Disorders Zachary McClain, Daniel H. Reirden, Donald F. Schwarz, and Rebecka Peebles 45 Sexually Transmitted Infections in Adolescents and Young Adults Nadia Dowshen, Sarah Wood, and Jessica Fowler 46 Abnormal Uterine Bleeding Alison J. Culyba and Michele L. Zucker

Section C: Allergy and Immunology 47 Anaphylaxis Jordan Scott and David Riester 48 Drug Allergy Jordan Scott and David Riester 49 Primary Immunodeficiency Diseases

Manish J. Butte and Jolan E. Walter 50 Immunoglobulin Joseph D. Hernandez and Manish J. Butte

Section D: Cardiology 51 The Cardiac Examination Robert L. Geggel 52 Electrocardiogram Interpretation Douglas Y. Mah and Laura M. Bevilacqua 53 Congenital Heart Disease Barry A. Love 54 Infective Endocarditis Michael H. Gewitz 55 Myocarditis and Cardiomyopathy Robert N. Vincent, Margaret J. Strieper, and Kenneth J. Dooley 56 Pericarditis Nicole Sutton 57 Acute Rheumatic Fever David R. Fulton

Section E: Dermatology 58 Purpura Bernard A. Cohen and Anna L. Grossberg 59 Vesicles and Bullae Andrea L. Zaenglein 60 Vascular Anomalies Lily Changchien Uihlein and Marilyn G. Liang 61 Atopic Dermatitis Albert C. Yan, Christine Lauren, Paul J. Honig, and Jonathan M. Spergel 62 Ecthyma Gangrenosum Julie V. Schaffer and Mary Wu Chang 63 Drug-Associated Rashes Cynthia M.C. DeKlotz and Lawrence F. Eichenfield

64 Erythema Multiforme Leslie Castelo-Soccio 65 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reena Jethva and James R. Treat 66 Skin Disease in Immunosuppressed Hosts Emily M. Berger and Marissa J. Perman 67 Epidermolysis Bullosa Benjamin S. Bolser and Kara N. Shah

Section F: Endocrinology 68 Diabetes Mellitus and Hyperglycemia Christine T. Ferrara, Amanda M. Ackermann, and Andrew A. Palladino 69 Disorders of Thyroid Hormone Katherine Lord and Andrew A. Palladino 70 Disorders of Pituitary Function Rachana Shah 71 Disorders of Calcium Metabolism Lisa Kenigsberg and Chhavi Agarwal 72 Disorders of the Adrenal Gland Jeffrey D. Roizen and Andrew A. Palladino

Section G: Fluids and Electrolytes 73 Dehydration Philip R. Spandorfer 74 Fluid and Electrolyte Therapy Daniel T. Coghlin

Section H: Gastroenterology and Nutrition 75 Biliary Disease Amethyst C. Kurbegov 76 Constipation Michelle W. Parker 77 Dyspepsia Oren L. Koslowe and Denesh K. Chitkara

78 Disorders of Gastric Emptying Richard J. Noel 79 Liver Failure Scott A. Elisofon 80 Inflammatory Bowel Disease Michael C. Stephens and Subra Kugathasan 81 Malnutrition Jennifer Maniscalco 82 Pancreatitis Amit S. Grover and Menno Verhave 83 Feeding Issues Beth D. Gamulka

Section I: Genetics and Metabolism 84 Genetic Syndromes Caused by Chromosomal Abnormalities Jennifer M. Kalish and Elaine H. Zackai 85 Hyperammonemia Karen Smith 86 Hypoglycemia Rebecca D. Ganetzky 87 Metabolic Acidosis David Adams and Charles P. Venditti

Section J: Hematology 88 Anemia Ian J. Davis and Rupa Redding-Lallinger 89 Management of Sickle Cell Disease Matthew M. Heeney and Venée N. Tubman 90 Neutropenia and Bone Marrow Failure John D’Orazio and Akshay Sharma 91 Thrombocytopenia Samuel Volchenboum 92 Disorders of Coagulation and Thrombosis Vlad Calin Radulescu

93 Transfusion Medicine Jeremy Ryan Andrew Peña and Steven R. Sloan

Section K: Infectious Diseases 94 Empirical Treatment of Bacterial Infections Talene A. Metjian and Jeffrey S. Gerber 95 Fever Samir S. Shah and Elizabeth R. Alpern 96 Prolonged Fever and Fever of Unknown Origin Samir S. Shah and Elizabeth R. Alpern 97 Fever and Rash Angela M. Statile and Corinne L. Bria 98 Central Nervous System Infections Kimberly C. Martin and José R. Romero 99 Complications of Acute Otitis Media and Sinusitis Karen E. Jerardi and Samir S. Shah 100 Neck and Oral Cavity Infections Andrew Shriner and Benjamin Bauer 101 Middle Respiratory Tract Infections and Bronchiolitis Todd A. Florin and Samir S. Shah 102 Lower Respiratory Tract Infections Derek J. Williams and Samir S. Shah 103 Gastrointestinal Infections Jaya Goswami and Karen Kotloff 104 Urinary Tract Infections in Childhood Nader Shaikh and Alejandro Hoberman 105 Bone and Joint Infections Sanjeev K. Swami and Stephen C. Eppes 106 Skin and Soft Tissue Infections Keith W. Morley and Howard B. Pride 107 Device-Related Infections Russell McCulloh and Joanna Thomson 108 Human Immunodeficiency Virus

Ari Bitnun 109 Infections in Special Hosts Kevin J. Downes and Lara A. Danziger-Isakov

Section L: Nephrology 110 Acute Renal Failure Lindsay Chase 111 Chronic Renal Failure Lindsay Chase 112 Glomerulonephritis Michelle A. Lopez 113 Hemolytic Uremic Syndrome Sowdhamini Wallace 114 Interstitial Nephritis Jorge F. Ganem 115 Nephrotic Syndrome Joyee G. Vachani 116 Renal Tubular Acidosis Vanessa L. Hill 117 Renal Venous Thrombosis Vanessa L. Hill

Section M: Neurology 118 Seizures Christelle Moufawad El Achkar, Paul E. Manicone, and Annapurna Poduri 119 Headache Christelle Moufawad El Achkar, Annapurna Poduri 120 Hypotonia and Weakness Sabrina W. Yum 121 Stroke, Arteriopathy, and Vascular Malformations Lauren A. Beslow and Lori Billinghurst 122 Demyelinating Disease Sona Narula and Amy T. Waldman

Section N: Newborn Medicine 123 Delivery Room Medicine Kelley Shultz 124 The Well Newborn Mfon Ekong 125 Birth Injury Mark D. Hormann 126 Congenital Anomalies Mary Beth Madonna and Jonathan Frederick Bean 127 Transient Tachypnea of the Newborn and Persistent Pulmonary Hypertension Ebony Beaudoin 128 Congenital and Perinatal Infections Neera Goyal 129 Hypoglycemia and Infants of Diabetic Mothers Laura Placke Ward 130 Neonatal Hyperbilirubinemia M. Katherine Loudermilk 131 Neonatal Abstinence Syndrome Kathy E. Wedig

Section O: Oncology 132 Childhood Cancer Barbara Degar and Michael Isakoff 133 Oncologic Emergencies Andrew E. Place 134 Hematopoietic Stem Cell Transplant Christine N. Duncan

Section P: Psychiatry 135 Depression and Physical Illness Harsh K. Trivedi and Katherine A.S. Gallagher 136 Assessment and Management of the Suicidal Patient Robert L. Kitts and Patricia I. Ibeziako

137 Conversion and Pain Disorders Ashley K. Storrs and Patricia I. Ibeziako 138 Agitation Colleen A. Ryan and Michael L. Trieu 139 New-Onset Psychosis Georgina Garcia

Section Q: Pulmonology 140 Apparent Life-Threatening Event, Infant Apnea, and Pediatric Obstructive Sleep Apnea Syndrome Craig C. DeWolfe, Angela M. Statile, and Aaron S. Chidekel 141 Asthma Sigrid Payne DaVeiga, and Jonathan M. Spergel 142 Aspiration Mark I. Neuman 143 Bronchopulmonary Dysplasia and Chronic Lung Disease of Infancy Ian MacLusky 144 Cystic Fibrosis Marie E. Egan 145 Choking and Foreign Body Aspiration Aaron S. Chidekel and Natalie Hayes 146 Pulmonary Function Testing Andrea. S. Garrod and Daniel J. Weiner

Section R: Rheumatology 147 Kawasaki Disease Elizabeth Ang and Robert Sundel 148 Henoch-Schönlein Purpura Elizabeth Ang and Robert Sundel 149 Juvenile Dermatomyositis Susan Kim 150 Juvenile Idiopathic Arthritis Sampath Prahalad

151 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome Melissa M. Hazen 152 Infection-Associated Arthritis Jonathan S. Hausmann and Melissa M. Hazen 153 Systemic Lupus Erythematosus Mindy S. Lo

Section S: Surgical Issues 154 Gastrointestinal Obstruction: Pyloric Stenosis, Malrotation and Volvulus, and Intussusception Julie Story Byerley 155 Appendicitis Eric Sundel 156 Hernias William H. Peranteau and Peter Mattei 157 General Trauma Anupam Kharbanda 158 Ear, Nose, and Throat Catherine K. Hart 159 Neurosurgical Issues Sarah F. Denniston and Tamara D. Simon 160 Ophthalmology Alison E. Niebanck and Robin Ray 161 Orthopedics Martin J. Morrison, III, David A. Spiegel, and B. David Horn 162 Burns and Other Skin Injuries Marisa B. Brett-Fleegler 163 Pneumothorax and Pneumomediastinum Joshua Nagler 164 Urology Bartley G. Cilento, Jr.

Section T: Toxins, Substance Abuse, and Environmental

Exposures 165 Stabilization and Hospitalization of the Poisoned Child Kevin C. Osterhoudt 166 Toxicity of Over-the-Counter Medications and Oral Hypoglycemic Agents Diana Felton and Michele M. Burns 167 Hazardous Household Chemicals: Hydrocarbons, Alcohols, and Caustics Kirstin Weerdenburg and Yaron Finkelstein 168 Lead, Other Metals, and Chelation Therapy Rahul Kaila and Jeffrey P. Louie 169 Drugs of Abuse Heather J. Becker and Carl R. Baum 170 Withdrawal Syndromes Robert J. Hoffman and Adhi N. Sharma 171 Fire-Related Inhalational Injury George Sam Wang and Jeffrey Brent 172 Heat Disorders Lise E. Nigrovic and Michele M. Burns 173 Hypothermia and Cold-Related Injuries Jeffrey P. Louie 174 Drowning Khoon-Yen Tay and Frances M. Nadel 175 Human and Animal Bites Rebecca G. Carlisle and Phyllis Lewis 176 Envenomation Christine S. Cho and Kevin C. Osterhoudt 177 Infant Botulism Michael Del Vecchio 178 Anticoagulants and Antithrombotics Michael Levine

Section U: Care of the Child with Medical Complexity

179 Introduction to the Child with Medical Complexity Rishi Agrawal and Nancy Murphy 180 Acute Care of the Child with Medical Complexity David E. Hall, Laurie Glader, and Sangeeta Mauskar 181 Managing Comorbidities in Children with Severe Neurologic Impairment Laurie Glader, Sangeeta Mauskar, and David E. Hall 182 Technologic Devices in the Child with Medical Complexity Jeremy Friedman and Michael Weinstein 183 Do-Not-Attempt-Resuscitation Orders Armand H. Matheny Antommaria

PART IV

Procedures

184 Procedural Sedation Mythili Srinivasan and Michael Turmelle 185 Radiology for the Pediatric Hospitalist Lindsay S. Baron, Horacio Padua, Frederick Grant, and Jeanne S. Chow 186 Ultrasonography for the Pediatric Hospitalist Matthew Garber and J. Kate Deanehan 187 Lumbar Puncture Timothy Gibson 188 Cerebrospinal Fluid Shunt Assessment Christine S. Cho and Jill C. Posner 189 Bladder Catheterization Sandra Schwab 190 Arterial Blood Gas Esther Maria Sampayo and Mirna M’farrej 191 Vascular Access Frances M. Nadel, Suzanne Beno, and Anne Marie Frey 192 Intraosseous Catheters Eron Y. Friedlaender and Lauren E. Marlowe

193 Umbilical Artery and Vein Catheterization Bryan Upham, revised by Julianne Prasto 194 Phlebotomy Christine S. Cho and Jill C. Posner 195 Noninvasive Positive-Pressure Ventilation Garrett Keim, Pamela A. Mazzeo, Raj Padman, and Vanda Passi 196 Emergent Airway Management Timothy Gibson 197 Replacing a Tracheostomy Tube Kathleen M. Cronan revised by Emily Roumm Kane 198 Thoracentesis Manoj K. Mittal 199 Arthrocentesis Eron Y. Friedlaender and Adelaide E. Barnes Index

Section Editors Christopher P. Landrigan, MD, MPH [Part I] Research Director, Boston Children’s Hospital Inpatient Pediatrics Service Director, Sleep and Patient Safety Program Brigham and Women’s Hospital Associate Professor of Pediatrics and Medicine Harvard Medical School Boston Children’s Hospital Boston, Massachusetts

Amanda S. Growdon, MD [Part II] Assistant in Medicine, Boston Children’s Hospital Instructor, Harvard Medical School Boston, Massachusetts

Katherine A. O’Donnell, MD [ Part II] Attending, Hospital Medicine & Toxicology Boston Children’s Hospital Instructor in Pediatrics Harvard Medical School Boston, Massachusetts

Celeste R. Wilson, MD, FAAP [Section A] Assistant Professor of Pediatrics Harvard Medical School Medical Director, Child Protection Program Boston Children’s Hospital

Boston, Massachusetts

Carol A. Ford, MD, FSAHM [Section B] Past-President, Society for Adolescent Health and Medicine (SAHM) Professor of Pediatrics, University of Pennsylvania Chief, Division of Adolescent Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Manish J. Butte, MD, PhD [Section C] Department of Pediatrics Division of Immunology, Allergy, and Rheumatology Stanford University Stanford, California

Jordan Scott, MD [Section C] UMASS/Memorial and Children’s Hospital Boston Harvard Medical School Northeast Allergy, Asthma and Immunology Leominster, Massachusetts

Robert L. Geggel, MD [Section D] Associate Professor of Pediatrics Harvard Medical School Director, Pediatric Cardiology Consult Service Department of Cardiology Boston Children’s Hospital Boston, Massachusetts

Albert C. Yan, MD, FAAP, FAAD [Section E] Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Pediatric Dermatology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Andrew A. Palladino, MD [Section F] Assistant Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician and Medical Director of Inpatient Endocrinology Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Marc H. Gorelick, MD, MSCE [Section G] Professor of Pediatrics (Affiliate), University of Minnesota President and Chief Operating Officer Children’s Hospital of Minnesota Minneapolis, Minnesota

Menno Verhave, MD [Section H] Clinical Director, Gastroenterology Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Matthew A. Deardorff, MD, PhD [Section I] Associate Professor Perelman School of Medicine at the University of Pennsylvania Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

John D’Orazio, MD, PhD [Section J] Associate Professor in Pediatrics, Hematology-Oncology University of Kentucky College of Medicine Chandler Medical Center Lexington, Kentucky

Samir S. Shah, MD, MSCE [Section K] Director, Division of Hospital Medicine James M. Ewell Endowed Chair

Attending Physician in Hospital Medicine & Infectious Diseases Cincinnati Children’s Hospital Medical Center Professor, Department of Pediatrics University of Cincinnati College of Medicine Cincinnati, Ohio

Ricardo A Quinonez, MD, FAAP, FHM [Section L] Associate Professor of Pediatrics Section Head and Service Chief Pediatric Hospital Medicine Baylor College of Medicine Texas Children’s Hospital Houston, Texas

Dr. Daniel Licht, MD [Section M] Director, June and Steve Wolfson Laboratory for Clinical and Biomedical Optics The Children’s Hospital of Philadelphia Associate Professor of Neurology Perlman School of Medicine of the University of Pennsylvania Philadelphia, Pennsylvania

Neera Goyal, MD, MSc [Section N] Assistant Professor of Pediatrics Division of Neonatology and Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jennifer Kesselheim, MD [Section O] Assistant Professor of Pediatrics Dana-Farber/Boston Children’s Cancer and Blood Disorders Center Director, Master of Medical Sciences (MMSc) in Medical Education Harvard Medical School Boston, Massachusetts

Patricia I. Ibeziako [Section P]

Director, Psychiatry Consultation Service Boston Children’s Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts

Aaron S. Chidekel, MD [Section Q] Associate Professor of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University Chief, Division of Pulmonology Nemours/Alfred I. duPont Hospital for Children Wilmington, Delaware

Melissa M. Hazen, MD [Section R] Assistant Professor of Pediatrics Harvard Medical School Program in Rheumatology and Department of General Pediatrics Boston Children’s Hospital Boston, Massachusetts

Robert Sundel, MD [Section R] Medical Director, Center for Ambulatory Treatment and Clinical Research Program Director, Rheumatology Boston Children’s Hospital Associate Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Erin Shaughnessy, MD, MSHCM [Section S] Division Chief, Pediatric Hospital Medicine Phoenix Children’s Hospital Phoenix, Arizona

Yaron Finkelstein, MD, FACMT [Section T] Divisions of Paediatric Emergency Medicine and Clinical Pharmacology and

Toxicology, Hospital for Sick Children Professor, Departments of Pediatrics and Pharmacology and Toxicology, University of Toronto Adjunct Scientist, Institute of Clinical Evaluative Sciences Toronto, Ontario, Canada

Eyal Cohen, MD, MSc, FRCPC [Section U] Division of Paediatric Medicine, Hospital for Sick Children Associate Professor, Department of Pediatrics, University of Toronto Toronto, Ontario, Canada

Rajendu Srivastava, MD, MPH [Section U] Assistant Vice President of Research Intermountain Healthcare Salt Lake City, Utah

James M. Callaghan, MD [Part IV] Division of Emergency Medicine Children’s Hospital of Philadelphia Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Contributors Amanda M. Ackermann, MD, PhD [68] Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

David Adams, MD, PhD [87] Deputy Director of Clinical Genomics Office of the Clinical Director, NHGRI and Undiagnosed Diseases Program National Institutes of Health Bethesda, Maryland

Chhavi Agarwal, MD [71] Assistant Professor of Pediatrics Albert Einstein College of Medicine Department of Pediatrics Division of Pediatric Endocrinology and Diabetes The Children’s Hospital at Montefiore Bronx, New York

Rishi Agrawal, MD, MPH [179] Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois

Elizabeth R. Alpern, MD, MSCE [95,96] Professor of Pediatrics

Division of Emergency Medicine Department of Pediatrics Ann & Robert H. Lurie Children’s Hospital of Chicago Northwestern University, Feinberg School of Medicine Chicago, Illinois

Elizabeth Ang, MBBS, MRCPCH, MMed [147,148] Rheumatology Fellow Boston Children’s Hospital Boston, Massachusetts

Armand H. Matheny Antommaria, MD, PhD [183] Director, Ethics Center Lee Ault Carter Chair of Pediatric Ethics Associate Professor Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Adelaide E. Barnes, MD [199] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Lindsay S. Baron, MD [185] Commonwealth Radiology Associates Director of Pediatric Imaging and Ultrasound Lowell General Hospital Lowell, Massachusetts

Benjamin Bauer, MD [100] Riley Hospital for Children at Indiana University Health Indianapolis, Indiana

Carl R. Baum, MD, FAAP, FACMT [169]

Professor of Pediatrics and of Emergency Medicine Yale University School of Medicine New Haven, Connecticut

Jonathan Frederick Bean, MD [126] Surgical Research Fellow Department of Pediatric Surgery Ann & Robert H. Lurie Children’s Hospital of Chicago Resident Physician Department of Surgery University of Illinois Hospital and Health Sciences System Chicago, Illinois

Anne K. Beasley, MD [38] Pediatric Hospitalist Phoenix Children’s Hospital Phoenix, Arizona

Ebony Beaudoin, MD [127] Assistant Professor of Pediatrics Houston, Texas

Heather J. Becker, MD [169] Clinical Fellow Pediatric Emergency Medicine Yale-New Haven Children’s Hospital New Haven, Connecticut

Suzanne Beno, MD [191] Assistant Professor, Department of Paediatrics School of Medicine, University of Toronto Fellowship Director, Pediatric Emergency Medicine Division of Emergency Medicine The Hospital for Sick Children (SickKids) Toronto, Ontario, Canada

Emily M. Berger, MD [66] Department of Dermatology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Lauren A. Beslow, MD, MSCE, FAHA [121] Assistant Professor of Neurology and Pediatrics Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Laura M. Bevilacqua, MD [52] Department of Cardiology Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts

Lori Billinghurst, MD, MSc, FRCPC [121] Clinical Assistant Professor of Neurology Perelman School of Medicine at The University of Pennsylvania Attending Physician, Division of Neurology Neurology Director, Neonatal Neurocritical Care Program The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Ari Bitnun, MD, MSc, FRCPC [108] Associate Professor, Department of Pediatrics, University of Toronto Staff physician, Division of Infectious Diseases, Hospital for Sick Children Toronto, Ontario, Canada

Benjamin S. Bolser, MD [67] Attending Physician, Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Christopher P. Bonafide, MD, MSCE [6] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician, Division of General Pediatrics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Fabienne C. Bourgeois, MD, MPH [19] Pediatric Hospitalist Children’s Hospital Inpatient Service Boston Children’s Hospital Instructor in Pediatrics Harvard Medical School Boston, Massachusetts

Jeffrey Brent, MD, PhD [171] Distinguished Clinical Professor of Medicine Clinical Professor of Pediatrics University of Colorado School of Medicine Denver, Colorado

Marisa B. Brett-Fleegler, MD [162] Attending Physician Division of Emergency Medicine Boston Children’s Hospital Assistant Professor Division of Emergency Medicine Harvard Medical School Boston, Massachusetts

Corinne L. Bria, MD, MEd [97] Assistant Professor of Pediatrics University of Cincinnati College of Medicine Attending Physician Division of Pediatric Emergency Medicine Cincinnati Children’s Hospital Medical Center

Cincinnati, Ohio

April Buchanan, MD, FAAP [25] Assistant Dean for Academic Affairs and Clinical Clerkship Education Associate Professor of Pediatrics University of South Carolina School of Medicine Greenville Pediatric Hospitalist Children’s Hospital of the Greenville Health System Greenville, South Carolina

Michele M. Burns, MD, MPH [166,172] Fellowship Director: Harvard Medical Toxicology Medical Director: Regional Center for Poison Control & Prevention serving MA & RI Staff Physician: Emergency Medicine Boston Children’s Hospital Boston, Massachusetts

Manish J. Butte, MD, PhD [49,50] Associate Professor and Division Chief Division of Immunology, Allergy, and Rheumatology, Dept. of Pediatrics Director, Jeffrey Modell Diagnostic and Research Center University of California, Los Angeles

Julie Story Byerley, MD, MPH [154] Professor General Pediatrics and Adolescent Medicine Vice Dean for Education, School of Medicine Vice Chair for Education, Department of Pediatrics University of North Carolina at Chapel Hill

Deirdre A.L. Caplin, MS, PhD [9] Associate Professor Division of Pediatric Behavioral Health Department of Pediatrics University of Utah School of Medicine

Intermountain Primary Children’s Medical Center Salt Lake City, Utah

Rebecca G. Carlisle [175] Assistant Professor of Pediatrics George Washington University College of Medicine Children’s National Medical Center Washington, DC

Leslie Castelo-Soccio, MD, PhD [64] Assistant Professor of Pediatrics and Dermatology, Perlman School of Medicine at the University of Pennsylvania and Attending Physician, Section of Pediatric Dermatology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Mary Wu Chang, MD [62] Associate Clinical Professor of Dermatology and Pediatrics University of Connecticut School of Medicine West Hartford, Connecticut

Lindsay Chase, MD [110,111] Associate Professor Director of the Section of Hospital Pediatrics Division of General Pediatrics and Adolescent Medicine University of North Carolina and NC Children’s Hospital Chapel Hill, North Carolina

Aaron S. Chidekel, MD [140,145] Associate Professor of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University Chief, Division of Pulmonology Nemours/Alfred I. duPont Hospital for Children Wilmington, Delaware

Denesh K. Chitkara, MD [77]

Pediatric Gastroenterology and Nutrition Goryeb Children’s Hospital Morristown, New Jersey

Christine S. Cho, MD, MPH, MEd [176,188,194] Associate Professor of Pediatrics USC Keck School of Medicine Fellowship and Education Director Division of Emergency Medicine Children’s Hospital Los Angeles Los Angeles, California

Jeanne S. Chow, MD [185] Associate Professor Harvard Medical School Director of Fluoroscopy and Uroradiology Department of Radiology Boston Children’s Hospital Boston, Massachusetts

Erica Chung, MD [27] Assistant Professor of Pediatrics The Warren Alpert Medical School of Brown University Pediatric Hospitalist Hasbro Children’s Hospital Providence, Rhode Island

Bartley G. Cilento, Jr. [164] Assistant Professor of Surgery (Urology) Harvard Medical School Department of Urology Boston Children’s Hospital Boston, Massachusetts

Susan E. Coffin, MD, MPH [5] Professor of Pediatrics UPENN School of Medicine

Associate Chief, Division of Infectious Diseases The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Daniel T. Coghlin, MD [74] Associate Professor of Pediatrics, Clinician Educator The Warren Alpert Medical School of Brown University Pediatric Hospitalist Hasbro Children’s Hospital Providence, Rhode Island

Bernard A. Cohen, MD [58] Professor of Dermatology and Pediatrics Johns Hopkins School of Medicine Director of Pediatric Dermatology Johns Hopkins Children’s Center Baltimore, Maryland

Kathleen M. Cronan, MD [197] Nemours/Alfred I. duPont Hospital for Children Wilmington, Delaware

Alison J. Culyba, MD, MPH [46] Adolescent Medicine Fellow Craig Dalsimer Division of Adolescent Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Lara A. Danziger-Isakov, MD, MPH [109] Professor, Department of Pediatrics University of Cincinnati College of Medicine Director, Immunocompromised Host Infectious Diseases Division of Infectious Diseases Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Sigrid Payne DaVeiga, MD [141] Attending Physician Division of Allergy and Immunology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Ian J. Davis, MD, PhD [88] G. Denman Hammond Associate Professor, Division of Hematology/Oncology Department of Pediatrics Department of Genetics Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill, North Carolina

J. Kate Deanehan, MD, RDMS [186] Assistant Professor, Pediatric Emergency Medicine Director of Emergency Ultrasound Associate PEM Fellowship Director Johns Hopkins Children’s Center Baltimore, Maryland

Barbara Degar, MD [132] Associate Director of Inpatient Oncology Boston Children’s Hospital Assistant Professor in Pediatrics Harvard Medical School Boston, Massachusetts

Cynthia M.C. DeKlotz, MD [63] Pediatric and Adult Dermatologist MedStar Washington Hospital Center/Georgetown University Hospital Assistant Professor of Clinical Medicine and Pediatrics Georgetown University School of Medicine Washington, DC

Michael Del Vecchio, MD [177] Professor, Clinical Pediatrics Department of Pediatrics Lewis Katz School of Medicine at Temple University Philadelphia, Pennsylvania

Sarah F. Denniston, MD [159] Assistant Clinical Professor of Pediatrics Department of Pediatrics Division of Hospital Medicine University of Washington School of Medicine Attending Physician Seattle Children’s Hospital Seattle, Washington

Bimal R. Desai, MD, MBI, FAAP [6] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Chief Health Informatics Officer The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Craig C. DeWolfe, MD, MEd [140] Director of Pediatric Medical Student Education Assistant Professor of Pediatrics George Washington University School of Medicine Pediatric Hospitalist Children’s National Health System Washington, DC

Kenneth J. Dooley, MD [55] Children’s Healthcare of Atlanta Associate Professor of Pediatrics Emory University School of Medicine Atlanta, Georgia

John D’Orazio, MD, PhD [90] Professor in Pediatrics, Hematology-Oncology University of Kentucky College of Medicine Markey Cancer Center Lexington, Kentucky

Kevin J. Downes, MD [109] Clinical Fellow Division of Infectious Diseases Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Nadia Dowshen, MD, MSHP [45] Director of Adolescent HIV Services Craig-Dalsimer Division of Adolescent Medicine Faculty, PolicyLab The Children’s Hospital of Philadelphia Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Christine N. Duncan, MD [134] Dana-Farber/Boston Children’s Caner and Blood Disorders Center Stem Cell Transplant Center Boston, Massachusetts

Marie E. Egan, MD [144] Director, Yale Cystic Fibrosis Center Professor, Departments of Pediatrics and Cellular and Molecular Physiology Yale University New Haven, Connecticut

Lawrence F. Eichenfield, MD [63] Professor of Dermatology & Pediatrics Vice Chair, Department of Dermatology Chief, Pediatric and Adolescent Dermatology

Rady Children’s Hospital, San Diego University of California, San Diego School of Medicine San Diego, California

Mfon Ekong, MD [124] Assistant Professor of Pediatrics Division of Community & General Pediatrics University of Texas Health Science Center - Houston Houston, Texas

Scott A. Elisofon, MD [79] Attending Physician Division of Pediatric Gastroenterology Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Stephen C. Eppes, MD [105] Director, Pediatric Infectious Diseases Christiana Care Health System Professor of Pediatrics Department of Pediatrics Jefferson Medical College Newark, Delaware

Mirna M’farrej, MD [190] Associate Professor Department of Pediatrics University of Pennsylvania School of Medicine Attending Physician Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Diana Felton, MD [166]

Toxicology Fellow Harvard Medical Toxicology Fellowship Boston Children’s Hospital Boston, Massachusetts

Christine T. Ferrara, MD, PhD [68] Clinical Fellow in Pediatric Endocrinology and Diabetes Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Chris Feudtner, MD, PhD, MPH [10,12] Professor of Pediatrics, Medical Ethics and Health Policy Perelman School of Medicine, University of Pennsylvania Attending Physician and Director of Research for the Pediatric Advanced Care Team Steven D Handler Endowed Chair of Medical Ethics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Erin Stucky Fisher, MD, MHM, FAAP [8] Professor of Clinical Pediatrics and Pediatric Hospital Medicine Fellowship Director Department of Pediatrics University of California, San Diego Medical Director for Quality Management Pediatric Hospitalist Rady Children’s Hospital and Health Center San Diego San Diego, California

Andrew M. Fine, MD, MPH [36] Assistant Professor of Pediatrics and Emergency Medicine Harvard Medical School Associate in Medicine Emergency Medicine Boston Children’s Hospital

Boston, Massachusetts

Yaron Finkelstein, MD, FACMT [167] Divisions of Paediatric Emergency Medicine and Clinical Pharmacology and Toxicology, Hospital for Sick Children Professor, Departments of Pediatrics and Pharmacology and Toxicology, University of Toronto Adjunct Scientist, Institute of Clinical Evaluative Sciences Toronto, Ontario, Canada

Amy Fleming, MD, MHPE [22] Associate Dean for Medical Student Affairs Associate Professor, Department of Pediatrics Monroe Carell Jr. Children’s Hospital at Vanderbilt Vanderbilt University School of Medicine Nashville, Tennessee

Todd A. Florin, MD, MSCE [101] Assistant Professor of Pediatrics University of Cincinnati College of Medicine Director, Research Operations Division of Pediatric Emergency Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jessica Fowler, MD, MPH [45] Chief Resident Pediatric Residency Program The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Susan H. Frangiskakis, MD [34] Pediatrician Wausau, Wisconsin

Anne Marie Frey, BSN, RN, CRNI, VA-BC [191]

Clinical Expert Vascular Access Service: I.V. Team The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Eron Y. Friedlaender, MD, MPH [192,199] Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Emergency Medicine Attending Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Jeremy Friedman, MB, ChB, FRCPC [182] Associate Paediatrician-in-Chief, Hospital for Sick Children Professor of Paediatrics, University of Toronto Toronto, Ontario, Canada

David R. Fulton, MD [57] Distinguished Tommy Kaplan Chair in Cardiovascular Sciences Chief, Cardiology Outpatient Services, Emeritus Department of Cardiology Boston Children’s Hospital Associate Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Katherine A.S. Gallagher, PhD [135] Assistant Professor of Pediatrics Baylor College of Medicine Psychology Section Texas Children’s Hospital Houston, Texas

Beth D. Gamulka, MDCM, FRCPC [83] Staff Pediatrician

Department of Pediatrics The Scarborough Hospital Division of Pediatric Medicine The Hospital for Sick Children (SickKids) Adjunct Clinical Assistant Professor, Department of Pediatrics University of Toronto Faculty of Medicine Toronto, Ontario, Canada

Jorge F. Ganem, MD, FAAP [114] Assistant Professor Department of Pediatrics University of Texas at Austin Dell Medical School Director Hospital Medicine Dell Children’s Medical Center of Central Texas Austin, Texas

Rebecca D. Ganetzky, MD [86] Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Division of Human Genetics and Metabolic Diseases Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Matthew Garber, MD, FAAP, FHM [186] Professor of Pediatrics, University of Florida COM Division Chief, Hospital Pediatrics UF Hospitalist, Wolfson Children’s Hospital Medical Director, Value in Inpatient Pediatrics Network Jacksonville, Florida

Georgina Garcia, MD [139] Children’s Hospital Boston Department of Psychiatry Cambridge Eating Disorder Center Director of Adolescent Services Cambridge, Massachusetts

Andrea S. Garrod, MD [146] Assistant Professor of Pediatrics University of Virginia Health System Charlottesville, Virginia

Robert L. Geggel, MD [51] Senior Associate in Cardiology and Director of Cardiology Consult Service Boston Children’s Hospital Associate Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Jeffrey S. Gerber, MD, PhD [94] Assistant Professor of Pediatrics and Epidemiology Perelman School of Medicine at the University of Pennsylvania Medical Director, Antimicrobial Stewardship Program Associate Director, Center for Pediatric Clinical Effectiveness Division of Infectious Diseases The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Michael H. Gewitz, MD [54] Physician-in-Chief Director, Pediatric Cardiology Maria Fareri Children’s Hospital Professor and Vice Chairman Department of Pediatrics New York Medical College Valhalla, New York

Timothy Gibson, MD [17,187,196] Clinical Associate Professor of Pediatrics University of Massachusetts Medical School Worcester, Massachusetts

Laurie Glader, MD [180,181]

Associate in Medicine Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Jaya Goswami, MD [103] Pediatric Hospitalist Division of Hospitalist Medicine St. Louis Children’s Hospital St. Louis, Missouri

Neera Goyal, MD, MSc [128] Assistant Professor of Pediatrics Division of Neonatology and Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Frederick Grant, MD [185] Assistant Professor in Radiology Harvard Medical School Division of Nuclear Medicine and Molecular Imaging Department of Radiology Boston Children’s Hospital Boston Massachusetts

Anna L. Grossberg, MD [58] Assistant Professor of Dermatology and Pediatrics Johns Hopkins School of Medicine Baltimore, Maryland

Amit S. Grover, MB BCh BAO [82] Director, Boston Children’s Hospital Program for Pancreatic Disease Attending Physician Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital Instructor in Pediatrics

Harvard Medical School Boston, Massachusetts

Amanda S. Growdon, MD [31] Assistant in Medicine, Boston Children’s Hospital Instructor, Harvard Medical School Boston, Massachusetts

Paul Hain, MD [4] Vanderbilt University School of Medicine Residency, Monroe Carell Jr. Children’s Hospital at Vanderbilt Nashville, Tennessee

David E. Hall, MD [180,181] Professor of Clinical Pediatrics Director, Program for Children with Medically Complex Needs Vanderbilt University School of Medicine Monroe Carrel, Jr. Children’s Hospital at Vanderbilt Nashville, Tennessee

Catherine K. Hart, MD [158] Assistant Professor Pediatric Otolaryngology Head & Neck Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jonathan S. Hausmann, MD [152] Program in Rheumatology Boston Children’s Hospital Division of Rheumatology Beth Israel Deaconess Medical Center Instructor in Medicine Harvard Medical School Boston, Massachusetts

Natalie Hayes, DO [145]

Department of Pediatrics Division of Pulmonology Wake Forest Baptist Health Brenner Children’s Hospital Winston-Salem, North Carolina

Melissa M. Hazen, MD [151,152] Assistant Professor of Pediatrics Harvard Medical School Program in Rheumatology and Department of General Pediatrics Boston Children’s Hospital Boston, Massachusetts

Matthew M. Heeney, MD [89] Assistant Professor of Pediatrics Harvard Medical School Associate Chief, Hematology Director, Sickle Cell Program Boston, Massachusetts

Joseph D. Hernandez, MD, PhD [50] Clinical Assistant Professor Department of Pediatrics (Immunology, Allergy and Rheumatology) Stanford University, Lucile Packard Children’s Hospital Stanford, California

Malinda Ann Hill, MA [10] Bereavement Coordinator The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Vanessa L. Hill, MD [116,117] Associate Professor Department of Pediatrics Division of Pediatric Hospital Medicine

Baylor College of Medicine Children’s Hospital of San Antonio San Antonio, Texas

Alejandro Hoberman, MD [104] Chief, Division of General Academic Pediatrics Professor of Pediatrics and Clinical and Translational Science Jack L. Paradise Professor of Pediatric Research Vice Chair for Clinical Research Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania

Sarah Hoehn, MD, MBE [12] Associate Professor of Pediatrics University of Kansas School of Medicine Kansas City, Kansas

Robert J. Hoffman, MS, MD [170] Director, Clinical Toxicology Department of Emergency Medicine Sidra Medical & Research Center Doha, Qatar

Paul J. Honig, MD [61] Professor Emeritus, Pediatrics and Dermatology Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Mark D. Hormann, MD [125] Associate Professor of Pediatrics McGovern Medical School at The University of Texas Health Science Center at Houston Medical Director, Newborn Nursery Children’s Memorial Hermann Hospital Houston, Texas

B. David Horn, MD [161] Associate Professor of Clinical Orthopedic Surgery Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Jonathan D. Hron, MD [21] Pediatric Hospitalist, Division of General Pediatrics Boston Children’s Hospital Instructor of Pediatrics Harvard Medical School Boston, Massachusetts

Jennifer Hwang, MD, MHS [10] Fellowship Director, Pediatric Advance Care Team The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Michael Isakoff, MD [132] Associate Professor of Pediatrics University of Connecticut School of Medicine Clinical Director, Division of Hematology and Oncology Director, Sarcoma and Adolescent and Young Adult Cancer Program Connecticut Children’s Medical Center Hartford, Connecticut

Patricia I. Ibeziako, MD [136,137] Director, Psychiatry Consultation Service Boston Children’s Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts

Karen E. Jerardi, MD, MEd [99] Assistant Professor, Department of Pediatrics University of Cincinnati College of Medicine

Associate Director, Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Reena Jethva, MD [65] Hackensack University Medical Center Hackensack, New Jersey

Rahul Kaila, MD [168] Assistant Professor Department of Pediatrics University of Minnesota Masonic Children’s Hospital Minneapolis, Minnesota

Jennifer M. Kalish, MD, PhD [84] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician, Genetics Division The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

David A. Kane, MD [20] Assistant Professor of Pediatrics Division of Pediatric Cardiology University of Massachusetts Medical School Worcester, Massachusetts

Tammy Kang [10] Chief, Section of Palliative Care at Texas Children’s Hospital Associate Professor of Pediatrics, Baylor College of Medicine Houston, Texas

Emily Roumm Kane, MD, MS [197] Division of General Pediatrics The Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

Garrett Keim, MD [195] Fellow, Pediatric Critical Care Department of Critical Care and Anesthesia The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Lisa Kenigsberg, MD [71] Albert Einstein College of Medicine Department of Pediatrics Division of Pediatric Endocrinology and Diabetes The Children’s Hospital at Montefiore Bronx, New York

Chén Kenyon, MD, MSHP [18] Assistant Professor of Pediatrics Perelman School of Medicine, University of Pennsylvania Pediatric Hospitalist The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Ron Keren, MD, MPH [2] Professor of Pediatrics and Epidemiology Perelman School of Medicine at the University of Pennsylvania Gerald D. Quill Distinguished Chair in the Department of Pediatrics Vice President of Quality and Chief Quality Officer The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Anupam Kharbanda, MD, MSc [157] Chief, Critical Care Services Children’s Hospital Minnesota Minneapolis, Minnesota

Juliann Lipps Kim, MD [35]

Department Lead, Pediatric Hospital Medicine Palo Alto Medical Foundation Adjunct Assistant Clinical Professor of Pediatrics Stanford University Palo Alto, California

Susan Kim, MD, MMSc [149] Associate Clinical Professor Pediatric Rheumatology UCSF Benioff Children’s Hospital University of California San Francisco, California

Robert L. Kitts, MD [136] Assistant Professor of Psychiatry, Harvard Medical School Attending Physician Department of Psychiatry, Massachusetts General Hospital Boston, Massachusetts

Paul K. Kleinman, MD, FAAP [41] Professor of Radiology Harvard Medical School Director of Musculoskeletal Imaging Boston Children’s Hospital Boston, Massachusetts

Joel B. Korin [13] Attending Physician Division of Emergency Medicine Nemours/Alfred I. duPont Hospital for Children Wilmington, Delaware

Karen Kotloff [103] Head, Division of Infectious Disease and Tropical Pediatrics

Professor of Pediatrics and Medicine Center for Vaccine Development Institute of Global Health University of Maryland School of Medicine Baltimore, Maryland

Subra Kugathasan, MD [80] Professor of Pediatrics & Human Genetics Marcus Professor of Pediatric Gastroenterology Emory University School of Medicine Atlanta, Georgia

Amethyst C. Kurbegov, MD, MPH [75] Assistant Professor of Pediatric Gastroenterology University of Colorado School of Medicine Colorado Springs, Colorado

Oren L. Koslowe, MD [77] Pediatric Gastroenterology and Nutrition Goryeb Children’s Hospital Morristown, New Jersey

Christopher P. Landrigan, MD, MPH [1] Research Director, Boston Children’s Hospital Inpatient Pediatrics Service Director, Sleep and Patient Safety Program Brigham and Women’s Hospital Associate Professor of Pediatrics and Medicine Harvard Medical School Boston Children’s Hospital Boston, Massachusetts

Christine Lauren, MD [61] Assistant Professor of Dermatology and Pediatrics Columbia University Medical Center New York, New York

Michael Levine, MD [178] Section of Medical Toxicology Department of Emergency Medicine University of Southern California Los Angeles, California

Phyllis Lewis [175] Assistant Professor of Pediatrics George Washington University College of Medicine Children’s National Medical Center Washington, DC

Marilyn G. Liang, MD [60] Associate Professor of Dermatology Boston Children’s Hospital Harvard Medical School Boston, Massachusetts

Daniel J. Licht, MD [10] Dir. June and Steve Wolfson Laboratory for Clinical and Biomedical Optics Associate Professor of Neurology The Children’s Hospital of Philadelphia and The University of Pennsylvania Philadelphia, Pennsylvania

Carrie B. Lind [22] Pediatric Hospitalist Division of Hospital Medicine Monroe Carell Jr. Children’s Hospital at Vanderbilt Assistant Professor of Clinical Pediatrics Vanderbilt University School of Medicine Nashville, Tennessee

Matthew T. Lister, MD [33] Division of Otolaryngology-Head and Neck Surgery UW Health Hospitals and Clinics

Clinical Associate Professor of Otolaryngology University of Wisconsin School of Medicine and Public Health Milwaukee, Wisconsin

Mindy S. Lo, MD, PhD [153] Division of Immunology Boston Children’s Hospital Instructor in Pediatrics Harvard Medical Schoo Boston, Massachusetts

Michelle A. Lopez, MD [112] Assistant Professor of Pediatrics Section of Pediatric Hospital Medicine Texas Children’s Hospital Houston, Texas

Katherine Lord, MD [69] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

M. Katherine Loudermilk, MD [130] Medical Director, Mother Baby Unit Good Samaritan Hospital Perinatal Institute Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jeffrey P. Louie, MD [168,173] Assistant Professor Department of Pediatrics University of Minnesota

Masonic Children’s Hospital Minneapolis, Minnesota

Barry A. Love, MD [53] Director Congenital Cardiac Catheterization Laboratory Kravis Children’s Hospital at Mount Sinai Assistant Professor of Pediatrics and Medicine Icahn School of Medicine at Mount Sinai New York, New York

Ian MacLusky, MBBS, FRCP [143] Chief Division of Respirology Children’s Hospital of Eastern Ontario Associate Professor, University of Ottawa Ottawa, Ontario Canada

Mary Beth Madonna, MD [126] Attending Physician Department of Pediatric Surgery Ann & Robert H. Lurie Children’s Hospital of Chicago Assistant Professor of Surgery Feinberg School of Medicine Northwestern University Chicago, Illinois

Douglas Y. Mah, MD [52] Assistant Professor of Pediatrics Harvard Medical School Department of Cardiology Boston Children’s Hospital Boston, Massachusetts

Paul E. Manicone, MD [118] Pediatric Hospitalist Children’s National Health System Washington, DC

Jennifer Maniscalco, MD, MPH, FAAP [81] Associate Professor of Clinical Pediatrics University of Southern California Keck School of Medicine Director, Pediatric Hospital Medicine Fellowship Children’s Hospital Los Angeles Los Angeles, California

Jonathan M. Mansbach, MD [3] Clinical Research Director, Boston Children’s Hospital Inpatient Pediatrics Service Assistant Professor of Pediatrics Harvard Medical School Boston Children’s Hospital Boston, Massachusetts

Lauren E. Marlowe, MD [192] Pediatric Hospitalist, CHOP at Virtua Clinical Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Voorhees, New Jersey

Kimberly C. Martin, DO, MPH [98] Assistant Professor of Pediatrics Division of Pediatric Infectious Diseases University of Oklahoma School of Community Medicine Tulsa, Oklahoma

Peter Mattei, MD [156] General, Thoracic and Fetal Surgery Children’s Hospital of Philadelphia Associate Professor, Dept. of Surgery Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Sangeeta Mauskar, MD, MPH [180,181]

Director, Complex Care Service, Inpatient Program Boston Children’s Hospital Instructor, Harvard Medical School Boston, Massachusetts

Oscar H. Mayer, MD [10] Associate Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Pulmonologist Director, Pulmonary Function Laboratory Division of Pulmonary Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Pamela A. Mazzeo, MD [195] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of General Pediatrics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Sarah C. McBride, MD [37] Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts

Zachary McClain, MD [44] Assistant Professor of Pediatrics Craig Dalsimer Division of Adolescent Medicine The Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Russell McCulloh, MD [107]

Divisions of Infectious Diseases and Hospital Medicine Children’s Mercy Kansas City Assistant Professor of Pediatrics and Internal Medicine UMKC School of Medicine University of Kansas Medical Center Kansas City, Missouri

Lisa McLeod, MD, MSCE [2] Director, Pediatric Surgical Outcomes Research Center (PSORC), Center for Children’s Surgery Assistant Professor, Pediatric Hospital Medicine, Children’s Hospital Colorado/University of Colorado School of Medicine Aurora, Colorado

Suzanne Swanson Mendez, MD [32] Pediatric Hospitalist Santa Clara Valley Medical Center San Jose, California Clinical Instructor in Pediatrics Stanford University Palo Alto, California

Talene A. Metjian, PharmD [94] Antimicrobial Stewardship Program Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Manoj K. Mittal, MD, MRCP (UK), FAAP [198] Associate Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Vineeta Mittal, MD [7]

Associate Professor of Pediatrics Division of Hospital Medicine Department of Pediatrics UTSW Medical Center & Childrens Health System of Texas Dallas, Texas

Keith W. Morley, MD [106] Pediatric Preliminary Resident Geisinger Medical Center Danville, Pennsylvania

Martin J. Morrison III, MD [161] Department of Orthopaedic Surgery Loma Linda University School of Medicine Loma Linda Medical Center Loma Linda, California

Christelle Moufawad El Achkar, MD [118,119] Assistant in Neurology Boston Children’s Hospital Instructor of Neurology Harvard Medical School Boston, Massachusetts

Nancy Murphy, MD, FAAP, FAAPMR [179] Professor and Chief, Division Pediatric PM&R University of Utah Department of Pediatrics Salt Lake City, Utah

Frances M. Nadel, MD, MSCE [174,191] Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Joshua Nagler, MD, MPHEd [163] Division of Emergency Medicine Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Sona Narula, MD [122] Assistant Professor of Clinical Neurology Division of Neurology The Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Mark I. Neuman, MD, MPH [142] Division of Emergency Medicine Boston Children’s Hospital Associate Professor of Pediatrics and Emergency Medicine Harvard Medical School Boston, Massachusetts

Alice W. Newton, MD, FAAP [40] Medical Director, Child Protection Program Department of Pediatrics Massachusetts General Hospital Boston, Massachusetts

Alison E. Niebanck, MD [160] Assistant Professor of Pediatrics Mercer University School of Medicine, Savannah Willett Children’s Hospital at Memorial Health University Medical Center Savannah, Georgia

Lise E. Nigrovic [172] Associate Professor of Pediatrics and Emergency Medicine

Harvard Medical School Division of Emergency Medicine Boston Children’s Hospital Boston, Massachusetts

Richard J. Noel, MD, PhD [78] Associate Professor of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin

Kevin C. Osterhoudt, MD, MS [165,176] Attending Physician, Division of Emergency Medicine Medical Director, The Poison Control Center The Children’s Hospital of Philadelphia Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Mary C. Ottolini, MD, MPH, MEd [15] Professor of Pediatrics George Washington University Vice Chair for Medical Education Children’s National Medical Center Washington DC

Raj Padman, MD [195] Medical Director Pulmonology, Asthma and Sleep Disorders Lutheran Children’s Hospital Fort Wayne, Indiana

Horacio Padua, MD [185] Assistant Professor Harvard Medical School Attending in Pediatric Interventional Radiology Department of Radiology

Boston Children’s Hospital Boston, Massachusetts

Andrew A. Palladino, MD [68,69,72] Assistant Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician and Medical Director of Inpatient Endocrinology Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Michelle W. Parker, MD [76] Cincinnati Children’s Hospital Medical Center Assistant Professor, Department of Pediatrics University of Cincinnati College of Medicine Cincinnati, Ohio

Sarah E.S. Parker, MD [24] Assistant Professor, Pediatrics Department of Pediatrics Division of General Pediatrics Monroe Carell Jr. Children’s Hospital at Vanderbilt Nashville, Tennessee

Vanda Passi, MD [195] Department of Pediatrics Division of Pediatric Pulmonology Nemours/Alfred I. DuPont Hospital for Children Wilmington, Delaware

Raina Paul, MD [36] Assistant Professor, Department of Pediatrics Division of Emergency Medicine Associate Medical Director, Center for Excellence, Ann and Robert H. Lurie Children’s Hospital of Chicago Feinberg School of Medicine at Northwestern University

Chicago, Illinois

Rebecka Peebles, MD [44] Co-Director of Eating Disorder Assessment and Treatment Program Craig-Dalsimer Division of Adolescent Medicine The Children’s Hospital of Philadelphia Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Jeremy Ryan Andrew Peña, MD, PhD [93] Director, Histocompatibility Laboratory Division of Laboratory and Transfusion Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

William H. Peranteau, MD [156] Attending Surgeon Division of Pediatric General, Thoracic and Fetal Surgery The Children’s Hospital of Philadelphia Assistant Professor of Surgery Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Jeannette M. Pérez-Rosselló, MD [41] Pediatric Radiologist Boston Children’s Hospital Assistant Professor of Radiology Harvard Medical School Boston, Massachusetts

Marissa J. Perman, MD [66] Assistant Professor of Pediatrics Department of Dermatology and Pediatrics Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

Andrew E. Place, MD, PhD [133] Assistant Professor of Pediatrics Harvard Medical School Dana-Farber/Boston Children’s Cancer and Blood Disorders Center Boston, Massachusetts

Annapurna Poduri, MD, MPH [118,119] Associate Professor in Neurology Epilepsy Genetics Program Division of Epilepsy and Clinical Neurophysiology Boston Children’s Hospital Boston, Massachusetts

Jill C. Posner, MD, MSCE, MSEd [188,194] Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Director of Medical Education, Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Sampath Prahalad, MD, MSc [150] Marcus Professor of Pediatric Rheumatology Chief, Division of Pediatric Rheumatology Professor of Pediatrics and Human Genetics Emory University School of Medicine Children’s Healthcare of Atlanta Atlanta, Georgia

Julianne Prasto, MD [193] The Children’s Hospital of Philadelphia University Medical Center of Princeton – Plainsboro The Children’s Hospital of Philadelphia Plainsboro, New Jersey

Genevieve Preer, MD [42] Pediatrician, Child Protection Team Boston Medical Center Assistant Professor of Pediatrics Boston University School of Medicine Boston, Massachusetts

Howard B. Pride, FAAD, MD [106] Pediatric Dermatology Geisinger Medical Center Danville, Pennsylvania

Vlad Calin Radulescu, MD [92] Assistant Professor University of Kentucky Lexington, Kentucky

Lindsay Burns Ragsdale, MD [10] Co-Director, Pediatric Advanced Care Team Associate Program Director, Pediatric Residency Program Kentucky Children’s Hospital Assistant Professor of Pediatrics University of Kentucky College of Medicine Lexington, Kentucky

Daniel A. Rauch, MD, FAAP, FHM [11,14,16] Visiting Associate Professor of Pediatrics Tufts University School of Medicine Chief of Pediatric Hospital Medicine at the Floating Hospital for Children at Tufts Medical Center Boston, Massachusetts

Robin Ray, MD [160] Vitreoretinal Service Georgia Eye Institute of the Southeast Savannah, Georgia

Rupa Redding-Lallinger, MD [88] Professor of Pediatrics and Internal Medicine Co-Director, UNC Comprehensive Sickle Cell Program Division of Pediatric Hematology and Oncology University of North Carolina Chapel Hill, North Carolina

Kris P. Rehm, MD [24] Associate Professor, Pediatrics Director, Division of Hospital Medicine Vanderbilt University School of Medicine Monroe Carell Jr Children’s Hospital at Vanderbilt Nashville, Tennessee

Daniel H. Reirden [44] Associate Professor of Medicine and Pediatrics Sections of Adolescent Medicine and Infectious Disease Aurora, Colorado

David Riester, MD [47,48] Northeast Allergy, Asthma and Immunology Leominster, Massachusetts

Jeffrey D. Roizen, MD, PhD [72] Assistant Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

José R. Romero, MD, FAAP, FDISA, FPIDS [98] Director, Section of Infectious Diseases Department of Pediatrics Horace C. Cabe Chair in Infectious Diseases University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Little Rock, Arkansas

Colleen A. Ryan, MD [138] Medical Director, Inpatient Psychiatry Service Boston Children’s Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts

Julia S. Sammons, MD, MSCE [5] Medical Director, Infection Prevention and Control The Children’s Hospital of Philadelphia Assistant Professor of Clinical Pediatrics UPENN School of Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Esther Maria Sampayo, MD, MPH [190] Assistant Professor, Department of Pediatrics Section of Emergency Medicine Baylor College of Medicine Texas Children’s Hospital Houston, Texas

Gina Santucci, RN, MSM, APRN-BC [10] Nurse Practioner Pediatric Advanced Care Team The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Michele Saysana, MD [4] Associate Professor of Clinical Pediatrics Medical Director Quality and Safety Department of Pediatrics Division of Hospital Medicine Indiana University School of Medicine Riley Hospital for Children at Indiana University Health Indianapolis, Indiana

Julie V. Schaffer, MD [62] Associate Professor of Dermatology and Pediatrics New York University School of Medicine New York, New York

Karen E. Schetzina, MD, MPH, CLC, FAAP [29] Professor Director, Division of Community Pediatrics Research Department of Pediatrics Quillen College of Medicine East Tennessee State University Johnson City, Tennessee

Sandra Schwab, MD, MSCE [189] Hilbert Pediatric Emergency Department Peyton Manning Children’s Hospital at St. Vincent Indianapolis, Indiana

Donald F. Schwarz [44] Robert Wood Johnson Foundation Princeton, New Jersey

Jordan Scott, MD [47,48] President of Northeast Allergy Asthma and Immunology President of Allergy & Asthma Physicians Clinical Instructor Umass/Memorial Community Medicine Leominster, Massachusetts

Steven M. Selbst, MD [13] Vice-Chair for Education Director, Pediatric Residency Program Attending Physician, Division of Emergency Medicine Nemours/Alfred I. duPont Hospital for Children Wilmington, Delaware Professor of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University

Philadelphia, Pennsylvania

Kara N. Shah, MD, PhD [67] President, Kenwood Dermatology Cincinnati, Ohio

Rachana Shah, MD [70] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Samir S. Shah, MD, MSCE [95,96,99,101,102] Director, Division of Hospital Medicine James M. Ewell Endowed Chair Attending Physician in Hospital Medicine & Infectious Diseases Cincinnati Children’s Hospital Medical Center Professor, Department of Pediatrics University of Cincinnati College of Medicine Cincinnati, Ohio

Nader Shaikh, MD, MPH [104] Associate Professor of Pediatrics University of Pittsburgh Children’s Hospital of Pittsburgh Division of General Academic Pediatrics Pittsburgh, Pennsylvania

Adhi N. Sharma, MD [170] Medical Director Case Management South Nassau Communities Hospital Baldwin, New York

Akshay Sharma, MBBS [90] Pediatric Hematology/Oncology Fellow, PGY-4St. Jude Children’s Research Hospital Memphis, Tennessee

Eric Shelov, MD [6] Associate Chief Health Informatics Officer Clinical Assistant Professor of Pediatrics Perelman School of Medicine University of Pennsylvania Division of General Pediatrics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Andrew Shriner, MD [100] Assistant Professor of Clinical Pediatrics Department of Pediatrics Division of Hospital Medicine Riley Hospital for Children at Indiana University Health Indianapolis, Indiana

Kelley Shultz, MD [123] Staff Physician Department of Neonatology and Pulmonary Biology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jeffrey Simmons, MD [4] Associate Professor, Department of Pediatrics University of Cincinnati College of Medicine Associate Director, Quality Division of Hospital Medicine Safety Officer, James M. Anderson Center for Health Services Excellence Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Tamara D. Simon, MD, MSPH [159] Associate Professor of Pediatrics Department of Pediatrics University of Washington School of Medicine Attending Physician Seattle Children’s Hospital Center for Clinical and Translational Research Seattle Children’s Research Institute Seattle, Washington

Steven R. Sloan, MD, PhD [93] Medical Director, Blood Bank Boston Children’s Hospital Boston, Massachusetts

Karen Smith, MD, MEd [15,85] Associate Professor of Pediatrics George Washington University Chief, Division of Hospital Medicine Children’s National Health System Washington, DC

Michael J.G. Somers, MD [26] Division of Nephrology Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts

Philip R. Spandorfer, MD, MSCE [73] Pediatric Emergency Medicine Associates Children’s Healthcare of Atlanta at Scottish Rite Atlanta, Georgia

Lisa Santos Spector, MD [43] Division of Child Abuse and Neglect

Director, Beyond Adverse Childhood Experiences (ACEs) Program Medical Director, Sexual Assault Nurse Examiner Program Children’s Mercy Kansas City Associate Professor UMKC School of Medicine Kansas City, Kansas

Jonathan M. Spergel, MD, PhD [61,141] Chief, Allergy Section Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Division of Allergy and Immunology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

David A. Spiegel, MD [161] Associate Professor of Orthopaedic Surgery Division of Orthopaedic Surgery The Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Mythili Srinivasan, MD, PhD [184] Associate Professor of Pediatrics Washington University School of Medicine St. Louis Children’s Hospital St. Louis, Missouri

Rajendu Srivastava, MD, MPH [1] Assistant Vice President of Research Intermountain Healthcare Salt Lake City, Utah

Angela M. Statile, MD, MEd [97,140] Assistant Professor, Department of Pediatrics University of Cincinnati College of Medicine Medical Director, Burnet Campus Division of Hospital Medicine

Assistant Program Director, Pediatric Residency Program Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Nicole E. St Clair, MD [33] Division of Pediatric Hospital Medicine UW Health, American Family Children’s Hospital Associate Professor of Pediatrics University of Wisconsin School of Medicine and Public Health Milwaukee, Wisconsin

Michael C. Stephens, MD [80] Assistant Professor of Pediatrics Mayo Clinic Rochester, Minnesota

Bryan L. Stone, MD, MS [28] Professor of Pediatrics University of Utah School of Medicine Pediatric Hospitalist Primary Children’s Hospital Salt Lake City, Utah

Ashley K. Crumby, MD (formerly Ashley K. Storrs) [137] Assistant Professor of Clinical Psychiatry Child and Adolescent Psychiatry Weill Cornell Medical College, New York, New York

Margaret J. Strieper, DO [55] Director, Pacing and Electrophysiology Associate Professor of Pediatrics Emory University Children’s Healthcare of Atlanta Atlanta, Georgia

Eric Sundel, MD [155] Pediatric Hospitalist Baltimore, Washington Medical Center University of Maryland Medical System Severna Park, Maryland

Robert Sundel, MD [30,147,148] Director of Rheumatology Boston Children’s Hospital Associate Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Nicole Sutton, MD [56] Associate Professor of Pediatrics Albert Einstein College of Medicine Children’s Hospital at Montefiore Bronx, New York

Sanjeev K. Swami, MD [105] Assistant Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Division of Infectious Diseases The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Khoon-Yen Tay, MD [174] Assistant Professor, Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician Division of Emergency Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Joanna Thomson, MD, MPH [107] Assistant Professor, Department of Pediatrics

University of Cincinnati College of Medicine Attending Physician Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Avram Z. Traum, MD [26] Division of Nephrology Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts

James R. Treat, MD [65] Associate Professor of Pediatrics and Dermatology Fellowship Director, Pediatric Dermatology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Michael L. Trieu, MD [138] Child and Adolescent Psychiatry Inpatient Service Boston Children’s Hospital Harvard Medical School Boston, Massachusetts

Harsh K. Trivedi, MD, MBA [135] President and CEO Sheppard Pratt Health System Professor of Clinical Psychiatry University of Maryland Baltimore, Maryland

Venée N. Tubman, MD, MMSc [89] Assistant Professor of Pediatrics Baylor College of Medicine / Texas Children’s Cancer and Hematology Centers Houston

Houston, Texas

Michael Turmelle, MD [184] Associate Professor of Pediatrics Division Co-Chief Hospitalist Medicine Medical Director St. Louis Children’s Hospital Children’s Direct Washington University School of Medicine One Children’s Place St. Louis, Missouri

Lily Changchien Uihlein, MD, JD [60] Dermatology Program Boston Children’s Hospital Boston, Massachusetts

Levon Utidjian, MD, MBI [6] Clinical Instructor in Pediatrics Perelman School of Medicine at the University of Pennsylvania Attending Physician, Division of General Pediatrics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Joyee G. Vachani, MD, MEd [115] Assistant Professor of Pediatrics Baylor College of Medicine Texas Children’s Hospital Houston, Texas

Charles P. Venditti, MD, PhD [87] Investigator National Human Genome Research Institute Genetics and Molecular Biology Branch National Institutes of Health Bethesda, Maryland

Menno Verhave, MD [82]

Clinical Director, Gastroenterology Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Robert N. Vincent, MD, CM [55] Children’s Healthcare of Atlanta Professor of Pediatrics Emory University School of Medicine Atlanta, Georgia

Samuel Volchenboum, MD, PhD [91] Assistant Professor of Pediatrics Director, Center for Research Informatics University of Chicago Chicago, Illinois

Michael T. Vossmeyer, MD [7] Associate Professor, Department of Pediatrics, University of Cincinnati College of Medicine Attending Physician and Medical Director for Community Integration, Division of Hospital Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Robert M. Wachter, MD [Foreword] Professor and Associate Chairman Department of Medicine Marc and Lynne Benioff Endowed Chair Chief of the Division of Hospital Medicine University of California, San Francisco Chief of the Medical Service UCSF Medical Center San Francisco, California

Amy T. Waldman, MD, MSCE [122] Division of Neurology, Children’s Hospital of Philadelphia Assistant Professor of Neurology Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Sowdhamini Wallace, DO, FAAP [113] Assistant Professor, Department of Pediatrics Section of Pediatric Hospital Medicine Baylor College of Medicine and Texas Children’s Hospital Houston, Texas

Jennifer K Walter, MD, PhD, MS [12] Assistant Professor of Pediatrics, Medical Ethics and Health Policy University of Pennsylvania School of Medicine Attending Physician General Pediatrics and Pediatric Advanced Care Team The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Jolan E. Walter, MD, PhD [49] Department of Pediatrics Division of Allergy and Immunology Massachusetts General Hospital for Children Harvard Medical School Boston Massachusetts

George Sam Wang, MD [171] Assistant Professor Department of Pediatrics Section of Emergency Medicine University of Colorado School of Medicine Children’s Hospital Colorado Aurora, Colorado

Laura Placke Ward, MD, IBCLC [129]

Assistant Professor of Pediatrics Division of Neonatology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Kathy E. Wedig, MD [131] Associate Professor of Clinical Pediatrics UC College of Medicine Attending Neonatologist Perinatal Institute Cincinnati Children’s Hospital Cincinnati, Ohio

Kirstin Weerdenburg, MD, FRCPC [167] Pediatric Emergency Medicine The Hospital for Sick Children (SickKids) Toronto, Ontario, Canada

Daniel J. Weiner, MD [146] Associate Professor of Pediatrics University of Pittsburgh School of Medicine Medical Director, Pulmonary Function Laboratory Director, Antonio J. and Janet Palumbo Cystic Fibrosis Center Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Michael Weinstein, MD, FRCPC [182] Associate Professor Department of Paediatrics Division of Paediatric Medicine University of Toronto The Hospital for Sick Children (SickKids) Toronto, Ontario, Canada

Derek J. Williams, MD, MPH [102] Assistant Professor of Pediatrics

Division of Hospital Medicine Monroe Carell, Jr. Children’s Hospital at Vanderbilt Vanderbilt University Medical Center Nashville, Tennessee

Celeste R. Wilson, MD, FAAP [39] Medical Director, Child Protection Program Boston Children’s Hospital Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Stephen D. Wilson, MD, PhD [23] Professor of Pediatrics Department of Pediatrics University of California, San Francisco San Francisco, California

Sarah Wood, MD [45] Attending Physician Special Immunology Service The Children’s Hospital of Philadelphia Clinical Associate Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Albert C. Yan, MD, FAAP, FAAD [61] Chief, Section of Pediatric Dermatology Children’s Hospital of Philadelphia Professor, Pediatrics and Dermatology Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Sabrina W. Yum, MD [120] Assistant Professor of Clinical Neurology and Pediatrics Departments of Neurology and Pediatrics

Perelman School of Medicine of the University of Pennsylvania Director, CMTA Center of Excellence Co-director, Brachial Plexus Injury Program Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Elaine H. Zackai, MD [84] Director, Clinical Genetics Division of Human Genetics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Andrea L. Zaenglein, MD [59] Professor of Dermatology and Pediatrics Penn State/Hershey Medical Center Hershey, Pennsylvania

David Zipes, MD FAAP, SFHM [11,14] Director, Henry County Pediatric Hospitalists Henry Community Health New Castle, Indiana Pediatric Hospitalists Peyton Manning Children’s Hospital at St. Vincent Indianapolis, Indiana

Michele L. Zucker, MD, MPH [46] Assistant Professor of Pediatrics Perelman School of Medicine at the University of Pennsylvania Craig Dalsimer Division of Adolescent Medicine The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Foreword There was a time in the early days of the hospitalist field that my colleagues and I wondered whether the pediatric portion of the field was here to stay. At the first few gatherings of the Society of Hospital Medicine (SHM; then called the National Association of Inpatient Physicians), we organized a pediatric track, but only a few people showed up. One lonely pediatric hospitalist served on the SHM board—he constantly had to remind us to pay attention to the pediatric perspective, and frequently apologized for being a nag. While the early leaders of the hospitalist field were committed to integrating pediatrics, there were times when we wondered whether our efforts were a well-intended act of futility. Luckily, we persevered, and so did those early pediatric leaders. Today, the annual meeting of SHM has a robust pediatrics track, and so do the meetings of major pediatric specialty societies. There are thriving pediatric hospital medicine programs at virtually every major children’s hospital in the United States, and also programs at large and even some not-so-large general hospitals. At my own hospital, UCSF Medical Center, pediatric hospitalists have major leadership roles not only within our children’s hospital but also for the entire institution—in areas ranging from performance improvement to medical education to information technology. I am blessed to have several med-peds trained hospitalists in my own adult hospitalist group, and have been pleasantly surprised by the degree to which these individuals serve as bridges between the worlds of adult and pediatric care. While they have taken advances from the adult side to pediatrics, I have found that the arrow usually points in the other direction. For example, our pediatric hospitalists were early adopters of patient- and family-centered rounding, even scheduling appointments on rounds so that families could plan for the team’s arrival, and

nurses, case managers, and specialists could sometimes attend. We on the adult side have been awed by, and tried to learn from, this effort. As long as I’m on the subject of leadership, it’s worth noting that as of this writing, the top physician at the Centers for Medicare & Medicaid Services—the federal agency that funds more than 40% of US healthcare, to the tune of nearly $1 trillion per year—is Dr Patrick Conway, a pediatric hospitalist. Since I co-wrote the first article on pediatric hospitalists,1 the growth and success of the field has been astonishing. As in adult medicine, this growth has been fueled by residency duty hour limitations in teaching hospitals, which created a substantial need for physician coverage on services previously supported by trainees. Another driver has been new collaborative arrangements, in which hospitalists have branched out from simply practicing general pediatrics in the hospital to co-managing all sorts of surgical patients, running procedure services, staffing rapid response teams, and serving as leaders in systems improvement work. It is easy to look at this burgeoning and think that it all was preordained. But it was not. In the late 1990s and the early 2000s, hospitalists were seen by many as an untested innovation; many people were skeptical, even downright hostile, to the model. Given this, the growth in pediatric hospitalists (and leaders) is a testament to the quality and can-do spirit of the early entrants to the field. Former Disney CEO Michael Eisner once observed, “A brand is a living entity—and it is enriched or undermined cumulatively over time, the product of a thousand small gestures.” It is these gestures—making a tricky diagnosis, effectively leading a quality improvement initiative, being an enthusiastic participant in an interdisciplinary team, dealing sensitively with the family of a dying child— that have enhanced our field’s brand, and this brand has been the engine fueling our unprecedented growth. What’s in store for the next several years? In the United States, the Affordable Care Act and other payment and structural changes are beginning to transform healthcare. With fewer patients lacking insurance, access has improved (although it is certainly not assured). We are witnessing a greater emphasis on population health and care across the continuum, and experiencing a mandate to improve not only quality and safety but also patient experience. In addition, the pressure to “bend the cost curve” is just

beginning to accelerate. This pressure makes it essential that all hospitalists learn to practice in more cost-effective styles, and also assume leadership roles in helping their system identify and root out wasteful care. Federal incentives designed to move healthcare from an analog to a digital industry have been successful in driving the electronic health record adoption curve way up. All of us can expect to practice in a computerized environment for the rest of our careers. What does all of this mean for pediatric hospitalists? The intense cost pressures will inevitably lead to the closure of some hospitals, but patients in the ones that remain will be even sicker. There will be a premium on delivering demonstrably high quality, safe, and satisfying care at the lowest possible cost. The amount of money available to support pediatric hospitalist programs will be constrained, and so hospitalist programs will be asked to unequivocally demonstrate their value to justify ongoing support. Under the threat of readmission penalties or in the face of new payment models such as Accountable Care Organizations or bundled payments, hospitals will no longer be able to act as silos; there will be much greater emphasis on seamless transitions. Computerized tools will become essential to clinical practice, and good clinical delivery systems will learn to take full advantage of the power of these tools while mitigating some of the awkward workflows and even the harms that are emerging. Just as physicians in small practices are migrating to larger groups, individual hospitals are forging new relationships with others. As hospitalist groups become larger and span multiple institutions, new opportunities but also daunting management challenges will be created. The pace of change is unlike anything I have experienced in my 30 years of practice and administration. At a departmental meeting not too long ago, a department leader was discussing all of these changes: new regulations and payment systems, public reporting, information technology, and more. I could see the faculty—particularly my senior colleagues—squirming in their chairs. Finally one of our most respected cardiologists, an elder statesman in the department, grabbed the microphone. “You know,” he said, “this could be worse.” I found this a very surprising remark from a senior faculty member, particularly one who had clearly thrived under the old rules. But then he finished his thought.

“I could be younger.” While I still chuckle about this, I have to say that I completely disagree with the message. My own sentiments were well captured in an article by Don Berwick and Jonathan Finkelstein (both pediatricians) in 2010.2 They wrote, We think that the anxiety, demoralization, and sense of loss of control that afflict all too many healthcare professionals today comes not from finding themselves to be participants in systems of care, but rather from finding themselves lacking the skills and knowledge to thrive as effective, proud, and well-oriented agents of change in those systems…. A physician equipped to help improve healthcare will be not demoralized, but optimistic; not helpless in the face of complexity, but empowered; not frightened by measurement, but made curious and more interested; not forced by culture to wear the mask of the lonely hero, but armed with confidence to make a better contribution to the whole. This seems right to me. More importantly, when I find myself in a crowd of young pediatric hospitalists, I am quite certain that they see themselves— quite proudly—as leaders of a new, and improved, healthcare system. As well they should. Robert M. Wachter, MD References 1. Bellet PS, Wachter RM. The hospitalist movement and its implications for the care of hospitalized children. Pediatrics 1999;103:473-477. 2. Berwick DM, Finkelstein JA. Preparing medical students for the continual improvement of health and health care: Abraham Flexner and the new “public interest”. Acad Med 2010; 85(9 Suppl):S56-65.

Preface Come gather around people Wherever you roam And admit that the waters Around you have grown And accept it that soon You’ll be drenched to the bone And if your breath to you is worth saving Then you better start swimming or you’ll sink like a stone For the times they are a-changing Bob Dylan For pediatric hospitalists, the Nobel Laureate’s words could not ring more true. From that gathering of 130 or so of us in San Antonio in November 2003 to the announcement of subspecialty certification a mere 13 years later, the times are certainly a-changing. When we reread the preface of our first edition in 2007, we were tickled to find that we wrote “it would not be surprising if 10 years from now the field will have evolved dramatically.” Who knew we would be such excellent prognosticators? In our first edition, we were also quite proud of whom our book represented. In this edition, we endeavored to include a wide breadth of contributors as well. We have close to 300 contributing authors from over 50 different institutions represented—large and small children’s hospitals, pediatric departments in academic medical centers, community hospitals, private practice, and everything in between. The common thread that

connects all of these immensely talented individuals is the desire to present the best possible care to the hospitalized pediatric patient. And while our field has “grown up” so quickly, let us all recognize that there is still so much left to do. As hospitalists, we must continue to reduce unnecessary utilization of resources and eliminate unwarranted variation in care. There are still healthcare disparities and inequities in the system that need to be confronted and addressed. And while we may feel completely at home on the wards, hospitalization represents a vulnerable time for patients and families and we need to continue to work to improve that experience. We give our deepest and sincerest thanks to all of the individuals who made this second edition possible. In particular, we would like to recognize our associate editors Brian, Sanjay, and Samir, without whom this project would not have been possible. We are also most appreciative of the folks at McGraw-Hill who saw the need with us for a second edition and supported us through this effort. Lisa B. Zaoutis, MD and Vincent W. Chiang, MD

PART

Inpatient Pediatric Medicine

I

Part Editor Christopher P. Landrigan, MD, MPH

1 Understanding the Value of Pediatric Hospitalists: Studies of Efficiency, Education, Care Processes, and Quality of Care 2 Variation in Healthcare 3 Evidence-Based Medicine 4 Overview: Quality of Care 5 Infection Control for Pediatric Hospitalists 6 Electronic Health Records and Clinical Decision Support 7 Family-Centered Care 8 Medical Comanagement and Consultation 9 Child Development: Implications for Inpatient Medicine 10 Palliative Care 11 Communication and Discharge Planning 12 Ethical Issues in Pediatric Hospital Practice 13 Medicolegal Issues in Pediatric Hospital Medicine 14 Hospitalist Professional Organizations and Models of Care 15 Careers in Hospital Medicine

CHAPTER

1

Understanding the Value of Pediatric Hospitalists: Studies of Efficiency, Education, Care Processes, and Quality of Care Rajendu Srivastava and Christopher P. Landrigan

CURRENT STATE OF AFFAIRS The field of pediatric hospital medicine has grown rapidly over the past 18 years, since the term “hospitalist” was first coined. The number of hospitalists, including pediatric hospitalists, has increased exponentially and is expected to keep growing.1-4 Numerous pediatric hospital medicine fellowship programs have arisen, producing a new generation of clinicianquality improvement experts and clinician-investigators. Ten years after the first pediatric hospitalist conference, sponsored by the Ambulatory Pediatric Association, which drew more than 120 participants from the United States and Canada, the meeting is now an annual event. Sponsorship comes from the Academy of Pediatrics, the Society of Hospital Medicine, and the Academic Pediatric Association (formerly known as the Ambulatory Pediatric Association, the name change prompted in part by the organization’s recognition of the growth of pediatric hospital medicine). Pediatricians’ organizations have expanded to meet the needs of hospitalists, and hospitalists’ organizations have expanded to meet the needs of their pediatric contingent. The American Academy of Pediatrics Section on Hospital Medicine has one of the largest section memberships in the American Academy of Pediatrics (AAP) and an extremely active listserv; the Academic Pediatric Association Special Interest Group on Pediatric Hospital Medicine is also one of the largest interest groups and has a vital presence at

the yearly Pediatric Academic Societies meeting, and the Society of Hospital Medicine (the largest hospitalist organization) continues to foster a home for pediatric hospitalists—several key organizational leadership positions are held by pediatricians. Important research networks and collaboratives have arrived. The Pediatric Research in Inpatient Settings (PRIS; pronounced prize) network is focusing on a series of complementary national funded studies ultimately intended to provide the tools to measure and improve the quality of inpatient care. In addition, the Value in Inpatient Pediatrics (VIP) Network has partnered with the Quality Improvement Innovation Networks (QuINN) to conduct grassroots quality improvement studies engaging clinicians. Finally, pediatric hospitalists are continuing to expand their nonclinical responsibilities to include leadership roles in administration (as division chiefs, medical directors, quality improvement officers, and leaders in patient safety and informatics), research (leading research networks, developing health services research laboratories, and training junior investigators to be competitive in obtaining grants), and education (as clerkship and residency directors). A tremendous amount of knowledge has been gained from critical early work in the value of pediatric hospitalists in inpatient care delivery. This chapter outlines what we have learned from these early studies, as well as what we still need to learn, and proposes mechanisms to accomplish next steps.

STUDIES ON EFFICIENCY A substantial number of studies have been conducted on the efficiency of care delivered in pediatric hospitalist models. These studies have been largely single-center studies using before-and-after study designs or interrupted time series analyses. Most (but not all) have found 10–20% shorter length of stay (LOS) and reduced resource utilization (measured as charges or costs) in pediatric hospitalist systems.5-11 The types of pediatric hospitalist services evaluated across studies vary, but collectively the studies include academic and nonacademic pediatric hospitalist systems, managed care organization hospitalist systems, and attending-only hospitalist systems—one service that focused on medically complex cases, and another that focused on common conditions—with comparisons to community, general academic pediatric, and specialist attending physician traditional care systems. These findings, in

conjunction with adult hospitalist studies12-18 showing similar improvements in LOS and total costs and similar preservation of quality outcomes, indicate that the argument for the value of pediatric hospitalist systems is both strong and sound.12 Future research in this area should attempt to add new knowledge rather than replicate well-established findings. For example, future studies might help answer questions about the advantages and disadvantages of specific types of pediatric hospitalist models, why they work, and which patient populations are most or least likely to benefit from such systems.

EDUCATION A few studies have examined the experiences of medical students and house staff in hospitalist systems. Hospitalists have been rated highly as educators, compared with either traditional academic attending physicians or subspecialists.19-24 Initial concerns regarding a decrease in students’ exposure to subspecialists and community pediatricians in some medical centers have been mitigated by strategies to give medical students exposure to faculty other than hospitalists during inpatient rotations. However it will be important to continue to ensure that trainees have varied attending types to learn from. The professional development of hospitalist educators is an important area, and more research is needed on the educational impact of the hospitalist model.21

PHYSICIAN ATTITUDES Some studies have documented the experiences and attitudes of primary care physicians (those who refer patients to hospitalists) and subspecialists (those who serve as consultants to hospitalists) with regard to hospitalist models in adult medicine. These studies have found that some primary care physicians and subspecialists are concerned about the quality of care, teaching, and patient satisfaction provided by the hospitalist model,25,26 but others are more positive about the model. One pediatric study found that community physicians and residents rated the hospitalist system as excellent, whereas subspecialty physicians rated it as average.27 Another study of the initiation of a pediatric hospitalist service at a tertiary care children’s hospital found

that community physicians were more ambivalent than specialty physicians; community physicians’ specific concerns included impaired communication and maintenance of long-term relationships with their patients.28 As hospitalist models in pediatrics have become more prevalent and are now the dominant inpatient model of care in some hospitals, it appears that the acceptance of, and satisfaction with, hospitalist services have grown, while new challenges such as optimal communication and transitions of care are new areas of research.29-32

QUALITY While the body of research evaluating hospitalist systems has become far more robust, measuring quality of care remains a challenge for pediatric hospital medicine, as inpatient quality measures are still largely underdeveloped in pediatrics. The Institute of Medicine defines quality care as that which is effective, efficient, safe, patient centered, timely, and equitable13 (see Chapter 4 for further discussion). Evaluating quality involves measuring processes and outcomes of care.

PROCESS MEASURES Early studies of adults cared for by hospitalists focused on process measures and found that the quality of the care processes used by hospitalist and nonhospitalist systems is similar, but that hospitalist systems reduce LOS and costs, yielding more efficient care.14,15 Process measures are particularly challenging in inpatient pediatrics, because few diseases have well-defined quality measures or strong evidence to link particular processes of care with improved outcomes. A notable exception is asthma, for which evidence-based quality metrics have been developed (e.g. the percentage of asthmatic children discharged from the hospital with an inhaled steroid). To measure quality of care using such a process marker, a hospital would need to measure the frequency with which children are sent home with inhaled steroids, ideally controlling for severity of illness and potential confounders. Early work has been conducted to study this particular measure (along with other process and outcome measures) in hospitalized children. One study of 30 children’s hospitals, examining three

asthma process quality measures (use of relievers, use of systemic corticosteroids, and use of a written home asthma action plan), found no observed decrease in asthma readmissions within 30 days of being discharged.33 Another single children’s hospital study, however, found that after an intense period of dissemination and implementation of evidencebased best practices there was a reduction in pediatric readmissions, but it took 9 months to observe this change, and only if the readmission time period was extended to 6 months (and not 30 days).34 Studies can evaluate other disease-dependent process measures, such as the use of inhaled ipratropium bromide on wards or the use of chest radiographs to rule out pneumonia. Unlike the example of post-discharge inhaled steroids, however, which has a strong evidence base to support it, many process measures have a weaker evidence base (i.e. adherence to that process measure has not been strongly linked to improved patient outcomes) and hence are subject to greater disagreement. For example, the clinical criteria to determine which hospitalized children with fever and respiratory symptoms, as well as a preexisting condition of asthma, should have chest radiographs have not been well studied; thus, it is difficult to define objectively what constitutes optimal care. Research is needed to identify such process measures across a range of conditions. Because most pediatric conditions do not have well-defined disease-dependent process measures, quality-of-care studies are challenging, particularly those assessing the quality of care in patients with uncommon conditions or complex diseases. The development of disease-dependent measures has been extremely limited in pediatrics for a number of reasons. One reason is that a very large number of pediatric diseases lead to hospitalization, whereas a relatively small number of acute conditions in adults (which have been more thoroughly studied) lead to hospitalization. Disease-independent process measures are one method of addressing quality of care in the face of such a large range of infrequent conditions. To take the handoff process as an example (between a change of house staff teams on the wards), one could operationalize, test, and validate measures of quality unrelated to a particular condition, such as the content, mode, and quality of handoffs between house staff, incidence of medical errors on the wards, frequency of timely, accurate transmission of information from inpatient to outpatient providers before the follow-up visit, and timing and appropriateness of—and patient satisfaction

with—follow-up visits with specialists involved in inpatient care. Recent work has found that implementation of interventions to improve handoffs can lead to substantive improvements in this care process, which have been linked to improvements in outcomes.35,36

OUTCOME MEASURES Quality of care can also be measured by looking directly at outcomes. Two studies of hospitalist care for adults demonstrated decreased mortality in hospitalist systems.16,17 In pediatrics, death is a rare outcome and is therefore an insensitive measure of quality of care. More recently, pediatric readmissions have been proposed as a possible measure of pediatric inpatient care quality. One large study in 72 children’s hospitals of more than 568,000 index admissions found an overall 30-day readmission rate of 6.5% (far lower than common conditions studied in adults), but with some significant variation in certain populations.37 This measure is complex and requires further understanding of the factors influencing pediatric readmissions (including the social determinants) before using this in quality-of-care outcome studies. Mortality and readmission rates have been unchanged in most studies comparing pediatric hospitalist systems with traditional care systems. Bellet et al.’s study found that the 10-day readmission rate increased from 1% to 3% in a hospitalist system (P = .006), but no other study has found hospitalist systems to be associated with increased readmissions.5 One study comparing survival and LOS in a pediatric intensive care unit found that patients cared for by hospitalists had an odds ratio of 2.8 for survival and a 21.1-hour shorter LOS (both P = .13), when adjusted for severity of illness, compared with patients cared for by residents.18 Patient satisfaction and experience can also be measured. Studies of patients’ and parents’ experiences in hospitalist systems have found either no difference or occasionally improved satisfaction with care provided by hospitalists compared with nonhospitalist (general academic or community) attending physicians.6,10

CURRENT DIRECTIONS: VARIATION IN CARE,

COMPARATIVE EFFECTIVENESS, AND DISSEMINATION AND IMPLEMENTATION STUDIES In the past few years, a number of studies have emerged documenting variation in care across pediatric hospitals and beginning to compare the effects of alternative approaches to the management of common conditions. In addition, hospitalists have begun to get involved in studies seeking to disseminate evidence-based care approaches, evaluating the effectiveness of dissemination and implementation efforts.

VARIATION IN HOSPITAL CARE Several studies have now documented the large variation in resource utilization across a variety of pediatric conditions in children’s hospitals using existing databases. In addition to variation in disease-dependent therapies (e.g. surgery and medication regimens) and diagnostic testing (e.g. radiological studies), several studies have demonstrated large variation in complications and readmissions38-40 (see Chapter 2 for a full discussion of variation in care).

COMPARATIVE EFFECTIVENESS RESEARCH Comparative effectiveness studies seek to rigorously compare outcomes when alternative approaches are used in the management of a particular problem. In inpatient pediatrics, because there is wide variation in care, there are numerous opportunities to conduct comparative effectiveness research using data currently being collected. For example, many studies using the Children’s Hospital Association’s Pediatric Health Information System (PHIS) administrative database have been carried out in the past decade, both documenting variation in care and seeking to assess the comparative effectiveness of diverse management strategies. PHIS+, an ongoing study being run through the Pediatric Research in Inpatient Settings (PRIS) hospitalist research network, is currently building on this work, conducting four comparative effectiveness research (CER) studies to compare common treatment strategies for costly conditions (osteomyelitis, appendicitis, pneumonia, and gastroesophageal reflux disease);41 this database takes advantage of an infrastructure of shared clinical data (specifically laboratory,

radiology, and microbiology data) that have been overlaid on top of the PHIS dataset for six children’s hospitals. Other CER treatment studies are also being conducted, such as the Pediatric Intravenous Versus Oral Antibiotic Therapy (PIVVOT) study. This study aims to compare the effectiveness of oral versus intravenous antibiotics (via a peripherally inserted central catheter (PICC) line) in children who require prolonged home therapy after hospitalization for complicated pneumonia, ruptured appendicitis, or osteomyelitis. Similar research carried out across a range of conditions will unquestionably be of major value to the field of pediatric hospital medicine in the years to come.

DISSEMINATION AND IMPLEMENTATION RESEARCH Finding the answers to what works best is only the first step. Implementing the findings in real-world settings and testing adherence to best practices and their effectiveness in real-world settings is the next natural extension of this work. In one study, I-PASS, a series of handoff interventions, have been disseminated to nine hospitals across North America. Studies of the effectiveness of adoption and downstream outcomes are underway. Further studies evaluating the effects of implementing evidence-based practices in inpatient pediatrics—both for particular conditions and across conditions— are needed.

DIRECTIONS FOR THE FUTURE There is still much work to be done. Future studies should expand to include a new focus on how current inpatient care is being delivered (measuring the quality of inpatient pediatric care) and how this can be improved both for children with common conditions and for medically complex children who are frequent users of inpatient resources and highly susceptible to a fragmented delivery system. One method of overcoming the challenges of studying vulnerable populations with small numbers or rare conditions is to take advantage of multicenter research and improvement networks, an effort that is well underway in pediatric hospital medicine. Both the PRIS network and the Value in Inpatient Pediatrics (VIP) network have membership from large numbers of hospitals and hospitalists. Through networks, opportunities exist

to reduce unwarranted variation in inpatient pediatric care and spread best practices. Two critical steps in research must occur to improve the current system of inpatient care. First, measures of inpatient processes of pediatric care must be explicitly defined, validated, and tested. Second, pediatric hospitalists must be studied in their natural laboratory (i.e. the hospital) to understand both the limitations and the possibilities of translating research findings into clinical practice using a variety of quality improvement techniques. As both these steps occur, the care delivered to hospitalized children will undergo a paradigm shift. We will be able to measure routine care, compare it against high performers, and improve it so that we can deliver care that is effective, efficient, safe, patient centered, timely, and equitable.

REFERENCES 1. Srivastava R, Landrigan C, Gidwani P, et al. Pediatric hospitalists in Canada and the United States: A survey of pediatric academic department chairs. Ambul Pediatr. 2001;1:338-339. 2. Landrigan C, Srivastava R, Muret-Wagstaff S, et al. Pediatric hospitalists: What do we know, and where do we go from here? Ambul Pediatr. 2001;1:340-345. 3. Lurie JD, Miller DP, Lindenauer PK, et al. The potential size of the hospitalist workforce in the United States. Am J Med. 1999;106:441445. 4. Landrigan CP, Srivastava R. Pediatric hospitalists: Coming of age in 2012. Arch Pediatr Adolesc Med. 2012 166(8):696-699. 5. Bellet PS, Whitaker RC. Evaluation of a pediatric hospitalist service: Impact on length of stay and hospital charges. Pediatrics. 2000;105:478484. 6. Landrigan CP, Srivastava R, Muret-Wagstaff S, et al. Impact of a health maintenance organization hospitalist system in academic pediatrics. Pediatrics. 2002;110:720-728. 7. Dwight P, MacArthur C, Friedman J, Parkin PC. Evaluation of a staffonly hospitalist system in a tertiary care academic children’s hospital. Pediatrics. 2004;114:1545-1549.

8. Srivastava R, Muret-Wagstaff S, Young P, James BC. Hospitalist care of medically complex children. Pediatr Res. 2004;55:314A-315A. 9. Maggioni A, Rolla F. Comparison of hospitalist and pediatric subspecialist care on selected APR-DRGs: Length of stay and hospital charges. Pediatr Res. 2004;55:315A. 10. Wells RD, Dahl B, Wilson SD. Pediatric hospitalists: Quality care for the underserved? Am J Med Qual. 2001;16:174-180. 11. Seid M, Quinn K, Kuttin P. Hospital based and community pediatricians: Comparing outcomes for asthma and bronchiolitis. J Clin Outcomes Manage. 1997;4:21-24. 12. Wachter RM, Goldman L. The hospitalist movement 5 years later. JAMA. 2002;287:487-494. 13. Institute of Medicine (US) Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001. 14. Lindenauer PK, Chehabeddine R, Pekow P, et al. Quality of care for patients hospitalized with heart failure: Assessing the impact of hospitalists. Arch Intern Med. 2002;162:1251-1256. 15. Rifkin WD, Conner D, Silver A, Eichorn A. Comparison of processes and outcomes of pneumonia care between hospitalists and communitybased primary care physicians. Mayo Clin Proc. 2002;77:1053-1058. 16. Auerbach AD, Wachter RM, Katz P, et al. Implementation of a voluntary hospitalist service at a community teaching hospital: Improved clinical efficiency and patient outcomes. Ann Intern Med. 2002;137:859865. 17. Meltzer D, Shah M, Morrison J. Decreased length of stay, costs and mortality in a randomized trial of academic hospitalists. J Gen Intern Med. 2001;16(Suppl):S208. 18. Tenner PA, Dibrell H, Taylor RP. Improved survival with hospitalists in a pediatric intensive care unit. Crit Care Med. 2003;31:847-852. 19. Hunter AJ, Desai SS, Harrison RA, Chan BK. Medical student evaluation of the quality of hospitalist and nonhospitalist teaching faculty on inpatient medicine rotations. Acad Med. 2004;79:78-82. 20. Kripalani S, Pope AC, Rask K, et al. Hospitalists as teachers. J Gen

Intern Med. 2004;19:8-15. 21. Hauer KE, Wachter RM. Implications of the hospitalist model for medical students’ education. Acad Med. 2001;76:324-330. 22. Landrigan CP, Muret-Wagstaff S, Chiang VW, et al. Effect of a pediatric hospitalist system on housestaff education and experience. Arch Pediatr Adolesc Med. 2002;156:877-883. 23. Landrigan CP, Muret-Wagstaff S, Chiang VW, et al. Senior resident autonomy in a pediatric hospitalist system. Arch Pediatr Adolesc Med. 2003;157:206-207. 24. Kemper AR, Freed GL. Hospitalists and residency medical education: Measured improvement. Arch Pediatr Adolesc Med. 2002;156:858-859. 25. Auerbach AD, Nelson EA, Lindenauer PK, et al. Physician attitudes toward and prevalence of the hospitalist model of care: Results of a national survey. Am J Med. 2000;109:648-653. 26. Auerbach AD, Davis RB, Phillips RS. Physician views on caring for hospitalized patients and the hospitalist model of inpatient care. J Gen Intern Med. 2001;16:116-119. 27. Ponitz K, Mortimer J, Berman B. Establishing a pediatric hospitalist program at an academic medical center. Clin Pediatr (Phila). 2000;39:221-227. 28. Srivastava R, Norlin C, James BC, et al. Community and hospital-based physicians’ attitudes regarding pediatric hospitalist systems. Pediatrics. 2005;115:34-38. 29. Auerbach AD, Aronson MD, Davis RB, Phillips RS. How physicians perceive hospitalist services after implementation: Anticipation vs. reality. Arch Intern Med. 2003;163:2330-2336. 30. Harlan G, Srivastava R, Harrison L, McBride G, Maloney C. Pediatric hospitalists and primary care providers: A communication needs assessment. J Hosp Med. 2009 Mar;4(3):187-193. 31. Snow V, Beck D, Budnitz T, et al. Transitions of Care Consensus policy statement: American College of Physicians, Society of General Internal Medicine, Society of Hospital Medicine, American Geriatrics Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine. J Hosp Med. 2009;4(6):364-370.

32. Landrigan C, Stucky E, Chiang VW, Ottolini MC. Variation in inpatient management of common pediatric diseases: A study from the Pediatric Research in Inpatient Settings (PRIS) network. Pediatr Res. 2004;55:315A. 33. Morse RB, Hall M, Fieldston ES, et al. Hospital-level compliance with asthma care quality measures at children’s hospitals and subsequent asthma-related outcomes. JAMA. 2011;306(13):1454-1460. 34. Fassl BA, Nkoy FL, Stone BL, et al. The Joint Commission Children’s Asthma Care quality measures and asthma readmissions. Pediatrics. 2012;130(3):482-491. 35. Starmer AJ, Sectish TC, Simon DW, et al. Rates of medical errors and preventable adverse events among hospitalized children following implementation of a resident handoff bundle. JAMA. 2013;310:22622270. 36. Starmer AJ, Spector ND, Srivastava R, et al.; for the I-PASS Study Group. Changes in medical errors after implementation of a resident handoff program. New Engl J Med. 2014;371:1803-1812. 37. Berry JG, Toomey SL, Zaslavsky AM, et al. Pediatric readmission prevalence and variability across hospitals. JAMA. 2013;309(4):372-380 38. Rice-Townsend S, Barnes JN, Hall M, Baxter JL, Rangel SJ. Variation in practice and resource utilization associated with the diagnosis and management of appendicitis at freestanding children’s hospitals: Implications for value-based comparative analysis. Ann Surg. 2014;259(6):1228-1234. 39. Brogan TV, Hall M, Williams DJ, et al. Variability in processes of care and outcomes among children hospitalized with community-acquired pneumonia. Pediatr Infect Dis J. 2012;31(10):1036-1041. 40. Simon TD, Hall M, Riva-Cambrin J, et al. Hydrocephalus Clinical Research Network. Infection rates following initial cerebrospinal fluid shunt placement across pediatric hospitals in the United States. J Neurosurg Pediatr. 2009;4(2):156-165. 41. Narus S, Srivastava R, Gouripeddi R, et al. Federating clinical data from six pediatric hospitals: Process and initial results from the PHIS? Consortium. In: Improving Health: Informatics and IT Changing the World. Proceedings of the AMIA 2011 Annual Symposium, Washington,

DC, October 22–26, 2011; 994-1003. Epub 2011 October 22.

CHAPTER

2

Variation in Healthcare Lisa McLeod and Ron Keren

If all variation were bad, solutions would be easy. The difficulty is in reducing the bad variation, which reflects the limits of professional knowledge and failures in its application, while preserving the good variation that makes care patient centered. When we fail, we provide services to patients who don’t need or wouldn’t choose them while we withhold the same services from people who do or would, generally making far more costly errors of overuse than of underuse. Mulley AJ. Improving productivity in the NHS BMJ 2010

INTRODUCTION Variation in the structures, processes, and organization of healthcare services in the United States has been studied for decades. As the field of hospital medicine grows, contributions from hospitalists in the fields of health services research and quality improvement have been instrumental in advancing our understanding of the drivers of variation and the impact of this variation on the cost, quality, and outcomes of care delivered to hospitalized children.

HISTORICAL PERSPECTIVES ON VARIATION The first population-based study of variation in pediatric healthcare was published by British researcher J. Allison Glover in 1938.1 Starting early in the 20th century, rates of tonsillectomies among school children in England and Wales rose dramatically. By 1931, the surgery made up three-quarters of all procedures performed in children in the United Kingdom. Across boroughs, however, the proportion of children having their tonsils removed varied in some cases by tenfold, even among areas with similar populations. Seeking to understand why these rates were so variable, Glover closely examined the hospital and education health records from several neighboring boroughs and found significant disparities in the rates of tonsillectomy. For

example, “well-to-do” vs. poor children were more likely to enter secondary school without their tonsils. However, neither socioeconomic status nor any other health service area or population characteristics explained why a child living in one borough had a higher probability of getting their tonsils removed than a similar child in a different borough. Put simply, Glover concluded that the variation “defie[d] explanation.” In the 1960s, John Wennberg—then a researcher at the Dartmouth School of Medicine—would refer to this type of unexplained geographic variation as unwarranted, or variation in the utilization of health care services that cannot be explained by patient illness, patient preferences, or evidence, but rather indicates differences in health system performance. Taking advantage of newly implemented health data systems in Vermont and other areas of New England, Wennberg and his colleagues at Dartmouth and Johns Hopkins used advanced statistical methods to analyze patterns in the healthcare utilization among neighboring hospital service areas.2,3 In what was a highly influential series of publications, the Dartmouth group reported wide geographic variation in hospital admissions, diagnostic testing, and surgical procedures —including a tenfold difference in rates of tonsillectomies. All findings were still highly significant after case-mix adjustments, including prevalence of disease, patient demographics, socioeconomic factors, and medical practice differences.2 Stemming from these early studies, Wennberg and colleagues would go on to found the Dartmouth Atlas Project (http://www.dartmouthatlas.org), a publically available series of reports providing comprehensive information and analysis about how healthcare resources (and healthcare quality) vary, even within very small areas, across the United States. The Atlas publications have played a significant role in moving forward the agenda to standardize the care delivered and improve the overall value of healthcare. Perhaps the most significant Dartmouth Atlas finding has been that greater healthcare spending does not always correlate with higher quality of care, and in some cases may be associated with care that is suboptimal.4

VARIATION STUDIES IN PEDIATRICS In many ways, the Atlas has formed the foundation for our understanding of variation in healthcare, but until recently had remained largely limited to

analyses of Medicare data from the adult population. The Atlas Project recently investigated geographic variation in pediatric health care across Maine, New Hampshire, and Vermont using data from commercial insurers and Medicaid. The Dartmouth Atlas of Children’s Health Care in Northern New England5 mimicked the adult analyses, reporting rates of utilization and spending for primary care, inpatient care, emergency room care, advanced imaging, surgical care, and medication use across regions and hospitals. In parallel with the growth of the Atlas, pioneers in hospital medicine have utilized health data systems in Boston, Rochester, and other US states to uncover wide variation in the management of inpatient conditions such as asthma, gastroenteritis, and lower respiratory tract infections.6-8 More recently, the broader availability of patient data from sources such as the Health Care Utilization Project (HCUP) Kids’ Inpatient Database (KID), and the Pediatric Health Information Systems Database have provided researchers with the opportunity to examine variation from the perspective of nationally representative pediatric patient samples.9-12

CONCEPTUAL FRAMEWORKS FOR VARIATION: UNWARRANTED OR UNEXPLAINED? The challenge of much of the work surrounding practice variation lies in defining what constitutes “unwarranted” differences in care. Variation in practice can occur for many legitimate reasons, leading some to argue that variation is only unwarranted if it deviates from evidence-based standards of care or has a significantly negative impact on outcomes. By these definitions, much of the observed variation in healthcare could be considered unexplained as opposed to unwarranted. This is especially the case for variation in the care provided to children, since there are few conditions with indisputable standards of care. Regardless of whether it is considered unwarranted or unexplained, a general framework for understanding variation and generating hypotheses about its sources and significance has emerged from the literature, and involves grouping care into three major categories: (1) supply-sensitive, (2) preference-sensitive, and (3) effective. Supply-sensitive care refers to healthcare services that appear to be utilized at higher rates in areas where there is greater availability of certain resources. In Wennberg’s early studies, this was demonstrated by

observations that patients living in areas with greater bed capacity were more likely to be hospitalized, patients living in areas with more surgeons were more likely to have a surgical procedure, and patients living in areas with more radiology services were more likely to get x-rays or Computerized Tomography Scans (CTs).13 The primary driver of this type of variation is felt to be the subtle influence of service availability on clinician decisionmaking in cases where the tradeoffs are not as well defined and choices to admit or test are at the discretion of the physician. An obvious negative effect of supply-sensitive variation is that it leads to greater resource utilization and higher per capita healthcare expenditures. Unfortunately, this high utilization has not been shown to lead to better outcomes or patient satisfaction, and often represents waste of healthcare dollars and lost opportunity costs. Many believe that with rapid growth of the healthcare system, greater system capacity will lead to rampant overuse of diagnostic and therapeutic services and may in fact be causing significant and as of yet under-measured patient harm.14,15 Fee-for-service payment systems are felt to be largely responsible for what has been unchecked overuse of supply-sensitive care. Accordingly, proposed strategies for reducing variation and lowering these costs involve payment model reforms such as transitioning to bundled payment systems, pay-for-performance, and implementing penalties for high utilizers of discretionary services. Accountable care organizations (ACOs) also show great potential for reducing variation in the use of hospital services. In the ACO model, healthcare organizations contract to provide comprehensive care to a population of patients for a fixed per-member price, and payments for each hospitalization are shared across all members of the hospital system’s medical staff, including providers responsible for the outpatient care of the child. ACOs are paid on a capitated basis and/or for achieving certain quality/cost targets, and thus are incentivized to more carefully manage the quality and utilization of care. In their early stages of development, some ACOs appear to be successful at reducing cost while improving quality, but more needs to be learned about which organizational factors most contribute to a successful ACO model.16 Preference-sensitive care entails the management of conditions for which there are several justifiable options for diagnosis and treatment. In some cases, there may be no evidence to support any single option. In others,

evidence does exist, but each option may involve important tradeoffs that should be considered on a patient-by-patient basis. One similarity between supply-sensitive and preference-sensitive care is the hypothesis that variation in physician practice styles, as opposed to differences in patient preferences, are the major driver of variation in care. While patient preferences will produce some degree of variation in care, management decisions such as opting to perform surgery on adults with chronic lower back pain appear to be clustered within health systems, making it highly unlikely that patient preferences alone are driving variation.17 The unbalanced influence of the physician on clinical decision-making has also been demonstrated for elective procedures in pediatrics. In a recent study by Fox et al., the decision to proceed with a fundoplication procedure in children with severe reflux was rarely based on definitive testing, and most physicians felt that family decisions to proceed with surgery were more strongly influenced by the preferences of subspecialists than by counseling from their primary provider.18 Since there is little evidence to guide the treatment of severe reflux, these decisions were likely guided by anecdotal experiences and the physicians’ own interpretation of existing literature rather than informed family preferences. Public reporting of quality ratings and outcomes will theoretically allow patients to become better informed on the tradeoffs involved with their medical decisions. However, interventions that occur closer to the point of care such as telephone coaching and use of decision aids may more effectively promote shared decision-making. In one study examining decision-making and outcomes for adults with lower back pain, use of these tools was associated with lower rates of preference sensitive procedures and lower rates of readmission for patients who had elected to have back surgery.19 For now, families continue to feel poorly informed of the negative consequences of different management options, and physicians often overestimate their alignment with patient preferences. Fortunately, federal and state efforts including policies within the Affordable Care Act and Medicare’s Pioneer Accountable Care Organization Program, as well as other government-supported programs such as the Centers for Medicare & Medicaid Services (CMS) Partnership for Patients, are now lending stronger support to shared decision-making as a tool for reducing variation in

management of preference-sensitive conditions. Effective care involves the management of conditions for which there is strong scientific evidence to support best practices. Although many inpatient conditions in pediatrics have limited evidence to support care, conditions such as asthma, urinary tract infections (UTIs), and community-acquired pneumonia (CAP) have evidence-based guidelines to support clinical decision-making. Most providers can agree that adherence to these guidelines is of great clinical importance and value to their patients, yet a high proportion of children continue to receive improper care for these conditions. For example, in a 2009 study examining the management of febrile UTIs in young children, Conway et al. found that 83% of children >2 months of age were admitted to the hospital for treatment despite American Academy of Pediatrics (AAP) recommendations for outpatient management in this population.9 A second study by Neuman et al. found that only 24% of children hospitalized for CAP received the recommended first-line antibiotic.20 Though many factors can contribute to deviations in the management of common conditions in children, these findings are too large to be attributed to patient differences alone. The first hurdle in reducing variation in effective care is overcoming the gap between scientific discovery and clinical practice. For conditions with high variation in effective care such as febrile UTIs and CAP, clinical practice guidelines (CPGs) have been an important tool for educating providers on evidence-based practice, and use of CPGs has resulted in improvements in adherence to care, reduced lengths of stay, and lower resource utilization. Even with CPGs, however, variation in adherence to effective care persists, indicating that these interventions alone are not always enough to change physician behavior. Additional tools have been developed to support implementation of CPGs and reduce variation in evidence-based care in clinical settings. The most widely studied CPG support tools are practice protocols and clinical pathways. Unlike CPGs, which typically only describe best practice and reference-supporting evidence, protocols and pathways are designed to enhance coordination of care and reliability in the execution of evidencebased care. Protocols are most appropriate for systematically guiding individual providers through treatment decisions by outlining specific evidence-based criteria under which a physician would or would not choose a

certain course of treatment (e.g. phototherapy vs. exchange transfusion for neonates with hyperbilirubinemia). Alternatively, clinical pathways aim to decrease variation in effective care by promoting the coordination of the care team in executing evidence-based management. A strength of pathways is that they often contain a built-in component for measuring defined outcomes (cost, treatment success, adherence) and providing feedback to clinicians. The literature contains several examples of both successful and unsuccessful applications of CPGs, pathways, and protocols for reducing variation in effective care, and it is likely that there is no one-size-fits-all strategy. In order to optimize their generalizability and effectiveness across hospital systems, future research will need to explore organizational factors that may act as barriers or facilitators to the effective implementation of these tools. On a national policy level, hospitals are being encouraged to learn from variation in effective care by forming partnerships with neighboring health centers. Using what is called a positive deviance approach, the CMSsponsored Hospital Engagement Networks (HENs) have committed to exploring factors that may facilitate high quality of care. By sharing information on processes of care, quality improvement tools, and implementation strategies, HENs work to collectively identify and implement standardized practices that consistently produce better outcomes. To date, HEN collaborations have minimized variation in care across networks and led to dramatic reductions in adverse events (http://www.jcrinc.com/CMSHospital-Engagement-Network).

VARIATION AND COMPARATIVE EFFECTIVENESS RESEARCH Even in the case of effective care, it may be difficult to determine what degree of variation is truly unwarranted, emphasizing the need to continuously monitor both processes and outcomes of care. In addition, variation in care may actually be informative, revealing new knowledge about what works and what doesn’t work in our traditional management. In this way, existing variation creates new opportunities for comparative effectiveness research (CER). With new resources and tools such as nationally representative administrative datasets, clinical registries, and more

advanced statistical methods, CER can now address clinical questions that previously would have been too costly and infeasible to study. Hospitalists in particular are utilizing these tools to produce high impact research— measuring important indicators of how hospitalists deliver care and generating hypotheses about which strategies may facilitate the most effective and highest value care. As this work moves forward, it will be important to define priorities for comparative effectiveness research in pediatric hospital medicine. Due to growing funding constraints and other challenges inherent to pediatric research (e.g. small sample sizes, relatively rare outcomes), the research community has a great responsibility to focus CER efforts on conditions for which the opportunity to impact patient outcomes and/or resource utilization is greatest. Strategies for determining high priority conditions will require knowledge of current disease prevalence, burden of illness, cost, gaps in evidence, feasibility of study, and importance of outcomes to patients. Currently, however, some or all of these measures are unknown for many pediatric conditions, and methods for efficiently and accurately defining them are still needed. One such method for ranking the priority of inpatient conditions used the PHIS database and a standardized costing method to identify the 100 most costly and prevalent pediatric inpatient conditions.21 The investigators then quantified the degree of variation in resource utilization for each of these costly and common conditions. Not surprisingly, conditions such as asthma, pneumonia, and gastroenteritis were found to be among the highest priority conditions. Also identified were conditions for which variation and the potential for clinical impact may have been underappreciated, such as diabetic ketoacidosis, scoliosis surgery, and tonsillectomy procedures. Researchers have begun to explore the potential drivers of variation in effective care for these high priority conditions. In one study looking at 12,605 children hospitalized with acute gastroenteritis (a condition with high variation in effective care) admission to hospitals that cared for fewer children with the illness was associated with a higher probability of having non-recommended blood testing or receiving antibiotics.22 In another study evaluating variation in prophylactic antibiotics in scoliosis surgeries at PHIS hospitals, several centers used broader spectrum antibiotics only in patients with diagnoses indicating higher presurgical risk of infection, others used

them for all patients, and still others rarely used them at all.23 In each case, variation in effective care could not be fully explained by hospital or patient factors and is therefore likely unwarranted. This variation, however, can be informative and has provided the basis for future research comparing the effectiveness of tools such as care pathways and antibiotic stewardship programs designed to reduce overutilization of hospital services and promote the appropriate use of evidence-based care.

CONTRIBUTIONS FROM HOSPITAL MEDICINE Given their understanding of complex hospital systems, specialists in pediatric hospital medicine are well suited to study variation and best practices in the delivery of pediatric care and to design system level interventions to reduce unwarranted variation and improve the value of care in their health systems. Networks such as the Pediatric Research in Inpatient Settings (PRIS) Network and the AAP’s Value in Inpatient Pediatrics (VIP) Network have made significant progress in these domains. As the field advances as an academic specialty, hospitalists involved in research and operational efforts to reduce and study variation have several important challenges to address. First, providers and hospital leaders need to advocate for payment reforms that incentivize high value care and reduce unwarranted variation in supply-sensitive care. Second, given diminishing availability of support from federal funders, hospitalists need to prioritize the subjects of their CER efforts, focusing efforts on conditions for which innovations in care will have a large impact on value and outcomes. Third, networks of researchers and providers need to continue to develop reliable and transparent data sources with which to longitudinally monitor processes and outcomes across health systems. Such data will promote a collective sense of accountability as well as encourage collaborative efforts to disseminate guidelines and reduce variation in effective care. Fourth, the scope of comparative effectiveness research needs to be broadened to account for the diversity and complexity of healthcare systems and gain a deeper understanding of the unique organizational barriers and facilitators to implementing effective and more patient-centered care. Finally, CER conducted by hospitalists needs to be methodologically rigorous, utilizing advanced methods for risk adjustment

and subpopulation analyses of observational data, and rigorous systematic reviews, and meta-analyses on existing data from the literature.

SUMMARY It is well known that healthcare services, resource utilization, quality, and outcomes vary tremendously across the United States. In some cases, this variation may be the result of appropriate decision-making and consideration of differing patient preferences, but much of this variation is likely unwarranted and unexplained by patient preferences or evidence-based practice. The consequences of unwarranted variation are profound, and include uncontrolled healthcare spending and large disparities in quality of care. Payment system reform, better tools for shared decision-making, public reporting of outcomes, and implementation of CPGs, pathways, and protocols all require more research to determine the most effective way to reduce variation, control cost, and optimize quality. However, variation also provides opportunities to study how we can improve our care, and offers many opportunities for comparative effectiveness research. Understanding the driving factors and consequences of variation—warranted and unwarranted—will be essential to improving value and reducing disparities in the care of hospitalized children in the US healthcare system.

REFERENCES 1. Glover JA. The Incidence of Tonsillectomy in School Children (Section of Epidemiology and State Medicine). Proc R Soc Med. 1938;31(10):1219-1236. 2. McPherson K, Wennberg JE, Hovind OB, Clifford P. Small-area variations in the use of common surgical procedures: An international comparison of New England, England, and Norway. N Engl J Med. 1982;307(21):1310-1314. 3. Wennberg JE, Freeman JL, Shelton RM, Bubolz TA. Hospital use and mortality among Medicare beneficiaries in Boston and New Haven. N Engl J Med. 1989;321(17):1168-1173. 4. Yasaitis L, Fisher ES, Skinner JS, Chandra A. Hospital quality and

intensity of spending: Is there an association? Health Aff (Millwood). 2009;28(4):w566-572. 5. Goodman DC, Morden NE, Ralston SL, Chang C, Parker DM, and Weinstein BA. The Darmouth Atlas of Children’s Health Care in Northern New England. Trustees of Dartmouth College 2013. Available at: http://www.dartmouthatlas.org/downloads/atlases/NNE_Pediatric_ Atlas_121113.pdf. 6. Perrin JM, Homer CJ, Berwick DM, Woolf AD, Freeman JL, Wennberg JE. Variations in rates of hospitalization of children in three urban communities. N Engl J Med. 1989;320(18):1183-1187. 7. McConnochie KM, Russo MJ, McBride JT, Szilagyi PG, Brooks AM, Roghmann KJ. Socioeconomic variation in asthma hospitalization: Excess utilization or greater need? Pediatrics. 1999;103(6):e75. 8. Homer CJ, Szilagyi P, Rodewald L, Bloom SR, Greenspan P, Yazdgerdi S, Leventhal JM, Finkelstein D, Perrin JM. Does quality of care affect rates of hospitalization for childhood asthma? Pediatrics. 1996;98(1):18-23. 9. Conway PH, Keren R. Factors associated with variability in outcomes for children hospitalized with urinary tract infection. J Pediatr. 2009;154(6):789-796. 10. Brogan TV, Hall M, Williams DJ, Neuman MI, Grijalva CG, Farris RW, Shah SS. Variability in processes of care and outcomes among children hospitalized with community-acquired pneumonia. Pediatr Infect Dis J. 2012;31(10):1036-1041. 11. Pati S, Lorch SA, Lee GE, Sheffler-Collins S, Shah SS. Health insurance and length of stay for children hospitalized with community-acquired pneumonia. J Hosp Med. 2012;7(4):304-310. 12. Patrick SW, Schumacher RE, Davis MM. Variation in lumbar punctures for early onset neonatal sepsis: A nationally representative serial crosssectional analysis, 2003-2009. BMC Pediatr. 2012;12:134. 13. Wennberg J, Gittelsohn. Small area variations in health care delivery. Science. 1973;182(4117):1102-1108. 14. Fisher ES, Wennberg JE. Health care quality, geographic variations, and the challenge of supply-sensitive care. Perspect Biol Med.

2003;46(1):69-79. 15. Fisher ES, Welch HG. Avoiding the unintended consequences of growth in medical care: How might more be worse? JAMA. 1999;281(5):446453. 16. Fisher ES, Shortell SM, Kreindler SA, Van Citters AD, Larson BK. A framework for evaluating the formation, implementation, and performance of accountable care organizations. Health Aff (Millwood). 2012;31(11):2368-2378. 17. Birkmeyer JD, Sharp SM, Finlayson SR, Fisher ES, Wennberg JE. Variation profiles of common surgical procedures. Surgery. 1998;124(5):917-923. 18. Fox D, Barnard J, Campagna EJ, Dickinson LM, Bruny J, Kempe A. Fundoplication and the pediatric surgeon: Implications for shared decision-making and the medical home. Acad Pediatr. 2012;12(6):558566. 19. Veroff D, Marr A, Wennberg DE. Enhanced support for shared decision making reduced costs of care for patients with preference-sensitive conditions. Health Aff (Millwood). 2013;32(2):285-293. 20. Neuman MI, Hall M, Hersh AL, Brogan TV, Parikh K, Newland JG, Blaschke AJ, Williams DJ, Grijalva CG, Tyler A, Shah SS. Influence of hospital guidelines on management of children hospitalized with pneumonia. Pediatrics. 2012;130(5):e823-830. 21. Keren R, Luan X, Localio R, Hall M, McLeod L, Dai D, Srivastava R. Prioritization of comparative effectiveness research topics in hospital pediatrics. Arch Pediatr Adolesc Med. 2012;166(12):1155-1164. 22. McLeod L, French B, Dai D, Localio R, Keren R. Patient volume and quality of care for young children hospitalized with acute gastroenteritis. Arch Pediatr Adolesc Med. 2011;165(9):857-863. 23. McLeod LM, Keren R, Gerber J, French B, Song L, Sampson NR, Flynn J, Dormans JP. Perioperative antibiotic use for spinal surgeries in US children’s hospitals. Spine (Phila Pa 1976). 2013;38(7):609-616.

CHAPTER

3

Evidence-Based Medicine Jonathan M. Mansbach

INTRODUCTION Ideal clinical care integrates a health care professional’s clinical experience, individual patient preferences and values, and current best clinical evidence. Every hospitalist has his or her own set of clinical skills and experiences and each patient has his or her own beliefs. The current best clinical evidence, however, is universal. How clinicians apply and explain this evidence to individual patients and integrate the evidence into care plans is the art of practicing evidence-based medicine (EBM). This chapter provides practical guidance on formulating questions and uses clinical examples to discuss how to efficiently and effectively use and search the medical literature.

FORMULATING QUESTIONS Caring for patients frequently generates clinical questions. A 1985 study found that general practitioners in an office-based practice formulated two important clinical questions for every three patients examined.1 Since there are millions of research articles in the world’s literature, finding relevant articles and assessing their quality can be time consuming. If a wellformulated clinical question is posed, the process of finding answers is easier. There are four parts of a clinical question: the patient population, the intervention being considered, the comparison group, and the measurable outcome. Including these four parts to formulate questions will help focus literature searches.2 A 7-month-old with bronchiolitis was admitted to your service last night. In considering how best to care for her, you formulate the following:

1. Patient population (includes patient problem)—in children < 2 years with bronchiolitis 2. Intervention (diagnostic test or treatment), Prognostic factor, or Exposure —do bronchodilators 3. Comparison group—compared with placebo 4. Measurable outcome—reduce hospital length of stay? Often, developing one critical clinical question will suffice, but a series of questions is sometimes required, especially when inpatients have complex medical problems. Clinical questions should be focused but not overly narrow, since too narrow a question may not have an answer, or may have an answer that does not apply to the individual patient. In pediatrics, defining the patient population is important. Many hospitalists care for patients ranging in age from infants to young adults, and judgments must be made if studies that do not include your patient’s age will apply. Frequently, a study in adults has been performed and the hospitalist must decide if the study applies to a particular pediatric or adolescent patient. Sometimes the question may not involve an intervention, and there may therefore be no comparison group to consider. For example, during morning rounds you hear about a 16-year-old female with anorexia nervosa admitted for bradycardia. You ask the question: In a female adolescent with a restrictive eating disorder and heart rate of 35, what is the risk of sudden cardiac death? This question considers the prognosis of a specific population. The measurable outcome chosen reflects the current clinical concerns, values, and preferences of the clinician and patient. When a child is admitted with right lower quadrant abdominal pain the clinician may be most concerned about how to best evaluate for appendicitis, but the patient and parent may be most concerned about pain control.

SEARCHING FOR BACKGROUND INFORMATION A solid comprehension of the disease process or syndrome usually must precede asking specific questions. Background information about pathophysiology, clinical presentation, treatment, complications, and outcomes may be found in print textbooks, review articles, or electronic textbooks. Print textbooks are valuable resources, particularly for well-

established information. For example, if a patient presents with a parapneumonic effusion, reading a chapter in a textbook will be helpful in understanding the underlying disease process. A textbook chapter, however, may not contain up-to-date information on management from recently published articles. If you require further background information about parapneumonic effusions, accessing electronic texts may be most helpful. You begin your reading by reviewing the topic of parapneumonic effusions in children on UpToDate (www.uptodate.com), an easily accessible electronic textbook that is frequently revised and contains good references. If you enter “parapneumonic effusion” in the search line, there is a reference entitled, “Management and prognosis of parapneumonic effusion and empyema in children.” You click on the article and note when the review was most recently updated and when it is due to be revised. In reading the review you remind yourself about the pathogenesis of pleural effusions and the differences between uncomplicated effusions, complicated effusions, and empyemas. There are 82 references, and each reference can be viewed by clicking on the title. Review articles are another starting place, and Medline searches can be focused to locate review articles by using the “limit” function. For example, if you type parapneumonic effusions.tw (word in title or abstract—see below) and limit the search to review articles and English language, there are 32 hits. The articles include a consensus guideline published in Chest, and Cochrane reviews. Note that a separate search would need to be conducted to find articles that specifically address the definition and management of empyema.

SEARCHING MEDLINE USING OVID After reminding yourself of definitions and reviewing data, if you have more specific questions, Medline is a good place to begin searching. Medline is a National Library of Medicine database derived from more than 4500 journals and includes over 10 million citations. PubMed, frequently used to access Medline, contains additional basic science and life science articles. Ovid is another means of accessing Medline and is the software referred to in this chapter. Before you begin searching it is helpful to understand how articles are indexed in Medline. One method of limiting the number of articles you wade

through is by attaching suffixes to the keyword. These suffixes allow you to search one journal, search by author, look for words in a title or abstract, or restrict the search by year of publication. Some useful suffixes are listed in Table 3-1. For example, if you search for articles related to bronchiolitis and type bronchiolitis.tw (searches for bronchiolitis as a textword in the title or abstract) you will have 4000 hits. Typing bronchiolitis.ti generates 1900 hits. TABLE 3-1

Suffixes

.ab

Word in Abstract

.au

Author

.jn

Journal

.ti

Word in title

.tw

Word in title or abstract

.yr

Year of publication

Medline is also indexed using Medical Subject Headings (MeSH) terms. The keyword you type will be mapped automatically to one of the subject headings. If you search for the term bronchiolitis, it will automatically be mapped to the MeSH terms: bronchiolitis, bronchiolitis obliterans, bronchiolitis viral, and bronchiolitis obliterans organizing pneumonia. If you include bronchiolitis and viral bronchiolitis, there are 2100 hits and only 9 overlapping articles. To see the diagram of how bronchiolitis is mapped to the MeSH terms, type tree bronchiolitis. If you receive too many articles to review, you may limit the search by using subheadings. Some helpful subheadings are listed in Table 3-2. For example, if you want to limit your search to articles published in 2003–2004 related to bronchiolitis therapy, you would limit the publication years to 2003–2004 (using the suffix .yr) and type bronchiolitis/dt (generates 46 articles) and also viral bronchiolitis/dt (generates 21 articles). TABLE 3-2

Subheadings

/ae

Adverse effects

/co

Complications

/di

Diagnosis

/dt

Drug therapy

/ep

Epidemiology

/hi

History

/th

Therapy

WHAT ABOUT THE QUALITY? Once you find articles through Medline, you still have to assess the quality of the studies and validity of the conclusions. To bypass this time-consuming step, you can change the database searched using Ovid, from Medline to EBM reviews. The EBM reviews contain American College of Physicians (ACP) Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CCTR), and Cochrane Database of Systematic Reviews (CDSR). If you find articles on the topic of interest in one of these four databases, the quality of the article or articles will be assessed for you. Each of the four databases is described below. The editors of the ACP Journal Club collection identify clinically relevant, methodologically sound articles from top journals and provide a commentary on the value of the article for clinical practice. If you search for bronchiolitis in the ACP, one interesting article is found reviewing dexamethasone for bronchiolitis. DARE contains critical assessments of systematic reviews covering diagnosis, prevention, rehabilitation, screening, and treatment. DARE is produced by the National Health Services’ Centre for Reviews and Dissemination at the University of York, England. If you search for bronchiolitis in DARE, six articles are found. The CCTR (Cochrane Controlled Trials Register) is a database of definitive controlled trials in the literature. The database is an unbiased source of data and information. The Cochrane group, National Library of

Medicine in Washington, DC, and Reed Elsevier of the Netherlands collaborate to identify relevant studies for inclusion in the database. The word bronchiolitis generates 239 articles in the CCTR. The CDSR includes Cochrane Collaboration’s regularly updated systematic reviews about therapy, intervention, or prevention. The Cochrane Collaboration was developed in 1992 on the premise that interventions would be more effective if based on recent evidence. The reviews are presented as complete reviews or protocols yet to be finished. The completed reviews have summary statements and graphs. There are 39 systematic reviews related to the word bronchiolitis.

OTHER WEB RESOURCES Other resources on the web include The National Guideline Clearinghouse (www.guidelines.gov). This is a database of evidence-based clinical practice guidelines (CPG) and related documents originally developed by the Agency for Healthcare Research and Quality (AHRQ). A search for bronchiolitis will yield a CPG from Cincinnati Children’s Hospital Medical Center. Another site, from the University of Michigan (www.med.umich.edu/ pediatrics), has put together a collection of critically appraised topics (CAT). These are short summaries and reviews of interesting articles in the literature. Many of the CATs are applicable to inpatient medicine. Another good site is www.intensivecare.com. This site has many EBM links and also has a searchable pediatric critical care medicine evidence-based journal club. Although the reviews deal with critical care, many are relevant for hospitalists.

VALIDITY The above databases and web sites may not address all of the problems a hospitalist will encounter, so having a basic understanding of how to assess an article’s validity is helpful. In Table 3-3, basic items are presented to help evaluate an article investigating a prognostic factor, a treatment, or a diagnostic test.2-4 TABLE 3-3

Validity

Prognosis The patient population should be defined and patients should be enrolled at a similar stage of illness. The follow-up rate should be high and patients need to be followed for enough time to allow for development of the chosen outcome. Better outcomes are objective and easily measured. Treatment The most valid treatment trials are randomized and blinded. The patients in each randomized group should be similar. An “intention-to-treat” analysis should be used; once the patient is randomized they are included in the analysis. The chosen outcomes are relevant, objective, and measurable. Diagnosis

The test being studied is explained in detail and compared to the best available standard. The cohort of patients tested is explained in detail and includes some measure of severity of illness.

APPLICABILITY How valid information is integrated into the care of individual patients is the art of practicing evidence-based medicine. For example, a double-blind randomized controlled trial has determined that when medicine Z is given to patients with bronchiolitis, it reduces the length of stay in the hospital. You determine that the study is valid, but wonder if the new study will apply to your individual patient. Does the population in the trial sufficiently match the age, past medical history, severity of illness, and so forth of your patient? Is it possible that your patient with congenital heart disease is different enough from the previously healthy children in the trial that the risk of treatment increases? Does drug Z interact with other medications, altering the risk/benefit ratio? Are there other social factors (financial constraints, beliefs about medicine, etc.) that should be considered?

PUTTING IT ALL TOGETHER

During morning rounds you are told about a 3-year-old child who has a history of present illness, physical exam, and chest radiograph consistent with the diagnosis of pneumonia with an effusion. You begin considering antibiotic choices, are wondering about further diagnostic tests, and are thinking about the merits of thoracentesis, video-assisted thorascopic surgery (VATS), and fibrinolytics. You decide you need more information and also want to review the most recent literature before making any decisions. You review background information on UpToDate (discussed earlier). After reviewing this information, you pose the following two questions: In toddlers with parapneumonic effusions does surgical management compared to nonsurgical management improve long-term lung function; and does it shorten length of stay? Entering parapneumonic effusion into the EBM review database generated three articles. One CDSR topic review investigated surgical (VATS) versus nonsurgical (chest tube drainage with streptokinase) management of pleural empyema. This topic review included only one randomized adult trial of 20 patients.5 Although it is not ideal to make recommendations from one small trial, the results of the trial demonstrated that the VATS group compared to the nonsurgical group had a significantly shorter length of stay in the hospital. The study does not mention long-term lung function. The possible benefits of shorter length of stay need to be weighed against the risks of general anesthesia and the necessity for transient one-lung ventilation due to the procedure. Additional risks and possible complications may not be apparent from such a small study. In addition, the hospitalist must decide if this adult study should apply to a pediatric patient. The process described (using UpToDate and Medline restricted to EBM reviews) will most likely take less than 30 minutes. In this 30-minute search not only will you have a better understanding of background information, but you will have also reviewed some of the most recent literature on the topic of interest. One of the drawbacks of EBM reviews, however, is the limited number of pediatric studies that have large sample sizes, are well designed, and apply to general pediatric inpatient medicine. Furthermore, the outcomes studied are not always relevant for the individual patient. Despite these drawbacks, searching for the most recent evidence always has merit. Having the knowledge that there are no studies adequately addressing the topic or problem at hand is informative in itself and will hopefully guide future research.

TEACHING EBM One difficulty for hospitalists who round with medical students, residents, and fellows is teaching how to practice EBM. Modeling for learners your evidence-based approach to caring for patients is one method. Another interesting method presented by Dr. David Sackett and colleagues is having an “evidence cart” during rounds. In this study, having quick and easy access to evidence altered patient care decisions and increased the incorporation of evidence into patient care.6 Effectively teaching specific evidence to fatigued residents and fellows is also difficult. However, the results of an interesting ambulatory study suggest that the learner-focused “one-minute preceptor model” may be a quick, effective method of teaching.7,8 As a group, hospitalists should not only continue to incorporate EBM into their practice, but also teach EBM to students, residents, fellows, and colleagues.

SUGGESTED READINGS Guyatt G. Users’ Guides to the Medical Literature: A Manual for EvidenceBased Clinical Practice, Third Edition. McGraw-Hill Publication. 2015. Moyer VA, Elliott E eds. Evidence Based Pediatrics and Child Health. London, UK: BMJ Books Blackwell Publishing; 2005. Sackett D. Evidence Based Medicine: How to Practice and Teach EBM. Churchill Livingstone; 4th edition, (17 Dec. 2010).

REFERENCES 1. Covell DG, Uman GC, Manning PR. Information needs in office practice: Are they being met? Ann Intern Med. 1985;103(4):596-599. 2. Moyer V, Elliott E, Davis R, et al., eds. Evidence Based Pediatrics and Child Health. London: BMJ Books; 2000. 3. Richardson WS, Wilson MC, Guyatt GH, Cook DJ, Nishikawa J. Users’ guides to the medical literature: XV. How to use an article about disease probability for differential diagnosis. Evidence-Based Medicine Working Group. JAMA. 1999;281(13):1214-1219.

4. Richardson WS, Wilson MC, Williams JW, Jr., Moyer VA, Naylor CD. Users’ guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group. JAMA. 2000;284(7):869-875. 5. Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of empyema therapy. Chest. 1997;111(6):1548-1551. 6. Sackett DL, Straus SE. Finding and applying evidence during clinical rounds: The “evidence cart”. JAMA. 1998;280(15):1336-1338. 7. Irby DM, Aagaard E, Teherani A. Teaching points identified by preceptors observing one-minute preceptor and traditional preceptor encounters. Acad Med. 2004;79(1):50-55. 8. Aagaard E, Teherani A, Irby DM. Effectiveness of the one-minute preceptor model for diagnosing the patient and the learner: Proof of concept. Acad Med. Jan 2004;79(1):42-49.

CHAPTER

Overview: Quality of Care

4

Jeffrey Simmons, Paul Hain, and Michele Saysana

INTRODUCTION If the value of a healthcare system is defined as the quality of the system divided by its cost, then the value of care in the United States is very low compared to other developed nations. The United States spent nearly 18% of GDP in 2012 on health care, while the next highest spending among developed nations was 12%.1 It is estimated that more than $700 billion of healthcare spending each year in the United States is waste.2 In the measure of outcomes, the US healthcare system ranks 37th globally.3 Low quality divided by high cost equals a system that has great potential for improvement. Inpatient hospital care accounts for nearly one quarter of the annual amount spent on child health,4 with that figure climbing even higher when emergency department visits are added. Therefore pediatric hospitalists are in a position to exert strong influence and leadership upon improving the value of that care by increasing the quality and decreasing the cost. Examples of quality projects in hospitals that have improved value include reduction of catheter-associated bloodstream infections (CLABSI),5 reduction in mortality through rapid response teams,6 reduction in codes outside of the ICU,7 increases in hand washing,8 decreases in contaminated blood cultures,9 and decreases in identification band errors.10,11 Payers have already begun to increase pressure on hospital systems to deliver value by implementing payment penalties for care that is perceived to be of low quality. The Center for Medicare and Medicaid Services (CMS) has issued instructions to stop paying for CLABSIs and pressure ulcers that occur during a hospital stay. Additionally, despite the ambiguity of evidence that unplanned readmissions

are either preventable or a marker of poor quality in pediatrics,12,13 many state Medicaid plans have begun to penalize hospitals for readmission rates that are perceived to be high. Historically, one of the barriers to improved quality was that the return on investment did not accrue to the hospital or the physicians. For example, decreasing a hospital’s CLABSI rate would lower charges and payments, thus lowering the revenue stream to the hospital and increasing profits for the payer. Over the previous decade, many individual quality measures had payment penalties associated with them as an incentive to the hospitals to improve. However, with the passage of the Patient Protection and Affordable Care Act (PPACA) in 2010, the potential for the incentives around quality improvement to align with both the payer and the hospital increased dramatically. One of the cornerstones of the PPACA was the creation of vehicles known as accountable care organizations (ACOs) that allow institutions to take financial risk for a group of patients.14 By taking on that risk, the increased value in the system that is created by quality improvement can accrue to the institution bearing the risk, instead of an insurance company.

EVIDENCE-BASED MEDICINE AND CARE PRACTICE GUIDELINES Using evidence-based medicine and the diffusion of new advances to change physician practice is challenging.15 Recently, however, it is becoming accepted that evidence-based medicine and care practice guidelines represent an excellent way to increase utilization of proven therapy processes, which commonly increase quality and decrease cost (as discussed further in Chapter 3)

QUALITY IMPROVEMENT TOOLS Walter Shewart and W. Edwards Deming are generally thought of as the fathers of the modern era of quality improvement, as they introduced new theories and techniques for process control and quality assurance.16 Many of their techniques are still in use today. What follows is a brief description of the most valuable of those techniques for improving hospital care.

PLAN-DO-STUDY-ACT Also known as the PDSA cycle, Plan-Do-Study-Act describes the four phases of a quality improvement project. The “plan” phase is comprised of an analysis of the deficiencies of the system to be improved and the actions that will be taken to improve it. Once the plan is established, the “do” phase begins, and the plan is put into action. While those actions are taking place, predefined measurements are collected, and an analysis is undertaken to “study” how well the original plan is providing a remedy for the deficiencies in the system. After understanding where the original plan needs to be altered, those changes are “acted” upon, and the cycle continues.

STATISTICAL PROCESS CONTROL Statistical process control (SPC) is a statistical tool that allows for representation of data on a graph that helps users to understand what parts of processes are due to “natural” or “common cause” variation in systems, and what parts are due to changes that were made to a system, or “special cause.” With this method, variation in processes and systems can be understood in significantly less time than it would take to sample every single event, or to establish control groups,17 which is often an impossibility in a hospital. (Having a process run differently every other day just to study which way is better would be impossible for most processes in a modern hospital.) The fundamental tool in SPC is the control chart. The control chart takes a run chart (a series of measurements plotted in chronological order around a mean) and adds an upper control limit (UCL) and a lower control limit (LCL). These control limits are calculated by known formulas that rely on the measurement of variation inherent to the system. Points that fall outside of one of the control limits is considered to be a result of a “special cause”; something new in the system caused the change, as opposed to the normal random fluctuations one sees between the control limits.18 An example of an SPC chart for an improvement project in reducing identification bands defects in a children’s hospital is shown in Figure 4-1.

FIGURE 4-1. Statistical Process Control Chart of Defective ID Bands, November 07–May 08. (Reproduced with permission from Hain PD et al. An intervention to decrease patient identification band errors in a children’s hospital. Qual Saf Health Care. 2010;19(3):244-247. DOI: 10.1136/qshc.2008.030388. With permission from BMJ Publishing Group Ltd.) SPC charts are the simplest and most powerful tools in the quality improvement arsenal to track the effects of a PDSA cycle project. Although it is relatively simple to create an SPC chart using published formulas, many commercial programs are available that will create the appropriate charts when the user simply enters the collected data.

THEORY OF CONSTRAINTS The Theory of Constraints was introduced by Eli Goldratt in his novel The Goal,19 an allegory that tells the story of a manager whose plant is about to be closed. Through a series of encounters with a physicist, the manager creates rules that allow the system to reduce bottlenecks (constraints) and improve efficiency. In practical usage, this technique allows quality improvement efforts to be focused where they will return the most improvement.

Consider, for example, a desire to decrease IV drug delivery times during the night shift. A hypothetical pharmacy system might work like this (see Figure 4-2): The pharmacy printer which receives the order can print 10 orders per hour → the tech can mix 6 orders per hour → the labeling machine can label 20 orders per hour → the pharmacist can check 8 orders per hour → the delivery person can distribute 5 orders per hour.

FIGURE 4-2. Theory of Constraints algorithm. If a hospital were to start a quality improvement project without first knowing all of the steps and constraints, it might add another tech with the expectation that the process rate would move to 8 doses per hour, as that is what the pharmacist can check. However, since the delivery person can only deliver 5 doses per hour, no improvements in IV drug delivery times would actually be seen. Mr. Goldratt provides five specific steps for solving production problems in his novel, but they essentially boil down to the example above. One must find the tightest bottleneck (constraint) in the system and solve that one before solving any others, as solving any bottleneck other than the tightest one produces no value.

LEAN SIX SIGMA Lean and Six Sigma began as two separate methodologies that have merged into one way of thinking in its application in healthcare. Originally, Lean was concerned with the reduction of waste in the process steps of a production schema, while Six Sigma was invented by Motorola as a method of describing statistically how many defects per million were produced.20 That is to say, Lean makes a process more efficient, while Six Sigma makes the output of that process have fewer defects.

Clearly, both improved efficiency and fewer defects are laudable goals in delivering care in a hospital setting, and thus Lean Six Sigma has been combined into one overarching strategy. In general, the Lean part of a project focuses on what is known as a “value stream map,” which organizes all parts of the process into “value added” and “non-value added” steps. The steps that do not add value are considered waste, and there is an attempt to eliminate or minimize those steps. Lean itself has a standard group of solutions that are often effective to deploy in process redesign. The Six Sigma part of a project focuses on the rate defects in the product. (Six Sigma takes its name from a six standard deviation in a bell curve, which amounts to 3.4 defects per million opportunities.) Six Sigma is in many ways similar to the PDSA cycle, but with a control phase at the end. It relies on a routine of Define, Measure, Analyze, Improve and Control (DMAIC).21 Often the control phase is monitored by an SPC chart. An in-depth explanation of Six Sigma is beyond the scope of this text, but the understanding of how Lean and Six Sigma complement each other and can be used simultaneously is valuable to those pursuing quality improvement.

PATIENT SAFETY: A QUALITY OF CARE PROBLEM As defined by the Institute of Medicine (IOM), patient safety is “freedom from accidental injury” acquired from medical care leading to harm or death. The IOM has estimated that medical error contributes to 98,000 deaths annually, which placed medical error as the sixth leading cause of death.22,23 While the study that led to this estimate of deaths due to medical error has not been repeated, rates of medical error and patient harm have been evaluated and have not shown substantial improvement.24 Woods and colleagues estimate that about 70,000 children hospitalized annually experienced an adverse event and approximately 60% of these could be prevented.25 For many years after the IOM report, the focus for improving patient safety was on system redesign. The focus of decreasing patient harm and improving safety has shifted to balancing system factors with personal accountability.2628 Issues such as developmental level, reliance on adult caregivers, medical condition, and demographics make children more susceptible to medication errors and harm.29 Pediatric hospitalists understand the needs of children and the complexity of the healthcare system while also serving in leadership

positions, which puts them in the position to improve patient safety.

ORIGINS AND EPIDEMIOLOGY OF MEDICAL ERROR Understanding the cause and magnitude of adverse events is one of the first steps in developing improvements. Woods and colleagues conducted a study to determine the types of all adverse events and those that are preventable. Birth-related adverse events (32.2%), followed by diagnostic errors (30.4%) and medication-related adverse events (21.3), were the top three causes of preventable adverse events. Surgical causes only accounted for 3.5% of the preventable adverse events.25 Children with chronic conditions have an even higher rate of medical errors, found by Ahuja and colleagues in a 2006 study using the Kids’ Inpatient Database.30 While there have been improvements since the IOM report, these have largely focused on adults. Computerized physician order entry systems designed for adults have not been as effective in reducing medication errors in children because many errors in pediatric patients tend to be due to weightbased dosing errors,31 and because of other computerized system design problems. A systematic review conducted by Miller and colleagues found that most of the research conducted on medication error in children has been limited primarily to the domain of prescribing errors, and the authors put forth the challenge for future research in areas of dispensing, administering, and documenting of medication administration.32 Many factors may contribute to diagnostic errors. A survey by Singh and colleagues found that over half of the pediatricians who responded had made a diagnostic error at least once per month, and nearly half of the respondents had a diagnostic error that led to harm once or twice per year. The most common error made was diagnosing a viral illness as a bacterial illness.33 In a study by Zwaan, diagnostic errors leading to patient harm often transpired when deciding what laboratory testing was necessary. Physicians were often unaware that their decisions were incorrect.34 While medication errors and diagnostic errors are common causes of harm in pediatric patients, other hospital-acquired conditions also contribute to the overall scope of harm. Catheter-associated blood stream infections, catheter-associated urinary tract infections, surgical site infections, and ventilator-associated pneumonia are some of the hospital-acquired infections

which also lead to extended hospitalization along with increased morbidity and mortality.35-39 (See Chapter 5 for further information on infection control.) Falls, pressure ulcers, and venous thromboembolism acquired in the hospital are some other hospital-acquired conditions contributing to patient harm. Reason’s Swiss cheese model of error may also be helpful in understanding how risks persist even in the face of systems established to prevent harm. When an error occurs there are multiple protective barriers in place within the system to block the error from reaching the patient and causing harm. For example, if a physician writes an erroneous order, a nurse, clerk, the computer physician order entry system, pharmacist, or parent of a patient may interrupt it before it reaches the patient. None of these barriers is flawless and sometimes will allow an error to reach the patient and cause harm. At times systems also have what Reason described as latent conditions, in which weaknesses in the system result from decisions made for other reasons and may cause errors.40

IMPROVING PATIENT SAFETY Reducing harm and improving patient safety in pediatric patients is imperative for many reasons. Not only are external agencies such as CMS, the Joint Commission, state boards of health concerned with patient safety,41 parents are as well. When parents perceive issues with handoffs and transitions, they also have an increased need to be present and oversee their child’s medical care to prevent error.42 Some hospitals have conducted widescale cultural and system changes using quality improvement methodology to decrease serious harm events in children. Significant reductions in serious safety event rates have been demonstrated.43,44 This section discusses ways to improve patient safety and how hospitalists can play a role in these strategies. Systems to detect harm in individual hospitals are one of the first steps to improving patient safety. Voluntary reporting of incidents has not adequately reflected the actual number of medical errors including near misses and harm events. Hospitalists should continue to emphasize the need to report errors. To further quantify harm, some hospitals have used retrospective review with the Institute for Healthcare Improvement’s Global Trigger Tool or a pediatric version of this trigger tool. Trained reviewers such as nurses, pharmacists,

and physicians review charts to identify signs which prompt further review of the patient’s medical record to identify whether harm occurred.45,46 Further review of findings from trigger tools can help guide hospital’s efforts to reduce medication-related harm.45 In 2011, the American Academy of Pediatrics Steering Committee on Quality Improvement and Management and Committee on Hospital Care released a policy statement about patient safety and decreasing harm due to medical care. The committee recommended three main strategies. The first is to increase patient safety knowledge among pediatricians. Patient safety– focused sessions at conferences and learning collaborative at the local, regional, and national levels are ways to accomplish this. Hospitalists can participate in these and learn from one another, and commit to sharing this knowledge with their practice group and institutions in which they care for patients. Another recommendation is the use of “bundles” to decrease harm.41 The Institute for Healthcare Improvement (IHI) described bundle theory as a set of evidence-based interventions applied to a certain population of patients that when used together will result in better outcomes than if the interventions were applied separately.47 Some examples of the use of bundles have been applied to decrease central line–associated bloodstream infections and ventilator-associated pneumonia.49,37 Hospitalists have participated in bundle development in areas such as improving the discharge process.49,50 All of these projects have utilized Quality Improvement (QI) methodology to implement these bundles. Another way to view this recommendation is in terms of high reliability organization (HRO) theory. HROs are organizations such as aviation or the nuclear power industry which operate under high-risk conditions daily but achieve high safety records. Weick and Sutcliffe have found five characteristics that HROs share: sensitivity to operations, preoccupation with failure, deference to expertise, resilience, and reluctance to simplify.51 These organizations rely on all members of the organization to have a focus on safety by constantly looking for risk points and ways to mitigate risk. Baker and colleagues described how teamwork is a vital piece of HROs in healthcare settings.52 Hospitalists play a critical role in leading healthcare teams. Other examples of creating high reliability in hospitals include the use of checklists, standardized communication procedures, and time-outs prior to

procedures. The Joint Commission developed the Universal Protocol for Preventing Wrong Site, Wrong Procedure and Wrong Person Surgery and requires it be used by the their accredited institutions.53 Utilizing systems which decrease medication errors due to human factors, such as bar code scanning for medication administration, are another example of mitigating risk. Promoting patient safety with a focus on the unique risk for pediatric patients is the last strategy.41 By practicing family-centered care, hospitalist teams can partner with patients and families to empower them to speak up at any time. The Agency for Healthcare Research and Quality has resources to help patients and families partner with their physicians to improve patient safety.54 Hospitalists should also advocate for pediatric-specific safety interventions such as pediatric-specific drug catalogs and weight-based dosing for CPOE and electronic prescribing.55 Leadership scholars Kouzes and Posner stress that leadership is best accomplished when there is a shared vision and all team members realize they have leadership potential.56 Hospitalists at all levels need to realize they have leadership potential within their local institution and more broadly to advocate for safety for all children.

REFERENCES 1. Organisation for Economic Co-operation and Development (OECD). How Does the United States Compare? 2012. Available at: http:// www.oecd.org/unitedstates/BriefingNoteUSA2012.pdf. Accessed June 29, 2013. 2. Kelly R. Where Can $700 Billion in Waste Be Cut Annually from the US Health Care System? White Paper. Oct, 2009. Thompson Reuters. 3. WHO. World Health Report 2000—Health Systems: Improving Performance. ISBN 92 4 156198 X. 4. Health Care Cost Institute. July 2012. Trends in Children’s Health Care Costs and Utilization. Available at: http://www.healthcostinstitute.org/ files/HCCI_RB1.pdf. Accessed June 29, 2013. 5. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J

Med. 2006;355:2725-2732. 6. Sharek PJ, Parast LM, Leong K, et al. Effect of a rapid response team on hospital-wide mortality and code rates outside the ICU in a children’s hospital. JAMA. 2007;298(19):2267-2274. 7. Brilli RJ, Gibson R, Luria JW, et al. Implementation of a medical emergency team in a large pediatric teaching hospital prevents respiratory and cardiopulmonary arrests outside the intensive care unit. Pediatr Crit Care Med. 2007;8(3):236-246. 8. Zerr DM, Allpress AL, Heath J, Bornemann R, Bennett E. Decreasing hospital-associated rotavirus infection: a multidisciplinary hand hygiene campaign in a children’s hospital. Pediatr Infect Dis J. 2005;24(5):397403. 9. Hall RT, Domenico HJ, Self WH, Hain PD. Reducing the blood culture contamination rate in a pediatric emergency department and subsequent cost savings. Pediatrics. 2013;131(1):2012-1030. 10. Hain PD, Joers B, Rush M, et al. An intervention to decrease patient identification band errors in a children’s hospital. Qual Saf Health Care. 2010;19(3):244-247. 11. Phillips SC, Saysana M, Worley S, Hain PD. Reduction in pediatric identification band errors: A quality collaborative. Pediatrics. 2012;129(6):2011-1911. 12. Hain PD, Gay JC, Berutti TW, Whitney GM, Wang W, Saville BR. Preventability of early readmissions at a children’s hospital. Pediatrics. 2013;131(1):2012-0820. 13. Srivastava R, Keren R. Pediatric readmissions as a hospital quality measure. JAMA. 2013;309(4):396-398. 14. Integrated Healthcare Association. Accountable Care Organization Provisions in the Patient Protection and Affordable Care Act. Available at: http://www.iha.org/pdfs_documents/home/IHA_ PPACAACOSummary.pdf. Accessed on line June 29, 2013. 15. Lomas J, Anderson GM, Domnick-Pierre K, Vayda E, Enkin MW, Hannah WJ. Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Engl J Med. 1989;321(19):1306-1311.

16. American Society for Quality. W. Edwards Deming. Available at: http:// asq.org/about-asq/who-we-are/bio_deming.html. Accessed June 29, 2013. 17. Wheeler DJ. Understanding Statistical Process Control. 2nd ed. Knoxville, TN: SPC Press; 1992. 18. Benneyan JC. Statistical process control as a tool for research and healthcare improvement. Qual Saf Health Care. 2003;12:458-464. 19. Goldratt EM. The Goal. 3rd rev. ed. Great Barrington, MA: The North River Press; 2004. 20. Chassin MR. Is health care ready for Six Sigma quality? Milbank Quart. 1998;76:565-591. 21. de Koning H, Verver J, van den Heuvel J, Bisgaard S, Does R. Lean six sigma in health care. J Healthc Qual. 2006;4-11. 22. Kohn LT, Corrigan J, Donaldson MS. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press. 2000; xxi, 287 p. 23. Murphy SXJK, KD, Deaths: Final Data for 2010. Vital Stat Rep. 2013;61(4):1-168. 24. Landrigan CP, Parry GJ, Bones CB, Hackbarth AD, Goldmann DA, Sharek PJ. Temporal trends in rates of patient harm resulting from medical care. N Engl J Med. 2010;363(22):2124-2134. 25. Woods D, Thomas E, Holl J, Altman S, Brennan T. Adverse events and preventable adverse events in children. Pediatrics. 2005;115(1):155-160. 26. Wachter RM, Pronovost PJ. Balancing “no blame” with accountability in patient safety. N Engl J Med. 2009;361(14):1401-1406. 27. Goldmann D. System failure versus personal accountability—the case for clean hands. N Engl J Med. 2006;355(2):121-123. 28. Marx D. Patient Safety and the “Just Culture”: A Primer For Health Care Executives. New York: Columbia University; 2001. 29. Santell JP, Hicks R. Medication errors involving pediatric patients. Jt Comm J Qual Patient Saf. 2005;31(6):348-353. 30. Ahuja N, Zhao W, Xiang H. Medical errors in US pediatric inpatients with chronic conditions. Pediatrics. 2012;130(4):e786-793.

31. Han YY, Carcillo JA, Venkataraman ST. Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system. Pediatrics. 2005;116(6):1506-1512. 32. Miller MR, Robinson KA, Lubomski LH, Rinke ML, Pronovost PJ. Medication errors in paediatric care: A systematic review of epidemiology and an evaluation of evidence supporting reduction strategy recommendations. Qual Saf Health Care. 2007;16(2):116-126. 33. Singh H, Thomas EJ, Wilson L, et al. Errors of diagnosis in pediatric practice: A multisite survey. Pediatrics. 2010;126(1):70-79. 34. Zwaan L, Thijs A, Wagner C, van der Wal G, Timmermans DR. Relating faults in diagnostic reasoning with diagnostic errors and patient harm. Acad Med. 2012;87(2):149-156. 35. Yogaraj JS, Elward AM, Fraser VJ. Rate, risk factors, and outcomes of nosocomial primary bloodstream infection in pediatric intensive care unit patients. Pediatrics. 2002;110(3):481-485. 36. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. JAMA. 1994;271(20):1598-1601. 37. Bigham MT, Amato R, Bondurrant P, et al. Ventilator-associated pneumonia in the pediatric intensive care unit: Characterizing the problem and implementing a sustainable solution. J Pediatr. 2009;154(4):582-587 e2. 38. Ryckman FC, Schoettker PJ, Hays KR, et al. Reducing surgical site infections at a pediatric academic medical center. Jt Comm J Qual Patient Saf. 2009;35(4):192-198. 39. Brindha SM, Jayashree M, Singhi S, Taneja N. Study of nosocomial urinary tract infections in a pediatric intensive care unit. J Trop Pediatr. 2011;57(5):357-362. 40. Reason J. Human error: Models and management. BMJ. 2000;320(7237):768-770. 41. Steering Committee on Quality Improvement and Management and Committee on Hospital Care. Policy statement—principles of pediatric patient safety: Reducing harm due to medical care. Pediatrics. 2011;127(6):1199-1210.

42. Cox ED, Carayon P, Hansen KW, et al. Parent perceptions of children’s hospital safety climate. BMJ Qual Saf. 2013;22(8):664-671. 43. Muething SE, Goudie A, Schoettker PJ, et al. Quality improvement initiative to reduce serious safety events and improve patient safety culture. Pediatrics. 2012;130(2):e423-431. 44. Peterson TH, Teman SF, Connors RH. A safety culture transformation: Its effects at a children’s hospital. J Patient Saf. 2012;8(3):125-130. 45. Takata GS, Mason W, Taketomo C, Logsdon T, Sharek PJ. Development, testing, and findings of a pediatric-focused trigger tool to identify medication-related harm in US children’s hospitals. Pediatrics. 2008;121(4):e927-e935. 46. Kirkendall ES, Kloppenborg E, Papp J, et al. Measuring adverse events and levels of harm in pediatric inpatients with the Global Trigger Tool. Pediatrics. 2012;130(5):e1206-e1214. 47. Resar RGF, Haraden C, Nolan TW. Using care bundles to improve health care quality. In: IHI Innovation Series White Paper. Cambridge, MA: Institute for Healthcare Improvement; 2012. 48. Miller MR, Griswold M, Harris JM, et al. Decreasing PICU catheterassociated bloodstream infections: NACHRI’s quality transformation efforts. Pediatrics. 2010;125(2):206-213. 49. Jack BW, Chetty VK, Anthony D, et al. A reengineered hospital discharge program to decrease rehospitalization: A randomized trial. Ann Intern Med. 2009;150(3):178-187. 50. Project BOOST Team. The Society of Hospital Medicine Care Transitions Implementation Guide. Project BOOST: Better Outcomes by Optimizing Safe Transitions. June 29, 2013. Available at: http:// www.hospitalmedicine.org. 51. Weick KE, Sutcliffe KM. Managing the Unexpected Resilient Performance in an Age of Uncertainty. San Francisco, CA: Jossey-Bass; 2007. 52. Baker DP, Day R, Salas E. Teamwork as an essential component of high-reliability organizations. Health Serv Res. 2006;41(4 Pt 2):15761598. 53. The Joint Commission. Facts about the Universal Protocol. Available

at: http://www.jointcommission.org/assets/1/18/Universal_Protocol_1_ 3_13.pdf. Accessed June 28, 2013. 54. AHRQ. 20 Tips to Help Prevent Medical Errors: Patient Fact Sheet. September 2011. Available at: https://archive.ahrq.gov/patientsconsumers/care-planning/errors/20tips/. Accessed April 27, 2017. 55. Johnson KB, Lehmann CU, Council on Clinical Information Technology of the American Academy of Pediatrics. Electronic prescribing in pediatrics: Toward safer and more effective medication management. Pediatrics. 2013;131(4):824-826. 56. Kouzes JM, Posner BZ. The Leadership Challenge: How to Make Extraordinary Things Happen in Organizations. 5th ed. San Francisco, CA: Jossey-Bass. 2012; xiii, 394 p.

CHAPTER

5

Infection Control for Pediatric Hospitalists Julia S. Sammons and Susan E. Coffin

INFECTION CONTROL: A PATIENT SAFETY ISSUE Nosocomial infections are the single most common adverse event experienced by hospitalized children and adults. A recent multicenter survey found that 6% of patients develop nosocomial infections during admission to an acute care hospital.1 A point prevalence study performed in 30 pediatric facilities in Canada found an 8.7% prevalence of healthcare-associated infections and the prevalence was greatest for patients in intensive care units and oncology wards.2 Healthcare-associated infections increase morbidity, extend hospital stays, and raise hospital charges, and they are also associated with substantial increases of in-hospital mortality. An analysis of discharge data from more than 5 million pediatric hospitalizations revealed that postoperative sepsis and infection as a result of medical care were common events among hospitalized children and had a remarkable impact on length of stay and hospital costs.3 These findings persisted even after adjustment for patient and hospital characteristics (Table 5-1). Additionally, patients with a healthcareassociated infection were more likely to require the use of isolation precautions and antimicrobial therapy.2 TABLE 5-1

Impact of Nosocomial Infections in Hospitalized Children Mean Increase in

Mean Increase in Hospital

Mean Increase in Hospital

Length Stay Charges (Days) (US$)

Mortality (OR)

30

121,010

2.2

Postoperative 26 sepsis

117,815

11

Infection as a result of medical care

Source: Data from Miller MR, Zhan C: Pediatric patient safety in hospitals: A national picture in 2000. Pediatrics. 2004;113:1741. OR, odds ratio.

Thus the risk of healthcare-associated infections is significant, and the consequences are great. It is critical that all members of a healthcare team remain vigilant in order to prevent their patients from acquiring nosocomial infections during hospitalization.

PREVENTING INFECTION To prevent nosocomial infections, healthcare providers must understand how organisms are transmitted, both between individuals and from the environment or an inanimate object to a patient, how and when colonizing organisms (often referred to as commensal organisms) can become pathogenic, and how host and environmental factors modify the risk of nosocomial infection.

HOW ORGANISMS ARE TRANSMITTED Three basic mechanisms explain how most microorganisms are transmitted from one person to another: contact, either direct or indirect; droplet transmission; and airborne spread. Contact is the most common route by which the vast majority of bacteria and viruses are spread among patients and healthcare workers. Viruses, such as respiratory syncytial virus (RSV), and bacteria, such as methicillinresistant Staphylococcus aureus (MRSA), are typically spread directly from one person to another, particularly when infected or colonized children play

together in hospital playrooms. Hands, particularly those of healthcare workers, are another critical method by which potentially pathogenic organisms spread between patients. Indirect contact or fomite transmission is yet another common way that organisms, especially those capable of surviving for long periods on inanimate objects, can spread within the hospital setting. Because many viruses such as RSV can survive in dried secretions for hours, commonly touched items, like bed rails, can become reservoirs for transmission in the absence of thorough disinfection between patients. Respiratory droplets are responsible for the transmission of many common pediatric pathogens, including influenza viruses. Large respiratory droplets that contain viral particles are expelled from the nose and mouth during coughing, sneezing, and talking or during procedures such as suctioning, bronchoscopy, and cough induction by chest physiotherapy. These droplets can travel 3 to 6 feet in the air before settling. Transmission typically occurs when droplets come into contact with mucous membranes. Thus, face-to-face encounters with infected individuals allow the transmission of many viral pathogens in the absence of direct physical contact. Inadvertent inoculation of the conjunctival mucosa has been shown to be an important route of transmission for viruses. Airborne transmission occurs by the dissemination of droplet nuclei (small particles ≤ 5 μm), which are evaporated droplets that contain infectious microorganisms. These droplet nuclei can remain suspended in the air for long periods, become airborne, and travel significant distances from their point of origin. Organisms such as Mycobacterium tuberculosis (MTB), varicella virus, and measles virus can survive desiccation and exist as droplet nuclei. The outbreak potential for these organisms is great.

HAND HYGIENE AND STANDARD PRECAUTIONS Hand hygiene is the most critical element in the prevention of nosocomial infections. Sadly, studies have repeatedly shown that healthcare workers frequently fail to clean their hands at the appropriate times while providing patient care.5 Thus, healthcare workers are one of the most common sources of transmission of infection among patients. Hands should be washed with soap and water before and after eating, after using the bathroom, and when

they are visibly soiled.4 At all other times, healthcare providers should use alcohol-based hand rubs. The World Health Organization specifies five opportunities for hand hygiene that may arise in clinical care: (1) before contact with the patient; (2) before an aseptic procedure is performed; (3) after blood and body fluid exposure; (4) after contact with the patient; and (5) after contact with the patient’s environment. One of the most common errors made by clinicians is failing to perform hand hygiene before donning and after removing gloves. Alcohol hand rubs are more effective than soap and water at reducing microbial colonization of the hands.6 In addition to performing hand hygiene before and after every patient contact, all healthcare workers should observe standard precautions with every patient. These are transmission-based precautions designed to protect healthcare workers from exposure to any known or unknown pathogens that might be transmitted by contact with blood or body fluids. Critical elements of standard precautions include: (1) hand hygiene; (2) use of gloves when touching blood, body fluids, mucous membranes, or nonintact skin; and (3) mask, gown, and eye protection during procedures that might result in sprays of blood or body fluids.

TRANSMISSION-BASED PRECAUTIONS AND THE USE OF PERSONAL PROTECTIVE EQUIPMENT In addition to standard precautions, transmission-based precautions markedly reduce the risk of spread of many common agents of healthcare-associated infections (Table 5-2).7 Because many community-acquired pediatric pathogens are easily spread in inpatient units, the use of transmission-based precautions is especially important for pediatric facilities. TABLE 5-2

Organism

Summary of Expanded Precautions for Selected Pathogens Precautions* Comments

Viruses Adenovirus

C+D

C only for patients with isolated

conjunctivitis or gastroenteritis Enterovirus

C

Influenza virus

D

Norovirus

C

Parainfluenza virus

C

Respiratory syncytial virus

C

Rotavirus

C

Rubeola virus (measles)

A

Varicella virus

C+A

Continue until all lesions are crusted; C only for immunocompetent patients with zoster

Bacteria Antibioticresistant organisms†

C

Bordetella pertussis

D

Continue for 5 days after initiation of appropriate therapy

Clostridium difficile

C

Continue until resolution of diarrhea

Mycobacterium A tuberculosis Mycoplasma

D

Only required for suspected cavitary, laryngeal, or miliary disease

pneumoniae Neisseria meningitidis

D

Continue for 24 h after initiation of appropriate therapy

*Specific recommendations for the proper use of personal protective equipment and patient placement can be found at http://www.cdc.gov/HAI/prevent/ppe.html. †Including

methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and pan-resistant gram-negative organisms, including extended β-lactamase producers. A, airborne precautions; C, contact precautions; D, droplet precautions.

Some infections can be spread in multiple ways, necessitating the simultaneous application of multiple types of precautions (e.g. contact and airborne precautions for primary varicella infection). Special air handling and ventilation, as well as respiratory protection with a National Institute for Occupational Safety and Health–approved N-95 or higher respirator mask, are required to prevent airborne transmission of some microorganisms, such as measles, tuberculosis, and varicella. Healthcare workers must recognize the need for transmission-based precautions and be familiar with the appropriate use of personal protective equipment. For example, there is convincing evidence that the use of barrier precautions can reduce the transmission of MRSA. In an investigation that included weekly cultures of specimens from patients and personnel, molecular typing of isolates, and decolonization of organisms in some patients, investigators found that MRSA was spread to other patients at a rate of 0.14 transmission per day when patients who had been colonized or infected with MRSA were not cared for under contact isolation precautions. In contrast, when healthcare workers caring for patients with MRSA used gowns and gloves, the rate of MRSA transmission to other patients was 0.009 transmission per day. Thus, the risk of transmission was reduced nearly 16fold when MRSA patients were cared for under contact isolation precautions.8

MINIMIZING THE RISK ASSOCIATED WITH MEDICAL DEVICES Medical devices greatly increase the risk of nosocomial infection. Central venous catheters, urinary catheters, and endotracheal tubes all provide portals

of entry that permit organisms to migrate from the skin and mucous membranes to sterile body sites. Implanted devices can also disrupt host defenses and provide a site sequestered from the surveillance of the immune system in which bacteria can flourish. Thus, strict adherence to aseptic technique when placing or manipulating a medical device is crucial to prevent device-related infection. The following sections outline additional strategies to reduce the risk of healthcare-associated infections in patients who require advanced medical technologies.

CENTRAL VENOUS CATHETERS Catheter-associated infections include localized infection at the site of catheter entry, phlebitis, and bloodstream infections. The last is among the most common type of healthcare-associated infection in hospitalized children, and the majority of these infections occur in patients with central venous catheters. Although the risk of bloodstream infection is greatest among patients with nontunneled central venous catheters, all vascular catheters, including subcutaneous ports and peripheral intravenous catheters, are associated with an increased risk of infection. Practices associated with a reduced risk of catheter-associated infection can be grouped into two major categories. First, adherence to proper insertion technique is critical and includes (1) use of maximal sterile barrier precautions (e.g. cap, mask, sterile gown, sterile gloves, and large sterile drape) during catheter placement; (2) use of 2% to 3% chlorhexidine gluconate-70% isopropyl alcohol or other appropriate antiseptic agents to prepare the skin before placement; and (3) appropriate hand hygiene prior to placement. Recent studies have demonstrated that many catheter-associated bloodstream infections develop more than one week after catheter placement, suggesting that the techniques used to access and maintain catheters are also critical to the prevention of these infections. Maintenance practices associated with reduced risk of catheter-associated bloodstream infections include (1) appropriate hand hygiene prior to manipulating a catheter or changing a dressing; (2) aseptic technique whenever a catheter is accessed or opened (for medication administration or cap changes); (3) aseptic technique for dressing changes; and (4) maintenance of a secure dressing over the catheter entrance sites. Finally, prompt removal of catheters when they are no longer required has also been demonstrated to reduce the risk of catheter infections.9 Other

interventions being adopted more frequently in pediatric settings include the use of antimicrobial-impregnated catheters and daily baths with chlorhexidine gluconate.

URINARY CATHETERS Similar to vascular catheters, the use of urinary catheters is associated with an increased risk of urinary tract infection. Experts estimate that catheterassociated urinary tract infections are the most common device-associated infection among hospitalized patients, although the burden of disease is likely greater in adult than in pediatric patients. Inappropriate and prolonged use of urinary catheters has been noted in as many as 50% of patients who develop catheter-associated urinary tract infections. Guidelines have focused on several practices that can reduce the risk of these infections.10 First, catheters should be placed in a sterile fashion. Second, a closed system for urine collection should always be maintained and urine should never be allowed to reflux from the collecting system or reservoir bag back into the bladder. Finally, the use of urinary catheters should be minimized by prompt removal whenever possible.

VENTILATORS An endotracheal tube provides an ideal portal of entry for the numerous organisms that colonize the oropharynx, allowing their migration to the lower respiratory tract. An artificial airway also provides an ideal substrate for the formation of biofilm and inhibits host defenses, such as the gag reflex and cilia function. Pediatric patients appear to be at less risk of ventilatorassociated pneumonia than adults, likely because they have fewer comorbid conditions such as chronic heart or lung disease or immunosuppressive conditions. However, pediatric intensive care physicians have developed strategies that reduce the risk of ventilator-associated pneumonia, including (1) use of noninvasive ventilation, (2) avoidance of nasotracheal intubation, (3) use of in-line suctioning to prevent aspiration of pooled tracheal secretions, (4) elevation of the head of the bed 45 degrees from horizontal, and (5) regular oral care.11 Finally, strategies that shorten the duration of intubation, such as weaning protocols and daily assessment of readiness for

extubation, can also reduce the risk of ventilator-associated pneumonia.

MANAGING PATIENTS WITH PROBLEM PATHOGENS ANTIBIOTIC-RESISTANT BACTERIAL ORGANISMS Within 3 years of the introduction of penicillin, some strains of Staphylococcus aureus developed resistance to this drug. By the 1960s, some strains of S. aureus had become resistant to methicillin, a semisynthetic penicillin. Over the past decade the epidemiology of MRSA has changed from an infection of primarily hospitalized patients to a relatively common cause of infection among otherwise healthy children in the community. Community-associated MRSA strains are now endemic in many institutions, posing a challenge to infection control professionals. Hospital epidemiologists still debate whether all patients admitted to the hospital should be screened to identify and isolate those colonized with MRSA.12 Contact precautions are commonly used to prevent patient-to-patient transmission of specific antibiotic-resistant bacteria. Because colonization with these organisms often persists for many months—even in the absence of ongoing exposure to antibiotics—precautions may be continued indefinitely for patients known to harbor organisms such as vancomycin-resistant enterococci and multidrug-resistant gram negative bacilli.

CLOSTRIDIUM DIFFICILE INFECTION The incidence of C. difficile infection (CDI) has increased dramatically over the past decade in conjunction with the emergence of a hypervirulent strain of C. difficile, referred to as the NAP1 strain. C. difficile is the most common cause of healthcare-associated diarrhea among adults in the United States, but is also a growing problem among hospitalized children. Several studies using national data have shown a rise in CDI-related hospitalizations among pediatric patients.15 C. difficile is transmitted between patients through either direct or indirect contact, and can be found on the hands of healthcare workers as well as in the patient’s immediate environment. The ability of C. difficile to form spores enables the bacteria to survive on environmental surfaces for prolonged

periods. Spores are also relatively resistant to disinfectants, posing a unique challenge in preventing spread of infection within healthcare facilities. Contact precautions should be used while caring for patients with CDI and continued until diarrhea has resolved. Strict adherence to hand hygiene and vigorous environmental cleaning is also important. Of these measures, the use of gloves has been shown to be the most effective measure in preventing C. difficile transmission.16 The use of dilute bleach for room disinfection may be an important adjunct to routine environmental cleaning while managing patients with CDI, particularly in outbreak settings.

MYCOBACTERIUM TUBERCULOSIS Unlike adults, many children infected with MTB are not considered contagious. Several factors explain the low rate of communicability associated with pediatric MTB infection.13 First, most children infected with MTB have latent infections and harbor small numbers of organisms that are well sequestered in granulomas. Second, children with active MTB infection rarely have endobronchial or cavitary lesions that communicate with the lower airways. Finally, young children typically do not generate sufficient intrathoracic pressure during coughing to raise MTB organisms into the oropharynx. As a result, healthcare-associated tuberculosis in pediatric facilities occurs almost exclusively due to transmission from infected adults (i.e. parents, visitors, and healthcare workers). Although airborne precautions are not routinely used for pediatric patients with MTB infection in many institutions because of the factors mentioned above, they may be indicated to prevent possible transmission from infected family members and visitors until their diseases status is verified. Airborne precautions (including patient placement in a negative-pressure room and the use of N-95 respirator masks by healthcare providers) should be instituted for pediatric patients with suspected endobronchial or cavitary lesions or miliary disease. Precautions should be continued until the patient is demonstrated to have no acid-fast organisms visible on three consecutive induced sputum or gastric aspirates.

PERTUSSIS

Outbreaks of pertussis in pediatric hospitals are well documented, and have often been related to spread by healthcare workers. During 2012, there was a dramatic increase in the number of pertussis cases reported throughout the country, underscoring the importance of control measures to prevent spread within pediatric facilities.17 The prevention of healthcare-associated pertussis includes (1) appropriate isolation and use of droplet precautions for children in whom infection is suspected, (2) antimicrobial treatment of confirmed pertussis cases, (3) chemoprophylaxis of exposed individuals, and (4) vaccination of healthcare workers through booster doses of pertussis vaccine (Tdap). Hospital staff with symptoms suggestive of pertussis should be evaluated promptly, and infected individuals should be excluded from work until the first 5 days of appropriate therapy have been completed.

VIRAL PATHOGENS During seasonal outbreaks, common pediatric viral pathogens can pose a significant risk to hospitalized children.14 Transmission of organisms such as RSV, influenza virus, norovirus, or rotavirus is facilitated in inpatient pediatric units because of the relative concentration of susceptible subjects (i.e. the patients), ongoing introduction of virus from the community (by visitors, staff, and newly admitted patients), and environmental contamination with organisms that can live for hours on fomites. Hospital outbreaks of RSV and rotavirus have been associated with insufficient staffing, sub-optimal environmental cleaning, and illness among visitors and staff, as well as poor hand hygiene practices by healthcare workers. Contaminated environmental surfaces are a particularly important contributor to transmission of healthcare-associated norovirus and may require additional measures for appropriate disinfection during outbreak settings.18

CONCLUSION Healthcare-associated infections are common and serious complications among pediatric patients. However, many of these infections are preventable through the appropriate use of standard and transmission-based precautions, uniform policies and procedures related to the insertion and maintenance of medical devices, and scrupulous attention to hand hygiene before and after

patient care, between procedures, and when in contact with the patient’s immediate environment.

REFERENCES 1. Magill SS, Hellinger W, Cohen J, et al. Prevalence of healthcareassociated infections in acute care hospitals in Jacksonville, Florida. Infect Cont Hosp Epidemiol. 2012;33:283-291. 2. Rutledge-Taylor K, Matlow A, Gravel D, et al. A point prevalence survey of healthcare-associated infections in Canadian pediatric inpatients. Am J Infect Cont 2012;40:491-496. 3. Miller MR, Zhan C. Pediatric patient safety in hospitals: a national picture in 2000. Pediatrics. 2003;113:1741. 4. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee. MMWR. 2002;71:1. 5. Erasmus V, Daha TJ, Brug H, et al. Systematic review of studies on compliance with hand hygiene guidelines in hospital care. Infect Cont Hosp Epidemiol. 2010;31:283-294. 6. Pittet, Didier, Allegranzi B, Boyce J. The World Health Organization guidelines on hand hygiene in health care and their consensus recommendations. World Health. 2009;30:611-622. 7. Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare Infection Control Practices Advisory Committee. Guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings. 2007. Available at: http://www.cdc.gov/ncidod/dhqp/pdf/ isolation2007.pdf. 8. Jernigan JA, Titus MG, Groschel DH, et al. Effectiveness of contact isolation precautions during a hospital outbreak of methicillin-resistant Staphylococcus aureus. Am J Epidemiol. 1996;143:496. 9. O’Grady NP, Alexander M, Burns, LA, et al. Guidelines for the prevention of intravascular catheter-related infections. 2011. Available at: http://www.cdc.gov/hicpac/pdf/guidelines/bsi-guidelines-2011.pdf. 10. Wong ES. Guideline for prevention of catheter-associated urinary tract

infections. Available at: http://www.cdc.gov/ncidod/hip/GUIDE/ uritract.htm. 11. Tablan OC, Anderson U, Besser R, et al. Guidelines for preventing healthcare-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep/ 2004;53:1. 12. Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and Enterococcus. Infect Control Hosp Epidemiol. 2003;24:362. 13. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376. 14. Siegel JD. Controversies in isolation and general infection control practices in pediatrics. Semin Pediatr Infect Dis. 2002;13:48. 15. Schutze GE, Willoughby RE. Clostridium difficile infection in infants and children. Pediatrics. 2013;131(1):196-200. 16. Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(Suppl 1):S81-S92. 17. Centers for Disease Control. Pertussis epidemic—Washington, 2012. MMWR. 2012;61(28):517-22. 18. MacCannell T, Umscheid CA, Agarwal RK, et al. Guideline for the prevention and control of norovirus gastroenteritis outbreaks in healthcare settings. Infect Control Hosp Epidemiol. 2011;32:939-969.

CHAPTER

6

Electronic Health Records and Clinical Decision Support Levon Utidjian, Eric Shelov, Bimal R. Desai, and Christopher P. Bonafide

INTRODUCTION Over the last 50 years, the electronic health record (EHR) has emerged as a critical tool in the delivery of safe, efficient, quality healthcare. EHR systems have evolved from basic single-office databases into sophisticated applications capable of managing clinical documentation, laboratory results, images, and other patient data across care settings as well as providing decision support to promote safe patient care, reduce errors, and support adherence to practice guidelines. Data captured within the EHR are used to support nearly every aspect of patient care, including related billing and auditing activities. Increasingly, these data are also being used for quality improvement and research. Hospitalists and the patients whom we treat stand to benefit greatly from well-implemented EHRs that provide tools to review growth data and immunization histories, to identify when vital signs and laboratory values exceed normal parameters for age, and to deliver age-, weight-, and condition-appropriate decision support for medication dosing and management. However, most commercially available EHR systems were designed with adult patients in mind. Configuring these systems to care for children often requires additional customization, which can translate to the need for hospitalists to invest time working with EHR implementation teams to ensure that safe, efficient, quality pediatric care can be delivered. This is especially important for hospitalists who work in pediatric units within larger adult-centered hospitals. In this chapter, we provide a brief background of EHR systems, discuss the role of clinical decision support (CDS) tools in

delivering safe, efficient, quality pediatric hospital care, and review important patient safety considerations for hospitalists who may be asked to participate in the design, implementation, or optimization of an EHR.

ELECTRONIC HEALTH RECORDS HISTORY OF HOSPITAL MEDICAL RECORDS The practice of keeping medical records is one of the cornerstones of medicine. Hippocrates, the ancient Greek physician and father of Western medicine, famously kept and advocated for the use of medical records as early as the fifth century BC.1 These earliest medical records were chronological accounts of individual patient cases and served as important tools in the initial understanding of the natural history of diseases, patient outcomes, and sharing of knowledge among practitioners. Such physicianbased records dominated medical documentation for centuries and relied on the diligence of the conscientious physician to accurately document, maintain and preserve this information. In the mid-nineteenth century, the emergence of record keeping in hospitals represented an early attempt to organize patient information primarily for tracking cases and billing.2 Some saw the additional value of the aggregate information from the hospital population for improving patient care. In 1863, social reformer, nurse, and statistician Florence Nightingale described the challenges presented by the limitations of medical record keeping at that time: I am fain to sum up with an urgent appeal for adopting… some uniform system of publishing the statistical records of hospitals. There is a growing conviction that in all hospitals, even in those which are best conducted, there is a great and unnecessary waste of life… In attempting to arrive at the truth, I have applied everywhere for information, but in scarcely an instance have I been able to obtain hospital records fit for any purposes of comparison… If wisely used, these improved statistics would tell us more of the relative value of particular operations and modes of treatment than we have means of ascertaining at present.”3

The call for structuring and standardizing the medical record to improve its usefulness for healthcare and research grew stronger in the twentieth century, at the same time the computer was emerging as a tool for business and research. In the 1960s, physician Lawrence Weed proposed transitioning

to a problem-oriented medical record to improve the ability of clinicians to identify, manage, and treat a patient’s problems in the context of a shared record, as well as to measure and advance the quality of care delivered. He advocated for the use of the computer as a tool to provide better access to the medical record and help guide care delivery.4,5 Weed’s concepts helped guide the design of early EHRs, and some of these concepts are now standard components of medical documentation.

STRUCTURE AND COMPONENTS OF MODERN EHRS Modern EHRs continue to evolve from their origins as basic databases into sophisticated applications capable of managing clinical documentation, laboratory results, imaging, and other patient data across care settings. Although many use the terms EHR and electronic medical record (EMR) interchangeably, there is a distinction: EMR classically refers to the electronic version of the paper chart contained in a single office, while EHR refers to the patient-based record of care across multiple care settings and providers.6 In 2003, the Institute of Medicine (IOM) developed the following definition of the EHR: An EHR system includes (1) longitudinal collection of electronic health information for and about persons, where health information is defined as information pertaining to the health of an individual or health care provided to an individual; (2) immediate electronic access to person- and population-level information by authorized, and only authorized, users; (3) provision of knowledge and decision-support that enhance the quality, safety, and efficiency of patient care; and (4) support of efficient processes for health care delivery.”7

To further illustrate this definition, the IOM broadly outlined EHR core functions, shown in Table 6-1. TABLE 6-1

Core Functionalities for an Electronic Health Record System

• Health information and data • Results management • Order entry/management • Decision support

• Patient support • Administrative processes • Reporting and population health management

• Electronic communication and connectivity Source: Reprinted with permission from Institute of Medicine. Board on Health Care Services. Key Capabilities of an Electronic Health Record System: Letter Report. Washington, DC: National Academies Press; 2003.

A hospital’s EHR provides these functions by integrating numerous components.8 The Admission, Discharge and Transfer (ADT) component manages patient location and identifying information. The Computerized Physician Order Entry (CPOE) component enables the entry of orders that can then be communicated to different staff members or to specific hospital departments like the pharmacy, radiology, and laboratory. The Laboratory Information System (LIS) component handles laboratory result data transmission, and a Picture Archive and Communication System (PACS) component manages radiographic images and reports. Additional components manage non-clinical functions, including billing and accounting services.

PEDIATRIC-SPECIFIC EHR FUNCTIONS The care of children presents many unique challenges for EHR systems. The American Academy of Pediatrics’ (AAP) Council on Clinical Information Technology identified many key EHR features for pediatricians practicing in ambulatory and inpatient settings.9 These features include immunization support, growth tracking, medication dosing, and age-based data norms (Table 6-2). Among the most often cited concerns surrounding pediatric EHR adoption is the lack of robust functionality within commercial systems for providing pediatric care.10-13 Most pediatric-specific features are not automatically built-in when a hospital purchases an EHR, and those that are included often require detailed configuration by teams of clinicians, pharmacists, and the EHR vendor. During this process, special attention must be paid to the complexities of caring for patients whose care needs, normal reference ranges for vital sign and laboratory data, and recommended best screening and treatment practices can vary greatly and change rapidly with age, body weight, physiology, and developmental level. TABLE 6-2

Key Pediatric EHR Functions

Examples of EHR Functions Immunization management

Recording immunization data Linking to immunization registry systems Immunization decision support

Growth tracking

Graphical representation with growth curves Percentile calculations

Medication dosing

Dosing by weight Dose-range checking Rounding to safe and convenient doses Age-based dosing decision support

Patient identification

Newborn and prenatal identification Name changes Ambiguous sex

Norms for pediatric data

Numeric – laboratory reference ranges, vital signs Non-numeric – normal exam findings by age Complex normative relationships – BP tables Gestational age and corrected age

Privacy

Adolescent privacy Children in foster or custodial care Consent Adoption Guardianship

Pediatric-specific terminology

Physical exam findings Developmental milestones

Diagnoses Data precision

Age time scales (days, weeks, months, years) Weight to the nearest gram in neonates

Source: Data from Spooner SA, and the Council on Clinical Information Technology. Special requirements of electronic health record systems in pediatrics. Pediatrics. 2007;119(3):631637.

To further address the need for standards in the development of EHRs that could help meet the needs of children, the Agency for Healthcare Research and Quality (AHRQ) recently developed the Children’s EHR Format.14 The goal of the format was to provide the many key stakeholders, including EHR developers, EHR purchasers, and the end user care providers, with an understanding of the minimum requirements for data standards and EHR features to optimize pediatric healthcare. These lists of features by the AAP and the AHRQ can serve as a useful starting point for hospitalists evaluating potential new EHR systems or optimizing the features of an existing system.

CURRENT STATE OF EHR ADOPTION IN CHILDREN’S HOSPITALS Although the first EHR systems were implemented in the 1970s, a recent survey of children’s hospitals revealed that only 17.9% had a basic EHR system, and only 2.8% met criteria for having a comprehensive EHR.12 While over 95% of hospitals had radiology images and lab results available electronically, fewer had drug-allergy alerts (62%), age-based dosing support (44%), CPOE (34%), problem lists (24%), and physician notes (13%). Financial costs were identified as the largest barrier to EHR adoption or comprehensive feature implementation. Recent efforts by the United States government to provide financial incentives for EHR use may stimulate advancement in these low adoption rates.

FEDERAL INCENTIVES FOR EHR ADOPTION In an effort to spur adoption of health information technology, the federal

government allocated 155 billion dollars in the American Recovery and Reinvestment Act of 2009 (ARRA) to fund Title XIII, the Health Information Technology for Economic and Clinical Health (HITECH) Act. The HITECH Act allocates nearly 26 billion dollars to incentivize the adoption and “Meaningful Use” of certified EHR systems, as strictly defined by the Office of the National Coordinator for Healthcare Information Technology (ONCHIT). These incentives are in the form of Medicare and Medicaid payments to eligible professionals and hospitals.15,16 The three stages of Meaningful Use are designed to help organizations guide their incremental implementations of EHR systems.17,18 The goal of Stage 1 is to implement an EHR capable of data capture and sharing, followed by Stage 2’s requirement to demonstrate more advanced clinical processes and finally Stage 3’s requirement to show improved patient outcomes19 (Table 6-3). Hospitals must attest that their EHR meets certain quality measures for certification in order to advance to the next stage. To aid providers in undertaking EHR implementations, the HITECH act also describes funding for the creation of Regional Extension Centers (RECs) to provide information technology support, as well as other workforce training and research programs in information technology.17 TABLE 6-3

Stages of Meaningful Use

Stage 1: 2011–2012 Capture and share data Meaningful use criteria focus on:

Stage 2: 2014 Advance clinical processes Meaningful use criteria focus on:

Stage 3: 2016 Improve outcomes Meaningful use criteria focus on:

Electronically capture health information in a standardized

Perform more rigorous health information exchange

Improve quality, safety, and efficiency, leading to improved health outcomes

format Use that information to track key clinical conditions

Meet increased requirements for eprescribing and incorporating lab results

Develop decision support for national highpriority conditions

Communicate that information for care coordination processes

Demonstrate electronic transmission of patient care summaries across multiple settings

Give patients access to self-management tools

Initiate the reporting of clinical quality measures and public health information

Improve electronic communication with patients and their families

Provide access to comprehensive patient data through patientcentered health information exchanges

Use that information to engage patients and their families in their care

Improve population health

Source: Adapted from Meaningful Use. HealthIT.gov. Available at: http://www.healthit.gov/ policy-researchers-implementers/meaningful-use. Accessed February 20, 2013.

To qualify for financial incentives at each stage of Meaningful Use, eligible professionals and hospitals must attest to achieving a number of EHR utilization requirements such as capturing an electronic problem list and performing medication reconciliation electronically. Hospital EHRs must also collect and capture a number of clinical quality measures such as statistics on emergency room throughput and performance on quality measures for stroke and venous thromboembolism care. Achieving Meaningful Use criteria poses unique challenges in pediatrics.20 These clinical quality measures are

primarily applicable to adults, highlighting the current paucity of validated pediatric quality measures. Failure to achieve these Meaningful Use thresholds will lead to financial penalties in the form of lower Medicare payments starting in 2015. Fundamentally, HITECH and Meaningful Use represent the most ambitious effort to date to promote the use of EHRs in the United States, and they underscore the belief that EHRs are a vital part of the efforts to overhaul and improve the US healthcare system. As a result of these national efforts to promote safe, efficient, and quality care through the use of EHRs, hospitalists will increasingly find themselves in the valued position of leading implementation projects or participating in workflow design efforts.

CLINICAL DECISION SUPPORT Among the most anticipated benefits of the modern EHR is its potential not only to serve as a repository of clinical data and billing information, but also to assist in diagnostic and therapeutic decision-making. By translating complex medical knowledge into evidence-based rules to be applied in specific patient care situations, these systems can help physicians provide higher quality care. Tools that can help physicians prescribe the right doses of medications, avoid dangerous drug-drug interactions, and guide evidencebased treatment decisions are just a few examples of what is collectively known as clinical decision support (CDS).

DEFINITION AND FORMS CDS is “knowledge- and person-specific information, intelligently filtered or presented at appropriate times, to enhance health and health care.”21 Although CDS existed long before the EHR in the form of paper-based templates of common orders for specific conditions, clinical algorithms, drug references, and treatment guides, these all required a provider to actively seek out information. Ideally, an EHR’s CDS system is able to retrieve pertinent clinical information and offer it to the clinician in a clear and concise manner in order to maximize the efficiency and effectiveness of the decision-making process. Forms of CDS include reminders of routine screenings or vaccinations, alerts for critical situations, CPOE order sets, clinical

guidelines, and user-friendly displays of general or patient-specific diagnostic and therapeutic information.22 Any CDS intervention should be viewed in the context of the “CDS Five Rights” to ensure delivery of the right information to the right person, in the right format, through the right channel, at the right time23 (Table 6-4). These rights serve not only to maximize the effectiveness of CDS, but also to reduce the likelihood of unintended consequences of CDS that may be detrimental to patient care. A review of randomized controlled trials suggested that CDS systems improved clinical practice in 68% of studies, and the four independent predictors of improvement were the use of a computerbased system, the automatic provision of CDS, provision of recommendations rather than assessments, and the delivery of these interventions at the time and place of decision-making.24 Common forms of CDS are reviewed and summarized below, with specific reference to the benefits and challenges of medication alerting, order sets, and clinical practice guidelines in a hospital setting. TABLE 6-4

Clinical Decision Support Five Rights

1. The right information: evidence-based, suitable to guide action, pertinent to the circumstance 2. To the right person: considering all members of the care team, including clinicians, patients, and their caretakers 3. In the right CDS intervention format: such as an alert, order set, or reference information to answer a clinical question 4. Through the right channel: for example, a clinical information system (CIS) such as an electronic medical record (EMR), personal health record (PHR), or a more general channel such as the Internet or a mobile device 5. At the right time in workflow: for example, at time of decision/action/need Source: Reproduced with permission from Osheroff JA. Improving medication use and outcomes with clinical decision support: a step-by-step guide. Chicago, IL: Healthcare Information and Management Systems Society Mission; 2009.

EXAMPLES Medication Alerts With estimates of 44,000 to 98,000 deaths attributable to medical errors annually, a significant proportion of which are related to medications, a clear potential benefit of CDS is to reduce the number of preventable Adverse Drug Events (ADEs).25 This potential benefit has been studied in both adult and pediatric settings, and many analyses have demonstrated statistically significant reductions in prescription errors and some reductions in ADEs.26-30 CDS interventions for medication order completion can range from fairly simple allergy and drug-drug interaction checking to more advanced support such as formulary-based dosing shortcuts, maximum dose alerts, indication-based dosing, and integration of pertinent patient data such as lab results. Ideally a system has tools to prevent errors of commission, when the action taken is incorrect like medication overdose, as well as errors of omission, when a needed therapy is not ordered, such as serum medication levels in a patient with poor renal function.31 In pediatrics, age- and weight-based dosing are the primary methods for prescribing medications. Variations in these patient characteristics can be gradual and predictable as in the yearly well-child visits at the pediatrician’s office, or volatile as in the daily fluctuations seen in a neonatal intensive care unit. Performing dose calculations is perhaps the most fundamental of pediatric CDS functions. In addition to performing calculations, the EHR should also support the physician in ensuring that the weight used is the most accurate and up-to-date as possible. Weight accuracy can be supported by comparing the recorded weight to standard norms (Centers for Disease Control [CDC] growth curves) and by alerting the clinician of significant deviation, as well as alerting for implausible changes in weight over short periods of time. In addition to supporting calculation of an appropriate medication dose, a CDS system should alert a prescriber when an ordered dose is too low or too high for the patient. This should include both weight-based dose checking and absolute maximum dose checking. More advanced systems would also include support for appropriate dosing by indication (e.g. different antibiotic doses for pneumonia vs meningitis) or by co-morbidity (e.g. recommending a modified dose for patients with renal insufficiency) by either prompting the user to specify these conditions or querying the patient’s problem list. In

addition, the format of alerts can vary with escalating levels of interruption and override requirements based on the severity of the alert. Order Sets Order sets in CPOE systems group associated orders for specific clinical situations, conditions, or workflows for rapid ordering and can help guide the delivery of safe, efficient, quality care. Examples include orders grouped for specific presenting symptoms, such as fever in young infants, for conditions such as asthma, or for workflows such as general pediatric admissions. Order sets can also be used to suggest corollary orders (e.g. serum antibiotic levels to be ordered with aminoglycoside antibiotics, or urine pregnancy tests to be ordered prior to radiology studies for female patients). Order sets constitute a form of CDS in that they present the most appropriate therapeutic interventions and diagnostic testing for a given situation, reflecting the accepted standard of care of an institution.22 The benefits of using order sets include improving the consistency of care delivered, as well as helping to decrease the cognitive workload on providers.32,33 In addition, by guiding clinicians to the correct initial decisions, order sets can reduce the number of workflow interrupting alerts faced later in the ordering process. The ability to create order sets is a feature present in most EHRs, and there are many guidelines and reviews of best practices for their design and effective implementation.34-37 Although commercial EHRs may include prepackaged “pediatric” order sets, it is important to check that they are clinically appropriate and fit into the workflow of the providers who will use them. A well organized, evidence-based order set may be of little use to providers if it does not fit into their actual workflow, is not readily accessible at the right time in their workflow, or if they are not aware of its existence.22,38 Clinical Practice Guidelines A clinical practice guideline (CPG) represents an evidence-based, systematically developed set of recommendations for the management of a specific condition.39 The use of such guidelines is intended to improve healthcare quality and decrease variation in care delivery. A review of barriers to physician adherence to CPGs highlighted the lack of provider awareness of guidelines, as well as limited time to access them and absence of reminders to use them.40 Such barriers can be overcome by integrating CPGs into the EHR: translating the

CPGs into rule-based alerts to identify clinical situations where guidelines are applicable, and using order sets to organize recommended tests and treatments. Such guideline-related CDS tools have been demonstrated in modern EHR systems and were shown to increase guideline adherence and positively influence clinical practice.41-43 Multiple challenges to the successful implementation of CPGs in the her exist. Many CPGs are long, complex documents and not suitable for onscreen display in their entirety. Efforts at simplifying guideline information while still providing access to the details of the full guideline is important in improving physician adoption.34 CPGs can require multiple pieces of patient data to aid in decision-making. The more automated the data collection process, and the less the user must manually enter, the more likely they are to use the system. Guideline maintenance is also very important, as the standard of care changes with time and so they should be reviewed regularly. As the EHR is a centrally managed system, rapid deployment of updates is possible and does not require the replacement of prior paper guidelines, thus avoiding the costs and issues of version control. This approach helps reduce system variation and can be a powerful tool in helping avoid errors and improving quality of care.44

THE EHR, CDS, AND PATIENT SAFETY Although the benefits of EHR adoption include mechanisms to improve safety and quality in the healthcare system, the EHR itself is not without its own safety risks. As the technology behind the EHR grows more sophisticated and intertwined with the operations of a healthcare organization, it is increasingly difficult to anticipate potential issues between the EHR and providers.45 An EHR will do exactly what it is programmed to do, but flaws in system design or integration into provider workflow can carry unintended consequences and adversely affect patients.46 In the rush to implement EHRs to meet Meaningful Use criteria, healthcare organizations without EHR experience are at higher risk for such consequences. Sittig and Singh recently called attention to the safety challenges associated with EHR technology, including the adverse impacts of downtime and the unintended consequences of failing to use EHRs appropriately.47 These are outlined briefly below.

DOWNTIME As an EHR implementation steadily progresses towards the ideal of a fully electronic, paperless system, a healthcare organization’s operations will become more and more reliant on the EHR being up and running without interruptions due to unplanned crashes or routine maintenance. Downtimes expose weaknesses in the organization’s network and EHR technology infrastructure, while forcing clinicians to deliver medical care without the safety net of clinical decision support that they may rely upon.48,49 The need to resort to paper-based documentation and ordering processes can have a major impact on efficiency and patient safety, particularly as each successive generation of care providers will be less and less familiar with practicing without the aid of a computer. The effect of lengthy downtimes on an entire healthcare system can be profound, slowing care processes to the point that it is difficult to safely assume care of new patients and leading to considerable losses in revenue. Even the most secure and highly reliable system is vulnerable to an unplanned downtime, and every organization should be ready for the possibility. Steps to prepare for downtimes include establishing a downtime policy and contingency plans for extended downtime periods.50,51 Support materials like paper forms for documentation and ordering, drug and laboratory reference books, and backup communication systems should be in place to ensure care can continue without the EHR. Planning must include not only for the downtime itself but also the recovery process to return to the pre-downtime state as well as activities like the re-entry of orders and clinical data into the EHR to ensure completeness of the medical record. Such operational and recovery plans are only as effective as provider familiarity with the plans, so providers should be trained on downtime procedures, even practicing them as one might practice a fire drill or other disaster preparedness exercise.

UNINTENDED CONSEQUENCES How an organization chooses to implement and use its EHR system can have major impacts on patient safety and workplace efficiency. Underestimating the need for clinical process requirements gathering, redesign, and validation during an EHR implementation can have direct adverse effects on patients.

As an often-cited example, Han et al. demonstrated that implementation of a new CPOE system was associated with an unexpected increase in mortality.52 The authors described difficulties in placing multiple orders quickly and efficiently, the inability to pre-order medications for critically ill patients en route to the hospital due to registration workflows, and delays in obtaining medications in emergent situations as contributing factors. However, their report was met with stiff criticism, and can serve as a case study on the effects of failing to appropriately plan for EHR implementation.36,53 As an example, carefully designed ICU-specific order sets could have reduced the time required to order urgent medications. Consideration of a “preregistration” process could have allowed the organization to enter orders on patients who were en route to the intensive care unit. Furthermore, the authors also noted that elimination of a satellite medication dispenser located in the ICU led to delays in medication availability, an issue that could have been detected through EHR workflow simulations prior to go-live. Learning from this experience, subsequent implementations at other hospitals have described successful CPOE system implementation without adversely impacting mortality rates.53,54 Even the best intentions to leverage and maximize the capabilities of an EHR’s CDS systems can introduce and facilitate new errors. CPOE systems can easily check the list of active medications for possible drug-drug, drugallergy, drug-food, and drug-condition interactions. Given a streamlined and clinically validated set of possible interactions, these systems can help prevent administration of potentially dangerous medications. However, when used indiscriminately, these same tools can lead to excessive alerting and overwhelm providers.46,49 The provision of too many alerts that are frequently overridden by prescribers can lead to “alert fatigue” and lead prescribers to unintentionally ignore important alerts.55 At the heart of this problem is that standards and best practices for alert content are lacking. Although work is underway to identify priority drug-drug interactions for adult and pediatric populations, it will be some time before these standards are easily implemented into vendor EHR systems.56,57 A related example of an alerting tool’s unintended consequences is the use of the “hard stop” alert that cannot be overridden. Such an alert may be meant to prevent a rare drug-drug interaction, but this could be of less risk than the risk of not giving the two medications in some clinical situations.

Furthermore, in a time-critical situation, a “hard stop” may be inappropriate and lead to potentially dangerous delays in care.58 These and many other examples of unintended consequences of EHR implementation and usage are, unfortunately, common. In response, the AHRQ has created a report and website geared to both future and current EHR users to help them identify and address these issues.59,60

CONCLUSION The EHR is a powerful tool for improving clinical care and augmenting the abilities of hospitalists to deliver that care safely and efficiently. As the use of EHR systems continues to increase, these systems will become the standard form of medical record keeping and care management. Learning how to maximize their potential will be critical for all healthcare providers. Given that the volume of patient health data is expected to grow more rapidly with the emergence of genomic and personalized medicine, the EHR will take on even greater importance in helping healthcare providers organize and interpret this information in the coming years.

REFERENCES 1. Reiser SJ. The clinical record in medicine. Part 1: Learning from cases. Ann Intern Med. 1991;114(10):902-907. 2. Siegler EL. The evolving medical record. Ann Intern Med. 2010;153(10):671-677. 3. Nightingale F. Notes on hospitals. Longman, Green, Longman, Roberts, and Green; 1863. 4. Weed LL. Medical records that guide and teach. N Engl J Med. 1968;278(11):593-600. 5. Weed LL. Medical records that guide and teach. N Engl J Med. 1968;278(12):652-7. 6. Garrett P, Seidman J. EMR vs EHR – What is the difference? HealthITBuzz. 2011. Available at: http://www.healthit.gov/buzz-blog/ electronic-health-and-medical-records/emr-vs-ehr-difference/. Accessed

February 5, 2013. 7. Institute of Medicine. Board on Health Care Services. Key Capabilities of an Electronic Health Record System: Letter Report. Washington, DC: National Academies Press; 2003. 8. Carter JH. Electronic Health Records. Philadelphia, PA: ACP Press; 2008. 9. Spooner SA, and the Council on Clinical Information Technology. Special requirements of electronic health record systems in pediatrics. Pediatrics. 2007;119(3):631-637. 10. Johnson KB. Barriers that impede the adoption of pediatric information technology. Arch Pediatr Adolesc Med. 2001;155(12):1374-1379. 11. Kim GR, Lehmann CU, and the Council on Clinical Information Technology. Pediatric aspects of inpatient health information technology systems. Pediatrics. 2008;122(6):e1287-e1296. 12. Nakamura MM, Ferris TG, DesRoches CM, Jha AK. Electronic health record adoption by children’s hospitals in the United States. Arch Pediatr Adolesc Med. 2010;164(12):1145. 13. Leu MG, O’Connor KG, Marshall R, Price DT, Klein JD. Pediatricians’ use of health information technology: A national survey. Pediatrics. 2012;130(6):e1441-e1446. 14. Whitesides GM. Children’s Electronic Health Record Format Documentation and User Guide. AHRQ Publication No 13-0020-EF. 2012. Rockville, MD: Agency for Healthcare Research and Quality; 2012:1-23. 15. Blumenthal D, Tavenner M. The “meaningful use” regulation for electronic health records. N Engl J Med. 2010;363(6):501-504. 16. Blumenthal D. Wiring the health system—origins and provisions of a new federal program. N Engl J Med. 2011;365(24):2323-2329. 17. Blumenthal D. Launching HITECH. N Engl J Med. 2010;362(5):382385. 18. Blumenthal D. Implementation of the federal health information technology initiative. N Engl J Med. 2011;365(25):2426-2431. 19. Meaningful Use. Available at: http://www.healthit.gov/policyresearchers-implementers/meaningful-use. Accessed March 11, 2013.

20. Burton OM. Letter to office of the national coordinator for health information technology. AAP Advocacy Site. Available at: http:// www2.aap.org/informatics/pdfs/Advocacy/HITPC-MU-S2.pdf. Accessed March 17, 2013. 21. Osheroff JA, Teich JM, Middleton B, Steen EB, Wright A, Detmer DE. A roadmap for national action on clinical decision support. J Am Med Inform Assoc. 2007;14(2):141-145. 22. Horsky J, Schiff GD, Johnston D, Mercincavage L, Bell D, Middleton B. Interface design principles for usable decision support: A targeted review of best practices for clinical prescribing interventions. J Biomed Inform. 2012;45(6):1202-1216. 23. Osheroff JA, Healthcare Information and Management Systems Society. Improving Medication Use and Outcomes with Clinical Decision Support: A Step-By-Step Guide. Chicago, IL: Healthcare Information and Management Systems Society Mission; 2009. 24. Kawamoto K, Houlihan CA, Balas EA, Lobach DF. Improving clinical practice using clinical decision support systems: A systematic review of trials to identify features critical to success. BMJ. 2005;330(7494):765. 25. Institute of Medicine, Committee on Quality of Health Care in America. In: Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academies Press; 2000. 26. Wang JK, Herzog NS, Kaushal R, Park C, Mochizuki C, Weingarten SR. Prevention of pediatric medication errors by hospital pharmacists and the potential benefit of computerized physician order entry. Pediatrics. 2007;119(1):e77-85. 27. Kaushal R, Shojania KG, Bates DW. Effects of computerized physician order entry and clinical decision support systems on medication safety: A systematic review. Arch Intern Med. 2003;163(12):1409-1416. 28. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA. 2001;285(16):2114-2120. 29. Walsh KE, Wright A, Krist AH, et al. Effect of computer order entry on prevention of serious medication errors in hospitalized children. Pediatrics. 2008;121(3):e421-e427.

30. Potts AL, Barr FE, Gregory DF, Wright L, Patel NR. Computerized physician order entry and medication errors in a pediatric critical care unit. Pediatrics. 2004;113(1 Pt 1):59-63. 31. Osheroff JA. Improving Outcomes with Clinical Decision Support: An Implementer’s Guide. Chicago, IL: HIMSS; 2012. 32. Bobb AM, Payne TH, Gross PA. Viewpoint: Controversies surrounding use of order sets for clinical decision support in computerized provider order entry. J Am Med Inform Assoc. 2006;14(1):41-47. 33. Avansino J, Leu MG. Effects of CPOE on provider cognitive workload: A randomized crossover trial. Pediatrics. 2012;130(3):e547-e552. 34. Bates DW, Kuperman GJ, Wang S, et al. Ten commandments for effective clinical decision support: Making the practice of evidencebased medicine a reality. AMIA. 2003;10(6):523-530. 35. Miller RA, Waitman LR, Chen S, Rosenbloom ST. The anatomy of decision support during inpatient care provider order entry (CPOE): Empirical observations from a decade of CPOE experience at Vanderbilt. J Biomed Inform. 2005;38(6):469-485. 36. Sittig DF, Ash JS, Zhang J, Osheroff JA, Shabot MM. Lessons from “Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system.” Pediatrics. 2006;118(2):797-801. 37. ISMP’s guidelines for standard order sets. Institute for Safe Medical Practices. Available at: http://www.ismp.org/tools/guidelines/ standardordersets.pdf. Accessed January 15, 2013. 38. McGreevey JD. Order sets in electronic health records - principles of good practice. Chest. 2013;143(1):228. 39. Institute of Medicine. In: Field MJ, Lohr KN, eds. Guidelines for Clinical Practice: From Development to Use. Washington, DC: National Academies Press; 1992. 40. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? JAMA. 1999;282(15):1458-1465. 41. Shiffman RN, Liaw Y, Brandt CA, Corb GJ. Computer-based guideline implementation systems: A systematic review of functionality and effectiveness. J Am Med Inform Assoc. 1999;6(2):104-114.

42. Damiani G, Pinnarelli L, Colosimo SC, et al. The effectiveness of computerized clinical guidelines in the process of care: A systematic review. BMC Health Serv Res. 2010;10(1):2. 43. Neuman MI, Hall M, Hersh AL, et al. Influence of hospital guidelines on management of children hospitalized with pneumonia. Pediatrics. 2012;130(5):e823-e830. 44. Reason J. Human error: Models and management. BMJ. 2000;320(7237):768-770. 45. Ash JS, Berg M, Coiera E. Some unintended consequences of information technology in health care: The nature of patient care information system-related errors. AMIA. 2004;11(2):104-112. 46. Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293(10):1197-1203. 47. Sittig DF, Singh H. Electronic health records and national patient-safety goals. N Engl J Med. 2012;367(19):1854-1860. 48. Kilbridge P. Computer crash—lessons from a system failure. N Engl J Med. 2003;348(10):881-882. 49. Campbell EM, Sittig DF, Ash JS, Guappone KP, Dykstra RH. Types of unintended consequences related to computerized provider order entry. J Am Med Inform Assoc. 2006;13(5):547-556. 50. Institute of Medicine. Health IT and Patient Safety: Building Safer Systems for Better Care. Washington, DC: National Academies Press; 2012. 51. Nelson NC. Downtime procedures for a clinical information system: A critical issue. J Crit Care. 2007;22(1):45-50. 52. Han YY, Carcillo JA, Venkataraman ST, et al. Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system. Pediatrics. 2005;116(6):1506-1512. 53. Del Beccaro MA, Jeffries HE, Eisenberg MA, Harry ED. Computerized provider order entry implementation: No association with increased mortality rates in an intensive care unit. Pediatrics. 2006;118(1):290295. 54. Longhurst CA, Parast L, Sandborg CI, et al. Decrease in hospital-wide

mortality rate after implementation of a commercially sold computerized physician order entry system. Pediatrics. 2010;126(1):14-21. 55. Isaac T, Weissman JS, Davis RB, et al. Overrides of medication alerts in ambulatory care. Arch Intern Med. 2009;169(3):305-311. 56. Phansalkar S, van der Sijs H, Tucker AD, et al. Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Inform Assoc. 2012. 57. Phansalkar S, Desai AA, Bell D, et al. High-priority drug-drug interactions for use in electronic health records. J Am Med Inform Assoc. 2012;19(5):735-743. 58. Strom BL, Schinnar R, Aberra F, et al. Unintended effects of a computerized physician order entry nearly hard-stop alert to prevent a drug interaction: A randomized controlled trial. Arch Inter. Med. 2010;170(17):1578-1583. 59. Jones SS, Koppel R, Ridgely MS, Palen TE, Wu S. Guide to Reducing Unintended Consequences of Electronic Health Records. AHRQ Publication No. 11-0105-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. 60. Guide to Reducing Unintended Consequences of Electronic Health Records. AHRQ Available at: http://www.ucguide.org/. Accessed February 10, 2013.

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Family-Centered Care Vineeta Mittal and Michael T. Vossmeyer

INTRODUCTION The approach to the hospitalized child and family has changed dramatically over the last decade. Physicians are rarely the sole decision makers when children are hospitalized. Patients and families expect to be actively involved in medical decision-making, and this expectation is strongly supported by leaders in health care and government. In 2001 the Institute of Medicine published a report outlining the six aims of a transformed health care delivery system in the United States. The report stated a health care system should be timely, effective, efficient, patientcentered, equitable, and safe. Inpatient care should be focused on achieving these aims. In recent years, healthcare reform in the United States has focused on cost-effective care and better patient outcomes. As many innovative models of healthcare emerge, new emphasis is on encouraging physicians, hospitals, and other healthcare providers to work more closely as a team and to better coordinate patient care through team-based approaches, therefore giving a greater role to patients in healthcare decision-making. Team-based care may help achieve improvement in health care at a reasonable cost. The health care teams may vary depending on setting (home, office, hospital), disease type (chronic care coordination vs. acute care or well checks), or personnel (care coordination, social worker, home health in a complex care setting vs. nursing, respiratory therapists, pharmacy in asthma centers). Healthcare teams may be large or small depending on the model of care provided. In high-functioning healthcare teams, patients are members of the team; they are the reason healthcare teams exist. “Nothing about me without me” conveys the powerful message of patients’ active involvement in care

decisions. This involves integrating patients, family, physicians, and other providers in healthcare teams.

HOW CAN HOSPITALISTS FACILITATE PATIENT- AND FAMILY-CENTERED CARE? Hospitalists play a crucial role in managing healthcare teams in the inpatient setting. They can incorporate the principles and values of family- and patientcentered care to improve quality as defined by outcomes, safety, and patient experience. A hospitalized child requires timely access to clinical services without delays attributable to system design. Variations in clinical care are frequently attributed to failures in clinical care. Systems that are well designed to ensure necessary levels of clinical reliability decrease variation and improve outcomes. Clinical care should be evidence based, and the implementation of evidence-based clinical guidelines decreases unnecessary variation in care and improves clinical outcomes. When there are no available guidelines, the original medical literature can be accessed and evaluated using generally accepted methods of critical appraisal. Equitable care must be available for all hospitalized children without regard to race, national origin, religious or cultural background, gender, or insurance status. Hospital systems must be designed to ensure patient safety and to dramatically decrease preventable sources of error. The use of computerized technologies, such as electronic medical records, computerized order entry systems, and automated safety triggers can increase the reliability of hospital systems. For successful transitions to occur, hospital cultures need to change from physician-centered to patient- and family-centered. Dimensions of care that patients and families value, including respect for preferences, involvement in decision making, access to care, coordination of care, information and education, physical comfort, emotional support, involvement of family and friends, and continuity in the transition from inpatient to outpatient or medical home setting should be the center of focus.

TRANSITION TO THE INPATIENT SETTING Hospitalization is a stressful event for both the child and family. Children and

families may experience feelings ranging from fear of the unknown to complete loss of control. These feelings complicate the clinical situation and detract from development of a healing environment. Physician and other healthcare professionals should address these stresses directly and provide an environment designed to preserve patient and family control. Whenever possible, the child and family should be prepared for the hospitalization; this allows them to be educated about the proposed care and can help clarify the expectations of the family and physicians. Such preparations also provide opportunity to initiate clear and open communication between physicians and prepare for safe handoffs of care and discharge planning. If possible, before a planned hospitalization, the child and family should be given an opportunity to tour the facility and meet the staff who will provide care. An active child life service can facilitate the prehospital activity. When hospitalization occurs urgently or emergently, the child life programs can provide support for children and families at the point of contact.

HOSPITAL CARE In the hospital setting, educating families about the roles of healthcare professionals improves satisfaction. Informing parents and families about daily ward routines including the timing of nursing shift change, the process of patient handoff, the timing of physician rounds, access to parking and meals, availability of interpreter services and guest relations, and role of medical emergency teams may alleviate parental anxiety associated with hospitalization. The amount of information given may be overwhelming, so multiple methods of communication including printed materials maybe helpful in educating patients and their families. Orientation to the hospital and the nursing unit with specific information about special services such as child life, social work, volunteers, and pastoral services is important. Patients and families will benefit from information about internet access, sport rooms, music, and access to movies for patients.

FAMILY-CENTERED ROUNDS Family-centered rounds (FCRs) are multidisciplinary rounds that take place in the patient’s room and involve active participation of the patient and

family in decision-making. FCRs involve medical decision-making, communication, teaching, discharge planning, and coordination of care. All healthcare professionals involved in the patient’s care, and the patient and families should participate in each of these processes. Involving patients and families as members of the healthcare teams is more than a shift in medical culture. It is crucial to incorporate values and principles of high-functioning healthcare teams to ensure successful culture change. Clear roles and responsibilities, mutual trust, effective communication, shared goals, honesty, discipline, and measurable processes and outcomes are important characteristics of high-functioning teams. Decision-making should be transparent to all involved. The family is often the best source of information about a child, but is frequently overlooked. Actively taking into account the family’s values, culture, race, and socioeconomic background as well as family members’ unique knowledge of the patient can assist in decision-making. All diagnostic and treatment decisions should be made with the full participation of the family. Healthcare teams members must be willing to work constructively with families even when their decisions do not coincide with the advice of the medical team. The use of evidence-based protocols can often facilitate a transparent decision-making process and establish a basis for the discussion of therapies with patients and families. Such protocols decrease variation among healthcare professionals that can confuse patients and families. Communication that recognizes the patient’s family as the driving force is central to their empowerment. A simple gesture such as asking patients or families about their preferences regarding rounds allows the family to regain a sense of control and involvement. Honest and open communication between medical professionals and families is vital to the success of the hospitalization. Total transparency in all aspects of hospitalization is necessary to maintain optimal lines of communication. FCRs present a venue for experienced physicians to teach aspects of core competencies to trainees that can only be taught at bedside. Trainees report improved physical examination and communication skills, and learn role modeling through attending physicians. Attending physician role modeling can help trainees learn about core aspects of compassion, accountability, and respect toward diverse populations. Communication skills cannot be taught as well in classrooms as observed and practiced in real time. Observing trainees

interact during rounds also allows for direct observation of trainees and realtime feedback, which is often under-reported and is highly valued by trainees. Trainees report that having a visual impression of a patient/disease condition and seeing how different physicians interact and respond to parental questions is a valuable learning experience. Unless families state otherwise, all critical discussions about medical care should occur in their presence. Morning rounds can and should be conducted with the family present. The patient is presented to the medical team in the presence of family, using language that can be understood by the patient and the family. Medical terminology should be minimized or explained in plain language. Interpreters should be present if there is a language barrier; it is not advisable to use family members as interpreters. FCRs help close the communication loop and bring all care givers including family to a common understanding. FCRs have been shown to improve parental satisfaction, parental understanding of discharge goals, discharge timeliness, and nursing satisfaction. Being present during the healthcare team’s discussion gives the family a great sense of control and dispels some fear of the unknown. Conducting FCRs can be challenging in certain situations. Hospitals with double rooms, patients on isolation precautions, certain unique circumstances like non-accidental injuries or teenagers with sexually transmitted diseases, teams with multiple consultants, and on healthcare teams where mid-level healthcare providers act as proxies for attending physicians pose unique challenges. Individual hospitals and units may need to develop their own rounding styles to ensure that core principles of patient- and family-centered care are carried out.

CHILD LIFE SERVICES The overall objectives of child life services are to recognize and address developmental issues related to healthcare experiences and to respond to fears and concerns of hospitalized children and their families. Child life professionals meet these objectives through a variety of activities, including creating opportunities for play and enhanced self-esteem, providing inpatient school work, assessing coping responses, minimizing stress, preparing children and families for healthcare experiences, facilitating family celebrations, and communicating these goals to the healthcare team.

The way a child plays often communicates his or her interpretation of medical care or illness in a manner that may be inaccessible to other healthcare professionals. Child life may correct misunderstandings that arise during play or relay critical developmental concerns to the family and other professionals on the child’s healthcare team. In addition, play is a method of coping in the foreign environment of the hospital. Therapeutic play can include dramatic play, artistic activity, pet therapy, sensory play (e.g. making dough), games, and attending special events such as musical performances. Medical play provides children with an open-ended opportunity to act, draw, or otherwise use creative media to explore medical equipment, situation, or themes. These activities familiarize children with their surroundings and help them better understand their own medical experiences. Child life specialists also provide educational resources and environments for family members to help them cope with a child’s illness. In-hospital libraries for families, educational video broadcasting in-hospital, and setting aside specific time for siblings in child life rooms can help alleviate a family’s anxiety during a child’s illness or hospitalization. Each child life specialist is a member of the comprehensive medical team caring for the patient and can serve as a valuable liaison between the family and child and healthcare professionals.

QUALITY AND OUTCOMES Hospitals strive to improve quality of care and better patient outcomes. Family/patient satisfaction correlates directly with physician and nursing communication. Involving patients and families in every aspect of hospitalization and having clear and open communication can help improve patient outcomes. Maintaining transparency in care and using lay language to improve family understanding of medical conditions may further help communication and parental satisfaction.

DISCHARGE PLANNING AND TRANSITION TO THE MEDICAL HOME An orderly transition from inpatient to ambulatory setting is important for continuity of clinical care. Discharge planning and discharge goals should be

established as soon as possible after admission. These goals should be reviewed and updated at least daily and discussed on rounds with the family and nurses. The more specific the discharge goals are, the more helpful they are to patients, families, and other team members. Once established, discharge goals facilitate ongoing care and discharge planning. Understanding discharge criteria and the role of care coordination is a valuable learning experience for trainees. Well-designed care systems are needed to facilitate discharges. The use of best-practice reminders embedded in the electronic medical record is helpful to remind healthcare professionals about discharge planning resources. Use of care coordinators or discharge planners may assist the primary medical team in accessing necessary outpatient services and proactively dealing with insurance-related issues. Communication with private/community physicians is also necessary before discharge and sets the stage for safe handoff of care and closes the communication loop. Gaining the support and cooperation of private physicians facilitates transition. Important items to discuss include discharge diagnosis, results of diagnostic testing, outstanding tests that need follow-up, discharge medications, follow-up appointments, and family concerns. This communication should supplement and not replace a written discharge summary and should optimally occur before the patient’s discharge from the hospital.

CONCLUSION A patient- and family-centered care approach to the hospitalized child uses dimensions of care that patients and families value. These dimensions of care include honoring patient’s and families’ preferences, showing respect, using effective communication techniques, developing shared goals, and being transparent about care processes and outcomes. Patient- and family-centered care includes evidence-based clinical care and addresses issues of timeliness, access, efficiency, and safety. Care that is system based and accounts for these aims will produce more satisfactory clinical outcomes. Pre-hospital preparation, orientation to hospital and the unit, and robust child life services can further enhance family comfort and the experience of hospitalization. Conducting daily FCRs to involve families in decision-making, improving communication, trainee education, and facilitating discharge timeliness is crucial. Attention must be paid to discharge planning and the transition from

inpatient to ambulatory settings. Good communication among healthcare providers supports a safe transition and handoff of care. Involving patients and their families at all levels of the care process can improve satisfaction with the healthcare delivery system and the quality of care delivered.

SUGGESTED READINGS Institute of Medicine. Crossing the Quality Chasm: A New Health Care System for the 21st Century. Washington, DC: National Academy Press; 2001. McLellan RK, et al. Optimizing health care delivery by integrating workplaces, homes, and communities: How occupational and environmental medicine can serve as a vital connecting link between accountable care organizations and the patient-centered medical home. J Occup Environ Med. 2012;54(4):504-512. Mittal V, et al. Pediatric resident perspectives on family-centered rounds: A qualitative study at two children’s hospitals. J Grad Med Educ. 2013;5(1):81-87. Moyer V, Williams K, Elliott EJ (eds.). Evidence Based Pediatrics and Child Health. London: BMJ; 2000. Wynia M, Kohorn I, Mitchell P. Challenges at the intersection of team-based and patient-centered health care. Insights from an IOM working group. JAMA. 2012;308(13):1327-1328.

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Medical Comanagement and Consultation Erin Stucky Fisher

INTRODUCTION Consultation and comanagement roles are still evolving for the pediatric hospitalist in the United States. Typically, hospitalists provide direct care for inpatients, seeking consultation from specialty colleagues as needed. For the past few years, however, hospitalists been called upon to provide consultation or comanage patients with another physician. The 2012 State of Hospital Medicine Report states that over 75% of pediatric hospitalists provide surgical or medical comanagement, with consultation roles less commonly (14% medical and 63% surgical, respectively).1 In the broader milieu of patient care, hospitalists practice comanagement daily. When a primary care provider asks a hospitalist to care for one of his or her inpatients, the hospitalist is in many respects comanaging the patient with the primary care provider. Rather than doing this simultaneously during the hospital stay (as is typically envisioned with comanagement), the patient is comanaged by the hospitalist and primary care provider sequentially. For the patient to receive optimal treatment, it is crucial that the two systems integrate. Viewing this relationship as comanagement rather than care transfer serves as a starting point for the concept of two physicians jointly managing patients, whether horizontally along a timeline, or vertically during a single episode of care. In other countries, hospital-based generalists have long been viewed as consultants to outpatient general practitioners. Studying the United Kingdom’s system of pediatrician hospitalists as consultants may aid in defining how hospitalists can serve as consultants in the United States. Specialist registrars in the United Kingdom who were asked to define key attributes of “the ideal hospital doctor” named the following eight areas as essential for the consultant: clinical knowledge and skills, clinically-related

non-clinical skills, self-directed learning and medical education, change management implementation, application of strategic and organizational skills, consultation (history and physical) skills, research, and key personal attributes.2 In the United States, pediatric hospitalists are more commonly now serving as clinical consultants and comanagers during a given hospital admission, working with other providers who serve as attending physicians of record. Pediatric hospitalists are called upon to provide a pediatrician’s view of global issues such as child development, pain management, and home health care, as well as to aid in the diagnosis and management of medically complex children.1 For hospitalists to provide optimal service to patients and providers in these consultant and comanagement roles, it is essential that definitions, expectations, and goals be clear. Consultation is defined as “a deliberation between physicians on a case or its treatment”3 to address a problem that has emerged.4 Management, on the other hand, is “to handle or direct with a degree of skill … the whole system of care and treatment of a disease or a sick individual”3 and is initiated at the onset of a care episode4 with provision of direct medical care in addition to advice.5 Comanagement implies that care is managed by more than one physician. To provide the “whole system of care” that patients deserve, physicians must work synergistically as a team. This chapter reviews consultation and comanagement in the current literature, defines goals of each, explores existing models, and examines future directions.

EVOLUTION OF HOSPITALISTS AS CONSULTANTS AND COMANAGERS: CURRENT LITERATURE Over the past 5 or 6 years, a number of studies have been published on the specific issues of hospitalist as consultant or comanaging physician. Though still limited in number, these studies address hospitalist and non-hospitalist physician experiences, opportunities and barriers, and impact on patient care outcomes. The literature regarding the use of hospitalists as consultants continues to be limited. One retrospective chart review of patients on which adult hospitalists were consulted by orthopedic surgeons for care of non-pathologic

hip fractures did not demonstrate significant improvements in osteoporosis treatment as defined by “addition of a medication for osteoporosis that strengthened treatment.”6 However, these patients had more comorbid illnesses and were significantly older than those receiving no consultation. One study of perioperative patients receiving a hospitalist medical consultation noted longer length of stay, higher cost, and no change in glycemic control and venous thromboembolism prophylaxis.7 However in this study only 9% of patients received consultation, and these patients more often had an American Society of Anesthesiologists score of 4 or higher, diabetes mellitus, vascular disease, or chronic renal failure. Moreover, consultations were requested due to a problem identified, which may have impacted the ability to anticipate and abate events. Literature on pediatric consultation is sparse.8 Canadian publications do note that consultation roles for inpatient (ward and interventional radiology)9 and ambulatory (hospital follow-up and general)10 settings exist, but no program or patient outcomes were reported. In addition to formal consults, hospitalists may be engaged in “curbside consultation,” defined as asking for advice, suggestions, or opinions about a patient’s care without asking the hospitalist to see the patient.11 In one recent study of 47 consultation events comparing curbside to formal consults performed by adult hospitalists on the same patients, curbside consults resulted in fewer questions asked and inaccurate or incomplete information received in 51% of cases.11 Formal consultation changed management in 60%, with the change deemed major in 36% of these cases. Although communication and leading a healthcare team are part of the pediatric hospital medicine core competencies,12 specific expectations for consultation are not highlighted. Implementing a formal curriculum may be a valuable consideration for hospitalists wishing to hone these skills.13 Results from comanagement studies are varied. Hospitalists and specialists in one model held different opinions regarding how the model should be implemented and whether the model improved patient care outcomes, but agreed on the need for “ownership of patients.”14,15 While reported impact on postoperative complications, mortality, and 6-month readmissions rates are conflicting,5,16,17 perceived improved communication by surveyed nurses and non-nursing staff has been noted.18 Pediatric

literature on comanagement is as limited as that for consultation. One small pediatric study of comanaged spinal fusion patients reported decreased length of stay and frequent information updates given to families as reported by hospitalists.19 Patient and family centeredness, medical errors, timeliness of care, and discharge coordination are other elements central to pediatrics yet not well studied.20,21

PEDIATRIC HOSPITALIST AS CONSULTANT: RECOMMENDED PRACTICES By definition, a pediatric hospitalist acting as consultant focuses on a specific question involving a given patient. Most consultations involve a single interaction. The goals should be to provide either diagnostic and therapeutic treatment options or a single comprehensive pediatric screening examination. Discussion of the findings and options with the requesting physician and communication with the family after that discussion are essential. When the pediatric hospitalist is consulted for a specific question but is interacting on a daily basis in a more broad capacity, the service requested is actually comanagement. The factor distinguishing consultation from comanagement is the lack of expectation for longitudinal care and coordination of all patient care needs. Pediatric hospitalist consultation almost always addresses one or more of the following questions: 1. Is this child stable for the planned procedure or intervention? This is answered by performing a global screening assessment and plan. 2. Are the evaluation and treatment appropriate? This requires a review of the plan of care. 3. What is the cause of and treatment for this problem? This requires a problem-focused assessment and plan. Each of these situations requires a thorough history and physical exam, but with a different emphasis. Even for the problem-focused question, however, the pediatric hospitalist should include relevant issues that are at the heart of general pediatrics and may not be thoroughly considered by consulting services, such as nutrition, pain management, psychosocial factors, and developmental needs. Any of these three key questions may be asked of a pediatric hospitalist

by any physician in the institution; however, certain trends have emerged. In particular, surgeons and specialists treating primarily adults may benefit from consistent, planned pediatric inpatient consultation for their patients.21 Expectations for facilities and personnel can also be a guide in determining the pediatric hospitalist’s level of involvement in acute care settings.22,23 Consultation may be requested on a case-by-case basis, or there may be an agreement that all patients in a particular group or setting will have a single initial consultation. Each pediatric hospitalist system must determine the best approach for their patients, community, and facility. Groups for whom routine consults might be considered include the following: Service specific: adult and pediatric surgeons, adult specialists, teaching service, family practitioners Acuity or site specific: newborn care (e.g. labor and delivery, newborn nursery, level II neonatal intensive care unit), pediatric intermediate care, non-pediatric emergency department Advice only: remote site, in hospital Although not as widespread, clinical consultation without chart review or patient examination is performed occasionally by hospitalists, both for patients on site or in remote locations. Academically based pediatric hospitalists are often asked diagnostic and treatment plan questions about patients not under their care. This often educational and uncompensated “curbside” consultation should be performed with acknowledgement of the risk for error.11,24 Remote consultation, usually done by phone, is of value for emergency department physicians as well as local community physicians. Clinical issues can vary from discussion of need for admission to highly complex emergency transport requirements. Pediatric hospitalists involved in coordinating and directing care teams for community wide emergency transport offer a unique and critical form of consultation. Regardless of the model used, guidelines should be developed for the hospitalist’s role as consultant to ensure that the requesting physician is satisfied, patient care is optimized, redundancies are removed, and communication is streamlined. When establishing guidelines, key issues to consider include determining whether consults are accessed by request only or through service agreements, defining who is responsible for communicating with the primary care physician, and clarifying whether the

consultant may write orders without approval of the primary attending physician. Basic tenets of effective consultation include determining the question, establishing the urgency, gathering data, generating succinct and specific recommendations that include solutions to anticipated problems, tactful communication, personal verbal or direct contact, and daily follow-up until the issue is not active.25

PEDIATRIC HOSPITALIST AS COMANAGER: RECOMMENDED PRACTICES Comanagement can be defined as a situation in which two or more physicians are involved in the ongoing care of a patient. As stated previously, comanagement routinely occurs between the hospitalist and primary care provider, with each physician filling a specific role. Additionally, just as primary care physicians’ office obligations preclude them from being available for inpatient care, surgeons’ operating room obligations may preclude them from being available for hospital management and timely discharge planning.4 Comanagement goals should be clearly laid out for each patient. In addition to addressing specific pediatric illness, the hospitalist may coordinate care, improve discharge planning, enhance communication with the primary care provider, and ensure care is family centered. Goals should include providing a comprehensive evaluation of all the patient’s needs, increasing team communication and patient engagement, decreasing errors and delays in decision-making, and assuring a sense of investment and accountability to the patient.26 Coordination of care is considered by many to be a significant strength of the pediatric hospitalist.20 The models for comanagement may have similarities to those described for hospitalist consultation and should be developed to fit individual community and hospital needs. As with consultation, guidelines must be established if comanagement is to succeed. Reason and sensitivity are required when treating physicians are in conflict over clinical management (including decisions to involve other consultants), or when there are conflicts with the family’s wishes. It is important to define which physician is the “captain of the ship.”26 Defining lines of authority is crucial, and these should be established upon assuming

care. Other expectations must also be addressed, including who will communicate with the primary care provider, the family, the patient, other consultants, nursing staff, and in academic settings, housestaff. Many models can be successful, as long as expectations are clear. For example, a 3-year-old child with cerebral palsy and a ventriculoperitoneal shunt presents with fever and renal failure. The hospitalist is the primary attending physician, comanaging with the patient’s neurologist and neurosurgeon. The decision to consult nephrology or infectious diseases is the hospitalist’s decision as the primary attending. In comparison, a 6-year-old child with known diabetes is admitted with fever and joint swelling. The patient’s endocrinologist manages the diabetes, and the hospitalist manages all other aspects of diagnostic and therapeutic evaluation, including the decision to consult orthopedics, if needed. In this scenario, the specialist manages specialty-related issues, leaving the hospitalist to manage all other aspects of care.

OTHER ISSUES Billing issues arise when the hospitalist serves as a consultant or comanages patients. Knowledge of initial consultation and follow-up codes will prevent billing confusion and delays. Only one physician per medical group can be the attending of record, requiring that other physicians bill as “consultants” (regardless of whether they are serving as consultants or comanagers of care, according to the definitions provided earlier). Contract, risk management, and Health Insurance Portability and Accountability Act issues should be considered by pediatric hospitalists performing “advice only” consulting. Pediatric hospitalists must acquire leadership skills to resolve differences of opinion regarding clinical care, particularly relevant in the arena of comanagement. These skills may also be used at an organizational level to institute consultation and comanagement policies and related changes, improve patient safety, streamline processes, advocate for new technology and services, and control costs.

FUTURE DIRECTIONS The pediatric hospitalist’s role as consultant and as partner in comanagement

is growing rapidly. Hospitalist comanagement and coordination of care vertically and horizontally are needed to ensure seamless care. Children with chronic complex conditions account for a growing percentage of pediatric admissions and over 25% of pediatric hospital days.27 These children stand to benefit most from a well-developed comanagement care model. However, such a model should also attend to the triple aim: improving population health, improving the patient experience of care (including quality and satisfaction), and reducing per capita costs of healthcare.28 In addition, the Accountable Care Organization model for healthcare challenges providers to bring coordinated care to the patient in a cost-conscious manner.29 Hospitalists should be accountable to these aims and challenges by consulting and comanaging with an acute and chronic view. The hospitalist can offer “anticipatory guidance” that includes avoidance of acute illness complications, incorporation of preventive care, and planning and execution of post-acute care. Studies are needed to demonstrate the variety and sources of consultations and comanagement, as well as effects on patients, specialist colleagues, resident trainees, hospital staff, and hospital administration. Methods should include surveys of those involved as well as studies of length of stay, cost, and clinical outcome data by disease type and acuity level. Multicenter data collection will be necessary to validate results in varied hospital settings. The impact on the hospitalist intensity of service, autonomy, schedules, and burnout should be studied. Training for current and future hospitalists should include lessons learned from these studies and from mature systems outside the United States. Current pediatric hospitalist task forces, with the leadership of the Joint Council of Pediatric Hospital Medicine and supporting groups—the Ambulatory Pediatric Association, American Academy of Pediatrics and the Society of Hospital Medicine, Pediatric Research in Inpatient Settings (PRIS) Research Network, and the Value in Inpatient Pediatrics (VIP) Quality Improvement30—are well positioned to study and refine expectations for the hospitalist as consultant and comanager in the ever-evolving healthcare system.

REFERENCES

1. Society of Hospital Medicine, Medical Group Management Association (MGMA). State of Hospital Medicine Report. Philadelphia; 2012. 2. Khera N, Stroobant J, Primhak RA, et al. Training the ideal hospital doctor: The specialist registrars’ perspective. Med Educ. 2001;35(10):957-966. 3. Merriam-Webster Medline Plus. Medical Dictionary. 2012. Available at: http://www.nlm.nih.gov/medlineplus/mplusdictionary.html. Accessed Jan 6, 2013. 4. Whinney C, Michota F. Surgical comanagement: A natural evolution of hospitalist practice. J Hosp Med. 2008;3(5):394-397. 5. Huddleston JM, Long KH, Naessens JM, et al. Medical and surgical comanagement after elective hip and knee arthroplasty: A randomized, controlled trial. Ann Intern Med. 2004;141(1):28-38. 6. Jachna CM, Whittle J, Lukert B, et al. Effect of hospitalist consultation on treatment of osteoporosis in hip fracture patients. Osteoporos Int. 2003;14(8):665-671. 7. Auerbach AD, Rasic MA, Sehgal N, et al. Opportunity missed: Medical consultation, resource use, and quality of care of patients undergoing major surgery. Arch Intern Med. 2007;167(21):2338-2344. 8. Vellody K, Zitelli BJ. Consultative pediatrics in the new millenium. J Hosp Med. 2010;5(1):E34-40. 9. Connolly B, Mahant S. The pediatric hospitalist and interventional radiologist: A model for clinical care in pediatric interventional radiology. J Vasc Intervention Radiol. 2006;17(11, Part 1):1733-1738. 10. Mahant S, Mekky M, Parkin P. Integrating pediatric hospitalists in the academic health science center: Practice and perceptions in a Canadian center. J Hosp Med. 2010;5(4):228-233. 11. Burden M, Sarcone E, Keniston A, et al. Prospective comparison of curbside versus formal consultations. J Hosp Med. 2013;8(1):31-35. 12. Stucky ER, Maniscalco J, Ottolini MC, et al. (eds.). The Pediatric Hospital Medicine Core Competencies Supplement: A Framework for Curriculum Development by the Society of Hospital Medicine with acknowledgement to pediatric hospitalists from the American Academy of Pediatrics and the Academic Pediatric Association. J Hosp Med.

2010;5(Suppl 2): i-xv, 1-114. 13. Wright R, Howell E, Landis R, et al. A case-based teaching module combined with audit and feedback to improve the quality of consultations. J Hosp Med. 2009;4(8):486-489. 14. Hinami K, Whelan C, Konetzka RT, et al. Effects of provider characteristics on care coordination under comanagement. J Hosp Med. 2010;5(9):508-513. 15. Hinami K, Feinglass J, Ferranti DE, et al. Potential role of comanagement in “rescue” of surgical patients. Am J Managed Care. 2011;17(9):e333-339. 16. Fisher AA, Davis MW, Rubenach SE, et al. Outcomes for older patients with hip fractures: The impact of orthopedic and geriatric medicine cocare. J Orthop Trauma. 2006;20(3):172-180. 17. Lucena JF, Alegre F, Rodil R et al. Results of a retrospective observational study of intermediate care staffed by hospitalists: Impact on mortality, co-management, and teaching. J Hosp Med. 2012;7(5):411415. 18. Auerbach A, Wachter RM, Cheng H, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010. 19. Simon TD, Eilert R, Dickinson LM, et al. Pediatric hospitalist comanagement of spinal fusion surgery patients. J Hosp Med. 2007;2(1):23-30. 20. Rappaport DI, Pressel DM. Pediatric hospitalist comanagement of surgical patients: Challenges and opportunities. Clin Pediatr. 2008;47(2):114-121. 21. Lye PS, American Academy of Pediatrics Committee on Hospital Care and Section on Hospital Medicine. Clinical report—physicians’ roles in coordinating care of hospitalized children. Pediatrics. 2010;126(4):829832. 22. Jaimovich DG, Committee on Hospital Care, Section on Critical Care. Admission and discharge guidelines for the pediatric patient requiring intermediate care. Pediatrics. 2004;113(5):1430-1433. 23. Rosenberg DI, Moss MM, Committee on Hospital Care, Section on

Critical Care. Guidelines and levels of care for pediatric intensive care units. Pediatrics. 2004;114(4):1114-1125. 24. Cotton VR. Legal risks of “curbside” consults. Am J Managed Cardiol. 2010;106(1):135-138. 25. Salerno SM, Hurst FP, Halvorson S, et al. Principles of effective consultation: An update for the 21st-century consultant. Arch Intern Med. 2007;167(3):271-275. 26. Hinami K, Whelan CT, Konetzka RT, et al. Provider expectations and experiences of comanagement. J Hosp Med. 2011;6(7):401-404. 27. Simon TD, Berry J, Feudtner C et al. Children with complex chronic conditions in inpatient hospital settings in the United States. Pediatrics. 2010;126(4):647-655. 28. Berwick DM, Nolan TW, Whittington J. The Triple aim: Care, health, and cost. Health Affairs. 2008;27(3):759-769. 29. United States Congress and the White House. Healthcare Reform: Affordable Care Act. 2010. Available at: http://www.whitehouse.gov/ healthreform/healthcare-overview#healthcare-menu. Accessed Oct 20, 2012. 30. Fisher ES. Pediatric Hospital Medicine: Historical Perspectives, Inspired Future. Curr Prob Pediatr Adolesc Health Care. 2012;42(5):107-112.

CHAPTER

9

Child Development: Implications for Inpatient Medicine Deirdre A.L. Caplin

UNDERSTANDING DEVELOPMENT Understanding child development and its associated constructs sets the care of children apart from the care of adults.1 There is consensus on the need to provide developmentally appropriate health care to children and adolescents, especially in the context of disability and chronic illness.2 When provided with an appropriate venue children across developmental ages can develop mastery in skills necessary to adapt and cope with illness, hospitalization, and treatment. They begin to understand many aspects of illness and treatment. Over time they are adept participants in care and treatment planning, able to communicate their needs as active partners in physician-patient-parent communication triads.3

DEVELOPMENTAL STREAMS AND MILESTONES Human development is a highly dynamic process that involves an interaction between the genetic and neurologic makeup of a child with the environment in which he or she lives.4 Children are typically monitored in health supervision visits across dimensions or streams of development including physical, social and emotional, language, and cognitive growth.1 Milestones are the myriad of developmental achievements that occur in typical patterns over predictable sequences in time.4 Knowledge of these sequences aids the inpatient medicine physician in being able to explain diagnosis, care, and treatment to patients and families, aid parents in helping their children adapt to hospitalization, and promote health and well-being in a developmentally

appropriate manner. Table 9-1 outlines the specific milestones for various developmental streams, with special attention paid to when the absence of a skill becomes a red flag for problems. TABLE 9-1

Major Developmental Milestones Age at Which Absence of Skill Is a “Red Flag”

Average Developmental Age Physical Tasks 3 months

Pulls to sit, rolls over

5 months

6 months

Sits without support

7 months

7 months

Stands while holding on

9 months

12 months

Walks

14 months

17 months

Walks up stairs

21 months

24 months

Jumps with both feet

28 months

30 months

Stands on one foot momentarily

36 months

3.5 years

Hops

4 years

4.5 years

Walks a straight line back 5.5 years and forth, balances on one foot

5.5 years

Skips, rides a bike with training wheels

6 years

6.5 years

Repeats a sequence of movements

7 years

7.5 years

Hops, moves in rhythm, throws a ball >25 feet

8 years

9.5 years

Intercepts path of objects 11 years thrown from a distance, can wash and dry own hair Social and Emotional Tasks

Birth

Shows interest, disgust, and distress

Birth

4-6 weeks

Shows recognition of familiar people

2 months

6-8 weeks

Displays social smile

3 months

2 months

Stops crying with anticipation

4 months

3.5 months

Experiences anger, surprise, sadness

4 months

3 months

Engages in interactive “play,” laughing

7 months

6 months

Shows fear, shame, shyness

8 months

8 months

Distressed with caregiver, leaving/excited at return, wary of strangers

12 months

10 months

Tests parent responses to new behavior

15 months

18 months

Reappearance of stranger anxiety, shows need for independence

24 months

24 months

Spontaneously expresses affection

4 years

24 months

Imitates adults and playmates

36 months

30 months

Objects to changes in routine

4 years

3 years

Respond to people with wide range of emotions

5 years

3.5 years

Aware of own gender/sexuality

5 years

3.5 years

Negotiates solutions (makes deals)

4.5 years

4 years

Tells stories, lies; relates day’s events

5 years

6 years

Friendships based on common interests

8 years

7 years

Worries focus on school, health, personal harm

9 years

8 years

Focus on rule-oriented games, competition Worries about friends, acceptance

11 years

11 years

Preference for friends over 15 years family members

12 years

Social awareness is abstract Language Tasks

16 years

3 months

Vocalizes when hears speech

5 months

4 months

Babbling

6 months

7 months

Imitates syllables of language

9 months

7 months

Says “dada” or “baba”

10 months

8 months

Responds to his/her name

10 months

9 months

Points to indicate interest or desire

12 months

10 months

Repeats sounds/gestures for attention

12 months

12 months

Knows one word of meaning

14 months

14 months

Has at least three words of 16 months meaning

15 months

Attends to simple commands/gestures

18 months

20 months

Points to simple body parts

24 months

21 months

Uses two-word phrases

24 months

24 months

Asks for common objects, food by name

30 months

24 months

Uses at least one personal 30 months pronoun

3.5 years

All speech is intelligible

4 years

3.5 years

Understands prepositions

4 years

4.5 years

Follows three-step commands

5 years

4.5 years

Understands time sequences

5 years

4.8 years

Uses future, past, present tense correctly

5.3 years

5.5 years

Uses irregular nouns correctly

6 years

6 years

Can articulate things that have not yet happened

7.5 years

7 years

Appreciates multiple meanings of words, puns, metaphors

9 years

10 years

Can articulate logical sequence of abstract events (more effective arguing)

13 years

11 years

Understands irony and sarcasm

14 years

12 years

Refined grammatical structures such as the passive voice

15 years

Cognitive Tasks 2 months

Tracks moving objects with eyes

3 months

3 months

Brings objects to mouth

4 months

8 months

Searches for hidden object 12 months

9 months

Uses gestures to indicate thoughts

12 months

12 months

Imitates correct use of objects (cup, brush)

15 months

12 months

Explores new object uses (shake, throw, pull)

18 months

20 months

Can give you “one” of something if asked

24 months

24 months

Begins make-believe play

36 months

30 months

Knows own full name

5 years

36 months

Can follow two-step directions

4 years

4 years

Count sequentially from 1 to 10

5 years

4.5 years

Can fully dress self

5 years

5 years

Knows own birthday or address

6 years

5.5 years

Reads four or more words

7 years

6 years

Understands common jokes/humor

7 years

7 years

Able to provide directions

11 years

12 years

Able to use deductive reasoning

16 years

12 years

Uses abstraction as method of communication and reasoning

16 years

Physical Development Beginning with neonatal reflexes, the development of both gross and fine motor skills is a process of extreme variability, both in the rate of maturation and in the way that skills are achieved.4 Despite the variation, there are constants in motor development that are largely universal. For example, reflexive movement always precedes voluntary movement, proximal control always precedes distal control, and pronation always precedes supination.5 In addition, children develop the ability for a particular action before they learn to inhibit it; if they begin to run, it may take a few falls before they learn how to stop. Social and Emotional Development The development of adequate social and emotional skills is one of the most complex and critical tasks of childhood. Social development is interdependent on other streams of development as well as influenced by environment. Attachments formed in infancy are critical for emotional, social, and behavioral self-regulation and the formation of social relationships with others.4,6 In the medical setting, coping with hospitalization, separation, and overall adjustment to disease and illness, as well as family adaptation and adherence to regimens are correlated to the social and emotional abilities of a chronically ill child.3 Language Development Language is part of a broader set of communication skills that involve a combination of speech content and character (e.g. intonation), nonverbal gestures, attention, and comprehension skills. These skills are thought to be the building blocks for socialization, memory formation, achievement, and learning. In medicine, patient-provider communication involves understanding the level at which your patient can communicate effectively to you, and is vital to quality patient care.7 Eliciting symptoms from children, explaining illness, procedures, and regimens adequately necessitates a developmentally sensitive approach, which requires a fundamental understanding of the basic developmental milestones of expressive and receptive communication. Cognitive Development Cognitive development is a known determinant of child understanding of illness and pain.8-10 Historically, research has explored how cognition shapes a child’s attitudes, beliefs, and behavior, as well as overall adjustment to disease, injury, and illness.8-10 According to Piaget’s theory, children progress through stages of development, each with tasks necessary for cognitive progression to the next stage. Piagetian stages

have persisted as the foundation for how children formulate ideas about their own health and illness (Table 9-2). Although type of information presented and prior experience can enhance understanding, it has been shown that cognitive developmental status predicts childhood understanding of disease and medical procedures better than age or other variables do.6,8-10 TABLE 9-2

Piagetian Stages and Understanding of Illness

Piagetian Stage

Developmental Ages Tasks/Status

Understanding of Illness

Sensorimotor period

0–2 years

Status: Developing schema to integrate and organize motor and sensory input from the environment Task: Intentional goal-directed behavior

• No real understanding of illness • Experience is largely sensory and immediate

Preoperational 2–7 period years

Status: Concrete thinking, irreversibility of experiences, fantasy-reality confusion, egocentrism, poor generalizability Task: Generation of a internal cognitive structure based on permanence and conservation

• Illness is a sensory experience • Cause and cure are often magical and illogical • View is an egocentric experience (not generalizable)

Concrete operational period

7–11 years

Status: Temporal and spatial understanding, reversibility, conservation all present. This allows for distinction between fantasy and reality and ability for rule orientation Task: Ability for logical thinking but still in concrete and experiential context

• Inaccuracies result as complexity of understanding increases • Cause of illness is external and concrete and control is related to avoidance • Able to describe body processes • Appreciate the reversibility of illness (cure)

Formal operational period

11+ years

Status: Thinking reflects logical causality with the ability for both inductive and deductive reasoning Task: Understanding of hypothetical and abstract events

• Able to perceive multiple causes and cures • Understand that their actions influence the disease process • Able to differentiate between physical and psychological domains of self • Aware that thoughts and feelings can affect how the body functions

“ON-THE FLY” ASSESSMENT IN MEDICAL SETTINGS Formal developmental assessment is not reasonable in a busy inpatient setting and although a sensitivity to and understanding of development are

helpful they are not typically the focus of inpatient care. However, despite its complexity, development may be rapidly and rather easily screened as part of every examination. Parents are an excellent source of information about development because most know what their child can do if asked. In addition to parents, Dixon and Stein note that “children will [often] do their own developmental assessment” if given the opportunity.11 Presenting pediatric patients with a means of communication (i.e. a toy, a crayon, a tongue blade or stethoscope, a challenge) will facilitate children letting practitioners know what they are capable of and how they think. Observing the parent-child dyad lets you see how the child is developing socially, how well the parent can read a child’s signals, and where a child’s communication skills are. The key to success is often knowing what to look for and knowing how to interpret one’s observations. As one developmental expert stated, “Knowledge of child development allows us to be efficient and even downright lazy as we get the child and family to do all the work.”4

DEVELOPMENTAL IMPLICATIONS FOR THE HOSPITALIZED CHILD INFANCY Adaptation to Illness, Hospitalization, and Treatment Infants, even the very young, are intuitive and reactive to their environment. Contact— physical and verbal—is important to creating a safe and comfortable environment for the infant patient. The body of literature on attachment suggests that even at young ages the infant recognizes primary caregivers as distinguished from the strangers typically caring for them in the hospital, suggesting that parents are critical to the care team.5 Additionally, disruptions of attachment are uncommon but they increase risk for problems with nutritional status, irritability, and responsivity to parents.6 Changes in routine can also disrupt feeding, sleeping, and temperament.4 Few behavioral changes are noted with hospitalization at this age, and young infants generally reestablish patterns quickly after hospital discharge. From a cognitive development perspective, infants do not have the ability to understand the concept of illness. However, most of what they learn in the sensorimotor period they learn from integrating sensory input with motor

responses, making it important to provide opportunities for motor and sensory exploration.1,4 Participation in Care Physicians should not expect the infant to participate directly in care. It is important to teach parents to be aware of and responsive to infant cues regarding symptoms and responses to treatment. This interaction provides a rich opportunity for early learning in successful disease management strategies, especially for children with chronic illness.6,10,12 Physician-Patient-Parent Communication For many families, diagnosis is a time of guilt, worry, and negative emotions that could have a significant impact on mental and physical health over time.6 Communication with parents of hospitalized infants should have as its goal to maximize the parent’s ability to engage in a meaningful way in order to provide appropriate interventions.6 For infants with chronic illness, the hospital stay provides an opportunity to assist families in the development of effective routines around treatment tasks that take into account the infant’s developmental limitations and strengths.

EARLY CHILDHOOD Adaptation to Illness, Hospitalization, and Treatment In the toddler and preschool years, behavioral changes associated with hospitalization are more pronounced and more prolonged than in younger infants. A toddler is wary of strangers and anxious about the separation from parents.4 Tolerance for separation improves as the toddler ages into preschool years. Young children develop a broader cognitive repertoire and can grasp the idea that an absent parent will return. Young children have a highly developed memory and imagination which results in inaccuracies and inconsistencies regarding illness.6,8,10,11 Attribution of illness often applies to magical things, superstitions, a finding that persists despite some young children’s ability to provide sophisticated and detailed dialogues about their disease.6 Evidence suggests that children at this age are better at remembering words spoken by doctors and parents about their illness but fail to retain an accurate meaning.9 Subsequently, children often develop their own causal hypotheses for illness and their role in it: “I

was bad, so I got sick. If I am good, I will get better.” Participation in Care Hospitalization can be threatening and difficult for a young child, which could result in resistance to or refusal of certain aspects of care. The burden of treatment may also increase opportunities for resistance in the context of an increased desire for the developmentally expected independence that occurs in the toddler years.6 The very behaviors that parents report as the focus of battles for independence in well child care, such as sleeping, feeding, dressing, and elimination, provide a potential source of contention with medical restrictions or requirements for care.4 Conversely, taking advantage of the young child’s natural curiosity, desire for independence, and ability for self-control can be a great asset in engaging them actively in their own care.4,6,11 Physician-Patient-Parent Communication Developmentally accurate information should be targeted for simplicity and accuracy, as the number of details and complexity interfere with comprehension in the preoperational child.9 Preschoolers have a tendency to confuse cause and effect, and have a poor perception of time.8 It is important for clinicians to take extra time to help their preschool-aged patients understand that body state, germs, or accidents may be the cause of their current illness, rather than say the doctor or being in the hospital. In addition, engaging parents and children together in care through well-developed treatment plans has been shown to increase tolerance for treatment and reports of satisfaction with care from parents of young children.6

MIDDLE CHILDHOOD Adaptation to Illness, Hospitalization, and Treatment Fewer behavior problems are expected in school-aged children because they have acquired many cognitive skills that help them process the stress of hospitalization. They are capable of comprehending the cause of their illness.4,6,8,9 Emotionally, children at this stage have emerging internal control over their behavior, allowing for greater self-regulation of response and use of problem-focused coping strategies (seeking support, planning) rather than emotion-focused coping (avoidance, distraction). Secondary strategies, such as self-talk, and active distraction are a feature of increasing

cognitive maturity, all of which require the use of more subtle cognitive processes achieved in this stage.10 Emotionally, school-aged patients rely heavily on peer engagement, organized activity, and a global sense of initiative, typically fostered by school, sports, and social activities. Identity and competence are largely assessed by comparison to peers.7,13 Prolonged hospital stays, disease management regimens, activity restrictions, and other challenges associated with a sick child are all potential impediments to expected tasks of the school-aged child, and if not addressed can become a source of emotional reactivity and poor adaptation. For some children, illness may interfere with an otherwise active and busy lifestyle. For others, responding to peer questions, dealing with teasing, or visible reminders of an illness can be sources of emotional distress.6,10,13 Participation in Care Middle childhood is the time when children become more active partners in their medical care.6,7,13,14 Readiness for self-care is more accurately marked by cognitive maturity rather than chronological age, and self-care abilities increase with maturity.14 Children as young as 5 to 8 years are aware of changes in body sensations that help them identify symptoms and care needs. By middle childhood, most children are able to read, to communicate on their own behalf, to solve everyday problems with concrete thought.14 At middle school age, children typically have an accurate understanding of illness causality and reversibility, and grasp the relationships between symptoms and body systems.13 Parents and physicians are both aware of the need for child participation in some aspects of care. However, there are documented differences in how much self-care should be expected and at what age.14 Encouraging parents and clinicians to have developmentally appropriate expectations for tasks and behaviors will likely facilitate full engagement of the child as part of his or her care team.6 Physician-Patient-Parent Communication Children achieve greater flexibility and organization in their grasp of illness concepts over time, which makes them easier to communicate with.9,13,14 However, school-aged children maintain a great deal of variability in both knowledge and application of logic, which may result in the backfiring of proactive

messages, regardless of how much illness education they have received.12 Communication with school-aged patients is dependent on many other factors including the emotional maturity of the child, parent expectations, and the physician expectations. Children report having their own priorities in health, which are not always recognized by clinicians and parents.6 Familyphysician interactions can result in marginalizing children at this age if they perceive that communications are only between the parent and the clinician. Alternatively, parents who foster communications directly between their school-aged child and their child’s physician are more likely to have children with more independence and initiative in their care.14

ADOLESCENCE Adaptation to Illness, Hospitalization, and Treatment Most adolescents have at least a concrete understanding of their own disease, but few achieve a formal operational understanding, even up to age 17.12 Cognition continues to refine in adolescence, becoming more abstract through experiences. Typically developing adolescents possess the cognitive skills needed to understand the cause of their illness and the need for hospitalization and treatment.6 However, at a time when peer influences and the need for autonomy are at a peak, hospitalization and the external structure that it imposes can be distressful. The disruption of present and perhaps future life may cause much psychic distress. Prolonged absences from school, reliance on parents and others for care, the somatic invasion associated with treatment, or a heightened sense of a potentially foreshortened future may interfere with normal developmental requirements.6,15 Secondary to the increased incidence of many chronic conditions in adolescence, hospitalization may carry with it lifelong changes in the context of individuation, identity development, and socialization.13 Potential threats to optimal social development and emotional maturation increase with prolonged or chronic illness, often because of the impact it has on school attendance and performance, and inhibition of social experiences.13 Participation in Care The capacity for self-management depends on developmental age, but is also influenced by context, task, and emotional

factors.15 Development in adolescence can be at odds with the behaviors necessary for positive disease management. A positive correlation between cognitive maturity and negative changes in health-related behaviors and adherence to medical regimens has been noted in adolescents with chronic conditions.6 The extent to which this finding exists in those teens with acute illness is unknown. However, with any adolescent patient, an approach that balances their expressed needs with parent involvement and physician support and patience is likely to improve adolescent motivation and commitment to the care plan. Physician-Patient-Parent Communication Communication with the adolescent patient is often “practice” for their adoption of adult roles over time.2 There is a significant literature on medical communication in this transitional period, most of it addressing the role of the adolescent in decision-making, autonomy in care, determination of competence, and readiness for transition to adult care settings.2,3,6,15 Studies have indicated that there is a great deal of variability in interest and commitment to healthcare by adolescents, resulting in an uneven process of negotiating with adolescents and their parents over long periods of time.13 Successful communication with adolescents often requires the clinician to bring their teen patients’ priorities to light and address them within the context of appropriate care, patience, and respect.2

SUPPORTING A DEVELOPMENTAL APPROACH IN MEDICAL SETTINGS The goal of hospitalization is to promote healing of the body as well as rapid recovery from the physical, psychological, and social impacts of the admission. A developmental approach to healthcare optimizes the ability of children and adolescents to be active members of the healthcare team.2 Many children’s hospitals are equipped with resources that can facilitate a developmental approach, including behavioral health teams, child life specialists, and social work teams. There are successful programs in place to acquaint children with hospital environments, prepare them for procedures, and encourage age-appropriate medical play and role-playing. Hospitals allow and encourage parents to room-in, as well as to visit liberally. As the

leader of this team, the hospital pediatrician is charged with supporting his or her team in understanding this relationship and accurately assessing each child’s developmental level. Accurate developmental information facilitates children participating at an age-appropriate level in their own care, coping with hospitalization and illness, and developing mastery of an often stressful experience.11

SUGGESTED READINGS American Academy of Pediatrics: Bright Futures: Tool and Resource Kit. Elk GroveVillage, IL: AAP Publications; 2008. Dixon S, Stein M. Encounters with Children: Pediatric Behavior and Development. 4th ed. St. Louis: Mosby, 2006.

REFERENCES 1. Hagan J, Shaw J, Duncan P. Bright Futures: Guidelines for Health Supervision of Infants, Children, and Adolescents. 3rd ed. Elk GroveVillage, IL: AAP Publications; 2008. 2. Sawyer S. Developmentally appropriate healthcare for young people with chronic illness: Questions of philosophy, policy, and practice. Pediatr Pulmonol. 2003;36:363-5. 3. Leatherman S, McCarthy D. Quality of Health Care for Children and Adolescents: A Chartbook. Chapel Hill, NC: University of North Carolina Program on Health Outcomes, 2004. 4. DeCivita M, Dobkin PL. Pediatric adherence as a multidimensional and dynamic construct, involving a triadic partnership. J Pediatr Psychol. 2004;29(3):157-169. 5. Dosman C, Andrews D. Anticipatory guidance for cognitive and socialemotional development. Pediatr Child Health. 2012;17(2):75-80. 6. Touwen BC. The neurological development of prehension: A developmental neurologist’s view. Int J Psychophysiol. 1995;19:115127. 7. Ernst MM, Johnson MC, Stark LJ. Developmental and psychosocial

issues in CF. Child Adolesc Psychiatr Clinics North Am. 2010;19(2):263-viii. 8. Redpath C, Rogers C. Healthy young children’s concepts of hospitals, medical personnel, operations, and illness. J Pediatr Psychol. 1984;9(1):29-40. 9. Potter PC, Roberts MC. Children’s perceptions of chronic illness: The roles of disease symptoms, cognitive development, and information. J Pediatr Psychol. 1984;9(1):13-27. 10. Band EB. Children’s coping with diabetes: Understanding the role of cognitive development. J Pediatr Psychol. 1990;15(1):27-41. 11. Dixon S, Stein M. Encounters with Children: Pediatric Behavior and Development. 4th ed. St. Louis: CV Mosby, 2006. 12. Berry AL, Hayford JR, Ross CK, et al. Conceptions of illness by children with juvenile rheumatoid arthritis. J Pediatr Psychol. 1993;18(1):83-97. 13. Clark NM, Dodge JA, Thomas LJ, et al. Asthma in 10 to 13 year olds: Challenges at a time of transition. Clin Pediatr. 2010;49(10):931-937. 14. Buford TA. Transfer of asthma management responsibility from parents to their school-age children. J Pediatr Nursing. 2004;19(1):3-12. 15. Sawyer S, Drew S, Yeo M, Britto M. Adolescents with a chronic condition: Challenges living, challenges treating. Lancet. 2007;369:1481-9.

CHAPTER

10

Palliative Care Tammy Kang, Lindsay Burns Ragsdale, Daniel J. Licht, Oscar H. Mayer, Gina Santucci, Malinda Ann Hill, Jennifer Hwang, and Chris Feudtner

The field of pediatric palliative medicine has undergone significant growth in the last decade. Palliative care services were once only considered appropriate for children who were imminently dying, but are now recognized as vital to the care of those with complex potentially life-threatening conditions. Hospitals that care for the approximately 55,000 children who die each year in the United States have an obligation to provide excellent pediatric palliative care.1-3 Although palliative care is becoming standard of care in many hospitals, on average only 10% of pediatric patients who are eligible receive palliative care.1 A recent survey by the Center to Advance Palliative Care found that although 69% of hospitals caring for children had a pediatric palliative care program, the staffing and scope of programs varied widely.4 Healthcare professionals find this domain of practice extremely difficult and referral for services is sometimes delayed or omitted. This chapter addresses the core challenges of providing palliative care, supplying practical and, to the extent possible, evidence-based answers to these challenges.

GOALS OF PALLIATIVE CARE Palliative care seeks to maximize quality of life for patients and families through an interdisciplinary approach to minimize distressing or uncomfortable symptoms that patients experience and maximizing the quality of their remaining lives, while providing support for decision making concentrating on aligning treatments with family and patient goals of care. These services are provided across the care continuum and across care locations in conjunction with disease-directed therapies. Collaboration and

communication among patients, families, and healthcare professionals is essential.

IDENTIFYING PATIENTS WHO REQUIRE PALLIATIVE CARE Figuring out which patients and families would benefit from palliative care, and when, is challenging for two main reasons. First, the prevailing medical model presents palliative care as a mutually exclusive alternative to curative care. This is a false dichotomy: patients can simultaneously receive care that seeks to cure disease or extend life while also receiving complementary care that seeks to minimize bothersome symptoms and maximize the quality of life (Figure 10-1). Second, among the approximately 55,000 children who die each year in the United States,5 several trajectories of dying exist, including6:

FIGURE 10-1. Palliative care should complement other modes of care. 1. Children who die suddenly, before any diagnosis is made (e.g. due to trauma or conditions such as sudden infant death syndrome or occult cardiac arrhythmias). These families warrant bereavement care.

2. Children whose conditions are inevitably fatal. This group can be subdivided into the following groups: a. Patients who will inevitably die relatively quickly after diagnosis (e.g. nonviable prematurity, inoperable brain tumor). All of these patients warrant palliative care immediately. b. Patients who will inevitably die, but years to decades after diagnosis (e.g. many neurodegenerative disorders). These patients warrant palliative care, but when to institute such care is debatable. We believe that, along with life-extending care, complementary palliative care and advanced-care planning should be initiated at the time of diagnosis. 3. Children who have conditions that make them extremely frail and vulnerable (e.g. severe spastic quadriplegia with swallowing dysfunction and risk of aspiration pneumonia; cancer that requires debilitating chemotherapy; sepsis that makes the child critically ill). Because of their fragile health, such children have an increased risk of dying on any given day; however, the risk is still low enough that although death is likely at some point, it is not inevitable in the next year or even the next decade. For these patients, complementary palliative care and advanced-care planning are warranted as early as possible, with a transition toward a more exclusive focus on palliative care if the condition progresses to the point where the benefits of life-extending care are outweighed by the suffering such care imposes. A study evaluated demographic and clinical features of 24,342 children who died >=5 days after admission in a sample of children’s hospitals, comparing those who did and those who did not receive a palliative care consultation. About 4% of children received palliative care. Palliative care was more common in older patients and was associated with fewer hospitalization days prior to death. Children who received palliative care in this study were less likely to have invasive interventions, received fewer medications, and were less likely to die in an ICU.7 Another study provides a snapshot of 515 children receiving palliative care by six hospital-based pediatric palliative care teams in the United States and Canada. The two most common principal underlying diagnoses in this cohort of children were genetic or congenital disorders (40.8%) and neuromuscular disorders (39.2%). The study further highlighted that

palliative care for children is principally about how to help children and families live with serious illnesses, as 69.7% of the patients were still alive at the end of the 12-month follow-up.8

DISCUSSING PALLIATIVE CARE Talking about pediatric palliative care with families is one of the most demanding and difficult tasks of clinical medicine. Dividing the task into two major components—what the patient and family are up against, and what can and will be done—and having a distinct plan for each aspect of the conversation (which will likely occur over several interactions) can be helpful. The first component focuses on delivering the bad news itself, which may be a new diagnosis or the latest in a long series of illnesses and deteriorating health. This bad news threatens the goals, plans, and hopes of patients and parents, and the resulting emotional tumult can make even the most seasoned clinician feel overwhelmed and desperate. Preparation is therefore essential: have a precise plan of what information is to be conveyed to whom, allow ample time to hold this meeting, and have the discussion in a private environment with appropriate support persons (e.g. other family members, nursing staff, social workers) present. After briefly reviewing the clinical events, preface your remarks with a warning, such as, “I’m sad to say that the news I have is bad,” and then state the new information as simply as possible, such as, “The tests show that your child has cancer.” Then stop talking and let the family assimilate this information. Your quiet, compassionate presence will be perceived as supportive. Answer questions as they are posed, avoiding the temptation to downplay or sugar-coat the bad news. Given the turmoil that such news often creates in the minds of those who receive it, simply relaying the information and responding to initial questions may be all that can be accomplished at the first meeting. Before ending the meeting, however, propose some specific plans for follow-up conversations or actions. For example, say, “I will be back to check on you and your child in 2 hours, and I can answer any additional questions that may have occurred to you and start to discuss plans at that point.” The second component of palliative conversations focuses on possible therapeutic actions and deciding on which ones to pursue.9,10 After the family

has had adequate time to absorb the bad news (which, depending on its severity and unexpectedness, can take from minutes to weeks or even longer), the objective of this conversation is to help formulate new goals, plans, and hopes in light of the constraints imposed by the diagnosis. Instead of focusing on dying and death per se, this conversation focuses on what the therapeutic alliance among patient, family, and care team can strive to accomplish, despite the fact that death is likely to occur in the near future. A useful way to proceed is along the following lines: “Learning that your child has an incurable condition that will shorten her [or his] life has been incredibly upsetting and difficult. Given the problems that the condition creates, I am wondering how we can best care for your child. What are your major hopes for her?” At this juncture, family members often both mourn the loss of hope for a normal life and mention the desire to keep pain or other forms of suffering to a minimum or quality-of-life goals, including social or spiritual concerns. These hopes provide the basic goals of all subsequent palliative and end-of-life care plans, and they are the compass by which the rest of clinical care is oriented.

DISPELLING THE MYTH THAT PALLIATIVE CARE MEANS GIVING UP One of the most challenging aspects of providing palliative care to children and families has been overcoming the stigma that palliative care entails giving up; that to receive palliative care services, parents must forego disease-directed treatments. Historically this has been the case when hospice services are engaged. Since palliative care and hospice care are often linked, the bias that families feel toward hospice has extended to palliative care teams. However, this provision changed in 2010 for patients under the age of 21 with the passing of the Patient Protection and Affordable Health Care Act (PPACA). This act includes a provision entitled “Concurrent Care for Children” which requires that programs for children in state Medicaid or Children’s Health Insurance Programs (CHIP) allow children under the age of 21 to receive hospice care while still receiving curative treatments, as discussed in further detail later in this chapter.11

COMPLEX CHRONIC CARE

The evidence is clear that pediatric patient care has become more complex and an increasing proportion of hospitalizations are attributable to pediatric patients with complex chronic conditions (CCC). Many of these patients receive palliative care consults to help with symptom management, qualityof-life issues, or end-of-life care. Despite the overlap of palliative care and the care for pediatric patients with CCC, these patients still require robust, dedicated primary and specialty care services and care coordination. Palliative care can be an important adjunct to the treatment team; however, the patients require ongoing care coordination sometimes out of the scope and staffing abilities of a palliative care team.12-14 Many hospitals have developed specialized pediatric medical teams to help manage and coordinate care for this population.15 More pediatric patients are able to pursue parallel disease-directed care and palliative care at the same time due to the “Concurrent Care” provision of new federal regulations. Palliative care can start at diagnosis of a life-limiting illness and patients can benefit from the depth of services throughout the disease process. In the future, we hope that pediatric patients can continue to benefit from concurrent palliative care to maximize their quality of life.

MINIMIZING UNPLEASANT SYMPTOMS Children who are dying often suffer with seven main symptoms that are managed most effectively within a holistic framework that includes but extends well beyond pharmacotherapy.16

NAUSEA AND VOMITING Many children experience nausea and vomiting for a variety of reasons, including chemotherapy, other drugs, metabolic disturbances, central nervous system tumors, vestibular or middle ear pathology, gastrointestinal pathology, and anxiety or other conditioned responses. Treatment includes both pharmacologic and nonpharmacologic approaches. Medications commonly used include prochlorperazine, ondansetron, granisetron, scopolamine, dexamethasone, and benzodiazepines (use of metoclopramide has decreased since the black box warning about tardive dyskinesia in 2009 by the FDA). Unfortunately, scant data support the effectiveness of these drugs in the

pediatric palliative care setting. Initial therapy should target the primary cause of the nausea or vomiting (e.g. dexamethasone for vomiting due to raised intracranial pressure from a brain tumor, or a benzodiazepine for nausea caused by anxiety). These medications can then be titrated to a maximal dose, and if that is ineffective, therapeutic control with another agent can be attempted. Often, symptom relief can be achieved only with multiple agents. Some of the most effective nonpharmacologic methods are providing small, frequent meals; giving medications after meals if possible; and eliminating smells and tastes that exacerbate the symptoms.17

FATIGUE Fatigue is one of the most prevalent symptoms in children at the end of life. The definition of fatigue in the palliative care setting varies, but in general, it refers to the subjective feeling of being tired or lacking energy. Fatigue usually stems from several concomitant causes (Table 10-1). Although assessment tools exist for fatigue in children, the diagnosis is based on subjective reports by the patient or parent.18-20 Treatment begins by addressing any possible underlying causes. Maximizing the patient’s rest is important, and this may involve the use of sleep-promoting agents. Increasing wakefulness may also be beneficial; the potent psychostimulant amphetamine has produced consistent improvements in validated measures of fatigue in randomized, controlled trials in adult patients with cancer, human immunodeficiency virus (HIV), chronic fatigue syndrome, and multiple sclerosis. Less potent psychostimulants, such as methylphenidate, dextroamphetamine, or corticosteroids, may also improve fatigue.18-20 TABLE 10-1

Common Causes of Fatigue in Palliative Care Settings

Depression Anxiety Pain Poor nutrition Medication side effects Hypoxia

Infection Dehydration

PAIN Most children experience pain at some point during their illness. Pain is a subjective symptom that is physically and emotionally distressing for both the patient and caregivers. The type of pain may be somatic, visceral, or neuropathic and may be the result of a combination of disease-related, treatment-related, and psychological causes. It is important to make a detailed assessment of pain, including location, duration, and possible causes. It is also important to assess the patient’s ability to take oral medications and the family’s reaction to the use of pain medications. Many parents are afraid to permit treatment with opioids owing to the widespread negative cultural perception of opiates as drugs of abuse, and they need reassurance. Any treatment must take into account the developmental level of the child as well as the environment (home, hospital, or health care facility) in which the child lives.21,22 The World Health Organization’s (WHO) treatment ladder is a reliable tool for managing pain (Figure 10-2); it guides physicians to escalate therapy depending on whether the degree of pain is mild, moderate, or severe and whether the previous level of treatment intensity eliminated the pain. Treatment should begin with mild analgesics such as nonsteroidal antiinflammatory drugs and acetaminophen and, based on the patient’s response, can escalate to opioids. Two of the essential components of good palliative care are to assess pain frequently and treat it aggressively (see Chapter 197). In 2012, the WHO excluded codeine from the pain treatment ladder for persistent pain in children.23 Codeine, which is a weak opioid, has known wide variability in metabolism and efficacy in children and is not recommended for pain relief in children.

FIGURE 10-2. This “ladder” approach (based on the World Health Organization’s approach to cancer pain management) can be used to guide the escalation of pain management for dying children. PCA, patient-controlled analgesia.

ANOREXIA Loss of appetite is common and often results from other symptoms, such as nausea, vomiting, constipation, pain, depression, gastritis, and weakness. It is important to treat the underlying causes if possible. As with nausea and vomiting, nonpharmacologic measures may be helpful, including giving small, frequent meals, removing unpleasant odors, and providing a relaxing atmosphere for meals. Pharmacologic therapies include corticosteroids, megestrol acetate, and dronabinol.17,24,25 Each of these therapies has adverse effects (e.g. anxiety, dizziness, hypertension, hyperglycemia, adrenal insufficiency, fatigue) that can limit their usage.

DYSPNEA The sensation of breathlessness commonly occurs in conditions with respiratory insufficiency. Patients experiencing dyspnea typically breathe in a shallow, rapid pattern as they struggle with musculoskeletal or pleuritic pain (which restricts the range of chest wall excursion), respiratory muscle weakness (as occurs with myopathies or cachectic states), poorly compliant lung tissue (due to infection, heart failure, and other conditions), or lung lesions that compromise the airway (e.g. bronchiectasis, tumor), fill airspaces (e.g. atelectasis, edema, pneumonia), or occupy space in the chest cavity (e.g. pleural fluid). Dyspnea should first be treated by correcting the underlying cause. The accompanying pain also requires effective treatment. The discomfort or fatigue associated with hypoxemia can be ameliorated by

administering supplemental oxygen (recognizing, however, that for patients with long-standing respiratory insufficiency, supplemental oxygen may suppress the hypoxic drive to breathe and cause respiratory suppression). Fatigued respiratory muscles (which contribute to the sense of dyspnea) can often be supported using noninvasive ventilation through a nasal or oronasal interface (see Chapter 209). With proper fitting of the mask and adjustment of the device, continuous or biphasic airway pressure can be delivered either at home or in a health care institution. Finally, the sensation of dyspnea and the associated anxiety can be abated directly with narcotic agents (e.g. morphine) or with anxiolytics (e.g. benzodiazepines), thereby reducing discomfort and maximizing quality of life.

CONSTIPATION This remarkably common and often neglected complaint of dying children requires a daily assessment of stool output and pain with defecation to determine whether treatment with polyethylene glycol (MiraLax), Colace, or senna is adequate. Treatment failure most often occurs because the starting dose of laxative proves to be too small to produce a soft, painless, daily bowel movement or because the laxative is used only intermittently after constipation recurs. Better results ensue when constipation is assessed every day so that if bowel movements are infrequent or painful, doses can be increased quickly to maximal amounts. Anecdotally, the combination of stool-softening agents (polyethylene glycol and Colace) and a peristalsisstimulating agent (senna) may work best for patients with difficult-to-manage constipation. Although enemas, suppositories, or GoLYTELY clean-outs may be useful for patients with neurologic bowel dysfunction, such measures should be used sparingly in other patients, whose persistent constipation should be treated with increased maintenance doses of laxatives (see Chapter 94).

SEIZURES Convulsions may occur as patients approach the end of life, and they are often particularly distressing to patients and family members. Indeed, many parents who witness their child convulsing express the hope that they never have to see a similar event.26 In the context of end-of-life care, clinical

decisions regarding the treatment of seizures are guided by the acuity of presentation, the presence of other organ damage or malfunction, and, most important, the wish to preserve or cloud the patient’s consciousness. Benzodiazepines are the mainstay of treating seizures acutely, but they cause substantial sedation and may cause respiratory depression. Newer oral anticonvulsants such as levetiracetam (Keppra) and oxcarbazepine (Trileptal) are options when sedation is undesirable. Both medications are available only in oral formulations, but they achieve good serum concentrations after only two doses, with negligible sedation and good overall tolerance. Valproic acid (Depakote) also causes negligible sedation and is available in both oral and intravenous formulations, but it should not be used in patients younger than 2 years or in those who have bleeding diatheses (valproic acid interferes with platelet function) or liver dysfunction (the metabolism of valproate is dependent on hepatic function and may interfere with the hepatic metabolism of other drugs). For a child in hospice care who experiences a first seizure, a good treatment plan would be the following: rectal valium (Diastat) (0.5 mg/kg for children younger than 5 years, 0.2 mg/kg for older children and adults) to terminate a seizure in progress, and oxcarbazepine (8–10 mg/kg divided twice a day) started as a scheduled medication. The dose of oxcarbazepine can be increased as needed until dose-limiting toxicity is manifested by double vision, vertigo, or ataxia.

MAXIMIZING QUALITY OF LIFE To support children nearing the end of life, as well as their families, healthcare professionals need to encourage them to maintain their normal lifestyles to the best of their ability and ensure that their philosophy of life is respected. In any discussion about quality of life, the healthcare team needs to take into consideration the family’s cultural values and traditions. In conversations with families, it is important to emphasize improving the quality rather than the quantity of one’s days. There are many ways to maximize quality of life for dying children. Because time is a paramount consideration, the focus should be on making each day meaningful. Healthcare providers should encourage the child and family to make memories out of big and small moments and to celebrate milestones—first tooth, first words, birthdays, graduations, religious ceremonies—while the child is still able to participate. Activities such as keeping a journal, making a

photo album, videotaping special occasions, making imprints of the child’s hands or feet, sharing stories, and keeping locks of hair all help create memories for the whole family.

CHOOSING TO GO HOME The decision about whether to have a child die at home or in the hospital is one of the most difficult that parents face. Not all families are comfortable having a child die at home; the choice depends on many factors, including medical resources, the child’s condition, and the family’s cultural belief system. Even when families decide to take a child home, they must be reassured that they can always return to the hospital. Going home is often a stressful time, especially for long-term patients, because it represents the first step toward separating from the acute medical facility and team and often symbolizes the beginning of the end-of-life journey. To make the transition as seamless as possible, the healthcare team needs to have a well-organized plan that is communicated to everyone involved. The most important consideration in discharge planning is to honor the child’s and family’s wishes. Ideally, the conversation between the healthcare team and the family about going home should take place as early as possible so that referrals to hospice or home care services can be made and strategies for improving the quality of life can be implemented. When raising the possibility of involving a hospice agency, one should anticipate several common misperceptions and address them proactively (Table 10-2). TABLE 10-2

Common Misperceptions about Hospice Care

Misconception

Reality

Hospice is about dying and death

Hospice is about living with life-limiting conditions, making the most of one’s quality of life

Patients need to be “at death’s door” or have less than 6 months to live to

Patients with longer life expectancies can enroll in hospice, and physicians should consider hospice enrollment

enroll in hospice

whenever the goals of care are palliative

Enrollment in hospice means that the patient cannot return to the hospital or receive any lifeextending care

Hospice patients can re-enter the hospital at any time and usually can receive many forms of life-extending care

Hospice enrollment entails stopping all other forms of home nursing care

This is sometimes, but not always, true; direct conversations with the patient’s insurance case manager can often result in more flexible arrangements

Transitioning a dying patient to home or to a hospice facility is best achieved through a concentrated, multidisciplinary team approach. As an advocate for the child and family, the healthcare team can help identify appropriate services and providers, as well as clarify the treatment plan and the patient’s needs with third-party payers to ensure maximum utilization of benefits. The healthcare team can facilitate the discharge planning process by working with its institutional system (e.g. case management, social work) to access all the necessary information and medical orders and to arrange the desired hospice or home care services. Children and families choose to manage their end-of-life care in a variety of ways. Some continue with home care, others transition to home care with hospice services, and still others choose to end their life’s journey in an inpatient hospice or hospital facility. The most important thing to remember is that the journey belongs to the child and the family, and their wishes should be supported.

CONCURRENT CARE FOR CHILDREN Engaging families in palliative care has often been difficult due to the perception that in order to receive palliative care services, one must abandon disease-directed treatments. Although this has not been the case for hospital and community-based palliative care services, it has historically been true for

families wishing for hospice services. In 2010, this requirement changed with the passing of the PPACA. This act includes the “Concurrent Care for Children” provision which requires that programs for children in state Medicaid or CHIPs allow children under the age of 21 to receive hospice care while still receiving curative treatments.27 This provision has the potential to expand hospice services to children and families who may still be receiving disease-directed treatments including chemotherapy, dialysis, private duty nursing, and technology support in the home including ventilators.11 Implementation of the provision has been challenging in many states and utilization of the provision has yet to be fully documented. However, concurrent care for children may open the doors for children requiring technology support at home that requires in-home nursing care to receive the addition of hospice services as their condition progresses. It has also allowed many parents to be able to use hospice services to help maximize quality time at home while still pursuing potentially life-extending treatments.

BEREAVEMENT Families whose children have died need help to heal and find new ways to live. Each member of the family struggles with intense grief and may experience and express that pain differently. During the period of grief, the physical and emotional well-being of the bereaved individual may be threatened. Although rigorous evidence is lacking that health risks and psychological problems can be alleviated or avoided if proper support and help are made available,28 we believe that this absence of evidence should not deter efforts to provide grieving individuals with emotionally supportive interventions to prevent long-term problems. With advances in diagnostic and therapeutic capabilities, the period between the diagnosis of a terminal illness and the moment of death is becoming longer, and people often have time to consider death and grief before the loved one dies. Known as anticipatory grief, this form of grieving may help families prepare for the loss and lower the degree and intensity of grief at the time of a child’s death. Physicians and nurses who detect that parents or other family members are filled with anticipatory grief and acknowledge this emotion (with simple comments such as “I can see how sad

you are”) can help them cope. A comprehensive bereavement program helps families start on the painful journey of grieving. A program should be tailored to meet the unique needs of each family, which includes providing a safe place to sit with sadness, acknowledging the many facets of grief, and helping the family glue the pieces of life back together over time. When parents who have experienced the loss of a child meet together in a grief support group, they often report a sense of peace, healing, and comfort, knowing they are not alone in their grief. Although the journey is not easy, support, hope, and guidance should be offered to families who must begin the process of healing. Grieving families should be provided with a number of services and encouraged to choose which, if any, suit their particular needs. Bereavement follow-up services may include needs assessments and consultations, crisis intervention and referrals, individual counseling (in person or by telephone), support groups (for parents, siblings, and extended family), follow-up mailings and phone calls, written materials and resources, and memorial services. Little is known, however, about the effectiveness of these interventions in assisting the bereaved.

SPIRITUAL ISSUES Most Americans have religious or spiritual beliefs of some kind. When people are confronting grave illness or death, these beliefs and associated rituals or practices are often of paramount concern.29 Accordingly, when caring for a critically ill or dying child, healthcare professionals should always ask patients or family members whether their religious or spiritual beliefs should be considered in the provision of care, and they should offer to arrange a meeting with the hospital’s pastoral care service.

DO-NOT-ATTEMPT-RESUSCITATION ORDERS Do-not-attempt-resuscitation (DNAR) orders are considered at the end of this chapter because there is so much more involved in pediatric palliative care. Indeed, because DNAR orders require a discussion among the healthcare team and the patient and family members about values, preferences, and

views regarding the quality of life—and about whether the patient’s or family’s therapeutic goals are best achieved through cardiopulmonary resuscitation or other modes of care—hospitalists who participate in these discussions should thoroughly understand and be capable of providing the other forms of care outlined in this chapter. The conversation, in other words, should be as much about what will be done to promote comfort as about what will not be done. Ultimately, tailoring the DNAR order to fit the personal therapeutic goals set by the patient or family is an expression of the patientand family-centered philosophy of care that lies at the core of excellent palliative care.

SUGGESTED READINGS American Academy of Pediatrics. Section on Hospice and Palliative Medicine and Committee on Hospital Care, Feudtner C, Friebert S, Jewell J. Pediatric palliative care and hospice care: Committments, guidelines, and recommendations. Pediatrics. 2013;132. doi: 10.1542/peds.2013-2731. Carter BS, Levetown M, Friebert S. Palliative Care for Infants, Children, and Adolescents: A Practical Handbook. Baltimore, MD: Johns Hopkins University Press. 2011. Goldman A, Hain R, Liben S. Oxford Textbook of Palliative Care for Children, 2nd ed. Oxford: Oxford University Press; 2012. Wolfe J, Hinds PS, Sourkes BM. Textbook of Interdisciplinary Pediatric Palliative Care. Philadelphia, PA: Elsevier/Saunders; 2011.

REFERENCES 1. Feudtner C. Perspectives on quality at the end of life. Arch Pediatr Adolesc Med. 2004;158(5):415-418. 2. Behrman RE, Field MJ, eds. When Children Die: Improving Palliative and End-of-Life Care for Children and Their Families. Washington, DC: The National Academy of Sciences; 2003. Institute of Medicine of the National Academies. 3. American Academy of Pediatrics. Committee on Bioethics and Committee on Hospital Care. Palliative care for children. Pediatrics.

2000;106(2 Pt 1):351-357. 4. Remke S AR, Feudtner C, Friebert S, Sieger CE, Weissman D, Wolfe J. Pediatric palliative care programs in children’s hospitals: A crosssectional national survey. 2013. Pediatrics. 132(6):1063-1070. 5. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff JM, Koepsell TD. Deaths attributed to pediatric complex chronic conditions: National trends and implications for supportive care services. Pediatrics. 2001;107(6):E99. 6. Wood F, Simpson S, Barnes E, Hain R. Disease trajectories and ACT/RCPCH categories in paediatric palliative care. Palliat Med. 2010;24(8):796-806. 7. Keele L, Keenan HT, Sheetz J, Bratton SL. Differences in characteristics of dying children who receive and do not receive palliative care. Pediatrics. 2013;132(1):72-78. 8. Feudtner C, Kang TI, Hexem KR, et al. Pediatric palliative care patients: A prospective multicenter cohort study. Pediatrics. 2011;127(6):10941101. 9. Levetown M ME, Gray D. Communication skills and relational abilities. In: Carter BS LM, Friebert S, eds. Palliative Care for Infants, Children and Adolescents. 2nd ed. Balitmore, MD: Johns Hopkins University Press; 2011:169-201. 10. Graham RJ LM, Comeau M. Decision making. In: Carter BS LM, Friebert S, eds. Palliative Care for Infants, Children and Adolescents. 2nd ed. Baltimore, MD: Johns Hopkins University Press; 2011:139-168. 11. Miller EG, Laragione G, Kang TI, Feudtner C. Concurrent care for the medically complex child: Lessons of implementation. J Palliat Med. 2012;15(11):1281-1283. 12. Morrison RS, Maroney-Galin C, Kralovec PD, Meier DE. The growth of palliative care programs in United States hospitals. J Palliat Med. 2005;8(6):1127-1134. 13. Klick JC, Hauer J. Pediatric palliative care. Curr Probl Pediatr Adolesc Health Care. 2010;40(6):120-151. 14. Johnston DL, Nagel K, Friedman DL, Meza JL, Hurwitz CA, Friebert S. Availability and use of palliative care and end-of-life services for

pediatric oncology patients. J Clin Oncol. 2008;26(28):4646-4650. 15. Bergstraesser E. Pediatric palliative care-when quality of life becomes the main focus of treatment. Eur J Pediatr. 2013;172(2):139-150. 16. Hain R, Zeltzer L, Hellstern M, Cohen SO, Orloff S, Gray D. Holistic management of symptoms. In: Carter BS LM, Friebert S, eds. Palliative Care for Infants Children and Adolescents. 2nd ed. Baltimore, MD: Johns Hopkins University Press; 2011:244-274. 17. Santucci G, Mack JW. Common gastrointestinal symptoms in pediatric palliative care: Nausea, vomiting, constipation, anorexia, cachexia. Pediatr Clin North Am. 2007;54(5):673-689, x. 18. Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med. 2001;161(3):411420. 19. Sarhill N, Walsh D, Nelson KA, Homsi J, LeGrand S, Davis MP. Methylphenidate for fatigue in advanced cancer: A prospective openlabel pilot study. Am J Hosp Palliat Care. 2001;18(3):187-192. 20. Ullrich CK, Mayer OH. Assessment and management of fatigue and dyspnea in pediatric palliative care. Pediatr Clin North Am. 2007;54(5):735-756, xi. 21. Friedrichsdorf SJ. Pain management in children with advanced cancer and during end-of-life care. Pediatr Hematol Oncol. 2010;27(4):257261. 22. Friedrichsdorf SJ, Kang TI. The management of pain in children with life-limiting illnesses. Pediatr Clin North Am. 2007;54(5):645-672, x. 23. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses. Geneva. 2012. 24. Tomiska M, Tomiskova M, Salajka F, Adam Z, Vorlicek J. Palliative treatment of cancer anorexia with oral suspension of megestrol acetate. Neoplasma. 2003;50(3):227-233. 25. Strasser F, Bruera ED. Update on anorexia and cachexia. Hematol Oncol Clin North Am. 2002;16(3):589-617. 26. van Stuijvenberg M, de Vos S, Tjiang GC, Steyerberg EW, Derksen-

Lubsen G, Moll HA. Parents’ fear regarding fever and febrile seizures. Acta Paediatr. 1999;88(6):618-622. 27. The District of Columbia Pediatric Palliative Care Collaborative and the National Hospice and Palliative Care Organization. Concurrent Care for Children Requirement: Implementation Toolkit. 2012. 28. Forte AL, Hill M, Pazder R, Feudtner C. Bereavement care interventions: A systematic review. BMC Palliat Care. 2004;3(1):3. 29. Lanctot D MW, Koch KD, Feudtner C. Spritual Dimensions. In: Carter BS LM, Friebert S, eds. Palliative Care for Infants Children and Adolescents. 2nd ed. Baltimore, MD: Johns Hopkins University Press; 2011:227-243.

CHAPTER

11

Communication and Discharge Planning Daniel A. Rauch and David Zipes

INTRODUCTION In discussing hospitalist models, it is essential to keep in mind the relationships between hospitalists and the wider pediatric community. Communication is at the forefront of any hospitalist model and can be the Achilles’ heel of an otherwise high-quality program. Excellent communication to and from primary care physicians (PCPs) can help a program thrive and prosper. PCPs who are kept in the loop regarding their patients’ hospital courses will likely support and continue to utilize the hospitalist service. By communicating in an effective and timely manner, one of the major potential downsides (loss of valuable information) of a hospitalist service can be avoided. Communication can positively or negatively affect a variety of issues, including but not limited to quality of care, cost of care, patient and physician satisfaction, and liability. With excellent communication, the transition from inpatient to outpatient settings (including transitional care units, chronic care facilities, and rehabilitation hospitals) can be smooth, with minimal to no loss of information.

HANDING OFF CARE The concept of assuming care for other physicians’ patients and then returning their care to the PCPs at discharge is an integral component of all hospitalist models. This is generally accomplished via a formal handoff, which is one of the more controversial and variable aspects of hospital medicine. The intentional creation of discontinuity of care permits a physician (hospitalist) to be present in the hospital for an extended period to

manage inpatients throughout the day. This ongoing presence is one of the biggest advantages of the hospitalist model. As with most things, however, one must accept the good with the bad. As a result of the handoff, the PCP, with whom the patient has fostered a trusting relationship and who knows the patient’s medical history best, is not caring for the patient when he or she is most ill. This situation can result in a loss of essential information (“voltage drop”) from the outpatient to the inpatient setting and vice versa. Complex and expensive laboratory and radiology data, as well as vital information concerning possible medical allergies, medications, code status, and patient’s likes and dislikes, can be lost or poorly or miscommunicated during the transfer. This could result in a variety of negative outcomes—some relatively benign, and others potentially life threatening. With excellent communication between the PCP and the hospitalist, voltage drop can be minimized. In a study of 400 discharged patients, researchers found that 19% of patients suffered adverse events soon after discharge; about half of these events would have been preventable if communication had been adequate.1 The Value in Inpatient Pediatrics (VIP) network has sought to standardize the discharge communication process with their “Pediatric Hospitalists Collaborate to Improve Discharge Communication” project. Additionally, The Pediatric Research in Inpatient Settings (PRIS) network is working on handoffs in the academic setting with their I-PASS project. To date, no standard for communication between the hospitalist and the PCP has been set, and there is significant variation from practice to practice. Communication may occur in person, via telephone, fax, e-mail, text or internet, or sometimes not at all. Maintaining compliance with Health Insurance Portability and Accountability Act (HIPAA) standards adds another challenge to the process. A task force formed by the Society of Hospital Medicine and the Society of General Internal Medicine to address continuity-of-care issues found that more than a quarter of PCPs do not receive discharge summaries on their patients. Additionally, the task force discovered that more than half of discharged patients made contact with their PCPs before the PCPs had received any discharge information—many PCPs did not even know that their patients had been admitted to the hospital. Only 17% of those surveyed stated that hospitalists had notified them before their patients were discharged to home.

The growth of information technology and easy access to e-mail, the internet, faxes, wireless communications, and handheld devices have created many effective modes of communication. New computer and handheld device programs to address communication issues have been developing at a rapid pace, and many of them are quite useful. Template-driven discharge summaries can simplify the process and help ensure that essential information is communicated. The technology to create real-time communication exists, although many hospitalist programs have not made the leap because of cost (both financial and time), unwillingness to change, lack of administrative support, inadequate staffing, or a variety of other reasons. The information communicated, such as discharge summaries or laboratory reports, should be filtered appropriately to maximize the efficiency of communication and reduce the time commitment for PCPs. Some information, such as social issues and end-of-life care discussions, does not lend itself well to electronic communication, and in these situations, the value of the telephone or face-to-face communication should not be overlooked. “Social rounds” by the PCP, either by phone or in person, are an excellent patient satisfaction tool and can help erode the voltage-loss issue and increase the family’s confidence in the hospitalist. One effective technique is for the hospitalist to call the PCP while in the patient’s room so that the family can hear that everyone is on the same page. Similarly, including the PCP in complicated social and medical discussions, such as end-of-life care, code status, case conferences, and major medical or surgical decisions, can be useful to all involved. Telemedicine has not been routinely implemented to communicate with PCPs but with easy access to programs such as Google Talk, Facetime and Skype this technology may be promising. One needs to be cognizant that the PCP will be dealing with the aftermath of the hospitalization. By working as a team, the PCP and the hospitalist can maximize the advantages of hospital medicine while minimizing its disadvantages. The AMA recently published a white paper, There and Home Again, Safely,2 that addresses the PCP’s responsibilities in transitions of care in and out of the hospital setting. It makes clear that communication around patient care is a bi-directional dialogue so that it is reasonable for the hospitalist to have an expectation of communication from the PCP.

DISCHARGE PLANNING Discharge planning is an integral part of hospitalization and is an area in which hospitalists should have a significant impact. Many of the inherent benefits of a hospitalist service, such as improved quality of care, efficiency, and communication, all culminate in effectively transitioning the patient out of the hospital setting. Discharge planning must begin on admission to the hospital and continue throughout the hospital stay. It should include communication with the PCP and appropriate follow-up services. It must encompass coordination with social services, the payer, and, of course, the family. It must also provide for follow-up with regard to any issues that are still pending at discharge. As discussed in previous chapters, hospitalists can play a significant role in determining who gets admitted to the inpatient service and in facilitating intra-hospital transfers. This involvement may vary from program to program and from patient to patient. Even when the hospitalist plays no role in screening admissions, it is incumbent on the hospitalist to clearly define the goal of an inpatient stay; the discharge criteria should follow from this. Anticipating at the outset the durable medical equipment, medications, and services that will be required at discharge can greatly facilitate timely and efficient discharges, even on weekends.

COLLABORATION Discharge planning, just as inpatient management itself, requires a team approach (Table 11-1). Optimally, the inpatient service has a multidisciplinary approach that includes at least nursing, social services, and a coordinator familiar with local payer structures and other outpatient and community resources, such as home care agencies and alternative care facilities. TABLE 11-1

Discharge Planning Team

Participant

Role

Hospitalist

Acts as team leader

Other medical providers with knowledge of current inpatients

Provide medical information

Nursing staff

Provide additional medical information and insight into patient– family dynamics

Social workers

Provide information to patient and family about necessary resources for discharge

Discharge planner

Coordinates discharge needs with outpatient services in context of patient’s insurance

Other: therapists (occupational, physical, speech), nutrition, child life

Provide unique patient information that may impact discharge

Nursing input is vital because nurses interface with patients and families in a different way than physicians; this allows valuable insight into the relative strengths and weaknesses of each patient and their care providers— information that is critical for appropriate discharge planning. Social workers bring another viewpoint that can shed light on the patient’s and family’s response to illness and their ability to manage post-hospitalization care. This perspective should help guide the timing of discharge and what postdischarge services will be necessary. The discharge planner begins reviewing charts on admission, looking for medical documentation of discharge goals. This allows the planner to immediately start coordinating with payers on issues such as anticipated length of stay and available outpatient services. For adult patients, experience with nurse discharge planners and comprehensive discharge planning demonstrates reduced costs and lengths of stay.3,4 Other possible members of a discharge team include therapists, nutritionists, and child life specialists, all of whom may have unique information that impacts discharge planning. Additionally, a post-discharge coordinator can follow up on pending laboratory results and ensure that the family is able to keep or

schedule appointments, obtain prescribed medicines, and follow through with other discharge plans. A weekly (or more frequent) meeting of all parties involved in discharge planning to review ongoing cases and the availability of additional consultation is an effective technique used by many hospitalist groups. This type of multidisciplinary approach can identify significant issues that may affect discharge planning and may serve as a source of quality improvement projects. The hospitalist should be involved in developing mechanisms to ensure the timely review of patient charts by related services to identify discharge issues and improve hospital resource utilization. Most important, patients and families must be partners in the discharge process. Clear goals for admission, as well as discharge criteria and anticipated obstacles, make it easier for the patient and family to follow the course of the hospitalization and prepare for discharge. The hospitalist must be aware of the prevailing Patients’ Bill of Rights regarding necessary notification of discharge, as well as the mechanisms for patients to dispute discharge decisions. Communication with the PCP is essential for appropriate discharge planning,5 and the American Academy of Pediatrics has established the following guidelines for minimum communication with the PCP: communication on admission, for any significant events, and on discharge.6 Good relationships and ongoing communication with referring physicians can help define the best means of communication. It is also important to clarify the capacity of outpatient services to handle ongoing medical needs. Because many factors influence the PCP’s ability to handle various levels of acuity and necessary follow-up after discharge, these issues must be considered during discharge planning. Likewise, it is important to establish open lines of communication with alternative care facilities so that transfer procedures can be initiated as soon as a potential transfer is anticipated. All communication of patient information must be mindful of HIPAA regulations.7

CONTINUITY OF CARE Many successful hospitalist practices have the policy of calling PCPs with every discharge—regardless of the time. This avoids middle-of-the-night telephone calls from patients or families to uninformed PCPs. There are inherent issues with routine discharge phone calls including the time needed

to reach the PCP and potential dissatisfaction from the PCP who is interrupted from sleep or office duties. The median time from a patient’s discharge to his or her first visit to the PCP is 6 days; knowledge of events in the hospital is often critical to a successful office visit and helps assure the patient that his or her care has been adequately coordinated. In addition to a discharge phone call, many practices fax a summary of pertinent information, including dates of admission and discharge, discharge diagnosis, procedures, medicines, change in code status, pertinent laboratory results and pending tests, consultations, disposition, and follow-up appointments. As noted previously, the VIP network has made significant strides toward creating guidelines for discharge communication that incorporate both PCP and hospitalist preferences. A typed discharge summary can also be generated and sent (generally via fax) for each discharged patient, and many electronic medical records allow easy electronic communication with PCPs. Although this can be time consuming, the benefits of effective communication are worth the extra effort. Discharge from the inpatient service is usually not the end of care for a patient. Many patients reach their goals for admission and are successfully discharged with various tests still pending and therapies needed (e.g. antibiotics, respiratory therapy). An important element of discharge communication is conveying information regarding pending tests and studies. This can prevent the repetition of studies that have already been done and ensures that data from the studies are conveyed to the outpatient care providers. The person responsible for following up on pending results can vary from practice to practice, and it is unclear who is medicolegally responsible for following up on tests after discharge. Regardless of the legal implications, the hospitalist should either follow up on pending tests or make sure that the PCP does so. Many practices have implemented post-discharge follow-up clinics for one to two visits. The PCP should be notified of these visits, and the patient should be “returned” to the PCP as soon as possible. One must be aware of the potential political ramifications of delving into the outpatient arena. Along the same lines, a focused post-discharge phone call from the hospitalist practice can help ferret out problems with prescriptions, follow-up appointments, or the patient’s condition.

CONCLUSION Excellent communication is essential to any successful hospitalist service, and adequate discharge planning is essential to the smooth operation of a hospitalist system. The hallmark of effective discharge planning is that it never unnecessarily extends the inpatient stay. By anticipating patient needs, hospitalists can not only improve the care their patients receive but also maintain efficient throughput and maximize the beds available to the inpatient service and the hospital as a whole. PCPs may be concerned with many aspects of their interaction with a hospitalist service, and effective discharge planning can have an important impact on acceptance.8,9

REFERENCES 1. Forster AJ, Murff HJ, Peterson JF, et al. The incidence and severity of adverse events affecting patients after discharge from the hospital. Ann Intern Med. 2003;138:161-167. 2. Sokol PE, Wynia MK, writing for the AMA Expert Panel on Care Transitions. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. Chicago IL: American Medical Association; 2013. 3. Palmer HC, Armistead NS, Elnicki DM, et al. The effect of a hospitalist service with nurse discharge planner on patient care in an academic teaching hospital. Am J Med. 2001;111:627-632. 4. Naylor MD, Brooten DA, Campbell RL, et al. Comprehensive discharge planning for the elderly: a randomized, controlled trial. J Am Geriatr Soc. 2004;52:675-684. 5. Goldman L, Patilat SZ, Whitcomb WF. Passing the clinical baton: 6 principles to guide the hospitalist. Am J Med. 2001;111:36S-39S. 6. Percelay JM, Committee on Hospital Care. Physicians’ roles in coordinating care of hospitalized children. Pediatrics. 2003;111:707709. 7. American Academy of Pediatrics. American Academy of Pediatrics Security Manual. Oct 2003.

8. Fernandez A, Grumbach K, Goitein L, et al. Friend or foe? How primary care physicians perceive hospitalists. Arch Intern Med. 2000;160:29022908. 9. Auerbach AD, Aronson MD, Davis RB, Phillips RS. How physicians perceive hospitalist services after implementation: anticipation vs reality. Arch Intern Med. 2003;163:2330-2336.

CHAPTER

12

Ethical Issues in Pediatric Hospital Practice Jennifer K. Walter, Sarah Hoehn, and Chris Feudtner

INTRODUCTION The ethical and moral dimensions of health and medicine pervade all aspects of clinical care. Providers of hospital care for children constantly encounter situations in which ethical considerations are vital, ranging from the routine task of obtaining parental permission for medical care to more rare quandaries regarding care deemed necessary (yet is refused) or futile (yet is requested). Competence in handling ethically problematic situations can be enhanced by expanding one’s perspective on ethical thinking, knowing what institutional resources are available to help resolve ethical problems, and learning how to approach specific common problems.

ETHICAL PERSPECTIVES RULES AND POLICIES There are many ways to approach ethical decision-making. An important practical starting point is the hospital’s rule or policy providing specific instructions regarding the issue at hand. For instance, hospitals typically provide guidance about when the general consent for care granted by a parent at the time of admission is inadequate and specific parental permission to perform certain diagnostic or therapeutic procedures must be obtained and documented. Such rules and policies can often be found in the medical staff bylaws or in national guidelines published by the American Academy of Pediatrics (AAP), American Medical Association, or other organizations. Ethically problematic situations are addressed by asking, “What rules and policies [or pertinent state or federal laws] govern our conduct and guide our

choices?”

DUTIES, RESPONSIBILITIES, AND COMMITMENTS Consideration of professionally defined duties and responsibilities can help guide decisions. A growing movement within medicine emphasizes the importance of professional duties, responsibilities, and commitments toward such ends as professional competence, just distribution of finite resources, the integrity and advancement of scientific knowledge, honesty with patients, patient confidentiality, maintenance of appropriate relations and boundaries with patients, improvements in quality of care and access to it, and maintenance of trust by managing conflicts of interest.1 To the degree that such commitments reflect professional consensus, they function as informal policies and guide our actions by telling us (less explicitly than policies) how to behave.

VIRTUES OR PERSONAL TRAITS An allied approach to ethics focuses on individual character traits such as honesty, compassion, competence, fortitude, temperance, fidelity, integrity, self-effacement, and wise and prudent decision-making. Here, however, the emphasis shifts away from what constitutes good behavior (which is the focus of policies or duties) and toward what constitutes a good person who will behave virtuously.2 When confronting ethically problematic situations, personal traits can be used to evaluate a proposed course of action: if I behave in this manner, will I be acting with honesty, fidelity, and fortitude? If not, why would I pursue this course of action? Can I chart another course with greater integrity and wisdom?

BIOETHICS PRINCIPLES To analyze what would be the “right” course of action, it may also be useful to consider the frequently cited core principles of bioethics as presented by Beauchamp and Childress (beneficence, non-maleficence, autonomy, and justice).3 These principles are described so that many different moral theories would endorse them. They offer a framework for how to approach an ethical

dilemma that speaks across different backgrounds because they are valued by many different moral traditions. Beneficence seeks to maximize the benefits caused by our actions, whereas nonmaleficence seeks to minimize the harm that our actions cause. Many therapeutic decisions involve some tradeoff between beneficence and nonmaleficence; simply making a list of the good and bad things that might happen, and how likely they are to happen, can help clarify some dilemmas. Autonomy seeks to enable an individual’s values to guide his or her medical care; respecting a patient’s autonomy is a central way we respect their dignity. Considerations of justice involve how the care of one person fits into the larger system of the care of all persons and can bring up issues of resource allocation and fair procedures to determine who gets what type of care. Understanding how these core principles may be in conflict with one another in specific situations can help elucidate why different individuals may view ethical dilemmas in different ways and may serve as a starting point for discussion and resolution of conflict.

MEDIATION OF HUMAN SOCIAL INTERACTIONS A final set of concepts focuses less on ethical theory and more on people’s understanding of a situation and their interactive behavior. Poor communication and misunderstandings lie at the heart of many conflicts that are perceived as ethical dilemmas. Patterns of interacting—ranging from hurried attempts to communicate complex information or bad news to vocal or body language expressions of anger or arrogance—can worsen misunderstanding and intensify noncooperation.4 If misunderstanding and mistrust are allowed to persist, the lines of the dispute can ossify into entrenched positions (e.g. “I will not permit such-and-such to be done under any circumstances”). Making progress in such cases takes time, patience, and a willingness to share control over the decision-making process. A mediation or negotiation model emphasizes, first and foremost, building mutual understanding and trust; only after these prerequisites have been created can one move on to problem solving.5

HOSPITAL RESOURCES When confronting ethically problematic situations, most pediatric physicians

can draw on valuable resources within their hospitals.

KEY PEOPLE To improve communication, build shared understanding, clarify goals, generate novel solutions, or mediate disputes, physicians may turn to professional translators or cultural mediators, social workers, nurses, pastoral care workers such as chaplains or rabbis, palliative care team members, legal counsel, or other physicians with particular skills in these areas.

ETHICS COMMITTEES Institutional ethics committees can develop or review hospital policies, perform clinical ethics consultations, mediate disputes or controversies, and educate healthcare professionals and patients.6,7 Seven principles guide the process of ethics consultation (Table 12-1).6 Overall, the quality of an ethics consultation rests on the committee’s preparation, including interviewing key stakeholders, gathering pertinent data, and reviewing pertinent literature,8 and its ability to provide an open forum for honest and confidential discussion. TABLE 12-1

Principles of Ethics Consultations

1. Any patient, parent or guardian, or family member can initiate an ethics consultation. 2. The patient and parent or guardian can refuse to participate in an ethics consultation. 3. The refusal of a patient or parent or guardian to permit an ethics consultation does not hinder the ability of an ethics committee to provide consultation services to physicians, nurses, and other concerned staff. 4. Any physician, nurse, or other healthcare provider involved in the care of the patient can request an ethics consultation without fear of reprisal. 5. The process of ethics consultation is open to all persons involved in the patient’s care but is conducted in a manner that respects

patient and family confidentiality. 6. Anonymous requests for ethics consultation are not accepted in the absence of an identified person who is willing to speak to the issue being raised. 7. The primary care pediatrician is invited to participate in the consultation to support existing physician–family relationships.

RESEARCH AND INSTITUTIONAL REVIEW BOARDS Children are allowed to participate in research only when the institutional review board determines that the risks are minimal, a minor increase over minimal risk, or that the pediatric subjects may benefit directly from participation in the research study.9 As always, fully informed permission or consent is a prerequisite for research conducted on human subjects (yet only a third of published pediatric studies include proper documentation of institutional review board approval and informed permission or consent).10

COMMON PEDIATRIC INPATIENT SITUATIONS Although rigorous estimates of the prevalence or incidence of ethically significant or problematic incidents in the inpatient setting are lacking, our experience suggests that hospital-based pediatricians will encounter most or all of the following situations.

OBTAINING PERMISSION, ASSENT, OR CONSENT In pediatric practice, there are three important processes by which parents or patients agree that the patient will receive certain medications, tests, or procedures.11 Informed permission is used when a pediatric patient lacks the necessary decision-making capacity and legal empowerment to make an autonomous decision, requiring the parent or designated surrogate caregiver to do so. Assent is sought when a child or adolescent has some decisionmaking capacity but is not yet legally empowered. Informed consent is used when an adolescent or young adult has legal authority to make decisions regarding his or her health care.

The processes of obtaining informed permission and informed consent include four key components: (1) appropriate disclosure of information, (2) adequate personal understanding of the information, (3) emotional capacity to make a decision, and (4) voluntariness or freedom from coercion.12 The process of seeking assent translates these elements into a developmental framework applicable to pediatric patients (Table 12-2). TABLE 12-2

Four Keys to Seeking Pediatric Patients’ Assent

1. Help the patient achieve a developmentally appropriate awareness of the nature of his or her condition. 2. Tell the patient what he or she can expect with regard to tests and treatments. 3. Make a clinical assessment of the patient’s understanding of the situation and the factors influencing how he or she is responding (including whether there is inappropriate pressure to accept testing or therapy). 4. Solicit an expression of the patient’s willingness to accept proposed care. Do not solicit a patient’s views without intending to weigh them seriously. Necessary urgent medical care should not be withheld because of a lack of consent.13 No evaluation of a life-threatening or emergency condition should be delayed because of a perceived problem with consent or payment authorization. A parent’s act of leaving his or her child with another custodian or the state represents implied consent when the parent is not immediately available for verbal consent and nonelective medical care is needed. These situations include relief of pain or suffering, suspected serious infectious disease, assessment and treatment of serious injuries and conditions that threaten life, limb, or central nervous system, and other potentially serious conditions.13

DETERMINING DECISION-MAKING CAPACITY AND COMPETENCE

When can an adolescent consent to medical care? The laws that govern this issue vary by state, so it is prudent to check with your hospital legal counsel. In general, however, persons are judged to be legally competent to consent to care when they are 18 years or older or when they have been emancipated from parental authority by circumstances such as being married, being pregnant or having borne a child, or living on their own. Adolescents seeking care for certain conditions (e.g. reproduction, emergencies, sexually transmitted diseases, drug and alcohol abuse) may also be deemed competent to consent to treatment without parental permission. Occasionally, pediatric hospitalists may be caring for persons 18 years or older who lack decision-making capacity (e.g. due to mental retardation). In such circumstances, the first step is to determine whether the patient has been determined by the legal system to be incompetent and, if so, who has been specified as the surrogate decision maker through either guardianship or durable power of attorney. Even more rarely, the decision-making capacity of a younger patient’s parent or guardian may be in doubt. In such an event, attending physicians should confer with other members of the healthcare team and perhaps hospital legal counsel before asking for a legal determination of incompetency and the specification of an authorized surrogate decision maker. Relevant criteria to be considered when determining decision-making capacity include the ability to communicate a choice for treatment, understanding the relevant information necessary for the decision, appreciating the situation and its consequences, and reasoning about the treatment options.14

BEING PURPOSEFULLY DECEPTIVE Although the use of deceptive practices by physicians and healthcare staff runs counter to the principle of truth-telling and the virtue of forthrightness, such practices still occur—in some cases, perhaps with justification—in the pediatric inpatient setting. Examples include the secretive use of placebos to determine whether a response to therapy is due to physiologic or psychological mechanisms, quasi-investigational feeding trials of a child with growth failure to determine whether the family is noncompliant with nutritional recommendations, and the use of covert surveillance video cameras to investigate potential cases of Munchausen syndrome by proxy. Recourse to these deceptive methods should be considered only after all other

possible nonsecretive means of addressing the situation have been exhausted, and then only if the potential benefits of deception greatly outweigh considerations of truth-telling, trustworthiness, and patient or parent autonomy, and only if the course of action has been evaluated by a sufficiently wide array of hospital staff (e.g. members of the ethics committee) to ensure that the two preceding conditions have been met.

MEDIATING DISPUTES REGARDING FUTILE OR ESSENTIAL CARE When parents want an increased level of technologic support for their child— often stated as wanting to “do everything”15—and health care providers disagree, the notion of futility is sometimes brought up.16—The Society for Critical Care Medicine defines futile treatments as those that will not accomplish their intended goal17 (although identifying clinical situations when we can predict with accuracy and assurance that interventions will have no chance of success is difficult18). Attempts have been made to better define futile treatments both quantitatively (e.g. treatment has been useless in the last 100 cases) and qualitatively (e.g. treatment will merely preserve permanent unconsciousness or fail to end total dependence on intensive medical care).19 Such definitions have been criticized, however, because of the imprecision of medical prognoses and because they are value laden and biased against technology-dependent children.20 Lacking a consensus definition of futility, many ethicists believe that parents’ wishes should be honored21 and that the treatment team’s attention should be focused on improving communication with the family, because poor communication often prompts such disputes.22,23 Failure to reach consensus after a team’s best efforts to improve communication is a good indication for an ethics consultation. In contrast to futile treatment disputes, parents sometimes refuse care that seems necessary. The AAP believes that all children deserve effective medical treatment that is likely to prevent substantial harm, suffering, or death.24 In addition, the AAP advocates that all legal interventions should apply equally whenever children are endangered or harmed, with no exemptions based on religious or spiritual beliefs—with the exception of

immunizations. The AAP does not support the application of medical neglect laws for failure to vaccinate unless there is substantial risk of serious harm, although it does endorse universal immunizations.25 In general, if the benefit of treatment is uncertain, the parents’ wishes should be honored. Some authorities also support pediatricians’ right to discontinue professional services due to vaccine refusal, but they still must comply with the applicable legal and ethical requirements to ensure that patients are not abandoned.26

DECIDING TO WITHHOLD OR WITHDRAW LIFESUSTAINING TREATMENT Within the medical ethics community, there is strong consensus that there is no salient ethical difference between withholding (i.e. never starting) and withdrawing (i.e. stopping) treatment. Simply stated, if the initiation or continuation of a potentially life-sustaining therapy adversely affects the likelihood of accomplishing therapeutic goals that the patient values above life (such as quality of life), therapy can be ethically withheld or stopped.27 Although most healthcare professionals are ethically comfortable withholding or withdrawing potentially life-sustaining high-technology therapy, many are uncomfortable with the practice of withholding or withdrawing fluids and nutrition administered through tubes, particularly for children who cannot consent for themselves.28 The AAP argues that intravenous infusions and tube feedings are no different from other forms of therapy that competent patients or their authorized surrogates have the right to refuse if the expected burden of the intervention to the patient exceeds the potential benefit.28 General consensus on these practices is lacking, however, and many states have ambiguous case law precedents that leave the legally sanctioned course of action unclear.

DISTINGUISHING BETWEEN TREATING SUFFERING AND PERFORMING EUTHANASIA Euthanasia is illegal throughout the United States,29 yet the proper management of a patient in severe pain or with some other form of intractable suffering sometimes requires doses of medications (especially opiates) that may hasten death and in other clinical circumstances would be considered

inappropriate. The goal of palliative care is to optimize the patient’s quality of life, and at times this may only be achieved by giving increasing doses of sedation that also may contribute to respiratory depression. If a patient or parent requests euthanasia, physicians should respond compassionately by looking to alleviate the sources of distress (e.g. concerns of abandonment, depression, loneliness, physical symptoms, or communication problems).30 Physicians committed to minimizing the suffering of dying patients can evaluate the ethical appropriateness of their actions by considering whether they can affirm the four rules of the doctrine of double effect (Table 12-3). TABLE 12-3

Four Rules Regarding the Doctrine of Double Effect

1. The intention when instituting treatment (typically, administering a drug) must be solely to relieve the patient’s suffering. 2. The treatment must be given in response to a sign or symptom of suffering (not a hypothetical potential for suffering to occur). 3. The potency of the treatment must be commensurate with the degree of suffering (not a massive overdose). 4. The treatment must not be given as a deliberate attempt to cause or hasten death.

ADVOCATING FOR PATIENTS AND ENHANCING QUALITY OF CARE Pediatrics as a profession has long recognized the need to advocate for children.31 Pediatric hospitalists have ethical obligations to improve how health care is delivered to their patients. Although these obligations are often most compelling on a case-by-case basis, hospitalists involved in the design of hospital practice guidelines or policies should also be mindful of how these practices can be evaluated from an ethical point of view. Enhancing access to care, ensuring that limited resources are allocated fairly, eliminating financial conflicts of interest, and improving the quality of care are all activities that can promote justice, equity, and beneficial outcomes in child

health care.

SOCIAL MEDIA AND RESPECTING PATIENT AND CLINICIAN BOUNDARIES The rapid expansion of online social networking sites has led to ethical challenges about protecting patient privacy and confidentiality, maintaining appropriate professional boundaries between physicians and patients, demonstrating respect for patients, and ensuring trust in physicians.32 While these technologies offer new opportunities for improving health care, they also present pitfalls that should be anticipated and preemptively avoided. This is a rapidly evolving area, and no clear consensus yet exists about appropriate versus inappropriate behavior. You should check with your hospital ethics committee to learn about your hospital’s policies regarding internet and social media use. If your hospital does not have a policy, you can learn more about the potential benefits, hazards, and recommendations around different online engagement in the American College of Physicians’ policy statement.32

REFERENCES 1. Medical professionalism in the new millennium: A physician charter. Ann Intern Med. 2002;136:243-246. 2. Pellegrino ED: Toward a virtue-based normative ethics for the health professions. Kennedy Inst Ethics J. 1995;5(3):253-277. 3. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 6th ed. Oxford: Oxford University Press; 2009. 4. Levetown M. American Academy of Pediatrics Committee on Bioethics: Communicating with children and families: from everyday interactions to skill in conveying distressing information. Pediatrics. 2008;121(5):e1441-1460. 5. Dubler NN, Liebman CB. Bioethics Mediation: A Guide to Shaping Shared Solutions. Revised and Expanded Edition. Nashville: Vanderbilt University Press; 2011. 6. American Academy of Pediatrics, Committee on Bioethics. Institutional

ethics committees. Pediatrics. 2001;107:205-209. [A statement of reaffirmation for this policy was published in Pediatrics 2009;123(5):1421]. 7. Spencer EM. A new role for institutional ethics committees: organizational ethics. J Clin Ethics. 1997;8:372-376. 8. Burns JP. From case to policy: institutional ethics at a children’s hospital. J Clin Ethics. 2000;11:175-181. 9. Shah S, Whittle A, Wilfond B, et al. How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA. 2004;291:476-482. 10. Weil E, Nelson RM, Ross LF. Are research ethics standards satisfied in pediatric journal publications? Pediatrics. 2002;110:364-370. 11. American Academy of Pediatrics, Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314-317. 12. Faden R, Beauchamp T. A History and Theory of Informed Consent. New York: Oxford University Press; 1986. 13. American Academy of Pediatrics, Committee on Pediatric Emergency Medicine. Consent for medical services for children and adolescents. Pediatrics. 1993;92:290-291. 14. Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357:1834-1840. 15. Feudtner C, Morrison W. The darkening veil of “do everything.” Arch Pediatr Adolesc Med. 2012;166(8):694-695. 16. Avery GB. Futility considerations in the neonatal intensive care unit. Semin Perinatol. 1998;22:216-222. 17. Consensus statement of the Society of Critical Care Medicine’s Ethics Committee regarding futile and other possibly inadvisable treatments. Crit Care Med. 1997;25:887-891. 18. Lantos J. When parents request seemingly futile treatment for their children. Mt Sinai J Med. 2006;73(3):587-589. 19. Schneiderman U, Jecker NS, Jonsen AR. Medical futility: response to critiques. Ann Intern Med. 1996;125:669-674.

20. Truog RD, Brett AS, Frader J. The problem with futility. N Engl J Med. 1992;326:1560-1564. 21. Nonbeneficial or futile medical treatment: conflict resolution guidelines for the San Francisco Bay area. Bay Area Network of Ethics Committees (BANEC) Nonbeneficial Treatment Working Group. West J Med. 1999;170:287-290. 22. Fins JJ, Solomon MZ. Communication in intensive care settings: the challenge of futility disputes. Crit Care Med. 2001;29(2 Suppl):N10N15. 23. Cogliano JF. The medical futility controversy: bioethical implications for the critical care nurse. Crit Care Nurs Q. 1999;22:81-88. 24. American Academy of Pediatrics, Committee on Bioethics. Religious objections to medical care. Pediatrics. 1997;99:279-281. 25. Diekema DS, American Academy of Pediatrics Committee on Bioethics. Responding to parental refusals of immunization of children. Pediatrics. 2005;115(5):1428-1431. 26. Gilmour J, Harrison C, Asadi L, Cohen MH, Vohra S. Childhood immunization: when physicians and parents disagree. Pediatrics. 2010;128(Suppl 4):S167-S174. 27. Casarett D, Kapo J, Caplan A. Appropriate use of artificial nutrition and hydration—fundamental principles and recommendations. N Engl J Med. 2005;353:2607-2612. 28. Diekema DS, Botkin JR, American Academy of Pediatrics Committee on Bioethics. Clinical Report—Forgoing medically provided nutrition and hydration in children. Pediatrics. 2009;124(2):813-822. 29. Feudtner C. Control of suffering on the slippery slope of care. Lancet. 2005;365:1284-1286. 30. American Academy of Pediatrics Committee on Bioethics and Committee on Hospital Care. Palliative care for children. Pediatrics. 2000;106(2):351-357. 31. American Academy of Pediatrics Committee on Bioethics. Professionalism in Pediatrics: Statement of Principles. Pediatrics. 2007;120(4):895-897. 32. Farnan JM, et al. Online Medical Professionalism: Patient and Public

Relationships: Policy Statement From the American College of Physicians and the Federation of State Medical Boards. Ann Intern Med. 2013;158:620-627.

CHAPTER

13

Medicolegal Issues in Pediatric Hospital Medicine Steven M. Selbst and Joel B. Korin

INTRODUCTION Legal risks are common in the care of hospitalized children. Pediatric hospitalists care for complex patients of all ages with a variety of medical conditions.1 Many are acutely ill with rapidly changing medical conditions. Hospitalists often find themselves juggling several ill patients simultaneously, and they must make critical decisions rapidly. The risk for error is high, and there is the possibility of a subsequent malpractice suit. In addition, certain hospital processes and situations pose a particular risk for lawsuits, including communication, informed consent, refusal of care, documentation, altering the medical record, use of consultants, treatment of incidental findings, patient confidentiality, and legal responsibility during discharge. The legal obligations surrounding each of these situations are described in this chapter. The hospitalist movement is relatively new, and little information has been generated regarding claims against these specialists. In general, pediatricians are less likely to be sued than other specialists, but they have the highest average indemnity payments ($521,000/claim) of all specialties.2 Evidence suggests that hospitalists reduce malpractice claims in the inpatient setting by improving quality of care and patient and parent satisfaction.3,4 In addition to improved quality of care, hospitalists have demonstrated enhanced efficiency.5 They often become team leaders in their hospitals, attempting to optimize quality and continuity while delivering evidencebased care for acutely ill patients.6,7 Hospitalists’ presence in the hospital enables the discovery and demonstration of best practices in detecting errors.5 Tenner’s retrospective study found that the quality of care of critically ill patients improved after

hours, when more experienced physicians provided care at the bedside; more specifically, patients cared for by pediatric hospitalists (general pediatricians who had completed training) had improved survival rates compared with patients cared for by pediatric residents who were supervised from a distance by intensivists.8 Thus, the use of hospitalists may lead to safe care, fewer adverse outcomes, and fewer malpractice suits. Like all physicians, hospitalists may face legal action when pediatric patients in their care have bad outcomes. When a lawsuit is instituted, the plaintiff must show that the physician had a duty to the patient, breached that duty, and did not meet the standard of care. The plaintiff must then show that this breach caused damage or injury to the patient.9

COMMUNICATION Good communication between the hospitalist and the patient and family is essential to prevent lawsuits. Poor communication can lead to angry feelings, omission or distortion of important information, and subsequent injury to the patient. Effective communication between the primary care physician (PCP) and the hospitalist is also crucial.10 One study showed a direct relationship between physicians’ enhanced communication skills and fewer malpractice suits.11 Another study of families that sued physicians (after infants suffered permanent injury or death) found that most were dissatisfied with physician-patient communication. They believed that the physicians would not listen to them (13%), would not talk openly (32%), attempted to mislead them (48%), or did not warn them about long-term neurodevelopmental problems (70%).12 The patient and family must perceive a caring attitude, openness, professional integrity, and standards of excellence; a sense of trust is also crucial. Patients are not always aware of the physician’s competence, but they are keenly aware of his or her manner. They remember how the physician looked, acted, spoke, and listened; whether he or she was neatly dressed; and whether the physician was pleasant or disinterested, serious or cavalier, haughty or condescending, polite or discourteous. Good eye contact and body language are important.13 No matter how tired, frustrated, or stressed the hospitalist feels, this should not be communicated to the family. Establishing good rapport with the family can sometimes be difficult, but it is essential.

The hospitalist should try to appear unhurried and ready to listen. An adverse outcome—even if inevitable—coupled with the parents’ feeling that the physician was rushed or was not sincerely interested in the child may provoke a lawsuit. Thus, when meeting with families, it is advisable to introduce oneself, shake hands, and sit down in the examination room. This gives the parents the message that, at least for the next few minutes, they have your undivided attention, no matter how many other children are in the hospital. Studies have shown that if the physician sits down in the presence of the patient, the perception of the time spent with the patient is doubled.14,15 The hospitalist must also establish rapport with the child. Avoid casual teasing, condescension, and talking about the child without attempting to include him or her in the discussion. Be careful not to violate modesty in school-age children. Speak at an age-appropriate level, and remember that even young children understand far more than they say. Try to be flexible, but do not offer choices when none exist.9 Keep the family informed about necessary procedures, suspected diagnoses, and the child’s overall progress. In addition, help the family understand the makeup of the health care team that is caring for the child. This is especially important in a teaching hospital, where residents, fellows, consulting physicians, and several nurses may participate in patient care. A recent American Academy of Pediatrics (AAP) policy statement recommends that providers conduct rounds in patients’ rooms, with family members present.16,17 This enhances communication and may reduce errors.17 At times, parents might insist on obtaining certain laboratory tests that the medical team believes to be unnecessary. The medical staff must then calmly and skillfully explain why such tests may not be needed. This need not become a point of contention if the parents recognize the physician’s sincere interest in the child. One study showed that patient satisfaction with care was related not to whether patients got antibiotics for respiratory infections but rather to their perception of the amount of time the physician spent explaining the illness and their understanding of the treatment.18 Discuss questions about pain management and convince the parents that everything possible is being done to relieve their child’s pain. Encourage parents to stay with their child for procedures whenever possible. Many parents can nurture the child through a painful procedure if they know what to expect.9,19 Take care when discussing the patient’s management with other staff

members in front of the family. Parents should not witness disagreements over plans for management, such as might occur if one staff member suggests ordering a specific laboratory test and the hospitalist disagrees. Likewise, it is not appropriate to reprimand or correct a nurse or physician-in-training in view of the family. This would undoubtedly create a feeling of uneasiness. In some cases, communication with a parent is particularly difficult. For example, parental anger can be predicted when they are informed that a report for suspected child abuse is being filed. Remain nonjudgmental in these circumstances. Tell the family that the physician is required by law to file such a report and that the medical staff is not accusing anyone of abuse.9 Finally, if a harmful medical error is made, explain to the family what has happened. It is best to be honest with parents about the mistake. If an error is merely suspected, do not admit negligence but rather explain that all will be done to investigate the situation and improve results.20 Lawsuits may be avoided if the physician is honest and forthright. As in politics, an attempted “cover-up” makes the situation worse. In all cases, follow hospital policies for disclosure of a medical error.

INFORMED DECISION-MAKING (INFORMED CONSENT) Parents have the right to be informed about their child’s medical care and to give consent for treatment. Parental rights are limited, however. For instance, adults can refuse treatment—even life-sustaining treatment—for themselves, but not for their children. Parents must act responsibly and in their child’s best interests. If they are neglectful or abusive, the courts can relieve them of decision-making and, if necessary, custody.21 Most states define informed consent as providing a description of the procedure or treatment and the risks and alternatives in such a way that a reasonably prudent person would be able to make an informed decision whether to undergo that procedure or treatment. Patients and parents are entitled to know the diagnosis, the nature and purpose of the proposed treatment or procedure, the risks, consequences, and side effects of the proposed procedure, reasonably available alternatives and their risks, and the anticipated prognosis without treatment. Be sure that the patient or parent understands the information given.21,22

In a true emergency, informed consent is not needed. When a hospitalist provides care in the emergency department, the legal guardian may not even be present. For an unconscious or severely injured child, no consent for treatment is necessary because it is assumed that a reasonable parent would want the physician to care for the child immediately. If it is not clear that a true emergency exists, it is generally best to treat the patient and get consent later.21 A physician is more likely to be sued for failure to treat without consent than for providing reasonable treatment without the guardian’s knowledge or approval. However, do not give a blood transfusion to a reasonably stable child or intravenous contrast material for a computed tomography scan if the risks and benefits have not been explained to the parents. It is conceivable that a patient could suffer a reaction to these procedures, and the guardian may sue the physician for failing to inform him or her of the risks involved.9 No patient or parent should be forced or influenced to make a specific decision; however, no decision by a parent is completely free of outside influences. Most parents need and want the physician’s opinion to help them decide what is best for their child. Finally, the physician has an ethical obligation to try to inform a minor child about the proposed treatment, to describe what he or she is likely to experience, and to get his or her assent to care, if possible.21,22 Consent forms are widely used at most hospitals and should be written at an appropriate level for most patients or parents (generally, a sixth- to eighthgrade reading level).21 Give parents the opportunity to ask questions after reading the form. Take language barriers into consideration. Parents usually sign a general consent form at the time of presentation to the hospital that allows for a general evaluation and treatment of the child. However, parental signing of such a form does not equate with informed consent. The patient or parent can still claim that the risks and benefits were not adequately explained.9,22 Patients and parents may not recall what was told to them when they were emotionally stressed. A signed consent form may provide some legal protection for the physician, because it documents that steps were taken to inform the parent about a procedure. However, a signed form is of little value unless a discussion about risks and benefits took place.22 Clear documentation in the record, noting what was explained to the parent, may be just as valuable as a signed consent form. Remember, informed consent is a process, not a paper. Table 13-1 summarizes procedures for assisting parents

with informed decision making. TABLE 13-1

Responsibilities for Informed DecisionMaking (Informed Consent)

Assess the patient’s or guardian’s decision-making capacity Provide the patient and guardian with appropriate information Diagnosis Nature of procedure or intervention Purpose of procedure or treatment Risks and benefits of procedure or treatment Alternative treatments and associated risks and benefits Prognosis with and without treatment Assess the patient’s or guardian’s comprehension of the discussion Ensure that the decision is made freely, not coerced After the discussion, obtain signed consent

REFUSAL OF CARE Despite all efforts, some patients or parents refuse treatment or leave the hospital against medical advice (AMA). This usually occurs when the patient or parent is angry, afraid, or disoriented or has certain religious beliefs. Emancipated minors and parents generally have the right to refuse treatment for themselves or their child. However, when a patient or family leaves the hospital without a full evaluation and complete treatment, everyone involved may suffer. The child may have persistent or worsening symptoms from a medical problem that has not been addressed. Likewise, the physician usually feels a sense of failure and frustration when advice and recommendations are not heeded. The hospital and physicians may be subjected to a lawsuit if the patient later suffers serious morbidity or dies, even if the family left voluntarily or signed out AMA. Therefore, the goal should always be to keep the child and family from leaving prematurely.9,23

UNDERSTANDING THE PATIENT

Some patients or parents wish to leave the hospital because they are angry about a long wait for medical treatment. Some may fear a prolonged or expensive hospitalization, or they anticipate unnecessary and painful procedures for their child. Others are afraid to learn of a serious diagnosis or are anxious about children left at home. Those who do not speak English may be especially frightened. Still others may fear teaching institutions in particular because they believe that students or residents “practice” on patients.9 Understandably, families may be less trusting of a hospitalist physician with whom they are not familiar.

PROVIDING TREATMENT If a true emergency exists, provide prompt medical intervention even over parental objections.21,24 It is extremely unlikely that the physician will be successfully sued for intervening and delivering care to a child in an emergency situation.22 In fact, the legal risk is much greater if emergency care is not given. Try to learn why the patient or family wishes to leave the hospital. If the patient or parent seems angry, allow him or her to express concerns without interruption. Remain courteous, concerned, and flexible in the treatment plan. It is never wise to challenge patients to sign out AMA, and they should not be threatened with a call to security officers. Call security only if necessary to maintain order.9 A social services worker may be extremely helpful in difficult cases. Further, a telephone call to a familiar PCP may allay the parent’s fears and convince the family to follow the proposed treatment. If a language barrier is a factor, provide a competent translator. Be sure the parents understand the risks and benefits of treatment and the risks of refusing treatment. Allow the patient and family to consider options in a low-pressure atmosphere so that they can make a rational decision.

DOCUMENTING EVENTS If a parent still wishes to leave the hospital despite all efforts to reach an agreement, ask the guardian or emancipated minor to sign a statement releasing the doctor and the hospital from all liability. Such statements may

have limited usefulness, because parents can later claim that they did not fully understand the risks involved in leaving AMA. However, a signed statement witnessed by one or two staff members may shift some responsibility to the parents in the event of an adverse outcome.9 Document in the hospital records exactly what was done for the child and what was told to the parents. Specifically, if the child was examined, record the findings and impression of the limited evaluation and what tests or treatment was contemplated. Also, document the parents’ reason for leaving AMA, as well as the risks of refusing treatment as they were explained to the parents. Tell parents (and document) that they can always return to the hospital for reevaluation if they change their minds or if the child’s condition worsens. It may be helpful to volunteer the names of alternative hospitals and doctors and to offer to arrange transportation, if feasible. This shows a sincere interest in the patient and may prevent litigation. Finally, if a parent refuses to officially sign out AMA before leaving the hospital, carefully document this, with a witness, in the medical record.9 In some situations, the patient cannot be permitted to leave the hospital under any circumstances. If the guardian is disoriented or intoxicated and cannot understand the risks and benefits of treatment or the consequences of refusing care, do not allow the patient to leave. A life-threatening medical problem also mandates immediate medical care. It is always better to win the cooperation of the parents, but if they refuse, the staff is justified in treating the child. Report the refusal to the proper authorities as medical neglect, and seek a court order while delivering emergency care. If it is unclear whether a life-threatening situation is present, err on the side of treatment.9,21,24 Similarly, in a case of suspected child abuse in which the perpetrator is unknown, do not release the child, despite the parents’ wishes or protests. In this situation, call the security staff to prevent the parents from removing the child from the hospital. The staff must contact the hospital lawyers, administrators, or a judge on emergency call to seek a verbal temporary restraining order. Record the conversation with the judge in the patient’s chart, including the specific actions authorized. The procedure to obtain court permission to treat a child may vary in different locales, and the hospitalist should be familiar with local and hospital policies.9

SPECIAL CASES HIV Testing Testing a pediatric patient for human immunodeficiency virus (HIV) is an important issue. HIV testing without a patient’s (or guardian’s) consent is illegal in almost every state. Occasionally, a staff member may unintentionally injure himself or herself with a needle stick and then request HIV testing of the patient. Follow the specific hospital policy for this event carefully. Lumbar Puncture Lumbar punctures arouse fear and concern among parents. Many parents have misperceptions about the procedure and an unwarranted fear of complications. Inform parents about the need to do this procedure—for instance, that a lumbar puncture is necessary to determine if a serious disease such as meningitis is present—and that there is no adequate alternative to establish the diagnosis. Inform them about the most common complications, such as local pain. Tell them that serious complications, such as apnea in a small infant who is curled for the procedure, are quite rare. There is no need to discuss possible herniation, because this is extremely rare when signs of increased intracranial pressure are absent. If such signs exist, withhold the procedure. If a parent refuses the lumbar puncture, the hospitalist may choose to treat the child for possible meningitis without doing the procedure. Tell parents of the inherent problems with this alternative plan, and pursue permission for the lumbar puncture after treatment is started.9 Blood Transfusions and Jehovah’s Witnesses If a parent refuses a blood transfusion because of religious beliefs, obtain legal counsel when time permits. A court order may be necessary. If the child’s life or health is in danger, nearly every state allows the physician to override the parents’ religious beliefs. Even for an older child or adolescent who holds the same beliefs, it is unlikely that the courts will uphold the minor’s right to refuse treatment if doing so means risking death.25 Still, it is best to avoid court action or coercing a teenager to accept treatment that is unwanted. Try to settle the affair with the patient and family whenever possible. Discuss the use of blood substitutes if time allows and if this is acceptable to the physician. If the patient is in shock and unable to consent, give blood as deemed necessary. A transfusion can also be authorized over a teenager’s objection if there is a question about the patient’s competency or if the state

can demonstrate an overriding interest.22

DOCUMENTATION—THE MEDICAL RECORD The importance of careful documentation cannot be overemphasized. Good documentation prevents lawsuits. The patient’s chart is almost always the first document reviewed by parents, attorneys, and their consulting physicians. A record that demonstrates a thorough examination and testing may convince the plaintiff’s attorney not to proceed further. A record that does not demonstrate conclusively whether an important test or portion of the examination was negative or positive may lead counsel to assume that it was not done. The record can also influence expert witnesses who will advise the attorneys whether the case has merit and should be pursued. Because one can never truly predict which patient will have a bad outcome and end up in litigation, prepare each chart carefully.9 Because of the extended statute of limitations for children, many years may pass before a physician is advised of malpractice litigation. The hospitalist often has little if any recollection of the treatment rendered without referring to the medical record. This document can prove to be the physician’s friend or foe, depending on how well it was prepared at the time of treatment. Many settlements have been offered even when good medical care was rendered but not substantiated in the medical records.9,26 The history of the present illness must be described completely but concisely. Even though there may be limited time for recording information, a note that is very brief and barely legible may convey a sense of carelessness and haste to a jury.26 Note any information that seems relevant to the chief complaint. Also record details about the child’s recent diet, level of activity, and medications given at home. Include a history of immunizations, allergies to any medications and underlying medical problems for every pediatric patient. Also, known exposure to infection may be important in many cases. For an adolescent girl, document the last menstrual period. For an injured child, describe how the injury occurred and whether the history is consistent with the physical examination. Note whether there is a concern about child abuse, as well as a decision to file a report with authorities.9 Record a thorough physical examination for each child, including a

complete, timed set of vital signs. Repeat abnormal vital sign. Make a note if the blood pressure or pulse is abnormal because the child is crying. Give particular emphasis to the child’s general appearance, state of hydration, and level of activity or playfulness. Be as descriptive as possible. For instance, “alert, interactive, playing with toys on mother’s lap” graphically depicts the general appearance of an infant. Rather than “irritable baby,” it is better to note “baby cries when approached but is easily consoled by mother.” For a febrile child or a complicated case, the chart should convincingly reflect that the child was well appearing at the time of discharge. In the emergency department, this may require that a second note, or progress note, be included in the chart. For an injured child, it may be best to use a picture or diagram to describe the trauma in detail.9,26 The medical record must reflect a timely process. All entries, including diagnostic or therapeutic orders, must be clearly written and the exact time of the entry noted. Likewise, date and time telephone conversations with consultants. For example, in the event of delayed surgery, recording the time when a consultant was called and when he or she arrived can prove useful years later when litigation begins. Document all laboratory test results or reports of procedures performed.26 The medical record must also include the physician’s clinical observations of the patient and the diagnostic impression formulated. Documenting one’s thought process can be helpful, especially if the case is complicated. For instance, if the physician initially orders laboratory tests and later cancels them, justify the reasons for this change in the management plan in the medical records (e.g. “child improved, drinking well, no need for spinal tap”).9,26 It is important that the hospitalist’s final disposition be reasonable and based on the history, physical examination, test results, and impression. For instance, if the final diagnosis is gastroenteritis, discharge the child only if the record reflects that he or she is well hydrated. The medical record should provide meaningful information to another practitioner if additional care is needed at a later time. It should also display a concerned, professional attitude toward the child and family. Although some charts use a checklist system in an effort to save time, always add pertinent positive and negative findings on the physical examination. For instance, in the evaluation of the skin of a febrile child, comments such as “no petechiae

or purpura” may be quite important. A chart in which the entire examination is merely checked off as “normal” will not convince a jury that a careful examination was performed. Do not include parts of the examination that were not done. For instance, the rectal examination should not be checked off as normal if no such examination was performed. This will damage the physician’s credibility and make a jury doubt that other parts of the examination were truly performed.9,26 The medical record will be made public if a lawsuit is filed. Therefore, only comments that one would be proud to read in front of a jury should be included. Illegible records can compromise the quality of care and make the hospitalist appear unprofessional. Fortunately, electronic medical records have reduced the likelihood of illegible records. Do not place insensitive terms in the record. A medical term such as “dysmorphic child” serves all parties better than “FLK” (funny looking kid). Avoid derogatory statements or descriptions of the parents as well. If the parents are angry during the evaluation, the note may reflect this; for example, “mother became upset during the exam and her concerns were addressed.” However, do not add any judgmental statements.9,23,26 If a patient returns to the hospital after a prior admission or emergency department visit, note the earlier treatment but avoid terminology that suggests that the initial care given was incomplete or careless. It is also advisable to avoid self-serving statements in the record that appear defensive. The purpose of the record is primarily to take care of the patient, and it should not look like it was written for legal defense purposes. The physician’s notes should be consistent with the nursing notes and those of any other disciplines. The hospitalist must read and acknowledge the nursing notes. If a physician disagrees with the nursing assessment (e.g. does not believe that a baby is lethargic), emphasize this in a non-combative manner in the record. It is important that nurses, physicians, consultants, and other members of the medical staff do not engage in intramural battles on the record. Settle disagreements before the patient goes home, and have the record reflect agreement among caretakers whenever possible. Do not write inflammatory remarks and omit extensive discussions about the frustrations of patient care from the record. When a child’s care is transferred to another physician, such as at a change of shift, the physician coming on duty can write a brief note to document the patient’s condition at that time. Document all procedures in a

detailed note, including how the child tolerated the procedure. Include brief descriptions of any conversations with the family and those with the PCP. Use abbreviations sparingly, and use only standard ones accepted by the medical records department of the hospital. Electronic health record systems are commonly used in hospitals across the United States. Electronic medical records may reduce medical errors and malpractice lawsuits. A study of office-based physicians showed that users of electronic health records were less likely to pay malpractice claims (over 10 years) than non-users (6.1% vs. 10.8%), but the difference was not statistically significant.27 However, electronic medical records are not without risk.28 Errors may occur when using drop-down lists in a hurry.29 Also, quickly clicking through a template without noticing that the language is inappropriate for a particular patient could compromise a physician’s defense in a malpractice suit.30 Furthermore, the temptation to copy and paste patient histories instead of taking new histories risks missing new information and perpetuates previous errors.28

ALTERING THE MEDICAL RECORD Correct written errors in a patient’s chart appropriately. Do not attempt to cover up mistakes by blacking out words or phrases, which tends to arouse suspicion. For hand-written notes, draw a single line drawn through the error, then initial and date it. Never attempt to “enhance” the medical record after the case is involved in litigation. It is likely that any change made to the record will be discovered and will be seen as a deliberate and dishonest cover-up. Especially for electronic medical records, it is easy to determine when a late entry into the chart was made. In general, it is easier to defend missing facts or a poor record than an altered one. Credibility is a key factor in any litigation, and an altered record frequently destroys the physician’s credibility.26 When there is a need to add clinical information after an untoward event occurs, it is best to do so in a confidential letter to the physician’s attorney rather than adding to the chart. Besides resulting in the loss of a lawsuit, tampering with the record can result in the award of “punitive damages,” intended to punish the physician for attempting to mislead the court. Some malpractice policies deny coverage

if it is determined that medical records were altered. In some states, altering medical records can be considered a criminal offense in certain circumstances. Finally, any attempt to destroy or “lose” the medical records will seriously hurt the physician’s ability to defend against the litigation.

CONSULTANTS No physician in the hospital works in isolation. There is often a need to consult with the PCP, critical care specialists, surgeons, and other physicians while caring for ill children. The hospitalist should call for help whenever he or she believes that the care required is beyond his or her expertise or when it appears that another opinion will be helpful. Failure to consult appropriately and in a timely manner can result in a lawsuit should there be a poor outcome.31 The hospitalist should generally complete a history and physical examination and obtain appropriate laboratory studies to ensure appropriate referral and avoid unnecessary consultation. However, if there is a true emergency, such as a surgical abdomen or testicular torsion, do not delay consultation by waiting for a urinalysis, Doppler studies, or other tests that may postpone definitive care.32 If the consultant does not arrive in a timely manner, consider calling the consultant’s supervisor, asking other sources for help, or transferring the child to another institution.31 Document the time the specialist was called, the time he or she arrived, and, if applicable, the time the consultant assumed care of the patient. The hospitalist is also responsible for making sure that the consultant is competent for the case in question. If appropriate consultation is not available, arrange safe transport of the child to another facility after discussion with the parents. If the hospitalist believes that consultation is warranted, do not be dissuaded by the PCP. Consider the opinion of the PCP advisory only. Further, if the family insists on consultation or a second opinion (e.g. a plastic surgeon to suture a facial laceration), it is wise to comply if the request is reasonable.33 Radiology consultation ensures proper reading of a film. The hospitalist may be found liable for misreading a child’s radiograph if a radiologist was available. The hospitalist will not be held to the same standard as a radiologist, but rather whatever expertise the jury believes the hospitalist

should possess.9,26

COMMUNICATION WITH THE CONSULTANT Good communication with the consultant is essential. Give appropriate information to the consultant and make certain that the specialist understands the reason for consultation or the question that needs to be addressed. The consultant should discuss his or her findings with the hospitalist, and the two should decide who will relay the information to the parents. Consultants should write complete notes and list clear reasons for their recommendations. For radiology consultations in particular, it is important to have a system in place so that reports of reread radiographs reach the hospitalist, especially any opinion that differs from that of the hospitalist. Telephone consultations without direct examination by the consultant pose a risk for both the consultant and the hospitalist. It is always possible that incomplete information will be provided to the consultant, resulting in incorrect advice. In general, the hospitalist should not allow the specialist to dictate care by phone or deem that consultation is unnecessary if the hospitalist is uncomfortable. If only phone advice is sought, record the gist of the conversation in the patient’s chart.32 Some hospitals allow consultants to write orders for the patient, whereas others request that specialists only give suggestions to the hospitalist. It should be clear to all parties who is placing the orders so that there is no confusion or omission of desired treatment. With most consultations, the hospitalist remains responsible for the patient. If care is to be formally transferred to a consultant who evaluates a child, document the time of transfer.

DISAGREEMENTS WITH CONSULTANTS Understandably, there are occasional disagreements about patient management. Do not take these lightly, because both physicians may be held responsible for a patient’s poor outcome. The hospitalist is not legally bound to accept the advice of a consultant. Blind acceptance of the consultant’s advice can leave the hospitalist liable if the child suffers.33 However, it is not advisable to reject the advice of a specialist without careful consideration of

the consequences. If there is a poor outcome, the consultant’s views as a specialist will be given great weight in court.31 If there are questions about care, discuss the case personally with the consultant. If the consultant’s recommendations are not followed, document why suggested studies were not obtained.31 Do not discuss disputes about care in front of the patient or family. Instead, try to resolve these disagreements amicably, away from the patient. If resolution cannot be reached, it may be appropriate to tell the family in a nonjudgmental way about the difference in opinion.32,33 If the family accepts the opinion of the consultant rather than the hospitalist, note this in the record, and transfer care to the consultant. Ideally, actions should be guided by hospital conflict resolution policies. Cordial, honest dialogue ensures a good outcome. If the hospitalist evaluates a child in the emergency department and believes that admission to the hospital is warranted, and the consultant disagrees, the specialist must come to the emergency department to evaluate the child. Responsibility for the disposition may still rest with the hospitalist, but there will probably be shared responsibility if both have evaluated the child.

TREATMENT OF INCIDENTAL FINDINGS Often a child is admitted to the hospital to manage a specific condition, and during the course of treatment another problem is identified. Whether the hospitalist is responsible for the workup of incidental findings (e.g. hypertension, scoliosis) is unclear.34,35 It depends somewhat on common practice in the particular area. Hospitalists may be held to the same standard as other pediatricians who discover an unexpected finding during an inpatient stay. It is in everyone’s best interest for the hospitalist to clarify who will manage the new incidental finding and whether it needs to be completed in an inpatient or ambulatory setting. If a patient or the family prefers an inpatient workup and it can be expeditiously and safely performed, it is reasonable for a hospitalist to pursue it. Regardless, inform the patient/parents of the findings and the need for follow-up. Document this conversation.

CONFIDENTIALITY

It is extremely important for the hospitalist to maintain patient confidentiality. Patients have filed many lawsuits because of breach of confidential information. Adolescent patients are particularly sensitive about confidentiality. Older adolescents (15–19 years old) might avoid health care in order to prevent parents from finding out confidential medical information.36 Patient privacy is governed by federal, state, and local laws, and the privacy of patient information has changed extensively with the implementation of the Health Insurance Portability and Accountability Act (HIPAA). Medical notes and patient-identifiable data are confidential and cannot be communicated to any third party without the patient’s or parent’s written consent. When conversing about a patient, pay attention to who is nearby and may overhear the conversation. Securely protect test results and other confidential information throughout the hospital. Be cautious when using a computer monitor that does not have a privacy screen.37 E-mail has become important in the practice of medicine. However, e-mail can result in a breach of privacy if the message is inadvertently sent to the wrong person or left unattended on a computer screen, where it can be viewed by another party.37 E-mail is discoverable in legal proceedings. Electronic medical records have the capacity to improve quality of care by compiling and centralizing all pertinent information related to the pediatric patient. The electronic medical records system must protect the privacy of patients’ health information by restricting access according to local and federal laws and policies.37 Electronic health record systems should also have the ability to protect adolescent privacy and prevent inadvertent disclosure through billing activities.38

DISCHARGE FROM THE HOSPITAL At the time of discharge from the hospital or from the emergency department, review the child’s problems and treatment and give directions for ongoing therapy. Write down the diagnosis, give written discharge instructions, and review these carefully with the guardian and the patient if he or she is old enough to understand.29 Nonspecific instructions to “give fluids” or “return as needed” are not helpful. Avoid abbreviations that may not be familiar to the parents or patient. Give clear instructions about medication regimens, use of inhalers, and how to taper steroids. Always include in the instructions a

few examples of worrisome signs to look for at home. Although it is not feasible to list every possible complication, the parents must have a general idea of when to visit the PCP and what warrants an immediate return to the emergency department. If no radiologist is available in the hospital during off-hours, tell the family that the hospitalist’s reading of the radiographs is preliminary and that the films will be reviewed by a radiologist and the family notified of any change in interpretation.9,29 This strategy may prevent anger or the feeling of poor care if they are called back for additional treatment or referral. Some authorities recommend that the parents read back the instructions to the physician to indicate that they can comprehend the treatment plan.29 Engel et al. found that many patients discharged from an emergency department do not understand their care or the discharge instructions.39 Of course, the physician must be sure that the parents understand English. Contact translators or translation services before the patient leaves the hospital whenever there is reason to believe that the family does not understand the instructions.9 Computer-generated discharge instructions, commonly used by many hospitals, are advantageous because they are legible and readable if designed at an appropriate reading level. Most can be personalized and edited. Many have the capability to produce the instructions in a foreign language or with large print for the visually impaired. They can be programmed to print disclaimers about final readings of radiographs and electrocardiograms, which many physicians may neglect to do if handwriting is required. An exit interview, during which important information is reviewed with the guardians, also improves their retention of discharge information. Return visits to the emergency department can be avoided with careful discharge instructions, including written material that is geared to the reading level of the patient.29 In all cases, ask the family to sign that they have received and understand the discharge instructions.26 A copy must become part of the medical record, because the physician will not remember what was discussed with the family years later. Good discharge instructions may prevent litigation or at least affect negotiations and damages in the event of a lawsuit.26,29 At the time of discharge, ask the guardians if they have any questions.

Likewise, investigate potential social problems, such as inability to obtain medications, need for transportation home, inability to be seen by the PCP, or other factors that may interfere with the care of the child. This must be done in a caring, non-obtrusive manner. The hospitalist has an obligation to protect the child if he or she is discharged on medications with potentially serious side effects. For example, if a teenager is discharged on a sedative medication or has an unusual condition that may predispose him or her to seizures or syncope, advise the patient not to drive.9 Table 13-2 lists responsibilities of the hospitalist at the time of patient discharge from the hospital. TABLE 13-2

Hospitalist Responsibilities when Discharging a Pediatric Patient

Give written instructions and review them verbally with the parent or guardian List medications and treatments clearly Ensure that the patient or parent understands discharge instructions and the importance of keeping appointments Have the parent sign a form indicating that he or she received the instructions and understands them Specify an interim plan if the patient becomes ill before the scheduled appointment with the PCP Be specific and clear about when to see the PCP and when to return to the emergency department or hospital Arrange appropriate follow-up care Communicate with the PCP Be certain that the discharge summary and important documents reach the PCP Develop a system to review and forward incoming results and reread radiographs after patient discharge PCP, primary care provider.

FOLLOW-UP CARE

One particular area of risk involves follow-up care for patients who were treated by the hospitalist. The duty to provide follow-up care is shared by the hospitalist and the PCP.34,35 The inpatient team is responsible for evaluating whether the outpatient treatment plan is feasible for the child’s family and modifying the plan if needed.34,35 The hospitalist has a duty to provide instructions to patients and parents regarding follow-up care. Some patients may have trouble getting medications prescribed or could develop new symptoms after discharge. In such cases, the patient needs to know who to call in the interim.35 If the patient calls the hospitalist about a change in condition, forward this information to the PCP. Counsel patients about the risks of failing to receive ongoing care, and ensure that the PCP has enough information about the hospitalization to provide high-quality care when the patient arrives for follow-up.34,35 Despite everyone’s best intentions, things can be overlooked during the transition from the hospital to the outpatient setting.35 Hospitalists may be held liable for failing to inform patients and the PCP of laboratory studies or test results that are received after discharge. The AAP has recently published guidelines for the role of each physician involved in the care of a hospitalized child. The AAP believes that if not directly involved in the hospital care, the PCP should be notified at the time of discharge.40 For a successful transition from the hospital to primary care, communication between hospitalists and PCPs must be consistent, timely, and informative.40,41 Ensure that relevant information, including the discharge summary, gets to the PCP. Timely dictation services are needed to forward complete and legible records. The PCP has a legal obligation to ensure follow-up once the hospitalist has communicated with him or her and an appointment has been scheduled. Be careful of weekends and holidays. For example, telling patients to follow up with the PCP in 2 days on December 23 would be worthless. There may be differences in expectations surrounding the timing and format of communication between inpatient and outpatient healthcare providers, who is responsible for managing clinical concerns immediately after discharge, and who should follow up any pending studies that remain at the time of discharge. These potential differences of opinion can lead to negative patient outcomes if they are not reconciled between healthcare providers.10

CONCLUSION Hospitalists have many medicolegal obligations in the care of hospitalized children. The risk of lawsuits can be greatly reduced through an understanding of these risks, good communication and documentation, and attention to the needs and wishes of patients and their families.

REFERENCES 1. Simon TD, Mahant S, Cohen E. Pediatric hospital medicine and children with medical complexity: Past, present, and future. Curr Probl Pediatr Adolesc Health Care. 2012;42(5):113-119. 2. Jenna AB, Seabury S, Lakdawalla D, et al. Malpractice risk according to physician specialty. N Engl J Med. 2011;365:629-636. 3. Narang AS, Ey J. The emerging role of the pediatric hospitalist. Clin Pediatr. 2003;42:295-297. 4. Wachter RM, Goldman L. The hospitalist movement 5 years later. JAMA. 2002;287:487-494. 5. Landrigan CP, Conway PH, Edwards S, Srivastava R. Pediatric hospitalists: A systematic review of the literature. Pediatrics. 2006;117(5):1736-1744. 6. Landrigan, CP Srivastava, R. Pediatric hospitalists: Coming of age in 2012. Arch Pediatr Adolesc Med. 2012;166(8):696-699. 7. Mussman GM, Conway PH. Pediatric hospitalist systems versus traditional models of care: Effect on quality and cost outcomes. J Hosp Med. 2012;7(4):350-357. 8. Tenner PA, Dibrell H, Taylor RP. Improved survival with hospitalists in a pediatric intensive care unit. Crit Care Med. 2003;31:847-852. 9. Selbst SM, Korin JB. Preventing Malpractice Lawsuits in Pediatric Emergency Medicine. Dallas, TX: American College of Emergency Physicians; 1999. 10. Ruth JL, Geskey JM, Shaffer ML, Bramley HP, Paul IM. Evaluating communication between pediatric primary care physicians and hospitalists. Clin Pediatr. 2011;50(10):923-928.

11. Adamson TE, Schann JM, Guillan DS, et al. Physician communication skills and malpractice claims: A complex relationship. West J Med. 1989;150:356-360. 12. Hickson GB, Clayton EW, Githens PB, et al. Factors that prompted families to file malpractice claims following perinatal injuries. JAMA. 1992;267:1359-1363. 13. Lester GW, Smith SG. Listening and talking to patients: A remedy for malpractice suits? West J Med. 1993;158:268-272. 14. Little NE. Image of the emergency physician. In Henry GL, Sullivan DJ eds. Emergency Medicine Risk Management: A Comprehensive Review. 2nd ed. Dallas, TX: American College of Emergency Physicians; 1997:9-13. 15. Barnett PB. Rapport and the hospitalist. Am J Med. 2001;111:31S-35S. 16. American Academy of Pediatrics, Committee on Hospital Care. Familycentered care and the pediatrician’s role. Pediatrics. 2003;112(3):691696. 17. Mittal VS, Sigrest T, Ottolini MC, Rauch D, Lin H, Kit B, Landrigan CP, Flores G. Family-centered rounds on pediatric wards: A PRIS network survey of US and Canadian hospitalists. Pediatrics. 2010;126(1):37-43. 18. Hamm RM. Antibiotics and respiratory infections: Are patients more satisfied when expectations are met? J Fam Pract. 1996;43:56. 19. Sachetti A, Guzzetta C, Harris R. Family member presence during resuscitation attempts and invasive procedures: Is there science behind the emotion? Clin Pediatr Emerg Med. 2004;4:292-296. 20. Loren DJ, Klein EJ, Garbutt J, et al. Medical error disclosure among pediatricians. Arch Pediatr Adolesc Med. 2008;163:922-927. 21. American Academy of Pediatrics, Committee on Pediatric Emergency Medicine and Committee on Bioethics. Consent for emergency services for children and adolescents. Pediatrics. 2011;128:427-433. 22. Kassutto Z, Vaught W. Informed decision making and refusal of treatment. Clin Pediatr Emerg Med. 2003;4:285-291. 23. McDonnell WM. Pediatric emergency medicine. In Donn SM, McAbee GN eds. Medicolegal Issues in Pediatrics. 7th ed. Elk Grove Village, IL:

American Academy of Pediatrics; 2012:141-152. 24. Diekema DS. Parental refusals of medical treatment: The harm principle as threshold for state intervention. Theor Med Bioth. 2004;25:243-264. 25. Sheldon M. Ethical issues in the forced transfusion of Jehovah’s Witness children. J Emerg Med. 1996;14:251-257. 26. Selbst SM, Korin JB. Malpractice and emergency care: Doing right by the patient—and yourself. Contemp Pediatr. 2000:17:88-106. 27. Virapongse A, Bates DW, Shi D, et al. Electronic health records and malpractice claims in office practice. Arch Intern Med. 2008;168:23622367. 28. Mangalmurti SS, Murtagh L, Mello MM. Medical malpractice liability in the age of electronic health records. N Engl J Med. 2010;363:20602067. 29. Yu KT, Green RA. Critical aspects of emergency department documentation and communication. Emerg Med Clin North Am. 2009;27:641-654. 30. AAP Department of Practice. Jury still out on whether EHRs reduce malpractice risk. AAP News. 2010;Feb:17. 31. Wilde JA, Pedroni AT. The do’s and don’ts of consultations. Contemp Pediatr. 1991;8:23-28. 32. Holliman CJ. The art of dealing with consultants. J Emerg Med. 1993;11:633-640. 33. O’Riordan WD. Consultations. In Henry GL, Sullivan DJ eds. Emergency Medicine Risk Management: A Comprehensive Review. 2nd ed. Dallas, TX: American College of Emergency Physicians; 1997;329334. 34. Alpers A. Key legal principles for hospitalists. Am J Med. 2001;111:5S9S. 35. Crane M. When a hospitalist discharges your patients. Med Econ. 2000;6:41-54. 36. Britto MT, Tivorsak TL, Slap GB. Adolescents’ needs for health care. Pediatrics. 2010;126:e1469-e1476. 37. McAbee GN, Brown JL. Legal issues related to e-mail, web sites and

telemedicine. In Donn SM, McAbee GN eds. Medicolegal Issues in Pediatrics. 7th ed. Elk Grove Village, IL: American Academy of Pediatrics. 2012:83-94. 38. American Academy of Pediatrics, Committee on Adolescence and Council on Clinical and Information Technology. Standards for health information technology to ensure adolescent privacy. Pediatrics. 2012;130:987-990. 39. Engel K, Heisler M, Smith D, et al. Patient comprehension of emergency department care and instructions: Are patients aware of when they do not understand. Ann Emerg Med. 2009;53:454-461. 40. Percelay CM, Strong GB, American Academy of Pediatrics Section on Hospital Medicine. Guiding principles for pediatric hospitalist programs. Pediatrics. 2005;115:1101-1102. 41. Lye P, American Academy of Pediatrics Committee on Hospital Care and Section on Hospital Medicine. Clinical report - Physicians’ roles in coordinating care of hospitalized children. Pediatrics. 2010;126:829832.

CHAPTER

14

Hospitalist Professional Organizations and Models of Care Daniel A. Rauch and David Zipes

PROFESSIONAL ORGANIZATIONS Since Wachter and Goldman coined the term hospitalist in 1996,1 the field has undergone tremendous growth and change and is now well established. The Academic Pediatric Association (APA), the American Academy of Pediatrics (AAP), and the Society of Hospital Medicine (SHM) are all strongly invested in pediatric hospital medicine. The three organizations each bring significant strengths to individual hospitalists and the field as a whole. All three organizations serve as sponsors of the annual Pediatric Hospital Medicine (PHM) conference, the largest national PHM gathering. The APA’s mission is to improve the health and well-being of all children and adolescents by promoting research, advancing a scholarly approach to education, developing innovations in healthcare delivery, advocating for an equitable child health agenda, and fostering leadership and career development of child health professionals. The APA sponsored the first national PHM conference in 2003 and provides PHM-specific content at the annual Pediatric Academic Societies conference through original science presentations and the Hospital Medicine Special Interest Group. Hospitalists are considered a core constituency and have been involved in development of the strategic plan, included as editors of the APA journal Academic Pediatrics, and have served as partial motivation for the change in name from the “Ambulatory” Pediatric Association to its current more inclusive Academic Pediatric Association. APA career development projects such as the Leadership in Academic Pediatrics conferences, the Educational Scholars Program, the Research Scholars Program, and the new Quality Scholars Program actively solicit participation of hospitalists.

The mission of the AAP is to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults. To advance that mission, the AAP has been a strong advocate of PHM. The Section on Hospital Medicine (SOHM) has been the fastest growing section in the AAP over the last 10 years and now counts almost 2000 members. The SOHM sponsored the development of the first journal dedicated to PHM, Hospital Pediatrics, as well as a forthcoming PHM PREP product. The SOHM created the national PHM Fellows Conference, sponsors a day-long program at the AAP National Conference and Exhibit, and supports grants for trainees and international hospitalists to the summer PHM conference. The SOHM was the first sponsor of the APEX (Advancing Pediatric Educator Excellence) Teaching program. The SOHM has seven subcommittees involving all aspects of PHM. The Committee on Hospital Care is a separate AAP entity from SOHM that includes hospitalists as well as other pediatricians involved in the care of hospitalized patients (surgeons, intensivists, etc.). It is charged with addressing AAP policy issues on all hospital care and so addresses many PHM activities. Many other AAP sections, committees and councils impact on care of the hospitalized child and so provide many opportunities for hospitalists to take on leadership roles within the AAP. The mission of the SHM is to promote the highest quality of care for all hospitalized patients and excellence in the practice of hospital medicine through education, advocacy, and research. Of the nation’s estimated 40,000 hospitalists, 12,000 are SHM members. SHM is a “big tent” organization that includes hospitalists from all disciplines (internal medicine, family medicine, pediatrics, and more recently general surgery, and obstetrics, as well as medical and surgical subspecialty fields) along with non-physicians such as physician assistants, nurse practitioners, and practice managers. SHM advocates for healthcare reform nationally, and many Medicare reform proposals are likely to impact Medicaid payment models in the future. Patient safety, quality improvement, leadership, and practice management efforts are directly parallel to issues pediatric hospitalists face, although clinical topics obviously vary. SHM sponsors an annual meeting that includes a pediatric track, publishes the Journal of Hospital Medicine, and has a specific Pediatric Committee that addresses pediatric-specific issues within and on behalf of SHM. SHM was the prime mover behind creation of recognition of focusedpractice in hospital medicine by the American Board of Internal Medicine

(ABIM). Under this model, ABIM-certified internists with 3 years of hospitalist experience may earn the above designation by completing hospital medicine–specific performance improvement and self-assessment modules and passing a secure hospital medicine–specific exam without any formal or informal fellowship training. More recently, several additional organizations have arisen that are also moving the field of PHM forward. The Pediatric Research in Inpatient Settings (PRIS) network is a research network focused on conducting multicentered studies in areas of inpatient care relevant to the clinician. PRIS has been successful in obtaining several large grants and has carried out several studies that promise to impact the practice of PHM. The Value in Inpatient Pediatrics (VIP) network is focused on process improvement projects with measurable outcomes. VIP has had several successful projects regarding bronchiolitis, patient identification, and discharge communication. VIP is part of the AAP Quality Improvement Innovations Networks. The Consortium of Pediatric Hospital Medicine (CPHM) includes representatives from the APA, AAP, and SHM, and helps coordinate activities between the organizations on behalf of PHM such as representation to the Council of Pediatric Subspecialties (CoPS) and the Pediatric Academic Societies’ Annual Meeting planning committee. The newly formed American Board of Pediatrics PHM sub-board is responsible for creating the certifying exam and MOC. The JCPHM includes representatives from the APA, AAP, SHM, and PRIS, as well as at-large members from the PHM community, including a dedicated spot for a community hospitalist. The JCPHM vision statement is “Pediatric hospitalists will transform the delivery of hospital care for children,” which will be attained through seven goals. The JCPHM convened the Strategic Planning Committee to thoughtfully examine the options for the field moving forward, ranging from American Board of Pediatrics (ABP) subspecialty recognition to maintaining the current status.

EMPLOYMENT AND COMPENSATION MODELS Multiple different employment and compensation models for hospitalists exist, and no one compensation model works for all situations. Each has different driving forces, advantages, and disadvantages. There are six basic employment categories: self-employed hospitalist-only groups, multistate hospitalist-only groups, hospital or hospital corporations, academic hospitals,

multispecialty groups, and insurance industry groups (managed care organizations). Certainly, there are permutations of and variations on these schemes, and as hospital medicine grows and evolves, other models may emerge. According to the SHM’s 2012 survey, most pediatric hospitalists are employed by hospitals or hospital corporations, with academic institutions running a distant second. The financial implications and limitations of each employment model are the driving forces behind their development and utilization. According to the SHM survey, when professional fees are compared with the costs of providing services, most groups are in the red. Most hospitalist programs therefore require external support to remain solvent. Although hospitalist systems yield cost savings to the system as a whole (usually more than accounting for their cost), largely owing to decreased lengths of stay and other benefits (e.g. system improvements, resident education), the decision of who should pay for these benefits varies considerably. Should it be the insurance companies, in the form of increased payments for inpatient care; the hospitals, in the form of bonuses, salaries, or subsidies; the PCPs; or the many other entities that benefit from a well-run hospitalist model? The SHM survey shows that currently hospitals (academic/university and community) employ almost 80% of all pediatric hospitalists. It is therefore not surprising that according to the PRIS survey, hospitals are also the most common source of external support for pediatric hospitalist programs.2 Cost-sharing models for the beneficiaries of hospitalist programs must be developed. If increased reimbursement for hospitalized patients can be achieved the employment models may shift, but for now, the trend of hospitals employing hospitalists will likely continue. The basic compensation models include salary only, productivity only (i.e. professional fees), and mixed productivity and compensation. Again, permutations and variations may exist, and new models may emerge in the future. According to the 2004 SHM productivity and compensation survey, more than 60% of all hospitalist programs receive money beyond what their professional fees generate; 80% of academic models receive supplementation. Among individual hospitalists, 38% are purely salaried, 8% earn productivity-based income, and 45% receive a combination of the two. Bonuses can be a variable in any of the three compensation models, and according to the survey, 61% of hospitalists receive some sort of bonus.

Although bonuses can certainly be an effective motivational tool, one needs to be cognizant of the potential legal ramifications of incentive systems. The Stark Law, for example, prohibits the referral of Medicare and Medicaid patients to an entity for the provision of certain health services if the physician or a member of the physician’s immediate family has a direct or indirect financial relationship with the entity. Bonuses can be interpreted as an indirect financial relationship. Consultation with legal counsel is strongly recommended during the development of incentive or bonus plans. Type of insurance (e.g. Medicaid, private, health maintenance organization, self-pay), reimbursement strategy (e.g. fee for service, capitated), inpatient volume, and type of hospital (e.g. community, academic) all have an impact on the type of employment and compensation models implemented. Much like Charles Darwin’s well-described Galapagos finches, the models that survive will be those that are well adapted to their particular environment. No one model works for every situation. Increased reimbursement for hospital care would likely affect compensation models as well as employment models.

SUBSPECIALTY HOSPITALIST MODELS A growing field that does not fit neatly into any of the previously described models is that of the subspecialty hospitalist. At present, neonatal (including well newborns and pediatric intensive care units) seem to be the largest employers of general pediatric hospitalists in positions traditionally filled by subspecialists. These hospitalists may work exclusively in the intensive care unit or both in that unit and on the general pediatric floor. Additionally, urgent care centers and emergency departments may employ hospitalists. The phenomenon of using hospitalists in other subspecialties is burgeoning in adult patient care but is just beginning to occur in the pediatric hospitalist community. Adult subspecialties that commonly use hospitalists include cardiology, hematology/oncology, neurology, obstetrics/gynecology, orthopedics, and pulmonology. These hospitalists can be trained in general pediatrics, internal medicine, or subspecialties. Any specialty with a large inpatient population can adopt this model. Freed et al.,3 in surveys sponsored by the ABP, showed that hospitalists are active wherever patients exist in the hospital. The relatively small inpatient volumes of most pediatric subspecialties (excluding neonatal and pediatric intensive care units) may

limit the cost-effectiveness of hiring hospitalists to care exclusively for patients of a particular subspecialty except in large academic centers, although models in which general pediatric hospitalists care for subspecialty patients as part of their job are emerging. The economic reality in smaller community hospitals has been a driving force for pediatric hospitalists to multitask and cover or cross-cover nurseries, NICUs, PICUs, emergency departments, and urgent care centers. Additionally, there are jobs focusing on single aspects or patient type within hospital medicine, such as care of the complex medical patient or sedation services.

SUGGESTED READINGS AHA survey, 2004, submitted for publication. AMA Physician Characteristics and Distribution in the US, 2004. Miller JA. The hospitalist movement: The quiet revolution in healthcare. HealthLeaders News. 2003;Jan 8. Pediatrician attitudes toward and experiences with pediatric hospitalists: A national survey. Society of Hospital Medicine Sixth Annual Meeting Abstracts, 2003. Shipman SA, Lurie JD, Goodman DC. The general pediatrician: Projecting future workforce supply and requirements. Pediatrics. 2004;113:435. Wachter RM. The hospitalist movement: Ten issues to consider. Hosp Pract (Minneapolis). 1999;34:95-98,104-106,111.

REFERENCES 1. Wachter RM, Goldman L. The emerging role of “hospitalists” in the American health care system. N Engl J Med. 1996;335:514. 2. Chiang VW, Landrigan CP, Stucky E, Ottolini MC. Financial health of pediatric hospitalist systems: A study from the Pediatric Research in Inpatient Settings (PRIS) network. Pediatr Res. 2004;55:1794. 3. Freed GL, Dunham KM; Research Advisory Committee of the American Board of Pediatrics. Pediatric hospitalists: training, current practice, and career goals. J Hosp Med. 2009;4(3):179186pmid:19301370

CHAPTER

15

Careers in Hospital Medicine Karen Smith and Mary C. Ottolini

BACKGROUND Adaptability is a core attribute for the successful Pediatric Hospitalist (PH). Perhaps it is because our specialty is so young that accepting and leading change seems to be woven into the PH’s DNA. Adaptability has served us well as our specialty has and continues to evolve to meet the changes in healthcare delivery models while striving to improve the care delivered to hospitalized children. In 1996 Dr. Robert Wachter defined a hospitalist as a physician dedicated to the delivery of comprehensive medical care to hospitalized patients, while engaging in clinical care, teaching, research, or leadership in the field of General Hospital Medicine. In addition, hospitalists work to enhance the performance of hospitals and healthcare systems.1 This definition for the hospitalist caring for adult patients also fits the pediatric hospitalist (PH), but in addition to providing expert care for infants and children, the PH must be proficient in providing family-centered patient care.2 Clinical expertise therefore, is another core attribute for PH. Pediatric Hospitalist Medicine (PHM) initially evolved to address the patient care needs of the hospitalized child. The PHM model of care diverged from the traditional model where pediatricians rounded on the ward and in the nursery at the beginning and end of the day, while spending the bulk of time caring for patients in the office setting. The traditional model worked because individual pediatricians generally had few inpatients with low acuity and relied on pediatric residents and subspecialists for hands-on management during office hours.3 Since the mid-1990’s care of the hospitalized child has become increasingly complex, both in terms of the nature of the underlying disease process, the complexity of the patient with respect to multisystem

chronic illness and survival based on medical technology.4 Increasingly, only the sickest of patients are hospitalized.5 The increased acuity and complexity of inpatient pediatrics coupled with external pressures focusing on patient safety and hospital utilization made the traditional model untenable for the majority of primary care pediatricians. What sets the PH apart from the primary care pediatrician however, is her/his focus on systems-based practice within the hospital setting. Essentially, everything that a PH does must be in the context of the impact on the healthcare system as well as that of the patient.6 Dr. Wachter stated during a recent American Public Media interview “…the doctor of the future has two sick patients. One is the patient they are taking care of. One is the system they are working in,”.7 This is especially true for PHs who are frequently the linchpin in effective patient management within the complex and expensive inpatient setting. In essence Wachter is saying that one of the keys to curing our healthcare system is preparing Hospitalists for effective careers. In this chapter we describe current career opportunities for pediatric hospitalists in a variety of settings. These include the tertiary care academic university/children’s hospital, the community hospital academically affiliated with a university program, and the non-affiliated community hospital with a smaller pediatric unit. We also describe possible career building experiences to achieve success in the various career roles for hospitalists in both community and academic settings. Finally, we look at building careers not only from the standpoint of the trainee or new hospitalist, but from the standpoint of the division chief who wants to develop the careers of the faculty within his or her division.

HOSPITAL SETTING TEACHING HOSPITAL Clinical Pediatric hospitalists fill a number of clinical roles in academic hospitals, and their careers can potentially focus on some or all of these roles. The clinical role of the PH is analogous to that of the utility infielder on a baseball team.8 The breadth of practice can range from caring for straightforward to medically complex patients,9 alone or as consultants or co-

managers with surgical subspecialists.10 Advances in pediatric medicine over the last generation have resulted in a population of medically complex patients, frequently with intellectual disabilities, who are growing into adulthood as disease processes that were once fatal have become treatable. The emerging field of complex care focuses on the holistic medical care of children with complex diseases.11 Many complex patients experience frequent hospitalizations as a result of exacerbations of chronic illness or technology malfunction.12 Their care requires general pediatric skills, expertise in coordination of care, and expertise in communication with patients’ families and other medical and nonmedical providers.13 PH are pivotal to providing the coordinated care needed care for these costly patients within accountable care organizations.14 PH are evolving models where they consult during pre-surgical outpatient visits to develop a plan of care that they later implement in the postoperative period.15 They are also critical to the smooth transition of the patient from the acute inpatient setting to home. Hospitalists increasingly staff follow-up clinics or transitional/rehabilitation facilities that serve to continue to provide care and coordinate the transition of responsibility back to the family and primary care provider and medical home.16 At the polar opposite of medically complex patients, PHs provide care for sick children increasingly classified as “observation patients”; previously healthy with an acute single-organ system disease process, such as asthma, necessitating brief hospital stays and rapid handoffs from the Emergency Department back to the Primary Medical Doctor (PMD).17 The PH must work with insurance payers and hospital utilization management departments to develop and continually refine evidence-based best processes to efficiently manage these patients at low cost in an inherently complex hospital environment. For both acute and complex patients, PHs often assume the role of proceduralists,18 performing conscious sedation, placing percutaneous catheters, etc.19 Some PHs also function as subspecialty PHs, extending the capability of subspecialists as an embedded member of the subspecialty inpatient team.20 Most subspecialty PHs obtain on-the-job training from subspecialists to be able to manage common problems that occur in that patient population. The PH remains present on inpatient units supervising

residents or ancillary staff and troubleshooting patient problems, while the subspecialist may be working in the outpatient clinic or doing procedures. Education In a typical Academic Children’s Hospital, the PH serves as the supervisor and team leader for pediatric residents medical students, and in some cases PH fellows. In this role they are responsible not only for day-today patient care decisions, but also for the education of trainees at a variety of levels.21 Numerous educational career opportunities exist for PHs. The role of the PH in medical education has increased dramatically over the past two decades. In a 1998 survey of academic pediatric department chairs in Canada and the United States, Srivastava et al. determined that 77% of respondents either had or were planning to institute pediatric hospitalists within their institutions.22 In those institutions with hospitals, two-thirds of hospitals were involved in teaching. By early 2008 approximately 75% of pediatric residents, program directors, and clerkship directors reported using PHs as teaching attendings.19 In a survey of a national sample of PHs, 94% of respondents reported teaching medical students and pediatric and housestaff, while 45% of respondents reported holding a leadership position in education.23 PH respondents to the 2007 PRIS (Pediatric Research in Inpatient Settings) network survey also reported intense involvement in medical education. Although most respondents reported teaching pediatric residents and medical students, up to 40% indicated that they were teaching other trainees, faculty members and community pediatricians.24 Hospitalists have been recognized by trainees as making exemplary teachers because of their enthusiasm, evidence-based practice, and ability to role-model core competencies such as interpersonal skills and professionalism through their daily interactions with parents/patients during family-centered rounds and interdisciplinary teams.25 These daily activities provide opportunities to also assess these skills in trainees, which is essential to collect data for the Milestones project.26 To be maximally effective in teaching activities, hospitalists must seek opportunities to further refine their teaching skills. Many residency programs now have RATS programs (Residents as Teachers)27 so that graduates pursuing hospitalist careers have an understanding of how to apply adult learning principles in their teaching strategies, and are effective at orienting

and providing feedback to learners. Hospitalists can learn teaching skills by attending workshops at regional and national conferences, such as the Pediatric Hospitalist Medicine Conference, the Society for Hospital Medicine annual conference, the Pediatric Academic Society Annual Meeting and the Pediatric Educational Excellence Across the Continuum (PEEAC) Conference.28 For more advanced study, there are several structured programs available through national organizations, such as the Academic Pediatric Association’s Educational Scholar Program (ESP),29 through institutions such as the Harvard Macy Foundation30 and formal universitybased Masters in Education certificate or degree programs (see Table 15-1). TABLE 15-1

Educational Resources

APA Educational Scholars Reference on Educator Portfolio Harvard Macy Foundation Michigan State Primary Care Faculty Development Program University of Chicago Master of health Professions Education The Master Teacher Leadership Development Course PEEAC Meeting Pediatric Academic Society Meeting SHM Academic Hospitalist Academy Association of Pediatric Program Directors Council on Medical Student Education in Pediatric Council of Pediatric Subspecialists Accreditation Council for Graduate Medical Education AAMC Member Communities Annual Meeting GRA- Group on Resident Affairs GEA- Group on Educational Affairs AAMC Group on Women in Medicine and Science Early Career Women Faculty Professional Development Mid Career Women Faculty Professional Development

Executive Leadership in Academic Medicine MedEdPORTAL To continually refine their teaching skills, hospitalists should reflect on feedback from their learners. They should encourage learners to provide qualitative feedback in addition to the standard numeric ratings.31 A safe learning climate is essential for this. In addition, peer feedback is invaluable to improving teaching techniques. Peer coaching serves several purposes in addition to providing feedback to the hospitalist being observed.32 By observing the practices of others, division members develop more uniformity in teaching and expectations for learners. Peer assessment makes teaching a more scholarly activity and raises its importance within the division and institution. Hospitalists are evolving the educational model in the inpatient setting. Traditional inpatient teaching has been carried out in teacher-led small groups using case-based didactics, where the attending described the epidemiology, clinical presentation, diagnostic testing, and management of a specific disease or syndrome. As PHs with advanced educational training assume leadership roles, they are incorporating best practices in adult learning theory to meet challenges posed by duty hour changes and make the most of opportunities afforded by technology. For example, PHs have developed and implemented a nighttime curriculum to enhance resident learning during the night shift.33 PHs lead simulation activities designed to provide deliberate practice in procedural skills and teamwork.34 Computer-based learning management systems provide PHs with a repository for e-learning modules—multimedia files and readings that can be delivered in a programmed sequence to learners so that they access and learn background information at their own pace and schedule.35 This “flipped classroom” approach allows small group teaching sessions to be learner-centered interactive discussions on how to apply background information to patients on the clinical service.36 Family-centered bedside rounds are an ideal setting for teaching and assessing communication, physical exam, diagnostic reasoning, and team leadership skills.37 Hospitalists are uniquely positioned to teach clinical reasoning skills, to emphasize the importance of good physical exam skills and judicious use of diagnostic testing. This is critical for reducing

unnecessary healthcare costs and to avoid diagnostic errors.38 PHs are in a unique position to advocate for optimal resident case experience and graduated autonomy, based upon entrustment decisions they can make through close working relationships with residents.39 PH educators can best position themselves to succeed in local leadership opportunities as the clerkship, residency, fellowship, or continuing medical education (CME) director by attending academic leadership conferences such as those sponsored by the Academic Pediatric Association or Society for Hospital Medicine. To advance academically as clinician-educators, PHs must produce scholarship that will advance the field. Scholarship in pediatric hospital medicine (PHM) need not be limited to published articles; it can include educational resources such as curricula and assessment tools that have been evaluated and posted on peer-reviewed repositories, such as Med Ed Portal.40 Research PH research has been rapidly advancing as the field as a whole has matured, and an increasing number of pediatric hospitalists are engaging in research as either the primary focus or as part of their professional careers. Initial hospitalist research focused on defining and characterizing the field. Much of the work was done through surveys of key stakeholders.41 The effectiveness and efficiency of hospitalist systems was also studied in initial hospitalist research.42,43 After these initial studies, PHM research began to focus on single- or multicenter retrospective studies that addressed critical PHM clinical issues.44 Large multicenter retrospective studies using administrative data such as the PHIS database have allowed PHs to compare variability in outcomes based upon treatment strategies.45 Variability of care across children’s hospitals has been described for a variety of diseases such as pneumonia and urinary tract infections.46 A problem with such studies is that it is difficult to definitively associate a specific treatment with an outcome. Prospective comparative effectiveness trials are needed to determine the impact of variability of different practices on patient outcomes in order to establish best evidence for practice. Once best practices are described, then quality improvement studies can help to implement and test the approach to determine the best process to adapt in a particular practice. Within PHM, several networks have evolved to enable research leaders across the country to collaborate in conducting clinical effectiveness and quality improvement

research. Two important networks focused on quality improvement and comparative effectiveness research are the PHM Value in Pediatrics Network,47 which merged with the American Academy of Pediatrics Quality Improvement Innovation Network (QuIIN),48 and PRIS.49,50 QuIIN is a network of practicing pediatricians and their staff that aims to improve care and outcomes for children and families through quality improvement (QI) projects. In 2010, PRIS partnered with the Child Health Corporation of America (CHCA) to create a national agenda for comparative effectiveness research QI studies conducted by PHs called the Prioritization Project.51 This project identifies inpatient medical and surgical pediatric conditions with the greatest opportunities to reduce patient costs and improve outcomes by decreasing variability in practice. Other PRIS studies such as the I-PASS study are designed to enhance patient safety by improving the handoff process through focused education and deliberate practice. The I-PASS project is an example of linking PH educational, QI, and leadership roles to effect rapid institutional change and measure the impact on patient outcomes, particularly medical errors. This is an example of a study looking at those processes that affects patient care as a whole, rather than for specific diseases.52 Working with electronic medical records and administrative data collected by CHCA, PRIS is trying to create a much more robust multicenter database that includes not only ICD-9 codes, but some clinical data— laboratory, radiology, and microbiology results. The success of PHM research in the future will require researchers with advanced training in study design, research methods, and data interpretation as well as the ability to reach out to colleagues to determine clinically meaningful research questions. Mentorship is needed to foster networking and success in competing for grant funding. This mentorship may occur informally within institutions and relationships developed at national meetings for PHs. However, to develop the critical mass of individuals needed to advance the specialty of PHM, a more formal approach will be needed through the rigorous training provided by PHM Fellowships focused on research training,53,54 and advanced degrees in clinical and translational science, Masters in Public Health or Quality Improvement/Informatics (see Table 15-2).

TABLE 15-2

Research Resources

ACADEMIC PEDIATRIC ASSOCIATION RESEARCH SCHOLARS PROGRAM PRIS APA YOUNG INVESTIGATOR AWARDS APA FELLOW RESEARCH AWARD NIH INTRODUCTION TO PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH NIH CAREER DEVELOPMENT AWARDS (K AWARDS) CTSA- CLINICAL TRANSLATIONAL SCIENCE AWARDS Masters Degree Programs in Clinical and Translational Science

ADMINISTRATION AND LEADERSHIP Health care’s new leaders must organize doctors into teams, measure their performance not by how much they do but by how their patients fare, deftly apply financial and behavioral incentives, improve processes, and dismantle dysfunctional cultures.55 Hospital medicine is well suited to produce leaders in hospital administration. Hospitalists are caring for an increasing number of patients either as the primary attending, co-manager, or consultant. As a result, there are many opportunities for leadership. Often the path begins as a leader of a QI initiative or committee, which then progresses to unit director, assistant chief, chief, and so on. Even with this trajectory, however, many studies have shown that most physicians have little or no formal training in business or leadership.56 The heavy clinical load and changing schedule of a hospitalist adds to the difficulty in obtaining formal education. However, there are now many opportunities for in-person as well as online, asynchronous, or shortterm educational courses for a degree or certificate. Table 15-3 provides examples of educational options for administrative leadership training. TABLE 15-3

Career Preparation

Administration can be broken down into the following categories: regulatory requirements, financial performance, staff development, and management. Regulatory requirements involve both healthcare regulations and human resource requirements. Healthcare regulations vary slightly based on the type of institution and location (city/state). Common sources of regulation include the Joint Commission, Centers for Medicare and Medicaid Services (CMS), and the local department of health. Human resource requirements involve

employment law and regulations (federal, state, and city). These are often outlined in hospital policy and procedures. Financial performance is coming under increasing scrutiny. This includes both the cost of hospital medicine programs and the service utilization per patient by the individual hospitalist that will affect the hospital’s bottom line and reimbursement by insurance companies. Key areas of importance are return on investment, maintaining a positive margin, and developing a business plan, or “pro forma,” for new projects. As an administrator there are basic management duties essential to the performance of a department or division. This includes developing a schedule, obtaining resources (space, computers, and equipment) and maintaining a structure for the functioning of the division. Often overlooked, these functions can have a significant impact on staff satisfaction. Lastly, the hospital medicine leader needs to inspire and develop the members of the division. This is especially crucial with junior faculty who may have varying levels of training. Strategies for staff development are discussed later in this chapter. Opportunities in administration can come from several sources: the university, hospital, and medical staff of the hospital. Depending on the employment model, hospitalist programs can be employed by the university, hospital, or as an independent company. Leadership positions can include director of a department or unit, chief of a division, chair of a department, or chief medical officer. In addition to these roles, every hospital is required to have a separate organized medical staff. These leadership opportunities include chief of pediatrics, medical executive committee member, and president of the medical staff.

COMMUNITY HOSPITALS Community hospitals provide an excellent opportunity for leadership in hospital medicine. Compared to academic institutions, there are very few providers in a community hospital with pediatric expertise. Therefore, a community hospital-based PH is frequently identified as the expert in all things pediatric. This can be a blessing or a curse. However, there is great reward in establishing a safe, effective pediatric service for the community. Key areas of focus include medication safety, managing emergencies for both

the individual decompensating patient and community disasters, improving hospital efficiency through pathways and protocols, and educating allied health providers and other physicians on pediatric topics. The key to success in community hospitals is building relationships. By developing strong personal relationships with other departments, allied health staff, and community providers, a PH’s input and leadership will be regarded as a benefit rather than a threat.

STRATEGIES FOR STAFF DEVELOPMENT Leaders of hospital medicine divisions and departments are challenged with the professional growth of a relatively young workforce with varying degrees of training and experience.57 Barriers to growth are many, including limited numbers of senior mentors in pediatric hospital medicine within an institution and nationally, heavy clinical load, and limited formal training. However, many leadership opportunities are available within this new field of medicine. It is crucial that leaders in hospital medicine assist junior staff to take on leadership roles in their department, institution, and nationally. Key factors that promote leadership development include: Mentorship/Coaching Goal setting Career tracking/Reflection Early leadership opportunities Removal of barriers Promotion of success The remainder of this chapter focuses on two valuable tools that are underutilized: mentorship and coaching.57 Mentorship focuses on the individual and has a broad focus and a long-term commitment. Mentors can be within or outside a department. Due to the young age of the field of hospital medicine, available mentors for PHs are often more easily identified from other specialties. A leader can help members identify and connect with these types of mentors. An alternative and sometimes more effective option is peer mentorship.58 Peer mentorship capitalizes on relationships between colleagues as a valuable source of emotional support, feedback, advice, and skill development. The advantages of peer mentorship include shared

generational values, lack of power differential, and a higher abundance of mentors compared to the traditional model of mentorship. Most peer mentorship groups consist of four to five members. Some but not all programs have included senior leadership as facilitators. Several programs have described their peer mentorship program including structure and outcomes.59-61 In fact, Poloi and Knight found that peer mentorship demonstrated the most gain for the members and the most consistent attendance compared to traditional mentorship.58 For short, time-limited performance improvement, coaching is a viable option. Coaches do not need to be experts, but should be proficient in a particular task. Similar to peer mentorship, coaching allows members of the same department to assist their colleagues in performance improvement. Coaching sessions usually occur in a dyad and can focus on a variety of performance measures including communication, procedures, team leading, and so forth. Compared to mentorship, coaching relationships are usually for a short time period until the performance goal is met.62 Every leader will need to adapt their strategies and processes for faculty development to meet the needs of their members in relation to the institutional requirements for promotion and growth. Table 15-3 provides additional examples and opportunities for faculty development based on the interests of the individual faculty member. The information provided is not meant to be exhaustive, but rather to inspire creativity in developing one’s own career or that of a hospitalist group. Before you are a leader, success is all about growing yourself. When you become a leader, success is all about growing others. Jack Welch

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3. Seelbach EB, Ottolini MC. Primary care physicians and hospitalists: two branches of the same tree. Pediatr Ann. 2010;39(2):84-88. 4. Simon TD, Berry J, Feudtner C, et al. Children with complex chronic conditions in inpatient hospital settings in the United States. Pediatrics. 2010;126(4):647-655. 5. Burns KH, Casey PH, Lyle RE, Bird TM, Fusell JJ, Robbins JM. Increasing Prevalence of medically complex children in US hospitals. Pediatrics. 2010;126:638-646. 6. Teufel RJ 2nd, Garber M, Taylor RC. Pediatric hospitalist: a national and regional trend. J S C Med Assoc. 2007;103(5):126-129. 7. Gorenstien D. From ‘god-like’ to team huddle: training doctors for a new health care future Marketplace Morning Report, American Public Media. March 15, 2013. 8. Fisher ES. Pediatric hospital medicine: Historical perspectives, inspired future. Curr Probl Pediatr Adolesc Health Care. 2012;42(5):107-112. 9. Srivastava R, Stone BL, Murphy NA. Hospitalist care of the medically complex child. Pediatr Clin North Am. 2005;52:1165-1187. 10. Rappaport DL, Pressel DM. Pediatric hospitalist comanagement of surgical patients: Challenges and opportunities. Clin Pediatr. 2008;47:114-121. 11. Cohen E, Kuo DZ, Agrawal R, et al. Children with medical complexity: An emerging population for clinical and research initiatives. Pediatrics. 2011;127:528-538. 12. Berry JG, Hall DE, Kuo DZ, Cohen E, Agrawal R, Feudtner C, et al. Hospital utilization and characteristics of patients experiencing recurrent admissions within children’s hospitals. JAMA. 2011;305:682-690. 13. Simon TD, Mahant S, Cohen E. Pediatric hospital medicine and children with medical complexity: Past, present, and future. Curr Probl Pediatr Adolesc Health Care. 2012;42(5):113-119. 14. Ovretveit J. Evidence: Does Clinical Coordination Improve Quality and Save Money? London: Health Foundation. 2011. 15. Simon TD, Eilert R, Dickinson LM, Kempe A, Benefield E, Berman S. Pediatric hospitalist comanagement of spinal fusion surgery patients. J Hosp Med. 2007;2(1):23-30.

16. Misky GJ, Wald HL, Coleman EA. Post-hospitalization transitions: Examining the effects of timing of primary care provider follow-up. J Hosp Med. 2010;392-397. 17. Chadaga SR, Maher MP, Maller N, et al. Evolving practice of hospital medicine and its impact on hospital throughput and efficiencies. J Hosp Med. 2012;7(8):649-654. 18. Connolly B, Mahant S. The pediatric hospitalist and interventional radiologist: A model for clinical care in interventional radiology. J Vasc Interv Radiol. 2006;17:1733-1738. 19. Turmelle M, Moscoso LM, Hamlin KP, Daud YN, Carlson DW. Development of a pediatric hospitalist sedation service: Training and implementation. J Hosp Med. 2012;7(4):335-339. 20. Nash KB, Josephson SA, Sun K, Ferriero DM. Should there be pediatric neurohospitalists? Neurology. 2013;80(10):957-962. 21. Freed GL, Dunham KM, Lamarand KE. Hospitalists’ involvement in pediatrics training: Perspectives from pediatric residency program and clerkship directors. Acad Med. 2009;84:1617-1621. 22. Srivastava R, Landrigan C, Gidwani P, Harary OH, Muret-Wagstaff S, Homer CJ. Pediatric hospitalists in Canada and the United States: A survey of pediatric academic department chairs. Ambul Pediatr. 2001;1(6):338-339. 23. Freed GL, Dunahm KM. Research Advisory Committee of the American Board of Pediatrics. Pediatric hospitalists: Training, current practice and career goals. J Hosp Med. 2009;4:179-186. 24. Maniscalco J, Ottolini MC, Dhepysasuwan N, Landrigan CP, Stuckey E. Current roles and training needs of pediatric hospitalists: A study from the Pediatric Research in the Inpatient Setting (PRIS) Network. EPAS2008:6725.4. Available at: Pas-meeting.org/2012/Boston/abstract_ archives.asp. 25. Fromme HB, Bhansali P, Singhal G, Yudkowsky R, Humphrey H, Harris I. The qualities and skills of exemplary pediatric hospitalist educators: A qualitative study. Acad Med. 2010;85(12):1905-1913. 26. Hicks PJ, Schumacher DJ, Benson BJ, Burke AE, Englander R, Guralnick S, Ludwig S, Carraccio C. The pediatrics milestones:

Conceptual framework, guiding principles, and approach to development. J Grad Med Educ. 2010;2(3):410-418. 27. Keller JM, Blatt B, Plack M, Gaba ND, Greenberg L. Using a commercially available web-based evaluation system to enhance residents’ teaching. J Grad Med Educ. 2012;4(1):64-67. 28. Pediatric Educational Excellence Across the Continuum (PEEAC) Conference. Available at: peeac.org/meeting/2011/Program_2011_ preliminary_v1.6FINAL.pdf. 29. Academic Pediatric Association’s Educational Scholar Program (ESP). Available at: ambpeds.org/education/educational_scholars_program_ description.cfm. 30. Harvard Macy Foundation. Available at: harvardmacy.org/programs/ overview.aspx. 31. Leslie K, Baker L, Egan-Lee E, Esdaile M, Reeves S. Advancing faculty development in medical education: A systematic review. Acad Med. 2013. 32. Sullivan PB, Buckle A, Nicky G, Atkinson SH. Peer observation of teaching as a faculty development tool. BMC Med Educ. 2012;12:26. 33. Blankenburg R, Black N, Maniscalco J, Fromme B, Augustine E, Myers J, et al. The new era of nighttime resident education: The 2011 ACGME work hour changes. Presented at Pediatric Academic Societies Meeting, Denver CO. May 2011. 34. International Network for Simulation-based Pediatric Innovation, Research, & Education. Available at: inspiresim.com. 35. Shaw T, Long A, Chopra S, Kerfoot BP. Impact on clinical behavior of face-to-face continuing medical education blended with online spaced education: A randomized controlled trial. J Contin Educ Health Prof. 2011;31(2):103-108. 36. Pierce R, Fox J. Vodcasts and active-learning exercises in a “flipped classroom” model of a renal pharmacotherapy module. Am J Pharm Educ. 2012;76(10):196. 37. Mittal VS, Sigrest T, Ottolini MC, Rauch D, Lin H, et al. Familycentered rounds: A new approach to patient care and teaching. Pediatrics. 2007;119:829-832

38. Singh H, Naik AD, Rao R, Petersen LA. Reducing diagnostic errors through effective communication: Harnessing the power of information technology. J Gen Intern Med. 2008;23(4):489-494. 39. Landrigan CP. Senior resident autonomy in a pediatric hospitalist system. Arch Pediatr Adolesc Med. 2003;157:206-207. 40. Med Ed Portal. Available at: mededportal.org. 41. Srivastava R, Nrolin C, Muret-Wagstaff S, Young PC, Auerbach A. community and hospital-based physicians’ attitudes regarding pediatric hospitalist systems. Pediatrics. 2005;115:34-38. 42. Freed GL, Brzoznowski K, Neighbors K, Lakhani I. Characteristics of the pediatric hospitalist worksource: Its roles and work environment. Pediatrics. 2007;120:33-39. 43. Landrigan CP, Srivastava R, Muret-Wagstaff S, Soumerai SB, et al. Impact of a health maintenance organization hospitalist system in academic pediatrics. Pediatrics. 2002;110:720-728. 44. Landrigan CP, Conway PH, Edwards S, Srivastava R. Pediatric hospitalists: A systematic review of the literature. Pediatrics. 2006;117:1736-1744. 45. Zaoutis T, Localio AR, Leckerman K, Saddlemire S, Bertoch D, Keren R. Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123:636-642. 46. Landrigan CP, Conway PH, Stucky ER, Chiang VW, Ottolini MC. Variation in pediatric hospitalists’ use of proven and unproven therapies: A study from the Pediatric Research in Inpatient Settings (PRIS) network. J Hosp Med. 2008;3(4):292-298. 47. Ralston S, Garber M, Narang S, et al. Decreasing unnecessary utilization in acute bronchiolitis care: Results from the value in inpatient pediatrics network. J Hosp Med. 2013;8(1):25-30. 48. American Academy of Pediatrics. Quality Improvement Innovation Network. Elk Grove Village, IL: American Academy of Pediatrics. Available at: aap.org/qualityimprovement/quiin. 49. Pediatric Research in Inpatient Settings (PRIS) Research Network. PRIS Network. Available at: prisnet.org.

50. Srivastava R, Landrigan CP. Development of the Pediatric Research in Inpatient Settings (PRIS) Network: Lessons learned. J Hosp Med. 2012;7(8):661-664. 51. Zimbric G, Srivastava R. Research in pediatric hospital medicine: How research will impact clinical care. Curr Probl Pediatr Adolesc Health Care. 2012;42(5):127-130. 52. Starmer AJ, Spector ND, Srivastava R, Allen AD, Landrigan CP, Sectish TC. I-PASS Study Group. I-pass, a mnemonic to standardize verbal handoffs. Pediatrics. 2012;129(2):201-204. 53. Freed GL, Dunham KM; Research Advisory Committee of the American Board of Pediatrics. Characteristics of pediatric hospital medicine fellowships and training programs. J Hosp Med. 2009;4(3):157-163. 54. Heydarian C, Maniscalco J. Pediatric hospitalists in medical education: Current roles and future directions. Curr Probl Pediatr Adolesc Health Care. 2012;42(5):120-126. 55. Lee, T. Turning doctors into leaders. Harvard Bus Rev. 2010. 56. Stockwell DC, et al. Leadership and management training of pediatric intensivists: How do we gain our skills? Pediatr Crit Care Med. 2005. 57. Reid MB, Misky GJ, Harrison RA, et al. Mentorship, productivity, and promotion among academic hospitalists. J Gen Intern Med. 2011;27(1):23-27. 58. Pololi L, Knight S. Mentoring faculty in academic medicine: A new paradigm? J Gen Intern Med. 2005;20:866-870. 59. Johnson KS, Hasting SN, Purser PT, Whitson HE. The junior faculty laboratory: An innovative model of peer mentoring. Acad Med. 2011;86:1577-1582. 60. Varkey P, Jatoi A, Williams A, et al. The positive impact of a facilitated peer mentoring program on academic skills of women faculty. BMC Med Educ. 2012;12:14. 61. Bussey-Jones J, Bernstein L, Higgins S, et al. Repaving the road to academic success: The IMeRGE approach to peer mentoring. Acad Med. 2006;81:674-679. 62. Kowalski K, Casper C. The coaching process: An effective tool for professional development. Nurs Admin Q. 2007;31(2):171-179.

PART

Common Presenting Signs and Symptoms Part Editors Amanda Growdon, MD Katherine A O’Donnell, MD

16 Abdominal Mass 17 Abdominal Pain 18 Acidosis 19 Altered Mental Status 20 Chest Pain 21 Cyanosis 22 Diarrhea 23 Failure to Thrive 24 Fever 25 Gastrointestinal Bleeding 26 Hypertension 27 Hypoglycemia 28 Hypoxemia 29 Irritability and Intractable Crying 30 Limp 31 Lymphadenitis

II

32 Oral Lesions and Oral Health 33 Neck Pain 34 Petechiae and Purpura 35 Respiratory Distress 36 Shock 37 Syncope 38 Vomiting

Abdominal Mass

CHAPTER

16

Daniel A. Rauch

BACKGROUND Although evaluation of an abdominal mass often occurs in an outpatient setting, pediatric hospitalists are often asked to expedite the initial assessment and coordinate the appropriate consultations. The diagnostic possibilities vary considerably, based on the patient’s age and associated symptoms. The most urgent considerations are acute surgical conditions and neoplasms. A careful history and physical examination should guide a directed laboratory and imaging evaluation, leading to the diagnosis.

PATHOPHYSIOLOGY There are many structures within the abdomen from which masses can arise (Table 16-1). Abdominal masses can represent abnormal tissue mass of a solid organ such as the liver, spleen, or kidney or abnormal filling of a viscous organ such as the bowel or bladder. The most common source of an abdominal mass besides constipation is kidney pathology. TABLE 16-1

Region

Possible Diagnoses of Abdominal Masses Organ or Site Diagnosis

Epigastrium Stomach

Flank

Distended stomach from pyloric stenosis, duplication

Pancreas

Pseudocyst

Kidney

Hydronephrosis, Wilms tumor,

dysplastic kidney, ureteral duplication Adrenal

Neuroblastoma, ganglioneuroblastoma, ganglioneuroma

Retroperitoneum Neuroblastoma, ganglioneuroblastoma, ganglioneuroma, teratoma Lower abdomen

Pelvic

Ovary

Dermoid, teratoma, ovarian tumor, torsion of ovary

Kidney

Pelvic kidney

Urachus

Urachal cyst

Omentum, mesentery

Omental, mesenteric, peritoneal cysts

Bladder, prostate

Obstructed bladder, rhabdomyosarcoma

Uterus, vagina

Hydrometrocolpos, hydrocolpos, rhabdomyosarcoma

Right upper Biliary tract quadrant Liver

Intestine

Cholecystitis, choledochal cyst Hepatomegaly from congestion, hepatitis, or tumor; mesenchymal hamartoma; hemangioendothelioma; hepatoblastoma; hepatocellular carcinoma; hepatic abscess; hydatid cyst Intussusception, duplication

Left upper quadrant

Spleen

Splenomegaly from congestion, infectious mononucleosis, leukemic infiltration, or lymphoma; splenic abscess; cyst

Right lower quadrant

Appendix lleum

Appendiceal abscess

Left lower quadrant

Meconium ileus, inflammatory mass (complication of Crohn disease), intestinal duplication Lymphatics

Lymphoma, lymphangioma

Colon Lymphatics

Fecal impaction Lymphoma, lymphangioma

Source: From Zitelli B, Davis H. Atlas of Pediatric Physical Diagnosis. 4th ed. Philadelphia: Elsevier; 2002.

HISTORY Abdominal masses present in two distinct ways: painless or with abdominal symptoms. A painless mass is the classic sign of abdominal malignancy, particularly Wilms tumor and neuroblastoma. However, painless masses may also be completely benign, such as a fecal mass in a constipated child, a horseshoe kidney, or a wandering spleen. Painless masses are usually identified incidentally, often by parents when bathing the child, and sometimes on routine physical examinations. Systemic symptoms such as weight loss, pallor, bruising, or bleeding are suggestive of a malignant process. Diarrhea can be a sign of a vasoactive secreting tumor, while hematuria strongly suggests renal involvement. Masses may cause or be the result of GI obstruction and can present with vomiting, abdominal pain, and constipation. Masses that are renal in origin can present with symptoms of urinary dysfunction and hematuria. Painful masses require an evaluation for possible urgent intervention for ischemic diseases like ovarian torsion or intussusception or the need for decompression of the bowel or bladder. Duration of the symptoms is an important consideration. Slowly growing masses are typical of some malignancies, while rapidly enlarging masses are

more typical of others. Chronic abdominal pain and abnormal bowel habits may point to constipation. Periodic pain may point to a recurrent process, either acutely, as in intussusception, or chronically, such as a volvulus. Age is an important factor to consider. Neonates can present with congenital anomalies such as cystic kidneys. Neuroblastomas and storage diseases typically present younger than 2 years old. Wilms tumors and other malignancies are more common in older children. Certain syndromes are at increased risk of Wilms tumors, such as Beckwith-Wiedemann.

PHYSICAL EXAMINATION A thorough physical examination will help determine the source of the mass. Tenderness will confirm the report of pain, and rebound tenderness indicates a more severe and acute process that has evolved into peritonitis. Localization of the mass aids the differential diagnosis. The abdomen is classically divided in four quadrants. The right upper quadrant contains the liver, gallbladder, and bowel. The liver is often palpated under the costal margin, and up to 2 to 3 cm below in infants. The liver may be displaced inferiorly with hyperaeration of the chest cavity. When the liver edge extends to the left of the midline, it is likely enlarged. Extreme hepatomegaly that extends to the right lower quadrant can be missed because the liver edge is not palpable anywhere in the right upper quadrant. The left upper quadrant contains the spleen, pancreas, stomach, and bowel. The spleen is a mobile structure so that palpation of a mildly enlarged spleen tip may move it beyond the tactile sensation of the following examiner. Both the right lower quadrant and the left lower quadrant contain bowel and the female reproductive organs. Aside from the liver, these intraperitoneal structures are not typically palpable. In young infants the bladder may be palpable in the suprapubic area, but this structure becomes intrapelvic in later infancy. Retroperitoneal structures, such as the aorta and kidneys, are not normally palpable. Normal structures may be felt in patients who are very thin and have relaxed abdominal musculature, especially the aorta, which can be appreciated as a pulsatile midline structure, and the tip of the spleen in the left upper quadrant. The female reproductive tract resides in the pelvis but can expand into the lower abdomen under certain circumstances. Ovarian cysts or, much less

commonly, neoplasms, can become large enough to be palpable by direct abdominal examination. An engorged uterus may be palpable in the suprapubic area with congenital vaginal atresia, and is seen with hydrometrocolpos. A gravid uterus extends beyond the pelvic brim at approximately 12 weeks’ gestation. Ectopic pregnancy within a fallopian tube is usually symptomatic before being palpable but should always be considered in patients with abdominal pain and a positive pregnancy test. An intravaginal-abdominal bimanual examination is appropriate for better palpation of the female reproductive organs. The bladder, which is a pelvic structure after infancy, can expand into the lower abdomen when enlarged. This may occur with urinary retention. Retroperitoneal structures such as the kidneys, adrenals, pancreas, and midline paravertebral nodes and vessels can be palpable through the abdomen when there is significant tissue bulk, as may be seen with neoplasms such as Wilms tumor, neuroblastoma, and lymphoma. Cystic kidney disease may present as an abdominal mass. Neonates may have a palpable right kidney, which may be completely normal. Mobile masses more commonly originate from the GI tract, while fixed masses are from the liver or retroperitoneal structures. Solid versus compressible can differentiate between solid and cystic masses. The classic extra-abdominal finding of neuroblastoma is “raccoon eyes,” and proptosis can also be observed. Aniridia is associated with Wilms tumors, as is hemihypertrophy.

DIFFERENTIAL DIAGNOSIS Focal areas of distention can present as a mass, such as in duplication, intussusception, volvulus, and constipation. GI duplications are rare and may present with obstruction or bloody diarrhea in addition to a palpable mass. Intussusception uncommonly presents with the classic triad of colicky abdominal pain, vomiting, and currant jelly stool. More typical is some combination of vomiting, lethargy, and abdominal pain, with a right upper quadrant sausage-shaped mass and an empty right lower quadrant (Dance sign) in an infant or toddler. Volvulus also presents with vomiting and pain associated with an acute obstruction. Constipation is the most common cause of a palpable abdominal mass in any of the quadrants; it is usually tubular,

mobile, and nontender. Hepatomegaly is a nonspecific finding that may represent primary liver pathology or myriad secondary processes. Enlargement may be due to an increase in the size or number of cells or structures in the liver, including the hepatocytes (e.g. glycogen storage diseases), biliary tree (cholelithiasis), and vascular spaces (e.g. congestive heart failure), or to an infiltrative process (e.g. neuroblastoma). A list of possible infectious causes is provided in Table 16-2. Other causes to consider are listed in Table 16-3. TABLE 16-2

Infectious Causes of Hepatomegaly

Bacteremia Infectious hepatitis Mononucleosis Syphilis Leptospirosis Histoplasmosis Brucellosis Toxoplasmosis Tuberculosis Ascariasis Amebiasis Pyogenic abscess Visceral larva migrans Q fever Gonococcal or chlamydial perihepatitis AIDS Neonatal enteroviral infection Gianottic-Crosti syndrome Cat-scratch disease (granuloma) Source: Reproduced with permission from Green M ed. The abdomen. In Pediatric Diagnosis: Interpretation of Symptoms and Signs in Children and Adolescents. 6th ed. Philadelphia: Saunders; 1998:97-98. Copyright © Elsevier.

TABLE 16-3

Noninfectious Causes of Hepatomegaly

Anemia (sickle cell disease) Passive vascular congestion (congestive heart failure) Metabolic disorders (mucopolysaccharidosis) Cholestatic disorders (biliary atresia) Neoplastic disease (Hodgkin disease) Cysts (congenital hepatic cyst) Fatty infiltration (idiopathic steatohepatitis) Trauma (subcapsular hematoma) Autoimmune (systemic lupus erythematosus) Hemosiderosis Poisoning (hypervitaminosis A) The spleen can enlarge in response to a wide range of insults. Many of the infectious, metabolic, neoplastic, and inflammatory disorders that can cause hepatomegaly can also cause splenomegaly, either in isolation or in combination. Hemolytic disorders can cause chronic splenomegaly or, as in the case of acute splenic sequestration of sickle cell disease, sudden splenic enlargement with profound anemia. Serum sickness and subacute bacterial endocarditis can cause splenomegaly, with deposition of immune complexes in the spleen. Chronic granulomatous disease can cause intrasplenic granuloma formation. Suprapubic masses can represent the bladder or the uterus. Enlarged bladders are typically painful and associated with urinary symptoms. Pregnancy should be considered in any pubertal girl. The abdominal wall is a rare source of abdominal masses, taking the form of incarcerated hernias or sarcomas.

DIAGNOSTIC EVALUATION Blood work should be directed toward the likely diagnosis. Initial tests can include a CBC looking for signs of cell line deficits, liver function tests,

inflammatory markers, and oncology markers for neuroblastoma. Hematuria can be found with Wilms tumors, and urine pregnancy tests should be done in pubertal girls. Imaging studies can help localize the mass, determine the origin, or identify the cause. Plain radiographs (flat plates) can identify some abnormalities (e.g. solid tumors with calcifications) but are more useful as part of an obstruction series. The additional views demonstrate the effect of gravity on the intra-abdominal structures and fluids, revealing patterns of bowel obstruction, abscess, or free air. Ultrasonography is a readily available, nonionizing imaging modality that usually does not require the patient to be sedated. It provides information regarding the consistency of the mass (e.g. solid vs. cystic), can readily identify an abscess, and can often identify the organ of origin. Cystic masses are usually from the GI or genitourinary tract and are less likely to be malignant than solid masses. Computed tomography and magnetic resonance imaging provide a more complete assessment and greater structural detail. Factors such as need for sedation, radiation exposure, availability, and likely yield are important considerations. In addition, when the diagnosis is likely to be a malignancy and additional body areas will need to be imaged for staging purposes, studies should be coordinated to the extent possible. Further discussion of imaging is provided in Chapter 185.

MANAGEMENT Treatment is entirely dependent on the ultimate cause of the abdominal mass and often involves coordination of care with nephrology, gastroenterology, infectious diseases, oncology, or genetics as appropriate.

SPECIAL CONSIDERATIONS Any evaluation that includes possible malignancy or other potentially fatal entities such as the storage diseases requires extreme sensitivity toward the patient and family. Families need to be engaged in the need for a prompt workup which necessitated the hospitalization and they should be kept abreast of the results of each study in a timely manner. Additionally, the

caregivers will direct how much information can be revealed to the child. A multidisciplinary approach including social work and child life can help families cope with the process and break any potential bad news to the child and other family members. The evaluation may require special testing that is not available at all hospitals, so prompt transfer to a tertiary care facility may be required to expedite certain tests. KEY POINTS The diagnostic possibilities for abdominal masses vary considerably, based on the patient’s age and associated symptoms. While the evaluation can often take place in an outpatient setting, pediatric hospitalists are often involved in the initial evaluation. Ultimate diagnosis may depend on testing that is not available at all centers, so appropriate referral may be required.

SUGGESTED READINGS Brodeur AE, Brodeur GM. Abdominal masses in children: neuroblastoma, Wilms tumor, and other considerations. Pediatr Rev. 1991;12:196-207. Golden CB, Feusner JH: Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin North Am. 2002;49:13691392. Green M ed. The abdomen. In Pediatric Diagnosis: Interpretation of Symptoms and Signs in Children and Adolescents. 6th ed. Philadelphia, PA: Saunders; 1998:97-98. Pearl RH, Irish MS, Caty MG, Glick PL. The approach to common abdominal diagnoses in infants and children Part II. Pediatr Clin North Am. 1998;45:1287-1326. Zitelli B, Davis H. Atlas of Pediatric Physical Diagnosis. 4th ed. Philadelphia, PA: Elsevier; 2002.

Abdominal Pain

CHAPTER

17

Timothy Gibson

INTRODUCTION Abdominal pain is one of the most common complaints encountered by pediatric hospitalists. Despite this, the evaluation is often exceedingly difficult, and in many cases no definitive diagnosis can be made. The most urgent matter for the hospitalist initially is to rule out a life-threatening surgical emergency. If an acute abdomen is suspected based on history and physical, prompt surgical consultation is imperative.

BACKGROUND Abdominal pain can be caused by inflammation of the abdominal organs themselves (or their visceral peritoneum) or by inflammation of the parietal peritoneum lying in proximity to the underlying inflammation. Irritation of the abdominal wall musculature can also lead to pain, and various extraabdominal processes have been associated with abdominal pain (e.g. diabetic ketoacidosis or lower lobe pneumonia). Pain due to a process in the small intestine is usually felt in the midline around the umbilicus initially; as the inflammation progresses, the parietal peritoneum in the area of inflammation becomes involved, allowing better localization of pain. The classic example is appendicitis, with a dull periumbilical ache early in the course followed by a progressive shift of pain to the right lower quadrant as the inflammation evolves. Certain elements of the history and physical examination findings may help identify the cause of abdominal pain (Table 17-1). TABLE 17-1

Using History and Physical Examination Findings to Diagnose Abdominal Pain

Findings

Possible Diagnosis

History of present illness Sudden onset

Ovarian or testicular torsion, intussusception, volvulus, trauma

Bilious emesis

Bowel obstruction

Bloody stools

IBD (older patients), intussusception (younger patients), infectious colitis

Recent weight loss IBD, malignancy Travel

Infectious colitis, parasitic infection

Fevers

Infectious colitis, IBD

Rash

Henoch-Schönlein purpura, IBD (erythema nodosum)

Menstrual history

Dysmenorrhea, pregnancy, mittelschmerz

Past medical history Pharyngitis

Mesenteric adenitis, EBV-associated splenic distention

Gastroenteritis

Intussusception, postinfectious gastroparesis

Abdominal surgery Obstruction from adhesions Family history IBD

IBD

Migraines

Abdominal migraines

Social history Pets, especially reptiles

Infectious colitis

Sexual history

Pelvic inflammatory disease, pregnancy, ectopic pregnancy

Physical examination Clubbing or pallor

IBD

Perianal skin tags

Crohn disease

Jaundice

Biliary disease

Bluish color of flank or umbilicus

Pancreatic disease, trauma

Hemorrhoids, caput medusae

Chronic liver disease

EBV, Epstein-Barr virus; IBD, inflammatory bowel disease.

ASSESSMENT The differential diagnosis of abdominal pain is extensive (Table 17-2). In addition to the typical history and physical examination, epidemiologic factors are extremely helpful in narrowing the differential diagnosis, including age, gender, season, locale, and the like. As stated above, a patient with peritonitis requires timely surgical evaluation. With several conspicuous exceptions, most patients with signs of peritonitis on examination progress to that point gradually. On history, these patients, if old enough, may report that the bumps in the road on the trip to the emergency department caused pain. These patients prefer to lie motionless and do not want their abdomens palpated. The examiner can check for signs of peritonitis immediately by “inadvertently” bumping the bed; a wince of pain from the patient is a sign that any movement at all is irritating to the inflamed parietal peritoneum. Bowel sounds may be hypoactive or absent at this late stage, reflecting an ileus. The abdomen may be rigid, and the patient may have voluntary or involuntary guarding, a mechanism to prevent painful manipulation of the underlying enflamed peritoneum. Patients with peritonitis are likely to have rebound tenderness; where the pain that is felt when the examiner releases the abdomen is greater than that caused by the palpation itself. Patients of any

age who fit this classic description of an acute abdomen are highly likely to require surgical intervention and rarely need further evaluation such as laboratory tests or radiographic studies, except possibly to assess their surgical risk. TABLE 17-2

Differential Diagnosis of Abdominal Pain

Gastrointestinal Viral gastroenteritis Bacterial infectious colitis Parasitic infection Constipation Colic Functional abdominal pain Abdominal migraine Acute cholecystitis, cholelithiasis Ulcer disease (gastric, peptic) Pancreatitis Hepatitis Inflammatory bowel disease Gastroesophageal reflux Esophagitis Gastroparesis, ileus Lactose intolerance Toxic megacolon Meckel diverticulum Hirschsprung disease Urologic Urinary tract infection Urolithiasis Testicular torsion Gynecologic

Ovarian torsion, cyst Pregnancy, ectopic pregnancy Pelvic inflammatory disease Dysmenorrhea Endometriosis Hematocolpos Ovarian neoplasm Rheumatologic Henoch-Schönlein purpura Familial Mediterranean fever Surgical Appendicitis Intussusception Malrotation with midgut volvulus Incarcerated inguinal hernia Trauma with associated hematoma Postsurgical obstruction Psoas (or other) abscess Toxicologic Heavy metal poisoning Food (toxin-mediated) poisoning Infectious Tuberculosis Zoster Mesenteric adenitis Mononucleosis Sepsis Pulmonary Lower lobe pneumonia Meconium ileus equivalent Endocrinologic

Diabetic ketoacidosis Hematologic Vaso-occlusive crisis Porphyria Oncologic Tumor (e.g. Wilms) Renal Nephrosis Spontaneous bacterial peritonitis Hemolytic uremic syndrome Cardiovascular Abdominal aortic aneurysm Psychiatric Somatoform or conversion disorder Unfortunately for physicians, most cases of abdominal pain are not this clear cut. For each disease process in the differential diagnosis, there is a wide range of severity. For example, a patient with severe constipation may be in extremis, whereas a patient with early appendicitis may have so little pain (or such a high tolerance for pain) that he or she is sent home without having had further workup. A full history and physical examination are paramount to determine the cause of the pain. It must be kept in mind that common benign diagnoses (e.g. viral gastroenteritis, constipation) occur commonly, but depending on the presentation are often diagnoses of exclusion. It is the examiner’s job to triage these patients appropriately while recognizing the red flags that point to less common entities or those that need more urgent evaluation or intervention.

HISTORY The timing, location, and progression of the pain should be elicited, as well as its quality and severity. Did the pain begin in the umbilical area and progress to the right lower quadrant, as occurs with appendicitis? Is the pain

burning or boring, as in ulcer disease, or sharp and stabbing, as in peritonitis? Does it come in waves, suggesting a blockage of peristalsis in a hollow viscus, such as the small bowel, biliary tree, or ureter? Is the pain relieved by meals, as in some peptic ulcer diseases, or is the pain exacerbated by oral intake, as in biliary disease and pancreatitis? Is there vomiting before the pain, as in viral gastroenteritis, or after the pain, as in appendicitis? The pain in patients subsequently found to have appendicitis can be variable. If the appendix ruptures, the patient’s pain will often improve briefly, but will return in a gradual localized fashion, often accompanied by fever, as a phlegmon organizes at the site of rupture in the right lower quadrant. If the patient has bilious vomiting, the patient has a surgical emergency until proven otherwise, as this is suggestive of a bowel obstruction distal to the sphincter of Oddi. Younger children, classically 18–36 months, who have abdominal pain and bilious vomiting without other symptoms have intussusception until proven otherwise. The pain of intussusception can be intermittent and is occasionally associated with mental status changes or lethargy. Any toxic-appearing child at any age with bilious vomiting should be evaluated for malrotation with midgut volvulus. In a verbal child, questions about urinary complaints should be included, such as dysuria, frequency, or discolored urine, suggesting a urinary tract infection, nephrolithiasis, or the nephritis of Henoch-Schönlein purpura. What is the patient’s baseline stooling pattern? Stools that are hard or extremely large suggest constipation, perhaps the most common cause for severe (but generally not dangerous) abdominal pain. If there is diarrhea, is it bloody, as in inflammatory bowel disease (IBD) or a bacterial infection? Are the stools melanotic, as in a bleeding duodenal ulcer? Are there red flags—weight loss, fatigue, night sweats—for a prolonged systemic disease such as Crohn disease? Are there extraintestinal manifestations that are suspicious for IBD, such as rash, arthralgias or arthritis, aphthous stomatitis, or eye problems? Is there a family history of gastrointestinal disorders, especially heritable disorders such as IBD? Is the patient on any medications that could predispose to abdominal pain, especially nonsteroidial anti-inflammatory drugs (suspected ulcer disease) or recent antibiotics (possible Clostridium difficile infection)? Is there anything relevant in the social history, such as recent sexual activity predisposing to a sexually transmitted disease or pelvic inflammatory disease, or difficulties at school or at home causing stress, suggesting a psychosomatic illness?

PHYSICAL EXAMINATION The physical examination starts with an evaluation of the vital signs. True abdominal catastrophes with associated abdominal pain (volvulus, perforated duodenal ulcer, splenic rupture following Epstein-Barr virus [EBV] infection, severe trauma) quickly progress to frank shock, with accompanying changes in hemodynamics and vital signs. Fever is often found with inflammatory and infectious processes. The degree of fever is not necessarily directly related to the severity of the eventual diagnosis. Fever of 104°F to 105°F is often seen with viral gastroenteritis, whereas the fever of appendicitis starts much lower and spikes to 104°F to 105°F only if perforation occurs. The importance of the patient’s general examination on presentation cannot be overstated. A toxic, shocky child needs emergent evaluation and intervention after ensuring that circulation, airway, and breathing are maintained, whereas a patient with normal vital signs who smiles and jokes while complaining of 10 out of 10 abdominal pain likely does not warrant admission. Examination of the acute abdomen was addressed earlier, with an emphasis on recognizing the signs of peritonitis. After inspection of the abdomen (for distension, discoloration, visible masses, etc.) bowel sounds should be assessed, because deep palpation can alter their character. Are the bowel sounds present? Are they high pitched, as in a bowel obstruction? Percussion of the abdomen is invaluable. Is the abdomen distended and tympanitic, potentially suggestive of increased intraluminal air proximal to an obstruction? Is there a fixed area of dullness, signifying organomegaly or a mass (malignant or otherwise, including a firm stool which may present with a left lower quadrant mass)? Is there a shifting dullness or a fluid wave, suspicious for ascites? Palpation is also important in evaluating for masses and organomegaly and for eliciting pain, and should be performed after auscultation and percussion. One should always begin palpating as far away from the reported location of the patient’s pain as possible. Having the child flex the hips and bend the knees is helpful to relax the abdominal musculature. The importance of distraction during palpation, especially for younger patient, cannot be overstated. The practitioner’s eyes should be fixed on the patient’s face, looking for even subtle signs of tenderness. The obturator sign and the psoas sign are suggestive of inflammation in or near those muscles, often secondary to organic abdominal pathology (described in Chapter 143). The Rovsing sign is present when palpation in the left lower

quadrant produces pain in the right lower quadrant, suggesting appendicitis. Rebound is thought to be sensitive for peritonitis, although many examiners feel that this is an unnecessarily painful maneuver that often adds little to the final evaluation. All children should have a full examination in addition to the abdominal examination, with an emphasis on findings that could be causing or contributing to the abdominal pain. Controversy exists over which children need rectal examinations and which females need pelvic examinations. In selected cases, either of these examinations can be immensely informative, and the need for them is dictated by the history.

EVALUATION As stated earlier, a patient with an obvious surgical abdomen often needs no further evaluation before surgical exploration is undertaken. For other patients, the question is whether to perform radiologic studies and/or laboratory tests.

RADIOLOGY The simplest and most widely available initial study is a supine plain radiograph of the abdomen (also known as a kidney, ureter, and bladder [KUB] study). Most findings are nonspecific and merely confirm the findings elicited by physical examination. Exceptions include a renal or ureteral calculus, the finding of a fecalith in the right lower quadrant, or a large amount of stool suggesting constipation. A fecalith is a small, radiointense mass of hardened stool that obstructs the lumen of the appendix, preventing the outflow of intestinal bacteria and predisposing the patient to appendicitis. Many surgeons will operate on a patient with an equivocal history based on a radiographic finding of a fecalith. Distended loops of bowel are common and nonspecific, as is scoliosis toward the side of pain. The addition of a second abdominal view in the upright or left lateral decubitus allows for effect of gravity on air and fluid to be examined. Air–fluid levels may be visible within bowel secondary to ileus or obstruction. Free air may be visible on the upright film, but these patients often have peritoneal signs on examination. Patients subsequently diagnosed with intussusception often have a paucity of air in the ascending colon, as this is the most common site for an

intussusception to occur. The radiologic evaluation of patients with suspected appendicitis has changed over the years. Many centers now use the Pediatric Appendicitis Score to determine which patients need further workup such as blood work or imaging, and which can be observed (see Chapter 155). Ultrasonography is a preferred initial modality, owing to the lack of radiation and its specificity for appendicitis. An added advantage of ultrasonography is the ability to assess blood flow in real time, which is particularly helpful in female patients with right lower quadrant pain, for whom ovarian torsion is in the differential diagnosis. Ultrasound can also be used in the evaluation of suspected intussusception to identify a “donut” (the intussusceptum within the lumen of the intussuscipiens). Air-contrast enema has the advantage of being able to both diagnose and treat intussusception, but because there is a small risk of perforation, this procedure should be performed only in centers staffed by surgeons competent in the care of small children. Computed tomography, especially when done with effective rectal or oral contrast, has high specificity for appendicitis, and is often undertaken if an initial ultrasound is equivocal. The radiologist is able to see signs of inflammation in the right lower quadrant, including free fluid and stranding in the pericecal fat. With effective contrast, an appendix that does not fill is presumed to be obstructed, confirming the diagnosis of appendicitis. The study is quite operator and hospital dependent, however. Other imaging studies that may be encountered in the evaluation of abdominal pain include barium swallows (effective for the evaluation of malrotation with intermittent volvulus and for IBD) and, rarely, nuclear medicine studies for gastrointestinal bleeding with associated abdominal pain. Magnetic resonance enterography is a new modality that is effective at finding and monitoring the small bowel inflammation in patients with IBD.

LABORATORY STUDIES As with radiologic studies, the history and physical examination guide the practitioner regarding laboratory studies. The result of all laboratory testing needs to be taken in context and cannot supercede physical findings or discount the importance of serial physical examinations. In patients with abdominal pain, a complete blood count (CBC) with

differential is helpful in the evaluation for inflammation, infection, or anemia. In general, an elevated high white blood cell (WBC) count with a neutrophilic predominance is more suspicious for an acute infectious or inflammatory cause of the patient’s pain, including appendicitis. However, a normal WBC count does not rule out appendicitis, and an elevated WBC count does not confirm it. Anemia, if observed, can be very helpful in pointing the practitioner toward a chronic disease such as IBD, especially if accompanied by a relative reticulocytopenia. A low mean corpuscular volume (MCV) suggests iron deficiency, perhaps suggestive of chronic blood loss. Sudden, acute blood loss may present with evidence of hemodynamic compromise before there is a fall in the hemoglobin level on an initial CBC. A basic chemistry panel with serum electrolytes, glucose, creatinine, and blood can help evaluate hydration status, acid–base balance, and electrolyte derangements, especially if vomiting, diarrhea, or inadequate oral intake is part of the clinical picture. These findings are typically less helpful in identifying the etiology of abdominal pain but are often needed for appropriate management. Evaluation of serum hepatic enzymes and bilirubin levels, often referred to as liver function tests, are useful for patients with right upper quadrant pain or tenderness, or with jaundice. These tests usually include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, γ-glutamyl transferase (GGT), and levels of both the conjugated and unconjugated fractions of serum bilirubin (see Chapter 79 for further discussion of these tests). Concern for mononucleosis should prompt, testing for EBV with either a heterophil antibody test (“monospot”) for children over 4 years of age or EBV serology. Elevations of pancreatic enzymes, amylase, and lipase are quite specific for pancreatitis, and these studies would be warranted in patients with epigastric pain or tenderness or prominent vomiting (see Chapter 82). Markers of inflammation, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated with chronic diseases like IBD, but again they are nonspecific and therefore can be elevated in many infectious, and inflammatory or malignant conditions. Newer serologic tests for IBD may be helpful in patients with a suggestive clinical picture, but definitive diagnosis still requires endoscopy with confirmatory tissue biopsy (see Chapter 80).

Urinalysis can provide information regarding hydration status (specific gravity) as well as indications of genitourinary involvement (e.g. red blood cells secondary to ureteral calculus or Henoch Schönlein purpura) or infection (e.g. nitrates and white blood cells secondary to pyelonephritis). Patients with appendicitis may have sterile pyuria if the inflamed appendix settles on the wall of the bladder. All stools for any child with abdominal pain should be tested for blood, and if there is concern for infectious gastroenteritis or colitis, appropriate samples should be sent to evaluate for the bacteria, toxins, parasites, or viruses of concern. Stool antigen for Helicobacter pylori can be sent if gastritis due to this entity is suspected (see Chapter 77).

TREATMENT The treatment of abdominal pain depends on what is discovered during the workup. Patients thought to have surgical pathology are given nothing by mouth and often need resuscitation with intravenous fluids before definitive surgical intervention. Particular attention should be paid to pain control, which often requires parenteral opioids. Surgery is undertaken when the patient is stable enough for anesthesia, or occasionally before this point if the patient is toxic and deteriorating. If bowel perforation is suspected, the patient is started on broad-spectrum antibiotics to cover enteric pathogens, including anaerobes. Patients who are admitted without a definitive diagnosis require close monitoring, and the importance of serial examinations cannot be overstated. Recent literature suggests that serial examinations by pediatric surgeons are as effective as radiologic evaluation in patients with suspected early appendicitis. Diligent monitoring of fluid intake and output, along with vital signs, can provide an early clue that a disease process is progressing. If there are stigmata of systemic gastrointestinal disease, consultation with a pediatric gastroenterologist, with an eye toward possible endoscopy, is appropriate. A number of treatments are available for constipation, and a child with viral gastroenteritis needs fluid resuscitation and tincture of time. As stated earlier, many patients who present with abdominal pain never receive a definitive diagnosis. When a symptomatic patient has been fully evaluated and organic disease has been ruled out, the goal of treatment is to control the patient’s symptoms and allow a return to the activities of daily living. A child must be able to tolerate enough by mouth to stay hydrated and

prevent weight loss. A school-age child must be able to attend school on most days. Above all, a patient with pain and a negative workup needs close follow-up, sometimes with a specialist, but always with the primary care physician. Literature increasingly suggests that patients with depression or anxiety may present with abdominal pain, and somatization disorder is a frequent cause of otherwise unexplained abdominal pain in the hospitalized patient. This clearly is a diagnosis of exclusion. In this case, a psychiatrist may need to be involved, both for the evaluation of nonorganic pain and for the teaching of coping strategies. For patients discharged to home, it should be stressed to parents that the workup is ongoing and will continue in the outpatient setting.

SUGGESTED READINGS Ashcraft KW. Consultation with the specialist: acute abdominal pain. Pediatr Rev. 2000;21:363-367. Boyle JT. Abdominal pain. In: Walker WA, Durie P, Hamilton J, et al., eds. Pediatric Gastrointestinal Disease. Hamilton, Ontario, BC: Dekker; 2000:129-149. Kliegman R. Acute and chronic abdominal pain. In: Kliegman R, ed. Practical Strategies in Pediatric Diagnosis and Therapy. Philadelphia, PA: WB Saunders; 2004:249-271. Kosloske AM, Love CL, Rohrer JE, et al. The diagnosis of appendicitis in children: outcomes of a strategy based on pediatric surgical evaluation. Pediatrics. 2004;113:29-34. Saito JM. Beyond appendicitis, evaluation and surgical treatment of pediatric acute abdominal pain. Curr Opin Pediatr. 2012;24:357-364.

CHAPTER

Acidosis

18

Chén Kenyon

BACKGROUND Acidosis is a common finding in many childhood disease states, ranging from self-resolving diarrheal illnesses to progressively degenerative mitochondrial disorders to acute septicemia and shock. Given the broad range of underlying illnesses and their disparate clinical consequences, identifying the specific etiology of acidosis is often crucial to a child’s hospital care. In circumstances where there is relative diagnostic certainty, appropriate identification and characterization of acidosis can contribute important clinical evidence for or against a prevailing diagnostic theory or management strategy. For patients whose illnesses have not been fully characterized, a rational approach to the interpretation of acidosis can help direct more specific diagnostic testing and further clinical evaluation. In this chapter, we discuss the pathophysiology, differential diagnoses, and workup strategies for acidosis, focusing primarily on metabolic acidosis. We include a section on respiratory acidosis in Special Considerations.

PATHOPHYSIOLOGY Acidosis is a metabolic state characterized by a relative excess of hydrogen ions (H+). This relative excess can result from a number of processes: (1) an increase in H+ generation, (2) a decrease in H+ elimination via the kidneys, (3) a decrease in basic buffer molecules, or (4) a combination of the three. These processes reflect imbalances in the various counter-regulatory systems involved with acid–base homeostasis. A growing child generates a net of 1–3 mEq/kg/day of acid through normal metabolic processes. To maintain the optimal conditions for

enzymatic activity (a pH between 7.35 and 7.45), the body must efficiently eliminate this and any additional acid load. Three primary mechanisms are responsible for maintaining this balance: the blood buffer system, respiratory ventilation, and renal excretion. Immediately upon exposure to excess acid, circulating buffers, including bicarbonate (HCO3−), bind excess H+, diminishing its concentration in the extracellular space. The excess H+ that binds to bicarbonate forms the “volatile” carbonic acid, which can then dissociate into carbon dioxide (CO2) and water. Assuming sufficient H+ excess and effective pulmonary ventilation, excess CO2 is then removed from the circulation through the pulmonary capillaries and alveoli. In response to persistently diminished pH, peripheral chemoreceptors and central respiratory centers increase minute ventilation to augment this process. Lastly, the proximal tubules in the kidney respond to excess H+ by increasing bicarbonate reabsorption and ammonia synthesis, the latter of which assists with renal hydrogen ion elimination in the form of ammonium ions (NH4+). Acidemia, defined as an arterial pH of less than 7.35, occurs when the body’s numerous compensatory mechanisms to address an acid load are overwhelmed or compromised. The compensatory mechanisms can be overwhelmed in the setting of excess “non-volatile” acid production, as occurs acutely in lactic acidosis, diabetic ketoacidosis (DKA), or more indolently in the organic acidopathies. The body’s buffer system can be compromised when there is a reduction in circulating bicarbonate from gastrointestinal losses (e.g. prolonged diarrheal illness) or renal losses (e.g. proximal renal tubular acidosis). Compromised ventilation from a number of etiologies diminishes the body’s ability to readily eliminate volatile acid in the form of CO2, leading to retained H+. Defects in the kidney’s ability to appropriately acidify urine, as occurs with renal tubular acidosis (RTA), comprise the last set of conditions that lead to imbalances of this intricate homeostatic system. DEFINITIONS Acidosis: A state of relative excess of hydrogen ions. Acidemia: Arterial pH less than 7.35.

Metabolic Acidosis: An acute or chronic state resulting from excess non-volatile H+ production, decreased H+ elimination via the kidneys, or diminished buffering capacity. Respiratory Acidosis: An acute or chronic state of excess H+ resulting from inadequate removal of volatile acid in the form of CO2 via the lungs.

PATIENT HISTORY Generally, the symptoms of acidosis are non-specific. History should be targeted toward identifying the source of the acidosis. Common features of metabolic acidosis are vomiting and tachypnea. Other symptoms may include fatigue, lethargy, seizures, and alterations in mental status. Children with diarrheal illness may have acidosis but this is not a symptom of the acidosis, rather the precipitant. Analogously, children with respiratory acidosis may present with decreased respiratory rate or respiratory failure, also conditions which led to the acidosis. History of ingestion is particularly important, as is history of medical conditions that may predispose the patient to acidosis. Among others, these include diabetes mellitus, prior diagnosis of metabolic disorder, seizure disorder on a ketogenic diet, and systemic lupus erythematosus (which can be associated with a distal RTA). A number of medications are also associated with acidosis, including acetazolamide and other medications that can inhibit carbonic anhydrase (i.e. some anti-epileptic medications) and amphotericin B or amiloride, that may mimic RTAs.

PHYSICAL EXAMINATION Physical examination findings for children with acidosis are similarly nonspecific. Signs of hypovolemia (tachycardia, hypotension, delayed capillary refill, etc.) and tachypnea are often present in children with a diarrheal cause of excess bicarbonate loss or in those with lactic acidosis or DKA. Children presenting with DKA may present with fruity smelling breath from increased acetone ventilation. Patients with severe acidosis may present with alterations in level of consciousness or obtundation.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for acidosis is broad. As with other clinical scenarios, a basic understanding of epidemiology helps to generate an ordered differential diagnosis by assessing the prior probability of a particular cause with respect to the individual characteristics, symptoms, and signs of the child before you. Etiologies such as diarrheal illness and lactic acidosis are most probable from the general population perspective. However, certain groups require special consideration, including toddlers, where ingestions are particularly common, and newborns, where undiagnosed inherited disorders of metabolism are more prevalent. While Bayesian logic helps to order the possible diagnostic options, a number of well-established and relatively formulaic strategies to characterize a child’s acidosis are valuable in guiding further evaluation. One such strategy is detailed in Figure 18-1.

FIGURE 18-1. Step-wise approach to evaluation of metabolic acidosis. The initial step in categorization is to determine whether acidemia (pH 14 mEq/L provides the clinician with evidence of both the presence and quantity of unmeasured anions, although gaps of up to 16 mEq/L may be normal in newborns.1 These unmeasured anions are generated through the buffering action of HCO3− in the presence of excess acid, as depicted in the following equilibrium: H+anion− + NaHCO3 ⇔H2O + CO2 + Na+anion− In this equilibrium, H+anion− represents the excess acid, such as keto-

acids, lactic acid, and organic acids. Through this reaction, HCO3− is metabolized, and the anion salt of the excess acid remains and serves to maintain serum electrochemical neutrality. When HCO3− is metabolized at a greater rate than the acid salt is eliminated and new HCO3− generated, an unmeasured anion will be detectable when calculating the anion gap. Etiologies of anion gap and non–anion gap acidosis are presented in Table 18-1, and the diagnostic evaluation of these categories is discussed in the next section. Of note, the calculated anion gap may be inappropriately low in the presence of unmeasured cations, as with lithium toxicity and hypermagnesemia, or in the setting of hypoalbuminemia, which is a potent contributor to the normal anion gap. In the setting of low albumin, an adjusted AG can be calculated using the following formula: TABLE 18-1

Etiologies of Anion Gap and Non–Anion Gap Metabolic Acidosis

Anion Gap Acidosis Ketoacidosis Diabetic ketoacidosis Alcoholic ketoacidosis Starvation Lactic acidosis Tissue hypoxia Shock Dehydration Hypoxia Carbon monoxide poisoning Increased production or decreased clearance of lactate Leukemia, lymphoma, large tumors Liver or renal failure Renal failure (especially if GFR 6 suggests the presence of a mixed disorder, such as a concomitant respiratory alkalosis in salicylate toxicity. Exceptions to this rule include lactic acidosis, where the increase in the anion gap can be as much as 1.6–1.8 times the decrease in serum bicarbonate, and diabetic ketoacidosis, where it is often less than 1:1, as ketoacids are lost in the urine.

DIAGNOSTIC EVALUATION The most important initial labs in the evaluation of metabolic acidosis are a basic metabolic panel and an arterial, venous, or capillary blood gas. While the latter three have been demonstrated to be highly correlated on all parameters except pO2 in the ICU setting,2 an appropriately collected and processed sample is critical in making appropriate inductions regarding the nature of the acidosis. Using a systematic approach to interpretation of these

simple tests, such as the step-wise method described above, the clinician can determine whether further diagnostic evaluation is necessary, and if so, engage in a rational and targeted approach. Depending upon the acuity of the child’s illness and the suspected causes, this evaluation may be relatively extensive. At this point, involvement of the appropriate specialist, if available, may be warranted.

EVALUATION OF ANION GAP ACIDOSIS As described above, an anion gap of >14 usually suggests the presence of unmeasured anions and may warrant further investigation. An anion gap of 20 or greater is more than 4 standard deviations above the mean and in this scenario, a metabolic acidosis is likely to be present, regardless of whether the pH or serum HCO3− are within the normal range. In those with an anion gap greater than 20, a specific cause for the metabolic acidosis will likely be discerned from the usual screening tests2 (Table 18-2). TABLE 18-2

Initial Laboratory Evaluation for Metabolic Acidosis

Standard Arterial blood gas Electrolytes (Na+, K+, Cl−, HCO3−) Blood urea nitrogen, creatinine Glucose Urine pH Consider urine electrolytes Based on clinical suspicion Serum toxicology screen or measurement of specific drug if suspected Complete blood count Bacterial cultures Hepatic enzymes and albumin determinations Prothrombin time

Screening tests for suspected metabolic disorder (see Table 18-3) Electrocardiogram TABLE 18-3

Laboratory Studies for Suspected Inborn Error of Metabolism

Blood Complete blood count with differential Blood gas Serum electrolytes Glucose Ammonia, lactate, and pyruvate Amino acid quantification Acylcarnitine profile Free and total carnitine Urine Urinalysis, including ketones Organic acids Acylglycines Depending on clinical suspicions as to the cause of the acidosis, a number of studies should be considered. A complete blood count may be abnormal in the setting of lactic acidosis from distributive shock secondary to infection or systemic illness. Elevated liver enzymes and abnormal function test results might indicate hepatic failure/dysfunction. In an infant or toddler with a history of poor growth or delayed development, recurrent vomiting or lethargy, or acidosis or hypoglycemia with illness, a metabolic disorder should be considered, and appropriate screening studies should be performed in consultation with a metabolism specialist (Table 18-3). An electrocardiogram should be done if there is evidence of severe acidosis or other electrolyte abnormalities such as hyperkalemia. Serum or urine toxicology screening can be obtained if there is concern for ingestion or if interpretation of the initial labs reveals a second metabolic process.

In the setting of an elevated anion gap and concern for ingestion, calculating the osmolal gap can be useful. Serum osmolality is calculated according to the following equation: osmolalitycalc (mOsm/kg) = 2 × Na+ (mEq/L) + blood urea nitrogen (mg/dL)/2.8 + glucose (mg/dL)/18 The osmolal gap (the difference between measured osmolality and calculated osmolality) is normally 10–15 mOsm/kg. If the measured osmolality exceeds the calculated osmolality by more than 15–20 mOsm/kg, this indicates an accumulation of osmolytes other than the sodium salts, urea, and glucose, as seen with ingestion of ethylene glycol or methanol.

EVALUATION OF NON–ANION GAP ACIDOSIS The urinary anion gap (UAG) can be useful in differentiating between two common causes of non–anion gap acidosis: gastrointestinal losses and renal tubular acidosis (RTA). The UAG is calculated by obtaining spot measurements of urinary Na+, potassium (K+), and Cl− (all units mEq/L): UAG = (Na+ + K+)urine − (Cl−)urine The UAG is an indirect measure of urinary ammonium (NH4+), the precursor of which (ammonia = NH3) is generated in the proximal tubules in the setting of acidosis. NH4+ is assumed to be present if the sum of the major urinary cations (Na+ + K+) is less than the major anion (Cl−); because electrochemical neutrality must exist in the urine, some cation must be balancing the apparent surplus in measured Cl−. In a metabolic acidosis from chronic diarrhea, the functioning kidneys increase proximal tubule NH3 synthesis, thus providing more urinary buffer. In RTA, the urinary NH4+ is low because of the kidney’s intrinsic inability to compensate for acid loads. Thus, a negative UAG usually suggests an extra-renal cause of non–anion gap acidosis (but can be negative with a proximal RTA), whereas a positive

UAG suggests a renal cause (specifically distal RTA) of non–anion gap acidosis. The UAG should be interpreted with caution in the setting of hypovolemia, as adequate distal delivery of Na+ is necessary for appropriate distal acidification, and when urinary pH >6.5, as HCO3− is likely present in the urine. With specific regard to RTA, the acidosis in a distal RTA is usually more profound than with proximal RTA. A urine pH >5.5 in the setting of acidosis may indicate impaired acidification of the urine, pointing toward a distal RTA. The urine pH in proximal RTA is variable, depending on the threshold of bicarbonate reabsorption. In general, children with proximal RTA can appropriately acidify the urine to 5.3 if above the child’s bicarbonate reabsorptive threshold. If proximal RTA is suspected based on above evaluation, other features of proximal tubular dysfunction (Fanconi syndrome) may be present, including glucosuria, hypokalemia, hypophosphatemia, generalized aminoacioduria, and so forth.

MANAGEMENT Management of metabolic acidosis is directed to treatment of the underlying cause. In general, treating the causes of anion gap acidosis can regenerate bicarbonate within hours; however, non–anion gap acidosis can take days to resolve and may require exogenous bicarbonate therapy. Insulin, hydration, and electrolyte repletion will correct the acidosis in diabetic ketoacidosis. Lactic acidosis will resolve with increasing tissue oxygenation using crystalloid, blood products, inotropic agents, and oxygen. Renal failure may require dialysis. Ethylene glycol and methanol ingestion can be treated with fomepizole, ethanol, and hemodialysis. Management of salicylate ingestion may include repeated doses of activated charcoal, alkalization of urine to optimize excretion, correction of metabolic derangements such as hypoglycemia and hypokalemia, and hemodialysis for severe ingestion. For acidosis secondary to metabolic disorders, the basic principle is to reverse counter-regulation and tissue catabolism with appropriate energy substrate (see section Inborn Errors of Metabolism under Special Considerations for details). Diarrhea can be managed with fluid and electrolyte repletion. Bicarbonate supplementation and management of calcium and potassium

homeostasis are effective in managing RTA, regardless of type. The use of sodium bicarbonate in the treatment of severe metabolic acidosis is controversial. Once considered a mainstay of acute therapy for severe acute metabolic acidosis, studies have failed to demonstrate benefit of sodium bicarbonate in a number of scenarios, including severe diabetic ketoacidosis,3 neonatal resuscitation,4 and preterm metabolic acidosis.5 This has led some to question whether it has any role in acute metabolic acidosis therapy,6 especially given the list of potential side effects. Most notably, in the setting of suboptimal ventilation, bicarbonate infusion can lead to increase intracellular [pCO2], as HCO3− undergoes rapid conversion to carbonic acid and dissociation to H2O and CO2, which will diffuse into the tissue without adequate elimination via ventilation. Despite accumulating evidence for lack of clear benefit, sodium bicarbonate is frequently used in the setting of severe acidosis (pH 10 g/kg/day in children younger than 3 years and >200 g/day in children older than 3. Diarrheal episodes are typically classified into acute and chronic, based on duration. Acute diarrhea is defined as an episode of diarrhea that is acute in onset and lasts less than 14 days. Chronic diarrhea is defined as an episode that lasts equal to or longer than 14 days. This distinction has implications for etiology, management, and prognosis.

PATHOPHYSIOLOGY In the normally functioning gastrointestinal tract, nutrients are absorbed via

active, carrier-mediated transport across the intact mucosal lining. Electrolytes such as sodium, potassium, chloride, and bicarbonate are transported via both active and passive mechanisms, with sodium transport creating the most significant gradient. This sodium gradient is responsible for promoting the passive transport of water across the mucosal lining. Under normal circumstances, there is a balance between the absorptive and secretory functions, which are the opposing unidirectional electrolyte fluxes. This results in a net water absorption, with 90% of the absorption occurring in the small intestine. Altered pathophysiologic mechanisms resulting in diarrhea can be divided into four categories: osmotic, secretory, inflammatory, and motility disorders. Osmotic diarrhea occurs when excessive amounts of solutes are retained in the lumen of the intestine, resulting in decreased water absorption. Osmotic diarrhea will typically cease with fasting or withholding of the poorly absorbed solute. Secretory diarrhea occurs when secretion of water into the lumen of the intestine exceeds absorption. In most cases, the diarrhea is not affected by alterations in enteral intake. Inflammation can cause diarrhea when there is mucosal damage resulting in decreased water absorption and increased fluid secretion. Inflammatory diarrhea may be associated with mucus, blood, and protein losses in the stool. Lastly, motility disorders cause either increased or decreased transit time in the intestine, leading to altered water absorption. A decreased transit time due to increased motility results in diarrhea.

PATIENT HISTORY The frequency, duration, volume, and character of the diarrhea (including smell, color, and presence of mucus or blood) should be determined during history-taking. It is important to understand the patient’s normal bowel habits to determine the degree of change from baseline. A careful diet history may help identify inciting factors contributing to osmotic diarrhea, as well as identify foods associated with food- or water-borne pathogens (Salmonella, Shigella, Escherichia coli, Giardia). Daycare attendance, sick contacts, exposures to pets, and recent travel history should also be explored. Giardia and Salmonella are the most common parasitic and bacterial pathogens, respectively, causing diarrhea in daycare attendees. One should inquire about

exposure to animal vectors such as reptiles, which can be associated with Salmonella, as well as travel to areas with common endemic parasitic or bacterial infections. A history of recent antibiotic use should be obtained. Antibiotic-associated diarrhea typically resolves with cessation of medication, but Clostridium difficile can be associated with persistent diarrhea or blood in stool following recent antibiotic use. It is also important to elicit any accompanying systemic symptoms. Fever is often associated with viral and bacterial infections. Rash or wheezing may accompany allergy-mediated diarrhea. Seizure activity associated with diarrhea in an otherwise healthy child can be seen with Shigella infection. Growth history and nutritional status should be obtained, especially when considering the cause of chronic diarrhea. One of the most common causes of chronic diarrhea in toddler-age children is a disorder of small intestinal motility called nonspecific diarrhea of childhood (“toddler’s diarrhea”). Post-infectious carbohydrate intolerance, a form of acquired lactose intolerance, can result in osmotic diarrhea in an otherwise well patient with recent acute gastroenteritis. Both nonspecific diarrhea of childhood and postinfectious carbohydrate intolerance may be related to ingestion of excessive amounts of sugary fluids (juice, soda). Constipation with encopresis should also be considered in children with chronic diarrhea, which actually represents leakage of watery stool around a blockage in a dilated colon. Plotting a careful growth curve can assist in making a diagnosis in children with chronic diarrhea. Patients with cystic fibrosis often have poor growth beginning soon after birth. In contrast, children with celiac disease typically exhibit poor growth after 4 to 6 months of age, coincident with the introduction of gluten-containing solids to the diet.

PHYSICAL EXAMINATION The physical examination should first focus on the patient’s hemodynamic stability and hydration status to determine whether immediate fluid resuscitation is needed. Comparison of premorbid weight to the weight at presentation is the most reliable method of determining the degree of dehydration, but this is not always feasible. Mild dehydration occurs when the patient is 3% to 5% dehydrated. Clinical signs are usually evident at ~3%. Moderate dehydration results from 6% to 9% body weight lost. Severe

dehydration occurs when the patient is greater than or equal to 10% dehydrated, and can be fatal. Fluid status should also be assessed by examination of mental status, mucous membranes, anterior fontanelle, skin turgor, capillary refill, and urine output. Because chronic diarrhea may represent underlying systemic illness as well as lead to the loss of calories, protein and other minerals and vitamins (including zinc and vitamin B2), the physical examination should also look for evidence of these deficiencies (Table 22-1). TABLE 22-1

Selected Physical Findings Consistent with Evidence of Malnutrition or Systemic Illness

Area of Examination Finding

Nutritional Deficiency/Systemic Illness

General

Underweight

↓ Calories

Edematous

↓ Protein

Hair

Easily pluckable, sparse

↓ Protein, zinc

Skin

Generalized dermatitis

↓ Zinc

Erythema nodosum

Inflammatory bowel disease

Subcutaneous tissue

Decreased

↓ Calories

Muscles

Decreased mass

↓ Calories, protein

Mouth/tongue

Glossitis, angular stomatitis

↓ Vitamin B2

Oral ulcers

Inflammatory bowel disease

Extremities

Digital clubbing

Cystic fibrosis

Anus/rectum

Rectal prolapse

Cystic fibrosis

Perianal tags, fissures, fistulas

Inflammatory bowel disease

DIFFERENTIAL DIAGNOSIS The list of possible causes of diarrhea is extensive (Table 22-2). Distinguishing acute diarrhea from chronic diarrhea can be helpful in creating a differential. Most commonly, the cause of acute diarrhea is infectious. Viral infection (rotavirus, Norwalk virus, enteric adenovirus, calicivirus) account for most cases of acute diarrhea. Other infectious causes include bacterial pathogens (E. coli, Salmonella, Shigella, Campylobacter) and parasites (Giardia). TABLE 22-2

Causes of Diarrhea

Infectious Viruses Rotavirus Norovirus and other caliciviruses Enteric adenovirus Astrovirus Bacteria Salmonella Shigella Campylobacter jejuni Escherichia coli Staphylococcus aureus Clostridium difficile Aeromonas hydrophila Plesiomonas shigelloides

Vibrio cholera Vibrio parahaemolyticus Yersinia enterocolitica Parasites Giardia lamblia Entamoeba histolytica Cryptosporidium Congenital Congenital microvillus atrophy Autoimmune enteropathy Hirschsprung disease Congenital chloride-losing diarrhea Intractable diarrhea of infancy Short-bowel syndrome Malabsorptive Celiac disease Cystic fibrosis Inflammatory bowel disease Monosaccharide deficiencies Disaccharide deficiencies Post-infectious enteropathy Motility disorders Irritable bowel syndrome Allergic or intolerance Eosinophilic enteropathy Cow milk or soy protein intolerance Systemic Hemolytic uremic syndrome Hyperthyroidism α1-Antitrypsin deficiency

Immune deficiency Intestinal lymphangiectasia Acrodermatitis enteropathica Pancreatic insufficiency Hormone-secreting tumors Adrenal insufficiency α-lipoproteinemia Protein calorie malnutrition Miscellaneous Toddler’s diarrhea Constipation with encopresis Antibiotic associated Chronic diarrhea involves a broad list of possible causes. When evaluating chronic diarrhea, the age of the patient is helpful in narrowing the differential. In children under 1 year of age, intractable diarrhea of infancy is a common diagnosis. This entity is associated with diffuse mucosal injury resulting in persistent diarrhea, malabsorption, possible hematochezia, and malnutrition beginning before the age of 6 months. It is most commonly related to either cow milk or soy protein intolerance or prolonged postinfectious mucosal injury. Between the ages of 1 and 5 years, post-infectious enteritis, giardiasis, and celiac disease are more common diagnoses. In children older than 5 years, inflammatory bowel disease, constipation with encopresis, and acquired lactose intolerance are more likely. It is also important to remember that chronic diarrhea may be a presenting symptom of an immune deficiency, including HIV.

DIAGNOSTIC EVALUATION In most cases of viral gastroenteritis, laboratory evaluation is not necessary. The laboratory evaluation for patients presenting with diarrhea is individualized, with attention paid to the acute versus chronic nature of the diarrhea. For some patients, the search for a specific cause should be explored, including hospitalized patients with nosocomial exposure,

immunocompromised patients, and young infants, and in those presenting with high fever, toxic appearance, grossly bloody stools, and with recent antibiotic use. When a diagnosis is necessary, stool should be sent based on history for any or all of the following: occult blood, presence of fecal leukocytes, fecal fat, bacterial culture, ova and parasites, rotavirus antigen testing, C. difficile toxin, and Giardia antigen assay. If there is concern for a particular bacterial pathogen, this should be communicated to the laboratory so that the specimen can be plated on the appropriate media. If carbohydrate malabsorption is suspected, stool pH (41°C (105.8°F).

PATIENT HISTORY A thorough history and physical examination usually provide the most important clues in determining the cause of fever. Fever may be a sign of a benign, self-limited condition or may be indicative of a life-threatening illness. Important historical clues include the duration of fever, pattern of fever, and associated symptoms. A single spike of fever is typically not associated with an infectious disease, though it may be due to manipulation of catheters, drugs, and blood infusions. Viral infections typically are associated with a slow decline in fever over a week, whereas uncomplicated bacterial infections are associated with prompt resolution of fever within 24 to 48 hours of effective antibiotic administration.2 Table 24-1 describes common fever patterns and the associated diseases. Since the fever pattern is so important, a home diary of daily fevers is an extremely valuable tool when evaluating a patient with prolonged fever. The past medical history of a patient with fever should include any history of immunodeficiencies, previous major illnesses, and immunization status. Additional information that is important to elucidate are sick contacts (especially those with similar symptoms), attendance in daycare or school, medications currently used (including prescriptions, over-the-counter medications, and alternative remedies), travel and exposure history (pets, insects, undercooked foods).2 TABLE 24-1

Patterns of Fever Fever Type

Description

Intermittent Exaggerated circadian rhythm that includes normal temperatures on most days Septic

Wide fluctuation in temperatures

Sustained

Persistent fever that does not fluctuate by more than 0.5°C in 24 h

Remittent

Persistent fever that varies by more than 0.5°C in 24 h (e.g. tuberculosis, viral fever, many bacterial infections)

Relapsing

Febrile periods separated by intervals of normal temperature (e.g. Borrelia infection, syphilis, histoplasmosis, Behcet disease, systemic lupus erythematosus)

Tertian

Fever that occurs on the first and third days (malaria caused by Plasmodium vivax)

Quartan

Fever that occurs on the first and fourth days (malaria caused by Plasmodium malariae)

Biphasic

Illness with two distinct periods of fever over ≥1 wk (e.g. poliomyelitis, enteroviral infections)

Periodic

Recurring illnesses with some periodicity (e.g. cyclic neutropenia, Periodic fever aphthous stomatitis pharyngitis adenopathy (PFAPA), familial Mediterranean fever)

Double Quotidian

Fever that peaks twice in 24 h (classically associated with inflammatory arthritis)

PHYSICAL EXAMINATION A thorough physical examination is often crucial to determining the etiology of fever. The overall appearance of the patient must be assessed (i.e. does the patient appear toxic or well?) in addition to a complete examination with attention to possible signs of infection (pain, erythema, swelling, tenderness). The skin in particular should be examined closely, because a number of rashes with fever may be diagnostic. A full lymph node examination should also be performed. A complete set of vital signs including pulse oximetry, as always, is necessary for evaluation of a febrile child. The relationship between the patient’s pulse rate and fever may also aid diagnosis. It is normal for a certain amount of tachycardia to accompany fever, but relative tachycardia, in which the pulse rate is elevated out of proportion to temperature, is suggestive of a noninfectious process such as a toxin-mediated illness. Relative bradycardia, when the pulse rate is low despite the temperature elevation, suggests typhoid fever, brucellosis, leptospirosis, Legionnaires’ disease, drug fever, or a cardiac conduction defect that may occur with acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis.2 When a patient has a fever greater than 41°C, noninfectious conditions should be considered, including central fever resulting from central nervous system dysfunction, drug fever, malignant neuroleptic syndrome, heatstroke, and malignant hyperthermia.2

DIFFERENTIAL DIAGNOSIS The differential diagnosis of fever is broad and generally falls into one of four categories: infectious disease, rheumatic disease, malignancy, or miscellaneous (drug reaction, heat disorders, etc.). A complete history and physical will provide essential information needed to narrow the differential diagnoses being considered for each patient and dictate if further workup is necessary. For example, postoperative patients may develop fever from a number of causes, most commonly including atelectasis, wound infection, bacteremia, and deep venous thrombosis. Patients who have had urinary bladder catheters in place are at increased risk for urinary tract infection. Further, any procedure involving the surgical placement of a device such as a

catheter, shunt, rod, or other hardware carries a risk of infection (see Chapter 107).

DIAGNOSTIC EVALUATION Fever is a sign of a condition that incites cytokine production, so the focus of the evaluation is identifying that inciting condition. This evaluation is often dependent upon the specific characteristics and circumstances of the child presenting with fever. Most febrile episodes in a normal host can be diagnosed by a thorough history and physical and require few, if any, laboratory or radiographic tests. However, in children with fever and no apparent source, additional testing may be warranted on a case-by-case basis. Chapter 95 discusses fever in infants and toddlers and Chapter 96 discusses illnesses associated with prolonged fever (i.e. fever of unknown origin). Fever in an immunocompromised host is discussed in Chapter 109. Elevations in body temperature that occur without an inflammatory trigger, as seen in heat disorders, are discussed in Chapter 172.

MANAGEMENT Antipyresis is controversial among clinicians, scientists, caregivers, and patients. “Fever phobia,” or an unrealistic concern based on misperceptions of fever, is prevalent.3 Many caregivers believe that fever is a disease (rather than a symptom) and fear that fever itself may have life-threatening or braindamaging effects. There is no evidence that children with fever as a result of endogenous and exogenous pyrogens are at increased risk of adverse outcomes such as brain damage.5 Interestingly, over half of parents consider a temperature of less than 38°C (100.4°F) to be a fever, one quarter of parents would give antipyretics for temperatures less than 37.8°C (100°F), and 85% of parents reported awakening their child from sleep to give antipyretics. Treating a fever is not without risk, as up to one half of parents administer incorrect doses of antipyretics, with 15% of parents giving supratherapeutic dosing.3,5 The drawbacks to treating fever include the concerns that lowering a fever may impair the body’s ability to fight off infection, remove important diagnostic clues regarding the pattern of fever, and interfere with the

interpretation of the response to therapy for the inciting condition. There is limited data suggesting that fever actually helps the body recover more quickly from viral infections, although the fever may result in discomfort in children.4,5 The benefits of fever reduction include patient comfort, improved oral intake, decreased insensible fluid loss, and improved ability to assess the patient’s demeanor.5 However, the fever’s response to antipyretics is not diagnostic and does not provide information about its cause. There is some evidence that the same pyrogenic cytokines responsible for fever have potentially detrimental effects, including increased oxygen consumption, carbon dioxide production, and cardiac output, all of which can worsen the condition of children in shock or with chronic diseases such as cardiac insufficiency, sickle cell disease anemia, pulmonary insufficiency, diabetes mellitus, or inborn errors of metabolism.2 Of note, there is no evidence that antipyretic therapy decreases the recurrence of febrile seizures.5 Antipyresis is most commonly pursued pharmacologically. PGE2, which is central to the production of fever, is synthesized from arachidonic acid, mediated by the enzyme cyclooxygenase (COX). There are two isoforms of this enzyme, COX-1 and COX-2. COX-1 is expressed throughout the body constitutively and is thought to be important for a variety of “housekeeping” functions to maintain homeostasis. COX-2 is inducible by a number of the pyrogenic cytokines and is thought to be the key provider of PGE2 during the febrile and inflammatory response.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen interfere with prostaglandin production through nonselective COX inhibition and down-regulation of the expression of COX enzymes. As a result, they have both antipyretic and anti-inflammatory effects. Selective COX-2 inhibitors were created to maintain the antipyretic and anti-inflammatory effects of the non-selective agents, but in theory cause fewer unwanted side effects of COX-1 inhibition, such as gastrointestinal bleeding. However, large clinical trials raised concerns that selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, leading to the removal of several of these drugs from the market in the United States and elsewhere.1 Surprisingly, the exact mechanism of action of acetaminophen, the most

commonly used antipyretic in pediatrics, remains unknown. It possesses excellent antipyretic but relatively weak anti-inflammatory effects. It is a weak inhibitor of COX, but its effect may be based on tissue-specific COX inhibitors. Acetaminophen penetrates the blood–brain barrier and causes a fall in central nervous system PGE2 production. Despite the controversies and uncertainties, virtually all parents expect their children to be treated for fever. It is of utmost importance that the goals of treating fever are discussed with families, emphasizing the therapeutic end-points of maximizing the child’s comfort and fluid intake rather than focusing on achieving normothermia. Families should be counseled to observe for signs of serious illness and discouraged from focusing on the fever alone. Acetaminophen (15 mg/kg every 4–6 hours, maximum of 5 doses in 24 hours) and/or ibuprofen (10 mg/kg every 6 hours in children over 6 months of age) are the mainstays of treatment. Aspirin should not be used due to the risk of Reye syndrome. Tepid sponge baths are not recommended to reduce fever because data have shown that they are no more effective than antipyretics alone and significantly increase patient discomfort scores. Alcohol baths are also discouraged because there have been reported adverse events associated with systemic absorption of alcohol.5 Some practitioners recommend using acetaminophen and ibuprofen in an alternating or combined fashion. While there are some studies that show lower temperatures, lower stress scores, and less time missed from child care in the combination treatment groups versus single-agent treatment groups, questions remain regarding the safety of this practice due to potential dosing confusion, whether it improves the comfort of the child, and whether this recommendation contributes to the fever phobia that already exists. Regardless of whether a single medication or alternating antipyretics are used, caregivers should be counseled on proper formulation, dosing (weightbased, not age-based), dosing intervals, and safe storage of these medications.5 Children should not receive cough and cold medications at the same time as antipyretics because there are often additional antipyretic medications in the cough and cold formulations. Families do not need to wake children for the purpose of administering antipyretic medications. It is often helpful for families, especially those with multiple caregivers, to keep a medication log to include the type of antipyretic, dose, and time given to

avoid inadvertent overdosing. Fever due to specific underlying etiologies resolves with appropriate treatment of the disease. Examples include administration of antibiotics for bacterial infections or administration of IVIG to treat Kawasaki disease. KEY POINTS Fever is a common presenting complaint prompting medical evaluation in children. Fever is a sign of an underlying pathology, not a disease itself. History and physical examination play an important role in determining diagnostic evaluation and management options. The differential diagnosis of fever is broad and generally falls into one of four categories: infectious disease, rheumatic disease, malignancy, or miscellaneous. Antipyresis using COX inhibition is the mainstay of treatment. The goal of treatment is patient comfort, not normothermia. Fever due to specific underlying etiologies resolves with the appropriate treatment of the disease.

REFERENCES 1. Kumar V, Abbas AK, Fausto N, eds. Acute and chronic inflammation. In Robbins and Cotran: Pathologic Basis of Disease. 8th ed. Philadelphia, PA: WB Saunders; 2010. 2. Nield LS and Kamat D. Fever. In: Kliegman RM, Stanton BF, St Gemell JW, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier; 2011:896e8-11. 3. Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics. 2001;107:1241-1246. 4. Ward M. Pathophysiology and management of fever in infants and children. UpToDate. 2013. 5. Section on Clinical Pharmacology and Therapeutics, Committee on

Drugs, Sullivan JE, Farrar HC. Fever and the antipyretic use in children. Pediatrics. 2011;127(3):580-587.

CHAPTER

25

Gastrointestinal Bleeding April Buchanan

BACKGROUND Gastrointestinal (GI) bleeding produces alarm and anxiety in parents and physicians. Most causes of GI bleeding do not result in significant blood loss, and many cases of GI bleeding cease spontaneously. Larger volume bleeding can lead to hemodynamic compromise that requires aggressive resuscitation and intervention. A systematic approach to diagnosis is required. DEFINITIONS Hematemesis: Vomiting of either fresh or altered blood (such as coffee grounds emesis). Implies recent or continuing bleeding proximal to the ligament of Treitz. Hematochezia: Bright red blood per rectum or maroon-colored stools. Usually originates in the colon. Upper GI hemorrhage can also present with hematochezia secondary to decreased transit time in infants or with brisk bleeding. Blood-streaked stools suggest a bleeding source in the rectum or anal canal. Melena: Dark or black, tarry stools with a characteristic odor. Indicative of blood that has been in the GI tract for a long time, allowing the denaturation of hemoglobin by bowel flora. Melenic stools are typically from a hemorrhage originating proximal to the ileocecal valve. Occult blood: Presence of blood in the stool that is not visible but is confirmed by chemical testing (i.e. guaiac.)

PATIENT HISTORY The history can be helpful in identifying the cause and location of bleeding in the GI tract (Table 25-1). Quantifying the volume and acuity of blood loss is important in understanding the risk of hemodynamic compromise. The character of the blood may indicate a more likely location of bleeding, though brisk bleeding from an upper GI source can cause hematochezia. Fever, recent travel, or known sick contacts may implicate an infectious source, while longer-standing symptoms and associated weight loss may indicate a more serious underlying cause such as inflammatory bowel disease (IBD). A complete medication history is essential, including recent use of nonsteroidal anti-inflammatory drugs (NSAIDs) or antibiotics. Certain foods (e.g. beets) or medications can also cause a red discoloration of GI fluids and be mistaken for hematemesis or melena. TABLE 25-1

Focused History

Characteristics of Bleeding Quantity: volume of blood (few drops vs. a cup) Duration: intermittent bleeding, isolated episode, ongoing bleeding Character: bright red blood, coffee grounds emesis, melena, hematochezia Abdominal Complaints Bowel patterns: diarrhea (infectious) or constipation (fissures), change in stool color Abdominal pain: indicates inflammation or ischemia of bowel wall Painless bleeding: indicates Meckel diverticulum, duplication, vascular malformation, or polyps Abdominal distention: possible bowel obstruction Tenesmus or urgency to defecate: consider IBD or infectious colitis Dietary History Cow milk or soy formula: consider allergic colitis Breastfeeding: consider ingested maternal blood Ingestion of products mistaken for hematemesis: artificial food coloring, gelatin, artificial fruit drinks, certain antibiotics, and cough

syrups Ingestion of products mistaken for melena: beets, iron supplements, dark chocolate, bismuth, spinach, blueberries, grapes, licorice, others Review of Systems General: fever, weight loss or gain, anorexia Skin: rash, vascular malformations, edema, jaundice, lymphadenopathy, easy bruising Extremities: arthralgia, arthritis, clubbing Genitourinary: hematuria Abdomen: distention, pain, bowel patterns, vomiting Ears, nose, and throat: pharyngitis, epistaxis Past Medical History Previous GI bleeding Liver disease: indicates possible variceal bleeding or coagulopathy Previous or recent hospitalization: stress gastritis Medications or ingestions: NSAIDs, aspirin, steroids, anticoagulants, alcohol, toxins (rat poison) Umbilical artery catheterization: risk for portal vein thrombosis Coagulopathy Recent antibiotic exposure: pseudomembranous colitis Presence of gastrostomy or nasogastric tube Family History IBD, peptic ulcer disease, polyposis, bleeding diatheses Social History Immediate contacts with similar symptoms: may indicate infectious cause Travel, camping, or daycare: consider infectious causes GI, gastrointestinal; IBD, inflammatory bowel disease; NSAID, nonsteroidal anti-inflammatory drug.

PHYSICAL EXAMINATION The physical examination can be helpful in determining the etiology of GI bleeding (Table 25-2). The first priority is a quick assessment to identify patients with hemodynamic compromise or shock who need immediate resuscitation. Vital signs should be monitored closely. Patients may lose up to 15% of blood volume without evidence of hemodynamic compromise, and the blood pressure may be maintained until the patient has lost as much as 30% of the blood volume.1 Once the patient is determined to be stable, a comprehensive history and physical examination should be pursued. TABLE 25-2

Directed Physical Examination Findings and Associated Diseases

Vital Signs Fever: infectious causes or inflammatory diseases (IBD or HSP) Weight loss: chronic diseases (IBD, cystic fibrosis, liver disease) Tachypnea: hemodynamic compromise or acidosis Tachycardia: earliest sign of hemodynamic compromise Hypotension: present with significant blood volume loss General Distressed or toxic-appearing patient: hemodynamic compromise from significant hemorrhage or underlying process causing systemic illness (toxic colitis, intussusception, ischemic bowel, necrotizing enterocolitis) Well-appearing patient: less urgent causes of bleeding Failure to thrive: malnutrition from chronic diseases (IBD, cystic fibrosis, liver disease) Head, Eyes, Ears, Nose, and Throat Nose: evidence of epistaxis Eyes: scleral icterus (liver disease), iritis (IBD) Oropharyngeal: mucosal trauma or bleeding from posterior pharynx Cardiovascular Evidence of hemodynamic compromise: tachycardia, gallop rhythm,

delayed capillary refill, poor perfusion Abdominal Abdominal tenderness: nonspecific but indicates inflammation or ischemic injury of the bowel Abdominal mass: intussusception, intestinal duplication may result in right lower quadrant masses Evidence of portal hypertension: hepatosplenomegaly, ascites Rectal examination: stool specimen for hemoccult testing, palpable polyp Perineal and anal inspection: skin tags (IBD), fissures, superficial skin breakdown or inflammation (streptococcal cellulitis) Extremities Clubbing: chronic diseases (cystic fibrosis, IBD, liver disease) Arthritis: IBD Skin Vascular malformations: syndromes with associated Gl vascular malformations (e.g. Klippel-Trénaunay syndrome, Rendu-OslerWeber syndrome) Cutaneous or oral pigmentation: Peutz-Jeghers syndrome Purpura or petechiae: vasculitis (HSP) or bleeding diathesis Erythema nodosum: IBD GI, gastrointestinal; HSP, Henoch-Schönlein purpura; IBD inflammatory bowel disease.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of GI hemorrhage can be divided into upper and lower GI bleeding. Although certain causes are more likely in certain ages, there is considerable overlap between age groups. Patients with complex medical issues have special diagnostic considerations in the evaluation of GI bleeding. The causes of upper and lower GI bleeding are summarized in Tables 25-3 and 25-4, respectively. TABLE 25-3

Causes of Upper Gastrointestinal

Bleeding Neonates and Young Infants

Older Infants, Children and Adolescents

Ingested maternal blood

Gastritis/ gastroduodenal ulceration

At delivery

Sepsis

During breastfeeding

Stress

Milk protein allergy

Medications

Trauma (nasogastric tube)

Ingestion

Gastritis

Burns

Overwhelming illness

Increased ICP

Medications

Ischemia

Idiopathic

Acidosis

Ischemia

Helicobacter pylori*

Acidosis

Esophagitis

Esophagitis

Reflux

Reflux

Infectious

Infectious

Ingestion

Necrotizing enterocolitis

Eosinophilic

Coagulopathy

Esophageal foreign body

Congenital malformations

Gastroesophageal varices

Duplication cyst

Cirrhosis

Vascular malformation

Extrahepatic portal vein thrombosis†

Budd-Chiari syndrome± Nasopharyngeal bleeding source Epistaxis Tonsils Tooth extraction Coagulopathy Hemobilia Hepatic injury Trauma to intestinal mucosa Nasogastric tube Gastrostomy tube Mallory-Weiss tear Prolapse gastropathy Vascular anomalies† Hemangioma Dieulafoy lesion Telangiectasia Other Henoch-Schönlein purpura Crohn disease Pulmonary hemorrhage Congenital malformations†

Duplication cyst *More common in older children and adolescents. †More

common in infants and young children.

± ICP, intracranial pressure.

TABLE 25-4

Causes of Lower Gastrointestinal Bleeding

Neonates and Infants Young Children

Older Children and Adolescents

Necrotizing enterocolitis

Anal fissure

inflammatory bowel disease

Anal fissure

Intussusception

Vasculitis

Allergic colitis

Juvenile polyps (>4 y)

Henoch-Schönlein purpura

Milk protein

Vascular lesions

Juvenile or inflammatory polyps

Soy protein

Hirschsprung enterocolitis

Colonic or rectal varices

Swallowed maternal blood

Intestinal duplication

Hemorrhoids

Meckel diverticulum

Infectious enterocolitis Anal or rectal fissure

Hirschsprung enterocolitis

Inflammatory bowel disease (>4 y)

Infectious enterocolitis

Infectious enterocolitis

Meckel’s diverticulum

Colonic or rectal ulceration

Malrotation or volvulus

Perianal streptococcal Bleeding diathesis cellulitis

Intestinal duplication

Henoch-Schönlein purpura

Eosinophilic gastroenteropathy

Bleeding diathesis

Hemolytic uremic syndrome

Rectal trauma

Typhlitis*

Typhlitis*

Eosinophilic gastroenteropathy Bleeding diathesis Colonic or rectal varices Lymphoid nodular hyperplasia Colonic or rectal ulceration Rectal trauma *lmmunocompromised patients.

UPPER GASTROINTESTINAL BLEEDING Some causes of upper GI bleeding are unique to neonates and young infants. Swallowed maternal blood from the birth process or from breastfeeding may cause hematemesis. To differentiate between maternal and fetal blood, an Apt test may be performed. Adult hemoglobin is reduced to a brown-yellow color, whereas fetal hemoglobin is resistant to reduction and remains pink. Esophagitis can lead to upper GI bleeding and may manifest with symptoms of dysphagia, regurgitation, cough, arching, or failure to thrive. It may be acid related, infectious, associated with a caustic ingestion, or allergic, as in the case of eosinophilic esophagitis. Children with neuromuscular diseases are more prone to severe gastroesophageal reflux disease that leads to esophagitis.

Esophageal varices can cause sudden, massive hematemesis, which can lead to hemodynamic compromise. Varices are associated with portal hypertension from both intrahepatic and extrahepatic causes. Portal vein thrombosis may be associated with umbilical artery catheterization or omphalitis, but it usually occurs in young, previously healthy children, and the cause is not identified.2,3 Thrombosis of the hepatic veins (Budd-Chiari syndrome) is usually associated with hypercoagulable states. Portal hypertension is most commonly caused by cirrhosis associated with chronic biliary diseases such as biliary atresia, cystic fibrosis, sclerosing cholangitis, and parenteral nutrition-induced cholestasis. Endoscopic evaluation of patients with known cirrhosis and esophageal varices is important, because the source of bleeding is commonly from gastric and duodenal ulcerations rather than varices.2 Patients with liver failure may develop GI bleeding from other mechanisms, such as associated coagulopathy. Forceful vomiting or retching may lead to a Mallory-Weiss tear or cause prolapse gastropathy, a phenomenon in which the gastric fundus is prolapsed into the esophagus, resulting in injury to the mucosa. Trauma to the esophageal or gastric mucosa may occur with nasopharyngeal suctioning or from nasogastric or gastrostomy tubes, which can lead to local irritation or laceration. Gastritis may be induced by many commonly used medications, including NSAIDs and steroids. Helicobacter pylori may cause gastritis and subsequent ulceration in children. Stress gastritis can occur in any age group and may be a complication of an overwhelming or life-threatening illness. Gastric or duodenal ulceration may also accompany head trauma, increased intracranial pressure (Cushing ulcer), or significant burns (Curling ulcer).

LOWER GASTROINTESTINAL BLEEDING Similar to upper GI bleeding, neonates and young infants have some unique causes of lower GI bleeding. In premature or young infants, necrotizing enterocolitis is a significant cause of morbidity and mortality and is an important diagnosis to exclude when evaluating hematochezia. Necrotizing enterocolitis typically presents with bloody stools, vomiting, abdominal distention, temperature instability, and discoloration or erythema of the abdominal wall. Volvulus is another diagnostic consideration when

evaluating lower GI bleeding in neonates and infants. Volvulus leads to ischemic injury of the bowel and can cause active bleeding; it is a surgical emergency. Hirschsprung colitis may also cause severe illness in young infants. A more common cause of bloody stools in well-appearing infants is allergic colitis, which is usually due to cow milk protein allergy. Soy protein intolerance is also common in these infants. Infectious enterocolitis can lead to bloody stools in infants and children. The classic pathogens include Salmonella, Shigella, Yersinia, Escherichia coli (enteroinvasive or enterohemorrhagic), Campylobacter jejuni, and Entamoeba histolytica. Viral pathogens such as rotavirus, Norwalk virus, and adenovirus 40/41 can also cause bloody stools. Antibiotic therapy puts patients at risk for the development of Clostridium difficile colitis; this should be considered in any patient who develops bloody stools with a history of recent antibiotic exposure. Meckel diverticulum is a remnant of the omphalomesenteric duct that can present with painless rectal bleeding. The rule of twos applies to Meckel diverticulum: it occurs in approximately 2% of the population, is located within 2 feet of the ileocecal junction, is around 2 inches long and 2 cm in diameter, has two types of ectopic mucosa (gastric and pancreatic), and has a 2:1 male-to-female ratio. In addition, Meckel’s presents before 2 years of age in 50% of patients. Bleeding is caused by ulceration of the ileal mucosa adjacent to the secretion-producing ectopic tissue. Duplications of the bowel may also contain ectopic mucosa and present with bleeding from a similar mechanism, or act as lead points for intussusception and subsequent ischemic injury. Painless, intermittent rectal bleeding may be caused by juvenile polyps, which are non-neoplastic inflammatory lesions found in the rectosigmoid region of school-age children. Bleeding diatheses are another cause of painless rectal bleeding in any age group. Henoch-Schönlein purpura (HSP) is a systemic vasculitis that affects primarily small vessels of the skin, joints, kidneys, and GI tract. The GI manifestations can precede the skin manifestations or occur days after. Bloody stools can result from diffuse mucosal hemorrhage or from intussusception resulting from HSP. Occasionally, HSP may result in massive hemorrhage. IBD is an important diagnostic consideration in older children and

adolescents with hematochezia. Ulcerative colitis is a diffuse mucosal inflammation limited to the colon. In contrast, Crohn disease may occur in any segment of the GI tract. Both may present with bloody mucopurulent diarrhea, abdominal pain, and weight loss, as well as extraintestinal manifestations.

DIAGNOSTIC EVALUATION LABORATORY STUDIES Laboratory studies are directed at determining both the extent of blood loss and the underlying cause. An initial complete blood count should be followed by serial hemoglobin measurements to assess ongoing bleeding. Thrombocytopenia can be associated with multiple systemic illnesses that cause GI bleeding, such as necrotizing enterocolitis, sepsis, idiopathic thrombocytopenic purpura, and hypersplenism. Eosinophilia may be present in allergic colitis or parasitic infections. Clotting studies should be performed to rule out a bleeding diathesis. Blood typing and cross-matching are necessary if there is any suggestion of profuse or ongoing bleeding or hemodynamic compromise. Routine chemistries, including renal and hepatic function, should be checked. Elevated blood urea nitrogen in the setting of a normal creatinine level may indicate a large amount of intraluminal blood in the small intestine with blood resorption. Azotemia may be present with hemolytic uremic syndrome or HSP. Elevated liver transaminases or bilirubin may indicate hepatic failure or cirrhosis, raising the suspicion for varices. In an ill-appearing neonate with bloody stools, a blood culture should be obtained. Inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein may be elevated in inflammatory diseases such as IBD or HSP. Infectious causes may also lead to increased inflammatory markers. Red dyes, fruit juices, tomato skins, and beets can cause the vomitus or stool to look reddish in color. In addition, grapes, spinach, blueberries, licorice, and iron can cause the stool to look dark. A stool guaiac test uses a leukodye that has an oxidative reaction in the presence of hemoglobin, producing a blue color. False positives can occur in the presence of certain ingested foods such as rare meat, turnips, tomatoes, horseradish, and cherries. False negatives can occur due to the consumption of vitamin C.4 The Hemoccult test is accurate on stool but is inactivated by acid; therefore,

gastric contents should be tested with the Gastroccult test. Stool studies should include fecal leukocytes, eosinophils, bacterial culture, ova and parasites, viral studies, and screening for C. difficile toxin A and B when appropriate.

IMAGING Imaging may be an important in the workup of GI hemorrhage to define the pathology or pinpoint the bleeding site. Some centers may offer interventional options as well. A barium study can detect abnormalities associated with infectious esophagitis, esophageal varices, or an esophageal foreign body. An upper GI study may demonstrate abnormalities associated with profound reflux, obstructive causes such as malrotation with midgut volvulus, or gastric or duodenal ulcers. Plain abdominal radiographs are helpful in the evaluation of GI bleeding to assess for an obstructive bowel gas pattern, intraperitoneal free air, and pneumatosis coli in necrotizing enterocolitis or typhlitis. However, computed tomography is the preferred imaging modality to confirm the diagnosis of typhlitis in immunocompromised children. A barium enema can reveal mucosal abnormalities associated with IBD and can demonstrate polyps. Extraluminal complications of Crohn disease, such as adhesions or abscess formation, are better evaluated with computed tomography or magnetic resonance imaging. An air-contrast enema can be diagnostic and therapeutic for intussusception. Nuclear medicine imaging using a tagged red blood cell scan can be helpful in pinpointing the location of bleeding. In one method, the patient’s blood is drawn, labeled with a marker, and then reinjected. The images are evaluated in 5-minute frames for up to 2 hours to localize a bleeding source. Another valuable nuclear medicine technique is the Meckel scan, which is designed to demonstrate the presence of ectopic gastric mucosa within the diverticulum. Technetium 99m pertechnetate is injected intravenously and concentrates in gastric mucosa. Serial images are then obtained in 5-minute intervals to determine the presence of ectopic mucosa within a Meckel diverticulum. In specialized centers, angiography of the celiac or superior mesenteric artery can be performed in cases of brisk bleeding that cannot be diagnosed with other approaches. Arteriography may allow for transcatheter therapy with vasopressin or embolization.

MANAGEMENT INITIAL STABILIZATION Patients with GI bleeding who present with evidence of hemodynamic compromise should have airway, breathing, and circulation (ABC’s) assessed (Figure 25-1). Once the airway and respiratory status are stabilized, the volume status should be addressed. Aggressive fluid resuscitation may be necessary, initially with crystalloid. Significant blood loss may require transfusion of blood products (red blood cells or fresh frozen plasma). In the case of any significant GI bleeding episode, a nasogastric tube should be placed and gastric lavage performed to assess for ongoing bleeding. Presence of blood in the nasogastric aspirate can confirm an ongoing upper GI bleed in patients with hematemesis or melena. The absence of blood in the nasogastric aspirate does not exclude upper GI bleeding from the postpyloric region in patients with hematochezia or melena with brisk bleeding. A gastroenterology consultation should be obtained for upper and/or lower endoscopy in cases of ongoing or severe bleeding or if a diagnosis cannot be established by other imaging modalities.

FIGURE 25-1. Diagnostic and treatment algorithm for GI bleeding.

PHARMACOLOGIC THERAPY Gastritis and peptic ulcer disease in children is effectively treated with H2antagonists and proton pump inhibitors, as well as bismuth preparations. Early use of acid-suppressive medications in critically ill patients or those on high-dose steroids or anti-inflammatory medications may be prudent. H. pylori infection in children is treated similarly to that in adults, with antibiotics, acid suppression, and bismuth preparation. C. difficile colitis requires antibiotic therapy. However, many bacterial pathogens causing bloody diarrhea do not require antibiotic treatment, and

appropriate therapy should be reviewed on a case-by-case basis. For esophageal varices, intravenous or intra-arterial continuous infusions of vasopressin, somatostatin, or octreotide may be administered. These therapies work by reducing splanchnic arterial blood flow, therefore reducing the amount of bleeding from the varices. There are many pharmacologic therapies available for the management of IBD. Use of these medications should be guided by a gastroenterologist (see Chapter 79).

ENDOSCOPY Upper GI endoscopy is the preferred procedure for the diagnosis and evaluation of acute, severe upper GI hemorrhage or persistent or recurrent upper GI bleeding. Endoscopy is sensitive and specific and may allow for immediate therapy. Endoscopic interventions are available for active bleeding ulcers and varices, and tissue specimens can be obtained by biopsy. Endoscopic sclerotherapy and elastic band therapy have been used successfully for esophageal varices in children. Lower GI bleeding that is persistent or recurrent can also be effectively evaluated and possibly intervened upon by endoscopy. Flexible sigmoidoscopy is usually sufficient to evaluate for colitis and polyps. Colonoscopy reaching the level of the terminal ileum may be needed to evaluate more proximal lesions. Lower endoscopy is a valuable diagnostic modality to detect vascular lesions. Polyps can frequently be removed with electrocautery through an endoscope.

SURGERY Surgical indications include bowel perforation, ischemic bowel from obstructive causes including irreducible intussusception, as well as ongoing or massive bleeding not amenable to control with endoscopy or interventional radiology. In cases of ulcerative colitis refractory to medical management, the disease can be cured with a total colectomy. Complications of Crohn disease, such as adhesions or fistula formation, may require surgical intervention. There are several surgical treatment options for portal hypertension and esophageal varices, including esophageal transection, portosystemic shunts,

and transjugular intrahepatic portosystemic shunts, which are most often used in children with extrahepatic portal vein obstruction. Candidates for these procedures should be determined by consultation with a gastroenterologist and a surgeon.

SPECIAL CONSIDERATIONS Immunocompromised patients may develop GI bleeding from some unique causes. They are at risk for esophagitis secondary to cytomegalovirus and fungi, as well as chemically induced mucositis from chemotherapeutic agents. Typhlitis is an important diagnostic consideration in immunocompromised patients with abdominal pain and lower GI bleeding. Immunocompromised patients with bloody diarrhea should be evaluated for opportunistic infections as well as cytomegalovirus colitis. KEY POINTS GI bleeding can present from infancy through adolescence, and the differential diagnosis changes with age. The most important initial step is hemodynamic stabilization, followed by a thorough evaluation of the likely location and source of bleeding. Evaluation and treatment can be guided by the age of the patient, the acuity of the patient, and presence or absence of continued bleeding. Treatment modalities include pharmacologic therapy, radiologic intervention, endoscopy, and surgical management.

SUGGESTED READING Boyle JT. Gastrointestinal bleeding in infants and children. Pediatr Rev. 2008;29:39-52.

REFERENCES

1. Rodgers B. Upper gastrointestinal hemorrhage. Pediatr Rev. 1999;20:171-174. 2. Karrer F, Narkewicz M. Esophageal varices: current management in children. Semin Pediatr Surg. 1999;8:193-201. 3. Lykavieris P, Gauthier F, Hadchouel P, et al. Risk of gastrointestinal bleeding during adolescence and early adulthood in children with portal vein obstruction. J Pediatr. 2000;136:805-808. 4. Liacouras CA, Piccoli DA, Bell LM, eds. Pediatric Gastroenterology: The Requisites in Pediatrics. 1st ed. Philadelphia, PA: Mosby; 2008:8797.

CHAPTER

26

Hypertension Avram Z. Traum and Michael J.G. Somers

BACKGROUND Although hypertension is a relatively uncommon disorder in pediatrics, its identified incidence is increasing, likely related to both heightened clinician awareness of the problem and increasing rates of obesity in children mediating earlier onset of high blood pressure.1-4 With adults, most hypertension is deemed to be primary or “essential” in etiology and often no diagnostic evaluation ensues. In children, on the other hand, primary hypertension has long been a diagnosis of exclusion and there has been consensus that hypertensive children need to undergo an evaluation to exclude any secondary causes to their hypertension, especially in the setting of significantly elevated blood pressures for a child’s age and body habitus. Regardless of its cause, depending on the degree of elevation and the duration of onset, hypertension can lead to both acute and chronic organ dysfunction. In ambulatory settings, otherwise healthy hypertensive children have been found to be more likely to have left ventricular hypertrophy, accelerated atherosclerosis, proteinuria, and decreased cognitive function. In hospitalized children, hypertension may complicate the management of coexisting clinical conditions and there is the additional burden of determining whether the high blood pressure is a primary problem or whether it stems from an ongoing condition or its treatment. Accordingly, a child who presents with hypertension often requires treatment while the diagnostic evaluation is ongoing. The approach to the evaluation and treatment of hypertension is often both more directed and more intensive in a hospitalized child than in an ambulatory setting. The extent of the blood pressure elevation and the degree of clinical concern for immediate harm to the child from the hypertension also guides the tempo of

diagnostic evaluation and therapeutic intervention.

ASSESSMENT AND DEFINITION MEASUREMENT OF BLOOD PRESSURE Blood Pressure Norms With adults, blood pressure standards are based on epidemiologic outcome measures related to chronic end-organ damage seen in patients followed longitudinally with high blood pressure. In contrast, hypertension standards in children are based on statistical population norms since end organ effects may take decades to manifest. Currently, the “Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents”5 is used widely in North America to define blood pressure norms in children, and is more comprehensive than previously published standards.6 In children, normal blood pressure is defined as blood pressure measurements consistently falling below the 90th percentile compared to a pediatric reference group of comparable gender, age, and height. Prehypertension (formerly known as high-normal blood pressure) is defined as blood pressure at the 90th percentile or higher but less than the 95th percentile. Stage One Hypertension is defined as blood pressure at the 95th percentile or greater, and Stage Two Hypertension—or what used to be called severe hypertension—is that exceeding the 99th percentile. Auscultation versus Oscillometry Accurate measurement of blood pressure is essential before any management decisions are made. Statistical blood pressure norms in pediatrics, such as those in the Fourth Report, are based on measurement by auscultation using a stethoscope. In spite of this, especially in hospitalized children and increasingly in the ambulatory office setting, oscillometric automated devices (e.g. Dynamap) are widely used to measure blood pressure because they are convenient and easy for any personnel to use. It is often not appreciated, however, that oscillometric measurements of blood pressure are typically at least 5 to 10 mmHg higher than those obtained by auscultation.7 This is true even in the hands of experienced clinical staff specifically trained to take blood pressures.8 As a result, blood pressure assessment by oscillometry is best used for screening, but any high blood

pressure measurements should be confirmed with auscultation to make sure oscillometric readings can be used to guide therapeutic intervention. Cuff Size and Location Cuff size is another important factor that impacts accurate blood pressure measurement. Cuffs that are too small tend to overestimate blood pressure, and cuffs that are too large may underestimate blood pressure, although not as significantly as the overestimation resulting from small cuffs. The most precise method for choosing an appropriate cuff size is controversial,9-11 but the recommendations of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents should be considered.5 Those guidelines delineate that the width of the cuff bladder should be at least 40% of the arm circumference measured midway between the olecranon and the acromion. This generally correlates with the bladder length covering 80% to 100% of the arm circumference. Appropriate-sized cuffs should be available from infant up to thigh-sized cuffs. In muscular or obese adolescents with large upper extremities, a thigh cuff may be necessary to cover the arm adequately. Cuff location can also significantly affect the blood pressure reading. Measurements on the upper arm should be made with the cuff at the level of the heart, whether the patient is in the upright or supine position. When the cuff is placed on the lower extremity, the patient should be supine for accurate measurement. The measurement will be elevated due to increased hydrostatic pressure if obtained on the lower extremity of a patient in a sitting or upright position. Auscultation Technique As noted earlier, auscultation is the preferred way to measure a child’s blood pressure and should be done to confirm hypertension. With the child at rest and acclimated to the local environment, the examiner places the diaphragm of the stethoscope over the brachial artery at the antecubital fossa. The right arm is used both for convenience and to allow the diagnosis of coarctation of the aorta; the left subclavian artery usually comes off the aorta after a thoracic coarctation and thus has normal blood pressure. The examiner inflates the cuff to a pressure above which a pulsatile sound can no longer be auscultated, at which point the cuff is deflated slowly. The systolic blood pressure is measured at the onset of the tapping, or what is termed the first Korotkoff sound; the diastolic blood pressure is measured at the disappearance of the Korotkoff sounds. In some children, the Korotkoff sounds may continue until the diastolic blood

pressure reaches zero. Although this is unlikely in the presence of significant hypertension, if it occurs, the diastolic blood pressure should be measured at the muffling or fourth Korotkoff sound. Ambulatory Blood Pressure Monitoring Over the past decade, there has been increasing use of ambulatory blood pressure monitoring to overcome the problems inherent in trying to diagnose hypertension from sporadic blood pressure measurements alone. These devices provide a 24hour log of blood pressures measured at regular intervals during normal activities. They also allow for assessment of diurnal variations in blood pressure for comparison with expected fluctuations, and provide a sense of the proportion of both systolic and diastolic blood pressures that are elevated, and the extent of these elevations. In the ambulatory setting, these devices can help distinguish between “white coat hypertension”—high blood pressure related to the medical office visit—and true sustained hypertension. In the hospitalized child, these devices have less applicability since it is easier to get multiple measurements by auscultation or oscillometry. Moreover, with the hospitalized patient, there is often more urgency in treating blood pressure elevations and erring on the side of overtreatment if there are concerns that blood pressure elevation may be clinically harmful.

PATHOPHYSIOLOGY As the incidence of obesity rises, so does the incidence of hypertension in children and the likelihood that children with hypertension will be cared for in the hospital.12 The etiology of hypertension in obese children is not clear, though many believe insulin resistance and subsequent vascular endothelial dysfunction play a key role. As a result, some argue that obesity-related hypertension is really a secondary form of hypertension and should not be lumped with primary hypertension in children. Regardless of body habitus, all children with evidence of sustained or recurrent hypertension should be evaluated for secondary hypertension in an individualized and stepwise fashion, guided by the findings on history, physical examination, and initial screening tests. Children with more significant and sustained elevations of blood pressure, as well as younger children, are more likely to have some specific cause of hypertension identified during the evaluation. The most common cause of secondary

hypertension in children is renal parenchymal disease,13 and the diagnostic evaluation should reflect this. An algorithm for the diagnostic evaluation of hypertension in hospitalized children is provided in Figure 26-1.

FIGURE 26-1. Algorithm for the evaluation and management of a hospitalized child with hypertension. BP, blood pressure; DMSA, dimercaptosuccinic acid.

EVALUATION HISTORY

In obtaining a history, the clinician should focus on disorders or conditions that predispose to hypertension and, in a hospitalized patient, should begin with the history of present illness leading to the child’s admission. For instance, in a postoperative patient who is otherwise healthy, pain or anxiety may play a role in hypertension. In a child hospitalized with severe reactive airway disease, steroid therapy or frequent administration of β-agonists may be problematic. In the absence of an obvious precipitating factor related to an acute illness or medical condition, the history should begin with the perinatal period. Prematurity is a risk factor for hypertension, because premature babies are born with fewer nephrons, have a reduced renal reserve, and may be more prone to hyperfiltration injury and glomerulosclerosis as both a child and adult. In addition, placement of umbilical catheters in the nursery or periods of hypotension early in life can mediate renal injury by thrombosis or hypoperfusion with increased risk for subsequent renal scarring. Especially in preschool children, febrile urinary tract infections commonly leave renal parenchymal scars that can then lead to hyperreninemic hypertension over time. These infections may have been misdiagnosed or even gone unappreciated, so any history of unexplained recurrent febrile illness should be elicited. Glomerulonephritis presents with edema, hematuria, and hypertension and may be isolated to the kidney or associated with systemic inflammatory disorders such as systemic lupus erythematosus. Relevant extra-renal findings include joint symptoms, rashes, and recurrent unexplained fevers or constitutional symptoms. Recent systemic infections may also lead to postinfectious glomerulonephritis and may be associated with gross hematuria or tea-colored urine in addition to high blood pressure. The family history focuses on relatives with pediatric or early-onset hypertension and inherited diseases that affect the kidneys, such as the polycystic kidney disease complexes, tuberous sclerosis, and neurofibromatosis. A strong family history of cardiovascular disease, such as coronary artery disease, stroke, and hyperlipidemia, suggests similar risk to a hypertensive child as adulthood is reached. Certain medications are known to cause hypertension, including oral contraceptives, corticosteroids, stimulants, decongestants, and the calcineurin inhibitors (cyclosporine, tacrolimus) that are the mainstay of

immunosuppression in transplant patients. Recreational drugs with stimulant effects, such as cocaine, nicotine, and ephedra, can also raise blood pressure, as can withdrawal from the effects of central nervous system depressants such as ethanol or narcotic analgesics. The review of systems should evaluate for symptoms such as headache, chest pain, visual changes, or mental status changes, because these may be related to severe hypertension or end-organ damage. Sweating, palpitations, and flushing are associated with states of catecholamine excess such as occurs with a pheochromocytoma.

PHYSICAL EXAMINATION The most essential part of the physical assessment of a child with suspected hypertension is accurate measurement of the blood pressure. Blood pressure should be measured in all four extremities. When measured at the same encounter with the same equipment, the blood pressure in the lower extremities is typically 10 to 20 mmHg higher than in the right arm. If lower extremity blood pressure is not higher, this suggests a coarctation or other narrowing of the aorta and is often associated with diminished femoral pulses. Height, weight, and body mass index should be measured to assess for growth anomalies or to document obesity. The physical examination should look for signs of end-organ damage from hypertension. This involves funduscopy and cardiovascular, pulmonary, and neurologic examinations. Although the finding is uncommon, the abdomen should be auscultated for abdominal bruits, which can be seen in renovascular hypertension. The physical examination should also look for findings of genetic syndromes that may explain the elevated blood pressure. These include neurofibromatosis (café au lait spots, axillary freckling, Lisch nodules), tuberous sclerosis (ash-leaf macules, shagreen patches, adenoma sebaceum, peri- or subungual fibromas, retinal hamartomas), Turner syndrome (short stature, shield chest, upturned mouth, webbed neck), and Williams syndrome (overfriendly personality, cognitive impairment, prominent ears).

LABORATORY AND RADIOLOGIC EVALUATION

A urinalysis should be preformed on a freshly voided urine sample, and if the dipstick is positive for blood or protein should include microscopy. Initial screening blood work should include electrolytes, blood urea nitrogen, and creatinine. This effectively evaluates renal function and screens for states of mineralocorticoid excess that lead to hypokalemia and alkalosis. All children with hypertension should undergo renal ultrasonography. An ultrasound study will uncover differential renal size, hydronephrosis, changes in parenchymal echogenicity, or diffuse cystic changes. More extensive areas of renal scarring will often be appreciated on ultrasound as thinning of the renal cortex or loss of parenchyma. Subtler scarring may not be seen on ultrasonography, but a size discrepancy of greater than 1 cm between the two kidneys is unusual and may reflect scarring in the smaller kidney. Since there is little yield in routinely doing other laboratory work or imaging studies with initial screening, each individual’s history and physical examination findings should guide further evaluation. For example, tachycardia suggests hyperthyroidism or high-catecholamine states and should trigger blood thyroid function tests and quantification of catecholamines. A history of urinary tract infections with unexplained fevers or positive urine cultures should precipitate a dimercaptosuccinic acid (DMSA) scan to determine the presence of cortical scars. Plasma renin activity and aldosterone levels are helpful only if the results are unequivocally low or very high. They are most useful when a diagnosis of mineralocorticoid excess is suspected, because plasma renin activity is typically suppressed. Aldosterone levels may be low or high, depending on the specific cause of the mineralocorticoid excess. The diagnosis of renal artery stenosis continues to be challenging in children. The gold standard study for diagnosis remains angiography. It allows for both diagnostic and therapeutic interventions, although the invasive nature of angiography limits its use as first-line approach. Doppler studies of renal vasculature can show changes in flow rates through areas of measurement and may suggest the presence of renovascular hypertension. A normal Doppler study does not, however, rule out renal artery stenosis, especially stenosis in the smaller segmental arteries that are not well visualized by Doppler. Computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) have been studied as alternate imaging modalities. MRA lacks the spatial resolution of CTA but avoids the

radiation exposure that comes with CT.14 One study in approximately 400 adults demonstrated that compared to conventional angiography, CTA had a sensitivity of 64% and sensitivity of 92%, and MRA had slightly lower values of 62% and 84%.15 No such comparison studies have been performed in children, and consultation with a pediatric radiologist is always recommended to decide which imaging study may be best, always considering that angiography may ultimately still be necessary if there is a high level of suspicion for renal artery stenosis. Echocardiography is necessary in any child suspected of having a structural lesion causing hypertension. In addition, echocardiography may be a sensitive tool to measure cardiac changes such as left ventricular hypertrophy that accompanies sustained hypertension, and can be used over time to document the effect of antihypertensive therapy on end-organ damage. Similarly, in some children with hypertension, formal ophthalmology examinations may provide initial information about the chronicity of a child’s hypertensive state and help document amelioration of vascular changes with therapy.

TREATMENT Acute Management Because hospitalization is an anxiety-producing experience for most children, if the blood pressure is elevated but lower than the 99th percentile, it is often best to monitor it with frequent readings to document the trend of measurements. As the child recovers and acclimates to the hospital, blood pressure often falls to normal ranges. If there is concern that the blood pressure may adversely affect a clinical condition or is directly related to a primary disease process (e.g. glomerulonephritis), more immediate measures may be necessary. If blood pressure readings are still consistently between the 90th and 99th percentiles by the time of discharge, it is prudent to arrange follow-up by the child’s primary care provider and further evaluation as an outpatient. In a child with sustained blood pressure exceeding the 99th percentile, diagnostic evaluation and therapy must be carefully considered. The tempo and urgency of the intervention are guided by the individual child’s clinical presentation and course.

Children with sustained blood pressure readings more than 30% above the 99th percentile are at particular risk of developing acute sequelae; even if they are asymptomatic, blood pressure control must begin immediately to prevent progression to a hypertensive urgency (severely elevated blood pressure that is potentially harmful but without evidence of end-organ damage or dysfunction) or emergency (severely elevated blood pressure associated with evidence of secondary end-organ dysfunction, such as hypertensive encephalopathy). Schemata outlining sequential approach to management of these conditions are found in Figures 26-2 and 26-3.

FIGURE 26-2. Algorithm for therapeutic intervention in a hypertensive emergency. See Table 26-1 for drug dosing. HTN, hypertension; BP, blood pressure; IV, intravenous.

FIGURE 26-3. Algorithm for therapeutic intervention in a hypertensive urgency. See Table 26-1 for drug dosing. BP, blood pressure; HTN, hypertension; IV, intravenous. Severe hypertension with actual acute end-organ dysfunction or impending end-organ dysfunction should be treated with short-acting intravenous antihypertensive medications. The medications most commonly used in a hypertensive crisis are outlined in Table 26-1. The blood pressure should be lowered by 20% to 30% in the first 2 to 3 hours. Once the blood pressure falls into a range that is not acutely dangerous for the patient, it should be lowered more gradually over the next few days, aiming eventually for pressures less than the 95th percentile for a patient’s age, gender, and height. TABLE 26-1

Medications for Pediatric Hypertensive Urgency or Emergency

Drug

Mechanism Dose

Onset

Duration

Hydralazine

Arteriolar dilator

IV: 0.1–0.4 5–15 mg/kg to max min dose of 20 mg

3–8 h

Labetalol

α- and (βadrenergic antagonist

Initial IV 5 min bolus: 0.25 mg/kg; repeat q15min at increasing doses up to 1 mg/kg until effective or to total dose of 4 mg/kg

2–6 h

Maintenance IV drip: 1–3 mg/kg/h Nitroprusside Venodilator and arteriolar dilator

IV: start at 0.5 1–2 min μg/kg/min

3–5 min

Nifedipine

Calciumchannel antagonist

PO: 0.25–0.5 mg/kg

10–20 min

3–6 h

Nicardipine

Calciumchannel antagonist

IV: 0.5–5 μg/kg/min

10 min

2–6 h

Esmolol

β-adrenergic antagonist

Loading dose: Seconds 10–20 min 500 μg/kg over 2 min Maintenance IV drip: 50– 250 μg/kg/min

Enalaprilat

ACE inhibitor

IV: 5–10 μg/kg q 8–24 h

0.5–4 h

6h

ACE, angiotensin-converting enzyme.

Hydralazine is a commonly used vasodilator with a rapid onset that can often be titrated to achieve good blood pressure control. It is well tolerated and can be given readily in a non–intensive care unit setting. Nifedipine is another short-acting agent and has the advantage of oral administration. Its use in adults is rare owing to reports of myocardial infarction.16 The use of short-acting nifedipine in children is safe, although a higher incidence of adverse events was seen in patients with preexisting central nervous system disease.17 The sublingual route is somewhat controversial because accurate dosing is problematic since it requires aspiration of liquid from within a capsule; moreover, its absorption is erratic. Nicardipine and isradipine can be used for vasodilation as intravenous calcium channel blocker in cases where oral nifedipine or intravenous hydralazine cannot be considered. Labetalol and esmolol can also be used as intermittent intravenous medications if necessary. Severe hypertension refractory to intermittent therapy may require continuous infusions to reduce blood pressure to safe levels. Historically, nitroprusside and labetalol have been used most commonly in children. Both agents are shorter acting than hydralazine, and continuous infusions may be titrated to achieve specific target blood pressures. These medications require an intensive care unit setting. Labetalol can be administered via both continuous infusion and scheduled intravenous dosing. It is the only drug that is both an α- and β-adrenergic blocker. Nitroprussside is a vasodilator with a wide dosage range. The drug is photosensitive and must be protected from light. Its use is limited by the toxicity of its metabolites; nitroprusside is converted to cyanide by tissue sulfhydryl groups, and cyanide is converted to thiocyanate in the liver. In patients with liver disease, cyanide levels should be followed. Thiocyanate levels should be monitored in patients on nitroprusside for more than 72 hours and in patients with renal insufficiency. Thiocyanate toxicity manifests primarily as neurotoxicity and includes psychosis, blurred vision, confusion, weakness, tinnitus, and seizures. An early sign of cyanide toxicity includes metabolic acidosis; other signs of

toxicity include tachycardia, pink skin, decreased pulse, decreased reflexes, altered consciousness, coma, almond smell on breath, methemoglobinemia, and dilated pupils. Continuous infusions of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat, the calcium-channel blocker nicardipine, or the βblocker esmolol have also been used in hypertensive children, and according to local experience may be used more routinely when continuous infusions are needed for hypertensive children. In most children who will require continuous infusions for a limited time, there is no specific advantage to using any of these therapies versus older therapies. Long-Acting Medications As blood pressure is controlled by intravenous medication, it is also important to initiate longer-acting oral antihypertensives to transition off infusions. Table 26-2 reviews the oral drugs used most often for antihypertensive therapy in pediatrics. The choice of antihypertensive agent should address the presumed underlying pathophysiology of the blood pressure perturbation. For instance, children with fluid overload related to glomerulonephritis should be treated with diuretics and vasodilators. Hyperreninemic hypertension due to renal parenchymal scarring should be treated with ACE inhibitors or angiotensin receptor blockers. TABLE 26-2

Drug

Long-Acting Antihypertensive Agents in Children Initial Dose (mg/kg/ day)

Maximal Dose (mg/ kg/day)

Dosing Frequency

Calcium channel antagonist Nifedipine

0.25

3

XL or SR forms, 2 times/day

Amlodipine

0.1

0.4

1–2 times/day

Isradipine

0.15

0.8, up to 20

1–2 times/day

mg/day

as SR

ACE inhibitor Captopril (neonate)

0.03–0.15

2

2–3 times/day

Captopril (child)

1.5

6

2–3 times/day

Enalapril

0.08

0.6, up to 40 mg/day

1–2 times/day

Lisinopril

0.07, up to 5 mg/day

0.6, up to 40 mg/day

Once a day

Benazepril

0.2, up to 10 mg/day

0.6, up to 40 mg/day

Once a day

Angiotension receptor blockers Losartan

0.7, up to 50 mg/day

1.4, up to 100 mg/day

Once a day

Irbesartan

6–12 years: 75 mg/day

150 mg/day

Once a day

≥13 years: 150 mg/day

300 mg/day

Once a day

1–1% drop with an upper respiratory infection.27-36 The limited data available in children living at moderate altitudes suggest they may experience chronic borderline hypoxemia and even more significant intermittent desaturations.37 There is inconclusive evidence with regard to adverse long-term consequence

of transient mild hypoxemia or intermittent SpO2 desaturation events in otherwise normal infants and children.38-42

SPECIAL CONSIDERATIONS Special cases of hypoxemia include variant hemoglobins and the dyshemoglobinemias, methemoglobinemia, and carboxyhemoglobinemia. Several hemoglobin variants have been identified that either have altered peak light absorption for oxyhemoglobin or altered oxyhemoglobin affinity resulting in falsely low SpO2 readings when tissue O2 delivery is normal. Examples include hemoglobins Bonn, Venusburg, Titusville, M, Lansing, Rothschild, Lake Tapawingo, and others. Unnecessary evaluations are common in undiagnosed patients. Anomalous hemoglobin should be considered in a child without clinical evidence of hypoxemia or hypoxia, but an unexpectedly low SpO2. An arterial blood gas can assist in the differential. Diagnostic evaluation may require hemoglobin electrophoresis, high performance liquid chromatography, hemoglobin gene sequencing, and spectral photometry.43,44 Methemoglobin is hemoglobin with the iron in the ferric state, which is unable to bind O2 and shifts the oxyhemoglobin dissociation curve to the left in the remaining hemoglobin molecules in the tetramer. Only about 1.5 g/dL methemoglobin in the circulation results in clinical cyanosis. A small amount of methemoglobin (1%) is normal, and there are cellular mechanisms to reduce iron back to the ferrous state, although these can be genetically absent (e.g. cytochrome b5 reductase deficiency). Exogenous agents such as nitrites, phenacetin, sulfonamides, lidocaine (including topical absorption45), and aniline dyes are known to cause methemoglobinemia. Pulse oximetry is not adequate to recognize methemoglobinemia; a blood gas sample (arterial, capillary, or venous) will confirm the diagnosis. In most cases, discontinuation of the offending agent is adequate treatment. Intravenous methylene blue acts as an electron acceptor in patients who are not glucose-6phosphate dehydrogenase (G6PD)-deficient (pretreatment screening is indicated in populations likely to be G6PD-deficient), and ascorbic acid may be useful in G6PD-deficient patients. In severe cases of methemoglobinemia, transfusion and hyperbaric O2 have been used.

Carboxyhemoglobin is hemoglobin with the iron bound to carbon monoxide (CO). CO binds with an affinity about 240 times stronger than O2, rendering the molecule unavailable to carry O2 until the complex dissociates. Carboxyhemoglobin also shifts the oxyhemoglobin dissociation curve leftward. Levels of 2% to 5% are normal, and levels of 5% to 10% are commonly observed in smokers. There are many sources of CO poisoning, including virtually any combustion process without proper venting, smoke inhalation, tobacco smoke exposure, and automobile exhaust. Carboxyhemoglobin is not differentiated from oxyhemoglobin by pulse oximetry. A blood gas sample (arterial, capillary, or venous) to measure SaO2 is required to determine the carboxyhemoglobin level. Treatment is O2, which competes with CO and reduces the binding half-life to about 90 minutes. Severe cases may need hyperbaric O2 treatment (see Chapter 184). KEY POINTS Hypoxemia is a low arterial O2 level and is one of four major categories of hypoxia. Clinically, pulmonary infection, chronic lung disease, or both are the most common causes of hypoxemia, with V/Q mismatch the most common pathophysiology. V/Q mismatch responds to O2 administration, which is the mainstay of treatment. The nuances of O2 delivery techniques need to be understood. Pulse oximetry can detect and monitor hypoxemia in most situations, and is adequate for titrating O2 therapy but has limitations that must be understood by the practitioner. Overreliance on and misunderstanding of pulse oximetry may lead to misdiagnosis, inappropriate evaluation and treatment, excess admissions, and delay in discharge. History, physical examination, and blood gas studies can add significantly to the understanding of a clinical presentation of hypoxemia.

SUGGESTED READINGS Silverman M, O’Callaghan CL eds. Practical Paediatric Respiratory Medicine. London: Arnold Publishing; 2001. West JB. Pulmonary Pathophysiology: The Essentials. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. West JB. Respiratory Physiology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

REFERENCES 1. Mason. Murray and Nadel’s Textbook of Respiratory Medicine. 4th ed. Saunders; 2005. 2. Miller R. Oxygen therapy. In: Anesthesia. 5th ed. New York: Churchill Livingstone 2000:715-718. 3. Weiskopf RB, Toy P, Hopf HW, et al. Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol. 2005;116:1028-1032. 4. Weiskopf RB, Aminoff MJ, Hopf HW, et al. Acute isovolemic anemia does not impair peripheral or central nerve conduction. Anesthesiology. 2003;99:546-551. 5. Lieberman JA, Weiskopf RB, Kelley SD, et al. Critical oxygen delivery in conscious humans is less than 7.3 ml O2 x kg(-1) x min(-1). Anesthesiology. 2000;92:407-413. 6. Buchta RM, Bickerton R. A case of profound iron deficiency anemia owing to corrosive esophagitis in a 20-year-old developmentally delayed male. J Adolesc Health. 1994;15:592-594. 7. Snider HL. Cyanosis. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. Boston, MA: Butterworth; 1990. 8. Snider HL, Roy TM. Deoxyhaemoglobin concentrations in the detection of central cyanosis. Thorax. 1988;43:801. 9. Goss GA, Hayes JA, Burdon JG. Deoxyhaemoglobin concentrations in the detection of central cyanosis. Thorax. 1988;43:212-213.

10. Scrase E, Laverty A, Gavlak JC, et al. The Young Everest Study: effects of hypoxia at high altitude on cardiorespiratory function and general well-being in healthy children. Arch Dis Child. 2009;94:621-626. 11. Wilson WC, Shapiro B. Perioperative hypoxia. The clinical spectrum and current oxygen monitoring methodology. Anesthesiol Clin North America. 2001;19:769-812. 12. Zhang L, Mendoza-Sassi R, Santos JC, Lau J. Accuracy of symptoms and signs in predicting hypoxaemia among young children with acute respiratory infection: a meta-analysis. Int J Tuberc Lung Dis. 2011;15:317-325. 13. Rojas MX, Granados Rugeles C, Charry-Anzola LP. Oxygen therapy for lower respiratory tract infections in children between 3 months and 15 years of age. Cochrane Database of Syst Rev (Online). 2009:CD005975. 14. Mower WS, Sachs C, Nicklin EL, Baraff LJ. Pulse oximetry as a fifth pediatric vital sign. Pediatrics. 1997;99 681-686. 15. Sandweiss DR, Corneli HM, Kadish HA. Barriers to discharge from a 24-hour observation unit for children with bronchiolitis. Pediatr Emerg Care. 2010;26:892-896. 16. Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis hospitalizations. Arch Pediatr Adolesc Med. 2004;158:527-530. 17. Cunningham S, McMurray A. Observational study of two oxygen saturation targets for discharge in bronchiolitis. Arch Dis Child. 2012;97:361-363. 18. Corneli HM, Zorc JJ, Holubkov R, et al. Bronchiolitis: clinical characteristics associated with hospitalization and length of stay. Pediatr Emerg Care. 2012;28:99-103. 19. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997. J Infect Dis. 2001;183:16-22. 20. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282:1440-1446.

21. Gerstmann D, Berg R, Haskell R, et al. Operational evaluation of pulse oximetry in NICU patients with arterial access. J Perinatol. 2003;23:378-383. 22. Langhan ML, Chen L, Marshall C, Santucci KA. Detection of hypoventilation by capnography and its association with hypoxia in children undergoing sedation with ketamine. Pediatr Emerg Care. 2011;27:394-397. 23. Kannikeswaran N, Chen X, Sethuraman U. Utility of endtidal carbon dioxide monitoring in detection of hypoxia during sedation for brain magnetic resonance imaging in children with developmental disabilities. Paediatr Anaesth. 2011;21:1241-1246. 24. Deitch K, Miner J, Chudnofsky CR, Dominici P, Latta D. Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial. Ann Emerg Med. 2010;55:258-264. 25. Myers T. AARC Clinical Practice Guideline: selection of an oxygen delivery device for neonatal and pediatric patients—2002 revision & update. Respir Care. 2002;47:707-716. 26. Gibson RC, PB, Beckham RW, McGraw CP. Actual tracheal oxygen concentrations with commonly used oxygen equipment. Anesthesiology. 1976;44:71-73. 27. Hunt CE, Corwin MJ, Weese-Mayer DE, et al. Longitudinal assessment of hemoglobin oxygen saturation in preterm and term infants in the first six months of life. J Pediatr. 2011;159:377-383 e1. 28. Beresford MW, Parry H, Shaw NJ. Twelve-month prospective study of oxygen saturation measurements among term and preterm infants. J Perinato.l 2005;25:30-32. 29. O’Brien LM, Stebbens VA, Poets CF, Heycock EG, Southall DP. Oxygen saturation during the first 24 hours of life. Arch Dis Child Fetal Neonatal Ed. 2000;83:F35-38. 30. Hunt CE, Corwin MJ, Lister G, et al. Longitudinal assessment of hemoglobin oxygen saturation in healthy infants during the first 6 months of age. Collaborative Home Infant Monitoring Evaluation (CHIME) Study Group. J Pediatr. 1999;135:580-586.

31. Poets CF, Stebbens VA, Lang JA, O’Brien LM, Boon AW, Southall DP. Arterial oxygen saturation in healthy term neonates. Eur J Pediatr. 1996;155:219-223. 32. Hunt CE, Hufford DR, Bourguignon C, Oess MA. Home documented monitoring of cardiorespiratory pattern and oxygen saturation in healthy infants. Pediatr Res. 1996;39:216-222. 33. Masters IB, Goes AM, Healy L, O’Neil M, Stephens D, Harris MA. Age-related changes in oxygen saturation over the first year of life: a longitudinal study. J Paediatr Child Health. 1994;30:423-8. 34. Poets CF, Stebbens VA, Samuels MP, Southall DP. Oxygen saturation and breathing patterns in children. Pediatrics. 1993;92:686-690. 35. Stebbens VA, Poets CF, Alexander JR, Arrowsmith WA, Southall DP. Oxygen saturation and breathing patterns in infancy. 1: Full term infants in the second month of life. Arch Dis Child. 1991;66:569-573. 36. Mok JY, McLaughlin FJ, Pintar M, Hak H, Amaro-Galvez R, Levison H. Transcutaneous monitoring of oxygenation: what is normal? J Pediatr. 1986;108:365-371. 37. Thilo EH, Park-Moore B, Berman ER, Carson BS. Oxygen saturation by pulse oximetry in healthy infants at an altitude of 1610 m (5280 ft). What is normal? Am J Dis Child. 1991;145:1137-1140. 38. Ibuki K, Watanabe K, Yoshimura N, et al. The improvement of hypoxia correlates with neuroanatomic and developmental outcomes: comparison of midterm outcomes in infants with transposition of the great arteries or single-ventricle physiology. J Thoracic Cardiovasc Surg. 2012;143:1077-1085. 39. Zhang J, Liu H, Yan X, Weng X. Minimal effects on human memory following long-term living at moderate altitude. High Alt Med Biol. 2011;12:37-43. 40. Urschitz MS, Eitner S, Guenther A, et al. Habitual snoring, intermittent hypoxia, and impaired behavior in primary school children. Pediatrics. 2004;114:1041-1048. 41. Bass JL, Corwin M, Gozal D, et al. The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics. 2004;114:805-816.

42. Oates RK, Simpson JM, Cartmill TB, Turnbull JA. Intellectual function and age of repair in cyanotic congenital heart disease. Arch Dis Child. 1995;72:298-301. 43. Zur B, Bagci S, Ludwig M, Stoffel-Wagner B. Oxygen saturation in pulse oximetry in hemoglobin anomalies. Klin Padiatr. 2012;224:259265. 44. Mounts J, Clingenpeel J, White N, Villella A. Apparent desaturation on pulse oximetry because of hemoglobinopathy. Pediatr Emerg Care. 2010;26:748-749. 45. Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature. Pediatrics. 2006;117:e806-809.

CHAPTER

29

Irritability and Intractable Crying Karen E. Schetzina

BACKGROUND Irritability and intractable crying may be the presenting complaint for a wide range of medical problems in infants and children, some of which are potentially serious. Recently it has been estimated that 5% of infants presenting to the emergency department with crying have a serious underlying illness and two-thirds of these cases may be identified through careful history and physical examination.1 Symptoms may also begin after hospitalization. Hospital providers must be able to differentiate significant irritability and intractable crying from developmentally appropriate crying. They must be familiar with the common causes of irritability and intractable crying as well as the more unusual causes and a stepwise approach to evaluation. Irritability is a state of increased sensitivity to stimuli; it may also be described by parents as fussiness, whining, or increased crying. Crying is the primary way that infants and young children express hunger, thirst, fear, fatigue, desire for attention, and discomfort or pain. When caregivers have taken the usual measures to address these common needs, such as feeding and holding the child and changing the diaper, yet the child continues to cry, the child is said to be inconsolable or to have intractable crying. The quantity as well as the quality of crying behavior should be considered. What qualifies as excessive crying varies based on the age and developmental level of the child, as well as the clinical scenario. Normal infants cry most during the first 3 months of life; during this period, serious illness may present with few or only subtle signs and symptoms, making evaluation in this age group particularly challenging. Crying should also be evaluated to determine whether it is appropriate for

the clinical scenario. For example, a febrile infant with a viral upper respiratory infection is likely to be irritable and may cry more than usual. However, crying with movement of the child’s lower extremities should lead to suspicion of an alternative cause, such as meningitis or a septic hip joint. Stranger anxiety—which appears at around 8 to 9 months of age, peaks at 12 to 15 months, and decreases thereafter—may manifest as inconsolable crying during examination; however, an otherwise healthy child should be comforted and calmed in the arms of a caregiver. A change in the character of a child’s cry may also be significant: louder, higher pitch, or more urgent tone or a weak, stridulous, or hoarse cry may suggest the presence of illness.

PATHOPHYSIOLOGY Irritability may result from pain, discomfort, or fatigue, direct neurologic insult, or altered metabolic or endocrine status. Crying in infants and young children is an involuntary action that serves physiologic and protective purposes. A newborn’s first cries enable essential changes in the cardiorespiratory system during the transition to postnatal life. Crying increases to almost 3 hours per day, on average, by 6 weeks of life and decreases thereafter. During this period of greatest crying, infants cry most during the late afternoon and evening hours, perhaps to release tension accumulated throughout the day from internal and external stimuli and maintain homeostasis. Crying is also a way for infants and children to express their emotional needs. DEFINITIONS Irritability: A state of increased sensitivity to stimuli. Intractable crying: Crying that persists despite usual efforts to comfort.

PATIENT HISTORY It is important to obtain a detailed description of the irritability and crying, as

delineated in Table 29-1. Note history of associated symptoms, including fever, malaise, feeding difficulty, respiratory symptoms, vomiting or bilious vomiting, stool patterns and composition, parents’ perception of the source of pain, limping or joint irritability, skin irritation or redness, poor weight gain, and developmental delay or regression. TABLE 29-1

Elements of the History Relevant to Intractable Crying

Normal or baseline crying behavior Duration of presenting crying episode Quality of crying Intensity Character Pitch Characteristics of crying episodes Duration of previous crying episodes Time of day Circumstances or triggers Efforts of caregivers to console child Conditions that make crying better or worse Associated symptoms Exposures, including recent immunizations Caregivers’ ideas regarding causes Normal and recent feeding patterns Normal and recent sleep patterns Growth pattern Birth history, including gestational age and any history of in-utero drug exposure Developmental history Past medical and surgical history Medications

Allergies

PHYSICAL EXAMINATION When examining the child, it is often helpful to observe respiration, movement, and behavior from across the room at first. This provides useful information and helps eliminate the confounding influences of stranger anxiety. With a frightened toddler, the parents can assist in the physical examination by exposing areas of skin and moving the extremities to check for tenderness while the examiner stands back several feet and observes. Use of distraction techniques can facilitate a complete physical examination. It is essential to examine the child from head to toe, fully exposed (removing clothes, shoes, socks, bracelets, barrettes, and so forth). Growth parameters, including head circumference in infants, should be assessed. Because of the extensive differential diagnosis, a stepwise approach is essential. The presence of fever makes an infectious cause more likely; other inflammatory processes and endocrine disorders must also be considered. It is important to remember that serious bacterial infections can be present in the absence of fever, particularly in neonates, and may also coexist with more benign conditions such as viral upper respiratory tract infections. Most common causes of irritability and intractable crying in afebrile patients are apparent after a careful history and physical examination. A period of observation may also be helpful. Bruising in perambulatory infants, particularly over the ears, facial injuries, limb swelling, or other signs of unexplained injury should raise concern for abuse. Evaluation for the presence of rib bruising or crepitus, a bulging fontanelle, and retinal hemorrhages should be included. Care must be taken not to routinely attribute irritability and crying to otitis media. In older infants with intact tympanic membranes, determining whether otitis media observed on physical examination is the cause of the symptoms can be accomplished by placing anesthetic drops in the affected ear and observing the patient’s response. If the irritability does not dramatically improve, another cause should be sought. Scrotal swelling that may or may not be tender may be seen with incarcerated inguinal hernia. Parents may not notice the presence of a hair tourniquet around an appendage such as a digit, penis, or clitoris, which can

cause swelling, ischemia, and pain. The band of hair may not be visible if it is buried beneath a fold of edematous tissue. In some cases, the hair may be so tightly wound that it is difficult to release, making it necessary to remove the hair. Applying a hair removal cream, such as Nair, to the affected area for about 10 minutes may dissolve the hair and relieve the constriction. Ocular abnormalities, including corneal abrasion and acute glaucoma, are difficult to discern by history or physical examination, because tearing and conjunctival injection are difficult to appreciate in the setting of excessive crying. If suspected, consider a topical anesthetic, fluorescein stain, ultraviolet light examination of both eyes, and lid eversion to rule out corneal abrasion or foreign body. Tonometry with evidence of increased intraocular pressure indicates acute glaucoma.

DIFFERENTIAL DIAGNOSIS If a child continues to cry inconsolably during a period of observation after the initial examination and no reasonable cause has been identified, admission for further evaluation and observation should be considered, because a serious occult condition may be present. At this point it is essential for the clinician to entertain an extensive differential diagnosis, focusing first on potentially serious or life-threatening conditions. The presence of tachypnea may suggest metabolic acidosis, respiratory tract infection, or cardiac dysfunction. Foreign body aspiration or other airway obstruction may produce symptoms of respiratory distress such as cyanosis, increased work of breathing, diaphoresis, drooling, stridor, wheezing, or rales. Evidence of recent trauma ascertained either by history or on physical examination should be investigated further. Evidence of injury in the absence of a history supporting a reasonable mechanism of injury is a red flag. An assessment of the family environment and social stressors and the observation of interactions among family members are also important to identify possible non-accidental trauma, such as shaken baby syndrome (see Chapter 40). Symptoms of altered sensorium, such as increased somnolence, lethargy, confusion, or agitation, may suggest central nervous system infection or injury, a metabolic disorder, drug ingestion or withdrawal, toxin exposure, or

cardiopulmonary failure. It is important to inquire specifically about toxins and medications (prescription, nonprescription, and traditional or homeopathic) that the child may have ingested or been exposed to. Loss of developmental milestones is suggestive of a metabolic or neurodegenerative disorder. Constipation is a common problem that can cause irritability. Further investigation of symptoms of gastrointestinal obstruction should be done expeditiously to evaluate for ischemia-inducing gastrointestinal disorders. Screaming attacks are a common presenting sign of intussusception, and are particularly concerning if accompanied by vomiting and/or lethargy. Crying associated with bilious emesis in the young infant is midgut volvulus, a surgical emergency, until proven otherwise Table 29-2 provides a list of causes to consider in the evaluation of prolonged irritability or intractable crying. Table 29-3 provides a list of conditions associated with recurrent irritability or crying episodes. TABLE 29-2

Causes of Irritability and Intractable Crying

General Infection Dehydration Anemia Leukemia Kawasaki syndrome Eyes, ears, nose, and throat Corneal abrasion Ocular foreign body Glaucoma Otitis media Thrush, herpangina, herpes stomatitis Teething Nasal, oropharyngeal, or otic foreign body Cardiovascular and respiratory

Supraventricular tachycardia Myocardial ischemia or infarction Congestive heart failure or congenital heart defect Respiratory distress or failure Gastrointestinal Incarcerated hernia Spontaneous perforation of bile duct Appendicitis Malrotation, volvulus, intussusception Henoch-Schönlein purpura Bowel perforation Constipation Anal fissure Genitourinary Testicular torsion Urinary tract obstruction Urethritis Meatal ulcer Sexual abuse Endocrine and metabolic Congenital adrenal hyperplasia Hyperthyroidism Syndrome of inappropriate antidiuretic hormone Hypoglycemia Electrolyte abnormalities (sodium, calcium, potassium) Hyperammonemia Metabolic acidosis Pheochromocytoma Reye syndrome Neurologic Central nervous system injury, hemorrhage, tumor, shaken baby

syndrome Meningitis, encephalitis, brain abscess Pseudotumor cerebri or hydrocephalus Migraine Spontaneous epidural hematoma Drugs and toxins Neonatal abstinence or other withdrawal syndromes Fetal alcohol syndrome Poisoning (e.g. lead, mercury, iron, carbon monoxide) Monosodium glutamate reaction Drugs (e.g. antihistamines, atropinics, phenothiazines, pseudoephedrine, albuterol, theophylline or other methylxanthines, metoclopramide, promethazine, barbiturates, tricyclic antidepressants, vitamin A, vitamin D, salicylates, amphetamines, cocaine, phencyclidine) Vaccine reaction Skin Hair tourniquet Insect, arachnid, or arthropod bite or sting Burn Herpes dermatitis (pain may precede vesicles) Paronychia Atopic dermatitis, acrodermatitis enteropathica, or other pruritic conditions Orthopedic Fracture Acute arthritis (infectious, postinfectious, inflammatory) Nursemaid’s elbow or joint dislocation Diskitis Osteomyelitis

TABLE 29-3

Syndromes and Conditions Associated with Chronic or Recurrent Irritability or Intractable Crying

Anomalous origin of the coronary artery Congenital heart disease (e.g. “tet” spells of tetralogy of Fallot) Gastroesophageal reflux, Sandifer syndrome Colic Milk protein intolerance Lactose intolerance Nutritional deficiencies (e.g. iron, zinc, vitamin C) Diabetes insipidus Sickle cell disease Metabolic and neurodegenerative disorders (e.g. glutaric aciduria type I, acute intermittent porphyria, Pompe disease, pyridoxine deficiency, tryptophan malabsorption, hypoglycinemia, arginemia, tyrosinemia, pyruvate carboxylase deficiency, biotin deficiency, argininosuccinate lyase deficiency, Krabbe disease, lipogranulomatosis) Genetic syndromes (e.g. Smith-Lemli-Opitz, Williams, de Lange) Unrecognized deafness Behavioral problems (e.g. attention-deficit hyperactivity disorder) Parent–child interactions, problems, or stress Mental illness (e.g. depression, bipolar disorder) Rheumatologic disorders (e.g. juvenile rheumatoid arthritis) Infantile cortical hyperostosis (Caffey disease)

DIAGNOSTIC EVALUATION There are no standard screening laboratory tests, with the possible exception of urinalysis and culture in females and uncircumcised males younger than 12 months and circumcised males younger than 6 months. Laboratory and radiographic evaluation should be guided by findings from the history and

physical examination.

MANAGEMENT A multidisciplinary, family-centered approach to care is recommended given how stressful irritability and intractable crying in infants and children can be to families. The opportunity to educate and advise parents on the care of their child should not be disregarded. Achieving a careful balance of not dismissing concerns as a benign condition without proper evaluation yet avoiding unnecessary testing or medical intervention can be challenging.

SPECIAL CONSIDERATIONS One in five infants may struggle with excessive crying or regulatory problems and these infants may be at increased risk of child abuse and future behavior problems in childhood.2,3 Mothers of these infants are at increased risk of postpartum depression and early breastfeeding cessation.4,5

COLIC, GASTROINTESTINAL DISTURBANCES, AND FEEDING PROBLEMS Clinicians should be familiar with the clinical features of colic—a common cause of excessive and intractable crying in infants—so that they can differentiate it from other conditions. Colic is characterized by episodes of inconsolable crying in an otherwise healthy infant and is a diagnosis of exclusion. The timing of colic parallels the normal peak of infant crying, usually beginning during the third week of life and resolving by 3 or 4 months of age. Colic is commonly defined by the “rule of threes”: crying for more than 3 hours per day, on more than 3 days per week, in an infant 3 months of age or younger. The crying episodes tend to occur suddenly during the late afternoon and evening hours and are often described as more intense than the infant’s usual crying. The episodes may be associated with facial flushing, abdominal distention, and increased tone. Colic likely stems from different causes in different infants. Proposed causes include immaturity of the nervous system, impaired intestinal absorption or motility, or a reflection of temperament or parent–child

interactions. Parental education, reassurance, and support are important aspects of management, and efforts to soothe the infant and limit air swallowing, improve burping, and minimize stimulation may be helpful. Medications such as simethicone may be used by parents, but use is not supported in trials. Colic can be extremely stressful for families and may have long-term effects on the parent–child relationship. Therefore, it requires individualized management and close outpatient follow-up. Excessive crying beyond 3 months of age might raise suspicion for a gastrointestinal disorder. While crying in infants is frequently attributed to gastroesophageal reflux disease (GERD) by both parents and clinicians, objective evidence that GERD underlies symptoms or that acid-suppressive medications are beneficial in this group are lacking. Food allergies, primarily cow milk protein allergy in infants, may present in both formula-fed and breastfed infants with irritability, eczema, bloody stools, and less commonly, vomiting, diarrhea, feeding difficulties, or failure to thrive. Protocols for allergen-eliminated diets in breastfeeding mothers have been published, and some evidence suggests that use of hypoallergenic formula may reduce crying in formula-fed infants.6,7 Congenital lactase deficiency is extremely rare, although secondary lactose intolerance may result from damage to intestinal villa, such as from gastroenteritis. Probiotics or use of lactose-free formula in non-breastfed infants may have a role in managing symptoms. Functional lactose overload in breastfed infants may produce excessive crying accompanied by poor satiety and frothy or explosive stools as a result of low milk fat content and rapid gastrointestinal transit, such as in instances of oversupply. Lactation consultation may be helpful in such instances.

NEW IRRITABILITY OR EXCESSIVE CRYING IN A HOSPITALIZED PATIENT Although the approach to irritability or inconsolability that develops in a hospitalized patient is similar, additional causes must be considered. Dietary, environmental, and sleep–wake schedule changes should be examined. For example, restricting oral intake before procedures could result in crying due to hunger. Patients with prolonged exposure during examinations and monitoring may become too cold, or infants under warmers may become

overheated. Intravenous catheter sites should be inspected for any evidence of thrombophlebitis, and the locations of other catheters, tubes, and probes should be examined for skin irritation, excessive traction, and infection. Adverse effects and interactions of medications started in the hospital should also be considered as possible contributors. Appropriate prevention and treatment of procedural pain must also be considered, including use of breastfeeding/breast milk, sucrose, and non-nutritive sucking in infants.8 KEY POINTS Crying that is concerning to parents is prevalent in infancy and a frequent reason for seeking care. A careful history and physical examination should identify most serious underlying causes of irritability and crying. Diagnostic examinations should be directed based on results of the history and physical.

REFERENCES 1. Freedman SB, Al-Harthy N, Thull-Freedman J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics. 2009;123:841. 2. Reijneveld SA. Can der Wal MF, Brugman E, et al. Infant crying and abuse. Lancet. 2004;364(9442):1340-1342. 3. Hemmi MH, Wolke D, Schneider S. Associations between problems with crying, sleeping, and/or feeding in infancy and long-term behavioral outcomes in childhood: a meta-analysis. Arch Dis Child. 2011:96(7):622-629. 4. Howard CR, Lanphear N, Lanphear BP, et al. Parental responses to infant crying and colic: the effect on breastfeeding duration. Breastfeed Med. 2006;1:146-155. 5. Vik T, Grote V, Escribano J, et al. Infantile colic, prolonged crying, and maternal postnatal depression. Acta Paediatr. 2009;98:1344-1348.

6. Academy of Breastfeeding Medicine. ABM clinical protocol # 24: allergic proctolitis in the exclusively breastfed infant. Breastfeed Med. 2011;6(6):435-440. 7. Douglas PS, Hiscock H. The unsettled baby: crying out for an integrated, multidisciplinary primary care approach. MJA. 2010;193(9):533-536. 8. Shah PS, Herbozo C, Aliwalas LL, et al. Breastfeeding or breast milk for procedural pain in neonates (Review). Cochrane Database Syst Rev. 2012;12:1-24.

CHAPTER

30

Limp Robert Sundel

BACKGROUND Musculoskeletal complaints account for a significant number of outpatient visits to the pediatrician—up to 10% of non–well-child appointments in some studies. Only a minority of these visits result in hospitalization, but in many cases, even these admissions could have been avoided if a logical, stepwise approach to evaluation and management had been used. This chapter focuses on the entities to consider in a limping child and the appropriate approaches to take with regard to the history, physical examination, and diagnosis.

PATHOPHYSIOLOGY The normal gait is the most efficient and stable means for humans to walk upright on two legs. For this gait to be altered, strong countervailing forces must be applied. These may be anatomic (e.g. broken bone, muscular weakness), neurologic (disrupted proprioception or balance), or nocioceptive in nature. Pain is the most common cause of an abnormal gait in children. Recognizing specific gait aberrations can facilitate the localization and identification of musculoskeletal pathology. For example, a psoas abscess is often difficult to diagnose because of poor localization of discomfort within the pelvis; pain may be perceived as occurring anywhere from knee to the diaphragm. Trying to walk with a psoas abscess, however, results in a characteristically altered gait, as contraction of the psoas muscle is avoided to minimize discomfort. This causes leaning to the involved side and using the bones of the pelvis and upper leg to substitute for the support usually provided by the psoas muscle. Further, the contralateral hemipelvis dips to keep the psoas muscle relaxed and thus avoid pain. The result is the

Trendelenburg gait, which can be caused only by a pathologic condition involving the proximal femur or muscles of the pelvis (Figure 30-1). Analogous effects of other sites of pathology on gait are listed in Table 30-1.

FIGURE 30-1. Trendelenburg gait, with pathology of the right proximal femur or adjacent muscles causing characteristic dipping of the contralateral hemipelvis.

TABLE 30-1

Characteristic Alterations in Gait Based on Location of Pathology

Location Effect on Gait Example

Result

Hip

Refusal to bear weight

Decreased or Avascular eliminated swing necrosis of phase femoral head Inguinal tendinitis

Circumduction or dragging of involved side

Knee

Decreased extension > flexion

Lyme arthritis

Stiff-kneed gait

Ankle

Decreased dorsiflexion

Chondrolysis

Ginger gait, like walking on coals

PATIENT HISTORY The key elements of the medical history that help identify the cause of a limp include the timing of the symptoms, the nature of the pain with regard to alleviating and exacerbating factors, particularly response to activity (Table 30-2), and the character of the pain, such as dull, sharp, radiating, or burning. TABLE 30-2

Characteristics of Musculoskeletal Pain

Pain Type

Morning Afternoon Nighttime Activity

Inflammatory (e.g. arthritis)

+++

+

–

Improves

Mechanical (e.g. overuse syndromes)

+/–

++

–

Worsens

Bone (e.g. tumors)

++

Neuropathic (e.g. + neuritis)

++

++

No change

++

+++

No change

While pain is the most common cause of a limp in children, it is not the only cause. When children do complain of pain, it may originate in sensory nerves of the skin, soft tissues, muscles, bone, or nerves. Joint nocioceptors found in the joint capsule and adjacent connective tissue are activated only by extreme mechanical or chemical irritation. This high threshold for sensing joint pain likely accounts for the fact that up to 80% of children with arthritis do not report pain. For example, an Oklahoma study found that children with arthritis typically presented with stiffness, avoidance of activities, or regression of skills, but only 13 of 226 children referred to a rheumatology clinic with joint pain actually had arthritis.1

INFLAMMATORY SYMPTOMS The most characteristic feature of discomfort related to inflammatory processes is the classic morning stiffness of arthritis. Difficulty may also be reported after other periods of inactivity, such as long car rides or sitting in school. Inflamed synovial joint tissue produces less hyaluronic acid, which causes gelling of joint fluid and decreased lubrication. This can be reversed by warming of the joint, returning the synovial fluid to the liquid state and once again permitting efficient, low-friction movement. Thus children with arthritis typically feel better after a warm bath or after several minutes of activity. These children may suffer joint stiffness in the morning but be quite comfortable exercising strenuously later in the day. Cold, damp weather or swimming in cool water also tends to disturb children with arthritis. Nighttime awakening is unusual with arthritis. Any atypical symptoms— especially nighttime pain or discomfort with activity—should raise the suspicion of an alternative diagnosis, even in the setting of otherwise typical signs of joint inflammation.

MECHANICAL SYMPTOMS

The timing of symptoms caused by mechanical factors is the mirror image of manifestations of inflammation (Figure 30-2). Children typically feel well in the morning, but become more uncomfortable with increasing activity. Like inflammation, however, mechanical pain generally does not awaken children from sleep. Rest and ice tend to alleviate mechanical symptoms. The precise type of overuse syndrome or injury causing a child’s symptoms can generally be determined from a careful history (e.g. Osgood-Schlatter syndrome in an adolescent male athlete, iliotibial band syndrome in an adolescent female runner) and physical examination.

FIGURE 30-2. Limp: diagnostic and treatment algorithm. ANA, antinuclear antibody; CBC, complete blood count; CF, cystic fibrosis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; NSAID, nonsteroidal anti-inflammatory drug; JIA, juvenile idiopathic (rheumatoid) arthritis; SLE, systemic lupus erythematosis; U/S, ultrasound.

BONE PAIN Pain originating in the osseous compartment tends to be constant and does not change significantly with activity. Bone pain raises concern for infection, trauma, and malignancy. This type of pain may awaken a child at night, particularly when it is related to leukemia or a tumor. Cytopenias are typically seen with leukemia, although a normal complete blood count does not exclude the possibility. Other tumors, such as sarcoma or metastatic neuroblastoma, are far less common but must be considered in children with significant nighttime pain. Osteomyelitis should be considered for patients with new onset of fever, localized pain, and decreased mobility; many patients will have a history of preceding trauma (see Chapter 70).

NEUROPATHIC PAIN Nerve pain tends to be worst at bedtime, when the usual distractions of daily activities abate and children are left to focus on their discomfort. In patients old enough to describe the sensation, neuropathic pain typically has a sharp, burning, or shooting character. It is also commonly associated with allodynia (a sense of discomfort from stimuli that normally do not cause pain) and hyperesthesia (a decreased threshold for discomfort in overlying tissues). Although joints may be involved, neuropathic pain generally encompasses extra-articular areas as well and can follow a dermatomal distribution. Activity does not have a significant effect on neuropathic pain. When nerve pathology due to severe trauma, tumor, or vasculitis cannot be identified, pain syndromes such as fibromyalgia or complex regional pain syndrome should be considered.

PHYSICAL EXAMINATION The four cardinal signs of inflammation (dolor, tumor, rubor, and calor) are the hallmarks of arthritis. The musculoskeletal examination should begin with careful observation of the extremities in a child who has removed his clothing and is robed in a gown. Whether assessing pain, swelling, changes in color, or variations in temperature, the most sensitive aspect of the examination is comparing the two sides of the body. Decreased extension of the right knee compared to the left, or an identifiably warmer or more

sensitive left ankle leads to rapid identification of likely pathology. Careful examination of all the joints is mandatory, even when the patient complains about a single joint, as the potential causes of a monoarticular process differ significantly from those of polyarticular conditions. Warmth and swelling are most characteristic of inflammatory arthropathies, while overlying erythema is more indicative of septic arthritis. An inflamed knee may exhibit a ballotable effusion, meaning that applying pressure directly to the patella forces it downward, displacing synovial fluid and causing a bounce against the femur. The characteristic springiness is not noted when fluid does not intervene between the patella and femur, as in healthy children. The joint may also be swollen from synovial proliferation, which has a boggier consistency than the free fluid of a joint effusion. Osteomyelitis most typically causes point tenderness on palpation of the involved bone, though in younger children precise localization of the discomfort can be more difficult. Careful examination of an inflamed joint may allow an estimation of the duration of the arthritis. Synovitis is characterized by increased blood flow, typically more pronounced in the portion of the joint compartment subjected to maximal force. In the knee, this is the medial aspect, where hyperemia leads to increased delivery of nutrients and accelerated growth. This may manifest initially as prominence of the medial femoral condyle, and later as genu valgus. Ultimately, the leg with the inflamed knee grows more rapidly, and a leg length discrepancy develops. The lower leg may bow to compensate for the greater length of the upper leg. At the same time, the knee loses extension and develops a flexion contracture, with resultant atrophy of the vastus medialis and wasting of the quadriceps muscle. In contrast, significant inflammation in the hip or the temporomandibular joint of the jaw often damages the growth plate and leads to shortening of the involved leg or hemimandible. Inflammation in other joints generally causes little demonstrable discrepancy in size.

DIFFERENTIAL DIAGNOSIS When a child presents with a complaint referable to the lower extremities, the list of possible causes is long and varied (Table 30-3). In the absence of an obvious explanation such as known trauma, it is helpful to start the evaluation by categorizing the type of pain or discomfort according to the nature of its

onset (acute vs. chronic), the number of joints involved, and whether extraarticular signs or symptoms such as fever or rash are present. Most normally active children have some history of trauma during the preceding 24 hours; however, unless the trauma is significant (e.g. football injury, automobile accident, bicycle fall), it is more likely to have unmasked a preexisting pathologic condition than to have caused damage to the child’s resilient tissues. TABLE 30-3

Common Causes of Arthritis

Monoarticular Acute onset Septic arthritis Reactive arthritis Trauma Hemophilia Lyme disease Chronic Juvenile rheumatoid arthritis Lyme disease Tuberculosis (rare without pulmonary disease) Tumor (pigmented villonodular synovitis most common, but rare) Polyarticular Juvenile rheumatoid arthritis Spondyloarthropathies Systemic autoimmune diseases Systemic lupus erythematosus Vasculitis Arthritis associated with inflammatory bowel disease Viral arthritis Reactive arthritis Serum sickness Rheumatic fever (migratory arthritis)

Malignancies Periodic fever syndromes

MONOARTHRITIS The potential causes of a monoarticular process can be narrowed by considering the acuity and duration of symptoms. Acute Onset When pain and swelling of a single joint start acutely, traumatic injury must always be considered. Documentation of antecedent trauma is helpful, but this may be difficult to elicit in young children who are unable to verbalize the specifics of the history. Routine daily activities may cause hemarthrosis in patients with an underlying bleeding disorder, but minor injuries are unlikely to lead to a recognizable gait disturbance in otherwise healthy children. Bacterial infection also must be considered in children with sudden onset of a red, swollen, painful, or hot joint. When accompanied by fever, arthrocentesis for cell count and culture is generally indicated. Treatment of septic arthritis must not be postponed (in contrast, for most types of inflammatory arthritis, a delay in the diagnosis by days or weeks has few long-term implications). Postinfectious or “reactive” arthritis may involve one or many joints, but it characteristically causes less inflammation than that seen with acute infection. Nonetheless, while postinfectious arthritis usually does not cause erythema overlying the joint, it may cause significant discomfort or even excruciating pain. Reactive arthritis generally responds well to nonsteroidal anti-inflammatory agents and is typically transient. Lyme disease may also be difficult to distinguish clinically from septic arthritis, although it more commonly causes indolent symptoms. Subacute Onset The diagnostic considerations in cases of an isolated, chronically swollen joint differ from those related to an acute arthritis. Bacterial infection is far less likely, but low-grade infections, especially Lyme disease in endemic areas, must be excluded. Chronic monoarthritis also may be caused by Mycobacterium tuberculosis, particularly in immunocompromised children. This category also includes chronic forms of juvenile arthritis, especially pauciarticular juvenile idiopathic (rheumatoid) arthritis (JIA), psoriatic arthritis, and juvenile spondyloarthritides. Less

prevalent inflammatory arthropathies, such as arthritis due to sarcoidosis, may also cause monoarthritis. Tumors of the cartilage and synovium, though extremely rare, also typically present in an indolent manner. The most common of these, pigmented villonodular synovitis, generally causes a chronically painful and swollen knee. A nontraumatic arthrocentesis that yields bloody fluid suggests the possibility of an articular tumor.

POLYARTHRITIS When several joints have objective evidence of inflammation, rheumatologic conditions rise to the top of the differential diagnosis. Most common among these is polyarticular JIA, although other autoimmune diseases, such as systemic lupus erythematosus and vasculitis, typically involve multiple joints as well. Infection is progressively less common as more joints are involved, with the exception of gonococcal arthritis in sexually active or abused children and salmonella arthritis in immunocompromised patients. Arthritis associated with systemic conditions, such as inflammatory bowel disease or cystic fibrosis, must also be considered. Usually, extra-articular involvement (e.g. a new murmur in rheumatic fever, hives in serum sickness) offers a clue to these conditions. The pattern of joint involvement may also be suggestive: rheumatic fever, vasculitis, and serum sickness characteristically cause a migratory polyarthritis, whereas most other conditions cause additive or fixed involvement of multiple joints. Children with polyarticular arthritis are particularly likely to benefit from consultation with a pediatric rheumatologist.

DIAGNOSTIC EVALUATION LABORATORY STUDIES Laboratory studies may be helpful in excluding infectious and malignant causes of a swollen joint, but they cannot confirm a diagnosis of arthritis; a child may have JIA despite uniformly normal laboratory studies. Even when laboratory studies support a diagnosis of JIA, they are nonspecific. Ultimately, a diagnosis of JIA rests on the history and physical examination. The laboratory studies most characteristic of arthritis are those that reflect systemic inflammation: elevated erythrocyte sedimentation rate, C-reactive

protein, and platelet count. In general, the elevation of acute-phase reactants is proportional to the number of joints involved. In a case of monoarticular arthritis, therefore, normal laboratory studies are the rule. Leukocytosis may be present in JIA, particularly in children with systemic-onset JIA; a mild to moderate anemia may also be seen in the setting of chronic inflammation. The serum antinuclear antibody (ANA) level is usually measured when a child is being evaluated for possible arthritis. This is rarely diagnostic, although an ANA at a titer of 1:1024 or higher is strongly suggestive of an autoimmune condition. At lower titers, a positive ANA result is nonspecific, occurring in conditions from arthritis and lupus to viral illnesses. Thus up to 2% of children have a positive ANA at any point in time (typically low titer), and most are healthy. A positive ANA assay in a child with known arthritis is a marker for an increased risk of developing anterior uveitis. One of the most overused tests in children with swollen joints is the rheumatoid factor (RF), an autoantibody directed against the Fc portion of the immunoglobulin-G (IgG) molecule. Unlike adult rheumatoid arthritis, in which 80% of cases are associated with a positive RF result, only 2% of more than 400 children seen at a rheumatology clinic in Philadelphia had a positive RF result, and many of these were considered to be false positives.2 The only setting in which RF is helpful in children is in cases of polyarticular JIA; those with a positive RF are more likely to have a severe, erosive course, warranting more aggressive management.

RADIOGRAPHIC STUDIES Imaging studies are essential for evaluating children with musculoskeletal pathology. They may be particularly helpful in confirming a clinical impression of arthritis by excluding other causes of joint pathology and by showing the characteristic changes caused by longstanding joint inflammation. Plain radiographs are usually the first imaging modality used to evaluate a child with joint complaints. In the initial stages of arthritis, the radiographs are generally normal or may show nonspecific findings such as soft tissue swelling, joint effusion, periarticular osteopenia, or periosteal new bone formation.3 Radiographs may help rule out fractures or foreign bodies. It is important to remember, however, that bone demineralization or callus

formation takes up to 10 days to become visible on x-rays. In longer-standing arthritis, more severe changes are evident on plain radiographs. Joint space narrowing reflects cartilage destruction, and it may be accompanied by other signs of inflammatory damage, including bony erosions and subchondral cysts. Such changes may be evident after several weeks in the case of untreated articular infections, or after months to years in inflammatory conditions. Epiphyseal maturation also tends to be accelerated in JIA, leading to asymmetric growth. Thus bilateral films to compare symptomatic areas with those on the uninvolved side may be particularly helpful. Plain radiographs provide limited information on the soft tissues of joints, restricting their utility in the evaluation of inflammatory synovitis and soft tissue infections. Accordingly, other imaging modalities may be preferable, particularly for detecting and assessing early disease. Magnetic resonance imaging (MRI) is able to demonstrate soft tissue masses, cartilage thinning, meniscal changes, joint effusions, and popliteal cysts. The sensitivity of MRI increases significantly when performed with gadolinium, which accumulates in tissues with increased vascularity, including inflamed synovium.4 Use of MRI is limited primarily by its cost and by the need to sedate young children. Ultrasonography is also used to assess arthritic joints, and in the hands of experienced operators may be useful for detecting joint effusions, popliteal cysts, lymph nodes, and to some degree, changes in articular cartilage. Although MRI is more sensitive than ultrasonography for most purposes, the latter is less expensive, and ultrasound images can be acquired rapidly and without sedation.5

MANAGEMENT Treatment of a limping child depends on the cause. If a child is unable to ambulate and initial outpatient or emergency department screening does not confirm a diagnosis, admission is generally appropriate. In general, the goal of therapy is to exclude acutely dangerous conditions, prevent irreversible sequelae, and restore full functioning. This is particularly important in a growing child, in whom inflammation may result in permanent derangements in joint development and function.6 Conversely, a growing child is also far better able to heal damage if the pathologic process is completely suppressed,

increasing the incentive to rapidly control the underlying disease. Indeed, evidence suggests that the longer an autoimmune condition persists, the more resistant to therapy it becomes.7 Treatments for extremity abnormalities can be divided into those that relieve symptoms but do not prevent joint damage, and specific therapies that alter the biology of the process. Although symptomatic relief may or may not be necessary, depending on a child’s level of discomfort, disease control is essential for preventing chronic joint changes due to ongoing inflammation.8

SYMPTOMATIC THERAPIES First-line agents for relief of joint pain are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 30-4). Although dozens of medications in this category are available, only a handful have been approved by the Food and Drug Administration for use in children. Ibuprofen is available over the counter as a suspension, so it is often prescribed for children. It should be given every 6 hours to optimize anti-inflammatory effects. Naproxen is more convenient because of its twice-daily dosing. Although all NSAIDs have potential gastrointestinal, hepatic, and renal toxicities, naproxen has an additional predilection for causing pseudoporphyria, especially in fair-skinned children. Up to 12% of pediatric patients develop this potentially scarring photosensitive eruption, so physicians should stress the need to use sunscreen. Parenteral NSAIDs such as ketorolac are significantly more expensive than oral anti-inflammatory agents, and offer no advantage for children who can take medications by mouth or nasogastric tube. TABLE 30-4

Dosages and Adverse Effects of Medications Used to Treat Juvenile Rheumatoid Arthritis

Drug Class

Typical Dosing

Side Effects

Nonsteroidal anti-inflammatory drugs Ibuprofen (Advil, Motrin)

10 mg/kg/dose every 6h

Gastric irritation, hepatotoxicity,

nephrotoxicity, headache, rash Naproxen (Aleve, Naprosyn)

10 mg/kg/dose every 12 h

Gastric irritation, hepatotoxicity, nephrotoxicity, headache, rash, pseudoporphyria

Diclofenac gel (Voltaren)

4 g of 1% gel to lower extremities, or 2 g to upper extremities to affected joint 4 times per day

Localized burning

Disease-modifying antirheumatic drugs Sulfasalazine (Azulfidine)

40–70 mg/kg/day divided into 2–3 doses

Gastrointestinal upset, aplastic anemia, photosensitive eruptions, StevensJohnson syndrome Contraindicated in children aged 2 cm), quality (matted or firm), and duration of swelling increase the possibility of malignancy. Focal oncologic processes such as soft tissue neoplasms may also mimic lymph node swelling. The location of the process plays an important role in determining whether congenital malformations and anatomic abnormalities are possible causes. In the head and neck region, midline thyroglossal duct cysts, lateral branchial cleft cysts, and dermoid cysts in a variety of locations may present with swelling, with or without superinfection; parotid or submental salivary gland dysfunction or infection may also be present. In the inguinal area, hydroceles and undescended testes or testicular torsion should be added to the differential diagnosis in males, whereas in females an entrapped ovary may present in the setting of a hernia. In either sex, entrapped intestine or omentum may be present in a hernia.5

DIAGNOSTIC EVALUATION

Laboratory testing is indicated if there is suspicion of a disease other than localized Staphylococcus or Streptococcus infection, thereby affecting treatment decisions. Bacteremia can occur in pediatric patients—particularly young patients with high fevers—with significant focal bacterial lymph node infections,1 so obtaining blood cultures may help identify a bacterial organism as well as its sensitivities. A complete blood count with leukocyte differential may be helpful to determine leukocytosis and indicate possible infectious mononucleosis or oncologic processes. Infectious mononucleosis is caused by EBV and commonly presents with atypical lymphocytosis, lymphadenopathy, and fever as well as exudative pharyngitis and hepatosplenomegaly.3 Initial testing for EBV may include heterophil antibody testing—most sensitive in patients older than 4 years—as well as EBV serum titers for immunoglobulins M and G; it is important to keep in mind that these tests are most sensitive after 2 to 3 weeks of illness.3 Cytomegalovirus infections can present similarly to EBV infections, so serum cytomegalovirus titers may be helpful. Depending on the differential diagnosis for a given patient, serologies for more unusual organisms may also be indicated. HIV testing should be performed if there is any history of HIV exposure or if the clinical history leads to suspicion of an underlying immune deficiency. In the setting of recurrent infections, an immunology consultation may be helpful in recommending further testing.1 If there is a history of travel to developing countries or other possible exposure to tuberculosis (TB), a Mantoux tuberculin purified protein derivative (PPD) test should be done. A negative PPD test should not be considered definitive in the setting of high clinical suspicion for TB, because 10% of immunocompetent children with culture-documented TB may have a negative PPD; this number is higher in immunocompromised patients and in those with disseminated TB.3 Atypical mycobacterial disease can sometimes cause a positive PPD.3 In the setting of a positive PPD test or supraclavicular adenopathy on examination, a chest radiograph can screen for pulmonary TB or other diseases, particularly oncologic processes in the chest, whose lymphatics may drain to a sentinel supraclavicular node. To visualize the presenting lesion itself—particularly if it is rapidly progressive, fluctuant, or close to vital structures—ultrasonography often provides distinct images of a superficial process without exposing the patient to radiation. If there is concern for a deeper or more widespread process, a

computed tomography scan may be more helpful. If the infection has a loculated component or an organized abscess, drainage may be therapeutic as well as diagnostic. Fine-needle aspiration, under ultrasound guidance if necessary, is a useful method of obtaining a fluid sample for bacterial, mycobacterial, and fungal stains and cultures. It is important to note that many organisms that cause lymphadenitis, especially mycobacteria, are fastidious and may not grow in culture.3 Incision for drainage can lead to a chronically draining sinus tract, particularly in the setting of a mycobacterial infection; in these cases, excisional biopsy is the preferred approach. If there is little concern about rare or resistant organisms and if a good response to antibiotic treatment alone is expected in a given patient, treatment is often initiated without obtaining microbiologic studies from the site of infection. When wound cultures cannot be obtained and concerns exist for resistant organisms, swabs from the nares, axilla, and/or rectum to detect for methicillin-resistant S. aureus (MRSA) colonization may be performed, though concordance of nasal carriage and infectious agent is not assured.6,7

MANAGEMENT After the initial assessment, which often occurs in a primary care setting, an important issue is whether a patient requires hospitalization. Possible criteria for hospital admission include toxic appearance, rapid progression of infection, airway involvement of a neck process, inability to tolerate enteral antibiotics or lack of clinical improvement on a prior trial of outpatient antibiotics, comorbid conditions, suspicion of an underlying secondary diagnosis, and possible bacteremia, particularly in a febrile infant or young child. If a case of likely bacterial lymphadenitis warrants hospital admission, intravenous (IV) antibiotics are usually the initial treatment. Antibiotic choice should be directed by the likely bacteria, mycobacteria, or fungi responsible for the process, as well as by patient allergies and recent antibiotic exposures. For lymphadenitis due to S. aureus or Streptococcus species, a βlactamase–resistant β-lactam antibiotic such as oxacillin or nafcillin is indicated; a combination of the β-lactam ampicillin and the β-lactamase inhibitor sulbactam sodium is also an option.3 Clindamycin may be another

good option for empirical treatment of these common pathogens as well as MRSA. However, susceptibility to MRSA varies widely by region and empirical therapy should be guided by local patterns of antibiotic resistance. If there is suspected or documented MRSA, IV vancomycin should be considered; for serious infections, vancomycin should be combined with a βlactamase–resistant β-lactam antibiotic.3 For lymphadenitis due to other bacterial, mycobacterial, or fungal causes, medication choices should be based on the likely organisms involved and their susceptibility profiles in the geographic region. The treatment course can be adjusted based on culture results and tested susceptibilities when those are available. Lack of clinical improvement typically dictates further therapeutic interventions or changes. An initial consideration is whether an unusual organism may be responsible for the process or whether the organism involved may demonstrate a degree of antibiotic resistance. In these cases, identifying the organism via stained and cultured tissue samples can be invaluable; consultation with an infectious disease specialist is also helpful. The possibility of immunocompromise in a patient who is not responding to conventional therapy should be reconsidered. The lymphadenitis lesion can be imaged or reimaged if it is not regressing. One possible reason for failed treatment response is low antibiotic penetrance into an organized, circumscribed abscess; penetrance into a walled-off loculation may be low despite relatively high vascular flow to inflamed surrounding tissues. For an identified abscess, drainage is often the most appropriate course of treatment. This can be performed via needle aspiration rather than open incision and drainage to reduce the risk of chronic drainage and scar formation.1 Excision is indicated for lesions with chronic drainage (as can occur with M. tuberculosis lymphadenitis) and for atypical mycobacteria, which are often multidrug resistant.1 Depending on the site in question, consultation with a general surgeon or otorhinolaryngologist is recommended. Discharge criteria for pediatric patients admitted with lymphadenitis include demonstration of significant clinical improvement, ability to receive enteral antibiotics for the remainder of the required course, and family support for treatment and follow-up. The choice of discharge antibiotics for likely or identified bacterial processes depends largely on the organisms

involved and the IV antibiotics used during the hospital stay. Common conversions to oral (PO) medications for pediatric lymphadenitis patients include IV oxacillin to PO dicloxacillin, IV ampicillin-sulbactam sodium to PO amoxicillin-clavulanate, IV to PO clindamycin, and IV cefazolin to PO cephalexin. KEY POINTS The history and physical examination are key to understanding the likely etiology of lymphadenitis and formulating the treatment plan. Concerning findings in a patient with lymphadenopathy include generalized lymphadenopathy, larger, matted or firm lymph nodes, or systemic symptoms. The most common causative organisms include Staphylococcus aureus and Streptococcal species; treatment is often started empirically directed toward these organisms. If there is inadequate response to the initial antibiotic regimen, consider antibiotic resistance (e.g. MRSA), unusual organisms, or development of an abscess.

SUGGESTED READINGS Camitta BM. The lymphatic system. In: Behrman RE, Kliegman RM, Jenson HB eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: WB Saunders, 2004:1677-1678. Davis HW, Michaels MG. Infectious disease. In: Zitelli BJ, Davis HW, eds. Atlas of Pediatric Physical Diagnosis. 4th ed. Philadelphia, PA: Mosby; 2002:396-454. Friedmann AM. Evaluation and management of lymphadenopathy in children. Peds Rev. 2008;29:53-60. Liu JH, Myer CM. Evaluation of head and neck masses. In: Rudolph CD, Rudolph AM, Hostetter MK, et al., eds. Rudolph’s Pediatrics. 21st ed. New York: McGraw-Hill, 2003:1279-1281.

REFERENCES 1. Davis HW, Michaels MG. Infectious disease. In: Zitelli BJ, Davis HW eds. Atlas of Pediatric Physical Diagnosis. 4th ed. Philadelphia, PA: Mosby, 2002:396-454. 2. LeBlond RF, DeGowin RL, Brown DD. Non-regional systems and diseases. In: LeBlond RF, DeGowin RL, Brown DD, eds. DeGowin’s Diagnostic Examination. 9th ed. New York: McGraw-Hill; 2009. Available at: accessmedicine.com/content.aspx?aID=3659310. Accessed April 26, 2013. 3. Pickering LK ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:189-692. 4. Liu JH, Myer CM. Evaluation of head and neck masses. In: Rudolph CD, Rudolph AM, Hostetter MK, et al., eds. Rudolph’s Pediatrics. 21st ed. New York: McGraw-Hill, 2003:1279-1281. 5. Fink DL, Serwint JR. The knotty problem in an infant girl’s groin. Contemp Pediatr. 2005;22:24. 6. Schleyer AM, Jarman KM, Chan JD, Dellit TH. Role of nasal methicillin-resistant Staphylococcus aureus screening in the management of skin and soft tissue infections. Am J Infect Control. 2010;38:657-659. 7. Chen AE, Cantey JB, Carroll KC, Ross T, Speser S, Siberry GK. Discordance between Staphylococcus aureus nasal colonization and skin infections in children. PIDJ. 2009;28(3):244-246.

CHAPTER

32

Oral Lesions and Oral Health Suzanne Swanson Mendez

BACKGROUND Pediatric dental disease is the most common chronic illness of school-aged children.1 It is five times more common than asthma and has lifelong health implications. Severe tooth decay can lead to bacterial infections within the tissues of the mouth, the bones surrounding the oral cavity, and the sinuses. Pediatric dental disease can lead to malnourishment and pain, and adult dental disease is associated with bacterial pneumonia, diabetes, heart disease, stroke, and poor pregnancy outcomes, including premature labor.1 It is important to include a close examination of the oral cavity on admission, as many children have not seen a dentist in the past and have undiagnosed pathology. In a study of 120 children on a pediatric ward, more than 40% had unmet oral health needs, as determined by a dental assessment.2 Dental caries lead to more cumulative missed school hours than any other chronic disease and can lead to difficulties with eating, drinking, speaking, and paying attention.1 Children with special healthcare needs are at particularly high risk of severe tooth decay due to their underlying medical issues and barriers to accessing dental care. Dental care remains the most frequently cited unmet health need for this population of children.3 Pediatric hospital medicine physicians can help fill this gap by addressing oral health concerns on admission and facilitating proper dental care after discharge from the hospital. Intraoral disease may be a primary indication for admission to the hospital (e.g. dental abscess) or may be a secondary finding on an inpatient examination (e.g. aphthous ulcers in lupus [Table 32-1] or delayed tooth eruption due to a genetic disorder [Table 32-2]). Oral lesions, commonly

caused by viruses (see Table 32-3) or candida may also lead to such significant difficulty with drinking and swallowing that infants and children may require admission for pain control and treatment of dehydration. See Chapter 70 for a review of causes of stomatitis. TABLE 32-1

Conditions with Oral Manifestations

Condition

Oral Signs or Symptoms

Cyclic neutropenia

Oral ulcers, early loss of primary teeth

Leukocyte adhesion deficiency disorder

Severe gingival inflammation around primary teeth, increased tooth mobility, early tooth loss

Systemic lupus erythematosus

Oral or nasal mucocutaneous ulcerations

Crohn disease

Recurrent oral abscesses, dry mouth, redness and scaling around the lips, angular chelitis

Scarlet fever

Red “strawberry” tongue

Kawasaki syndrome

Dry, fissured lips and “strawberry tongue”

Stevens-Johnson syndrome

Fragile mucosal bullae, shallow oral ulcers with a gray or white membrane

Peutz-Jeghers syndrome

Melanotic spots on lips and buccal mucosa

Iron-deficiency anemia

Burning sensation of the tongue, pallor of oral mucosa, atrophy of papillae on tongue

Osler-WeberRendu disease

Telangiectasia of oral mucosa

Acrodermatitis enteropathica

Angular chelitis, glossitis

Porphyria

Possibly reddish brown discoloration of teeth

Acute myelogenous leukemia

Subtypes can present with gingival hyperplasia, oral ulcers

Primary HIV infection

Oral ulcers, pharyngitis, cervical lymphadenopathy

HIV, human immunodeficiency virus.

TABLE 32-2

Syndromes Associated with Delayed Tooth Eruption

Albright hereditary osteodystrophy Apert syndrome Cornelia de Lange syndrome Hunter syndrome Incontinentia pigmenti Miller-Dieker syndrome Osteogenesis imperfecta type I Progeria syndrome TABLE 32-3

Cause

Viral Stomatitis Lesion

Site and Distribution

Inflamed gingiva and mucosa, followed by vesicles that promptly rupture to reveal characteristic irregular, painful, superficial ulcers

Anterior: gingival, labial, lingual, and buccal mucosa; floor of mouth; extension to perioral skin involvement and “drop” lesions

HSV Primary (herpes stomatitis)

Posterior: hard palate and tonsils Recurrent

Single or small clusters of vesicles

Mucocutaneous junction of lips

Varicellazoster HHV-6

Shallow, non-painful ulcers

Palate

Erythematous papules

Soft palate and base of uvula

Rubeola (measles)

Mottled erythema in prodromal phase; grayish white granular lesions on pronounced erythematous mucosa (Koplik spots) on about day 10

Prodromal findings: palate Koplik spots— initially, buccal mucosa adjacent to lower molars; subsequently extends throughout oral mucosa

Enteroviruses

Rapidly-ulcerating vesicles, painful

Lingual and buccal surfaces; soft palate

Several coxsackie- and echoviruses Coxsackievirus A16 (handfoot-andmouth disease) HHV-6, human herpesvirus 6; HSV, herpes simplex virus.

Traumatic mucosal injuries are the most common type of oral injury in infants and young children and may be caused by burns, either chemical (e.g. alkali) or thermal (e.g. hot drinks); by sucking on a pacifier or finger; by sharp objects inserted into the mouth, resulting in abrasions or lacerations; or

by blunt trauma.4 Many children presenting with mucosal trauma also have injuries involving the teeth.

PATHOPHYSIOLOGY Dental abscesses generally result from untreated tooth decay, which leads to a deep cavity within a tooth, penetrating through the enamel and dentin into the central pulp. Abscesses can also develop after trauma causes a deep crack in a tooth. Once the pulp is exposed, bacteria can invade, causing the pulp to necrose and resulting in pockets of pus at the base of the tooth (see Figure 32-1 for tooth anatomy).

FIGURE 32-1. Tooth anatomy. DEFINITIONS Enamel: Hard mineralized external layer covering the crown of the tooth (above the gumline) Cementum: Calcified substance covering the root of the tooth and assisting in tooth support in the bone, along with the

periodontal membrane Dentin: An inner, second layer of calcified material, located deep to the enamel of the tooth (above the gum line) or cementum (below the gum line) Pulp: The central inner section of the tooth, composed of connective tissue, blood vessels and nerves Apical: Describes a direction toward the root tip(s) of the tooth Coronal: Direction toward the crown of the tooth or something related to the crown itself Root canal: A canal extending from the central pulp to the root, or apex, of the tooth Root canal treatment: Dental procedure which removes the infected or necrosed pulp of the tooth in order to save the tooth from possible extraction

PATIENT HISTORY Children with dental abscesses may present with excruciating pain and swelling within the mouth. Other symptoms may include fever, pain with chewing, sensitivity of the tooth to hot or cold, bad breath, a bitter taste in the mouth, general discomfort, or feeling unwell. The child may also have nausea, vomiting, diarrhea, chills, or sweats. If the abscess has spread, a child may present with complaints of facial swelling, trismus, symptoms of maxillary sinusitis, or difficulty swallowing or speaking.5 Of note, a child with a dental abscess may also be asymptomatic, with the infection only noted on thorough examination, particularly if an abscess is draining spontaneously through a sinus tract. Past medical history may reveal a history of dental caries or trauma to the teeth. Children with a history of osteogenesis imperfecta and other conditions resulting in abnormal dentin are at higher risk of developing dental abscesses from dental caries. Spontaneous dental abscesses are also frequently noted in familial hypophosphatemia or vitamin D–resistant rickets, due to hypomineralization of the dentin and enlargement of the pulp. Children with diabetes and boys are also at higher risk.6 Soft tissue injuries within the mouth are generally quite painful and are

noted shortly after the trauma occurs. Cuts of the lower lip or tongue are usually caused by biting down during a fall. A child who falls with an object in his mouth such as a pencil or toothbrush may have serious injuries to the posterior oral cavity or pharynx.

PHYSICAL EXAMINATION On physical examination, the child with a dental abscess may have fever or tachycardia, and depending on the extent of illness, the child may appear sick or uncomfortable. On focused examination of the oral cavity, the gums surrounding an infected tooth are often reddened and swollen, and one may be able to express pus from the base of the tooth. Pain is often elicited on palpation of the tooth, and the tooth may feel loose. Swelling may extend along the base of several teeth. If the infection tracks into the soft tissues of the neck, it can lead to airway compromise, and drooling or a muffled voice may be noted. The abscess also may cause trismus due to pain and swelling.5 If the abscess has spread to involve the soft tissues of the face, the child may have notable unilateral swelling of either the jaw or the upper face, depending on whether the lower teeth or upper teeth are involved. The facial skin may be erythematous and warm, particularly when compared to the opposite side of the face. The maxillary sinus can become involved with a dental abscess of the upper teeth, and unilateral maxillary sinus tenderness may be noted on percussion. There may also be unilateral cervical lymphadenopathy, and this may be the only external sign in early dental infections. Children with thermal or chemical burns may have areas of mucosal erythema or sloughing, and as healing proceeds an adherent white material appears. The distribution may include the palate, the lips, or the peripheral areas of the tongue. These lesions may be painful but generally heal within 2 weeks. Ulcers from sucking are usually found on the hard palate.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for dental abscesses includes inflammation or infection of the surrounding tissues (Table 32-4). For children with intraoral injuries, one must consider the possibility of inflicted trauma. Child abuse should be considered with any signs of facial or oral trauma, particularly with

lacerations of the oral frenulae or bruising of the labial sulcus (lower border between the lip and gums) in a child who is not yet walking. The head, face, and neck are the most common sites affected by physical abuse and may be the only manifestation on physical examination. Other orofacial injuries suggestive of child abuse include swollen lips with underlying ecchymoses and tooth fractures without an adequate history. Sexual abuse may present with oral findings, such as bruising of the hard and soft palates, tears of the lingual frenulum, or oral lesions associated with a sexually transmitted disease.4 Neglect may be suspected in a child with severe, untreated dental caries and oral infection, but this can be difficult to differentiate from parental ignorance of proper dental hygiene or difficulty with obtaining a dental care provider. TABLE 32-4

Differential Diagnosis for Dental Abscess

Acute inflammation of the salivary glands (e.g. parotitis, mumps) Periorbital cellulitis Peritonsillar abscess Sinusitis Burkitt’s lymphoma Unerupted tooth or impaired eruption of tooth

DIAGNOSTIC EVALUATION The diagnosis of a dental abscess is mostly clinical (Figure 32-2). However, if there is concern for involvement of the upper airway or the spread into the lateral pharyngeal space, a CT of the neck may be helpful to determine if a procedure is needed. If a dentist is involved with the child’s care while in the hospital, x-rays of the teeth and surrounding structures may be requested. Routine laboratory studies are not indicated. A blood culture may be considered in cases of dental abscess complicated by osteomyelitis or with signs of septicemia or endocarditis.

FIGURE 32-2. Suspected dental abscess: diagnostic and treatment algorithm.

If the abscess is surgically drained or is spontaneously draining through a sinus tract, the material may be sent for gram stain and culture. However, with intraoral drainage, the culture can be contaminated by normal oral flora if not properly obtained, so the utility of the results may be limited. An acute dental abscess usually is polymicrobial in origin, comprised of both facultative anaerobes (e.g. viridans group streptococci) and strict anaerobes (e.g. Prevotella and Fusobacterium) as well as possible aerobes.7,8 For intraoral injuries, clinical examination should reveal the extent of damage but radiographs of the teeth and surrounding bones may be indicated. Head or neck CT or CTA may be needed for possible retained foreign bodies or to evaluate for associated arterial injury. There is a small risk (0.6% incidence in recent studies) of internal carotid artery damage or thrombosis with lateral soft palate or peritonsillar injury.9,10 If child abuse is suspected, radiographs may reveal multiple healed fractures of the teeth and jaw. Unexplained oral bleeding in an infant warrants investigation with a complete blood count and coagulation studies. If sexual abuse is suspected, testing for sexually transmitted infections such as herpes, gonorrhea, or syphilis may be indicated. (See Chapter 40 for more on child abuse injuries.)

MANAGEMENT DENTAL ABSCESS Treatment of an uncomplicated dental abscess without facial swelling or severe pain may be with a dental procedure alone. For an infected primary tooth, the treatment is extraction. For an infected permanent tooth, the infected pulp material is removed and root canal treatment is performed instead of extraction. No antibiotics are needed if the infection is limited to the tooth and its root(s).8,11 If facial swelling or severe pain is present, oral antibiotics are given first to reduce the inflammation, followed by a dental examination in 1 week. Amoxicillin or penicillin should cover the flora in most dental abscesses. However, if local epidemiologic patterns reveal a high resistance rate to amoxicillin alone, or if the child is at higher risk of resistant organisms, alternative regimens include amoxicillin with clavulanic acid, clindamycin, or

a combination of metronidazole plus amoxicillin or a macrolide.8 For penicillin-allergic children, oral clindamycin is the recommended alternative agent. Once the swelling and severe pain have resolved, treatment can proceed with either extraction or root canal therapy as above. If the swelling or severe pain do not resolve or worsen after 1 week of oral antibiotics, the child may need a different oral antibiotic or admission for an intravenous (IV) antibiotic. Recommended regimens include ampicillin plus sulbactam or clindamycin or metronidazole plus ampicillin/sulbactam, depending on which antibiotics have been utilized as an outpatient and the extent of the infection. For infections involving the deep neck tissues, coverage of Staphylococcus aureus and Group A Streptococcus organisms is particularly important. Inpatients also often require IV fluids to treat dehydration, and most will require pain control with either oral or IV medications. The pain may improve if the abscess begins to spontaneously drain, but the abscess still requires treatment. Warm saltwater rinses of the mouth may also help with pain and discomfort. If a dentist is available for pediatric inpatient consultation, he/she should be contacted upon the child’s admission to the hospital. An otolaryngology (ENT) consult may be needed if there is extension of the abscess into the soft tissues of the neck or pharynx. Additional complications of dental abscesses are listed in Table 32-5. TABLE 32-5

Possible Complications from Dental Abscess

Dental cyst

Septicemia

Facial cellulitis

Endocarditis

Sinusitis

Pneumonia

Osteomyelitis

Brain abscess, meningitis

Airway compromise

Cavernous sinus thrombosis

Septic thrombophlebitis (Lemierre syndrome)

Sublingual or submandibular cellulitis (Ludwig angina)

Discharge criteria include improvement in any facial swelling or erythema, an ability to take enteral fluids and antibiotics, adequate pain control on oral medications, and adequate treatment of any complications such as osteomyelitis. Fortunately, the risk of recurrence of a dental abscess is relatively slim and most patients can wait 1 to 2 weeks to see their dentist, but close follow-up must be assured prior to discharge.11 More than 20 million children lack dental insurance, and for those on Medicaid, it can be difficult to find a dental provider.1 Thus, a dentist must be identified for follow-up prior to discharging the patient home. Many children with dental abscesses suffer from poor oral health in general. Prevention is key in order to avoid future dental problems. (See Box, Prevention of Dental Abscesses.) PREVENTION OF DENTAL ABSCESSES Most, if not all, dental abscesses are preventable with good dental hygiene and prompt attention to any dental trauma. Children should have their first visit to the dentist by age 3 and have a dental home as well as a medical home. If the family’s tap water is not fluoridated sufficiently, the child should be on daily oral fluoride supplementation (see American Academy of Pediatrics recommendations for dosages). The risk of dental caries is increased with a diet high in sugars and with the intake of sodas and sports drinks.

ORAL TRAUMA Treatment for children with mucosal injuries depends on the etiology but is largely supportive, and most children who seek care at the hospital are discharged from the emergency department. Bleeding from the oral mucosa often initially appears to be more significant due to mixing with saliva but should resolve within 10 minutes with direct pressure. Lacerations of the lower lip do not usually penetrate the entire lip and do not need suturing unless the outer cut is gaping or involves the vermillion border. Tongue lacerations also tend to heal on their own, provided any gaping resolves when

the tongue is relaxed. Lacerations of the hard or soft palate or involving the tonsils may need surgical repair, although observation may be an option for smaller lacerations provided no foreign body is retained. Children with dental injuries are also typically cared for in the outpatient setting. Injuries to primary teeth involve different strategies than injuries to permanent teeth, as damaged or missing permanent teeth can have significant negative functional, cosmetic, economic, and psychological effects.12 A severe dental injury (e.g. an avulsed permanent tooth), requires emergent dental evaluation, whereas a loose permanent tooth or fractured permanent tooth without exposure of the pulp should be evaluated by a dentist within 24 hours. Less significant injuries such a non-painful fracture to a primary or permanent tooth may be followed up on a less urgent basis. If a primary tooth is slightly loose after trauma, it should be left in place, as many of these injuries will heal on their own. A soft diet is recommended for 1 to 2 weeks and good oral hygiene is important to reduce the chance of infection.4 However, if the primary tooth is extremely loose, it may need to be removed to reduce the risk of aspiration of the tooth. A primary tooth that is completely avulsed out of the socket should not be replaced, as this can damage the permanent tooth beneath the gums. An avulsed permanent tooth is a true dental emergency, and a dentist should be contacted immediately if the tooth is located and the child is stable. The avulsed tooth should be held by the crown, gently rinsed in saline or tap water, and then placed back into the socket and held there by the child by biting down on gauze or with finger pressure. Alternatively, a temporary splint comprised of aluminum foil placed over the tooth and surrounding teeth can be used until dental intervention is available.13 Ideally, the tooth should be replaced in the socket within 15 minutes to an hour, but the tooth may remain viable for longer if placed in a container of cold milk or tooth storage media. Displaced permanent teeth due to luxation injuries will have the best possible outcome with urgent repositioning by a dentist within a few hours. Subluxed teeth, or loose teeth in normal position, must be followed closely and seen by a dentist as soon as possible for stabilization, ideally within 24 hours.13 Permanent teeth that are fractured with exposure of the pulp should be seen by a dentist within 24 hours. Tooth fragments should be located and

saved in tooth storage media or tap water. (Cold milk is not necessary, as the fragments do not contain live fibroblasts, but the tooth fragments will become discolored if not kept wet.14) If the fracture does not involve the pulp of the tooth, the fracture is not usually painful or at high risk for infection, so dental evaluation can wait up to 7 days.

SPECIAL CONSIDERATIONS During hospitalization, good oral hygiene should be taught and emphasized for all patients, with a particular focus on children with special healthcare needs. Teeth should be brushed twice daily with a small amount of water, and for children over age 2 years, a pea-sized amount of fluoridated toothpaste should be added. The teeth do not need to be rinsed after brushing, as the fluoride in the toothpaste has a beneficial topical effect. Children with tight spaces between primary teeth or with permanent teeth should also floss at least once a day.15 Children who are NPO or exclusively tube-fed should receive the same oral care as other children and are at higher risk for alterations in oral pH. Bruxism in children with cerebral palsy can erode the enamel and lead to a higher chance of tooth decay. Also, children with gastroenteritis, gastroesophageal reflux disease, or bulimia need to have the stomach acids removed from their teeth to prevent decalcification.15 Pediatric oncology patients are at higher risk of mucositis if oral hygiene is not maintained, and saliva provides an important barrier of defense against infection. For children at risk of gum bleeding, brushing should be done gently and the use of mouthwashes encouraged. Medications may also increase the risk of oral health problems. Some medications may decrease salivary flow, increasing the risk of dental decay (see Table 32-6), while others such as phenytoin may cause gingival hyperplasia, making plaque more difficult to remove.15 Also, many oral medications for children are given in sugar-based syrups, which lead to a higher risk of tooth decay. Children receiving these types of medications on a frequent or chronic basis may need to brush more often or use antibacterial mouthwashes. TABLE 32-6

Medication Classes Associated with

Decreased Salivary Flow Anticholinergics

Benzodiazepines

Antidepressants

Cytotoxic drugs

Antihistamines

Diuretics

Antihypertensives

Opiates

ADHD medications

Proton pump inhibitors

KEY POINTS A periapical abscess can be dangerous and may cause both local and systemic complications. Indications for admission include dehydration, worsening facial or neck swelling, inability to handle oral secretions, concern for airway compromise, systemic involvement, or failure of outpatient therapy. Antibiotics should cover both anaerobes and strict aerobes. Include Group A Strep and Staph aureus coverage for neck involvement.

ACKNOWLEDGMENT Special thanks to Dr. Rex Kido and Dr. Charles Klass for their assistance with this chapter and its preparation.

REFERENCES 1. US Department of Health and Human Services. Oral Health in America: A Report of the Surgeon General–Executive Summary. Rockville, MD: US Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health; 2000. 2. Nicopoulos M, Brennan MT, Kent ML. Oral health needs and barriers to

dental care in hospitalized children. Spec Care Dentist. 2007;27(5):206211. 3. Lewis CW. Dental care and children with special health care needs: a population-based perspective. Acad Pediatr. 2009;9(6):420-426. 4. American Academy of Pediatric Dentistry. Guideline on management of acute dental trauma. 2001, 2004, 2007, 2010, 2011. Available at: aapd.org/media/Policies_Guidelines/G_trauma.pdf. 5. Walsh LJ. Serious complications of endodontic infections: some cautionary tales. Aust Dent J. 1997;42(3):156-159. 6. Seow WK. Review: diagnosis and management of unusual dental abscesses in children. Aust Dent J. 2003;48:(3):156-168. 7. Robertson D, Smith AJ. The microbiology of the acute dental abscess. J Med Microbiol. 2009;58(2):155-162. 8. Brook I. Microbiology and management of endodontic infections in children. J Clin Pediatr Dent. 2003;28(1):13-7. 9. Randall DA, Kang DR. Current management of penetrating injuries of the soft palate. Otolaryngol Head Neck Surg. 2006;135(3):356-360. 10. Soose RJ, Simons JP, Mandell DL. Evaluation and management of pediatric oropharyngeal trauma. Arch Otolaryngol Head Neck Surg. 2006;132(4):446-451. 11. Kido R. Personal communication. February 2012. 12. Lee J, Divaris K. Hidden consequences of dental trauma: the social and psychological effects. Pediatr Dent. 2009;31(2):96-101. 13. Emerich K, Wyszkowski J. Clinical practice: dental trauma. Eur J Pediatr. 2010;169(9):1045-1050. 14. Macedo GV, Diaz PI, De O Fernandes CA, Ritter AV. Reattachment of anterior teeth fragments: a conservative approach. J Esthet Restor Dent. 2008;20(1):5-18; discussion 19-20. 15. Blevins JY. Oral health care for hospitalized children. Pediatr Nurs. 2011;37(5):229-235.

CHAPTER

33

Neck Pain Matthew T. Lister and Nicole E. St Clair

BACKGROUND Although neck pain is a common presenting symptom, it is rarely a discharge diagnosis. Estimates of the incidence of neck pain necessitating admission to a hospital do not exist, but data from a regional children’s hospital with 40,000 emergency department visits per year suggest that less than 10% of patients seen with a complaint of neck pain are admitted. This chapter emphasizes the most common diagnoses associated with neck pain that result in hospital admissions for children. DEFINITIONS A variety of terms deserve attention in the description and management of neck pain symptoms. Neck stiffness refers to an abnormal preferred position of the neck or a normal position with restricted range of motion. Meningismus indicates neck stiffness related to meningeal irritation or inflammation. Torticollis (Latin for “twisted neck”) refers to neck stiffness associated with the child holding his or her head to the side with the chin rotated in the opposite direction. Trismus refers not to neck stiffness, but stiffness and limited opening of the jaw. Various neck spaces or potential spaces deserve description (Figure 33-1), as infection of a certain space often indicates likely pathophysiology, determines the symptomatology and examination presentation, and dictates treatment of the disorder. The sublingual space (supramylohyoid space, a subdivision of the submandibular space) is that space beneath the tongue, medial to

the body of the mandible and superior to the myelohyoid muscle. The peritonsillar space is a potential space between the capsule of the pharyngeal or palatine tonsil and the superior constrictor muscle of the pharynx. The danger space is a potential space that is bound superiorly by the skull base, anteriorly by the alar fascia, and posteriorly by the prevertebral fascia, extending down to the diaphragm. The retropharyngeal space is anterior to the danger space and posterior to the visceral space containing the esophagus and trachea. It potentially communicates laterally with the parapharyngeal and danger spaces.1 The parapharyngeal space (also pharyngomaxillary space or lateral pharyngeal space) is best described as an inverted pyramid with the base at the skull base and the apex at the greater cornu of the hyoid bone, lateral to the superior pharyngeal constrictors, medial to the parotid gland, mandible, and lateral pterygoid muscles, anterior to the prevertebral fascia, and posterior to the pterygomandibular raphe. General definitions applicable to a description of infections anywhere in the body include cellulitis, phlegmon, and abscess. Cellulitis is a superficial infection, usually with signs of induration, erythema, and warmth. A phlegmon is an infection deeper in tissue with signs including induration, edema of surrounding tissues on imaging, possible necrosis of tissues within a given area, but no clearly-defined capsule or enhancing rim on contrast imaging. It may or may not be possible to obtain fluid from a phlegmon using needle or open techniques. An abscess is a walled-off collection of necrotic tissue and purulent material which typically exhibits an enhancing rim on imaging.

FIGURE 33-1. Lateral pharyngeal, retropharyngeal, danger, and prevertebral spaces and their relationship with each other. (A) Midsagittal section of the head and neck. (B) Coronal section in the suprahyoid region of the left side of the neck. (C) Cross-section of the neck at the level of the thyroid isthmus. a, artery; m, muscle; v, vein; 1, superficial space; 2, pretracheal space; 3, retropharyngeal space; 4, danger space; 5, prevertebral space. (From Chow AW. Lifethreatening infections of the head and neck. Clin Infect Dis. 1992;14:992; with permission from Oxford University Press and Dr. Anthony Chow.)

PATHOPHYSIOLOGY Neck pain can be caused by various pathologies. Because of the complicated anatomy and diverse structure in the neck, diseases of widely different etiologies may present with similar symptoms and can include infectious,

vascular, inflammatory, neoplastic, iatrogenic, congenital, autoimmune, traumatic, neurologic, and idiopathic etiologies (Table 33-1). TABLE 33-1

Differential Diagnosis of Neck Pain in Children

Diagnostic Category Diagnosis Infectious

Cervical lymphadenitis Peritonsillar abscess Retropharyngeal abscess Parapharyngeal abscess Jugular septic thrombophlebitis (Lemierre syndrome) Dental abscess Submandibular space infection (Ludwig angina) Sialadenitis Meningitis Cervical osteomyelitis Suppurative thyroiditis Infected branchial cleft cyst Infected thyroglossal duct cyst

Vascular

Vertebral artery dissection Stroke

Inflammatory/Idiopathic Atlantoaxial instability

Cervical spine stenosis Acute cervical disk calcification Relapsing polychondritis Neoplastic

Posterior fossa, spinal canal, and neck tumors Osteoid osteoma

Iatrogenic

Non-traumatic atlantoaxial rotatory subluxation Conditions associated with surgical positioning

Congenital/CNS

Chiari I malformation

Autoimmune

Arthritis and spondyloarthropathy

Traumatic

Vertebral fracture Spinal epidural hematoma Esophageal injury Laryngotracheal injury

CNS, central nervous system.

EVALUATION The diagnostic evaluation of neck pain is guided by findings from the history and physical examination. The need for and direction of more urgent evaluation is often evident on initial assessment. In cases involving stridor or respiratory distress (posturing, drooling, accessory muscle use, retractions), specialty evaluation by otolaryngology, airway films, or fluoroscopy may be warranted. With fever, lethargy, and/or meningismus, lumbar puncture with or without preceding head computed tomography (CT) to identify cases of increased intracranial pressure related to meningitis should be considered. In

cases of trauma, existing protocols, mechanism of injury, and examination findings dictate the initial steps taken. If there is altered mental status and/or cranial neuropathy, gait abnormality, or hemiparesis, then urgent CT or MR angiography or other modality may be warranted to rule out stroke or vessel dissection. Additional laboratory studies including blood cultures, complete blood count, erythrocyte sedimentation rate, and C-reactive protein may be helpful for suspected infectious or inflammatory problems. If indicated by examination, rapid strep antigen test, throat culture, or culture of purulent drainage from a lymph node, ear, or other non-oral source may be helpful prior to initiation of antibiotic therapy. Radiologic studies are often helpful in the diagnosis of neck pain. Depending on the history and physical examination findings, a cervical spine series can identify any fracture, dislocation, or instability. A CT scan with contrast is useful for evaluating the soft tissue structures of the neck and can suggest a diagnosis of phlegmon or abscess. Lateral neck films can also serve as an initial screening tool when retropharyngeal abscess or even epiglottitis/supraglottitis is suspected, as they may reveal widening of the retropharyngeal space, or a thumbprint sign from a thickened, edematous epiglottis. Widening can also be seen in normal patients with inadequate neck extension or inspiration, so the finding should be interpreted in the proper clinical context. Following trauma, in addition to identifying fractures or dislocations and evaluating for soft tissue injury, a CT scan can identify or raise suspicion of injury to the trachea or esophagus although crepitus, respiratory distress, and other history and examination findings are at least as important in alerting the practitioner to these entities. MRI is indicated if cervical osteomyelitis is suspected and for the evaluation of certain tumors.

HISTORY A thorough history and physical examination are warranted in all children presenting with neck pain. A few pieces of information from the history can quickly guide the examiner. Specifically, the presence or absence of fever and related complaints such as a sore throat, ear pain, dental pain, headache, or vomiting might point one toward an infectious or inflammatory cause. Important information in the history of present illness includes the temporal onset of pain, whether it is progressive or static, location of pain, radiation of

pain, and presence of associated neurologic symptoms, including bowel or bladder dysfunction, gait disturbance, or mental status change. Often a history of trauma is obvious or known, but eliciting a history of more subtle trauma is important. Systemic findings such as weight loss, fatigue, or night sweats can be suggestive of oncologic problems. Family history can be helpful in some cases if the cause is rheumatologic or vascular. Because of the known associations among some conditions or syndromes, it is important to obtain a thorough past medical and surgical history, including medication use, genetic syndromes, bleeding disorders, and immunodeficiency.

PHYSICAL EXAMINATION On inspection, it is important to note the general appearance of the patient, including his or her position of comfort. Signs of respiratory distress could include difficulty managing saliva and other secretions, stridor, posturing such as tripod posture with trunk leaning forward and neck extended, retractions, and paradoxical movement of the abdomen. Asymmetry in the neck, face, or any paired structures should be noted and investigated. Eye examination should include taking note of pupils, conjunctivae, extraocular movements, and gross visual acuity when possible. Oral examination includes assessment of jaw opening, teeth and gums, the floor of examination, tonsils, posterior oropharynx, uvula and palate. External ear (including position with notation of proptosis or mastoid tenderness), ear canal, and middle ear assessment should be completed. Inspection of the nasal tissues should be performed with an otoscope. Neck examination should assess for decreased mobility, torticollis, head tilt, stiffness, meningeal irritation, masses, lymphadenopathy, crepitus, fluctuance, tenderness, bruits, sterdor or stridor, and skin lesions. Finally, a complete neurologic examination is important to rule out mental status changes, nerve palsy, motor weakness, sensory deficit, and gait abnormality.

DIFFERENTIAL DIAGNOSIS AND TREATMENT When neck pain is a presenting symptom, the underlying cause must be determined to guide diagnostic studies and appropriate consultation or

treatment (Table 33-1). Diagnostic considerations recommendations can include the following.

and

treatment

INFECTIOUS CAUSES Cervical Lymphadenitis The most common infection associated with neck pain is cervical lymphadenitis. Often these infections resolve with antibiotics alone, but they may require surgical or needle drainage if an abscess forms. Children typically present with a unilateral enlarged, tender lymph node or nodes with overlying erythema (compared to children with generalized reactive lymphadenopathy, which is non-erythematous and occasionally tender); most have fever. The most common causative bacteria are Staphylococcus aureus and group A β-hemolytic streptococcus (GABHS). Cervical lymphadenitis can also be caused by viruses, mycobacteria, and other atypical organisms such as Bartonella henselae (the cause of cat scratch disease). The diagnosis is often made based on clinical presentation, but a CT scan or ultrasound may be indicated to identify other causes of a neck mass or abscess formation. Successful treatment most commonly involves empiric anti-staphylococcal agents or other antibiotics dictated by culture results, if available. Drainage of associated lymph node abscess may also be necessary. Deep Neck Space Infections Peritonsillar abscess presents in patients of all ages, more commonly in older children and adolescents. There may be an antecedent tonsillar or upper respiratory infection (URI), but symptoms typically progress rapidly once unilateral throat pain begins. Symptoms include severe unilateral tonsillar pain, otalgia, odynophagia, and sometimes fevers. Signs include trismus, drooling, tender cervical adenopathy, asymmetry of tonsils with edema and intense erythema of the soft palate, and uvular deviation. Treatment includes specialty consultation with otolaryngology for localization and drainage of the abscess and possible tonsillectomy followed by IV or oral antibiotic therapy. Peritonsillar “cellulitis” or phlegmon may have a similar presentation, but may respond to oral antibiotics and pain medication without the need for drainage. A CT scan is not always indicated, but may be helpful in cases with atypical presentation or in younger children (Figure 33-2).

FIGURE 33-2. Computed tomography of a peritonsillar abscess. (Used with permission from Children’s Hospital of Wisconsin Imaging Department, David Gregg, MD.) Retropharyngeal phlegmons and abscesses occur most commonly in preschool children. They are usually the result of a suppurative lymph node infection in the retropharyngeal space. There is often an antecedent history of URI, and occasionally with the presence of neck stiffness and pain. Hallmarks include high fever, drooling, torticollis, dysphagia, odynophagia, edema or mass of the posterior pharyngeal wall, and airway distress. Diagnostic studies include lateral neck films, which are abnormal 90% of the time, and for more detail, CT scans (Figures 33-3 and 33-4). Typical pathogens include β-hemolytic streptococci, respiratory anaerobes, and S. aureus.1 Children with retropharyngeal infections should be hospitalized, started on empiric broad-spectrum antibiotics, and managed in consultation with an otolaryngologist. Patients with airway compromise should undergo immediate surgical drainage. Patients with early retropharyngeal disease without associated abscess (retropharyngeal cellulitis or phlegmon) may respond to antibiotics alone and not require surgical drainage. For stable

patients with small or immature retropharyngeal abscesses, there is growing evidence to support initial management with antimicrobial therapy and close observation, and surgical drainage if there is not a clinical response within 24 to 48 hours; those with mature retropharyngeal abscesses, particularly if >2 cm, generally require both drainage and antimicrobial therapy.2,3

FIGURE 33-3. Enlarged retropharyngeal space secondary to soft tissue swelling anterior to the upper cervical bodies seen in a retropharyngeal abscess. (Used with permission from Children’s Hospital of Wisconsin Imaging Department, David Gregg, MD.)

FIGURE 33-4. Computed tomography of a retropharyngeal abscess. (Used with permission from Children’s Hospital of Wisconsin Imaging Department, David Gregg, MD.) Suppurative infections can also occur in the parapharyngeal space. Patients tend to be older than those with retropharyngeal abcesses. Dysphagia and trismus are common; patients may also develop a Horner syndrome on the affected side and other unilateral cranial nerve deficits.1 An associated complication is septic jugular vein thrombophlebitis (Lemierre syndrome). The most useful imaging study is a CT scan with contrast to determine whether there is abscess formation. Treatment involves empirical coverage with broad-spectrum intravenous antibiotics. If there is no response to medical therapy within 24 to 72 hours, or an abscess is clearly identified, incision and drainage may be warranted. Jugular Septic Thrombophlebitis (Lemierre Syndrome) Patients with Lemierre syndrome present with systemic findings concurrent with or following pharyngotonsillitis, dental infection, deep neck infection, mastoiditis, or sinusitis. The classic presentation is associated with a dental

infection and foul-smelling breath. Most patients with jugular septic thrombophlebitis have unilateral neck pain below the mandibular angle along the sternocleidomastoid muscle with severe tenderness, but no discrete mass or other associated findings to account for the tenderness. Patients often present with shaking chills, spiking fevers, and possibly dyspnea. The most common organism identified is Fusobacterium necrophorum, although this infection is usually polymicrobial. The diagnosis is suggested if F. necrophorum grows from a blood culture, and it can be confirmed by contrast CT scan of the neck. Treatment is a 4- to 6-week course of broad-spectrum antibiotics to cover aerobic and anaerobic bacteria, and supportive care. Anticoagulation is recommended only if there is evidence of continued propagation of the thrombus. Dental Abscess Dental abscess is typically caused by mouth flora in the setting of dental caries. It typically presents with face or neck swelling, pain, and fever. A fluctuant area near the affected tooth or gum is sometimes palpable. The acute treatment is intravenous or oral antibiotics to cover aerobic and anaerobic organisms, followed by definitive dental treatment. Submandibular Space Infection (Ludwig Angina) Ludwig angina is a cellulitis of the connective tissue, fascia, and muscles of the submandibular space. The source is usually a dental infection. In its most severe and lifethreatening form, induration of the submandibular tissues can force the tongue base to occlude the airway. It occurs most often in older children and adolescents. The clinical presentation includes a toxic-appearing patient with fever, foul breath, drooling, odynophagia; frequently the voice is affected. Physical examination characteristics include an erythematous, tender, and indurated floor of mouth, swollen and tender neck, and an elevated tongue. This is a rapidly progressive illness and represents a true airway emergency. Nearly all children require emergent intubation or tracheotomy. Treatment involves controlling the airway and administering broad-spectrum intravenous antibiotics; abscess is usually not identified, and imaging is not usually helpful in the initial assessment and management. Sialadenitis Inflammation or infection of the major salivary glands may be a cause of neck pain. The most commonly affected are the parotid glands and submandibular glands. Edema, induration, tenderness, and occasionally warmth and erythema may be present and are usually unilateral. Causes of infection or inflammation include viral illnesses, ductal obstruction due to

stones, dehydration leading to thickening of secretions and poor salivary flow with secondary infection, thickened secretions due to medications such as antihistamines and anticholinergics, autoimmune conditions associated with Sjogren syndrome, prior treatment with radiation or chemotherapy, and trauma to ducts. The most common pathogens are Staphylococcus species or other oral flora. Treatment includes aggressive oral hydration when feasible, IV hydration when necessary, IV or PO antibiotic therapy, heat over the affected gland, pressure/massage to encourage drainage of infected saliva, removal of obstructing debris or stone by an otolaryngologist if needed, and the use of sialogogues such as sour candy or lemons. Meningitis The classic clinical presentation of meningitis is fever, meningismus, irritability, and vomiting in a toxic-appearing patient. It is usually associated with viral or bacterial infections. Diagnosis is made by evaluation of cerebral spinal fluid (CSF) from a lumbar puncture; CSF pleocytosis is present in most cases. Bacterial culture and viral studies can provide a definitive diagnosis. Appropriate treatment includes supportive care and empiric or targeted antimicrobial treatment. Please refer to Chapter 97 for further details pertaining to the evaluation and management of meningitis. Cervical Osteomyelitis The clinical presentation of osteomyelitis of the cervical spine includes focal tenderness, limited range of motion, and fever. This infection occurs most often in children older than 8 years. The most common organism identified is S. aureus. Evidence of infection is supported by magnetic resonance imaging (MRI) or bone scan. Cultures of the blood or bone obtained by biopsy are useful in choosing antibiotics, but in their absence, treatment should be a prolonged course of antibiotics covering S. aureus and GABHS, with consideration of Kingella kingae for younger children (see Chapter 105). Surgical debridement is indicated if the patient does not demonstrate clinical improvement after appropriate treatment. Suppurative Thyroiditis This rare disease typically occurs after an upper respiratory infection and presents with the acute onset of fever, chills, and a tender, enlarged thyroid gland. Infection is most often caused by S. aureus, Streptococcus, and Enterobacter. Diagnosis is made by ultrasound-guided needle aspiration or biopsy with culture. Thyroid function tests are rarely abnormal. Many cases may turn out to be related to a persistent thyroglossal duct, though some children have a pyriform sinus fistula.1 After treatment of acute infection, endoscopy, CT, or a barium swallow is recommended to

identify a communication with the pyriform sinus. Initial treatment is empiric IV antibiotics to cover S. aureus, Streptococcus pneumoniae, and Enterobacter. Treatment can be narrowed based on culture results. Other Infections Infections in congenital abnormalities such as a branchial cleft cyst/sinus or a thyroglossal duct cyst are not uncommon. Commonly, there is a history of antecedent upper respiratory illness, followed by swelling of a midline neck cyst (in the case of a thyroglossal duct cyst) or a cyst along the sternocleidomastoid anterior border (in the case of a second branchial cleft cyst), which may then become painful, tender, and fluctuant. There may be overlying skin erythema, and drainage from a sinus tract in the case of a branchial cleft abnormality. Treatment is with needle aspiration or drainage procedures along with oral antibiotics covering Staphylococcus species for less severe infections.

VASCULAR CAUSES Spontaneous Arterial Dissection Dissection of the cervical and intracranial portions of the carotid and vertebrobasilar arteries may occur spontaneously or in association with trauma or other underlying risk factors. Classically, patients present with head and neck pain in association with ataxia, vomiting, or other focal neurologic signs. Dissection is a known cause of stroke in children. In one study of vertebral artery dissection in children, half of those who had cervical radiographs had associated cervical anomalies.4 Causes of dissection include trauma and vasculopathy; in some cases, the cause is unknown. Dissection can occur at any age; a review of 68 cases by Hasan and colleagues showed a 6.6:1 male predominance and a median age of 9 years.4 The diagnosis is made most accurately by angiography; magnetic resonance angiography may also be useful. Limited data are available regarding the most effective medical treatment of dissection in children and young adults. Most physicians consider antiplatelet and/or anticoagulation therapy. Interventional neuroradiology may offer an approach in difficult cases.

INFLAMMATORY/IDIOPATHIC Upper Cervical Spine Instability Atlantoaxial instability is typically

caused by congenital abnormalities of the odontoid process or ligamentous hyperlaxity, and it affects as many as 15% of children with Down syndrome. It can also be caused by inflammatory conditions such as juvenile idiopathic arthritis (JIA). Patients with cervical spine instability may be totally asymptomatic or they may have severe neck pain and neurologic deficits. The diagnosis is made using plain films of the cervical spine or three-dimensional CT reconstruction. Treatment is surgical fusion; however, the decision to treat should be individualized, because many children with radiographic evidence of instability do not exhibit symptoms. As many as 15% of children with Down syndrome have cervical spine instability, but most experts agree that operative fusion should be performed only on those who are symptomatic or have neurologic symptoms. Cervical Stenosis In children, cervical stenosis is most often associated with achondroplasia. All children with this condition have abnormal growth of the pedicles with associated spinal stenosis. One third of patients with achondroplasia have symptomatic stenosis by age 15 years. Patients present with pain in the lower back and legs that is exacerbated by activity. MRI is diagnostic and can identify the extent of the stenosis. The treatment is surgical decompression. Acute Cervical Disk Calcification Disk calcification is thought to be due to a nonspecific inflammatory process. The child usually presents with fever and a painful, stiff neck. Examination reveals tenderness over the affected disk, most commonly in the cervical area. Radiographs show calcification of the intervertebral disk space 1 to 3 weeks after the onset of symptoms. Treatment is symptomatic, with a cervical collar and antiinflammatory medication. Most cases resolve within 2 to 3 weeks. Relapsing Polychondritis Relapsing polychondritis is a rare condition involving inflammatory changes in cartilage and other connective tissue, and can occur in both children and adults. Episodes occur with rapid onset of inflammatory symptoms and signs over cartilage in the head and neck as well as in other joints, causing pain, erythema, warmth, and tissue swelling usually involving the auricular cartilage. The inflammation may last 1 to 2 weeks and is occasionally treated with systemic steroids. Diagnosis is clinical, with laboratory testing notable only for nonspecific signs of inflammation.1

NEOPLASTIC Posterior Fossa, Spinal Canal, and Neck Tumors Tumors causing neck pain can occur in a variety of locations, and the signs and symptoms vary with location. In general, pain is a prominent symptom. Patients often have associated neurologic deficits involving the cranial nerves or motor function; sensory deficits are uncommon. Up to 25% of patients with neck or spinal tumors present with secondary scoliosis; torticollis can be seen with posterior fossa tumors. Diagnosis is usually made by CT scan or MRI. Treatment is dependent on the cause of the tumor. Osteoid Osteoma Osteoid osteomas are benign bone tumors characterized clinically by localized pain over the affected region. They most commonly occur in the lower extremities but may occur in the spine as well, in which case a painful secondary scoliosis may be evident. The cause of these lesions is unclear. They most commonly occur in older children and adolescents, with a 2:1 male predominance. The diagnosis can be made by plain films; a bone scan or CT provides more detail if needed. Most osteoid osteomas are self-limited and gradually calcify and blend into surrounding bone. Treatment with nonsteroidal anti-inflammatory drugs is sufficient in most cases, with some requiring surgical excision of the nidus.

IATROGENIC Non-Traumatic Atlantoaxial Rotatory Subluxation (Grisel Syndrome) Grisel syndrome is rare, and presents with painful torticollis, most commonly after otolaryngologic procedures such as adenoidectomy. The cause is thought to be hyperemia of the tissues, leading to laxity of the atlantoaxial joint. The diagnosis is made by CT scan with three-dimensional reconstruction. Treatment consists of a cervical collar and anti-inflammatory medications until symptoms resolve. If reduction does not occur, cervical traction may be necessary. Conditions Associated with Surgical Positioning In the appropriate clinical setting, disorders of the neck musculature and joints including the temporomandibular joint can present after surgery. These may be simply related to muscle strain or spasm from a period of neck rotation, flexion, or extension during a procedure or may relate to intubation or use of jaw-

opening devices and retractors during surgery in the mouth or throat. Management is through the use of anti-inflammatory medications, heat, and possibly physical therapy in the case of muscle strain/spasm, with more urgent intervention if jaw dislocation is suspected.

CONGENITAL In addition to infectious processes involving congenital cysts, some conditions may present with neck pain as a symptom of other pathology affecting the central nervous system (CNS) and spine. Chiari I Malformation Type I Chiari malformation is defined as descent of the cerebellar tonsils more than 5 mm below the foramen magnum. The cause is unknown. Classically, it presents with occipital headache or posterior neck pain lasting seconds to minutes, which is worsened by Valsalva maneuvers. Although associated neurologic deficits are common, many patients with this malformation are asymptomatic. Up to 50% of individuals with type I Chiari malformation have an associated syrinx, or a collection of fluid caused by obstruction of CSF flow. The incidence of Chiari malformation has dramatically increased with the advent of MRI scanning, the diagnostic test of choice. Treatment, if indicated, is surgical decompression.

AUTOIMMUNE Arthritis and Spondyloarthropathy Although uncommon, neck stiffness can be the presenting sign of diagnoses such as JIA and psoriatic arthritis. The affected joints have limited motion and are warm, tender, and swollen. The cause of most inflammatory joint diseases is unknown. With the spondyloarthropathies, involvement of the cervical spine increases with age and disease duration. The diagnosis is made by history and physical examination findings. Laboratory tests such as sedimentation rate, HLA typing, or specific antibodies may help support the diagnosis (see Chapter 150).

TRAUMATIC CAUSES Discussion of traumatic causes of neck pain is beyond the scope of this

chapter. Most significant trauma in children is managed by a trauma team. Less obvious forms of trauma, such as an unwitnessed fall from a bed or a hyperextension injury from gymnastics, are important considerations when a child presents with neck pain that does not appear to have an infectious cause. In nonverbal children, it is important to consider non-accidental trauma as a possible issue. When neck trauma is suspected, priority should be placed on cervical spine immobilization with appropriate imaging and evaluation. KEY POINTS Etiologies of neck pain in children can vary widely, but for hospitalized children the diagnoses often require prompt evaluation and management. For young children, neck pain can be subtle and often the only indication of pain is the presence of limited neck movement. Careful head, oropharyngeal, neck, and neurologic examinations are indicated, and the presence of fever should warrant exclusion of meningitis and deep neck space infections.

ACKNOWLEDGMENT This chapter has been revised from the original version, which was authored by Nicole Frei, MD.

SUGGESTED READINGS American Academy of Pediatrics Committee on Sports Medicine and Fitness. Atlantoaxial instability in Down syndrome: subject review. Pediatrics. 1995;96:151-154. Bliss SJ, Flanders SA, Saint S. Clinical problem-solving: a pain in the neck. N Engl J Med. 2004;350:1037-1042. Coticchia JM, Getnick GS, Yun RD, Arnold JE. Age-, site-, and time-specific differences in pediatric deep neck abscesses. Arch Otolaryngol Head Neck Surg. 2004;130:201.

Craig FW, Schunk JE. Retropharyngeal abscess in children: clinical presentation, utility of imaging, and current management. Pediatrics. 2003;111:1394-1398. Greenlee JD, Donovan KA, Hasan DM, Menezes AH. Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under age 6 years. Pediatrics. 2002;110:1212-1219. Nicklaus PJ, Kelley PE. Management of deep neck infection. Pediatr Clin North Am. 1996;43:1277-1296. Peters TR, Edwards KM. Cervical lymphadenopathy and adenitis. Pediatr Rev. 2000:21;399-405. Pharisa C, Lutz N, Roback MG, Gehri M. Neck complaints in the pediatric emergency department: a consecutive case series of 170 children. Pediatr Emerg Care. 2009;25:823. Sia KJ, Tang IP, Kong CK, Nasriah A. Grisel’s syndrome: a rare complication of tonsillectomy. J Laryngol Otol. 2012;126:529. Silverboard G, Tart R. Cerebrovascular arterial dissection in children and young adults. Semin Pediatr Neurol. 2000;7:289-300. Subach BR, McLaughlin MR, Albright AL, Pollack IF. Current management of pediatric atlantoaxial rotatory subluxation. Spine. 1998;23:2174-2179. Yassari R, Frim D. Evaluation and management of the Chiari malformation type 1 for the primary care pediatrician. Pediatr Clin North Am. 2004;51:477-490.

REFERENCES 1. Lee KJ. Essential Otolaryngology Head and Neck Surgery. 8th ed. New York, NY: McGraw Hill; 2003:426-436, 489, 628, 828, 1035. 2. Page NC, Bauer EM, Lieu JE. Clinical features and treatment of retropharyngeal abscess in children. Otolaryngol Head Neck Surg. 2008;138:300. 3. Wong DK, Brown C, Mills N, Spielmann P, Neeff M. To drain or not to drain - management of pediatric deep neck abscesses: a case-control study. Int J Pediatr Otorhinolaryngol. 2012;76(12):1810-1813. 4. Hasan I, Wapnick S, Tenner MS, Couldwell WT. Vertebral artery dissection in children: a comprehensive review. Pediatr Neurosurg.

2002;37:168-177.

CHAPTER

34

Petechiae and Purpura Susan H. Frangiskakis

INTRODUCTION Petechial and purpuric rashes can cause even seasoned clinicians to become very concerned because they can signify dangerous disease such as meningococcemia, as well as more benign disorders such as viral infections. It is important for the pediatric hospitalist to have an approach to the evaluation and management of patients with petechiae or purpura. A more complete discussion of the individual disease entities associated with thrombocytopenia and coagulation disorders are provided in Chapters 9 and 92. Petechiae and purpura are hemorrhages in skin or mucous membranes that are less than 2 mm in diameter or greater than 2 mm in diameter, respectively. These lesions do not blanch under diascopy. Ecchymoses are subcutaneous hemorrhages that are greater than 1 cm. Purpura fulminans is a progressive condition in which cutaneous infarctions occur and result in extensive skin necrosis.

PATHOPHYSIOLOGY Petechiae and purpura can occur from a variety of pathophysiologic mechanisms that interfere with the complex process of hemostasis. Platelets, von Willebrand factor, and the coagulation cascade are essential for hemostasis. Thrombocytopenia, abnormal platelet function, von Willebrand factor defects, and clotting factor deficits can result in petechiae and purpura. Disruption of normal vascular integrity, such as occurs with endothelial injury as a result of infection or inflammation, can cause petechiae and purpura. Mechanical causes, such as trauma or increased intravascular

pressure from coughing or vomiting, can cause petechiae and purpura by this mechanism as well. Intrinsically abnormal vascular components, such as collagen defects in connective tissue disorders, can result in these lesions. Ecchymoses are most often caused by trauma. Purpura fulminans typically occurs in the setting of bacterial sepsis and disseminated intravascular coagulopathy (DIC).

DIFFERENTIAL DIAGNOSIS Because a number of different pathophysiologic mechanisms can cause petechiae or purpura, the differential diagnosis is extensive (Table 34-1). The clinical manifestations of bleeding disorders vary according to the underlying defect. Thrombocytopenia and abnormal platelet function typically result in petechiae, ecchymoses, and persistent bleeding from superficial cuts and mucosal membranes. Infection and vasculitis can cause petechiae or purpura, which can be palpable. Clotting factor deficits and other coagulation disorders typically cause hemarthroses, soft tissue bleeding, and prolonged bleeding, but they can also cause petechiae or purpura. Von Willebrand disease is usually manifested as mucosal membrane bleeding, postsurgical bleeding, and menorrhagia, but it can result in petechiae. Disorders of vascular fragility can give rise to ecchymoses, as well as petechiae and purpura. TABLE 34-1

General Mechanism

Causes of Petechiae and Purpura Categories Examples

Disrupted vascular Infection integrity

Bacterial (meningococcemia, pneumococcal or Haemophilus influenzae sepsis, group A streptococcal infections) Viral (adenovirus, enteroviruses, influenza A virus, Epstein-Barr virus, parvovirus B19)

Rickettsial (Rocky Mountain spotted fever) Vasculitis

Henoch-Schönlein purpura, Kawasaki disease, systemic lupus erythematosus

Mechanical

Trauma (accidental, nonaccidental, or birth related), coughing, vomiting

Abnormal vascular components

Collagen vascular disorders (Ehlers-Danlos syndrome), vitamin C deficiency (scurvy)

Thrombocytopenia Decreased platelet production Increased platelet destruction

Leukemia, aplastic anemia, medications (sulfonamides, carbamazepine, valproic acid), vitamin B12 or folate deficiency Idiopathic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

Splenic Hypersplenism, consumptive sequestration hemangioma (Kasabach-Merritt syndrome) Platelet dysfunction

Coagulation defects

Hereditary

Bernard-Soulier syndrome, Glanzmann thrombasthenia, storage pool disease

Acquired

Medications (aspirin, nonsteroidal anti-inflammatory drugs), uremia

Hereditary

Factor deficiencies, factors VIII and IX most commonly

(hemophilia A and B); von Willebrand disease; fibrinogen disorders Acquired

Liver disease, vitamin K deficiency, medications (heparin, warfarin), disseminated intravascular coagulopathy, clotting factor inhibitors

Note: Some causes may result in petechiae or purpura by more than one mechanism.

HISTORY AND PHYSICAL EXAMINATION Some key information from the history and physical examination can help determine the most likely cause of the petechiae or purpura and help direct the appropriate steps in evaluation of the patient. See Table 34-2 for focused history questions and Table 34-3 for directed physical examination items. TABLE 34-2

Focused History

Characteristic Questions Onset and duration of lesions

Acute? Rapidly progressing? Recurrent or chronic?

Location of the lesions

Only above the nipple line? Only on the buttocks and lower extremities? In a stocking-glove distribution? Generalized? Involving the mucous membranes?

Predisposing factors

Coughing? Vomiting? Recent trauma? Recent illness such as an upper respiratory infection? Bloody diarrhea? Medications?

Systemic signs or symptoms

Fever? Irritability? Lethargy?

Review of systems

Headache? Stiff neck? Bleeding from other sites such as epistaxis or per rectum? Darkened urine? Joint pain or swelling? Abdominal pain? Bone pain? Myalgias?

Past medical history

Immunization status? History of prolonged bleeding?

Birth history for neonates

Was the mother ill? Did the mother have any medical conditions such as preeclampsia or lupus? Was the mother taking any medications?

Family history

Bleeding disorders? Siblings with conditions such as neonatal thrombocytopenia?

TABLE 34-3

Directed Physical Examination

System

Physical Examination Findings

Vital signs

Febrile? Hypotensive?

General

Well or toxic appearing? Irritable? Lethargic?

HEENT

Bulging fontanelle? Pupils equal and reactive? Photophobia? Palatal petechiae? Erythematous oropharynx? Tonsillar exudates?

Neck

Nuchal rigidity? Kernig or Brudzinski signs?

Cardiovascular

New murmur? Capillary refill and extremity perfusion?

Abdomen

Hepatomegaly or splenomegaly? Tenderness?

Musculoskeletal Joint swelling? Joint pain on movement? Neurologic

Mental status? Focal findings?

Skin

Location of the lesions (e.g. at the site of the blood

pressure cuff? Above the nipple line only? On the buttocks and lower extremities primarily? In a stocking-glove distribution or generalized?) Characteristics of the lesions (e.g. are the lesions palpable?). Quantity of lesions present? HEENT, head, ears, eyes, nose, and throat.

The anatomic location of the skin lesions is suggestive but not definitive of certain disease processes. In general, petechiae solely above the nipple line suggest a benign cause such as vomiting or coughing. These Valsalva-like maneuvers cause spikes in intravascular pressure in the venous system of the head and neck. Lesions primarily on the buttocks and lower extremities are suggestive of Henoch-Schönlein purpura. Lesions in a stocking-glove or generalized distribution are more concerning for bacterial disease, although viruses can also give rise to this pattern; for instance, papularpruritic gloveand-stocking syndrome caused by parvovirus B19.

EVALUATION Children presenting with petechiae and purpura often warrant a complete blood count (CBC), including a platelet count and white blood cell (WBC) differential, peripheral blood smear, partial thromboplastin time (PTT), and prothrombin time (PT) performed to direct the remainder of the evaluation. Children who present with fever and petechiae or purpura warrant immediate attention because this can be a medical emergency (see Chapter 58). Approximately 0.5% to 11% of children presenting with fever and petechiae or purpura have a serious bacterial infection. In addition to the initial screening laboratory tests mentioned, a blood culture and cerebrospinal fluid (CSF) studies, including cell counts, glucose, protein, Gram stain, and culture, should be obtained. If infection by group A β-hemolytic streptococcus is suspected, a rapid streptococcal test or culture of the oropharynx, or both, are indicated. Testing for viruses, such as adenovirus and influenza, may be performed, depending on the level of clinical suspicion. Other studies such as enteroviral polymerase chain reaction assay on CSF or Rocky Mountain spotted fever antibody titers may also be helpful in some settings. If DIC is suspected, flbrinogen, fibrin degradation product,

and D-dimer studies of blood should be obtained. Children with an ill appearance, hypotension, decreased perfusion, or mental status changes, including irritability or lethargy, are more likely to have a serious bacterial infection. Laboratory evidence supporting a potential serious bacterial cause includes an abnormal peripheral WBC count, elevated C-reactive protein, abnormal PT, and abnormal CSF studies. If the child does not have a fever or does not appear acutely ill and infection is not likely, the evaluation should be directed by the type of bleeding and clinical scenario. See Table 34-4 for suggested studies to work up various causes. Some conditions such as viral infections, idiopathic thrombocytopenic purpura, and Henoch-Schönlein purpura are more common causes of petechiae and purpura in children. If the child is otherwise well and recently had a viral infection, idiopathic thrombocytopenic purpura would be likely. The child would be expected to have a decreased platelet count with a normal WBC count and hemoglobin. If this patient has an abnormal WBC count or is anemic, in addition to having thrombocytopenia, evaluation of a peripheral blood smear and assessment by a hematologist for conditions such as leukemia are indicated. If the child has abdominal pain, arthritis, and hematuria, Henoch-Schönlein purpura should be considered, provided that the CBC, peripheral smear, PT, and PTT are normal (see Chapter 58). TABLE 34-4

Condition Suspected

Evaluation of Petechiae and Purpura Recommended Studies

Acute lymphocystic leukemia

CBC with platelet count and WBC differential, peripheral blood smear, PT, and PTT

Infection

Blood culture, CSF studies, CRP; consider a rapid streptococcal antigen test or oropharyngeal culture, respiratory viral cultures, specific viral antibody titers, RMSF antibody titers

Vasculitis

ESR, CRP, ANA, anti-double-stranded DNA

antibody, complement levels (C3, C4, CH50); consider other specific autoantibody titers Mechanical

Imaging studies for trauma, including head CT scan and skeletal survey for suspected nonaccidental trauma

Abnormal vascular Skin biopsy for Ehlers-Danlos syndrome or components other collagen vascular disorders, ascorbic acid level Thrombocytopenia Consider bone marrow biopsy; urinalysis, BUN, creatinine Platelet dysfunction

Bleeding time, platelet aggregation studies, clot retraction assay, BUN, creatinine

Coagulation defect

Specific clotting factor assays, thrombin time, fibrinogen level; bleeding time, factor VIII activity, von Willebrand factor antigen level, and ristocetin cofactor activity for von Willebrand disease; liver function tests, correction of PT and PTT after administration of vitamin K, mixing studies to detect factor inhibitors

ANA, antinuclear antibody; BUN, blood urea nitrogen; CBC, complete blood count; CH50, 50% hemolyzing dose of complement; CRP, C-reactive protein; CSF, cerebrospinal fluid; CT, computed tomography; ESR, erythrocyte sedimentation rate; PT, prothrombin time; PTT, partial thromboplastin time; RMSF, Rocky Mountain spotted fever; WBC, white blood cell.

TREATMENT Treatment of petechiae and purpura is based on the underlying cause. Aggressive management with the administration of antibiotics and supportive care is warranted in cases concerning possible serious infectious disease (see Chapter 58). For example, meningococcemia can progress very rapidly because of the release of a potent endotoxin, with the development of shock, purpura fulminans, and respiratory failure, and the patient can potentially die within hours of presenting. It is imperative that the administration of

antibiotics not be delayed if there is difficulty obtaining the screening tests or cultures. Admission to a pediatric intensive care unit in cases of suspected bacterial sepsis is warranted for supportive care and frequent monitoring of vital signs, mental status, and the development of shock, respiratory failure, or DIC. Hemorrhage from other sites needs to be evaluated in these patients. In some circumstances patients may require transfusions with red blood cells, platelets, fresh frozen plasma, or cryoprecipitate (see Chapters 92 and 93).

SPECIAL CONSIDERATIONS NEONATAL PETECHIAE OR PURPURA Petechiae and purpura in a neonate can be due to a number of unique causes in addition to those listed earlier, including birth trauma, TORCH (toxoplasmosis, other infection, rubella, cytomegalovirus, herpes simplex virus), other infections such as syphilis or human immunodeficiency virus infection, neonatal alloimmune thrombocytopenic purpura, congenital thrombocytopenic syndromes such as thrombocytopenia-absent radius syndrome, and congenital abnormalities of platelet function. It is critical to determine whether the neonate is well or ill in order to direct the investigation. If the neonate is ill, sepsis and DIC must be strongly considered and addressed appropriately. If the neonate is well, one can proceed with the basic screening laboratory tests as stated earlier. Depending on these results, further investigation under the guidance of a hematologist or neonatologist may be helpful. KEY POINTS Children who present with fever and petechiae or purpura warrant immediate attention because this can be a medical emergency. Treatment of petechiae and purpura is based on the underlying cause.

SUGGESTED READINGS Brogan PA, Raffles A. The management of fever and petechiae: Making sense of rash decisions. Arch Dis Child. 2000;83:506-507. Mandl KD, Stack AM, Fleisher GR. Incidence of bacteremia in infants and children with fever and petechiae. J Pediatr. 1997;131:398-404. Nielsen HE, Anderson EA, Anderson J, et al. Diagnostic assessment of haemorrhagic rash and fever. Arch Dis Child. 2001;85:160-165. Wells LC, Smith JC, Weston VC, et al. How likely is meningococcal disease in a child with a non-blanching rash: A prospective cohort study. Arch Dis Child. 2001;84(Suppl 1):A10-A68.

CHAPTER

35

Respiratory Distress Juliann Lipps Kim

BACKGROUND Respiratory distress is one of the most common reasons for a child to present to the emergency department or a practitioner’s office. Respiratory distress can result from disorders in the respiratory system or in organ systems that control or influence respiration. Young children have an increased risk for respiratory distress because of their anatomy and physiology. Nearly 20% of all emergency department visits for children younger than 2 years are for respiratory disease.1 The causes of respiratory distress are vast, and practitioners caring for children should have a systematic approach to its diagnosis and management. Cardiopulmonary arrest in children is largely due to respiratory failure (in adults, cardiac causes are most common). Rapid evaluation and management of severe pediatric respiratory disease may be necessary to prevent respiratory failure.

PATHOPHYSIOLOGY Understanding respiratory physiology can aid the practitioner in diagnosing the cause of respiratory symptoms. The main goals of respiration are oxygen uptake and elimination of carbon dioxide. Secondary goals include acid–base buffering, hormonal regulation, and host defense. To achieve the goals of respiration, three main functional components of the respiratory system are used: (1) mechanical structures (including chest wall, respiratory muscles, and pulmonary circulation), (2) membrane gas exchanger (interface between airspace and pulmonary circulation), and (3) regulatory system (network of chemical and mechanical sensors throughout the circulatory and respiratory systems). All three components are tightly integrated, and dysfunction of one

can lead to respiratory distress or failure. Respiratory function is tightly controlled by a complex network of central and peripheral chemoreceptors and mechanoreceptors responding to information from the body about the status of the respiratory system. This network modulates the neural output to the respiratory muscles, affecting the timing and force of respiratory effort. Central chemoreceptors in the ventral reticular nuclei of the medulla are sensitive to changes in pH and partial pressure of carbon dioxide (PCO2) of cerebrospinal fluid. The intrinsic brainstem function of the dorsal and ventral respiratory centers of the medulla controls inspiration and expiration, respectively. The apneustic center in the pons increases the depth and duration of inspiration, whereas the pneumotaxic center decreases depth and duration. The cerebellum, hypothalamus, motor cerebral cortex, and limbic system also play a role in mediating respiration. Carotid and aortic bodies are peripheral chemoreceptors sensitive to the partial pressure of oxygen (PO2), PCO2, and pH in arterial blood. Mechanoreceptors (stretch, juxtacapillary, and irritant reflex) distributed along the airways, lung parenchyma, and chest wall respond to lung volume, changes in pulmonary microvasculature, chest wall muscle activity, and environmental irritants. Information from central and peripheral receptors is integrated in the brainstem, and efferent impulses are transmitted to alter respiratory function and maintain homeostasis. Even slight alterations in arterial pH, PO2, or PCO2 stimulate the respiratory centers to modify the respiratory pattern. Increased arterial PCO2 and decreased arterial PO2 lead to an increase in respiratory drive and increased neural output to respiratory muscles. The resulting increase in ventilation can be achieved by increases in tidal volume or respiratory rate, because the product of these two factors determines the minute ventilation. Respiratory insufficiency or the more severe entity, respiratory failure, occurs when regulatory systems or the effector organs (lungs, respiratory muscles) are impaired or overwhelmed. This results in diminished oxygenation (decreased arterial PO2), retention of carbon dioxide (increased arterial PCO2), and acidosis (decreased arterial pH). Disruption of the mechanics of the lung or chest wall results in the majority of respiratory disease in children.2 Obstructive or restrictive disease leads to increased work of breathing and increased energy demands on the

respiratory muscles to meet the body’s needs. This increased work manifests itself clinically as respiratory distress, evidenced by increased work of breathing. When demand exceeds capability, the result is respiratory insufficiency, which can progress to respiratory failure. In respiratory muscle dysfunction, neural output is sent to the respiratory muscles but they are unable to respond adequately to increase respiratory effort. The physical signs of respiratory failure in this setting are more subtle, and the signs of increased work of breathing may not be present. When the difficulty involves the control of breathing, there is an inadequate neural response to hypoxemia or hypercarbia. Arterial hypoxemia or hypercarbia without an increase in respiratory effort should lead one to suspect an anomaly in the neural control of breathing caused by central nervous system injury, drug-induced inhibition, or dysfunction of spinal motor neurons or nerve fibers innervating the respiratory muscles.

INITIAL ASSESSMENT The first priority in evaluating a child with respiratory distress is to assess the airway, breathing, and circulation (ABC’s). Rapid assessment and intervention can prevent the progression from respiratory compromise to respiratory failure. To assess the airway, determine whether it is patent, stable, and maintainable. If not, such an airway must be established (e.g. repositioning, instrumentation). Once these three criteria are met, the breathing process is evaluated by determining the respiratory rate, oxygen saturation, adequacy of breath sounds, and quality of respiratory effort (e.g. labored, use of accessory muscles). Determination of arterial blood gas levels may be needed if there is evidence of respiratory insufficiency or failure. If spontaneous ventilation is inadequate, assisted breathing with positive pressure, initially via a bag-mask device, is indicated. Assessment of the patient’s circulation and mental status are other key aspects of the initial evaluation. Based on this rapid assessment, the clinician obtains information about the severity of the patient’s condition and how rapidly interventions must be performed. Providing supplemental oxygen is an important first step for a child presenting in distress, especially with hypoxemia demonstrated by oximetry. Oxygen can be delivered by multiple devices, and the choice depends on the child’s clinical status and oxygen needs (see Chapter 195). Some of these

devices can agitate a child further, worsening respiratory compromise and increasing the metabolic demand for oxygen. Allow the child to remain with the parent as much as possible, and use the least noxious form of oxygen delivery necessary. In a small number of children, airway adjuncts such as a nasopharyngeal airway, oropharyngeal airway, or assisted ventilation are needed. An oropharyngeal airway holds the tongue forward to prevent airway obstruction, so it will not be tolerated in a conscious or semiconscious patient with an intact gag reflex, and it may induce vomiting. A nasopharyngeal airway can be used in a conscious or unconscious patient but should be avoided in those with facial trauma. Continuous positive airway pressure may assist inspiratory efforts as well as provide positive end-expiratory pressure (PEEP). PEEP provides resistance to expiration, which may help expand atelectatic portions of the lung and thereby reduce ventilation-perfusion mismatch. Bilevel positive airway pressure provides inspiratory and expiratory pressure via a firmly fitting facemask, which may be uncomfortable and not well tolerated in infants or young children (see Chapter 195). Careful reevaluation after every intervention is critical to the care of a child with respiratory compromise. This confirms proper application of the intervention and monitors the patient’s response.

PATIENT HISTORY Therapeutic interventions in an ill child should not be delayed to perform a detailed history. A focused history includes an assessment of respiratory and systemic symptoms (Box 35-1). The history will guide the practitioner toward the diagnostic possibilities and appropriately focus the management. For children with special needs or chronic respiratory problems, ask about the child’s baseline respiratory status, how this episode is different, and what interventions have been successful in the past. Box 35-1 Components of a Focused History Onset, duration, chronicity, character of symptoms Alleviating and provoking factors Treatment to date

Activity level Respiratory symptoms Cold symptoms Cough (wet, dry, time of day) Trouble breathing (rapid breathing, retractions, abdominal muscle use, “seesaw” respirations, positional distress) Color change (pale, cyanotic) Altered pattern of breathing (periodic, shallow or deep, bradypnea, apnea) Inability to clear upper respiratory tract because of weakness or poor gag Systemic symptoms Fever Poor feeding, fluid intake Urine output Weight loss or failure to gain weight Emesis or diarrhea Past medical history Special healthcare needs or preexisting medical conditions (complex heart disease, chronic infections, prematurity) Respiratory disease (asthma, cystic fibrosis) Family history of atopy, cardiac or respiratory disease Medications (respiratory treatments, oral medications, herbal supplements) Allergies (medications, foods, environment) Immunization status Last oral intake (in case airway management becomes necessary)

PHYSICAL EXAMINATION

Certain features of the physical examination are particularly important in determining the severity of respiratory distress and localizing the primary cause (Box 35-2). Vital signs help determine cardiopulmonary status but may be influenced by various factors. Fever increases the respiratory rate by approximately three to seven breaths per minute for each degree Celsius above normal.3,4 Tachycardia commonly occurs as a response to the increased sympathetic tone in a child with respiratory distress; sympathetic tone is also increased with fever. Bradycardia is a late and ominous sign of severe hypoxia. Pulsus paradoxus (>10 mmHg decrease in blood pressure during inspiration) can occur with severe pulmonary disease. Cyanosis is not evident until more than 5 g of hemoglobin are desaturated, which correlates with an oxygen saturation of less than 70% to 75%. Central cyanosis is evidenced by blue, gray, or dark purple discoloration of mucous membranes, most reliably assessed at the lips and tongue. Perioral cyanosis is not indicative of central cyanosis and likely represents local venous congestion. It is often seen with Valsalva-like maneuvers (e.g. crying) in fair-skinned infants. Acrocyanosis is often present in healthy newborns; in older children, it may be more suggestive of cardiovascular status (e.g. peripheral vasoconstriction secondary to hypotension). Pulse oximetry is a useful, noninvasive means of assessing hypoxia, but it has some limitations. It can be unreliable with low blood pressure, movement, or arterial PO2 less than 50 mmHg, if hemoglobin is bound to molecules other than oxygen (e.g. carbon monoxide), or if significant methemoglobinemia is present. Box 35-2 Directed Physical Examination General Level of consciousness (alertness, responsiveness) Preferred position of child Color Failure to thrive Signs of prematurity or trauma Vital signs Respiratory

Airway Nasal flaring Inspiratory noises: seal-like barking, sonorous (nasal or pharyngeal), harsh (tracheal), high pitched (intrathoracic), stertor (gurgling) Symmetry of palate and tonsils Prominence of posterior pharynx Drooling, dysphagia Inspection Depth and quality of respirations Retractions (subcostal, supraclavicular, intercostal) Accessory muscle use Symmetry of chest wall movement Shape of chest (scoliosis, pectus excavatum or carinatum) Auscultation Air entry Inspiration-to-expiration ratio Rales or crackles Wheezing (inspiratory or expiratory) Symmetry of breath sounds Presence of pleural rub Cardiac Murmur Rhythm Heart sounds Thrill, rub, gallop Quality of pulses Capillary refill time Color Abdomen

Hepatomegaly Splenomegaly Mass Ascites Extremities Clubbing Deformities Neurologic Focal deficit Cranial nerves Muscle tone and strength Evidence of increased intracranial pressure Restlessness or anxiety is associated with early hypoxia (“air hunger”), but the mental status can progress to somnolence and lethargy with hypercarbia and severe hypoxemia. The position of comfort can provide information about the location of dysfunction. Children with upper airway obstruction often sit upright with the neck extended to open the airway. Infants with laryngomalacia have more pronounced stridor in the supine position compared with the prone position. Inspiratory and expiratory noises can help localize the underlying process and may suggest cause. Stridor is a predominantly inspiratory monophasic noise indicating an extrathoracic airway obstruction. Upper airway obstruction can lead to acute deterioration and severe morbidity and mortality. Expiratory wheezing or stridor usually reflects intrathoracic obstruction; however, biphasic stridor may suggest a fixed lesion at any point along the airway. Grunting represents a child’s attempt to increase the PEEP and raise the functional residual capacity by closing the glottis during expiration. Auscultation along the entire airway, including the nose, mouth, neck, and chest, may provide localizing information. The presence of rales, wheezing, or asymmetrical breath sounds and the duration of inspiration versus expiration are particularly noteworthy. The ratio of inspiration to expiration (I/E) is normally 1:1. Extrathoracic obstruction tends to prolong

the inspiratory phase (e.g. I/E ratio of 3:1), whereas lower airway obstructive pathology, such as asthma or bronchiolitis, produces a prolonged expiratory phase (e.g. I/E ratio of 1:3). Respiratory distress may be caused by nonrespiratory pathology or may have an impact on other organ systems. Detailed cardiac, abdominal, musculoskeletal, skin, and neurologic examinations should be performed.

DIFFERENTIAL DIAGNOSIS Respiratory difficulties may result from abnormalities within the respiratory system or from the dysfunction of organ systems influencing the respiratory system. Within the respiratory system, problems can arise from upper airway obstruction, lower airway obstruction, changes in gas diffusion from the alveolus to the capillary, abnormal pulmonary blood flow, or alterations in nerves and muscles that control breathing. Disease in other organ systems can compromise respiratory function directly or may induce compensatory respiratory mechanisms (Tables 35-1 and 35-2). TABLE 35-1

Differential Diagnosis of Respiratory Distress

Respiratory System

Other Organ Systems

Upper airway (nasopharynx, oropharynx, larynx, trachea, bronchi)

Central nervous system

Anatomic: craniofacial abnormalities, choanal atresia, tonsillar hypertrophy, macroglossia, midface hypoplasia, micrognathia, laryngomalacia, tracheomalacia, hemangioma, webs, cysts, laryngotracheal cleft, papilloma, subglottic stenosis, vocal cord paralysis,

Structural abnormality: agenesis, hydrocephalus, mass, arteriovenous malformation Infectious: meningitis, encephalitis, abscess, poliomyelitis Dysfunction or immaturity:

tracheal stenosis, fistula, bronchomalacia, bronchogenic cyst

apnea, hypoventilation, hyperventilation

Infectious: nasal congestion, peritonsillar abscess, tonsillitis, croup, epiglottitis, retropharyngeal abscess, tracheitis, bronchitis

Inherited degenerative disease: spinal muscular atrophy

Environmental or traumatic: chemical or thermal burn, aspiration of foreign body

Intoxication or toxins: alcohol, barbiturates, benzodiazepines, opiates, tetanus

Mass, including malignancy Inflammatory: angioneurotic edema, anaphylaxis

Seizure Trauma: hemorrhage, birth asphyxia, spinal cord injury, anoxic encephalopathy

Lower airway (bronchioles, acini, interstitium) Inflammatory: asthma, allergy, angioneurotic edema, meconium aspiration, near drowning, gastroesophageal reflux, aspiration

Other: transverse myelitis, acute paralysis, myopathy

Infectious: bronchiolitis, pneumonia (bacterial, viral, atypical bacterial, Chlamydia, Pertussis, fungal, Pneumocystis), abscess, empyema

Peripheral nervous system

Congenital malformation:

Phrenic nerve injury

congenital emphysema; cystic adenomatoid malformation; sequestration; pulmonary agenesis, aplasia, or hypoplasia; pulmonary cyst

Environmental or toxins: tick paralysis, heavy metal poisoning, organophosphates, botulism, snakebite

Environmental or traumatic: thermal or chemical burn, smoke, carbon monoxide, hydrocarbon, drug-induced pulmonary fibrosis, bronchopulmonary traumatic disruption, pulmonary contusion

Metabolic: inborn errors of metabolism, carnitine deficiency, porphyria

Other: bronchiectasis, interstitial lung disease, bronchopulmonary dysplasia, cystic fibrosis, pulmonary edema, hemorrhage, embolism, atelectasis, mass

Other: Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, muscular or myotonic dystrophy, muscle fatigue

Chest wall and intrathoracic Pneumothorax, tension pneumothorax Pneumomediastinum Pleural effusion Empyema Chylothorax Hemothorax

Inflammatory: dermatomyositis, polymyositis

Cardiovascular Structural: congenital heart disease, pericardial effusion, pericardial tamponade, aortic dissection or rupture, mass, coronary artery dilation or aneurysm, pneumopericardium, great vessel anomalies Other: arrhythmia, myocarditis, myocardial ischemia or infarction, congestive heart failure

Diaphragmatic hernia Cyst, mass Spinal deformity (kyphoscoliosis)

Gastrointestinal

Pectus excavatum or carinatum

Appendicitis

Rib fracture, flail chest

Necrotizing enterocolitis Mass (including hepatomegaly, splenomegaly) Ascites Obstruction Perforation, laceration Hematoma Contusion Esophageal foreign body Abdominal pain Metabolic and endocrine Acidosis: fever, hypothermia, dehydration, sepsis, shock, inborn errors of metabolism, liver disease, renal disease, diabetic ketoacidosis, salicylates

TABLE 35-2

Common Causes of Respiratory Distress

Neonate

Infant or Child

Transient tachypnea of the newborn

Bronchiolitis

Sepsis

Pneumonia

Respiratory distress syndrome

Asthma

Pneumonia

Croup

Nasal obstruction or airway anomalies

Foreign body aspiration

Congenital heart disease

Fever Sepsis Metabolic derangements Allergy

DIAGNOSTIC EVALUATION Further workup may be indicated to evaluate the severity of illness or its cause and should be guided by the clinical assessment. In children with chronic disease, compare laboratory studies and radiographs to previous studies, if available. Pulse oximetry can detect hypoxemia but does not provide direct information about the adequacy of ventilation. Exhaled carbon dioxide levels can be measured with noninvasive devices, but this determination is used most often in the setting of endotracheal intubation. Arterial blood gas analysis can assess oxygenation (arterial PO2) and ventilation (arterial PCO2) and detect metabolic derangements of pH, bicarbonate, and base excess. Venous blood samples can provide some information about ventilation but are less useful for assessing oxygenation. The utility of obtaining other laboratory studies depends on the clinical setting and the diagnostic considerations. Radiographs may be an important adjunct in the evaluation of a child

with respiratory disease. Chest radiographs (anteroposterior and lateral views) are performed upright and on full inspiration whenever possible. Quality images can assist in the identification of airspace disease, hyperinflation, effusion, mass, foreign body, chest wall deformity or trauma, or cardiac abnormality. If an effusion is suspected, decubitus films may be helpful to determine whether the fluid shifts with gravity (“layers out”). Inspiratory and forced expiratory or bilateral decubitus chest films are useful to evaluate for the presence of a foreign body or other localized lower airway obstruction. An obstructing lesion can cause air trapping distal to the site. On an expiratory film, the unobstructed lung tissue decreases in volume and appears more dense, whereas the obstructed region is relatively hyperlucent. With decubitus films, the dependent (inferiorly positioned) lung should decrease in volume and appear denser, except for an obstructed region that remains inflated due to air trapping. When the patient’s position is switched, the affected lung is superior and appears fully aerated, making the obstructed portion difficult to appreciate. If the obstruction is long-standing, the obstructed portion may become atelectatic or fluid filled and appear as a persistent density in the various views. Lateral and anteroposterior radiographs of the neck are useful for the evaluation of upper airway obstruction, allowing the visualization of retropharyngeal, supraglottic, and subglottic spaces. These films may be useful to diagnose retropharyngeal abscess, epiglottitis, foreign body aspiration, or tracheitis. Ill children with suspected upper airway obstruction should not be sent to the radiology department unattended or should have films deferred until they are stabilized. Other imaging modalities to consider are computed tomography (CT), magnetic resonance imaging (MRI), airway fluoroscopy, and barium swallow studies. CT evaluates cervical and thoracic structures in greater detail and may help identify areas of intrinsic or extrinsic compression. Mediastinal, pleural, and pulmonary parenchymal abnormalities are well identified with CT. MRI is particularly helpful to delineate hilar and vascular anatomy. Airway fluoroscopy provides dynamic pictures of the respiratory system, including the airways and diaphragm. Barium swallow studies are helpful in the evaluation of patients with recurrent pneumonia, persistent cough, stridor, or wheezing. The anatomy of the gastrointestinal tract from the mouth to the stomach is revealed, and compression along the esophagus may suggest a lesion that is compressing the airway as well. Contrast material is mixed with

substances of different consistencies and textures, ranging from thin liquids to thick liquids to solids. Barium swallow studies evaluate swallowing mechanics and the presence of vascular rings, tracheoesophageal fistulas, and gastroesophageal reflux.

MANAGEMENT Acute interventions should not be delayed in a child with respiratory distress, regardless of the underlying cause. Restoration of oxygenation and ventilation is the main priority. Airway patency should be established and maintained, followed by a rapid assessment of breathing and circulation. Oxygen delivery should be initiated using the least noxious form possible that provides an adequate fraction of inspired oxygen (FIO2), and the child should be placed on cardiopulmonary monitors, including pulse oximetry. Airway adjuncts may be necessary to maintain patency. If these are unsuccessful, or if oxygenation and ventilation are inadequate, endotracheal intubation may be indicated. Breathing treatments (albuterol, racemic epinephrine, ipratropium bromide) may be useful in certain clinical situations, including asthma, bronchiolitis, or croup. Further therapies are determined by the underlying cause of respiratory distress. KEY POINTS Do not delay the management of a compromised child to perform detailed history and physical examination. Clinical history and physical examination are critical to determining likely etiologies of respiratory compromise. Respiratory difficulties may arise from causes other than abnormalities within the respiratory system.

SUGGESTED READINGS Barren JM, Zorc JJ. Contemporary approach to the emergency department management of pediatric asthma. Emerg Med Clin North Am. 2002;20:1. Haddad GG, Palazzo RM. Diagnostic approach to respiratory disease. In:

Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia: WB Saunders; 2004:1363-1370. Infosino A. Pediatric upper airway and congenital anomalies. Anesthesiol Clin North Am. 2003;20:4. Ruddy RM. Evaluation of respiratory emergencies in infants and children. Clin Pediatr Emerg Med. 2002;3:156-162. Stevenson MD, Gonzalez del Rey JA. Upper airway obstruction: infectious cases. Clin Pediatr Emerg Med. 2002;3:163-172.

REFERENCES 1. Weiner DL. Respiratory distress. In: Fleisher GR, Ludwig S, eds. Textbook of Pediatric Emergency Medicine. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:553-564. 2. Perez Fontan JJ, Haddad GG. Respiratory pathophysiology. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia: WB Saunders; 2004:1376-1379. 3. O’Dempsey TJ, Laurence BE, McArdle TF Todd JE, Lamont AC, Greenwood BM. The effect of temperature reduction on respiratory rate in febrile illnesses. Arch Dis Child. 1993;68(4):492. 4. Gadomski AM, Permutt T, Stanton B. Correcting respiratory rate for the presence of fever. J Clin Epidemiol. 1994;47(9):1043.

Shock

CHAPTER

36

Raina Paul and Andrew M. Fine

BACKGROUND Shock is a clinical condition that occurs when there is inadequate delivery of oxygen and other nutrients to meet the metabolic demands of the tissues. If left untreated, shock results in irreversible cell and organ damage and death. The clinician must be able to recognize shock early, initiate therapy rapidly, and arrange safe transport of the patient to an intensive care facility. These lifesaving tasks require that the clinician have a fundamental knowledge of the causes, presentations, therapies, and complications of shock. Physiologically, shock can be classified as compensated, when the patient is able to maintain a normal blood pressure for age, or decompensated, when deterioration has led to hypotension. In general, compensated shock progresses to decompensated shock if left untreated, which emphasizes the importance of early recognition and intervention. Children can generally maintain a normal blood pressure until advanced stages of shock; therefore hypotension (see Table 36-1 for age-based definitions of hypotension) in a pediatric patient is an ominous sign of impending circulatory collapse. When measuring blood pressure with a sphygmomanometer, it is important to select the smallest cuff that covers two-thirds of the upper arm or leg. TABLE 36-1

Hypotension Parameters

Age

Minimum Systolic Blood Pressure (mmHg)

Term neonate (0–28 days)

60

Infant (1–12 mo)

70

Child (1–10 y)

70 + (2 × age in years)

Older than 10 y

90

PATHOPHYSIOLOGY AND DEFINITIONS Shock can also be classified by cause, with the main types being hypovolemic, cardiogenic, and distributive shock, which includes septic shock. The mechanisms may differ, but inadequate tissue perfusion is the common final pathway.

HYPOVOLEMIC SHOCK Hypovolemic shock, by far the most common type of shock in children, occurs when a decrease in intravascular volume leads to decreased venous return and subsequently, decreased preload. Decreased preload results in decreased stroke volume. An increase in heart rate often maintains cardiac output initially, but when this compensatory response is inadequate, cardiac output diminishes. The formula that defines this relationship is as follows: Cardiac output = Heart rate × Stroke volume Decreased cardiac output results in decreased delivery of oxygen and other substrates to the tissues. The two main categories of hypovolemic shock are hemorrhagic and non-hemorrhagic; examples are provided in Table 362. TABLE 36-2

Causes of Hypovolemic Shock

Nonhemorrhagic

Hemorrhagic

Vomiting or diarrhea

Trauma

Diabetes insipidus, diabetes mellitus

Gastrointestinal bleeding

Heat stroke

Postsurgical bleeding

Burns

Sequestration crisis

Intestinal obstruction

Splenic rupture

Water deprivation Adrenal insufficiency Hypothyroidism In the early stage of hypovolemic shock, autoregulatory mechanisms shunt blood flow preferentially to the brain, heart, and adrenal system thus preserving blood pressure. Because flow is diverted from less critical organs, patients may present initially with cool or mottled extremities and decreased urine output. Other signs may include dry mucous membranes, absence of tears, and abnormal skin turgor. Hemorrhagic shock due to known trauma is typically diagnosed at the initial presentation; however, hemorrhagic shock can present during hospitalization, especially in postoperative patients. Victims of child abuse are also at risk for delayed diagnosis of hemorrhagic shock because the initial history may be incomplete, inaccurate, or misleading, and symptoms may progress over time. Nonhemorrhagic shock may present in patients with ongoing fluid losses (e.g. vomiting, diarrhea, gastric suctioning, burns), especially if there is inadequate replacement.

DISTRIBUTIVE SHOCK Distributive shock is caused by a decrease in systemic vascular resistance. Abnormalities in vasomotor tone cause peripheral pooling of blood, which leads to a diminished effective preload, decreased cardiac output, and inadequate tissue perfusion. This process can occur without frank fluid loss. Causes of distributive shock are listed in Table 36-3. TABLE 36-3 Anaphylaxis Medications Foods

Causes of Distributive Shock

Envenomations or stings Blood products Latex Neurologic Head injury Spinal shock Septic shock Drugs Septic Shock Sepsis is a clinical syndrome that results from overwhelming infection creating a cascade of endogenous inflammatory mediators resulting in widespread tissue injury. Shock occurring during sepsis begins with volume maldistribution due to leaky vessels, resulting in intravascular volume depletion, decreased flow to vital organs including the heart, and ultimately metabolic derangements at the cellular level. It is important to consider septic shock early, because a seemingly stable patient with minimal findings of infection can quickly progress to sepsis. In the early (compensated) phase, often designated as “warm shock,” septic shock may present with a hyperdynamic state including decreased vascular resistance, widened pulse pressure, increased cardiac output, tachycardia, tachypnea, warm extremities, and normal urine output. As it progresses to the decompensated phase, patients develop intravascular volume depletion, myocardial depression, cool extremities, thready pulses, central nervous system changes, respiratory distress, and decreased cardiac output, often denoted as “cold shock.” Although anyone can develop septic shock, risk factors include young age, chronic medical condition, presence of central intravenous (IV) catheters, immunocompromise, burns, and malnutrition. Septic shock can result from bacterial, viral, or fungal infection. It is important to note that septic shock can occur when cultures or other diagnostic tests do not yield a definitive organism. Several studies have demonstrated that an organism is recovered only 50% of the time in the pediatric population. Shock can also develop from localized bacterial infections that produce toxins; this is referred to as toxic shock. This form of shock is most commonly associated with toxin-producing strains of group A Streptococci and Staphylococcus

aureus. Other Forms of Distributive Shock Anaphylactic shock occurs when an exogenous stimulus causes an allergic systemic immunoglobulin E–mediated response that triggers the release of histamine and other vasoactive factors from mast cells, with resulting vasodilation (see Chapter 47). Neurogenic shock may occur with spinal cord transection above the first thoracic level, with severe injuries to the brainstem or with isolated intracranial injuries. An injury to the cervical cord may result in unopposed parasympathetic tone and subsequent vasodilation. Some drugs can cause severe vasodilation, resulting in shock; these drugs include those that cause anaphylaxis and those that cause severe hypotension (e.g. β-antagonists and calcium channel antagonists).

CARDIOGENIC SHOCK Cardiogenic shock occurs when there is decreased cardiac output caused by pump failure. The main causes are listed in Table 36-4. Excluding patients with congenital heart disease, cardiogenic shock is much less common in children than in adults because of the relatively low incidence of coronary artery disease and congestive heart failure in the pediatric population. Cardiogenic shock should be strongly considered in the following clinical scenarios: no history of fluid losses, physical examination reveals hepatomegaly or rales, chest radiograph demonstrates cardiomegaly, and when there is no clinical improvement despite oxygenation and volume expansion. Worsening symptoms, including persistent tachycardia or shortness of breath, during volume resuscitation should also heighten one’s suspicion for cardiogenic shock. TABLE 36-4

Causes of Cardiogenic Shock

Cardiomyopathies Familial Infectious Infiltrative Idiopathic Arrhythmias

Ventricular fibrillation Supraventricular tachycardia Bradycardia Complete heart block Mechanical defects Congenital heart disease Coarctation of the aorta Cardiac tumor Obstructive disorders Pulmonary embolism Tension pneumothorax Constrictive pericarditis Pericardial tamponade Pulmonary hypertension Ischemia or infarction Anomalous coronary artery Kawasaki disease Management of cardiogenic shock should focus on correcting arrhythmias if present, improving preload and cardiac contractility, and reducing afterload. The stress on the heart can be minimized by decreasing metabolic demand including achieving normothermia, correction of anemia if present, and sedation, intubation, and mechanical ventilation if necessary. Although cardiogenic shock is uncommon as the primary cause of shock in children, it may be a late manifestation of other forms of shock.

PROGRESSION OF SHOCK In early, or compensated, shock, pediatric patients are able to maintain cardiac output and blood pressure by increasing the heart rate and peripheral vascular resistance. With further compromise of cardiac function, the compensatory tachycardia is insufficient to maintain cardiac output. Decreased perfusion affects many systems, causing metabolic acidosis,

oliguria, elevated transaminases from hepatocellular injury, cool extremities, mottling of the skin, and ileus. Tachypnea develops to increase the elimination of carbon dioxide, which helps compensate for the metabolic acidosis. In the late stages of shock, end-organ failure may manifest as central nervous system depression (ranging from confusion and agitation to coma), anuria, uremia, hyperkalemia, acute respiratory distress syndrome, and coagulopathies. Specific organ dysfunctions that are the result of shock are outlined in Table 36-5. TABLE 36-5

Organ Dysfunction in Shock

Cardiovascular • Decreased BP 50% FiO2 needed for sat >92% • CO2 >65 mm Hg on blood gas • PaO2/FiO2 2 × upper limit of normal or 2-fold increase in baseline Hepatic • bilirubin ≥4 mg/dL (not for newborns)

• ALT 2 × upper limit of normal

PATIENT HISTORY Early recognition of shock is important. Table 36-6 identifies patients at increased risk for developing shock. The history should elicit whether the patient falls into one of these high-risk categories. Additional questions should be directed at recent exposures through travel, trauma or infectious agents, recent therapies such as medications, fluids, and procedures, and allergies to medications, foods, and environmental chemicals such as latex. TABLE 36-6

Patients at Increased Risk for Shock

Febrile infants Immunocompromised patients Neonates Patients with congenital heart disease Patients with excessive fluid losses Patients with central venous catheter

PHYSICAL EXAMINATION The physical examination (Table 36-7) should focus on aspects that will help the clinician distinguish among the different causes of shock. TABLE 36-7

Directed Physical Examination

Vital signs Skin Rash Petechiae Ecchymosis Erythroderma Mottling

Head, eyes, ears, nose, and throat Evidence of head trauma Pupil size and reactivity Conjunctival pallor Central cyanosis (lips, tongue) Neck Meningismus Cervical spine tenderness Lungs Abnormal breathing pattern (e.g. Kussmaul) Retractions Wheezes or rales (focal or bilateral) Diminished breath sounds or dullness to percussion Heart Hyperdynamic Murmur Rub Gallop Abdomen Tenderness, rebound, or guarding Distention or ascites Mass or organomegaly Extremities Temperature Peripheral pulses Clubbing Neurologic Mental status Food deficit

DIFFERENTIAL DIAGNOSIS Shock, once recognized, should be treated immediately and attention to specific underlying causes should be pursued only after the basic resuscitation needs are met. Shock in a neonate may be the result of any of the previously mentioned causes, but the differential diagnosis of neonatal shock should also include those listed in Table 36-8. Likewise, the diagnosis of shock may be more challenging in medically complicated patients as they can have abnormal vasomotor responses resulting in widely variable blood pressures and heart rates. These patients may also be unable to mount an adequate immune response, or possess internal hardware that could harbor infection. TABLE 36-8

Special Considerations in Neonatal Shock

Congenital adrenal hyperplasia Inborn errors of metabolism Left-sided cardiac obstructive lesions Aortic stenosis Hypoplastic left heart syndrome Critical coarctation of the aorta Interrupted aortic arch Blood loss at delivery Perinatal infection Abdominal catastrophe (midgut volvulus)

DIAGNOSTIC EVALUATION Diagnostic tests should focus on the aforementioned organ dysfunctions and tests that may aid identify the inciting cause of shock (Table 36-9). A lactate should always be checked, though elevation often occurs only late in disease course. Many pediatric patients in shock will have a normal lactate and thus the clinician should not be falsely reassured. TABLE 36-9

Diagnostic Tests Considered for Patients

in Shock Complete blood count with differential Serum chemistries Electrolytes Blood urea nitrogen Creatinine Glucose* Liver enzymes including bilirubin Pancreatic enzymes Cardiac enzymes Lactic acid Coagulation studies Prothrombin time Partial thromboplastin time Fibrinogen Fibrin split (degradation) products Arterial blood gas Type and crossmatch Cultures Blood Urine Cerebrospinal fluid Pleural fluid Abscess drainage Toxicology Urine Serum Urinalysis Imaging Chest radiograph

Abdominal radiograph or obstruction series Electrocardiogram *Consider a bedside rapid blood glucose test (Dextrostix).

MANAGEMENT A pediatric patient in shock represents a medical emergency. For this reason, identification of the precise cause of shock may be delayed while resuscitation and stabilization proceed. Attention to the ABCs (airway, breathing, and circulation) remains a basic principle in the initial assessment and management. In general, increasing oxygen delivery to the tissues and decreasing oxygen demand are key. General time goals for resuscitation are delineated in Figure 36-1. It is imperative that the entire care team is aware of the timing of the resuscitation interventions. Use of a visible countdown clock is often helpful in keeping these time constraints at the forefront of resuscitation efforts. Adherence to timely fluid and algorithm goals has been shown to decrease hospital and intensive care length of stay as well as decrease mortality in the community setting. Using a standardized protocol is useful in ensuring all algorithm components are met. If there is suspicion of trauma, cervical spine immobilization should be maintained until the spine can be evaluated. The primary survey of a pediatric patient in shock is directed toward the rapid identification of immediately life-threatening conditions that should be addressed before a more extensive evaluation.

FIGURE 36-1. Resuscitation goals in shock. (Data from Pediatric Advanced Life Support Manual. American Heart Association; 2010 and Brierley J, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal shock. Crit Care Med. 2009;37(2):666-88.) A stable airway should be established and maintained, and supplemental oxygen should be provided to keep arterial oxygen saturation greater than 95%. Hypoxemia should be corrected with generous oxygen supplementation, but all patients should receive oxygen even if the saturation is normal. Evaluating peripheral perfusion and pulses provides a rapid assessment of the circulation. Continuous cardiorespiratory monitoring and frequent blood pressure measurement are important to assess the response to intervention. The standard of two large-bore IV lines may not be feasible, especially in very young pediatric patients in shock, but the goal is to maintain reliable intravascular access through which vigorous resuscitation can proceed. If peripheral IV access is not immediately obtained, intraosseous access should be considered. (see Chapter 192). Unless the patient has myocardial or known chronic renal disease, the initial therapy should be 20 mL/kg of isotonic fluid (normal saline or lactated Ringer’s) administered intravenously as rapidly as possible. This may be repeated two more times, to a total of 60 mL/kg, with close clinical assessment of vital signs, perfusion, urine output, and mental status for improvement. A fourth bolus for a total of

80 mL/kg is often needed. In the case of hemorrhagic shock, blood products should be used as soon as possible. Until appropriate blood products are available, isotonic IV fluids are used as a temporizing measure to restore intravascular volume. If the patient remains hypotensive and poorly perfused despite 60 mL/kg of IV fluids, termed fluid-refractory shock, inotropic support should be strongly considered. Dopamine IV infusion is commonly initiated at a rate of 10 μg/kg per minute and then titrated to improve and maintain blood pressure, peripheral perfusion, and urine output. In patients who do not respond to dopamine, IV epinephrine, norepinephrine, or both may be considered. These three vasoactive agents can be initiated peripherally for up to 4 hours until central access is obtained. Hydrocortisone (1–2 mg/kg IV) should also be considered for patients who show resistance to vasoactive agent or have adrenal suppression, usually from chronic medications such as steroids. A chest radiograph may be helpful to assess the presence of cardiomegaly, fluid overload, pulmonary edema, pneumonia, pleural effusion, or pneumothorax. Central venous pressure is also helpful, if obtainable, so that the degree of volume repletion can be assessed. Antipyretics should be administered, when feasible, to a febrile patient to decrease metabolic demand. Conversely, warming should be instituted in a hypothermic patient (see Chapter 173). Broad-spectrum antibiotics should be given intravenously or intraosseously unless it is known that infection is not the cause of the patient’s condition. The choice of antibiotic is driven by the likely pathogens (Table 36-10) and the age of the patient (Table 36-11). TABLE 36-10

Pathogens in Septic Shock

Neonate and Young Infant

Infant and Young Child

Group B streptococci

Neisseria meningitides

Escherichia coli and other gram-negative bacilli

Streptococcus pneumoniae

Enterococci

Haemophilus influenzae type B

Herpes simplex virus

TABLE 36-11

Group A streptococci Staphylococcus aureus Rickettsieae

Antimicrobials in Shock

Age

Antimicrobial Agent

Initial IV Dose (mg/kg)

0–4 wk

Ampicillin

50–100*

plus Gentamicin

2.5

or

>4 wk

Cefotaxime

50

Ceftriaxone

50–100*

Consider adding vancomycin

10–15*

Immunocompromised Cefepime

25–75*

or Piperacillin/tazobactam 100+ Consider vancomycin

10–15*

Possible rickettsial infection

Add doxycycline

2.2

Allergic to cephalosporins

Clindamycin and

25–40

Gentamicin

2.5–7.5

*Higher dosing recommended for possible meningitis. †Based

on piperacillin component.

In a neonate with shock in whom a duct-dependent cardiac lesion is a possible cause, prostaglandin E1 should be considered to maintain patency of the ductus arteriosus. Preparation should be made for the possibility of intubation, because prostaglandin E1 may cause apnea. The decision to administer prostaglandin E1 is usually made in consultation with a neonatologist or pediatric cardiologist. Anaphylactic shock management should include administration of intramuscular epinephrine, antihistamines such as diphenhydramine, and corticosteroids in addition to supportive measures listed above. Continuing monitoring is essential, as development of a biphasic reaction can occur (see Chapter 47).

SPECIAL CONSIDERATIONS TRANSPORT OF THE PATIENT IN SHOCK Early initiation of transport can be life- and limb-saving for patients in shock. The child should be hospitalized in an intensive care unit capable of invasive monitoring and airway intervention and with personnel who are experienced in managing critically ill children. If transfer to another institution is necessary, the clinician has the challenging task of weighing the risks and benefits of the different modes of transportation (see Chapter 11). In every case, whether the patient is transferred to another facility or from one unit to another within the same facility, it is essential that the team transporting the patient have the appropriate personnel and equipment to do so safely. In addition, the receiving facility or unit must be ready for the patient’s arrival. Communication of the patient’s condition and the interventions performed is key, and medical records, imaging studies, and laboratory results should accompany the patient whenever possible. KEY POINTS Shock can be classified as hypovolemic, cariogenic, or distributive. Hypotension is often a late finding in pediatric shock. Early recognition of shock and rapid intervention is crucial.

SUGGESTED READINGS Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002;30:1365-1378. Cruz AT, Perry AM, Williams EA, et al. Implementation of goal-directed therapy for children with suspected sepsis in the emergency department. Pediatrics. 2011;127:e758-766. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2013;39:165-228. Larsen GY, Mecham N, Greenberg R, et al. An emergency department septic shock protocol and care guideline for children initiated at triage. Pediatrics. 2011;127:e1585-e1592. Pediatric Advanced Life Support Provider Manual. Dallas, TX: American Heart Association; 2010. Paul R, Neuman MI, Monuteaux M, Melendez E. Adherence to PALS sepsis guidelines and hospital length of stay. Pediatrics. 2012;130:e273-e280.

CHAPTER

37

Syncope Sarah C. McBride

BACKGROUND Syncope, also described as “fainting” or “blackouts,” is defined as a transient period of unconsciousness that is brief and abrupt in onset and resolves spontaneously to a restored level of function. It is a symptom rather than a diagnosis and does not necessarily indicate disease. The causes of syncope in children are heterogeneous and are most often benign in nature. Nevertheless, syncopal events can cause significant distress among patients, families, school personnel, and physicians. Since it is a relatively common occurrence in childhood, hospitalists should have a practical approach to the evaluation of pediatric syncope, focusing on identification of those rare individuals who are at risk for serious underlying disease.

PATHOPHYSIOLOGY Patients experience syncope when inadequate cerebral perfusion results in a transient loss of consciousness and postural tone. Presyncope describes a similar event without full loss of consciousness. Girls present more commonly for the evaluation of syncope than boys, with a peak incidence between 13 and 19 years of age.1 Most syncope in pediatric patients is autonomic in origin, isolated, and benign. In fact, the risk of sudden death among pediatric patients with prior syncopal events has been found to be equivalent to the risk of sudden death in the general population.2

PATIENT HISTORY History and physical examination can provide valuable clues to the probable

cause of a syncopal episode and may curtail or circumvent the need for further diagnostic evaluation. Important historical features of a patient presenting with syncope are included in Table 37-1. Recent circumstances and those immediately preceding the syncopal event should be thoroughly explored. Because patients are often unable to provide details of an episode, witnesses to the event are important. Past medical history, especially with regard to previous syncopal episodes, cardiac or neurologic conditions, and medications, should always be obtained. Specific inquiries about family history should include sudden death, syncope, sudden infant death syndrome, congenital heart disease, seizures, and congenital deafness (associated with a genetic disorder that includes Long-QT). A patient’s baseline level of health should also be ascertained, including any overall changes in energy level, exercise tolerance, nutritional status, or the development of new respiratory symptoms, chest pain, or tightness and any emotional stressors. TABLE 37-1

Directed Patient History for Syncope

Environmental factors/triggers (posture, temperature, hydration status, fatigue, illness) Frequency and duration of syncope Level of activity just prior to syncopal episode (exertion*) Elements of history from any witnesses (cyanosis*) Medication history (potential for lengthening QTc or arryhthmogenic*) Baseline level of health Generalized symptoms of concern (fatigue, cough, weight loss, shortness of breath, chest pain*) Personal or family history of any of the following conditions* congenital heart disease sudden cardiac death Long-QT syndrome sensorineural hearing loss other familial heart diseases *Increased concern for cardiac causes

PHYSICAL EXAMINATION Although the findings are often normal, a thorough physical examination should be performed. Global mental status should be evaluated and compared to the patient’s baseline level of function. Blood pressure measurements and evaluation of distal pulses in both the supine and upright positions and from both upper extremities and a lower extremity should be obtained. Cardiac examination may reveal a gallop, murmur, or click and there may be hepatomegaly or crackles on lung examination. Any of these examination findings raises the concern for cardiac disease. In addition, a complete neurologic examination is indicated. In young children and infants, a thorough skin and musculoskeletal examination should be performed to assess for any signs of trauma.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of pediatric syncope is listed in Table 37-2. The etiologies of childhood syncope can be divided into three major categories: (1) autonomic, (2) cardiac, and (3) metabolic. Regardless of the cause, syncope is the end result of inadequate cerebral perfusion, oxygen, or glucose delivery to the brain. TABLE 37-2

Differential Diagnosis of Syncope

Cardiac Obstruction to blood flow Hypertrophic cardiomyopathy Valvular aortic stenosis Primary pulmonary hypertension Eisenmenger syndrome Myocardial dysfunction Dilated cardiomyopathy Arrhythmogenic right ventricular dysplagia/cardiomyopathy (ARVD/C) Mitral valve prolapse (with severe mitral valve regurgitation)

Neuromuscular disorders Inflammatory disease (e.g. Kawasaki disease, viral myocarditis) Ischemia (e.g. anomalous coronary artery) Arrhythmias Long QT syndrome (congenital or acquired) Supraventricular tachycardia Sinus node dysfunction Atrioventricular block Arrhythmogenic right ventricular dysplasia Brugada syndrome Autonomic Reflex (neurocardiogenic, situational) Dysautonomic (familial dysautonomia, drugs/toxins, immunemediated) Metabolic Hypoglycemia Electrolyte derangement Endocrine disorders Toxins and drugs

AUTONOMIC SYNCOPE Autonomic syncope is the most common cause of syncope in pediatrics and can be further described as either reflex or dysautonomic. Of these two types, reflex syncope is more common. Many triggers are known to precipitate autonomic syncope. Although their exact mechanisms of action are not clearly understood, physical stressors such as anemia, dehydration, hunger, illness, heat, and physical exhaustion can predispose patients to autonomic syncopal episodes. Orthostatic hypotensive syncope occurs during an excessive or prolonged decrease in blood pressure when an individual suddenly assumes an upright position or after prolonged standing. Patients with high basal vagal tone are at higher risk for autonomic syncope.

Neurocardiogenic syncope (often referred to as vasovagal or vasodepressor syncope) is the most common type of reflex syncope and can usually be diagnosed by gathering a careful and complete history, performing a thorough physical examination, and with minimal use of diagnostic testing. Postural changes and variation in cardiac output or blood volume are triggers for pressure sensors that send signals to the medulla by vagal C fibers. This signaling causes compensatory changes in heart rate, ventricular contractility, and blood vessel compliance by neurohormonal transmitters as a way to maintain cerebral perfusion. A common clinical presentation begins with a prodrome lasting seconds to minutes, followed by a brief period of unconsciousness, after which the patient returns to a previous level of alertness. The premonitory symptoms may include lightheadedness, dizziness, nausea, pallor, shortness of breath, diaphoresis, and visual changes. Figure 37-1 depicts one hypothesized mechanism for neurocardiogenic syncope, called the hypotensive cardioinhibitory response (Figure 37-2).

FIGURE 37-1. Autonomic syncope cascade. LV, left ventricular.

FIGURE 37-2. Hyypotensive cardioinhibitory response algorithm. a: exertional syncope, history of cardiac surgery, palpitations, chest pain, or shortness of breath; b: first-degree relative or multiple family members with sudden death before age 50 years, cardiomyopathy, pulmonary hypertension, or familial arrhythmia; c: pathological murmur, gallup, rub, loud or single S2, toxic appearance, marked tachycardia, tachypnea, peripheral edema, crackles on lung examination, hepatomegaly, or irregular heart rhythm. Dysautonomic syncope is caused by dysfunction of the autonomic nervous system and can occasionally lead to syncope in children. Pediatric causes for autonomic failure include familial dysautonomia, toxin exposure, and infectious or inflammatory disease. Syncope caused by a more variable dysfunction of the autonomic nervous system beyond what is typically seen in more straightforward neurocardiogenic syncope but without serious underlying disease, has been termed “postural orthostatic tachycardia syndrome” (POTS) or “chronic orthostatic intolerance.” Children and adolescents with more constant symptoms and disability related to orthostatic

intolerance fall into this category. Although the complete pathophysiology is not understood, a hallmark finding is tachycardia during upright posture.

CARDIAC SYNCOPE Syncope may occur when there is obstruction to cardiac outflow, myocardial dysfunction, or a cardiac arrhythmia. Patients who have a prior history of surgery for congenital cardiac lesions are often at increased risk for acquired and residual structural lesions, myocardial dysfunction, and supraventricular or ventricular arrhythmias. Therefore, a cardiologist should evaluate any patient with a prior cardiac history who presents with syncope. Cardiac syncope that is caused by an obstruction to blood flow usually occurs in association with exertion or exercise. It is often related to a fixed or dynamic obstruction to cardiac output due to a structural lesion or related to pulmonary vascular disease. Myocardial dysfunction may cause syncope due to an associated cardiac arrhythmia. However, when the myocardial dysfunction is severe enough to lessen stroke volume and cardiac output is inadequate to meet increased physical demands (e.g. exertion) syncope can result even in the absence of an arrhythmia. Bradycardia and tachycardia may also lead to syncope if effective stroke volume is detrimentally affected. Syncope due to isolated bradycardia in pediatrics is uncommon and is usually due to a medication effect, cardiac manifestations of severe anorexia, or central nervous system trauma. Sinus node pauses and first- and second-degree heart block do not commonly cause syncope. Tachycardia, originating from the sinus node or from an ectopic supraventricular focus, may lead to syncope and is often associated with chest pain, palpitations, lightheadedness, pallor, or nausea. Ventricular arrhythmias, such as Long-QT syndrome and Brugada syndrome, can occur in the absence of structural heart disease. Long-QT syndrome is characterized by a prolonged QT interval due to either a genetic defect in cardiac potassium or sodium channels with a resultant delay in repolarization. Syncope among patients with Long-QT syndrome is an ominous finding and is presumed to relate to an episode of torsades de pointes that terminates spontaneously. Brugada syndrome is caused by a genetic defect in cardiac sodium channels, which can lead to polymorphic ventricular tachycardia. ST segment elevation may be seen in the anterior precordial leads by electrocardiogram (ECG) in Brugada syndrome, but these

findings may also be intermittent. Even though mitral valve prolapse is generally asymptomatic in the pediatric population, it is worth mentioning because of its prevalence. It is now believed that when syncope occurs in patients with mitral valve prolapse, the causes are multifactorial and may involve either autonomic dysfunction or arrhythmia, depending on the nature and severity of mitral valve dysfunction.3

METABOLIC SYNCOPE Metabolic derangements that can lead to syncope include hypoglycemia, hypoxia, and hyperventilation. In general, these conditions produce more persistent symptoms that require medical intervention and are usually unaffected by position or activity. Presentations may include a depressed level or loss of consciousness or seizure activity. Diaphoresis, tremor, and altered mental status may precede an episode of hypoglycemic syncope. Hypoxia leading to syncope may initially present with agitation and increasing somnolence as the hypoxemic state continues. Hyperventilation may lead to a loss of consciousness if cerebral vasoconstriction occurs due to resultant hypocapnia. Drugs and toxin exposure can cause syncope or altered consciousness due to metabolic derangement. Certain drugs may also induce cardiac arrhythmias, which can present as a syncopal episode. Breath-holding spells are common among young children. They typically start with crying, followed by apnea (often at end-expiration), then cyanosis or pallor, and ultimately a brief syncopal event. Patients promptly return to a normal level of consciousness following the event. Hypoxia and hypocapnia are thought to be significant factors that lead to loss of consciousness in these instances. A number of conditions that can mimic true syncope are listed in Table 37-3. For example, a seizure may mimic a syncopal episode but generally lasts longer than several seconds and may include a preceding aura, abnormal movements, and a postictal period. Atypical migraines can present with syncope-like spells and may include a preceding aura or severe headache. Psychogenic episodes such as panic attacks or hyperventilation can mimic true syncope and occur most often among adolescent patients. Breath holding in a younger child may lead to syncope and self-resolves as soon as the child resumes normal breathing. A detailed history of the event usually supports

the diagnosis and may include a preceding period of stress or hyperventilation while in the presence of others. Patients who have a full recollection of the event are less likely to have suffered a full loss of consciousness. Although uncommon, malingering, Munchausen syndrome, or Munchausen syndrome by proxy may present with a history of a syncope-like episode. Features that support these diagnoses include the patient’s or parent’s strong desire for extensive or invasive evaluation or therapy. TABLE 37-3

Conditions That Mimic Syncope

Neurologic Seizure Migraine Psychogenic Panic attacks Breath-holding Conversion disorder Malingering Munchausen syndrome Munchausen syndrome by proxy

DIAGNOSTIC EVALUATION Diagnostic evaluation of the patient with syncope is aimed at detecting those few individuals with serious underlying cardiac or non-cardiac disease. The diagnosis of myocardial dysfunction can usually be achieved by clinical examination, ECG, and echocardiography. An ECG should be performed as part of all initial evaluations for syncope, with special attention paid to the QT interval corrected for heart rate (QTc) interval and T-wave morphology for evidence of Long-QT syndrome. In addition, voltage criteria for ventricular hypertrophy suggestive of an obstructive lesion, the pre-excitation of Wolff-Parkinson-White syndrome, and ectopy and conduction disturbances should be ruled out during ECG interpretation. In a patient with a normal ECG but a history suspicious for cardiac arrhythmia, a 24-hour ambulatory Holter monitor may aid in the

diagnosis if the episodes are frequent. In a patient whose episodes are isolated or less frequent, an event monitor that can be turned on to record during symptomatic events may be more appropriate. In general, a more extensive cardiovascular evaluation is indicated if syncope occurs with exertion and in cases in which there is chest pain preceding the loss of consciousness, recurrent syncope, or an abnormal cardiac examination. It is important to realize that cardiac causes of syncope may be accompanied by seizures that result from global cerebral hypoperfusion. Supraventricular arrhythmias generally cause palpitations rather than syncope. However, atrioventricular nodal bypass tracts, which occur in Wolff-Parkinson-White syndrome, may cause rapid conduction of atrial flutter or fibrillation to the ventricles, resulting in syncope or sudden death. Ventricular arrhythmias occur more frequently in postoperative patients with congenital heart disease but may also be seen in patients with structurally normal hearts. Long-QT syndrome predisposes patients to ventricular arrhythmias by its characteristic prolongation of the QTc, which places patients at risk for a polymorphic ventricular tachycardia known as torsades de pointes. If prolonged, torsades de pointes can lead to cardiac arrest or death as it degenerates into ventricular fibrillation. In some patients, an ECG demonstrating borderline QTc prolongation may be consistent with the upper range of normal but should be put into context with other features of the syncopal event and past medical history. Some ECG abnormalities may become more exaggerated with an increased heart rate as the QTc fails to shorten appropriately with the R-R interval. Brief and self-resolving periods of rhythm disturbances causing syncope may be precipitated by exercise or a startling experience. Genetic causes of Long-QT syndrome are due to either a defect in cardiac potassium or sodium channels. Acquired causes of Long-QT include electrolyte disturbances (e.g. hypokalemia, hypocalcemia, hypomagnesemia), increased intracranial pressure, and medications (e.g. tricyclic antidepressants, phenothiazines, antiarrhythmics) and should be considered based on laboratory data, neurologic examination, or by medication history. Laboratory testing for metabolic or endocrine derangements associated with syncope is easily performed and should include a blood glucose level, electrolyte panel, and complete blood count. If a toxic ingestion is suspected, a serum and urine toxicology screen should be obtained. Anemia can predispose to syncope when it is severe or more acute in onset. Because

hypoxia due to carbon monoxide poisoning can lead to syncope, co-oximetry with a carboxyhemoglobin level should be considered when indicated by circumstances. A pregnancy test is also indicated in teenage girls with syncope. An electroencephalogram or imaging of the central nervous system is often part of an evaluation when epilepsy or other neurologic causes for syncope are being considered. The use of upright tilt table testing has not been shown to be reliable in improving diagnostic accuracy during the general evaluation of syncope, or in guiding management or prognosis.6

MANAGEMENT Therapeutic intervention to prevent or treat recurrent syncope depends on the pathogenic cause and the frequency and severity of the episodes. Standard resuscitative interventions should be instituted for acute syncopal events. Patients who have known structural heart disease or other cardiac disease should be admitted to the hospital and evaluated by a cardiologist. The treatment of cardiogenic syncope is generally overseen by a cardiologist and is based on a careful and thorough diagnostic evaluation to determine the underlying abnormality. Suppression of symptomatic supraventricular arrhythmias is often managed with medication, but treatment varies based on the inciting or propagating feature of the disorder. Patients with Long-QT syndrome may benefit from β-adrenergic antagonists to prevent exerciseinduced ventricular arrhythmia, but pacemakers or implanted cardiac defibrillators are necessary in some cases. Surgical intervention may be needed for structural abnormalities, and intensive care interventions are required for those with progressive or unstable conditions. Autonomic syncope is considered a benign illness, and in most cases, prophylaxis against presyncope or “near syncope” is sufficient intervention. Educating patients and families generally results in earlier awareness of symptoms and the ability to abort episodes by assuming a recumbent posture. Additional measures for prophylaxis include the avoidance of dehydration, a salt-enriched diet, and in some cases the use of mineralocorticoids to induce salt and water retention. When simple prevention strategies fail, treatment with β-adrenergic receptor blockade is often used to decrease stimulation of

the cardiac mechanoreceptors. Disopyramide, an anticholinergic, negative inotropic, and vasoconstrictive agent, is effective in some patients. Finally, direct α-adrenergic receptor stimulation and stimulation of peripheral norepinephrine release can be tried. It is important to remember that no single pharmacologic agent has been consistently efficacious in clinical trials and often a combination of therapeutic strategies is necessary to manage symptoms effectively.4-6 Atrioventricular pacing has been used in some patients with frequent episodes of symptomatic bradycardia, but this is reserved for refractory cases when pharmacologic agents are unsuccessful. The treatment of metabolic or other systemic causes of syncope focuses on the underlying process, both in the acute resuscitation phase and in the prevention stage. Identification of a causative entity often allows patients and families to prevent future syncopal events or to manage such events safely if and when they reoccur.

SPECIAL CONSIDERATIONS The diagnosis of heritable conditions during an evaluation for syncope necessitates genetic counseling for family members. When underlying heart disease is identified as a cause for syncope, evaluation and management should address both the underlying disease condition itself and the potential for an associated life-threatening arrhythmia. Cerebrovascular events are rare in children but should be considered in patients with underlying disease affecting the peripheral vasculature who present with syncope. KEY POINTS Syncope in children is most often benign and self-limited. History and physical examination are the most important initial diagnostic tools in the evaluation of syncope. Evaluation of a patient presenting with syncope is geared toward identifying those few patients who are at high risk for serious underlying disease.

REFERENCES 1. Anderson JB, Czosek RJ, Cnota J, et al. Pediatric syncope: National Hospital Ambulatory Medical Care Survey results. J Emerg Med. 2012;43:575-583. 2. Driscoll DJ, Jacobsen SJ, Porter CJ, Wollan PC. Syncope in children and adolescents. J Am Coll Cardiol. 1997;29:1039-1045. 3. Boudoulas H, Wooley CF. The floppy mitral valve, mitral valve prolapse, and mitral valvular regurgitation. In: Allen HD, Gutgesell HP, Clark EB, Driscoll DJ, eds. Moss and Adam’s Heart Disease in Infants, Children, and Adolescents. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:964. 4. Massin MM. Neurocardiogenic syncope in children: current concepts in diagnosis and management. Pediatr Drugs. 2003;5:327-334. 5. Strickberger SA, Benson DW, Biaggioni I, et al. AHA/ACCF Scientific Statement on the evaluation of syncope: from the American Heart Association Councils on Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the Young, and Stroke, and the Quality of Care and Outcomes Research Interdisciplinary Working Group; and the American College of Cardiology Foundation: in collaboration with the Heart Rhythm Society: endorsed by the American Autonomic Society. Circulation. 2006;113:316. 6. Sapin SO. Autonomic syncope in pediatrics: A practice-oriented approach to classification, pathophysiology, diagnosis, and management. Clin Pediatr. 2004;43:17-23.

CHAPTER

38

Vomiting Anne K. Beasley

BACKGROUND Vomiting is a common chief complaint for hospitalized pediatric patients. It is more often a symptom than a diagnosis and can be a presenting sign of illness in nearly every organ system. Investigation into the etiology of vomiting can help prevent metabolic-, nutritional-, and trauma-related complications as well as diagnose potentially life-threatening but treatable conditions.

PATHOPHYSIOLOGY Vomiting is a highly coordinated, centrally mediated reflex. It occurs when the contents of the stomach are forcefully expelled out of the mouth. Descent of the diaphragm and constriction of abdominal musculature occurs simultaneously with the relaxation of the gastric cardia, forcing the contents of the stomach retrograde into the esophagus. The vomiting centers of the brain, which reside in the reticular formation of the medulla, receive sensory input from a number of sources that trigger vomiting. These include afferent signals from the gastrointestinal (GI) tract arising from the vagus nerve and other sympathetic nerves, afferent signals from outside the GI tract originating from organs located in the thorax and abdomen, as well as sensory input received from the vestibular nucleus. Additionally, the chemoreceptor zone in the brainstem detects chemical abnormalities in the body, such as uremia or ketoacidosis. In the setting of cerebral trauma, extramedullary centers in the brain receive afferent signals as a result of signals from other areas of the brain. By understanding the pathophysiology of vomiting, one can appreciate that vomiting can be a

manifestation of disease not only in the GI tract but in multiple organ systems.

PATIENT HISTORY A thorough history should be conducted in all children presenting with vomiting. The examiner can be guided by a few key elements of the history. What is the age of the patient? What is the character of the emesis? Bilious or nonbilious? Bloody or nonbloody? What is the nature of the emesis? Is it projectile? What was the onset? What is the timing? Is it associated with eating? Does it only occur in the morning? Are the vomiting episodes cyclical in nature? How have the symptoms progressed? Are there associated complaints within the GI tract? Are there associated systemic signs and symptoms such as fever or weight loss? Additionally, completing a comprehensive review of systems is a helpful adjunct in guiding the examiner toward an appropriate workup and ultimately in yielding a diagnosis.

PHYSICAL EXAMINATION The physical examination in the evaluation of the vomiting child begins with an overall assessment. Is the patient ill or toxic appearing? Next, a careful review of the vital signs with attention to age-appropriate normal ranges can help to guide the assessment of hydration status, acuity of the illness, and overall cardiovascular stability. A complete head-to-toe physical examination must be performed including a careful examination of the abdomen to determine presence of abdominal pain and distension. Assessing the overall patient and doing a thorough examination will help the examiner to narrow a very broad differential diagnosis for what is a common and often nonspecific presenting sign and symptom.

DIFFERENTIAL DIAGNOSIS1-3 It is helpful to think through the differential diagnosis of vomiting in terms of gastrointestinal versus non-gastrointestinal pathologies as well as by age of the patient. (Tables 38-1 to 38-4).

TABLE 38-1

Causes of Vomiting by Organ System

Gastrointestinal Esophageal Stricture Web Ring Atresia Tracheoesophageal fistula Achalasia Foreign body Stomach Pyloric stenosis Web Duplication Ulcer Gastroesophageal reflux disease Small Intestine Duodenal atresia Malrotation with midgut volvulus Duplication Intussusception Foreign body Bezoar Pseudo-obstruction Necrotizing enterocolitis Colon Hirschsprung disease Meconium plug or ileus Microcolon Imperforate anus

Bezoar Foreign body Helicobacter Pylori Celiac disease Milk/soy protein allergy Food allergies Inflammatory bowel disease Pancreatitis Hepatitis Cholecystitis, cholelithiasis, choledocholithiasis Abdominal trauma Neurologic Intracranial mass lesion Hydrocephalus Intracranial bleed Cerebral edema Pseudotumor cerebri Migraine headache Cyclic vomiting syndrome Abdominal migraine Seizure Meningitis Kernicterus Vestibular system disruption Genitourinary Obstructive uropathy Pyelonephritis Renal insufficiency Renal tubular acidosis Glomerulonephritis Metabolic

Hypercalcemia Hypokalemia Hyperammonemia Urea cycle defects Amino acidopathy Organic acidopathy Glycogen storage disease Fatty acid oxidation defects Galactosemia Lysosomal storage diseases Peroxisomal disorders Endocrine Diabetic ketoacidosis Congenital adrenal hyperplasia Adrenal insufficiency Infectious Viral gastroenteritis Bacterial gastroenteritis Post-viral gastroparesis Appendicitis Pneumonia Bronchiolitis Pertussis Sinusitis Pharyngitis Meningitis Encephalitis Sepsis Cardiac Arrhythmias

Heart failure Miscellaneous Psychiatric Anorexia nervosa Bulimia Hyperventilation Anxiety Ingestions Drug toxicities Child abuse TABLE 38-2

Common Causes of Vomiting in Newborns and Infants

Benign Overfeeding Aerophagia Innocent spitting Excessive handling Parental anxiety Neurologic Hydrocephalus Subdural bleeding Cerebral edema Kernicterus Genitourinary Obstructive uropathy Pyelonephritis Pulmonary Bronchiolitis Pertussis

Reactive airway disease Pneumonia Metabolic or endocrine Urea acid cycle defects Aminoacidopathies Organic acidopathies Hypercalcemia Glycogen storage disease Fatty acid oxidation defects—MCAD deficiency Galactosemia Congenital adrenal hyperplasia Gastrointestinal Gastroesophageal reflux Milk protein intolerance Allergy Eosinophilic enteritis Lactobezoar Gastritis Intestinal atresia, stenosis, or webs Intestinal duplication Hiatal or diaphragmatic hernia Pyloric stenosis Malrotation with midgut volvulus Meconium plug or ileus Annular pancreas Hirschsprung disease Hepatitis Pancreatitis, necrotizing enterocolitis, imperforate anus, microcolon Other infections Meningitis

Gastroenteritis Other Medications Child Abuse MCAD, Medium-chain acyl-CoA dehydrogenase.

TABLE 38-3

Common Causes of Vomiting in Infants and Toddlers

Neurologic Hydrocephalus Subdural bleeding Cerebral edema Kernicterus Benign paroxysmal vertigo Migraine Cyclic vomiting Intracranial mass lesion Genitourinary Obstructive uropathy Pyelonephritis Renal insufficiency Glomerulonephritis Renal tubular acidosis Ovarian or testicular torsion Metabolic or endocrine Urea acid cycle defects Aminoacidopathies Hypercalcemia Glycogen storage disease Congenital adrenal hyperplasia

Fatty acid oxidation defects Gastrointestinal Gastroesophageal reflux Milk/soy protein intolerance Lactose intolerance Food allergy Eosinophilic enteritis Celiac disease Bezoar Foreign body Gastritis Intestinal stenosis or adhesions Intestinal duplication Hiatal hernia Malrotation with midgut volvulus Annular pancreas Hepatitis Pancreatitis Intussusception Incarcerated hernia Meckel diverticulum Infections Meningitis Gastroenteritis Appendicitis Otitis Sinusitis Postviral gastroparesis Bronchiolitis Pertussis Pneumonia

Other Medications Toxic ingestions Child abuse Psychogenic TABLE 38-4

Common Causes of Vomiting in Children and Adolescents

Neurologic Intracranial bleeding Cerebral edema Benign paroxysmal vertigo Migraine Cyclic vomiting Intracranial mass lesion Concussion Genitourinary Obstructive uropathy Pyelonephritis Renal insufficiency Ovarian or testicular torsion Pregnancy Metabolic or endocrine Inborn errors of metabolism Diabetic ketoacidosis Adrenal insufficiency Gastrointestinal Gastroesophageal reflux Lactose intolerance Allergy

Eosinophilic enteritis Celiac disease Inflammatory bowel disease Bezoar Foreign body Gastritis Gastric or duodenal ulcer Intestinal stenosis or adhesions Hiatal hernia Malrotation Volvulus Annular pancreas Hepatitis Pancreatitis Cholecystitis, cholelithiasis Intussusception Incarcerated hernia Meckel diverticulum Other infections Meningitis Encephalitis Gastroenteritis Appendicitis Otitis Sinusitis Helicobacter pylori Postviral gastroparesis Pertussis Pneumonia Rheumatologic or immunologic Scleroderma

Chronic granulomatous disease Other Medications Toxic ingestions Child abuse Psychogenic Anorexia nervosa Bulimia

GASTROINTESTINAL CAUSES The causes of vomiting within the GI tract are numerous, and can be divided by age and by obstructive versus non-obstructive causes. Obstructive Vomiting in the first few days of life can be a sign of serious pathology. Nonbilious emesis is a sign that the obstruction is proximal to the ampulla of Vater. Esophageal atresia presents with nonbilious emesis in an infant where a nasogastric tube cannot be passed into the stomach and where an abdominal film shows a paucity of bowel gas. The caveat to these x-ray findings would be if there is the presence of a tracheoesophageal fistula in addition to the esophageal atresia. In this setting, air could be delivered into the stomach due to a connection distal to the atretic esophagus. Duodenal atresia can present with nonbilious emesis depending on the level of atresia. It usually presents within hours of birth and rarely is associated with abdominal distension due to the proximal nature of the obstruction. The abdominal film would show the classic “double bubble” appearance due to air within the stomach as well in the first portion of the duodenum proximal to the atresia. Bilious emesis is indicative of more distal congenital obstructive GI malformations such as duodenal or jejunal atresias, intestinal duplication, malrotation with midgut volvulus, meconium plug or ileus, colonic atresia or stenosis, imperforate anus, microcolon, or Hirschsprung disease. The more distal jejunal obstructions usually present within the first 24 hours of life and are associated with abdominal distension. Malrotation with midgut volvulus usually presents within the first week after birth with bilious emesis. A

meconium plug or ileus can cause bilious emesis that either resolves as the meconium passes or may require surgical intervention. This diagnosis should always raise clinical suspicion for cystic fibrosis. Hirschsprung disease should be considered in cases of colonic obstruction where there is a history of failure to pass meconium. Abdominal radiographs showing marked dilation throughout the bowel would accompany bilious emesis. Beyond the immediate newborn period, nonbilious emesis can be a sign of pyloric stenosis. The classic history includes that of projectile vomiting in a hungry infant that continues to desire to feed despite persistent emesis. A palpable “olive” on examination in the epigastric region due to pyloric hypertrophy is often a late finding. Lactobezoars, a conglomeration of milk and mucous, can be a rare cause of gastric outlet obstruction and nonbilious emesis in milk-fed infants. Bilious emesis should always raise the suspicion for intestinal obstruction and prompt urgent evaluation into the etiology. Bowel strangulation and ischemia can occur outside the newborn period in the setting of malrotation due to increased risk of volvulus secondary to lack of mesenteric anchoring to the retroperitoneum. In addition to bilious emesis, infants would present with abdominal distension, electrolyte abnormalities, irritability, lethargy, and even shock due to bowel ischemia and acidosis. Obstructive pathologies beyond infancy can include intussusception, achalasia, cricopharyngeal incoordination, hiatal and diaphragmatic hernias, duodenal webs, duodenal hematomas, intestinal strictures, and vascular rings and slings. Stridor can be present in the setting of a vascular ring, as the aberrant vessel compresses the trachea in addition to the esophagus. Additionally, superior mesenteric artery syndrome should be considered in a child who has had rapid weight loss resulting in the loss of the fat pad that normally is situated between the superior mesenteric artery and the duodenum, causing compression of the duodenum and eventual obstruction and emesis. Intussusception should be suspected in patients presenting with paroxysms of severe pain, vomiting, and lethargy. Currant jelly stools are a late finding indicative of bowel ischemia and necrosis. A torsed Meckel diverticulum, incarcerated hernias, and adhesions in the setting of prior abdominal surgeries should be on the differential of vomiting due to obstruction beyond infancy. A history of abdominal trauma should raise suspicion for a duodenal hematoma or other bowel trauma that could lead to an obstructive process. Lastly, it is important to remember that the ingestion of foreign bodies can obstruct the pylorus or esophagus in toddlers. This can

include coins or other nonfood items, as well as bezoars that build up over time due to chronic ingestion of hair, carpet, or other unusual items. Non-Obstructive Non-obstructive causes of vomiting within the GI tract in the immediate newborn and infant period include those ranging from necrotizing enterocolitis and inborn errors of metabolism to milk/soy protein allergy, gastroesophageal reflux, overfeeding, and improper mixing of formula. Necrotizing enterocolitis can present with bilious or nonbilious emesis and should be suspected in a toxic-appearing infant with abdominal distension and x-ray evidence of pneumatosis intestinalis and, after perforation, hepatic portal venous gas. Inborn errors of metabolism are a rare cause of vomiting but should be suspected in the vomiting, acidotic, or hypoglycemic infant. In infants and beyond into the early childhood period, dietary protein intolerance can be an etiology of emesis, diarrhea, bloody stools, irritability, and failure to thrive. The most commonly implicated proteins include milk, soy, and egg. Gastroesophageal reflux can affect children of any age. A history of emesis, back arching, crying with feeds, or symptoms that intensify with supine positioning should raise the suspicion for gastroesophageal reflux disease. If undiagnosed or untreated, reflux can lead to apnea, aspiration, and Sandifer syndrome. Food allergies should be considered as a source of emesis, especially if accompanied by urticaria, respiratory distress, edema, abdominal pain, and anaphylaxis. Gastritis and gastric or duodenal ulcers can occur secondary to stress, allergies, medications, or Helicobacter pylori infections. Eosinophilic enteritis can present with emesis, abdominal pain, reflux, and food refusal. It can affect any portion of the GI tract and is often associated with food or other allergies. Celiac disease should be considered in an infant or child with failure to thrive, vomiting, and diarrhea. Gluten sensitivity leads to villous atrophy and malabsorption that resolves with a gluten elimination diet. Inflammatory bowel disease such as Crohn disease or ulcerative colitis can also cause emesis along with a constellation of other symptoms including hematochezia, weight loss, and abdominal pain. Additional non-obstructive causes of vomiting in the older child include cholecystitis, cholelithiasis, and choledocholithiasis. Biliary pathologies tend to present with right upper quadrant abdominal pain that is colicky in nature and associated with meals. This should be suspected in children with rapid red blood cell turnover, those with prolonged parenteral nutrition, or it can be

medication induced. Pancreatitis can occur in the pediatric population secondary to trauma, viral infection, or may be medication induced. It also may be due to structural causes, or can be genetic in etiology. In many cases, however, it may be idiopathic in nature. The hallmark of pancreatitis is nausea, emesis, and severe epigastric abdominal pain. Hepatitis secondary to viruses, toxins, drugs, and metabolic or autoimmune causes can also present with emesis.

NON-GASTROINTESTINAL CAUSES Neurologic Vomiting may be the presenting sign of serious neurologic sequelae, including increased intracranial pressure (ICP). Increased ICP may also be associated with headache, vision changes, and, in signs of impending herniation, cranial nerve palsies and vital sign changes including hypertension, bradycardia, and abnormal respirations. Increased ICP may be due to a mass lesion, hydrocephalus, vascular malformations, or hematomas. An expanding mass lesion may lead to intractable vomiting, headaches that awaken a child from sleep, or one that worsens with Valsalva maneuvers. Idiopathic intracranial hypertension can stimulate nausea and vomiting as well as a positional headache and visual field deficits. Vomiting can also occur in association with seizure activity or may be indicative of an intracranial infection such as meningitis or encephalitis. Migraine headaches are associated with nausea and emesis. Cyclic vomiting syndrome and abdominal migraines are thought to share pathophysiologic mechanisms. The former is characterized by recurrent episodes of nausea and vomiting where no organic cause is identified. There must be at least three episodes of recurrent vomiting, intervals of normal health, episodes stereotypic for rapid onset and duration of hours to days, and lack of evidence to support an alternative diagnosis. Abdominal migraines involve episodic abdominal pain and emesis associated with nausea, anorexia, photophobia, headache, and pallor, and usually occur in the setting of a family history of migraines. A history of intervals of normal health between episodes also exists. Disruption of the vestibular system as in otitis media or in cases of benign paroxysmal positional vertigo can also cause vomiting.

Genitourinary Pyelonephritis, nephrolithiasis, ureteropelvic junction obstruction, hydronephrosis, glomerulonephritis, renal tubular acidosis, and renal insufficiency can all present with emesis. Torsion of the ovary or testes can present with severe abdominal pain and emesis. Adolescent females presenting with vomiting should undergo routine pregnancy testing prior to any radiographic imaging to diagnose an etiology of emesis. Metabolic An underlying metabolic or mitochondrial process should be considered in an infant or young child with persistent emesis and electrolyte abnormalities. Hypercalcemia, hypokalemia, hypoglycemia, and hyperammonemia can all cause vomiting. Urea acid cycle defects such as ornithine transcarbamylase deficiency generally present in newborns with emesis, lethargy, coma, and death if not recognized and treated aggressively. Even those with partial defects may have more exaggerated vomiting illnesses in childhood. Aminoacidopathies such as tyrosinemia can present with vomiting in children aged 2 weeks to 1 year. Organic acidopathies such as maple syrup urine disease, isovaleric acidemia, mevalonic acidemia, propionic acidemia, and methylmalonic acidemia present with vomiting in infancy. Lactic acidosis, fatty acid oxidation defects, particularly mediumchain acyl-CoA dehydrogenase deficiency, glycogen storage disease, and galactosemia have vomiting as a primary presenting feature as well. Porphyria can present with periods of vomiting, change in mental status, or rash, depending on the subtype. Mitochondrial diseases are often associated with intestinal dysmotility or pseudo-obstruction. These children often have a long history of gastroesophageal reflux, feeding intolerance, abdominal pain, constipation or diarrhea, and failure to thrive. Leigh disease, also known as subacute necrotizing encephalomyelopathy, usually presents in infancy with feeding or swallowing difficulties, failure to thrive, and vomiting. Endocrine Diabetic ketoacidosis can lead to intractable vomiting in the setting of worsening ketosis and acidosis. Salt-wasting congenital adrenal hyperplasia should be suspected in a vomiting female infant with any signs of virilization. Male infants usually have normal genitalia, leading often to a delayed diagnosis. Adrenal insufficiency can present with emesis during a crisis. Hypothyroidism and associated constipation may also lead to vomiting. Infectious Infectious etiologies of vomiting are numerous. The majority of cases are caused by viral infections that are self-limited in nature. Bacterial

causes of emesis should be considered in a history consistent with certain food exposures. Examples include Staphylococcus aureus, Bacillus cereus, Shigella, Salmonella, Escherichia coli, Yersinia enterocolitica, and Campylobacter jejuni. Parasitic infections such as ascariasis or giardiasis can lead to emesis, diarrhea, and obstructive pathology causing emesis. Appendicitis should be considered in the child presenting with fever, anorexia, nausea, emesis, and periumbilical pain that migrates to the right lower quadrant. Viral or bacterial meningitis can present with vomiting in addition to headache and vision changes, as noted above. A child presenting with emesis in the setting of a preceding viral illness may have post-viral gastroparesis leading to delayed gastric emptying and emesis. This process can take days to months to resolve. Sinusitis or pharyngitis can also present with nausea and emesis, as can any infection causing excessive coughing leading to post-tussive emesis such as pertussis or bronchiolitis. It is important not to forget pneumonia as a cause of emesis and not to overlook a lower-lobe pneumonia as an etiology of abdominal pain and emesis in the setting of fever, tachypnea, and cough. Generalized sepsis syndromes can also cause vomiting. Cardiac Cardiovascular etiologies of vomiting generally involve arrhythmias such as supraventricular tachycardia in the irritable infant, or can occur in the setting of heart failure where an infant may have emesis and feeding intolerance in addition to poor weight gain. Myocarditis may also present with vomiting.

MISCELLANEOUS Psychiatric etiologies of emesis should not be overlooked when the history supports a diagnosis such as anorexia nervosa, bulimia, hyperventilation, or severe anxiety. Additional causes of vomiting include intentional or unintentional ingestions, drug toxicities, and child abuse.

MANAGEMENT The management for vomiting4-6 is dependent on the etiology and pathophysiology of the organ system involved (Figures 38-1 and 38-2). A thorough history and physical examination will help to guide a focused

diagnostic evaluation of the vomiting infant or child. If clinical concern for obstruction exists, a nasogastric tube should be placed immediately, followed by abdominal radiographs and appropriate contrast imaging to help pinpoint a diagnosis. Urgent surgical consultation should be obtained early in the diagnostic workup if a bowel obstruction is suspected. An upper GI series is diagnostic in the setting of malrotation with midgut volvulus, although abdominal ultrasound maybe used to reveal an abnormal relationship of the superior mesenteric vessels. Urgent surgical intervention is key to preventing continued bowel ischemia necessitating intestinal resection and resultant short gut syndrome.

FIGURE 38-1. Diagnosis of vomiting.

FIGURE 38-2. Treatment of vomiting. In general, after life-threatening etiologies are ruled out and initial diagnostic evaluation yields a diagnosis, management of the vomiting child should focus on rehydration and correction of any electrolyte abnormalities. The World Health Organization and Centers for Disease Control advocate oral rehydration therapy in children with mild to moderate dehydration due to gastroenteritis with the ability to tolerate oral fluids. In the critically ill child, fluid resuscitation with isotonic fluids should be the mainstay of initial rehydration. The use of antiemetic therapies such as ondansetron (being cognizant of the potential risk for QTc prolongation) have been shown to reduce vomiting, improve tolerance of oral fluids, and reduce hospital admissions and length of stay in children with gastroenteritis. Additional medication regimens may be considered in the setting of refractory vomiting or specific diagnoses (i.e. cyclic vomiting syndrome). Several studies exist showing acupuncture to be as effective as antiemetic medications in the treatment of vomiting related to medication side effects such as anesthesia and chemotherapy. KEY POINTS

Vomiting is a common presenting sign and symptom in the pediatric population and can be an indicator of pathology in nearly every organ system. A thorough history and physical examination should be conducted in every child presenting with vomiting to help narrow what is a very broad differential diagnosis and help guide diagnostic evaluation. A history of bilious emesis can be a sign of a surgical emergency and should prompt urgent evaluation and treatment. Management of vomiting, after initial stabilization of the critically ill child, should focus on rehydration and correction of electrolyte abnormalities. Peer-reviewed literature supports the use of antiemetic medications in the acute setting once the etiology of emesis is determined to be due to gastroenteritis.

REFERENCES 1. Kleigman RM, Behrman RE, Jenson HB, Stanton BF. Major symptoms and signs of digestive tract disorders. In: Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders; 2007:1523-1524. 2. Zitelli BJ, Davis HW. Surgery: gastrointestinal obstruction. In: Atlas of Pediatric Physical Diagnosis. 5th ed. Philadelphia, PA: Mosby; 2007:632-641. 3. Chandran L, Chitkara M. Vomiting in children: reassurance, red flag, or referral? Pediatr Rev. 2008;29(6):183-192. 4. King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children: oral hydration maintenance and nutritional therapy. MMWR Morbid Mortal Weekly Report. 2003;52(RR16):1-16. 5. Fedorowicz Z, Jagannath VA, Carter B. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database. 2011;9:CD005506. 6. Anders EF, Findeisen A, Lode HN, Usichenko TI: Acupuncture for treatment of acute vomiting in children with gastroenteritis and

pneumonia. Klin Padiatr. 2012;224(2):72-75.

PART

Systems Approach

III

Section A Abuse and Neglect 39 Cutaneous Injuries of Concern for Nonaccidental Trauma 40 Abusive Head Trauma 41 Imaging of Child Abuse 42 Medical Child Abuse: Münchausen Syndrome by Proxy and Other Manifestations 43 Legal Issues Section B Adolescent Medicine 44 Eating Disorders 45 Sexually Transmitted Infections in Adolescents and Young Adults 46 Abnormal Uterine Bleeding Section C Allergy and Immunology 47 Anaphylaxis 48 Drug Allergy 49 Primary Immunodeficiency Diseases 50 Intravenous Immunoglobulin Section D Cardiology 51 The Cardiac Examination 52 Electrocardiogram Interpretation

53 Congenital Heart Disease 54 Infective Endocarditis 55 Myocarditis and Cardiomyopathy 56 Pericarditis 57 Acute Rheumatic Fever Section E Dermatology 58 Purpura 59 Vesicles and Bullae 60 Vascular Anomalies 61 Atopic Dermatitis 62 Ecthyma Gangrenosum 63 Drug-Associated Rashes 64 Erythema Multiforme 65 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 66 Skin Disease in Immunosuppressed Hosts 67 Epidermolysis Bullosa Section F Endocrinology 68 Diabetes Mellitus and Hyperglycemia 69 Disorders of Thyroid Hormone 70 Disorders of Pituitary Function 71 Disorders of Calcium Metabolism 72 Disorders of the Adrenal Gland Section G Fluids and Electrolytes 73 Dehydration 74 Fluid and Electrolyte Therapy Section H Gastroenterology and Nutrition

75 Biliary Disease 76 Constipation 77 Dyspepsia 78 Disorders of Gastric Emptying 79 Liver Failure 80 Inflammatory Bowel Disease 81 Malnutrition 82 Pancreatitis 83 Feeding Issues Section I Genetics and Metabolism 84 Genetic Syndromes Caused by Chromosomal Abnormalities 85 Hyperammonemia 86 Hypoglycemia 87 Metabolic Acidosis Section J Hematology 88 Anemia 89 Management of Sickle Cell Disease 90 Neutropenia and Bone Marrow Failure 91 Thrombocytopenia 92 Disorders of Coagulation and Thrombosis 93 Transfusion Medicine Section K Infectious Diseases 94 Empirical Treatment of Bacterial Infections 95 Fever 96 Prolonged Fever and Fever of Unknown Origin 97 Fever and Rash 98 Central Nervous System Infections

99 Complications of Acute Otitis Media and Sinusitis 100 Neck and Oral Cavity Infections 101 Middle Respiratory Tract Infections and Bronchiolitis 102 Lower Respiratory Tract Infections 103 Gastrointestinal Infections 104 Urinary Tract Infections in Childhood 105 Bone and Joint Infections 106 Skin and Soft Tissue Infections 107 Device-Related Infections 108 Human Immunodeficiency Virus 109 Infections in Special Hosts Section L Nephrology 110 Acute Renal Failure 111 Chronic Renal Failure 112 Glomerulonephritis 113 Hemolytic Uremic Syndrome 114 Interstitial Nephritis 115 Nephrotic Syndrome 116 Renal Tubular Acidosis 117 Renal Venous Thrombosis Section M Neurology 118 Seizures 119 Headache 120 Hypotonia and Weakness 121 Stroke, Arteriopathy, and Vascular Malformations 122 Demyelinating Disease Section N Newborn Medicine

123 Delivery Room Medicine 124 The Well Newborn 125 Birth Injury 126 Congenital Anomalies 127 Transient Tachypnea of the Newborn and Persistent Pulmonary Hypertension 128 Congenital and Perinatal Infections 129 Hypoglycemia and Infants of Diabetic Mothers 130 Neonatal Hyperbilirubinemia 131 Neonatal Abstinence Syndrome Section O Oncology 132 Childhood Cancer 133 Oncologic Emergencies 134 Hematopoietic Stem Cell Transplant Section P Psychiatry 135 Depression and Physical Illness 136 Assessment and Management of the Suicidal Patient 137 Conversion and Pain Disorders 138 Agitation 139 New-Onset Psychosis Section Q Pulmonology 140 Apparent Life-Threatening Event, Infant Apnea, and Pediatric Obstructive Sleep Apnea Syndrome 141 Asthma 142 Aspiration 143 Bronchopulmonary Dysplasia and Chronic Lung Disease of Infancy 144 Cystic Fibrosis

145 Choking and Foreign Body Aspiration 146 Pulmonary Function Testing Section R Rheumatology 147 Kawasaki Disease 148 Henoch-Schönlein Purpura 149 Juvenile Dermatomyositis 150 Juvenile Idiopathic Arthritis 151 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 152 Infection-Associated Arthritis 153 Systemic Lupus Erythematosus Section S Surgical Issues 154 Gastrointestinal Obstruction: Pyloric Stenosis, Malrotation and Volvulus, and Intussusception 155 Appendicitis 156 Hernias 157 General Trauma 158 Ear, Nose, and Throat 159 Neurosurgical Issues 160 Ophthalmology 161 Orthopedics 162 Burns and Other Skin Injuries 163 Pneumothorax and Pneumomediastinum 164 Urology Section T Toxins, Substance Abuse, and Environmental Exposures 165 Stabilization and Hospitalization of the Poisoned Child 166 Toxicity of Over-the-Counter Medications and Oral Hypoglycemic Agents

167 Hazardous Household Chemicals: Hydrocarbons, Alcohols, and Caustics 168 Lead, Other Metals, and Chelation Therapy 169 Drugs of Abuse 170 Withdrawal Syndromes 171 Fire-Related Inhalational Injury 172 Heat Disorders 173 Hypothermia and Cold-Related Injuries 174 Drowning 175 Human and Animal Bites 176 Envenomation 177 Infant Botulism 178 Anticoagulants and Antithrombotics Section U Care of the Child with Medical Complexity 179 Introduction to the Child with Medical Complexity 180 Acute Care of the Child with Medical Complexity 181 Managing Comorbidities in Children with Severe Neurologic Impairment 182 Technologic Devices in the Child with Medical Complexity 183 Do-Not-Attempt-Resuscitation Orders

SECTION A Abuse and Neglect

CHAPTER

39

Cutaneous Injuries of Concern for Nonaccidental Trauma Celeste R. Wilson

BACKGROUND The topic of child abuse and neglect is often a source of anxiety and discomfort for even the most seasoned of pediatric medical providers. While disheartening to even consider the possibility of a child being intentionally injured by a trusted caretaker, pediatric providers are uniquely positioned to identify situations concerning for child maltreatment and intervene accordingly. Each year, nearly one million children in the United States are abused or neglected.1 The majority of these children are victims of neglect, with the remaining being physically or sexually abused. For the purpose of this section, we will concentrate on the various aspects of child physical abuse (Chapters 38-41), as well as the legal issues which are inherent in all cases of child maltreatment (Chapter 42). Cutaneous injuries are the most noticeable telltale sign suggesting that a child has been physically abused.2 They should be documented and carefully considered in the context of the child’s overall history and presentation. Although alone not specific for nonaccidental trauma, the presence and particular characteristics of skin findings such as bruises, lacerations, abrasions, burns/thermal injuries, and bite marks can raise suspicion for an abusive etiology.

CLINICAL PRESENTATION The clinical presentation of the child with cutaneous lesions can vary widely.

Regardless of whether the child is presenting with a stated concern for a skin injury or one is detected as an incidental finding, the medical provider should be prepared to seek additional information if the child’s injury is not consistent with the history provided.

BRUISES Bruises are a common cutaneous finding in the ambulatory child seeking to explore his/her environment. However, when present in the nonambulatory child, bruises should raise concern for possible physical abuse or an underlying medical condition. In a population of 973 children less than 36 months of age attending well-child care visits, Sugar and colleagues found that “those who don’t cruise rarely bruise.”3 That is, bruising was more common among those children who were cruising (17.8%) and walking (51.9%). Bruises were rare (2.2%) in those who were not yet walking with support (cruising). Moreover, the location of the bruises in the ambulatory children was noteworthy. Bruises typically occurred over anterior surfaces or bony prominences. The most common sites of bruising were the anterior tibia or knee, forehead, scalp, and upper leg. It was far less common for children to have bruising over posterior surfaces, chest, face (except for forehead), buttocks, or hands.3 Hence bruising in these areas as well as protected areas such as the abdomen, genitalia, and ears in infants and toddlers is extremely worrisome for the possibility of inflicted trauma.3,4 In addition to correlating the bruise with the developmental stage of the child, providers should pay careful attention to patterned features of bruises that may belie the device or implement used to cause the injury. Children struck with linear objects (e.g. rods, rulers, belts) may present with linear configured scars. Likewise, flexible implements which are doubled over (e.g. ropes, cords, chains) can leave a loop-configured bruise, abrasion, or scar at the site of contact. Slap marks may appear as a negative image such that an outline of the handprint is created on the skin as a result of blood extravasating from vessels into the surrounding interstitial space. Binding devices (e.g. wires, ropes, cords) may manifest as circumferentially configured bruises, lacerations, or abrasions involving the neck, wrists, ankles, or oral commissure. The combined presence of patterned cutaneous findings appearing over unusual locations (e.g. posterior surfaces, soft

tissues, genitalia) should raise grave concern for child abuse.5

BURNS No matter the etiology, burns of any type are particularly concerning for abuse and/or neglect. Of children who are physically abused, it has been estimated that burns account for nearly 25% of cutaneous injuries.6 The mere presence of a burn does not distinguish between an accidental or intentional event; rather, it is necessary to examine the features of the injury and correlate the injury with the explanation provided. In the pediatric population, the scald burn resulting from contact with a hot liquid is the most frequently encountered burn injury.7 In young children, the scald injury can inadvertently occur when the child overturns a hot beverage onto himself or bumps into another person carrying a hot beverage. In those situations, the most significant area of skin involvement is located at the site of initial contact with less skin involvement distally, as a result of the liquid cooling while traveling away from the central point of contact. Of course, it is entirely plausible that the caretaker intentionally threw the hot substance onto the child, as this would result in a similar pattern of injury. The immersion burn is most closely associated with inflicted trauma. This type of burn results from a child being placed, thrown, or held in a hot substance. Characteristically, the burn will have a sharp demarcation between the burned and unburned skin (i.e. water level) and uniformity of burn severity. If the extremities were immersed into the hot liquid, the child can present with a patterned and localized stocking (i.e. feet/leg) or glove (i.e. hand/arm) distribution of burned skin. Immersion of the child in a flexed position can result in skip areas, whereby the creased skin is protected relative to the surrounding exposed areas. If the buttocks comes into contact with the cooler surface (e.g. bathtub bottom), there may be a region of spared skin over the buttocks as a result. Kicking of the extremities and other physical efforts to resist the immersion event may result in splashing of the hot substance and subsequent “splash marks” (i.e. round areas of burned skin). Similar to bruises, burns in a patterned configuration are strong indicators of abuse. Cigarettes, automobile cigarette lighters, steam irons, radiator grids, and blow dryer gratings are only a few commonly recognized burn patterns.

Children burned by cigarettes typically present with a 6- to 8-mm round burn, with the center of the burn being most heavily affected due to the hot embers. Burns from automobile cigarette lighters produce a characteristic round burn containing concentric circles. Visualization of a burn pattern depicting round holes and a triangular tip is strongly suggestive of a steam iron burn. Similarly, the parallel and perpendicular pattern created by contact with a hot radiator grid or inner blow dryer grating is easily identifiable. Other types of burns less frequently encountered include flame, electrical, and chemical burns. Obtaining an appropriate history can be most helpful in discerning their etiology.

BITE MARKS The identification of bite marks on a child warrants special consideration. These lesions typically appear as an interrupted ovoid-shaped lesion. There may be surrounding edema or ecchymosis. Adult bite marks can be distinguished from those made by a child by measuring the maxillary intercanine distance. In adults, the standard maxillary intercanine distance ranges from 3 to 4 cm, whereas in children it is 98th percentile

S wave in V1 >98th percentile

Upright T wave in V1† Supplemental

Supplemental

Q wave in V1

Deep Q wave in V6

Right axis deviation

Left axis deviation

Source: From Gunn V, Nechyba C, eds. Harriet Lane Handbook. 16th ed. St Louis: Mosby; 2002. *At least one criterion must be present to entertain the diagnosis. †In

patients between 3 days and 10 years old.

Abnormal depolarization within the ventricles results in widening of the QRS complex. In complete right or left bundle branch block the QRS duration exceeds 0.12 seconds. As seen in Figure 52-6A, a right bundle branch block has a small R wave in V1 followed by a tall, slurred R’ reflecting late right ventricular depolarization. Figure 52-6B shows a left bundle branch block in which V6 has a tall, notched R wave and no septal q wave. Incomplete right bundle branch block, also called right ventricular conduction delay, has a similar pattern to right bundle branch block, though the QRS duration measures within normal limits. This may be a normal variant in children. Of note, neither the presence of ventricular hypertrophy nor the QT interval can be reliably assessed in the context of a bundle branch block. Bundle Branch Block

FIGURE 52-6. (A) Complete right bundle branch block. (continued)

FIGURE 52-6. (Continued) (B) Complete left bundle branch block.

Q WAVE With normal ventricular activation, the septum is the first to depolarize. This gives a q wave in the left precordial and inferior leads. Enlargement of the left ventricle, either through hypertrophy or dilation, can alter this q wave. Q Wave Abnormalities Small or absent q waves may be due to concentric left ventricular hypertrophy. Deep q waves (>5 mm) can result from septal hypertrophy or left ventricular dilation. Wide q waves (>40 ms) may represent an infarction.

ST SEGMENT This is isoelectric on a normal ECG. A key component of the ST segment is the J-point, or the point at which the S wave stops and meets the isoelectric segment. The J-point should not deviate more than 1 mm from the baseline. ST Segment Abnormalities Changes in the ST segment may reflect electrolyte imbalance, myocardial injury or ischemia, pericarditis, central nervous system disease, drug effect (eg, digoxin), ventricular hypertrophy, metabolic perturbations, hypothermia, or ventricular hypertrophy. Clinical

correlation is required to interpret ST segment irregularities (Figure 52-7).

FIGURE 52-7. ECG demonstrating diminished voltages, ST depression with downward T waves in V2 and V3, and flattened T waves in many leads in this patient with myopericarditis. (Used with permission from Dr. Michael Saalouke.) Frequently seen in adolescents, early repolarization results in a J-point elevation of 2 to 4 mm in the lateral and inferior leads. This can be a normal finding, especially in males and athletes. Early Repolarization

Diffuse ST elevation can result from pericardial inflammation. If the inflammation continues, this can be followed by normalization of the ST segment, followed by T-wave flattening and then inversion. Pericarditis

T WAVE The T wave direction changes by age in the precordial plane. In the right precordium (V1–V2), the T wave is positive from birth to approximately 7 days of age. After this, the T wave inverts until adolescence, after which it becomes positive again. In general, by 6 months of age, the QRS and T wave axis in the frontal plane are similar, differing by at most 60 degrees. Tall, peaked T waves may signify hyperkalemia, or accompany tall R waves in ventricular hypertrophy (Figure 52-8).

FIGURE 52-8. ECG demonstrating peaked T waves in a patient with hyperkalemia. There is also gradual prolongation of the PR interval, with a nonconducted P wave after the sixth QRS complex, consistent with Wenckebach second–degree heart block. (Used with permission from Dr. Michael Saalouke.)

QT INTERVAL Accurate measurement of the QT interval is important in determining if a patient has important depolarization abnormalities. The QT is longest in leads II and V5, and should always be measured in these leads. A tangent should be drawn from the steepest downslope of the T wave to the baseline. The QT interval is measured from the onset of the q wave to where the tangent and baseline intersect.3 This should then be corrected for heart rate by dividing it by the square root of the preceding RR interval (Bazett’s formula). QT Abnormalities Normal values for the corrected QT interval (QTc) vary by age and gender. In children less than 12 years of age, the QTc should be ≤450 ms. In adults, gender plays a more significant role, with women having longer corrected QT intervals than pre-adolescent girls. Males should continue to have QTc 2 mm in more than one right precordial lead (Figure 52-9). Clinical manifestations and/or family history are needed in addition to the ECG pattern to properly diagnose this syndrome.5

FIGURE 52-9. Patient with Brugada pattern on ECG. This is a type 1 pattern with a coved appearance to the ST segment elevation in leads V1 and V2.

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disorder that results in fibrofatty replacement of the ventricular myocardium, predominantly in the right ventricle, but can involve the left ventricle as well. This can lead to ventricular tachycardia and sudden death. Although there are recessive forms, ARVC is usually autosomal dominant with variable penetrance. Diagnostic criteria have been published,6 with classic ECG findings including right ventricular conduction delay and inverted T waves in the right precordial leads (V1–V3). An epsilon wave (high frequency signal in the ST segment) may also be seen.

CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) have a normal ECG at baseline but during periods of stress or exercise develop an array of arrhythmias, both atrial and ventricular, that can lead to polymorphic ventricular tachycardia and sudden death. It is caused by a mutation in either the ryanodine receptor or calsequestrin protein within the heart, both responsible for myocardial calcium regulation. A distinctive tachycardia seen in CPVT is bidirectional ventricular tachycardia, in which the QRS axis flips with every other beat. This pattern can also be seen in Andersen’s syndrome (Long QT type 7) and digoxin toxicity. KEY POINTS The electrocardiogram can be a powerful diagnostic tool. Using a systematic approach to interpret ECGs is imperative for accurate diagnosis and management. Caution should be used when reading ECGs in isolation, as a good history and physical examination can shed light on the significance of potential abnormalities. Since the ECG changes with age, pediatric standards should always be used when interpreting ECGs in the young.

REFERENCES 1. Rijnbeek PR, Witsenburg M, Schrama E, Hess J, Kors JA. New normal limits for the paediatric electrocardiogram. Eur Heart J. 2001;22(8):702-711. 2. Walsh EP, Berul C, Triedman JK. Cardiac Arrhythmias. In: Keane JF, Lock J, Fyler DC, eds. Nadas’ Pediatric Cardiology. 2nd ed. Philadelphia, PA: Saunders Elsevier; 2006:477-524. 3. Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm. 2008;5(7):1015-1018.

4. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-1339. 5. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111(5):659-670. 6. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121(13):1533-1541.

CHAPTER

53

Congenital Heart Disease Barry A. Love

BACKGROUND Excluding patent ductus arteriosus of the premature infant, congenital heart disease is estimated to occur in about 0.8% of all children.1 Fortunately, most of these problems are minor or self-limited and do not require intervention. Congenital heart disease requiring intervention is less common—about 3 to 4/1000.2 For this important group of patients with heart disease, the past 70 years have witnessed a remarkable advance in diagnostic and therapeutic techniques such that many of these children with previously lethal defects may now lead relatively normal lives. Congenital heart disease ranks ninth in cause of death of infants 200 Torr almost always excludes cyanotic congenital heart disease. A value lower than that or an infant who has poor perfusion or remains critically ill despite the usual treatment measures for these other conditions should have a complete echocardiogram performed and interpreted by a physician qualified to diagnose complex congenital cardiac disease. In those infants suspected of having critical heart disease, empiric therapy with intravenous prostaglandin E-1 should be commenced immediately at a dose of between 0.01 μg/kg/min and 0.05 μg/kg/min. Prostaglandin E-1 will reopen a closing ductus arteriosus and restore pulmonary or systemic flow in critical heart disease, temporizing the situation and allowing time for diagnosis and planned intervention. Side effects of prostaglandin include apnea, hypotension, tachycardia, and fever. Two points are important to make at this juncture: 1. A “normal” fetal ultrasound or even an echocardiogram should not be reason to exclude the consideration of serious congenital heart disease. The fetal diagnosis of congenital heart disease is a very operatordependent test. There are many instances where infants with hearts diagnosed as “normal” in-utero turn out to have critical congenital heart disease. 2. An echocardiogram done on a critically ill newborn is a very difficult test to perform and interpret accurately. The infant may be ventilated on an oscillator, be very labile with blood pressure or saturation to even brief imaging, and a whole other host of hemodynamic factors may make the acquisition and interpretation difficult. In addition, some of the most difficult diagnoses to make by echocardiogram (such as obstructed total anomalous pulmonary venous return) typically present in this fashion. While more neonatologists, radiologists and hospitalists are acquiring advanced training in pediatric echocardiography, it is imperative that the physician caring for the critically ill infant does not overstep his/her degree of expertise when assessing for potential critical heart disease.6

DIAGNOSTIC EVALUATION FOR CONGENITAL HEART DISEASE

The recognition of congenital heart disease rests on the foundation of a good clinical history and physical examination. The electrocardiogram may add supplemental information to the assessment of cardiac anatomy, and is necessary for diagnosis of rhythm problems. The diagnosis of congenital heart disease has been revolutionized by two-dimensional echocardiography. Echocardiography provides a detailed anatomic and physiologic diagnosis of congenital heart disease, is noninvasive, and is performed at the bedside. Coupled with the Doppler technique, blood velocity may also be assessed, and this can be used to estimate chamber pressures and presence of heart or great vessel obstruction or valve regurgitation. Because almost all the ultrasound waves are reflected at tissue–air interfaces, echocardiography is limited to views where the lungs do not obstruct the path between the ultrasound beam and the heart. Factors that limit the usefulness of transthoracic echocardiography include obesity, obstructive lung disease, and certain chest wall deformities. Three-dimensional echocardiography is in the early stages of clinical application and may provide additional understanding of the anatomic information Magnetic resonance imaging (MRI) is increasingly being used for diagnostic evaluation of congenital heart disease. Advantages of cardiac MRI include excellent anatomic detail that is not limited by lung tissue, and MRI is therefore an especially good modality for imaging the great vessels. A major disadvantage is the requirement for sedation and the relatively long post-processing and interpretation time. Functional assessment of blood flow by MRI is possible and in many instances may be more accurate than echocardiography. Implanted metal such as surgical clips or embolization coils render bothersome imaging artifacts in many patients when performing cardiac/thoracic MRIs. MRI is generally contraindicated in patients with pacemakers and defibrillators. Cardiac catheterization with angiography was once considered the gold standard for anatomic diagnosis. However, echocardiography and MRI have now almost completely supplanted cardiac catheterization for anatomic diagnosis. Cardiac catheterization remains the gold standard for hemodynamic assessment, and increasingly cardiac catheterization is being used as an interventional rather than diagnostic tool.

MANAGEMENT OF CONGENITAL HEART DISEASE Definitive treatment of congenital heart disease is complex due to the wide variety of anatomy, the physiologic changes that occur over time (e.g. fall in pulmonary vascular resistance), and growth. Straightforward heart lesions are approached with surgical or transcatheter techniques that address a single problem (e.g. atrial septal defect). More complex forms of congenital heart disease are approached by cardiologists and cardiovascular surgeons by first attempting to decide if there are enough required cardiac “parts” to immediately or eventually repair the heart in such a way that it is physiologically, if not anatomically, correct. A “complete” or “two-ventricle” repair entails having separate systemic and pulmonary circuits, each with its own ventricle and atrioventricular valve able to pump deoxygenated blood to the lungs and oxygenated blood to the body. Although this type of repair is referred to as a “complete,” the resulting cardiac anatomy is often very different from normal. Where possible, complete repair is generally the preferred option. If there are insufficient “parts” to perform a complete repair (e.g. hypoplastic left heart syndrome, tricuspid atresia) then a single ventricle pathway must be pursued. The single ventricle pathway typically follows as a series of palliative surgeries that culminate with a Fontan procedure. This staged cardiac surgery ultimately results in a circulation where the venous blood return is passively routed to the lungs without passing though a ventricle, and then returns to a functionally single ventricle that pumps to the body. For this type of repair to succeed, the patient must have a relatively competent atrioventricular valve, good systolic ventricular function, unobstructed outflow from the heart, widely patent pulmonary arteries, and low pulmonary vascular resistance. The vascular resistance of the neonatal pulmonary vascular bed is too high to accept the passive pulmonary flow of a Fontan, and so a series of operations is necessary to ultimately achieve this type of palliation.

STAGE I: SINGLE VENTRICLE PATHWAY (Figure 53-1) The first stage of the single ventricle pathway provides for adequate pulmonary blood flow and unobstructed systemic flow in the newborn period. If the original cardiac anatomy is such that there is insufficient pulmonary

flow, a shunt is surgically placed to provide flow from the systemic circulation to the pulmonary circulation taking the place of the ductus arteriosus. One of the more common types of shunt is the modified BlalockTaussig shunt, which is a synthetic tube, placed from the subclavian artery to the ipsilateral pulmonary artery. There are many types of shunts and modifications of techniques, which depend on the individual anatomy and operator preference.

FIGURE 53-1. Stage I single ventricle pathway for hypoplastic left heart syndrome (see Figure 53-8 for unrepaired anatomy). 1. Right modified Blalock-Taussig shunt. 2. Large (surgically created) atrial septal defect. 3. Main pulmonary artery has been detached form branch pulmonary arteries. 4. Unobstructed egress of blood from the heart to the body has been achieved by using the main pulmonary artery and native aorta with additional patch material. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http:// www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March 21, 2017.)

The infant with an “ideal” physiology following a shunt has a systemic oxygen saturation of about 80%. Empirically this saturation has been found to be the best balance between systemic oxygen delivery and pulmonary overcirculation. Because blood circulating to the lungs is already partially saturated, shunt physiology is inefficient, and even with this “ideal” saturation of 80%, there is still about twice as much blood being circulated to the lungs as to the body. If the original cardiac anatomy dictates the single ventricle pathway but there is too much pulmonary flow such that the pulmonary pressures are high and/or the infant is in congestive heart failure, then the first stage in palliation is a pulmonary artery band (PAB). A PAB is a surgical “noose” placed around the pulmonary artery that creates an artificial stenosis and limits pulmonary flow. Of great importance in the single ventricle pathway is the provision for an unobstructed pathway for systemic blood flow. The proximal pulmonary artery and aorta are often used together to recreate a single unobstructed outflow from the heart in this first stage.

STAGE II: BIDIRECTIONAL GLENN (Figure 53-2) At about 4 to 8 months of age, the pulmonary vascular resistance has typically decreased sufficiently to accept a portion of the venous return in a passive manner. The second step of cardiac palliation for children proceeding down the single ventricle pathway is the “bidirectional Glenn,” or stage II. This involves connecting the superior vena cava directly to the pulmonary arteries and eliminating any previous shunted source of pulmonary blood flow. The arterial saturations are usually about the same before and after the procedure (~80%); however, this type of circulation is preferable because it is more efficient. In the shunted scenario, the single ventricle pumps blood to both the body and the lungs, and the blood pumped to the lungs is partially saturated—an inefficient type of arrangement. After the stage II repair, the heart is only pumping blood to the body, and only desaturated blood is flowing to the lungs, thereby increasing the efficiency.

FIGURE 53-2. Stage II single ventricle pathway for hypoplastic left heart syndrome. 1, 2. The right modified Blalock-Taussig shunt that was created at the stage 1 repair has been removed. The superior vena cava is divided and the proximal portion is attached directly to the right pulmonary artery, allowing the blood from the superior vena cava (SVC) to flow to both lungs (“bidirectional Glenn”). “Bidirectional” refers to the SVC blood flowing to both the right and left lungs. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http:// www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March 21, 2017.)

STAGE III: FONTAN (Figure 53-3) The third stage (Fontan completion) consists of redirecting the blood from the inferior vena cava to the lungs, thereby separating the pulmonary and systemic circuits. Directing the inferior vena cava blood to the lungs may be accomplished by use of a synthetic tube lateral to the heart (external conduit)

or using part of the right atrium as a wall (lateral tunnel). Often a small communication is left in the tube (fenestration) that may later be closed in the cardiac catheterization lab. After closure of the fenestration, these patients have normal oxygen saturations. Stage III is usually performed between ages 2 to 5 years, depending on center preference and technique.

FIGURE 53-3. Stage III –single ventricle pathway for hypoplastic left heart syndrome. 1. A tube has been placed within the right atrium to direct the blood from the inferior vena cava to the superior vena cava. The superior vena cava is reattached to the undersurface of the pulmonary artery. 2. Fenestration: a small hole is left in the tube to allow some of the venous blood to bypass the lungs. The fenestration keeps the venous pressure from rising too high after the Fontan operation, but results in some desaturation. The fenestration may be optional in some patients, but if desired can be easily closed in the cardiac catheterization laboratory afterward. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http:// www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March

21, 2017.) Postoperative problems encountered by patients with Fontan-type repairs include early problems such as prolonged pleural effusions, and late problems such as increased risk for stroke and thrombus formation in the Fontan, arrhythmia development (especially atrial flutter), and protein-losing enteropathy.

CRITICAL NEWBORN HEART DISEASE CRITICAL NEWBORN HEART DISEASE: PATENT DUCTUS ARTERIOSUS AUGMENTS Pulmonary Blood Flow In this set of lesions, a portion of the normal anatomy supporting pulmonary blood flow (tricuspid valve, right ventricle, pulmonary valve, and pulmonary arteries) is small or absent. The ductus arteriosus provides pulmonary blood flow by shunting systemic blood flow to the lungs. While d-transposition of the great arteries (d-TGA) is also included in this section, the physiology of this lesion is somewhat different, as explained below. Tricuspid Atresia (Figure 53-4) The tricuspid valve is atretic in this lesion and the right ventricle is typically severely hypoplastic. The pulmonary artery arises from the right ventricle, and there may be a ventricular septal defect. When the ventricular septal defect and/or pulmonary artery are hypoplastic, pulmonary blood flow is inadequate and the ductus arteriosus is required to support pulmonary blood flow. In some instances, there may be adequate pulmonary flow through the ventricular septal defect, and in other cases the ventricular septal defect and pulmonary artery may be so large that the infant has too much pulmonary blood flow.

FIGURE 53-4. Tricuspid atresia (normal great arteries). 1. Patent foramen ovale with flow right to left. 2. Atretic tricuspid valve. 3. Ventricular septal defect (VSD). Size of VSD and amount of restriction is variable. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March 21, 2017.) If the pulmonary flow is inadequate, a systemic-to-pulmonary artery shunt is required. If there is too much pulmonary flow, the infant may require a pulmonary artery band to reduce the amount of pulmonary flow. In some instances, nature provides just enough pulmonary stenosis so that the child is not in congestive heart failure with adequate systemic saturations. In any case, the infant with tricuspid atresia also follows a single ventricle pathway. In some instances, tricuspid atresia is also found with transposition of the great arteries. These infants will require a repair similar to hypoplastic left heart syndrome, as the aortic valve and arch are typically hypoplastic when the great arteries are transposed. Tetralogy of Fallot (Figure 53-5) This condition arises when the

ventricular septal muscle between the aorta and the pulmonary artery is deviated anteriorly. This causes the pulmonary outflow area to be stenotic, a special type of ventricular septal defect to be present under the aorta (anterior malalignment), and the aorta to then be aligned over the ventricular septal defect and crest of the ventricular septum (overriding aorta). There is usually accompanying right ventricular hypertrophy, which completes the four parts of the tetralogy. While simple in its description, there is a huge variation in the severity of this disease that is largely dependent upon the pulmonary artery architecture. When there are well-developed pulmonary arteries and mild or moderate pulmonary stenosis, this lesion is not critical. Systemic oxygen saturations from 80% to 95% are possible, and infants may undergo elective complete repair between 3 and 12 months of age. Surgical repair in these cases involves closing the ventricular septal defect and relieving the pulmonary obstruction by patching the right ventricular outflow tract, pulmonary valve, and main pulmonary artery as needed.7

FIGURE 53-5. Tetralogy of Fallot. 1. Pulmonary valve and subvalvar stenosis. 2. Hypertrophied right ventricle. 3. Overriding aorta. 4. Ventricular septal defect. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994.

2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) More severe obstruction at the pulmonary valve and right ventricular outflow tract may lead to more profound cyanosis and ductal dependency. These infants may require a shunt to increase pulmonary flow in anticipation of a complete repair at an older age, or they may undergo complete repair as infants. At the extreme, there may be complete atresia of the pulmonary valve, and only a thread-like main pulmonary artery. Associated with this more severe obstruction are downstream architectural abnormalities of the pulmonary arteries, with stenosis or absence of branches of the pulmonary arteries and the presence of collateral vessels from the aorta to the pulmonary arteries that may supply multiple segments of the lung. Presence of these aorto-pulmonary collateral vessels and small, stenotic pulmonary arteries makes definitive surgical repair a challenge, and is individualized for each patient’s anatomy, usually requiring a series of staged operations and cardiac catheterizations for dilation of stenotic pulmonary arteries.8 Important pediatric concerns of infants with tetralogy of Fallot, especially when associated with pulmonary atresia, is the association with the 22q deletion/velocardiofacial/DiGeorge syndrome complex. Infants with this heart disease should have genetic testing (fluorescence in situ hybridization (FISH)) done for the 22q deletion, and calcium levels should be monitored in the newborn period. If positive, immunologic workup and genetic and anticipatory guidance should be provided to patients and families. Another important issue for patients with tetralogy of Fallot is the possibility of experiencing “tet-spells,” which are sudden episodes of profound desaturation. The classic explanation of the pathophysiology of this condition is “spasm” of the muscle under the pulmonary valve leading to decreased pulmonary flow and increased cyanosis, though this is certainly an oversimplified mechanism. Tet-spells can be treated by increasing the systemic resistance to force more blood across the pulmonary circuit. This can be done mechanically by putting the patient in a knee-to-chest position, or pharmacologically by administering intravenous phenylephrine. Supplemental oxygen may be of some benefit as is the administration of subcutaneous or intravenous morphine as a sedative. Ketamine is an especially useful drug in managing tet-spells, as it provides both sedation and

increased systemic vascular resistance, and it can be administered intravenously or intramuscularly. Patients who have had one or more tetspells should be considered for surgical palliation or repair, as these spells, if prolonged, can be associated with morbidity and mortality. d-Transposition of the Great Arteries (Figure 53-6) In dtransposition of the great arteries (d-TGA), the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. This leads to systemic blood returning from the body, recirculating to the body, and pulmonary blood recirculating to the lungs (parallel circulations), and profound cyanosis. Survival depends on mixing of the two circulations at the atrial, ventricular, or great vessel levels. Prostaglandin E-1 temporizes this condition by increasing the amount of blood in the pulmonary system, which encourages mixing at the atrial or ventricular level. For prostaglandin to work, there must be an atrial or ventricular septal defect. If no septal defect is present, or if mixing is inadequate as evidenced by oxygen saturation less than 80%, an atrial septal defect may need to be created, or an existing one enlarged, to stabilize the infant in anticipation of corrective surgery. This procedure (balloon atrial septostomy) is accomplished by passing a balloon catheter through the atrial septum, inflating the balloon, and pulling it back across the atrial septum to tear a hole in the atrial septum, thereby creating an atrial septal defect. This procedure can be performed at the bedside under echocardiographic guidance alone, or in the cardiac catheterization laboratory under fluoroscopic guidance.9

FIGURE 53-6. d-Transposition of the great arteries. 1. Patent foramen ovale with left-to-right flow. 2. Transposed great arteries. Aorta arises from right ventricle. 3. Ductus arteriosus with flow from aorta to pulmonary artery. 4. Transposed great arteries. Pulmonary artery arises from left ventricle. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) Definitive therapy for d-TGA is surgical. Since the mid-1980s, the procedure of choice for this lesion is the “arterial switch,” where the aorta and pulmonary arteries are transected above the valves and reattached to their physiologically correct ventricle. The Achilles-heel of this procedure is transfer of the coronary arteries, which must be removed separately and reattached to the aorta. The coronary artery anatomy is variable and makes preoperative definition of this anatomy important and appropriate surgical planning imperative.10 Associated lesions are usually corrected at the same surgery, which may include ventricular septal defect and coarctation of the aorta. The prognosis for children with d-TGA is generally excellent.

Postoperative problems related to coronary artery obstruction can occur, as can residual lesions related to the surgical correction.

CRITICAL NEWBORN HEART DISEASE: PATENT DUCTUS ARTERIOSUS AUGMENTS SYSTEMIC BLOOD FLOW In this set of lesions, a portion of the normal anatomy supporting systemic blood flow (mitral valve, left ventricle, aortic valve, and aorta) is narrowed, small, or absent. The ductus arteriosus provides systemic blood flow by shunting some of the pulmonary blood through the ductus arteriosus to the aorta. Infants with these lesions often present with shock or decreased femoral pulses as the ductus arteriosus closes. Critical aortic stenosis, interrupted aortic arch, and critical coarctation of the aorta are all examples of critical left heart disease that require prostaglandin to stabilize and temporize, but can all have repairs that result in a complete repair. Hypoplastic left heart syndrome is an extreme form of left heart obstructive disease that requires a single ventricle surgical approach.

CRITICAL AORTIC STENOSIS In this lesion, the aortic valve opening is narrowed by partial fusion of the leaflets and there is severe obstruction to outflow from the left ventricle. Before repair, most of the blood returning from the left atrium passes across the foramen ovale to the right atrium and subsequently to the right ventricle and main pulmonary artery, where a portion of the blood passes across the ductus arteriosus to the body and a portion passes to the lungs. For this lesion to be defined as critical aortic stenosis rather than hypoplastic left heart syndrome, the left ventricle, and mitral valve need to be of normal size, though the left ventricular function is often severely depressed before intervention. Treatment of this condition is usually transcatheter balloon dilation of the aortic valve. This procedure relieves the narrowing at the valve sufficiently to permit recovery of left ventricular function, allowing the left ventricle to pump all the systemic blood. Prostaglandin can be discontinued after the dilation once the left ventricle has recovered adequately, but this may take

several days. There is usually residual aortic stenosis of a mild to moderate degree after neonatal dilation, and these patients usually require further interventions for the aortic valve later in infancy or childhood.11

COARCTATION OF THE AORTA AND INTERRUPTED AORTIC ARCH In coarctation of the aorta, the aorta is severely narrowed at or just beyond the origin of the left subclavian artery. In interrupted aortic arch, there is a discontinuity of the aorta at a point between one of the head and neck vessels (usually between the left carotid and left subclavian arteries). Both lesions typically present with shock and/or decreased femoral pulses as the ductus arteriosus closes and are temporized by prostaglandin E-1, which opens the ductus arteriosus, supplementing systemic blood flow. The treatment of either lesion is surgical repair in the neonatal period. The surgical repair for critical coarctation usually involves removing the narrowed segment and rejoining the descending aorta to the aortic arch in an unobstructed fashion.12 The repair is usually done without the need for cardiopulmonary bypass. The repair of interrupted aortic arch is a much more complex arch reconstruction requiring the use of cardiopulmonary bypass. A ventricular septal defect—associated with the most common type of interrupted aortic arch—is repaired at the same surgery. Interrupted aortic arch (type B) is also associated with the 22q deletion/DiGeorge complex and as with tetralogy of Fallot, these patients should have appropriate calcium monitoring, and genetic and immunologic workup.

HYPOPLASTIC LEFT HEART SYNDROME (Figure 53-7) When the left-sided heart structures (mitral valve, left ventricle, aortic valve, and aortic arch) are too small to support the cardiac output needed for the body, the condition is referred to as hypoplastic left heart syndrome. The mitral or aortic valves may be so small as to be atretic. In the unrepaired state, the right ventricle pumps the combined venous return from the body and from the lungs to the pulmonary artery, where a portion of the blood passes to the lungs and a portion passes through the ductus arteriosus to supply the body. The degree of cyanosis depends on the proportion of

pulmonary to systemic blood flow. As the ductus arteriosus closes, more blood is directed to the lungs and less to the body, leading to higher systemic saturations but signs and symptoms of low cardiac output and ultimately shock. Prostaglandin E-1 opens the ductus arteriosus and temporizes the situation.

FIGURE 53-7. Hypoplastic left heart syndrome. 1. Atrial septal defect with left-to-right flow. 2. Coarctation of the aorta. 3. Patent ductus arteriosus with flow from pulmonary artery to aorta. 4. Hypoplastic ascending aorta. 5. Small mitral valve—sometimes atretic. 6. Small Aortic valve—sometimes atretic. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) Surgical repair of this condition follows the principles of the single ventricle pathway outlined in a subsequent section and involves three stages. The first stage is more involved than most other types of first-stage single ventricle palliations because the main pulmonary artery must be used along with the native (small) aorta and prosthetic patch material to refashion the

aortic arch. Pulmonary blood flow is provided by placing a tube graft from either a subclavian artery to pulmonary artery (modified Blalock Taussig shunt) or from the right ventricular outflow tract to the pulmonary artery (Sano modification13). The initial palliation strategy for hypoplastic left heart syndrome is technically difficult and even in the best centers has one of the higher mortalities for congenital heart disease surgery. As a result, the past decade has seen the development and refinement of an alternative strategy called a “hybrid stage I” (Figure 53-8). This technique is a hybrid surgical and transcatheter technique where a surgical noose (band) is placed on each pulmonary artery to limit pulmonary blood flow, and a stent is placed in the ductus arteriosus to maintain systemic perfusion. The atrial septum is also enlarged if needed using catheter balloon and/or stent techniques. This hybrid stage I approach results in a much more stable infant post-procedure. The infant is then adequately palliated until he/she is about 4 to 6 months of age and then undergoes a “comprehensive stage II” procedure where the ductal stent and pulmonary artery bands are removed, and then the previously described first-stage operation is performed, with the exception that a Glenn shunt (superior vena cava to pulmonary artery) is used rather than a systemicpulmonary artery shunt. This makes for a more complex stage II procedure, but at a time when the infant is much bigger, making the procedure easier. In addition, the Glenn shunt is a more stable source of pulmonary blood flow than is a systemic-pulmonary artery shunt. The infant then continues down the single ventricle pathway to arrive at a Fontan procedure typically between 3 to 5 years of age. These two techniques in multicenter series appear to have similar outcomes, but some centers prefer one technique over the other depending on their center-specific outcomes for both approaches.

FIGURE 53-8. Hypoplastic left heart syndrome after hybrid stage I palliation. 1. Stent in atrial septum (sometimes required). 2. Pulmonary artery bands on right and left pulmonary arteries. 3. Stent across ductus arteriosus. Note that stent often covers the origin of the aortic arch. Blood traverses through the struts of the stent to reach the head and perfuse the coronary arteries. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) Another strategy for managing patients with hypoplastic left heart syndrome is infant heart transplantation. Despite significant advances in immunosuppressive regimens, success of the heart transplantation strategy for hypoplastic left heart syndrome has been limited by a lack of donor organs and late graft failure, which occurs over decades in virtually all transplanted hearts.14

CRITICAL NEWBORN HEART DISEASE: PATENT

DUCTUS ARTERIOSUS NOT REQUIRED Total anomalous pulmonary venous return (TAPVR) with obstruction is the classic example of newborn heart disease that is not temporized by prostaglandin E-1. In this lesion, the pulmonary veins do not return to the left atrium, but communicate with the systemic veins by means of a supplemental venous channel. This channel may be obstructed, leading to progressive pulmonary edema, “whiteout” on chest x-ray, and an inability to ventilate or oxygenate. This lesion is the one most often mistaken for pulmonary disease in the newborn. If a newborn has progressive pulmonary disease and is failing conventional treatment, the diagnosis of congenital heart disease— especially obstructed TAPVR—should be entertained and an echocardiogram obtained. Repair consists of reattaching the pulmonary venous chamber to the left atrium.

LESIONS PRESENTING WITH CONGESTIVE HEART FAILURE OR MURMUR IN INFANCY As the pulmonary vascular resistance falls in the first weeks of life, lesions that permit the transmission of high flow or pressure to the lungs become manifest. These lesions include ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and patent ductus arteriosus (PDA).

VENTRICULAR SEPTAL DEFECT (Figure 53-9) The ventricular septum is a complex anatomical structure dividing the left and right ventricles. Near the aortic valve, the septum is a thin membrane (membranous septum) whereas it is a thick muscle in other parts. A defect in the wall is called a ventricular septal defect (VSD). The most common defects occur in the membranous septum, but they can occur anywhere in the wall, and may be multiple. The presentation of VSD is dependent on two factors—the size of the ventricular septal defect and the pulmonary vascular resistance.

FIGURE 53-9. Ventricular septal defect. 1. Ventricular septal defect (VSD) with flow from left ventricle to right ventricle. Position of VSD in ventricular septum determines type. More common type located just underneath the aortic valve (membranous). (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http:// www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March 21, 2017.) Small VSD A small muscular ventricular septal defect presents in the first days to weeks of life with a high-pitched, asymptomatic murmur. When the resistance in the pulmonary circulation falls, so too does the right ventricular pressure, creating a large pressure difference between the left and right ventricles. A small hole between the ventricles creates a turbulent left-to-right flow jet, and a loud murmur is heard. In this scenario, the total amount of blood recirculated through the lungs and back to the left ventricle is minimal. Moderate VSD If the VSD is somewhat larger, as the pulmonary resistance falls, the VSD may still be small enough to limit the pressure transmitted to the right ventricle but large enough to admit more blood flow. In this

circumstance, the amount of extra blood flow to the lungs recirculating back to the left heart may be significant, and the infant may have respiratory symptoms and perhaps some degree of congestive heart failure. A loud murmur will be present as the pressure gradient and flow are high. Large VSD At a certain point, the VSD is so large as to be unable to limit the pressure transmitted by the left ventricle. As the pulmonary resistance falls, there is more and more blood recirculating to the lungs, but the pressure in the right ventricle and pulmonary artery remains at systemic levels (socalled “unrestrictive” defects). The intensity of the systolic murmur is proportional to the degree of left-to-right shunting; however, there is often only a relatively soft murmur because there is little turbulence across the large VSD. With excessive pulmonary blood flow, infants typically display failure to thrive. If left uncorrected for a prolonged period of time, these infants run the risk of developing irreversible changes to the pulmonary vasculature that progresses even after the defect is corrected. Pulmonary blood vessels when exposed to high pressure for too long develop irreversible changes called pulmonary vascular obstructive disease (PVOD). PVOD is averted by limiting the pressure to which the lung vasculature is exposed by either closing the VSD or applying downstream resistance to flow by placing a pulmonary artery “band.” Irreversible PVOD does not usually develop until after age 1 year, although the time course after this point is remarkably variable. Patients with Down syndrome seem to be at higher risk at an earlier age and intervention is recommended before age 9 months in this subgroup.15 Although most infants with large VSDs with left-to-right shunt present with congestive heart failure as the pulmonary resistance falls, there is a small group of patients with unrestrictive VSDs in whom the pulmonary resistance falls very little or not at all. These infants will not develop congestive heart failure, and if the pulmonary resistance is very high, may not have much additional pulmonary flow. There is little if any heart murmur as there is no restriction to flow at the ventricular level and not enough increase in pulmonary flow to produce an appreciable flow murmur. The only cardiac sign may be relatively subtle—a single, loud second heart sound. These children often have frequent respiratory illness, which may further limit the ability of the pediatrician to clearly auscultate the heart. With no loud murmur demanding attention, and the more subtle signs often masked by respiratory noise, these children may go undiagnosed for a prolonged period

and are therefore at high risk of developing PVOD. The pediatric hospitalist should keep this infrequent presentation of congenital heart disease in mind when assessing and treating infants and young children with frequent respiratory problems. Surgical closure of a VSD is indicated in infancy (less than 1 year of age) if there is persistent congestive heart failure, or if the pulmonary pressures remain high. As some VSDs get smaller with time and even close, medical management with anticongestive medications (lasix, digoxin, angiotensinconverting enzyme inhibitors) may be indicated for a period in some infants with moderate and large VSDs. More complex decision-making is required for VSDs that are multiple—especially those located at the apex of the heart. This location is typically difficult to approach surgically. In this instance, a pulmonary artery band may be placed to limit pulmonary flow and pressure until the child is larger. Transcatheter closure devices may be another option in selected children–, sometimes combined with a surgical approach.16 Moderate ventricular septal defects are usually followed through infancy and early childhood as many become small and not require intervention. Closure is recommended for VSDs that remain moderate with a pulmonary to systemic flow ratio of more than about 2:1. Transcatheter closure devices for membranous VSDs are in clinical trials. These devices need special design and delivery systems to avoid interfering with the aortic valve, which forms the superior border of the membranous septum.17 Atrioventricular Septal Defect (Figure 53-10) The atrioventricular septal defect (AVSD) is a more complex form of heart disease than simply a combination of an atrial and ventricular septal defect. It involves an incomplete separation of the embryonic common atrioventricular valve into separate tricuspid and mitral components. In addition, there is both a ventricular and atrial septal defect in the portion of the septa that are immediately adjacent to the atrioventricular valve. This lesion is often associated with Down syndrome. Presentation is similar to those patients with moderate or large ventricular septal defects. The septal defects do not close spontaneously and so all patients with AVSD will require surgical repair to partition the atrioventricular valve and close the atrial and ventricular septal defects. Partitioning the atrioventricular valve is surgically challenging so as not to produce mitral stenosis or regurgitation. Most centers perform

complete repairs on these children between 3 and 6 months when the infants are somewhat larger, but soon enough to prevent the development of pulmonary vascular disease.18

FIGURE 53-10. Atrioventricular septal defect. 1. Atrial septal defect (ostium primum type). 2. Right side of common atrioventricular valve (incompletely formed tricuspid valve). 3. Left side of common atrioventricular valve (incompletely formed mitral valve). 4. Ventricular septal defect (of “inlet” ventricular septal type). (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http:// www.pediatriccardiacinquest.mb.ca/pdf/index.html. Accessed March 21, 2017.) Patent Ductus Arteriosus (Figure 53-11) The ductus arteriosus is the conduit for fetal blood to bypass the lungs in utero. After birth, the ductus usually closes in the first days of life. If it does not close, as pulmonary vascular resistance falls, blood shunts from the aorta into the pulmonary artery. Depending on the size of the ductus arteriosus and the pulmonary vascular resistance, the ductus will shunt a variable amount of blood similar

to the physiology of a ventricular septal defect, and this lesion may present with congestive heart failure if large, or a murmur if the ductus is smaller.

FIGURE 53-11. Patent ductus arteriosus. 1. Ductus arteriosus with flow from aorta into pulmonary artery. (Reproduced from Sinclair CM. The Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) The treatment of a patent ductus arteriosus is surgical or transcatheter closure. Transcatheter closure is now routine in children and infants older than 6 months.19 Surgical closure is indicated for refractory heart failure in smaller infants, premature infants, or in those where there is other accompanying heart disease that requires surgical intervention. A small patent ductus arteriosus associated with a murmur—even in the absence of significant shunting—is closed in the catheterization laboratory to prevent the lifelong risk of endarteritis of the ductus, which is estimated at ~0.45%/year.20

The general consensus is that a small ductus arteriosus found by echocardiography without an associated murmur should not be closed, as the risk of endarteritis does not appear to be higher than that of the general population. Coarctation of the Aorta When severe, this lesion presents in the newborn period as a critical newborn heart lesion with shock or cyanosis. If milder, this lesion may present with a murmur, or more commonly, with the astute pediatrician noting decreased intensity of the femoral pulses. Repair of this lesion is usually done surgically. Diagnosis of coarctation later in childhood is sometimes made by the finding of upper extremity hypertension. Therapeutic options later in childhood and through adulthood include surgery or transcatheter balloon dilation with stent placement. Later diagnosis and repair of this lesion may lead to persistent hypertension even after repair.

LESIONS PRESENTING WITH A MURMUR IN CHILDHOOD Less severe obstructions and shunts typically present with a murmur in childhood. Stenosis of the semilunar valves (aortic stenosis or pulmonary stenosis) as well as atrial septal defects may present in this time frame.

PULMONARY STENOSIS AND AORTIC STENOSIS These lesions, when severe, present as critical heart disease in the newborn, as previously discussed. When milder, they present as a murmur. Treatment is undertaken for pulmonary stenosis when the narrowing is moderate or severe, and consists of transcatheter balloon dilation of the valve. Such intervention is highly effective and typically does not need to be repeated.21 Treatment is undertaken for aortic stenosis when the gradient is moderate to severe. The first approach is usually balloon dilation of the valve. The success of aortic balloon dilation may be good, but relief of stenosis in many patients is often accompanied by creation of aortic regurgitation. Surgical valve repair, replacing the aortic valve with the patient’s own pulmonary valve (Ross procedure), or prosthetic valve replacement are all options. Prosthetic valve replacement is undesirable in small children because of the limited lifespan of these valves, and growth considerations.

ATRIAL SEPTAL DEFECT (Figure 53-12) The atrial septum divides the right and left atria. A defect in the wall is called an atrial septal defect (ASD). Blood returning to the left atrium passes from left to right across the ASD and recirculates to the lungs, placing a volume load on the right ventricle, pulmonary vascular bed, and atria. The amount of excess blood flow (or “shunt”) is determined by both the size of the defect as well as the balance between the diastolic compliance of the left and right heart. In infancy, the right ventricle is relatively noncompliant, and there may be minimal flow across even a large ASD. During childhood the right ventricle becomes more compliant while the left ventricular compliance decreases, thereby increasing the amount of shunting. The consequences of an unrepaired ASD include right ventricular dysfunction and atrial arrhythmias from chronic volume load, the potentially devastating complication of pulmonary hypertension and pulmonary vascular disease— which may develop in up to 5% to 10% of these patients during adult life— and risk of paradoxical embolus.

FIGURE 53-12. Atrial septal defect. 1. Atrial septal defect with flow from left atrium into right atrium. (Reproduced from Sinclair CM. The

Report of the Manitoba Pediatric Cardiac Surgery Inquest: An Inquiry Into Twelve Deaths at the Winnipeg Health Sciences Center in 1994. 2000. Available at http://www.pediatriccardiacinquest.mb.ca/pdf/ index.html. Accessed March 21, 2017.) If there is evidence of right ventricular volume overload by echocardiography, then the lesion should be closed. Usually this decision is made after age 2 years, as some ASDs will get smaller over the first years of life. If the defect is of the secundum type it may be closed in the cardiac catheterization laboratory with specially designed closure devices.22 If the defect is large or is located in other anatomic regions of the atrium, then surgery is required for closure.

ADMISSION AND DISCHARGE CRITERIA Patients who present critically ill obviously require admission. Infants with congestive heart failure may require admission for initiation or optimization of medical management that may include diuretics, digoxin, and supplemental caloric addition and/or nasogastic feeding to assist with growth. Patients with congenital heart disease may require admission for intercurrent illness such as respiratory syncytial virus and other viral or bacterial infections. Infants with congenital heart disease may have a more severe course with a higher risk of complications than other children. Discharge of patients after congenital heart disease surgery has been evolving. There has been a greater move to “fast-track” patients with congenital heart disease after surgery with a view toward early extubation, early removal of central lines and chest tubes, and ultimately early discharge. The average length of stay in some centers for simple congenital heart disease surgery is now 1 day for atrial septal defect and 3 days for VSD repair.23 When properly implemented, this has been shown to not increase mortality or readmission rates. Infants and children are discharged postoperatively once all the acute surgical issues are resolved, they are able to be fed, pain is well controlled, and they are on an oral medical regimen. Early discharge, however, also mandates close early follow-up. For infants with shunt-dependent pulmonary blood flow or those with hypoplastic left heart syndrome after conventional stage I or hybrid stage I, a

significant “interstage” mortality has been recognized. Some of these children will die at home or present in extremis to the emergency department for anatomic problems that can arise insidiously. For this reason, many centers have taken the approach that a very close monitoring program will lead to decrease in interstage mortality if these children can be monitored very closely at home and appropriate intervention undertaken preemptively. These conditions include development of residual arch obstruction, shunt narrowing, atrial septal narrowing, and other issues. Preliminary research seems to support this hypothesis.24 Many centers have established intensive home monitoring programs where parents are provided with an oxygen saturation monitor and a scale to monitor daily oxygen saturations and at least biweekly weights. Some programs use visiting nurse checks one a week or more to ensure medication compliance, verify oxygen saturation and weight checks, and communicate with the cardiology and pediatric team.

CONSULTATION Close collaboration between the pediatric cardiologist and the pediatrician is essential for successful outcomes in patients with complex congenital heart disease. Other teams that are frequently consulted include: Genetics: In many children, there may be an underlying genetic syndrome or genetic etiology that is important for prognosis, anticipatory guidance and reproductive counseling. Neurology: Congenital heart disease may be associated with neurologic deficits or these may develop as a result of neurologic injury during interventions, primarily cardiac surgical. Developmental and behavioral pediatrics: Many children with complex congenital heart disease will require assessment for developmental and behavioral needs so they can be provided with the needed services. Social work: The social work team is invaluable in assessing the needs of the patient and family with regard to access to care, insurance, social supports, ability of parents and caregivers to care for a child with additional needs, etc. Other subspecialty consultations may be needed as indicated.

SPECIAL CONSIDERATIONS FOR THE PEDIATRIC HOSPITALIST CARING FOR PATIENTS WITH CONGENITAL HEART DISEASE ENDOCARDITIS PROPHYLAXIS Most congenital heart lesions put patients at risk for the development of endocarditis. Children with congenital heart disease should have regular dental care and maintain good oral hygiene. It used to be recommended that antibiotics be given prior to dental and other gastrointestinal procedures for most patients with congenital heart disease. These recommendations were recently revised and have generally been lifted except for patients with unrepaired cyanotic congenital heart disease and others with turbulence adjacent to prosthetic material (see Chapter 54, Infective endocarditis).

RESPIRATORY SYNCYTIAL VIRUS Respiratory syncytial virus (RSV) may produce severe disease in children less than 2 years of age with cyanotic heart disease, single ventricle anatomy pre or post surgery, dilated or hypertrophic cardiomyopathy, pulmonary hypertension, or significant left-to-right shunts requiring medication to control pulmonary vascular congestion. In such patients the American Academy of Pediatrics recommends monthly passive immunization during the RSV season with palivizumab.25 Steps should be taken to minimize the risk from this potentially life-threatening illness. If a congenital heart lesion needs repair, consideration should be given to timing the repair before the RSV season which typically extends from November through March. Appropriate reverse isolation of hospitalized children with heart disease at high risk should be undertaken to prevent nosocomial transmission.

PACEMAKERS AND IMPLANTABLE DEFIBRILLATORS Children with congenital heart disease may have congenital or iatrogenic surgical conduction defects that necessitate pacemaker placement. Pacemakers work by emitting an electric current that stimulates cardiac depolarization. Though pacemakers are very reliable, the interface between the pacemaker and the heart (the leads) are prone to a variety of problems.

Extreme physiologic changes (e.g. acidosis) in the patient may also increase the amount of energy needed to depolarize the heart above that set by the pacemaker. In-hospital monitoring of children with pacemakers using a cardiac monitor is insufficient, as these monitors will usually detect the pacemaker impulse even when not followed by a cardiac depolarization. A physiologic monitor such as a pulse oximeter or arterial waveform should be used to confirm heat rate in paced patients. Similarly, during resuscitation, one should not mistake the pacemaker impulse as a cardiac depolarization, and physiologic parameters (e.g. palpation of a pulse) should be used to determine the cardiac rate. Patients with pacemakers or implantable defibrillators requiring non– cardiac surgery may need the device reprogrammed prior to surgery to avoid oversensing, and electrocautery should be avoided. Patients with these devices may not undergo MRI examinations with the exception of the Medtronic Revo dual chamber pacemaker system with both atrial and ventricular leads in place and the pacemaker verified and programmed for MRI use.

CENTRAL ACCESS AND PARADOXICAL EMBOLIZATION Central access may be difficult in patients with congenital heart disease because of vein occlusion owing to previous long-term access lines or cardiac catheterization access. Central access in the internal jugular or subclavian veins is usually discouraged in patients who are progressing down the single ventricle pathway because of the risk of possible superior vena cava obstruction making the Fontan palliation problematic. In children with any right-to-left shunting, bubbles or clots introduced in the venous system risk traveling to the cerebral circulation, causing strokes. Intravenous lines should be meticulously cleared of air prior to infusion to prevent this potential problem, and indwelling lines should be heparinized.

FEEDING/GROWTH ISSUES Infants with congenital heart disease and pulmonary overcirculation have significantly increased caloric needs. Infants may require more than 160

Kcal/kg/day to grow with these increased metabolic demands. In addition, infants may be less able to tolerate normal feeding volumes due to tachypnea. Increased caloric density of feeds is usually required and tube feeding is sometimes required to assist these infants.

PREVENTION There have been studies showing a decrease in the incidence of congenital heart defects in infants of mothers taking multivitamins with folic acid during the periconceptual period compared to a similar group of mothers who did not take supplements. A case-control study in Atlanta showed a 24% decrease in the incidence of congenital heart disease,26 and a study in California had similar results. These studies are not definitive, but folate appears to be a reasonable preconceptual regimen, and the additional riskreduction of neural tube defects appears to make this recommendation compelling. Other than folate, there have been no other preventative measures identified that may decrease the risk of congenital heart disease. Fetal diagnosis may provide the option of termination for those defects with poor prognosis if the parents so choose. KEY POINTS The incidence of congenital heart disease is 0.8%, while the incidence of congenital heart disease requiring intervention is lower—about 3 to 4/1000. Nonetheless, congenital heart disease remains in the top 10 causes of death for children 2 positive cultures of blood samples drawn >12 h apart, or All of 3 or a majority of >4 separate blood cultures (with first and last samples drawn >1 h apart) Evidence of endocardial involvement Positive echocardiogram for IE defined as: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve New valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor Criteria Predisposition: predisposing heart condition or IV drug use Fever: temperature >38°C

Vascular phenomena: major arterial emboli, septic pulmonary infarct, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor Microbiologic evidence: positive blood culture that does not meet major criteria (see above) or serologic evidence of active infection with organism consistent with IE Echocardiographic findings: consistent with IE but do not meet major criteria (see above) Source: Reproduced with permission from Durack OT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-209. Copyright © Elsevier. *Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis. HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae.

TABLE 54-3

Clinical Criteria for the Diagnosis of Infective Endocarditis (IE)

Definite IE Pathologic criteria Microorganisms: demonstrated by culture or histology in a vegetation that has embolized or in an intracardiac abscess, or Pathologic lesions: vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis Clinical criteria (as defined in Table 54-2) 2 major criteria, or 1 major criterion and 3 minor criteria, or 5 minor criteria Possible IE Findings consistent with IE that fall short of “definite” but not “rejected” Rejected

Firm alternative diagnosis for manifestations of endocarditis, or Resolution of manifestations of endocarditis with antibiotic therapy for >4 days, or No pathologic evidence of IE at surgery or autopsy, after antibiotic therapy for >4 days Source: Reproduced with permission from Durack OT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-209. Copyright © Elsevier.

IMAGING Echocardiography with Doppler color flow mapping is the standard diagnostic modality in patients with suspected infective endocarditis. It can identify valvular vegetations (Figure 54-1) as well as impaired cardiac performance, prosthetic valve dehiscence, disturbed conduit flow, and abscess. Moreover, echocardiography can define the presence of an occult structural abnormality, such as a bicuspid aortic valve, thus identifying a clinically silent risk factor. It has been well established that echocardiography can detect cardiac involvement in patients with otherwise occult infective endocarditis,12 and this has been confirmed in children.13

FIGURE 54-1. Two-dimensional echocardiogram from a child with tricuspid valve vegetation (outlined). LA, left atrium; LV, left ventricle; MV, mitral valve; RA, right atrium; RV, right ventricle. For

most

infants

and

children,

unlike

adults,

transthoracic

echocardiography is usually sufficient to establish a diagnosis. In certain circumstances, however, transesophageal imaging is required, particularly in children with previous cardiothoracic surgical procedures, pulmonary problems that confound imaging windows, or substantial obesity. A transesophageal study may be superior, however, to detect paravalvar leakage or dehiscence, aortic root abscess development, and prosthetic valve endocarditis.14 Serial echocardiographic Doppler studies are also useful to gauge the response to therapy and assess for potential complications. For example, vegetation size and mobility may be an indicator of risk for embolization.14,15 Importantly, in a patient undergoing treatment for infective endocarditis, the diagnosis of myocardial abscess causing a new arrhythmia or progressive aortic root enlargement could suggest the need for a shift in treatment, including surgical intervention.

LABORATORY STUDIES Large-volume blood cultures are mandatory in all patients with suspected infective endocarditis. This includes any patient with a history of fever without an obvious explanation who has known heart disease or who has had endocarditis previously. Multiple cultures (three to five) are best, with 1- to 3-mL/culture in infants and 5- to 7-mL/culture in older children usually being sufficient. In children who have been on antibiotics, greater numbers of cultures over an extended period may be required. It is useful to notify the laboratory that infective endocarditis is suspected so that prolonged (>2 weeks) incubation of culture specimens will be done. Gram-negative rods (the HACEK [Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae] organisms), for example, are typically slowly growing organisms. In organisms successfully cultured, testing for antibiotic susceptibility is extremely important for clinical management. Measurement of the minimum inhibitory concentration of the particular antibiotic chosen is the standard guide to therapeutic efficacy. While the minimum bactericidal concentration is not usually employed, it may be of use in particular situations, based on the advice of an infectious disease specialist. Use of antibiotics may be delayed in selected patients who are not acutely ill, in order to obtain additional blood cultures if the initial set remain negative after preliminary incubation.2

Other laboratory markers of infection and inflammation can be useful, serially, as guides to therapy. Acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein) are usually elevated, and hypergammaglobulinemia may be noted. Rheumatoid factor may initially be elevated and can be followed as confirmation of response to therapy. Although the presence of leukocytosis (white blood cell count >15,000) is variable, increased segmented neutrophils or other immature forms (bands) are typical. Thrombocytopenia and mild anemia can be present. Abnormal liver function tests are less common without heart failure or hepatic emboli, but abnormalities in urinary sediment are frequently present. Hematuria may represent either an embolic process or glomerular nephritis. Signs of an immune complex nephritis can include proteinuria, red cell casts, and abnormal renal function measures, including creatinine and blood urea nitrogen. Low serum complement levels support the diagnosis of glomerular nephritis, but this is not definitive.

TREATMENT ANTIBIOTIC REGIMENS Owing to the tenacious nature of these infections, a prolonged course of parenteral antibiotics is required. Several factors contribute to the difficulty of eradicating the source of the infection. As described earlier, the microbial organisms are layered within elements of the vegetation, which sequesters them from the immune system and antibiotic exposure. Organisms with limited antibiotic susceptibilities may also require prolonged treatment for eradication. Tables 54-4 to 54-6 outline antibiotic regimens for childhood infective endocarditis in a variety of settings.2,16 TABLE 54-4

Treatment Regimens for Native Valve Infective Endocarditis Caused by Viridans Streptococci, Streptococcus bovis, or Enterococci Dosage (per

Organism Penicillinsusceptible streptococci (MIC ≤0.1 μg/mL)

Antimicrobial kg/24 Agent h)*

Frequency of Duration Administration (wk)

Penicillin G†

200,000 U IV

q4–6h

4

Ceftriaxone

100 mg IV

q24h

4

Penicillin G†

200,000 U IV

q4–6h

2

100 mg IV

q24h

2

Gentamicin

3 mg IM or IV

q8h‡

2

Penicillin G†

300,000 U IV

q4–6h

4

100 mg IV

q24h

4

3 mg IM or IV

q8h‡

2

300,000 U IV

q4–6h

4–6¶¶

or

or Ceftriaxone plus

Streptococci relatively resistant to penicillin (MIC>0.1– 0.5 μg/mL)

or Ceftriaxone plus Gentamicin

Enterococci,§ Penicillin G† nutritionally variant

viridans streptococci, or high-level penicillinresistant streptococci (MIC >0.5 μg/mL)

plus Gentamicin

3 mg IM or IV

q8h¶

4–6¶¶

Source: Reproduced with permission from Ferrieri P, Gewitz MH, Gerber MA, et al. Unique features of infective endocarditis in childhood. Circulation. 2002;105:2115-2127. © 2002 American Heart Association, Inc. *Dosages are for patients with normal renal and hepatic function. Maximum dosages per 24 h are as follows: penicillin, 18 million U; ampicillin, 12 g; ceftriaxone, 4 g; gentamicin, 240 mg. The 2-wk regimens are not recommended for patients with symptoms of infection lasting >3 mo, an extracardiac focus of infection, myocardial abscess, mycotic aneurysm, or infection with nutritionally variant viridans streptococci (Abiotrophia species). †Ampicillin

300 mg/kg per 24 h in 4–6 divided dosages may be used as alternative to

penicillin. ‡Studies

in adults suggest that the gentamicin dosage may be administered in single daily dose. If gentamicin is administered in 3 equally divided doses over 24 h, adjust the dosage to achieve peak and trough concentrations in serum of ≈3 and 1 g)

Source: Adapted with permission from Gewitz MH, Taubert KA. Infective endocarditis. In: Moller JH, Hoffman JIE, eds. Pediatric Cardiovascular Medicine. 2nd ed. Chichester, UK: Wiley-Blackwell; 2012. Copyright © 2012 Blackwell Publishing Ltd. *Single dose 30–60 min before procedure.

KEY POINTS The incidence of endocarditis is steady or increasing owing to increases in populations susceptible to the disease. Gram-positive bacteria represent the largest subgroup of causative organisms in infective endocarditis, although infections with gram-negative bacteria and fungi occur, especially in specific subgroups. Blood cultures and echocardiography with Doppler color flow mapping are the standard diagnostic modalities in patients with

suspected infective endocarditis; echocardiography is also used to assess the effectiveness of therapy. Complications of infective endocarditis can be severe and include mechanical obstruction by vegetations or emboli, cardiac dysfunction (including arrhythmias and heart block), and systemic infection.

ACKNOWLEDGMENTS The author appreciates the assistance of Ms. Patty Libby in the preparation of this chapter.

SUGGESTED READINGS Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2005;111:e394-e434. Day MD, Gauvreau K, Shulman S, et al. Characteristics of children hospitalized with infective endocarditis. Circulation. 2009;119:865-887. Gewitz MH. Infective endocarditis. In: Moller M, Hoffman JH, JIE, eds. Pediatric Cardiovascular Medicine. 3nd ed. Chichester, UK: WileyBlackwell; 2011. Wilson W, Taubert KA, Gewitz MH, Lockhart P, et al. Prevention of infective endocarditis. Guidelines the American Heart Association. Circulation. 2007:116:1736-1754.

REFERENCES 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2005;111:e394-434. 2. Baltimore RS, Gewitz MH, Baddour LM, et al. Infective endocarditis in childhood: 2015 update: a scientific statement from the American Heart Association. Circulation. 2015;132:1487-1515.

3. Morris CD, Reller MD, Menashe VD. Thirty year incidence of infective endocarditis after surgery for congenital heart defect. JAMA. 1998;279:599-603. 4. Stockheim JA, Chadwick EG, Kessler S, et al. Are the Duke criteria superior to Beth Israel criteria for diagnosis of infective endocarditis in children? Clin Infect Dis. 1998;27:1451-1456. 5. Tunkel AR, Scheld WM. Experimental models of endocarditis. In: Kaye D, ed. Infective Endocarditis. 2nd ed. New York, NY: Raven Press; 1992:3756. 6. Saiman L, Prince A, Gersony WM. Pediatric infective endocarditis in the modern era. J Pediatr. 1993;122:847-853. 7. Baddour LM, Bettmann MA, Bolger AF, et al. Nonvalvular cardiovascular device-related infections. Circulation. 2003;108:20152031. 8. Opie GF, Fraser SH, Drew JH, Drew S. Bacterial endocarditis in neonatal intensive care. J Paedtr Child Health. 1999;35:545-548. 9. Durack OT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-209. 10. Li JS, Sexton OJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633-638. 11. Del Pont JM, DeCicco LT, Vartalis C, et al. Infective endocarditis in children: clinical analysis and evaluation of two diagnostic criteria. Pediatr Infect Dis J. 1995;14:1079-1086. 12. Fowler VG, Li JS, Corey GR, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia. J Am Coll Cardiol. 1997;30:1072-1078. 13. Valente AM, Jain R, Scheurer M, et al. Frequency of infective endocarditis among infants and children with Staphylococcus aureus bacteremia. Pediatrics. 2005;115:e15-e19. 14. Barbour SI, Louoie ED, O’Keefe IP. Penetration of the atrioventricular septum by spread of infection from aortic valve endocarditis: early diagnosis by transesophageal echocardiography. Am Heart J.

1996;132:1287-1289. 15. DiSalvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37:1069-1076. 16. Ferrieri P, Gewitz MH, Gerber MA, et al. Unique features of infective endocarditis in childhood. Circulation. 2002;105:2115-2127. 17. Berkowitz FE. Infective endocarditis. In: Nichols DG, Cameron DE, Greeley WJ, et al., eds. Critical Heart Disease in Infants and Children. St Louis, MO: Mosby-Year Book; 1995;961-986. 18. Cobell CH, Lerakis S, Selton-Sutty C, et al. Cardiovascular risk factors and outcomes in patients with definite endocarditis: findings from 1024 patients in the ICE prospective cohort study [abstract]. Circulation. 2003;108:IV-432. 19. Stinson EB. Surgical treatment of infective endocarditis. Prog Cardiovasc Dis. 1979;22:145-168. 20. Shamszad P, Kahn MS, Rossano JW, et al. Early surgical therapy of infective endocarditis in children. J Thorac Cardiovasc Surg. 2013;146:1-6. 21. Strom BL, Abrutyn E, Berlin JA, et al. Risk factors for infective endocarditis: oral hygiene and nondental exposures. Circulation. 2000;102:2842-2848. 22. Wilson W, Taubert KA, Gewitz MH. Prevention of infective endocarditis. Circulation. 2007;116:1736-1754. 23. Gould FK, Elliott TSJ, Foweraker J, et al. Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2006;10:10931121.

CHAPTER

55

Myocarditis and Cardiomyopathy Robert N. Vincent, Margaret J. Strieper, and Kenneth J. Dooley

BACKGROUND Myocarditis is a pathologic process characterized by inflammation of the myocardium leading to cellular necrosis and myocardial dysfunction. Although often thought of as a viral or post-viral process, causes of myocarditis are numerous and include infectious (viral, bacterial, fungi, yeast, rickettsial, protozoal, and parasitic) as well as non-infectious (toxins, drugs, autoimmune diseases, and Kawasaki disease) etiologies. Cardiomyopathy is a general term referring to diseases of the myocardium. Clinically and pathologically, cardiomyopathy can be divided into dilated, hypertrophic, and restrictive types. As myocarditis is a precursor to and one of the causes of dilated cardiomyopathy, the two will be considered together.

DILATED CARDIOMYOPATHY CLINICAL PRESENTATION The presentation of a child with dilated cardiomyopathy (DCM) depends on the age of the patient and the acuteness of the illness. Aggressive acute viral myocarditis may present as cardiovascular collapse and cardiac arrest over a very short period of time. Other causes of DCM in general, and occasionally myocarditis as well, may have a more progressive subacute to chronic course. Unless the disease process progresses to the point of causing significant myocyte necrosis and myocardial dysfunction, clinical symptoms may be absent. A slow decrease in ventricular function over many months or years may go unnoticed, whereas a rapid drop in ventricular function over several

days may result in severe heart failure and cardiovascular collapse, as compensatory mechanisms have not set in. However, the chronic stable patient has little cardiac reserve, and therefore an unrelated illness such as an upper respiratory infection may result in cardiac decompensation. The history of an antecedent viral infection in the child presenting with a new-onset DCM may not herald the initiation of cardiac disease, as it is possible that the viral illness merely unmasked the chronic compensated form of DCM. The usual presentation of DCM is that of congestive heart failure and low cardiac output. Signs and symptoms of heart failure and low cardiac output in newborns and infants include fussiness, poor appetite, poor feeding, fever, listlessness, diaphoresis, and respiratory distress. Physical examination generally demonstrates a patient with tachypnea, tachycardia, cardiomegaly, and hepatomegaly with pallor or an ashen appearance. The older child and adolescent will generally have a history of a viral illness 7 to 14 days prior to presentation with myocarditis. Findings of poor appetite and abdominal pain due to hepatic congestion, lethargy, exercise intolerance, malaise, and fever may also be present. Findings of heart failure including jugular venous distention and rales as well as low cardiac output may be present on physical examination in an older child, whereas the findings of rales and jugular venous distention are often absent in the newborn and infant.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of DCM based on age is seen in Table 55-1. All attempts should be made to diagnose the treatable causes of cardiomyopathy such as structural heart disease, underlying arrhythmias, and vitamin deficiencies. Although structural heart defects and arrhythmias are not truly diseases of the myocardium, they are listed, as they may present similar to a DCM and must be considered in the evaluation of these children. TABLE 55-1

Differental Diagnosis of Dilated Cardiomyopathy Based on Age

Fetal AV malformation (vein of Galen) Myocarditis

Severe outflow obstruction Severe valve insufficiency Tachyarrhythmias Severe anemia (immune hydrops) Bradyarrhythmias (congenital complete heart block) Newborn–1 year old Myocarditis Endocardial fibroelastosis (EFE) Barth syndrome Carnitine deficiency Selenium deficiency Anomalous left coronary artery from pulmonary artery (ALCA) Kawasaki disease (KD) Critical aortic stenosis (AS) Supraventricular tachycardias (SVT) Arterio-venous malformation (especially vein of Galen) Calcium deficiency Hypoglycemia Left ventricular non-compaction Mitochondrial cardiomyopathy Nemaline myopathy Minicore-multicore Myopathy Myotubular myopathy 1–10 years old Familial dilated cardiomyopathy (FDCM) Barth syndrome Myocarditis Arrhythmogenic right ventricular dysplasia Endocardial fibroelastosis (EFE) Carnitine deficiency

Selenium deficiency Anomalous left coronary artery from pulmonary artery (ALCA) Kawasaki disease (KD) Supraventricular tachycardias (SVT) Toxic (adriamycin) β-ketothiolase deficiency Ipecac toxicity Systemic lupus erythematosus Polyarteritis nodosa Hemolytic–uremic syndrome Mitochondrial cardiomyopathy Nemaline myopathy Minicore-multicore myopathy Myotubular myopathy >10 years of age Familial dilated cardiomyopathy X-linked dilated cardiomyopathy (XLCM) Myocarditis Supraventricular tachycardia (SVT) Congenital heart disease (Ebstein’s, etc.) (CHD) Postoperative congenital heart disease (P/O CHD) Mitochondrial cardiomyopathy Chagas disease Arrhythmogenic right ventricular dysplasia (ARVD) Eosinophilic cardiomyopathy Adriamycin toxicity Pheochromocytoma Duchenne muscular dystrophy/Becker muscular dystrophy (DMB/BMD) Emery-Dreifuss muscular dystrophy (EDMD) Hemochromatosis

Limb-girdle muscular dystrophy Myotonic dystrophy Peripartum cardiomyopathy Alcoholic cardiomyopathy

DIAGNOSTIC EVALUATION Table 55-2 is a list of studies that may be performed in the evaluation of a patient with newly diagnosed DCM. The extent of evaluation will depend on initial findings of some of the more specific tests and history (e.g. a history of adriamycin administration or cocaine abuse likely point to the etiology). When identifiable causes are excluded or point to a familial or inherited disorder, family screening becomes important. TABLE 55-2

Evaluation of Newly Diagnosed Dilated Cardiomyopathy

• Chest x-ray • ECG • Echocardiogram (including relatives and tissue Doppler imaging) • Urine Organic acids including 3-methylglutaconic acid UA Amino acids • Blood Lactic acid Pyruvate SMA-7 Glucose Ca2+ Mg2+ Selenium CBC with diff

CPK (MM, MB, total) Troponin T or I Liver function studies Carnitine Acylcarnitine profile Cholesterol Thyroid function studies Plasma for amino acids ESR Viral serologies including adenovirus Cytogenetics • Skeletal muscle biopsy Histology EM Mitochondrial respiratory chain analysis, acyl CoA DH analysis • Endomyocardial biopsy (with hemodynamic catheterization and angiographic evaluation of structural lesions) Histology EM PCR for vital genome Mitochondrial respiratory chain analysis • Blood for cell lines Genetics consultation to include comprehensive metabolic/enzymatic evaluation Strong consideration of drawing all transplant labs particularly before administration of IV gamma globulin Chest X-Ray A chest x-ray is often the first test done and is often performed for reasons other than suspicion of cardiomyopathy. Radiography demonstrates cardiomegaly and increased pulmonary venous markings with or without pulmonary edema or pleural effusion. The chest x-ray is often ordered because the child presents with some degree of respiratory distress.

Electrocardiogram The electrocardiogram (ECG) is usually nonspecific but may show decreased QRS voltages and low voltage or inverted T waves in myocarditis. Q waves in lead I and aVL due to myocardial infarct are very suspicious of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). Ectopic beats should raise the suspicion of poorly controlled supraventricular tachycardia or ventricular arrhythmias, although in severe cardiac dysfunction, ventricular arrhythmias may occur secondary to the myocardial disease. Echocardiogram The echocardiogram establishes the diagnosis of a dilated poorly contracting left ventricle (Figure 55-1A, 1B), while at the same time should exclude all structural causes of left ventricular (LV) dysfunction (LV outflow tract obstruction and anomalous origin of the left coronary artery). Structural and treatable anomalies that cannot be excluded with certainty, such as ALCAPA, require further diagnostic testing. Although ventricular dysfunction is usually in the form of global hypokinesis, segmental wall motion abnormalities may be present. The evaluation should also search for the presence of a thrombus in the left atrium or ventricle (Figure 55-1C).

FIGURE 55-1. A. Two-dimensional echocardiogram and color Doppler of a patient with DCM, demonstrating a dilated LV cavity and

mitral regurgitation. B. M-mode echocardiogram demonstrating a dilated LV cavity and poor systolic function (shortening fraction 15%, ejection fraction 28%). C. Two-dimensional echocardiogram demonstrating a large thrombus in the apex of the left ventricle. Pericardial and pleural effusions are not uncommon, and Doppler cardiography will often demonstrate mitral as well as tricuspid insufficiency. Right ventricular (RV) size and function may be spared early on but the RV may also dilate and demonstrate poor contractility as well. There may be secondary pulmonary hypertension arising from LV dysfunction. Doppler interrogation of the tricuspid regurgitation jet provides quantitation of RV systolic pressure. Cardiac Catheterization Catheterization is rarely undertaken as a diagnostic test unless it is utilized to obtain baseline hemodynamics, perform an endomyocardial biopsy, or exclude structural disease not eliminated by echocardiography. Baseline hemodynamics are useful in evaluating right and LV filling pressures as a prognostic sign, even if only for the short term. Patients with poor ventricular function and low biventricular filling pressures usually respond well to medication symptomatically, even if they do not improve echocardiographically. Patients with extremely elevated biventricular filling pressures are less likely to do well over the short term. Endomyocardial biopsy was previously used to make the diagnosis of myocarditis. A positive biopsy using the Dallas criteria1 had been used to establish the diagnosis (although a negative biopsy did not exclude it), but the Dallas criteria are limited by variability of interpretation and low sensitivity.2,3 Newer criteria based on immunoperoxidase staining seem to have greater sensitivity,4 as does testing the sample for viral genomes (PCR test).5 As myocarditis is a patchy non-homogenous infiltrate, it may be missed on random sampling of the right ventricle. Because the procedure is not without complication, especially in infants and young children, obtaining numerous samples to get a power value to diagnose 80% of myocarditis cases (17 samples) is unquestionably too dangerous and generally not performed to this extent.3 Currently, endomyocardial biopsy is considered on the basis of the likelihood of finding a specific treatable disorder6 (e.g. giant cell myocarditis).

MANAGEMENT Viral myocarditis may rapidly deteriorate, follow a chronic course, or have progressive resolution. The old adage of a third, a third, and a third for those who get worse, stay the same, or get better still holds fairly true today. Patients with dilated cardiomyopathy of familial, idiopathic, or untreatable etiologies may have some improvement in LV function as well as symptomatology with medical therapy, but generally have a progressive deterioration over many years or may deteriorate rapidly to the point that medical therapy is no longer effective. Medical Therapy Acute medical therapy consists of sympathomimetic inotropic agents, often dobutamine (5–10 μg/kg/min) and if necessary dopamine (3–10 μg/kg/min) for maintenance of blood pressure. Practitioners try to avoid higher doses due to the negative effect on myocardial oxygen consumption and wall stress in the already decompensated heart. Patients requiring more support should be considered for mechanical support. Epinephrine is not used unless the child is in cardiovascular shock and the other medications are not effective at maintaining heart rate and blood pressure. For chronic oral inotropic therapy, digoxin is used (10 μg/kg/day divided BID, maximum starting dose 250 μg/day). Vasodilation with milrinone and/or nesiritide is used in virtually all patients in the acute setting. Milrinone is a positive inotropic agent with vasodilatory and lusitropic effects (positive lusitropic effects are a more rapid phase of myocardial relaxation).7 The pharmacologic effect is seen rapidly with an initial loading infusion but also within 30 minutes of starting a continuous infusion without a loading dose.7 The infusion dose is 0.25 to 1.0 μg/kg/min with or without a loading dose of 50 μg/kg. Nesiritide, a brain (Btype) natriuretic peptide, has been shown to cause arterial and venous dilation, enhanced sodium excretion, and suppression of the reninangiotensin-aldosterone and sympathic nervous systems.8 Although early reports demonstrated efficacy in the treatment of heart failure in adults8,9 and preliminary evidence had been favorable in pediatric patients,10 it is not commonly used in pediatric centers as there has been little evidence to support improvement over milrinone. It is administered as a bolus infusion of 1 μg/kg followed by a continuous infusion of 0.01 to 0.03 μg/kg/min. The lower dose is usually adequate. For chronic oral therapy, angiotensin-

converting enzyme (ACE) inhibitors are recommended in adults and children with heart failure.11,12 The use of beta-blocking agents with their negative inotropic effects for the treatment of heart failure seems paradoxical. However, numerous wellcontrolled studies have demonstrated the effectiveness of beta-blocker therapy in reducing symptoms and improving survival when added to ACE inhibitors in adults.13,14 Beta blockade in the intensive care unit is usually carried out with esmolol (50–250 μg/kg/min for heart failure, higher for supraventricular tachycardia), as it has a very short half-life. Chronic oral therapy is beneficial for children as well as adults.13-16 One of the newest agents to gain widespread acceptance is carvedilol. It is a nonselective thirdgeneration beta-blocking as well as alpha-adrenergic blocking agent, giving it vasodilatory properties as well.17 In addition to improving LV systolic performance, it also improves diastolic filling.18 A recent study in adults was stopped because there was a clear survival advantage in the carvedilol-treated group.13,19 A double-blind placebo-controlled study in children failed to show efficacy, however, likely due to the small number of patients.20 Nevertheless, based on the experience in adults as well as improvement in aspects of LV function in the above study, many cardiology practices are using carvedilol in infants and children.16,17,20-22 Diuretics are used for symptoms of pulmonary and hepatic congestion. Routine intravenous or oral doses of furosemide, chlorothiazide, bumetanide (and any other preferred diuretic) are used in combination with sodium and fluid restriction when appropriate. Spironolactone, an aldosterone antagonist and weak diuretic with potassium sparing properties also has benefits in reducing mortality and morbidity in heart failure patients.23,24 When used with ACE inhibitors, which also cause potassium retention, serum potassium should be monitored carefully. With severe LV dysfunction, anticoagulation with heparin or coumadin is indicated. Mechanical Therapy In patients with progressive deterioration, there should be consideration for mechanical ventricular assistance in the younger patient, including intubation and ventilation, intra-aortic balloon pump, left ventricular and biventricular assist devices (LVAD or BiVAD), or extracorporeal membrane oxygenation (ECMO). Patients requiring mechanical support and not improving should be considered for cardiac

transplantation. Institution of ventricular assist therapy may lead to cardiac recovery. In children presenting with suspected acute fulminant myocarditis, 80% who required mechanical circulatory assistance survived (they either weaned from support or bridged to transplant).25 Recovery after ventricular mechanical assist therapy has also been reported in non-myocarditis DCM, and new initiatives of immunoadsorption therapy to remove autoimmune antibodies and cytokines may prove beneficial in postponing or avoiding heart transplantation.26 Immunosupression As the cellular inflammation in myocarditis resembles that seen in cardiac transplant rejection, physicians have hypothesized that immunosuppression in myocarditis might be beneficial. Experimental results in murine myocarditis have been mixed.27-29 Despite numerous case reports on the treatment of myocarditis with immunosuppression, including steroids, cyclosporine, azothiaprine, and OKT3, there is no longitudinal data to support this form of therapy. In a randomized adult trial using steroids with either cyclosporin or azathioprine in patients with biopsy-proven myocarditis, there was no benefit in the treated group.30 However, based on a small study which did not reach clinical significance,31 many pediatric centers adhere to the concept that intravenous gamma globulin (IVIG) has a benefit and routinely use it (1–2 g/kg over 12– 24 h). If this is to be used and the child may require cardiac transplantation, all transplant labs should be drawn before the IVIG is given. For noninfectious myocarditis, specifically autoimmune disease, immunosuppression may be of benefit.32

ADMISSION AND DISCHARGE CRITERIA Admission A symptomatic patient with a new diagnosis of DCM and poor LV function should be admitted to hospital for medical therapy and observation until the course of the illness can be established. Admission to an intensive care unit for observation and therapy is recommended until an idea of the course of the illness can be established. Those treated with intravenous medications who are stable for 48 hours can often be switched to oral medications, whereas those who are going to rapidly deteriorate are best off in an ICU setting where further therapy is easily at hand. For patients who are fairly stable with abnormal but reasonable ventricular function, observation in

a non-ICU setting can be considered. Discharge Patients who remain stable in the hospital and can be switched to oral medication are ready for discharge. Newborns and infants must be able to feed and show adequate caloric intake with minimal symptoms of congestive heart failure. The older child and adolescent should be ambulatory and stable for several days on chronic medication. They should be arrhythmia free or have a stable arrhythmia on or off antiarrhythmic therapy.

HYPERTROPHIC CARDIOMYOPATHY BACKGROUND Hypertrophic cardiomyopathy (HCM) is a heterogeneous, familial disorder of cardiac muscle that affects sarcomeric proteins, resulting in myocyte and myofibrillar disorganization and fibrosis. HCM has an autosomal dominant pattern of inheritance, although morphologic evidence of disease may be absent in 20% of carriers.33-39 Mutations in any of 11 or more genes that code for sarcomeric proteins may result in HCM; some mutations are relatively benign, whereas others are associated with early death.40

PATHOPHYSIOLOGY Although various parts of the ventricle can undergo myocytic hypertrophy, involvement of the anterior ventricular septum is the most common pattern, accounting for more than 80% of cases of HCM. Characteristically, this results in a stiff left ventricle with impaired diastolic filling, which may lead to left atrial enlargement and pulmonary venous engorgement, producing congestive symptoms.41 In addition, the cellular disarray and hypertrophy can cause electrical instability and arrhythmias. About 25% of patients with HCM develop outflow tract obstruction when there is systolic anterior motion of the mitral valve against the hypertrophied ventricular septum. In this situation, outflow obstruction increases with high outflow velocities. Thus lowered systemic vascular resistance or hypovolemia may increase the obstruction, whereas interventions such as intravascular volume expansion or increased systemic vascular resistance may lessen the obstruction. Young children may also demonstrate fixed RV

outflow tract obstruction. Changes also occur in the coronary arteries, such as thickening of the walls with collagen in the intimal and medial areas.41 Mismatch between myocardial mass and coronary circulation leads to episodes of ischemia, cell death, and replacement with scar tissue.

CLINICAL PRESENTATION Common features associated with HCM can be traced to the pathologic changes. Chest pain may result from impairment of myocardial perfusion. Arrhythmias can cause palpitations, syncope, or sudden death. Left-sided failure produces dyspnea and exercise intolerance. Syncope with exercise has a high correlation with disease severity. Patients may also present with the onset of a new murmur (usually a medium-pitched systolic ejection murmur). Many asymptomatic patients are found on screening after identification of a family member with HCM. The estimated overall annual mortality is 1% when HCM is diagnosed in adults;40 it is higher (2%) in children and adolescents.40 Sudden death is more common in children than in adults, and risk is highest if HCM is diagnosed before 1 year of age.

DIFFERENTIAL DIAGNOSIS Patients presenting with hypertrophic cardiomyopathy in infancy should be evaluated for metabolic disorders and syndromes associated with HCM, such as Noonan syndrome, Pompe disease, and mitochondrial myopathies. The treatment and prognosis for these are different than for those with sarcomeric hypertrophic cardiomyopathy.

DIAGNOSTIC EVALUATION The 12-lead ECG is abnormal in 90% to 95% of patients with HCM,42 but the changes are not specific to this disorder. Common abnormalities include increased R-wave voltages in V5 and V6 and abnormal T waves and Q waves in the lateral precordial leads due to septal hypertrophy. Young children with subpulmonic obstruction may demonstrate changes of RV hypertrophy.

Abnormal ECG findings may be present before diagnostic echocardiographic features. Echocardiography can reveal abnormal hypertrophic areas of the myocardium as well as define outflow tract obstruction and abnormalities of systolic and diastolic function. Up to 40% of carriers may not have diagnostic criteria until later in life. Hypertrophic cardiomyopathy is a progressive disorder and patients will need lifelong follow-up. For individuals with a positive family history, screening and follow-up screening are recommended depending on the age of the patient. If the ECG and echocardiogram are normal, follow-up is recommended every 3 to 5 years if they are less than 12 years of age.43 In children aged 12 to 21, screening is recommended every 12 to 18 months, because this is the age group in which the disease progression occurs at an accelerated rate.

MANAGEMENT The goals of treatment include relief of symptoms, control of complications, and prevention of sudden death. Implantable defibrillators are the only treatment strategy that has been proven to alter the natural history of HCM.44 Beta-blockers reduce LV contractility and heart rate and therefore myocardial wall stress, oxygen requirements, and outflow gradients, all of which may improve symptoms of chest pain and pulmonary congestion.45 Verapamil, a calcium channel–blocking agent, has been demonstrated to improve exercise capacity in adults with or without obstruction.46 There is no evidence that the combined use of a beta-blocker and verapamil is better than either alone, and there are no data to support medical therapy of asymptomatic individuals to prevent congestive symptoms or obstruction. Relief of LV outflow obstruction is indicated in symptomatic patients with significant obstruction (gradient >50 mmHg). The most common procedure performed is surgical myotomy-myectomy, which involves resection of the basal septum.47 Although relief of obstruction results in symptomatic improvement in 70% of patients, it does not prolong life and therefore should not be performed in asymptomatic or mildly symptomatic individuals.45 Attempts have been made to relieve outflow tract obstruction by changing the pattern of ventricular contraction through dual-chamber pacing,48-50 and more recently, radiofrequency ablation. Alcohol septal

ablation is effective in reducing the outflow gradient in adults by causing a myocardial infarct in the septum.51 However, the scar it produces may be proarrhythmogenic, and this procedure is not recommended in children. Atrial fibrillation occurs in 20% to 25% of patients (usually adults) and is associated with left atrial enlargement. Treatment includes pharmacologic rate control, cardioversion, and anticoagulation to prevent complications, which include stroke and heart failure. Sudden death is often the first symptom of HCM, and HCM is the most common cause of sudden death in children and adolescents.41 It is thought to be due to ventricular arrhythmia. Sudden death is rare before age 10 years, and in teens it most commonly occurs with exercise. Any patient with the diagnosis of hypertrophic cardiomyopathy (phenotype positive) should be disqualified from competitive sports.43 Insertion of an implantable cardioverter defibrillator is recommended for those who are thought to be high risk (Table 55-3).44,45 Infrequently, patients may develop end-stage HCM; the cardiac muscle can become “burned out,” resulting in DCM. In this case, it is managed as outlined in the previous section. TABLE 55-3

Risk Factors for Sudden Death in Hypertrophic Cardiomyopathy

Definite Family history of premature HCM-related sudden death Prior cardiac arrest or spontaneous occurring and sustained ventricular tachycardia Identification of a high-risk genotype Syncope or near syncope (non-neurocardiogenic), particularly recurrent and exercise related Multiple episodes of non-sustained ventricular tachycardia (Holter) Abnormal blood pressure response with exercise LV wall thickness > 30 mm Possible Tunneled left anterior descending coronary artery in children (consider surgical unroofing)

Outflow gradient > 50 mmHg

CONSULTATION A pediatric cardiologist should be involved with the evaluation and management of children with suspected or confirmed HCM. First-degree family members of patients with HCM should be referred for outpatient evaluation.52

ADMISSION AND DISCHARGE CRITERIA Hospitalization post cardiac arrest is necessary to establish cardiovascular stability and for full evaluation. Most other patients can be evaluated as outpatients. The evaluation would include exam, ECG, echocardiogram, stress testing for exercise tolerance, cardiac MRI to evaluate for delayed gadolinium enhancement that would suggest scar tissue and the nidus for possible arrhythmia initiation.53 If a patient with known HCM is admitted for a non-cardiac procedure and sedation or general anesthesia is necessary, the patient should not be allowed to become intravascular-depleted, and an IV for fluids should be started early if there is a wait for the procedure. Anesthesia should be aware of the diagnosis and should use sedatives that do not decrease the systemic vascular resistance, as the LV outflow tract gradient will increase and cardiac output will decrease. Discharge is appropriate when the patient has demonstrated clinical stability and outpatient follow-up has been established.

RESTRICTIVE CARDIOMYOPATHY BACKGROUND Restrictive cardiomyopathy is the least common form of cardiomyopathy. Patients with restrictive cardiomyopathy have abnormal diastolic function as the noncompliant ventricular myocardium impedes ventricular filling, resulting in decreased cardiac output. Normal activity is not affected, but exercise reveals shortness of breath and fatigue. Systolic function is relatively unimpaired.

CLINICAL PRESENTATION Early on, patients with restrictive cardiomyopathy are asymptomatic. With advanced disease, exercise intolerance is a frequent complaint caused by an inability to increase cardiac output during exercise.54 Weakness and shortness of breath are common, and chest pain occasionally occurs.55 In advanced cases, signs of right heart failure may be evident, with elevated central venous pressure, peripheral edema, ascites, and anasarca. On physical examination, jugular venous distention that doesn’t change with inspiration, along with an S3 or S4 gallop, may be present; occasionally, systolic murmurs of AV valve insufficiency may be heard. The liver is often enlarged and rales are present secondary to pulmonary edema.

DIFFERENTIAL DIAGNOSIS Causes of restrictive cardiomyopathy are summarized in Table 55-4. An important entity with a remarkably similar presentation is constrictive pericarditis. This is a treatable condition that is managed with surgical removal of the pericardium. Although rare, autosomal dominant genetic forms with variable penetrance exist. Five generations of one family demonstrated restrictive cardiomyopathy associated with heart block and muscular weakness. Recently, studies have identified several genes associated with this disorder. These include TNNI3 (associated with defective cardiac troponin I, and affecting the cardiac protein complex and restricting relaxation), ACTC1 (coding the actin link), MYH7 (coding the myosin link) and TNNT2 (associated with myosin binding). Phenotypic association with identified gene abnormality has been found in between 30% and 60% of patients.56 TABLE 55-4

Causes of Restrictive Cardiomyopathy

• Idiopathic • Endomyocardial fibrosis (endemic in parts of Africa, India, South and Central America, and Asia) • Loefflers disease (eosinophilia syndrome) • Infiltrative disorders (amyloidosis, hemochromatosis, sarcoidosis, carcinoid syndrome, and systemic sclerosis)

• Treatment-induced (radiation therapy to the chest, anthracycline cardiotoxicity) • Malignant (metastatic tumors)

DIAGNOSTIC EVALUATION A 12-lead ECG often shows evidence of left and right atrial enlargement, which occurs secondary to high diastolic pressures within the stiff ventricles. Echocardiogram characteristically demonstrates enlarged left and right atria with normal ventricular systolic function and decreased diastolic function due to ventricular wall noncompliance. AV valve flow velocity is increased. In cases of infiltrative disease, ventricular walls maybe thickened. Chest x-ray reveals a normal to slightly increased heart size, occasionally with evidence of atrial enlargement. The lungs may show signs of pulmonary edema and pleural effusion. Additional studies may include CT, MRI, urine and serum protein level, complete metabolic panel, iron studies, CBC (eosinophilia), and BNP (which is elevated in restrictive cardiomyopathy but not in constrictive pericarditis). Catheterization defines the hemodynamics and helps differentiate restrictive from constrictive disease. Characteristic hemodynamic findings at cardiac catheterization include a deep and rapid early decline in ventricular pressure at the onset of diastole, with a rise to a plateau phase (the square root sign) similar to that seen in constrictive pericarditis.57 Both left and right atrial pressures are elevated, although the left atrial pressure is generally higher than the right; in contrast, in constrictive pericarditis, the right and left atrial pressures are usually identical.55 Endomyocardial biopsy is useful in evaluating patients with restrictive cardiomyopathy due to amyloidosis and other specific causes (e.g. metabolic storage disease such as glycogen storage, hemochromatosis, or sarcoidosis).58 Findings of fibrosis in the absence of other specific causes suggests the diagnosis of restrictive disease; however, a normal biopsy does not exclude it.

MANAGEMENT Once restrictive cardiomyopathy becomes symptomatic, it is usually

progressive. Occasionally, the disease process can be slowed with treatment, especially if the underlying cause can be determined and is amenable to therapy. For example, for patients with hemochromatosis, therapy aimed at iron binding may be beneficial to slow ongoing iron deposition and resultant damage to the myocardium. Symptomatic treatment generally involves the use of diuretics to treat high atrial pressures and the congestive symptoms they cause. The diastolic relaxing effects of carvedilol may offer some therapeutic benefit. Vasodilators may be used, but monitoring for hypotension is vital. As the disease progresses, AV valve regurgitation will occur due to fibrosis of the valves. Fibrosis may also involve the sinus and AV nodes, leading to arrhythmias possibly requiring insertion of a pacemaker. Dilatation of the atria may also lead to atrial fibrillation requiring arrhythmia management. Heart rate must be maintained at a rate slow enough to allow maximal ventricular filling. Outlook for survival is 9 years after diagnosis. Eventually, cardiac transplantation may be required.

SUGGESTED READINGS Maron BJ, Wolfson JK, Epstein SE, et al. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1986;8:545-557. Tanaka M, Fujiwara H, Onodera T, et al. Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation. 1987;75:11301139.

REFERENCES 1. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis: a histopathologic definition and classification. Am J Cardiol. 1978;41:887-892. 2. Grogan M, Redfield MM, Bailey KR, et al. Long-term outcome of patients with biopsy-proven myocarditis: comparison with idiopathic

dialted cardiomyopathy. J Am Coll Cardiol. 1995;26:80-84. 3. Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol. 1989;14:915-920. 4. Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation. 2006;113:593-535. 5. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis: rapid diagnosis by PCR in children. Circulation. 1994;90:330-333. 6. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation. 2007;116:2216-2233. 7. Baruch L, Patacsil P, Hameed A, Pina I, Loh E. Pharmacodynamic effects of milrinone with and without a bolus loading infusion. Am Heart J. 2001;191 (2):266-273. 8. Colucci W, Elkayam U, Horton D, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343:246-253. 9. Silver MA, Horton D, Ghali J, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol. 2002;39:798803. 10. Marshall J, Berkenbosch J, Russo P, Tobias J. Preliminary experience with nesiritide in the pediatric population. J Int Care Med. 2004;19:164170. 11. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Circulation. 2001;104:2996-3007. 12. Lewis AB, Chabot M. The effect of treatment with angiotensinconverting enzyme inhibitors on survival of pediatric patients with

dilated cardiomyopathy. Pediatr Cardiol. 1993;14(1):9-12. 13. Yancy CW. Clinical trials of β-blockers in heart failure: a class review. Am J Med. 2001;110(5A):7S-10S. 14. Packer M. β-Blockade in heart failure: basic concepts and clinical results. AJH. 1998;11:23S-37S. 15. Shaddy R, Tani L, Gidding S, et al. Beta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children: a multiinstitutional experience. J Heart Lung Transplant. 1999;18:269-274. 16. Williams R, Tani L, Shaddy R. Intermediate effects of treatment with metoprolol or carvedilol in children with left ventricular systolic dysfunction. J Heart Lung Transplant. 2002;21:906-909. 17. Azeka E, Ramires JA, Valler C, Bocchi E. Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment. J Am Coll Cardiol. 2002;40:2034-2038. 18. Palazzuoli A, Carrera A, Calabria P, et al. Effects of carvedilol therapy on restrictive diastolic filling pattern in chronic heart failure. Am Heart J. 2004;147(1):E2. 19. Packer M. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Trial). Data presented at 22nd Congress of the European Society of Cardiology, Amsterdam, August 2000. 20. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298:1171-1179. 21. Giardini A, Formigar R, Bronzetti G, et al. Modulation of neurohormonal activity after treatment of children in heart failure with carvedilol. Cardiol Young. 2003;13(4):333-336. 22. Bruns L, Chrisant MK, Lamour J, et al. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. J Pediatr. 2001;138:505-511. 23. Rousseau M, Gurne O, Duprez D, et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure. J Am Coll Cardiol. 2002;40:1596-1601. 24. Pitt B, Zannad F, Remme J, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J

Med. 1999;341:709-717. 25. Duncan B, Bohn D, Atz A, et al. Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg. 2001;122:440-448. 26. Matoba Y, Okubo H, Nose Y. Therapeutic left ventricular assist device and apheresis on dilated cardiomyopathy. Artif Organs. 2004;28(2):171181. 27. Yokoyama T, Kanda T, Suzuki T, et al. Effects of lobenzarit on murine acute viral myocarditis. Cardiovasc Drugs Ther. 1992;6(4):403-407. 28. Takada H, Kishimoto C, Kuroki Y, et al. Effects of lobenzarit disodium, a novel immonomodulator, upon murine coxsackievirus B3 myocarditis. Heart Vessels. 1993;8(2):59-66. 29. Sato Y, Maruyama S, Kawai C, et al. Effect of immunostimulant therapy on acute viral myocarditis in an animal model. Am Heart J. 1992;124(2):428-434. 30. Mason J, O’Connell J, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med. 1995;333:269-275. 31. Druker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation. 1994;5(1):6569. 32. Noutsias M, Pauschinger M, Poller WC, et al. Immunomodulatory treatment strategies in inflammatory cardiomyopathy: current status and future perspectives. Expert Rev Cardiovasc Ther. 2004;2(1):37-51. 33. Thierfelder L, Watkins H, MacRae C, et al. α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701-702. 34. Charron P, Dubourg O, Desnos M, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation. 1998;97:22302236. 35. Coviello DA, Maron BJ, Spirito P, et al. Clinical features of hypertrophic cardiomyopathy caused by “hot spot” in the alpha tropomyosin gene. J Am Coll Cardiol. 1997;29:635-640.

36. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for human cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248-1257. 37. Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and α-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995;332:1058-1064. 38. Moolman JC, Corfield VA, Posen B, et al. Sudden death due to troponin T mutations. J Am Coll Cardiol. 1997;29:549-555. 39. Morgensen J, Klausen IbV, Pedersen AK, et al. α-Cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest. 1999;103:R39-R43. 40. Decker JA, Rossano JW, Smith EO, et al. Risk factors and mode of death in isolated hypertrophic cardiomyopathy in children. J Amer Coll Card. 2009;54:250-254. 41. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381:242-255. 42. Charron P, Dubourg O, Desnos M, et al. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation. 1997;96:214-219. 43. Maron BJ, McKenna WJ. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;42(9):1-27. 44. Maron BJ, Shen WK, Link MS, et al. Efficacy of the implantable cardioverter-defibrillator for the prevention of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365-373. 45. Maron BJ, Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation. 2010;121:445-456. 46. Rosing DR, Condit JR, Maron BJ, et al. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. III: effects of long-term administration. Am J Cardiol. 1981;48:545-553. 47. Morrow AG, Reitz BA, Epstein SE, et al. Operative treatment in

hypertrophic subaortic stenosis: techniques and the results of pre- and postoperative assessments in 83 patients. Circulation. 1975;52:88-102. 48. Nishimura RA, Trusty JM, Hayes DL, et al. Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, doubleblind cross-over study. J Am Coll Cardiol. 1997;29:435-441. 49. Maron BJ, Nishimura RA, McKenna WJ, et al. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a double-blind cross-over study (M-PATHY). Circulation. 1999;99:29272933. 50. Linde C, Gadler F, Kappenberger L, et al. Placebo effect of pacemaker implantation in obstructive hypertrophic cardiomyopathy. Am J Cardiol. 1999;83:903-907. 51. Seggewiss H, Gleichmann U, Faber L, et al. Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: acute results and 3-month follow-up in 25 patients. J Am Coll Cardiol. 1998;31:252-258. 52. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54:201-211. 53. Maron MS, Maron BJ, Harrigan C, et al. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol. 2009;54:220-228. 54. Oakley CM. Clinical recognition of the cardiomyopathies. Circ Res. 1974;34/35(Suppl):11. 55. Meaney E, Habetai R, Bhargava V, et al. Cardiac amyloidosis, constrictive pericarditis and restrictive cardiomyopathy. Am J Cardiol. 1978;38:547. 56. Bahl A, Saikia UN, Khullar M. Idiopathic restrictive cardiomyopathy – perspective from genetics studies. Is it time to redefine these disorders. Cardiogenetics. 2012;2:e4. 57. Hansen AT, Eskildsen P, Gotzsche H. Pressure curves from the right auricle and right ventricle in chronic constrictive pericarditis. Circulation. 1951;3:881.

58. Schoenfield MH, Supple EW, Dec GW Jr, Fallon JT, Palacios IF. Restrictive cardiomyopathy versus constrictive pericarditis: role of endomyocardial biopsy in avoiding unnecessary thoracotomy. Circulation. 1987;75:1012.

CHAPTER

56

Pericarditis Nicole Sutton

BACKGROUND/PATHOPHYSIOLOGY Pericarditis is an inflammation of the pericardium, a two-layered structure that surrounds the heart. The inner layer adheres to the heart. There is usually about 15 to 35 mL of serous fluid in the pericardial space. This fluid provides lubrication during the contraction of the heart. The pericardial sac functions as a barrier to protect the heart from infection from the lungs, fix the heart to the mediastinum, prevent extreme dilation of the heart, equalize compliance between the right and left sides of the heart, and reduce friction between the heart and the surrounding structures. Pericarditis can be acute or chronic, and has a variety of causes.

CLINICAL PRESENTATION Pericarditis can present along a wide spectrum of symptoms ranging from mild chest pain to severe cardiovascular compromise and shock, depending on the size of the effusion and the rate at which it accumulates. However, there are features that are common to most cases. Acute pericarditis typically presents with fever, tachypnea, and chest pain. However, in studies of patients presenting to the emergency department with chest pain, the vast majority of patients do not have pericarditis.1 The chest pain is located in the midsternal or left precordial region, occasionally radiates to the left shoulder, has a sharp or stabbing quality, and is positional, increased when the patient is supine and less intense when the patient is sitting or leaning forward. The chest pain may get worse with inspiration. Some patients with acute pericarditis will report abdominal pain, either isolated or with chest pain. On physical examination, patients may be tachpneic and tachycardic.

Patients with a small or moderate pericardial effusion may have a pericardial friction rub, a high-pitched sound commonly described as crinkling paper or rubbing two pieces of sandpaper together. This sound is best heard over the third to fourth left intercostal interspace with the patient sitting, leaning forward in expiration. Patients with large effusions do not have a rub because the pericardial and epicardial surfaces do not contact each other. Patients with large effusions can also have pallor, altered mental status, hypotension, narrowed pulse pressure, distant muffled heart sounds, jugular venous distension, prolonged capillary refill, and hepatomegaly. Increased pulsus paradoxus is an early sign of cardiac tamponade (Figure 56-1). There is normally a change in the blood pressure during the respiratory cycle and this is exaggerated in cardiac tamponade. With inspiration, there is increased filling of the right atrium and increased capacity in the pulmonary vascular bed, resulting in decreased left-sided filling and decreased cardiac output. Clinically this produces a difference in systolic blood pressure during inspiration and expiration that is normally 10 mmHg. To check for pulsus paradoxus, the patient should be seated comfortably and the blood pressure checked manually on the brachial artery. The cuff pressure should be released until the first Korotkoff sound is heard only during expiration. Once this systolic pressure is noted, the cuff pressure should be lowered until the first Korotkoff sound is heard throughout the respiratory cycle; the difference between these two systolic pressures represents the pulsus paradoxus. Patients with pericarditis can develop tamponade with a variable amount of pericardial fluid; the faster the fluid accumulates, the lower volume that is necessary to cause tamponade. If the fluid collection increases very slowly, a larger volume of fluid can accumulate without signs of tamponade.

FIGURE 56-1. Physiology of pulsus paradoxus (IV interventricular). (Reprinted with permission from Spodick DH. The Pericardium: A Comprehensive Textbook. New York: Marcel Dekker; 1996:193. Copyright © Taylor and Francis, LLC.) The history and presentation provide clues to the cause of pericarditis. Viral pericarditis generally is associated with a history of a viral upper respiratory infection or gastroenteritis 10 days to 2 weeks before presentation with symptoms of pericarditis. Patients with purulent pericarditis present with a more acute course and generally appear toxic. These patients may present with signs of another infection such as pneumonia. It is important to remember that purulent pericarditis can develop in a patient who is being treated for another infection. If there is a worsening of the patient’s condition with an enlarged heart size on chest radiography, pericarditis should be suspected. Patients who are immune-compromised may present with purulent pericarditis from an opportunistic infection, such as fungus or tuberculosis. In patients with symptoms of pericarditis, a history of collagen vascular disease or a history of symptoms consistent with collagen vascular disease should increase the suspicion of pericarditis. Likewise, a patient with a history of preceding open heart surgery in the prior 2 weeks presenting with

chest pain, fever, and a pericardial friction rub should be evaluated for postpericardiotomy syndrome.

DIFFERENTIAL DIAGNOSIS VIRAL AND IDIOPATHIC The vast majority of cases of pericarditis will be considered idiopathic after a workup to determine the cause. Identifiable causes of pericarditis are listed in Table 56-1. The most common infectious cause of pericarditis is viral infection. Many patients present with an antecedent history of an upper respiratory infection. Viral infection can result in direct infection of the pericardium or produce a secondary immune mediated inflammation of the pericardium. This may be the basis for idiopathic pericarditis. The viruses most commonly associated with pericarditis are adenovirus or coxsackie virus. TABLE 56-1

Causes of Acute Pericarditis

Idiopathic Infectious Viral Bacterial Fungal Protozoal Collagen vascular/autoimmune Juvenile rheumatic arthritis Systemic lupus erythematosus Rheumatic fever Kawasaki disease Medications Metabolic Uremia Hypothyroidism

Chylopericardium Post-pericardiotomy syndrome Malignancy Trauma

BACTERIAL PERICARDITIS Bacterial pericarditis is a direct infection of the pericardial space with a bacterial agent. This is also referred to as purulent pericarditis. It can develop spontaneously, in relation to a concurrent infection and result from direct spread (e.g. pneumonia), or from hematologic spread (e.g. osteomyelitis). These patients are extremely ill appearing. Common etiologic agents include Staphylococcus aureus and Group A streptococcus.2 Streptococcus pneumoniae and Haemophilus influenzae type B were common causes of purulent pericarditis before the vaccines were developed. Meningococcus can also be associated with purulent pericarditis. It has also been reported in association with the smallpox vaccine, and in one case with the meningococcus vaccine.3

TUBERCULOUS PERICARDITIS Tuberculous pericarditis is most commonly reported in the third world but has been increasing in frequency due to human immunodeficiency virus infection in the United States. It can spread directly from the lungs or lymph nodes in the chest. Most often it is an insidious infection that can lead to constrictive pericarditis. It can less frequently present with the rapid development of pericardial effusion and tamponade. The rapid diagnosis and treatment of tuberculous pericarditis can prevent the development of constrictive pericarditis. In cases of constrictive pericarditis, it is often necessary to biopsy the pericardium to confirm the diagnosis of tuberculosis.4

COLLAGEN VASCULAR DISEASE Patients with collagen vascular disease frequently develop pericardial effusions. They can present with an insidious onset or a more acute onset of

symptoms. Occasionally the pericardial effusion can be one of the presenting symptoms of the disease. Up to 50% of patients have been found to have clinically silent pericardial effusions during disease flares. Symptomatic pericarditis can develop in up to 50% of patients with systemic lupus erythematosus.5 Some medications can cause pericardial effusions as part of a lupus-like syndrome (Table 56-2). The pericardial effusions in these cases will improve with treatment of the underlying disorder. TABLE 56-2

Medications That Cause Pericarditis

Cyclosporine Dantrolene Doxorubicin Hydralazine Isoniazid Mesalamine Methylsergide Methyldopa Phenytoin Procainamide Rifampin

METABOLIC DISTURBANCES Metabolic disturbances such as uremia and hypothyroidism can lead to the development of pericardial effusions. Pericardial effusions can also develop with derangements of chylous metabolism. These patients get better with treatment of the underlying diagnosis. Pericardial effusions have been reported in 6% to 10% patients with end-stage renal disease. They generally resolve with dialysis.6

POST-PERICARDIOTOMY SYNDROME Post-pericardiotomy syndrome is another cause of pericarditis. Patients

generally present 7 to 14 days after open heart surgery. Children generally present with fever, irritability, and a pericardial friction rub. It has been reported in 1% to 50% of patients in surgical series, and may be more common after atrial septal defect surgery.7 It is uncommon under 2 years of age and responds well to nonsteroidal anti-inflammatory drugs (NSAIDs).

MALIGNANCY Malignancy can be another cause of pericardial effusion. It is rare for the malignancy to be related to the pericardium directly. Radiation therapy can also cause pericarditis. Acute pericarditis from radiation is rare. Constrictive pericarditis can be a long-term sequelae of radiation therapy. Trauma can also lead to the development of pericarditis due to blunt or penetrating injury to the mediastinum.

DIAGNOSTIC EVALUATION An electrocardiogram (ECG) is abnormal in 90% to 100% of children who present to the emergency department with pericarditis.1,2 Initially there are diffuse ST changes with ST elevations in I, II, III, aVL, aVF, and V2–V6 with ST depressions in aVR and V1 (Figure 56-2). The PR interval may also become depressed. Several days to 2 weeks later in the disease course, the ST and PR intervals will normalize and the T waves flatten and invert. Within 4 to 6 weeks, the ECG usually normalizes but the T wave changes can become permanent. With large effusions, the ECG will have low voltages and occasionally electrical alternans due to movement of the heart within the effusion. In patients with constrictive pericarditis, there may be low voltages and nonspecific ST changes.

FIGURE 56-2. Electrocardiogram of a patient with acute pericarditis showing diffuse ST segment elevations in leads I, II, II and in the precordial chest leads V1–V6. There are also mild PR segment depressions seen. The chest radiograph may be normal in acute pericarditis without a significant pericardial effusion. A larger pericardial effusion is usually necessary to result in an enlarged cardiac silhouette on chest radiography (Figure 56-3).

FIGURE 56-3. Chest x-ray of a patient with acute pericarditis showing an enlarged cardiac silhouette seen in a patient with acute pericarditis

and a large pericardial effusion. The echocardiogram is the gold standard for diagnosing pericardial effusion associated with pericarditis. Echocardiography will show the size and distribution of pericardial effusion (Figure 56-4). A normal echocardiogram does not rule out the diagnosis of pericarditis, because not all patients with pericarditis will have an effusion, and there may be fluid accumulation in an area that is loculated or cannot be visualized. In cardiac tamponade, there can be marked respiratory variation in peak Doppler velocity of flow across the valves, right atrial free wall collapse, or bulging of the interventricular septum toward the left ventricle. In patients with constrictive pericarditis, the echocardiogram can show pericardial thickening, and provides a method to evaluate the movement and filling of the cardiac chambers.

FIGURE 56-4. Echocardiogram of a patient with acute pericarditis showing a large concentric pericardial effusion. Chest tomography or cardiac magnetic resonance imaging (MRI) is generally not necessary in the evaluation of pericarditis. These tests can be helpful if the echocardiogram shows a loculated effusion or if pericardial thickening is suspected. Cardiac MRI can distinguish between constrictive pericarditis, restrictive cardiomyopathy, and pancarditis or myopericarditis. Pancarditis is an inflammation of the myocardium and pericardium; these patients will have changes consistent with pericarditis as well as depressed ventricular function, and evidence of myocardial inflammation with late gadolinium enhancement and should be treated as patients with myocarditis.

Laboratory evaluation can show non-specific findings of inflammation including elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell count. Troponin I levels are often elevated and may reflect inflammation of the nearby myocardium. The yield for positive troponin in patients with a normal ECG is low.8 There is no correlation between troponin levels and prognosis in patients with myopericarditis.9 Additional studies depend on potential etiology of the pericarditis and can include viral titers, blood culture, thyroid screen, collagen vascular workup, and assessment of renal function. Pericardiocentesis is generally reserved for patients with cardiac tamponade, but occasionally is done for diagnostic purposes when purulent or malignant pericarditis is suspected or when the course of pericarditis is atypical. Pericardiocentesis is generally performed with echocardiographic guidance. A needle is advanced usually from the sub-xiphoid space aiming for the largest pocket of fluid seen on echocardiogram. The complications of pericardiocentesis include myocardial puncture, coronary artery laceration, atrial or ventricular arrhythmia, pneumothorax or pneumopericardium, hemopericardium, aortic laceration, liver laceration, and infection. Recent studies have reported a complication rate of about 4.8%, including patients anticoagulated at the time of the pericardiocentesis.10 The tests that should be performed on the effusion are listed in Table 56-3. These results will help to determine the type of effusion and guide the treatment. TABLE 56-3

Tests Be Performed on Pericardial Effusion

Cell count with differential Gram stain AFB stain Glucose Protein Triglyceride Lactate dehydrogenase Aerobic and anaerobic culture Cultures for Mycobacterium tuberculosis, fungi, and viruses

PCR for viruses

MANAGEMENT Most patients with viral or idiopathic pericarditis respond well to oral NSAIDs (ibuprofen or naproxen). The addition of colchicine to the oral regimen likely reduces the risk of a recurrent episode of pericarditis, which has been reported to occur in 15% to 30% of adults with idiopathic or viral pericarditis.11,12 Steroids are often not necessary in this patient group and should be avoided in the initial treatment because their use is associated with an increased risk for recurrent episodes of pericarditis.11,12 The NSAIDs should be continued until the inflammatory markers (ESR and CRP) become normal, and colchicine should be used for a total of 3 months. A proton pump inhibitor (omeprazole) is useful for gastrointestinal prophylaxis. Recurrent episodes can be treated with a similar regimen. Some patients who are steroid dependent or resistant to colchicine have responded to interleukin-1β receptor antagonists.13 Patients with purulent pericarditis will need an extended course of antibiotics with duration of at least 4 weeks. The antibiotic selection is initially broad-spectrum and then refined when drug sensitivities are reported. If patients do not respond to antibiotics or constriction of the pericardium develops, patients may need pericardiectomy or creation of a pericardial window.14 Tuberculous pericarditis requires long-term treatment that will depend on the sensitivity profile. When pericarditis is secondary to another cause such as collagen vascular disease, treatment of the underlying disorder usually results in resolution of the pericarditis. Patients with cardiac tamponade require pericardiocentesis. Since diastolic filling is compromised in cardiac tamponade, the first line of treatment is fluid replacement, 10 to 20 cc/kg prior to anesthesia/sedation. Some patients may be unable to lie flat, and the pericardiocentesis can be performed with the patient sitting upright. Pericardiocentesis can be performed in this situation with minimal sedation as long as adequate local anesthesia is given. For sedation, it is useful to have assistance from an anesthesiologist familiar with this condition and who can focus on this aspect of care during the procedure. For patients in tamponade, pericardiocentesis should be performed emergently with mostly local anesthesia and intravenous

fluids running. If there is time for sedation, it should be performed by anesthesia.

ADMISSION AND DISCHARGE CRITERIA Patients who are clinically well with mild symptoms of pericarditis (i.e. chest pain that responds to treatment with NSAIDs, no pericardial effusion or fever) can be reassured and do not need to be admitted to the hospital if they have close follow-up. Patients who are clinically well but present with pericardial effusion should be admitted and started on treatment to make sure that they respond to treatment (i.e. defervesce, effusion stabilizes or improves, and chest pain resolves). Any patients who appear toxic on presentation or who have signs of cardiac tamponade will need to be admitted to the hospital, most likely an intensive care unit. The length of hospitalization will depend on the underlying cause of the pericarditis and response to treatment. As a general guide for discharge readiness, patients should be free from fever and chest pain, and the pericardial effusion should be resolving. Follow-up should be arranged with pediatric cardiology.

CONSULTATION All patients with suspected pericarditis should have a cardiology consult. Cardiology will be key in the interpretation of the ECG and echocardiogram as well as determining the need for pericardiocentesis. Other consults may be necessary based on the presentation of the patient and the suspected cause of the pericarditis. Other services that may need to be consulted include infectious disease, rheumatology, and oncology. Cardiac surgery may need to be involved if considering pericardiectomy or pericardial window. KEY POINTS Pericarditis is a rare disease in children in which inflammation of the pericardium can result from many different sources. Most cases of pericarditis in children are viral or idiopathic, and require symptomatic treatment only with NSAIDs and colchicine. It is important to recognize pericardial tamponade, and treat it

rapidly. Patients who are toxic appearing, have poor cardiac output or pulses paradoxus need rapid treatment. Intravenous fluids can support the blood pressure while preparing for pericardiocentesis.

REFERENCES 1. Drossner DM, Hirsh DA, Sturm JJ, et al. Cardiac disease in pediatric patients presenting to a pediatric ED with chest pain. Am J Emerg Med. 2011;29:632. 2. Pemira SM, Tolan RW. Invasive froup A Streptococcus infection presenting as purulent pericarditis with multiple splenic abscesses: case report and literature review. Clin Pediatr. 2011;51(5):436. 3. Ratnapalan S, Brown K, Benson L. Children presenting with acute pericarditis to the emergency department. Pediatr Emerg Care. 2011;27(7):581. 4. Zamirian M, Mokhtarian M, Motazedian MH, Monabati A, Rezaian GR. Constrictive pericarditis: detection of mycobacterium tuberculosis in paraffin-embedded pericardial tissues by polynmerase chain reaction. Clin Biochem. 2007;40:355. 5. Imazio, M. Pericardial involvement in systemic inflammatory diseases. Heart. 2011;97:1882. 6. Feldman V, Dovrish Z, Weisenberg N, Neuman Y, Amital H. Uremic pericarditis. Israel Med Assoc J. 2011;13:256. 7. Gill P, Forbes K, Coe JY. The effect of short-term prophylactic acetylsalicylic acid on the incidence of postpericardiectomy syndrome after surgical closure of atrial septal defects. Pediatr Cardiol. 2009;30:1016. 8. Liesemer K, Casper TC, Korgenski K, Menon SC. Use and misuse of serum troponin assays in pediatric practice. Am J Cardiol. 2012;110:284. 9. Kobayashi D, Aggarwal S, Kheiwa A, Shah N. Myopericarditis in children: elevated troponin I level does not predict outcome. Pediatr

Cardiol. 2012;33:1040. 10. Inglis R, King AJ, Gleave M, Bradlow W, Adlam D. Pericardiocentesis in contemporary practice. J Invasive Cardiol. 2011;23(6):234. 11. Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis. Circulation. 2005;112:2012. 12. Imazio M, Brucato A, Maestroni S, et al. Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis. Circulation. 2011;123:1092. 13. Picco P, Brisca G, Traverso F, et al. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1β receptor antagonist (anakinra); an unrecognized autoinflammatory disease? Arthritis Rheum. 2009;60(1):264. 14. Megged O, Argaman Z, Kleaid D. Purulent pericarditis in children: is pericardiotomy needed? Pediatr Emerg Care. 2011;27:1185.

CHAPTER

57

Acute Rheumatic Fever David R. Fulton

BACKGROUND Acute rheumatic fever (ARF) is an inflammatory condition manifested by the nonsuppurative sequelae of a preceding group A β-hemolytic streptococcal (GAS) pharyngitis. ARF involves the heart, central nervous system, joints, and skin and is the most common cause of acquired heart disease in many regions of the world. Historically, the relationship between streptococci and rheumatic fever was not evident; however, investigation over the past several decades has shown that only GAS infections are associated with ARF. Diagnosis of the disease relies on the identification of major and minor criteria that include clinical observations and laboratory data, an approach that has been modified occasionally since its introduction in 1944 by Jones.1 The greatest impact of the illness lies in its potential to cause progressive valvular heart disease, which is more likely with recurrent episodes of ARF. Antibiotic prophylaxis is therefore important to minimize the likelihood of recurrent GAS pharyngitis.

EPIDEMIOLOGY It is well accepted that the frequency of ARF has declined in part because of the use of antibiotics to treat pharyngitis. Investigations have shown that appropriate antimicrobial therapy has led to fewer episodes of ARF in the United States,2-4 although the prevalence remains high in many parts of the world, especially in crowded populations of lower socioeconomic status.5,6 Nevertheless, sporadic outbreaks have been identified in the United States among populations not thought to be at risk for such events.7-11 Given the frequency of ARF as well as the clinical presentation among different

populations, the Jones Criteria was modified recently to define the two populations more precisely.12

PATHOPHYSIOLOGY Only GAS pharyngitis is rheumatogenic,13 and certain types of group A streptococci predispose to the development of ARF, based on the virulence of the organism. Group A streptococci with high concentrations of M protein, a component of the cell wall, are believed to be the most virulent strains and therefore the most likely to cause ARF. These types of streptococci often form mucoid-appearing colonies in culture. The number of M serotype GAS infections decreased in association with a similar decline in the incidence of ARF.14 The actual pathogenetic mechanism by which GAS pharyngitis leads to ARF is still somewhat speculative. The organism adheres to the pharyngeal mucosa, with subsequent destruction of epithelial cells. The immune reaction to this interaction results in both a humoral and a cell-mediated response to streptococcal antigens of the cell membrane. These antigens mimic those of cardiac tissue, whereas M proteins have similar antigenicity to myosin and sarcolemma,15,16 as well as cartilage and synovium.17 The cross-reactivity may result in damage to these target tissues. In addition, the GAS carbohydrate components mimic antigens of cardiac valves, a possible explanation for valvular involvement in ARF.18 Cell-mediated involvement in the pathogenesis is supported by the presence of CD4+ helper cells in heart valves.19 It is possible that the M protein and streptococcal pyrogenic exotoxins may act as superantigens in the immune response.20,21 A genetic basis for predisposition to development of rheumatic fever following GAS infection has been entertained for many years without definitive proof, but a recent report found the presence of potential rheumatic epitopes in the S2 region of human cardiac myosin.22 The initial pathologic lesion in ARF is edema of the ground substance in connective tissue, with accompanying cellular infiltration of T and B lymphocytes. Degenerative deposition of eosinophils in these regions is described as fibrinoid necrosis. Although these pathologic findings are present early in the process, with the administration of anti-inflammatory

therapy they regress. This stage of inflammation is followed by the more chronic and pathognomonic change known as the Aschoff body.23 This pathologic lesion is characterized by an area of central necrosis encircled by mononuclear and polynuclear cells. Most observers link this lesion to connective tissue; however, at least one investigator has postulated that the Aschoff body is located in myocardial cells.24 Some have posited that the lesion is the result of endothelial disruption of cardiac lymphatics.25 Pathologic changes can be found in all layers of the heart. Myocarditis is seen microscopically in ARF, with inflammatory cells noted in perivascular regions as well as near areas of Aschoff bodies.26 Though these changes are subclinical in many patients, other affected individuals may have pronounced heart failure in the acute phase of the disease. Pericardial inflammation is manifested as a serofibrinous reaction with pericardial fluid production. Although adhesions can ensue, constrictive changes are unlikely. Valvular inflammation is well described, involving primarily the aortic and mitral valves. Deposition of platelet fibrin collections is seen on the valve leaflets in the acute phase. Over many years, the leaflets may develop progressive fibrosis and contraction, as do the chordae tendineae of the mitral valve. These changes limit excursion of the valves, manifested as stenosis or a lack of coaptation of the leaflets and resulting regurgitation. The tricuspid and pulmonic valves are involved infrequently. Joint inflammation is common in ARF, leading to the clinical manifestation of arthritis. Pathologically, a serous effusion is seen in the joint space, with inflammation of the articular surfaces; however, long-standing arthritis is not a sequela of the disease. Sydenham chorea is characterized pathologically by cellular infiltration and neuronal loss of the basal ganglia,27-29 supported by findings of focal striatal enlargement by magnetic resonance imaging.30 Anti–basal ganglia antibodies have been demonstrated in the sera of patients with Sydenham chorea in both acute and chronic settings.31 Subcutaneous nodules are located over the extensor surfaces of the large joints, typically the elbows and knees, and are composed of fibrinoid necrosis similar to that seen in Aschoff bodies. These nodules are rarely seen clinically in this era.

CLINICAL PRESENTATION

The onset of ARF occurs after a variable latent period—typically, 10 to 30 days—following streptococcal pharyngitis; however, many patients give no history of a preceding pharyngitis. In particular, when the primary manifestation of the illness is chorea, the latent period from the streptococcal infection can be as long as 6 months. The diagnosis is established by meeting the criteria established by Jones,1 modified in 199232 and again in 201512 (Table 57-1). A history of appropriate therapy for streptococcal pharyngitis does not preclude the diagnosis, since ARF has occurred following GAS treatment.33,34 TABLE 57-1

Revised Jones Criteria

A. For all patient populations with evidence of preceding GAS infection Diagnosis: initial ARF

2 Major manifestations or 1 major plus 2 minor manifestations

Diagnosis: recurrent ARF

2 Major or 1 major and 2 minor or 3 minor

B. Major criteria Low-risk populations*

Moderate- and high-risk populations

Carditis† • Clinical and/or subclinical

Carditis • Clinical and/or subclinical

Arthritis • Polyarthritis only

Arthritis • Monoarthritis or polyarthritis • Polyarthralgia‡

Chorea

Chorea

Erythema marginatum

Erythema marginatum

Subcutaneous nodules

Subcutaneous nodules

C. Minor criteria Low-risk populations*

Moderate- and high-risk populations

Polyarthralgia

Monoarthralgia

Fever (≥38.5°C)

Fever (≥38°C)

ESR ≥60 mm in the first hour and/or CRP ≥3.0 mg/dL§

ESR ≥30 mm/h and/or CRP ≥3.0 mg/dL§

Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)

Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)

Source: Reproduced with permission from Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography. A scientific statement from the American Heart Association. Circulation. 2015;131:1806. Copyright © 2015 American Heart Association, Inc. ARF; acute rheumatic fever; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GAS, group A streptococcal infection. * Low-risk populations are those with ARF incidence ≤2 per 100 000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1000 population per year. †

Subclinical carditis indicates echocardiographic valvulitis as defined in Table 57-3.

‡

See section on polyarthralgia, which should only be considered as a major manifestation in moderate- to high-risk populations after exclusion of other causes. As in past versions of the criteria, erythema marginatum and subcutaneous nodules are rarely “stand-alone” major criteria. Additionally, joint manifestations can only be considered in either the major or minor categories but not both in the same patient. §

CRP value must be greater than upper limit of normal for laboratory. Also, because ESR may evolve during the course of ARF, peak ESR values should be used.

Early in the disease, complaints may center on a migratory polyarthritis involving the large joints, including the knees, wrists, elbows, and ankles. Fever between 38°C and 39°C is often an accompanying sign. The cardiac examination is notable for tachycardia at rest exacerbated by the fever, but the heart rate is also generally elevated in afebrile patients who have carditis.

The precordium is hyperdynamic in the face of the fever-associated tachycardia, myocardial dysfunction, moderate mitral or aortic regurgitation, or the additive effects of mitral and aortic regurgitation producing left ventricular volume overload. The most common murmur is a blowing pansystolic regurgitant murmur heard best at the apex and left lower sternal border with radiation to the axilla. When the regurgitation is moderate or greater, the diastolic rumble of relative mitral stenosis (Carey Coombs murmur) is present at the apex, sometimes best heard with the patient rotated in the left lateral recumbent position using the bell of the stethoscope. Highfrequency diastolic murmurs of aortic regurgitation are heard best using the diaphragm of the stethoscope with the patient seated and leaning forward, with the breath held in expiration. In patients with heart failure, S3 gallops are present, heard best at the apex with the bell. A three-component pericardial friction rub is heard in the presence of serofibrinous pericarditis, although the sound may be muted when a moderate to large effusion is present. Cardiac tamponade is extremely rare in ARF. Pulses and perfusion are well maintained, except in the unusual case of severe myocardial decompensation. Erythema marginatum is a serpiginous, salmon-colored eruption characterized by lesions with clear centers over the extremities and trunk. It is evanescent, noted more frequently during febrile episodes or after a bath or shower. Although subcutaneous nodules were once a classic part of the description of ARF, they are now infrequent findings. When present, they are nontender, knobby lesions usually palpated over the extensor surfaces of the elbows or knees, but can also occur around wrists, ankles or spine. Sydenham chorea is a purposeless, involuntary movement disorder of the extremities and face that is exacerbated during periods of stress. Irritability and emotional outbursts are common. The onset may be gradual, but the symptoms may persist for many months, making speech or writing difficult and thereby limiting attendance at school. Carditis and arthritis are generally not noted in combination with chorea. The neurologic signs resolve without long-term sequelae. Given the frequency of ARF in certain populations at higher risk, additional criteria have been adopted by the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease. The presence of subclinical carditis, monoarthritis, and polyarthralgia now constitute major criteria, while monoarthralgia and fever >38° are new minor categories.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of ARF is wide, given the systemic nature of its manifestations. Arthritis is present in many acute illnesses, including juvenile idiopathic (rheumatoid) arthritis, post-streptococcal arthritis, Lyme disease, septic arthritis, infective endocarditis, leukemia, and sickle cell disease. These diseases can be identified by careful consideration of the constellation of history, physical findings, and laboratory tests, including complete blood count with smear, blood cultures, and joint aspiration. Some consider poststreptococcal arthritis to be a separate entity from ARF, but others consider these two disorders to be different presentations of a common disease. Implications for the prevention of recurrence make this an important but controversial point of distinction.

DIAGNOSTIC EVALUATION The diagnosis of ARF relies on criteria derived from the physical examination and laboratory findings. In the setting of a preceding GAS infection, patients with two major manifestations or one major manifestation and two minor manifestations (see Table 57-1) meet the criteria for the diagnosis of ARF. Because the index of suspicion is higher in an individual with previous ARF, the diagnosis of recurrent ARF is accepted if, in the presence of a preceding streptococcal infection, one major or two minor manifestations are present. Fever is present in virtually all patients with ARF and should be documented carefully during hospitalization as a marker of the inflammatory process. In addition, the erythrocyte sedimentation rate and C-reactive protein level, nonspecific indicators of inflammation, are elevated in ARF. In a patient with chorea, however, both values might be normal, because the condition can follow the inciting event by a number of months. In the setting of severe heart failure, the erythrocyte sedimentation rate may be within the normal range, but the C-reactive protein is usually elevated. Both values improve after the institution of anti-inflammatory therapy and are useful for following the course of the acute illness. Laboratory tests that support the likelihood of a preceding streptococcal infection are important for establishing the diagnosis of ARF. All patients should have throat cultures to identify the presence of a GAS infection.

Because throat cultures are often negative after patients have been treated, however, and because signs of ARF may not appear until some time after the streptococcal infection, streptococcal antibody tests are useful to establish a recent infection.35 The antistreptolysin test (ASO) identifies the presence of an antibody to streptolysin O, an extracellular product of β-hemolytic streptococci. ASO titers less than 250 Todd units are considered normal; titers of 500 Todd units or more are considered positive. Values falling between 250 and 500 units are supportive but not diagnostic of a preceding infection. Elevated titers of other serologic tests, including antideoxyribonuclease B (anti-DNAase B), antihyaluronidase, and antistreptokinase, suggest a preceding streptococcal infection and may be helpful when ASO titers are not definitive. In the setting of chorea, these tests may be normal, given the latent period between streptococcal exposure and the onset of neurologic signs. Cardiac testing for ARF includes an electrocardiogram, which can show prolongation of the PR interval (a minor manifestation) or higher degrees of atrioventricular block, providing evidence of conduction system inflammation. Echocardiography plays a pivotal role in the assessment of a patient with presumed carditis because it can confirm the presence of mitral or aortic regurgitation by color flow Doppler interrogation of the valves. (Table 57-2) In the presence of a single non-cardiac major manifestation, aortic or mitral insufficiency not evident by physical examination can be identified, thus adding a second major manifestation. Use of portable echocardiography to evaluate for subclinical cases of ARF and RHD has potential benefit in endemic areas to identify patients for strep prophylaxis.3638

TABLE 57-2

Doppler Findings in Rheumatic Valvulitis

Pathological mitral regurgitation (all 4 criteria met) Seen in at least 2 views Jet length ≥2 cm in at least 1 view Peak velocity >3 m/s Pansystolic jet in at least 1 envelope Pathological aortic regurgitation (all 4 criteria met) Seen in at least 2 views

Jet length ≥1 cm in at least 1 view Peak velocity >3 m/s Pan diastolic jet in at least 1 envelope Source: Reproduced with permission from Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography. A scientific statement from the American Heart Association. Circulation. 2015;131:1806. Copyright © 2015 American Heart Association, Inc.

MANAGEMENT All patients with the presumptive diagnosis of ARF should be hospitalized for observation and treatment until their condition stabilizes. The therapy for ARF is supportive and nonspecific. The goal is to reduce inflammation and treat underlying carditis if it is hemodynamically significant. Most clinicians continue to use aspirin as the drug of first choice to reduce fever and control the pain associated with arthritis. Aspirin is administered at a dose of 60 to 100 mg/kg daily divided every 6 hours to achieve a therapeutic salicylate serum level of 10 to 20 mg/dL. The response to aspirin is often dramatic, occurring within 1 to 2 days. The medication is continued over several weeks and then tapered slowly. Nonsteroidal antiinflammatory medications have not been studied rigorously in this disease. Despite the availability of steroid therapy for the past 50 years, its superiority over aspirin in reducing rheumatic heart disease has not been firmly established. An extensive meta-analysis of the treatment of rheumatic carditis failed to show a convincing superiority of steroids over aspirin for the reduction of rheumatic heart disease a year after the acute illness.39 With regard to the treatment of acute myocarditis, intravenous gamma globulin infusion has not proved to be of benefit in ARF,40 but a single report suggests its use may moderate the course of Sydenham chorea.41 In the setting of carditis, individuals with symptoms of heart failure should be treated with diuretics but rarely require inotropic support or afterload reduction therapy. Restraint from physical activity is mandatory; in fact, complete bed rest for several weeks to months was the rule for many decades. Although these restrictions are somewhat less stringent today, individuals with acute carditis should remain at home and abstain from exertion and sports until the clinician is confident that the ventricular

dysfunction or the degree of aortic or mitral regurgitation has stabilized. Restriction from physical activity is warranted for at least one month, with relaxation of the limitations based on echocardiographic reassessment at frequent intervals. Given the extended period needed for resolution, homebased tutoring should be implemented for school-aged children. In rare circumstances, acute rheumatic carditis does not respond to conventional diuretics, aggressive anticongestive measures, antiinflammatory therapy, and rest. Heart failure is usually the result of marked left ventricular dysfunction with accompanying mitral or aortic regurgitation. In these refractory cases, cardiac surgical intervention with mitral or aortic valve replacement, or both, may be necessary. Continued intense medical therapy is required postoperatively until the underlying hemodynamic derangement improves.

MANAGEMENT OF RECURRENT ACUTE RHEUMATIC FEVER The Jones criteria are intended for the diagnosis of a first attack of ARF. The diagnosis of a recurrent bout of ARF is straightforward when the Jones criteria are met; however, the diagnosis may be elusive, given the presence of residual mitral or aortic valve disease from the first episode. In these cases, using carditis as a manifestation may not be possible in the presence of a febrile illness. In such situations, polyarthritis along with a minor criterion should be considered diagnostic, as should the presence of chorea. Another confounding issue is the diagnosis of poststreptococcal reactive arthritis, which tends to follow streptococcal pharyngitis by 3 to 14 days. The arthritis can be nonmigratory, persisting longer than that seen with ARF. Often the arthritis does not respond to salicylates, unlike the response generally seen in ARF. When the Jones criteria are met, the patient should be considered to have ARF. For individuals who do not meet the criteria, treatment should occur if all other diagnoses have been considered and ruled out.

ADMISSION AND DISCHARGE CRITERIA All patients with the presumptive diagnosis of ARF or recurrent ARF should be hospitalized. Discharge criteria are summarized in Table 57-3.

TABLE 57-3

Discharge Criteria for Hospitalized Patients with Acute Rheumatic Fever

• Establishment or elimination of the diagnosis of ARF. • Completion of an observation period to confirm that the course of the illness has stabilized. • Completion of diagnostic testing to identify the severity of illness, especially cardiac involvement. • Initiation of appropriate treatment for the primary GAS infection and for ARF symptoms and signs. • Education of the patient and caregivers regarding endocarditis prophylaxis. • Institution of a secondary prophylaxis regimen for the prevention of subsequent GAS infection. • Establishment of follow-up with primary care clinician and appropriate subspecialists. ARF; acute rheumatic fever; GAS, group A streptococcal infection

CONSULTATION Cardiology subspecialists are routinely involved in the initial evaluation and management. They are also part of the long-term follow-up of patients after discharge.

SPECIAL CONSIDERATIONS PRIMARY PREVENTION The prevention of ARF is based on the prompt treatment of GAS pharyngitis, the only infection known to cause ARF. Positive throat swabs for rapid antigen testing or culture for GAS in patients with pharyngitis indicate the need for antibiotic therapy. In developed countries, where the prevalence of ARF is low, a 10-day course of oral penicillin V is the routine treatment of documented GAS pharyngitis (Table 57-4). Despite reports of scattered development of resistance of GAS, penicillin is still the first line agent for prevention of ARF.42 A single intramuscular injection of benzathine

penicillin is recommended in areas with a high prevalence of rheumatic fever to ensure compliance.43-45 Mass prophylaxis has been implemented at military bases, successfully aborting outbreaks of ARF.46 TABLE 57-4

Agent

Primary Prevention of Rheumatic Fever (Treatment of Streptococcal Tonsillopharyngitis) Dose

Mode

Penicillin V Children: Oral (phenoxymethyl 250 mg 2–3 penicillin) times daily for ≤27 kg (60 lb); children >27 kg (60 lb), adolescents, and adults: 500 mg 2 to 3 times daily

Duration Rating 10 days

IB

10 days

IB

Or Amoxicillin

50 mg/kg once daily (maximum 1 g)

Oral

Or Benzathine penicillin G

600 000 U for patients ≤27 kg (60 lb); 1200 000 U for patients >27

Intramuscular Once

IB

kg (60 lb) For individuals allergic to penicillin Narrowspectrum cephalosporin* (cephalexin, cefadroxil)

Variable

Clindamycin

20 mg/kg per day divided in 3 doses (maximum 1.8 g/d)

Oral

10 days

IB

Oral

10 days

IIaB

Oral

5 days

IIaB

10 days

IIaB

Or

Or Azithromycin

12 mg/kg once daily (maximum 500 mg) Or

Clarithromycin

15 mg/kg Oral per day divided BID (maximum 250 mg BID)

Source: Reproduced with permission from Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119:1541. Copyright © 2009 American Heart Association, Inc. Rating indicates classification of recommendation and LOE (eg, IB indicates class I, LOE B);

BID, twice per day. The following are not acceptable: sulfonamides, trimethoprim, tetracyclines, and fluoroquinolones. *To be avoided in those with immediate (type I) hypersensitivity to a penicillin

Repeat throat culture is not necessary in patients who have received adequate treatment. Despite completion of appropriate therapy, approximately 20% of patients with resolved pharyngitis may continue to test positive for group A streptococci in the throat. However, the strains present lose M proteins and virulence after treatment. In areas where rheumatic fever is not present, the colonization that persists is not considered a threat to the population.47

SECONDARY PREVENTION All patients with ARF should receive long-term therapy to prevent the recurrence of infection (Table 57-5).42 With regard to long-term prophylaxis, the intramuscular administration of benzathine penicillin every 3 to 4 weeks is preferred, although penicillin twice daily is an acceptable alternative.48,49 In low-resource settings, once-daily treatment with amoxicillin has been shown to reduce recurrence rate of ARF.50 TABLE 57-5

Secondary Prevention of Rheumatic Fever (Prevention of Recurrent Attacks)

Agent

Dose

Mode

Benzathine penicillin G

600,000 U for children ≤27 kg (60 lb), 1,200,000 U for those >27 kg (60 lb) every 4 wk*

Intramuscular IA

Penicillin V

250 mg twice daily

Oral

IB

Oral

IB

Sulfadiazine 0.5 g once daily for patients ≤27 kg (60 lb), 1.0 g once daily for patients >27 kg (60 lb)

Rating

For individuals allergic to penicillin and sulfadiazine Macrolide or azalide

Variable

Oral

IC

Source: Reproduced with permission from Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119:1541. Copyright © 2009 American Heart Association, Inc. Rating indicates classification of recommendation and Level of Evidence (eg, IA indicates class I, LOE A). *In high-risk situations, administration every 3 weeks is justified and recommended.

The risk of a first episode of ARF following untreated streptococcal pharyngitis is 1% to 3%; however, the risk of recurrent attacks of ARF with subsequent streptococcal infections increases dramatically to as high as 50%. Individuals manifesting carditis with the first attack of ARF are at significant risk for recurrent carditis during subsequent episodes, so prophylaxis is particularly critical in this group. Recommendations regarding the duration of prophylaxis have changed over the past half century. Initially, all patients were advised to take penicillin prophylaxis for life; however, many clinicians now suggest discontinuing such therapy after the age of 21 years if there is no carditis during the episode of rheumatic fever. If carditis is present but there is no residual heart disease, prophylaxis is recommended for age 10 years or well into adulthood, whichever is longer. If carditis is present and there is residual heart disease, prophylaxis is recommended for at least 10 years after the last episode or until age 40 years48; lifetime prophylaxis may be recommended if the individual is regularly exposed to populations with a high prevalence of streptococcal infections, such as teachers or day-care workers. In individuals with a recurrence of ARF, these boundaries for prophylaxis should be extended, and the frequency of benzathine penicillin administration may need to be increased to every 3 weeks.48

PREVENTION OF ENDOCARDITIS In patients with rheumatic heart disease, chemoprophylaxis for endocarditis

for procedures such as dental work is not recommended unless the patient falls into a high-risk category by virtue of prior mechanical valve placement or a documented episode of subacute bacterial endocarditis (SBE).51 KEY POINTS Although less common than in previous decades, ARF continues to affect children, despite the availability of therapy that could eliminate the presumed inciting agent. The diagnosis of ARF requires application of the modified Jones criteria, after which treatment of the streptococcal disease is instituted. Doppler echocardiography should be performed in all suspected cases of ARF to identify the presence of subclinical mitral or aortic regurgitation. Anti-inflammatory therapy ameliorates the arthritis associated with ARF, and high-dose aspirin is the first-line choice over steroids or other therapies. Rest and anticongestive medications are the mainstays of treatment for aortic or mitral carditis, which often persists for several months. Long-term penicillin prophylaxis is mandatory to prevent recurrent streptococcal pharyngitis and the likelihood of additional episodes of ARF. Successful reduction of recurrent ARF minimizes the risk for hemodynamically significant rheumatic heart disease in the ensuing 2 to 3 decades. Small outbreaks of ARF were reported in the United States in the last 2 decades of the 20th century,52-55 and the incidence remains high among children of Polynesian descent in Australia, Hawaii, and New Zealand.56,57 Cardiac screening of children with presumed ARF or RHD in endemic areas using portable echocardiographic units may better target those who would benefit from treatment to prevent recurrent episodes of ARF and is the subject of continued discussion by the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in

the Young. Efforts continue to create a vaccine that targets the rheumatogenic strains of group A streptococci.

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Association. Circulation. 2015;131:1806. 13. Wannamaker LW. Differences between streptococcal infections of the skin and of the throat. N Engl J Med. 1970;282:23. 14. Stollerman GH, Siegel AC, Johnson EE. Variable epidemiology of streptococcal disease and the changing pattern of rheumatic fever. Mod Concepts Cardiovasc Dis. 1965;34:45. 15. Dale JB, Beachey EH. Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart. J Exp Med. 1982;156:1165. 16. Dale JB, Beachey EH. Epitopes of streptococcal M proteins shared with cardiac myosin. J Exp Med. 1985;162:583. 17. Baird RW, Bronze MS, Kraus W, et al. Epitopes of group A streptococcal M protein shared with antigens of articular cartilage and synovium. J Immunol. 1991;146:3132. 18. Goldstein I, Halpern B, Robert L. Immunologic relationship between streptococcal A polysaccharide and structural glycoproteins of heart valve. Nature. 1967;214:44. 19. Raizada V, Williams RC, Chopra P, et al. Tissue distribution of lymphocytes in rheumatic heart valves as defined by monoclonal anti-T cell antibodies. Am J Med. 1983;74:90. 20. Marrack P, Kappler J. The staphylococcal exotoxins and their relatives. Science. 1990;248:705. 21. Smeesters PR, Dreze P, Perez-Monga D, et al. Group A streptococcus virulence and host factors in two toddlers with rheumatic fever following toxic shock syndrome. Int J Infect Dis. 2010;14:e403-409. 22. Ellis N, Kurahara DK, Vohra H et al. Priming the immune system for heart disease: a perspective on Group A streptococci. J Infect Dis. 2010;202,1059-1067. 23. Gross L, Ehrlich JC. Studies on the myocardial Aschoff body. II. Life cycle, sites of predilection and relation to the clinical course of rheumatic fever. Am J Pathol. 1934;10:489. 24. Murphy GE. Nature of the rheumatic heart disease with special reference to myocardial disease and heart failure. Medicine. 1960;39:289. 25. Wedum BG, McGuire JW. Origin of the Aschoff body. Ann Rheum Dis.

1963;22:127. 26. Coombs CF. The myocardial lesions of the rheumatic infection. BMJ. 1907;2:1513. 27. Sydenham T. On St Vitus Dance: The Works of Thomas Sydenham, MD. vol 2. London, UK: Sydenham Society; 1850:257. 28. Colony HS, Malamud N. Sydenham’s chorea: a clinicopathologic study. Neurology. 1956;6:672. 29. Greenfield JG, Wolfsohn JM. The pathology of Sydenham’s chorea. Lancet. 1922;2:603. 30. Giedd JN, Rapoport JL, Kruesi MJ, et al. Sydenham’s chorea: magnetic resonance imaging of the basal ganglia. Neurology. 1995;45:2199. 31. Church AJ, Cardoso F, Dale RC, et al. Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology. 2002;59:227. 32. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992;268:2069. 33. van Driel ML, De Sutter AI, Keber N, Habraken H, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database Syst Rev. 2010;(10):CD004406. 34. Logan LK, McAuley JB, Shulman ST. Macrolide treatment failure in streptococcal pharyngitis resulting in acute rheumatic fever. Pediatrics. 2012;129(3):e798-802. 35. Widdowson JP, Maxted WR, Notley CM, et al. The antibody responses in man to infection with different serotypes of group A streptococci. J Med Microbiol. 1974;7:483. 36. Marijon E, Celermajer DS, Tafflet M, et al. Rheumatic heart disease screening by echocardiography: the inadequacy of World Health Organization criteria for optimizing the diagnosis of subclinical disease. Circulation. 2009;120:663. 37. Webb RH, Wilson NJ, Lennon DR, et al. Optimising echocardiographic screening for rheumatic heart disease in New Zealand: not all valve disease is rheumatic. Cardiol Young. 2011;21;436.

38. Beaton A, Okello E, Lwabi P, et al. Echocardiography screening for rheumatic heart disease in Ugandan schoolchildren. Circulation. 2012;125:3127. 39. Albert DA, Harel L, Karrison T. The treatment of rheumatic carditis: a review and meta-analysis. Medicine. 1995;74:1. 40. Voss LM, Wilson NJ, Neutze JM, et al. Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial. Circulation. 2001;103:401. 41. Walker K, Brink A, Lawrenson J, et al. Treatment of Syndenhan chorea with intravenous gammaglobulin. J Child Neurology. 2012;27:147. 42. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119:1541. 43. Wood HF, Feinstein AR, Taranta A, et al. Rheumatic fever in adolescents: a long-term epidemiologic study of subsequent prophylaxis, streptococcal infections and clinical sequelae. III. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infections and rheumatic recurrences. Ann Intern Med. 1964;60(Suppl):31. 44. Lennon D, Kerdemilides M, Arroll B. Meta-analysis of trials of streptococcal throat treatment programs to prevent rheumatic fever. Pediatr Infect Dis J. 2009;28:e259. 45. Spinetto H, Lennon D, Horsburgh M. Rheumatic fever recurrence prevention: a nurse led programme of 28-days penicillin in an area of high endemnicity. J Pediatr Child Health. 2011;47:228. 46. Centers for Disease Control. Acute rheumatic fever among army trainees–Fort Leonard Wood, Missouri, 1987-1988. MMWR Morb Mortal Wkly Rep. 1988;37:519. 47. Stollerman GH. Rheumatic fever. Lancet. 1997;349:935.

48. Bonow RO, Carabello B, de Leon AC Jr, et al. ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol. 1998;32:1486. 49. Lue HD, Wu MH, Wang JK, et al. Long-term outcome of patients with rheumatic fever receiving benzathine penicillin G prophylaxis every three weeks versus every four weeks. J Pediatr. 1994:125:812. 50. Lennon DR, Farrell E, Martin DR, Stewart JM. Once-daily amoxicillin versus twice-daily penicillin V in group A beta-haemolytic streptococcal pharyngitis. Arch Dis Child. 2008;93:474. 51. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1736. 52. Hoffman TM, Rhodes LA, Pyles LA, et al. Childhood acute rheumatic fever: a comparison of recent resurgence areas to cases in West Virginia. W V Med J. 1997;93:260. 53. Veasy LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr. 1994;124:9. 54. Westlake RM, Graham TP, Edwards KM. An outbreak of acute rheumatic fever in Tennessee. Pediatr Infect Dis J. 1990;9:97. 55. Hosier DM, Craenen JM, Teske DW, Wheller JJ. Resurgence of acute rheumatic fever. Am J Dis Child. 1987;141:730. 56. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis. 2004;4:240. 57. Pope RM. Rheumatic fever in the 1980s. Bull Rheum Dis. 1989;38:1.

SECTION E Dermatology

Purpura

CHAPTER

58

Bernard A. Cohen and Anna L. Grossberg

BACKGROUND Purpura, or bleeding into the skin, may be an innocent finding in minor trauma or the first sign of a life-threatening disease. Pinpoint areas of hemorrhage are called petechiae; large, confluent patches are referred to as ecchymoses. Purpura may result from extravascular, intravascular, or vascular processes. Nonpalpable purpuric lesions develop from extravascular and intravascular phenomena, whereas those that are palpable result from a vascular process. Conditions associated with each type are listed in Table 581. TABLE 58-1

Pathophysiology of Purpura

Extravascular Trauma Accidental Nonaccidental (iatrogenic, self-induced, abuse) Defective collagen synthesis Nutritional deficiency (vitamin C, protein, calorie) Hereditary disorders (Ehlers-Danlos syndrome) Intravascular Thrombocytopenia Autoimmune thrombocytopenic purpura Systemic lupus erythematosus Marrow failure (leukemia, lymphoma, aplastic anemia)

Drug induced Infection and disseminated intravascular coagulation Hereditary coagulation defects Factor VIII or IX deficiency or dysfunction Vascular Small-vessel leukocytoclastic vasculitis Henoch-Schönlein purpura Drug induced Collagen vascular disease (systemic lupus erythematosus) Medium-sized arteritis Polyarteritis nodosa Lymphocytic vasculitis Progressive pigmented purpuric dermatosis Autoimmune (Sjögren syndrome, drug reaction)

PATHOPHYSIOLOGY Extravascular Purpura Trauma is the most common cause of extravascular purpura in children. Nonblanching, nonpalpable purple patches following accidental trauma vary from a few millimeters to many centimeters in diameter and are usually located over bony prominences such as the knees, elbows, extensor surfaces of the lower legs, forehead, nose, and chin. In otherwise healthy children, petechiae occur occasionally on the face and chest after vigorous coughing or vomiting and in dependent areas after standing in place or engaging in vigorous physical activity for long periods. The presence of purpura on protected or unexposed sites, such as the buttocks, spine, genitalia, upper thighs, and upper inner arms, suggests the possibility of nonaccidental trauma (Figure 58-1). In some cases, the shape of the bruise provides a clue as to the object used to inflict the injury (see Chapter 39).1

FIGURE 58-1. Belt-buckle imprint from a beating (arrow). Scars, nutritional deficiencies (e.g. vitamin C, protein), hereditary defects in collagen synthesis (e.g. Ehlers-Danlos syndrome), and other factors that increase skin fragility and decrease the tensile strength of the tissue surrounding vessels in the dermis and fat increase the risk of extravascular purpura after trauma. Intravascular Purpura Intravascular purpura results from disorders that interfere with normal coagulation. Nonpalpable petechiae and large ecchymoses may be present, and mucosal bleeding may be evident; in severe cases, bleeding may occur in the joints, deep soft tissues, kidneys, gastrointestinal tract, central nervous system, and other viscera. Disorders associated with intravascular purpura may result from abnormalities in platelet number or function, or from deficiencies in coagulation factors. These disorders include autoimmune thrombocytopenic purpura, acute leukemia with thrombocytopenia, aplastic anemia, sepsis with disseminated intravascular coagulation (DIC), and various coagulation factor deficiencies. Primary immune thrombocytopenic purpura (ITP) is the most common type of intravascular purpura in previously healthy children. This condition was previously termed idiopathic thrombocytopenic purpura. Patients typically present acutely 2 to 4 weeks after a viral illness with petechiae and ecchymoses after minimal or no apparent trauma (Figure 58-2). The incidence peaks in the later winter and early spring. Occult blood can often be detected in the stool and urine, but clinically significant hemorrhage is unusual. ITP is associated with the development of immunoglobulin (Ig) G antibodies that bind to platelets and trigger increased destruction by the reticuloendothelial system. Platelet counts may dip below 10,000/mm3 for

several weeks but usually return to normal within 4 to 6 weeks. Other cell lines are unaffected, and patients appear well without fever or other systemic symptoms. Antiplatelet antibodies and thrombocytopenia can also develop in other less common disorders, including systemic lupus erythematosus, leukemia, lymphoma, and drug reactions.

FIGURE 58-2. Autoimmune thrombocytopenic purpura, petechiae, and bruises in a 10-year-old boy. Purpura can be an early manifestation of leukemia or aplastic anemia. These disorders may also be associated with anorexia, weight loss, fatigue, joint pain, and a persistent flulike illness. Hepatosplenomegaly, lymphadenopathy, and bone tenderness may be prominent. Bone marrow dysfunction from both leukemia and aplastic anemia may affect all cell lines, and patients may present with serious cutaneous infections or sepsis. Purpura fulminans presents with rapidly progressive ecchymoses that

may cover large areas of skin (Figure 58-3). It represents the cutaneous manifestation of sepsis and DIC. Hemorrhage into multiple organs may also occur in this life-threatening process. Purpura is usually associated with ischemia, and in patients who survive, large areas of necrosis can develop. In normal children, meningococcal and Rocky Mountain spotted fever infections are probably the most common cause of purpura fulminans followed by Streptococcus, Haemophilus, and Staphylococcus sepsis, particularly in asplenic patients. A number of other bacterial, viral, and fungal organisms have been implicated in immunocompromised patients.2,3 Finally, DIC may result from acquired or occult heritable protein C or protein S deficiency after benign childhood infections such as varicella.

FIGURE 58-3. Purpura fulminans. Widespread purpura in a 9-year-old girl with disseminated intravascular coagulation following group A βhemolytic streptococcal infection secondary to varicella. Other heritable coagulation defects can also be associated with nonpalpable purpura. Children with hereditary deficiency or dysfunction of coagulation factors, most commonly factor VIII or IX, bruise easily but are less likely to develop petechiae. Patients with less than 1% of normal factor activity develop spontaneous hemorrhage and are usually diagnosed in early infancy; those with 1% to 5% of normal factor activity develop exaggerated bleeding at sites of trauma. Individuals with moderate reductions in factor function may not demonstrate cutaneous bleeding, and diagnosis may be delayed until they bleed excessively after major trauma or surgery. Vascular Purpura Vascular purpura develops when an inflammatory process involves the vessel wall, resulting in vasculitis. Leukocytoclastic vasculitis (LCV) is mediated by immune complex formation and fibrin deposition in the vascular basement membrane zone, with subsequent

activation of complement and influx of neutrophils. The inflammatory process and subsequent destruction of vessels result in hemorrhagic papules and nodules referred to as palpable purpura. Lesions tend to produce angulated and starburst patterns conforming to the area of distribution of the involved vessels.4 Infectious agents, medications, autoimmune disorders, and malignancies can trigger LCV. Infectious agents (e.g. Rocky Mountain spotted fever, meningococcemia) can also invade and damage the vascular endothelium directly, followed by leukocyte invasion. Therefore, the purpura associated with these infectious agents may be nonpalpable (related to DIC and sepsis), palpable (infectious vasculitis), or both. Henoch-Schönlein purpura (HSP) is the most common primary systemic vasculitic process in children, and most commonly affects individuals between 3 and 10 years of age.5 In HSP, a small-vessel LCV typically results in palpable purpuric lesions less than 1 cm in diameter on the extensor surfaces of the arms, legs, buttocks, cheeks, and ears. Although early lesions may appear urticarial, as they evolve, confluent lesions may produce larger areas of purpura, bullae, necrosis, and ulceration (Figure 58-4). HSP is also characteristically associated with crampy abdominal pain and periarticular swelling, but patients often appear well and are usually afebrile. Recurrences are seen in about half of patients for up to several months, but these episodes are usually mild. In most cases, visceral disease is self-limited. However, renal involvement, consisting of nephritis or nephrosis, may precede, accompany, or follow the cutaneous manifestations. Systemic corticosteroids have not been shown to prevent renal complications in HSP, and their use is not routinely advocated.5 Patients with prolonged or serious cutaneous lesions may be at greater risk for the development of chronic renal disease.6 HSP is discussed in greater detail in Chapter 148.

FIGURE 58-4. Leukocytoclastic vasculitis in 10-year-old boy with Henoch-Schönlein purpura. LCV in HSP involves small dermal blood vessels, usually postcapillary venules. Classic histologic findings include endothelial swelling, fibrin deposition within and around vessels, neutrophilic infiltrate within the vessel walls, and nuclear dust (scattered nuclear fragments from neutrophils). Direct immunofluorescence from biopsies of fresh skin lesions demonstrates IgA and C3 deposition around dermal blood vessels. A normal blood count, platelet count, and coagulation studies help differentiate HSP from disorders causing intravascular purpura. Further laboratory workup may include serum chemistries, stool guiaic testing, abdominal imaging, urinalysis, and kidney biopsy. Typical clinical findings and clinical course, histopathology, and other screening laboratory studies exclude lupus and other connective tissue disorders. Medication-induced LCV, or hypersensitivity vasculitis, can produce a similar clinical and histologic picture, but immunofluorescence findings are negative or nonspecific. Although many drugs have been implicated as triggers of LCV, the most commonly reported medications include antibiotics, nonsteroidal anti-inflammatory drugs, anticonvulsants, and thiazide diuretics. Hypersensitivity vasculitis can also be triggered by infectious processes including hepatitis C and B and streptoccocal infection, in addition to several others. Polyarteritis nodosa (PAN) is an LCV involving small and medium-sized arteries but is rare in children. A systemic form presents acutely with high fever, weakness, abdominal pain, and cardiac failure. Despite aggressive

treatment with anti-inflammatory and immunosuppressive medications, death may ensue quickly from renal failure, gastrointestinal bleeding, and bowel perforation. Nonspecific cutaneous findings include livedo reticularis, erythema, and purpura on the extremities. Livedo reticularis appears as a red to purple fishnet-like blanching or marbling of the skin. Cutaneous PAN is a distinct variant in which skin findings predominate and systemic disease is minimal. Crops of painful purpuric nodules and annular plaques erupt on the hands, feet, and less commonly, on the trunk, face, and neck. Urticaria, livedo reticularis, and ulcerations may develop. Although life-threatening visceral disease does not occur in this form of PAN, fever, arthralgias, myalgias, and periarticular swelling may accompany flares of cutaneous lesions. Often there is an accompanying leukocytosis, and erythrocyte sedimentation rate will also be elevated. PAN is diagnosed by skin biopsy, and patients require longterm monitoring to exclude progression to systemic disease.7,8 Management options include systemic corticosteroids, nonsteroidal anti-inflammatory agents, and steroid-sparing immunomodulatory medications. Lymphocytic vasculitis refers to a reaction pattern in the skin that is associated with a number of disorders in which lymphocytic inflammation predominates in the walls and around superficial dermal capillaries. Lymphocytic vasculitis has been described in cutaneous drug reactions, Sjögren syndrome, and the late phase of LCV. Progressive pigmented purpuric dermatosis (PPPD) is the only disorder in which lymphocytic vasculitis occurs consistently (Figure 58-5). The development of asymptomatic patches of petechiae and confluent purpura, particularly on the lower extremities, characterizes PPPD. Hemosiderin deposition and postinflammatory hyperpigmentation in the chronic lesions lead to shades of brown, gold, and bronze as the lesions evolve (Figure 58-6). Although the lesions are usually macular, subtle eczematous and lichenoid papules may develop in certain subtypes of PPPD. Eruptions may persist for years, but systemic symptoms do not occur, and laboratory studies are normal.9

FIGURE 58-5. Progressive pigmented purpura in a 14-year-old with chronic bronze-red macules on the extremities for more than 1 year.

FIGURE 58-6. Pigmented purpura.

CLINICAL PRESENTATION Any child who presents with purpura requires a complete history, review of systems, family history, and physical examination with an emphasis on cutaneous and systemic findings that may provide diagnostic clues (Figure 58-7).

FIGURE 58-7. Algorithm for the diagnosis of purpura. CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time. Purpura may resemble hyperemia that results from increased blood flow through dilated vessels. Diascopy is used to differentiate hyperemia from the cutaneous hemorrhage of purpura. Diascopy involves applying pressure to the skin either by pressing it apart between the thumb and index finger or by applying a glass or plastic slide over the involved skin surface. Hyperemic areas blanch with diascopy, but purpuric lesions do not. During the first few minutes of the visit, the clinician should determine whether the child is acutely ill. A toxic-appearing patient with fever, headache, hypotension, or diffuse purpura requires an immediate evaluation for septicemia and DIC. Transfer to a facility that can provide rapid clinical and laboratory assessment, cardiovascular and respiratory support, and prompt initiation of therapy (e.g. empirical antibiotics) is required. In a well-appearing child, a thorough history and physical examination can be completed. Aside from a description of the rash and its evolution and the events surrounding its appearance, questions regarding recent illnesses or medication use should be asked. Exploration of the child’s past medical history should include previously diagnosed coagulation disorders or collagen vascular diseases, unusual diet, weight loss, bone pain, anemia, joint laxity, poor wound healing, abnormal scarring, or easy bruising. A surgical history is important to determine whether abnormal bleeding was detected. Children with suspected nonaccidental trauma, as well as healthy children with no history of trauma or unusually shaped skin lesions, warrant

laboratory evaluation. Consultation with a child protective agency may be indicated. A family history of skin fragility, poor skin healing, wide disfiguring scars, increased bruising, anemia, hemophilia, or collagen vascular disease should prompt an evaluation for hereditary disorders that predispose to bleeding and cutaneous purpura. In a well-appearing child with unexplained petechiae or purpura, the entire skin surface and the mucous membranes should be examined, and all findings should be carefully documented. Bruises in unusual shapes suggesting nonaccidental trauma should prompt an evaluation for other signs of occult physical trauma and child abuse, and cutaneous findings should be photographed.

DIAGNOSTIC EVALUATION When the cause of cutaneous bleeding is not apparent, a complete blood count and coagulation studies can help exclude intravascular purpura. When indicated, specific quantitative and functional coagulation factor studies should be performed. In children with doughy or hyperextensible skin and wide disfiguring scars, particularly if there is a family history of similar findings, a skin biopsy for routine pathology or electron microscopy may confirm the suspicion of Ehlers-Danlos syndrome or other genodermatoses associated with increased bruisability. The evaluation of palpable purpura should include a biopsy with direct immunofluorescence. When septicemia is suspected, tissue should also be submitted for bacterial and fungal culture. Tissue may also be subjected to marker studies (polymerase chain reaction, immunoperoxidase, double fluorescent antibody) for specific organisms, if available. PPPD can be confirmed by characteristic histologic findings, though biopsy is often not necessary in most clinical settings.

MANAGEMENT Treatment should be tailored to the specific disorder when a cause is identified, such as coagulopathy (see Chapter 92), malignancy, autoimmune disorder, or infection (see Chapter 97).2 Patients with hyperextensibility

syndrome and Ehlers-Danlos syndrome should take precautions to protect the skin from trauma. There is no uniformly effective therapy for PPPD. However, treatment with topical steroids, topical nonsteroidal antiinflammatory agents, yellow pulsed-dye laser, and phototherapy has been successful in some patients. KEY POINTS Nonblanching red eruptions in the skin should prompt an evaluation for purpura. The initial evaluation should promptly determine whether a lifethreatening infectious process is present. Purpura can arise from intravascular, extravascular, and vascular causes. Intravascular and extravascular purpura cause nonpalpable lesions; a vascular process leads to palpable lesions. Trauma is the most common cause of purpura, but nonaccidental injury should be considered when the distribution is not typical of accidental injury or the history is not consistent with a plausible mechanism of injury.

REFERENCES 1. Mudd SS, Findlay JS. The cutaneous manifestations and common mimickers of physical child abuse. J Pediatr Health Care. 2004;18:123129. 2. Warren PM, Kagan RJ, Yakaboff KP, et al. Current management of purpura fulminans: a multicenter study. J Burn Care Rehabil. 2003;24:119-126. 3. Chalmers E, Cooper P, Forman K, et al. Purpura fulminans: recognition, diagnosis, and management. Arch Dis Child. 2011;96:1066-1071. 4. Yalcindag A, Sundel R. Vasculitis in childhood. Curr Opin Rheumatol. 2001;13:422-427. 5. Eleftheriou D, Dillon M, Brogan P. Advances in childhood vasculitis.

Curr Opin Rheumatol. 2009:21:411-418. 6. Piram M, Mahr F. Epidemiology of immunoglobulin A vasculitis (Henoch-Schonlein): current state of knowledge. Curr Opin Rheumatol. 2013;25:171-178. 7. Bauzo A, Espana A, Idoate M. Cutaneous polyarteritis nodosa. Br J Dermatol. 2002;146:694-699. 8. Siberry GK, Cohen BA, Johnson B. Cutaneous polyarteritis nodosa: report of cases in children and review of the literature. Arch Dermatol. 1994;130:884-889. 9. Tristani-Firouzi P, Meadous KP, Vanderhooft S. Pigmented purpuric eruption of childhood. Pediatr Dermatol. 2001;18:299-304.

CHAPTER

59

Vesicles and Bullae Andrea L. Zaenglein

BACKGROUND The diagnosis of vesicular and bullous diseases in childhood can be a difficult task. To better understand the defining characteristics of vesiculobullous disorders, a general knowledge of skin anatomy is helpful. Figure 59-1 illustrates normal skin histology. The numerous causes of blistering can be divided into those with neonatal versus childhood onsets. Additionally, secondary characteristics, such as distribution and morphology, can further limit the differential diagnosis.

FIGURE 59-1. Normal skin histology. It is important to have a clear understanding of the terminology used to describe vesicular or bullous lesions and their associated physical features. A vesicle is a fluid-filled, dome-shaped lesion of 0.5 cm or less; if such a lesion is greater than 0.5 cm, it is termed a bulla. The fluid inside may be clear or

hemorrhagic in nature. If the material is purulent, the lesion is called a pustule. Secondary lesions, including crusting, excoriation, scaling, milia, and scarring, may also be noted. An erosion is a superficially denuded vesicle with damage confined to the epidermis. Ulceration is a deeper lesion, with loss of the entire depth of the epidermis. Secondary scarring does not usually result from erosion, except if secondary infection occurs, but is common with ulceration given the depth of the injury (Table 59-1; Figure 59-2). Milia (small, white, superficial epidermal cysts) may result from a healing blistering process.

FIGURE 59-2. Clinical examples. A. Vesicle (scabies). B. Bulla (adverse reaction to topical cantharidin). C. Pustules (transient

neonatal pustular melanosis). D. Erosion (eczema herpeticum). E. Ulcer (ulcerated infantile hemangioma). TABLE 59-1

Definition of Vesiculobullous Lesions: Primary and Secondary Findings

Lesion

Definition

Primary Vesicle

Fluid-filled lesion 0.5 cm

Pustule

Blistering lesion filled with purulent exudate

Secondary Erosion

Partial loss of epidermis

Ulceration

Complete loss of epidermis with extension into dermis

Excoriation Scratched primary lesions; may be linear or crusted Scaling

Dry, superficial accumulations of keratin

Crusting

Dried serous, hemorrhagic, or purulent exudate (i.e. scabbing)

Milia

Small 1- to 2-mm epidermal cysts

Whether the vesicle or bulla is flaccid or tense, is another defining characteristic. A tense bulla suggests a deeper process in which the split in the epidermis lies below the level of the lamina lucida located in the basement membrane zone. This gives the lesion enough support to hold the fluid tense under pressure. In contrast, a flaccid bulla is a more superficial process that generally occurs higher in the epidermis, where skin tension may easily disrupt the lesion’s integrity (Figure 59-3). Helpful in differentiating a tense from a flaccid bulla are the Nikolsky and Asboe-Hansen signs. A

positive Nikolsky sign occurs when a blister is induced by rubbing normalappearing skin with the eraser of a pencil. The Asboe-Hansen sign is elicited by applying lateral pressure to the edge of a bulla away from the center. If the lesion extends, the split is higher up in the epidermis and the lesion is classified as flaccid. If the lesion does not extend, a deeper split is suggested, and the lesion is defined as tense.

FIGURE 59-3. Flaccid (open arrow) and tense (solid arrow) bullae in a patient with recessive dystrophic epidermolysis bullosa.

CLINICAL PRESENTATION The clinical presentation of the numerous vesiculobullous conditions varies tremendously, depending on whether the lesion is a primary process or a manifestation of an underlying illness. A complete history should include the duration of disease, previous or current infection, other family members affected, recent travel, environmental or household exposures, and associated symptoms. A thorough review of systems can help ascertain the severity of the illness, and systemic complaints such as fever, arthralgias, lethargy, and weight loss may help define a cause. Special care must be taken in the evaluation of neonates, because associated symptoms are not always well defined in this age group, and occult infection can easily be missed. If an adverse drug reaction is suspected, a detailed drug history is essential. Even regularly used over-the-counter medications, such as nonsteroidal antiinflammatory drugs, can cause blistering reactions, including bullous fixed drug reactions, pseudoporphyria, or even toxic epidermal necrolysis. A detailed family history is vital to the diagnosis of many genetic vesiculobullous disorders, including various forms of epidermolysis bullosa

simplex and Hailey-Hailey disease. A positive family history of autoimmune diseases may also assist in making a diagnosis. Aside from identifying the nondermatologic features on physical examination, a clear description of the skin lesions is necessary, using the terms defined earlier. Delineating the nature of the lesions, the pattern of eruption, and its arrangement and distribution can be invaluable in differentiating among vesiculobullous diseases. Note whether the lesions are grouped or scattered, localized to a specific area or generalized, or linear or annular in configuration; note whether they follow the lines of Blaschko or occur in a dermatomal distribution. It is also important to identify the duration and timing of the lesions. The history should reveal whether the lesions are acute, subacute, or chronic in duration. Lesions may appear at the same time, in crops, or follow a cyclical pattern, with periods of activity followed by resolution. The lesions may appear to be recently erupted, resolving, or a mixed pattern. Attention to the mucosal surfaces is important, because many systemic blistering disorders involve the oral, genital, or ocular mucosal surfaces.

DIFFERENTIAL DIAGNOSIS As noted above, the age of onset of a disorder is an important clue in the diagnosis of vesiculobullous disorders. The differential diagnoses of neonatal and childhood vesiculobullous disorders are described in Tables 59-2 and 593, respectively.1-6 Lesions that appear in the neonatal period may be genetic, infectious, or even iatrogenic. Infectious causes should always be considered in a newborn with vesiculobullous findings. If the lesions are congenital, a genetic blistering disorder should be considered. Some autoimmune disorders can be transferred through the presence of maternal antibodies, up to about 6 months of age. Disorders in this category include neonatal lupus, neonatal pemphigus, and pemphigus foliaceus. TABLE 59-2

Disorder

Neonatal Vesiculobullous Disorders Onset and Duration

Clinical Characteristics

Diagnosis

Benign, transient erythema toxicum neonatorum

24–72 hr after birth; lasts 1 wk

Neonatal acne Weeks to months

Blotchy erythema Clinical, Gram stain: with small central eosinophils pustule; generalized, except palms and soles; full-term, healthy infants

Erythematous Clinical, stains papules and mostly negative, but pustules on face and may see yeast forms chest; healthy neonates

Transient neonatal pustular melanosis

Birth; Pustules without hyperpigmentation erythema; collarette lasts months when wiped away; heals, but hyperpigmentation lasts months; generalized, palms, and soles; healthy neonates; more common in darker pigmented skin types

Clinical, Gram stain: neutrophils

Miliaria (rubra or crystal lina)

Days to months; lasts hours to days

Small erythematous papules (rubra) to clear vesicles (crystallina) on forehead, upper chest, and back; history of fever, overheating

Clinical, all stains negative

Extremely pruritic vesicles and

Clinical, biopsy Biopsy

Infantile Days to months; acropustulosis may last 2–3 yr

pustules occurring in crops on hands and feet Eosinophilic pustular folliculitis

Birth to 1 yr; may last years

Pruritic follicularbased papules and pustules on scalp and face; very rare

Biopsy

Congenital langerhans cell histiocytosis

Birth to days

Vesicles to crusted papules, petechiae; solitary to numerous; scalp, groin, flexures most common

Biopsy, electron microscopy

Sucking blister Birth or later

Noninflamed blister; Clinical, all stains usually solitary; negative most often on hands or wrists

Inflammatory mastocytosis

Mastocytoma: solitary pink, tan, or brown macule to indurated plaque with overlying bullae

Birth to several months

Urticaria pigmentosa: multiple lesions as described for mastocytoma Diffuse cutaneous mastocytosis: peau d’orange (indurated yellowish orange skin) with vesicles and bullae at sites of

Clinical, all stains negative, biopsy showing mast cells

trauma Infectious syphilis

Birth

Vesicles and bullae, Serology, DFA; often eroded; darkfield perioralo (snuffles), examination hands, and feet; may be localized or generalized; associated with hepatosplenomegaly and pseudoparalysis

Candidiasis, congenital

Birth to 24 hr; lasts 2 wk

Generalized erythema and pustules or vesicles

KOH: pseudohyphae

Candidiasis, neonatal

Past 1 wk of age

Erythematous macules or papules with satellite pustules; diaper area and flexures most commonly affected

KOH: pseudohyphae

Herpes simplex

Birth to weeks

Vesicles or pustules; Tzanck, DFA, PCR, erosions to scarring; culture, or serology localized to generalized

Varicella

Birth

Linear scarring, erosions; often affects extremities; fetal anomalies occur with first- or second-trimester infection

Tzanck, DFA, PCR, culture, or serology

Scabies

Weeks

Vesicles to crusted

Mineral oil

papules, nodules preparation with burrows; hands, feet, axilla, scalp Genetic incontinentia pigmenti

Birth

Linear and whorled vesicles along lines of Blaschko; progresses to verrucous lesions; localized to limb or generalized; may be associated with seizures, retinopathy, and eosinophilia

Biopsy, genetic testing (NEMO gene)

Epidermolysis bullosa

Birth to teens (for certain forms such as WeberCockayne)

Noninflammmatory vesicles, bullae; often eroded; milia with dystrophic forms; extremities most often affected; severity depends on type; some forms associated with pyloric atresia, Gl involvement, failure to thrive

Biopsy, electron microscopy, genetic testing (keratins 5/14, plectin, laminin 5, collagen XVII, α6β4 integrin, collagen VII)

Transient bullous dermolysis of the newborn

Birth; resolves within months

Extensive blistering due to transient defect in collagen VII

Biopsy, electron microscopy

Generalized erythema and scaling with bullae

Biopsy, genetic testing (keratins 1/10)

Epidermolytic Birth hyperkeratosis (bullous

congenital ichthyosiform erythroderma)

and erosions; evolves to generalized ichthyosis with flexural predominance

Ichthyosis bullosa of siemens

Birth

Milder blisters and erosions than epidermolytic hyperkeratosis; episodic superficial peeling

Clinical, biopsy; genetic testing (keratin 2e)

AEC syndrome birth (HayWells)

Birth

Associated with erosive scalp dermatitis

Clinical, genetic testing (p63

Ectodermal Birth dysplasia; skin fragility syndrome

Generalized Biopsy, genetic erythema with testing (plakophilin) superimposed bullae, erosions; perioral redness and desquamation; sparse hair and dystrophic nails; abnormal sweating

Congenital erosive and vesicular dermatosis

Premature infants; diffuse vesicles, erosions, and crusting; palms, soles, face relatively spared; heals with reticulated scarring

Birth; heals in weeks to months

Biopsy

Kindler syndrome

Birth to months

Acral blistering that later develops poikiloderma

Biopsy, electron microscopy

Metabolic acrodermatitis enteropathies

Birth to 6 mo

Copper-colored Low serum zinc patches and level, low alkaline plaques; perioral phosphatase region, groin, hands, and feet; overlying vesicles and bullae

Autoimmune herpes gestationis

Birth; resolves in weeks

Very pruritic, urticarial plaques with overlying tense vesicles, bullae; results from transfer of maternal antibodies; selflimited

Biopsy, direct and indirect immunofluorescence

Neonatal pemphigus

Birth; resolves in a Pruritic, urticarial few weeks plaques with flaccid bullae, erosions; occurs in infants of mothers with active pemphigus vulgaris or foliaceus due to transfer of maternal antibodies

Maternal history, biopsy, direct and indirect immunofluorescence

AEC, ankyloblepharon-ectodermal dysplasia-clefting; DFA, direct fluorescent antibody; Gl, gastrointestinal; KOH, potassium hydroxide; NEMO, NF-kappa B essential modulator; PCR, polymerase chain reaction.

TABLE 59-3

Infantile and Childhood Vesiculobullous Disorders Clinical

Disorder

Characteristics

Diagnosis

Psoriasis (pustular)

Widespread erythematous, welldefined papules with overlying pustules; may be exacerbated by systemic corticosteroid use

Biopsy, Giemsa stain shows sterile neutrophils

Allergic contact dermatitis

Very pruritic; may be Clinical, biopsy localized or generalized; erythematous papulovesicles to bullae; linear distribution with poison ivy

Dyshidrotic eczema

Erythematous papulovesicles to bullae on hands and feet; may have generalized reaction

Clinical, biopsy

Erythema multiforme

Targetoid to bullous erythematous macules or maculopapules; palms, soles, mucous membranes frequently affected; HSV most common trigger

Clinical, biopsy

StevensJohnson syndrome; toxic epidermal necrolysis

Generalized erythematous macules to morbilliform eruption, with frequent progression to flaccid

Clinical, biopsy

Acquired

bulla formation and widespread desquamation; mucosal involvement common; drugs, infections, vaccinations may trigger Phototoxic; drug

Erythematous macules or papulovesicles with vesicle or bulla formation in photodistribution

Clinical, biopsy

Acute generalized exanthematous pustulosis

Generalized Clinical, biopsy erythematous small papules or erythroderma studded with numerous small pustules; associated with sudden fever; drug, viral, mercury, immunization triggers possible

Burn

Well-defined to figured erythema with overlying vesicle or bulla formation; may be sign of abuse

Clinical

Friction blister

Noninflamed vesicle to bulla at site of friction

Clinical

Coma blister

Noninflamed bulla occurring in comatose patient; possible associated bruising;

Clinical

generally occurs 24 hr after onset of coma Hydroa vacciniforme

Crusted erosions with varioliform scarring; photodistribution

Clinical

Pemphigus vulgaris

Generalized flaccid, easily eroded, crusted bullae; Nikolsky sign positive; may be drug induced

Biopsy with direct and indirect immunofluorescence

Pemphigus foliaceus

Erythematous, very superficially crusted, eroded, polycyclic plaques; most common on the head and neck

Biopsy with direct and indirect immunofluorescence

Paraneoplastic pemphigus

Generalized pemphigus Biopsy with direct lesions with severe and indirect mucosal lesions immunofluorescence common; often refractory to treatment; may be associated with lymphoma or Castleman tumor

Epidermolysis bullosa acquista

Skin fragility to tense bulla formation; healing with scarring and milia; mucous membranes may be involved

Biopsy with immunofluorescence

Bullous

Urticarial plaques with

Biopsy with direct

Autoimmune

pemphigoid

overlying tense bullae; may be annular or polycyclic; facial and palmar or plantar involvement more common in children

and indirect immunofluorescence

Bullous lupus erythematosus

Generalized, pruritic, tense bullae; predominantly photodistributed; very rare in childhood

Biopsy with immunofluorescence, antinuclear antibodies

Dermatitis herpetiformis

Intensely pruritic papulovesicles to vesicles; symmetrical over extensor surfaces; often associated with gluten-sensitive enteropathy

Biopsy with immunofluorescence

Linear IgA disease (chronic bullous disease of childhood)

Abrupt onset of tense vesicles or bullae, often in string-of-pearls configuration; groin and perioral region favored; mucous membrane involvement common

Biopsy with immunofluorescence

Moist, erythemtous, eroded plaques in flexures; may have vesicles or pustules; presents in second to fourth decades

Biopsy, family history, genetic testing (ATP2C1 gene)

Genetic Hailey-Hailey disease

Epidermolysis bullosa

Noninflammatory bullae appearing at sites of trauma; may present from birth to teen years

Biopsy, family history, genetic testing

Pachyonychia congenita

Hypertrophic nails, hyperkeratotic palms and soles, leukokeratosis beginning in infancy to childhood; bullae may form at sites of friction usually in late childhood

Clinical, genetic testing (keratins 6/16 or 17)

Porphyrias (congenital erythropoietic porphyria, porphyria cutanea tarda, variegate porphyria)

All may have varying degrees of photosensitivity with blistering; severe types present early, porphyria cutanea tarda in childhood

Biopsy, porphyrin testing

Honey-colored, crusted, oozing vesicles with erythema; may be primary infection (common in perioral, perinasal regions) or secondary infection (atopic dermatitis, varicella); caused by Staphylococcus, Streptococcus, or both

Clinical, Gram stain, culture

Infectious Impetigo

Blistering distal dactylitis

Erythema with bullae on Clinical, Gram stain, distal fingers; caused by culture β-hemolytic streptococci

Staphylococcal scalded skin syndrome

Painful erythema with localized flaccid bullae; may generalize to erythroderma; patient is ill appearing, with malaise, fever; Nikolsky sign positive; neonates most susceptible; caused by staphylococcal exfoliative toxins

Clinical, cultures from mucosal surfaces and blood

Scabies

Vesicles to crusted papules or nodules with burrows; hands, feet, axilla, scalp (in infants)

Mineral oil preparation

Bullous arthropod reaction

Pruritic vesicles, bullae, pustules on exposed areas; causes include fleas, red ants

Clinical, biopsy

Herpes simplex

Grouped vesicles on erythematous base; erosions may heal with scarring; painful oral ulcerations in primary outbreaks; localized (perioral, genital) to generalized (eczema herpeticum)

Tzanck, DFA, PCR, culture, or serology

Varicella

Crops of pruritic

Clinical, DFA, PCR,

(chickenpox)

vesicles that are pustular and crusted; can heal with scarring; caused by varicellazoster virus

Zoster

Dermatomal distribution Clinical, DFA, PCR, of urticarial papules or culture plaques to vesicles; pain may be associated, but less than in adults

Dermatophytosis Annular, pink, scaling pruritic plaques; often bullous on the feet or hands Hand-foot-andmouth disease

culture

KOH

Oval vesicles and bullae Clinical PCR, culture on hands and feet; painful erosions in mouth; most caused by coxsackievirus A16; severe blistering with A6 strain

DFA, direct fluorescent antibody; HSV, herpes simplex virus; KOH, potassium hydroxide; PCR, polymerase chain reaction.

DIAGNOSTIC EVALUATION Although in many cases the clinical picture is sufficient to determine the diagnosis, laboratory testing is indicated in certain situations. The laboratory workup of a patient with a vesiculobullous disorder should include investigations to rule out plausible causes and those that may place the patient at risk for significant morbidity or mortality, whether benign, infectious, acquired, or genetic. If a viral cause is suspected, a Tzanck smear, rapid fluorescent antibody stain, polymerase chain reaction assay, or viral culture should be considered to rule out herpes and varicella infections. If a

bacterial cause is suspected, a Gram stain and appropriate cultures can aid in the diagnosis of gram-positive and gram-negative bacterial infections. A Wright stain can help elucidate the predominant inflammatory cell type (e.g. neutrophils, eosinophils, or mixed infiltrates). For suspected fungal infections, Giemsa stain or a potassium hydroxide preparation can help identify hyphal and yeast forms. A particularly thorough workup should be done in neonates and in immunocompromised children of all ages. Infectious diseases can present atypically in these special patients, and without timely diagnosis and treatment the outcome can be devastating. The workup of a neonate with a blistering disorder of unknown cause is outlined in Table 594. TABLE 59-4

Workup for Unidentified Vesicular or Pustular Rash in Neonates

Study

Cause

Direct preparations Tzanck

Herpesviruses

Gram stain

Bacteria

Potassium hydroxide

Fungal elements

Mineral oil

Scabies

Giemsa or Wright

Inflammatory cell type

Darkfield

Syphilis

Fluorescent antibody testing

Herpes simplex virus, varicella-zoster virus, syphilis, immunobullous disorders

Histology Biopsy

If cause cannot otherwise be ascertained

Electron

Epidermolysis bullosa, Langerhans cell

microscopy

histiocytosis

Laboratory Complete blood count with differential

Infectious and parasitic causes, incontinentia pigmenti (eosinophils)

Zinc, alkaline phosphatase

Acrodermatitis enteropathica

Polymerase chain reaction

Herpes simplex virus, varicella-zoster virus, enterovirus

Porphyrins

Porphyria

Antinuclear antibody

Lupus erythematosus

MANAGEMENT Aside from treatment of the underlying cause or condition, there are some general principles regarding the management of vesicles and bullae. As a rule, vesicles and small bullae should not be disturbed. Open lesions should be kept clean by gentle washing with a soapless cleanser, coated with bland petrolatum (Aquaphor is typically used in the neonatal population), and covered with a sterile bandage if needed. If a large bulla is intact and in an area that causes pain, or if it keeps expanding due to pressure, the fluid can be drained using a sterile large-bore needle or number 11 blade. A linear incision should be made near the base of the bulla to allow drainage of the fluid contents. The incision should be large enough to ensure that the bulla will not reform after drainage but small enough to keep the blister roof in place, because unroofed lesions are more painful. With extensive denudation, fluid and electrolyte management may be challenging owing to the increased insensible losses. Temperature control may be disrupted, especially in neonates. Pain may be significant and requires special attention. Pain control may be needed around the clock or during certain activities such as dressing changes and physical therapy.

CONSULTATION Dermatology for assistance with diagnosis, inpatient management, and if the condition is ongoing, outpatient follow-up. Infectious diseases for recommended testing and interpretation of results, empirical antibiotic therapy, and adjustment of therapy. Critical care or burn center when cardiorespiratory support is needed, the extent of bedside interventions exceeds the capacity of a noncritical care setting, or resources and expertise are unavailable at the existing institution. Physical or occupational therapy for maintaining or reestablishing mobility, reconditioning, or implementing medical equipment (e.g. splints). Plastic surgery for management of skin lesions that may require grafting or scar revision.

ADMISSION CRITERIA Because neonates with blistering conditions are at high risk for serious infectious or other life-threatening conditions, they require hospitalization to conduct an appropriate evaluation, initiate therapy, and manage potential complications. Infants and children with vesiculobullous eruptions warrant admission when a serious condition is suspected that requires prompt diagnosis or therapy. Patients demonstrating rapid progression or extensive skin involvement merit hospitalization. Patients unable to tolerate sufficient oral intake or manage skin care in the outpatient setting should be admitted.

DISCHARGE CRITERIA Stabilization of the patient and control of the underlying condition. Ability to complete necessary therapy in the outpatient setting. Adequate follow-up in place.

KEY POINTS Vesiculobullous disorders constitute a wide variety of conditions, including some that are benign and self-limited, acute or chronic, disfiguring, debilitating, or even life-threatening. The clinical presentation often provides sufficient diagnostic information, but when a serious causative or underlying condition is suspected, appropriate infectious, immunologic, genetic, or autoimmune testing is indicated. Many vesiculobullous conditions are self-limited, but complications of the skin lesions can include scarring, deformities, recurrence, superinfection, fluid and electrolyte imbalance, and pain. In general, skin care involves gentle cleansing and application of bland petroleum jelly to all open areas. Any infectious causes should be treated concomitantly.

REFERENCES 1. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed. Philadelphia: Elsevier; 2006. 2. Goddard DS. Gilliam AE, Frieden IJ. Vesiculobullous and erosive diseases in the newborn. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 3rd ed. London: Mosby; 2003:523-538. 3. Lucky AW. Transient benign cutaneous lesions in the newborn. In: Eichenfield LF, Frieden IJ, Esterly NB, eds. Textbook of Neonatal Dermatology. 2nd ed. Philadelphia: WB Saunders; 2008:85-98. 4. Frieden IJ, Howard R. Vesicle, pustules, bullae, erosions and ulceration. In Eichenfield LF, Frieden IJ, Esterly NB, eds. Textbook of Neonatal Dermatology. 2nd ed. Philadelphia: WB Saunders; 2008:131-158. 5. Van Praag MCG, Van Rooij RWG, Folkers E, et al. Diagnosis and treatment of pustular disorders in the neonate. Pediatr Dermatol. 1997;14:131-143. 6. Meadows KP, Egan CA, Vanderhooft S. Acute generalized

exanthematous pustulosis, an uncommon condition in children: case report and review of the literature. Pediatr Dermatol. 2000;17:399-402. 7. van Doornum GJ, Guldemeester J, Osterhaus AD, Niesters HG. Diagnosing herpesvirus infections by real-time amplification and rapid culture. J Clin Microbiol. 2003;41:576-580. 8. Ferrari S, Pellegrini G, Mavilio F, De Luca M. Gene therapy approaches for epidermolysis bullosa. Clin Dermatol. 2005;23:430-436.

Vascular Anomalies

CHAPTER

60

Lily Changchien Uihlein and Marilyn G. Liang

BACKGROUND More than one-third of infants are born with a vascular birthmark.1 Although most of these lesions are benign and uncomplicated, a minority require treatment and inpatient care. The pediatric hospitalist should be able to recognize major types of vascular anomalies and identify lesions requiring referral to, or immediate medical care in collaboration with, vascular anomaly specialists in fields such as dermatology, surgery, hematology/oncology, pathology, orthopedics, and radiology. In 1996, vascular anomalies were reclassified into two main categories: malformations and tumors (Table 60-1).2,3 Vascular malformations are comprised of structurally abnormal vessels with normal endothelial turnover, and are subcategorized based on their endothelial components (e.g. capillary, venous, lymphatic, and/or arteriovenous) and flow characteristics (i.e. slow flow vs. fast flow). These anomalies may be stable or progressive; they generally do not regress. In contrast, vascular tumors arise by endothelial hyperplasia, and may be benign, borderline, or sometimes malignant. TABLE 60-1

Biological Classification of Vascular Birthmarks

Tumors

Malformations

Infantile hemangioma

Capillary

Congenital hemangioma

Venous

Kaposiform

Arterial

hemangioendothelioma Tufted angioma

Lymphatic Combined

Source: Used with permission from Mulliken JB, Glowacki J Plast Reconstr Surg. 1982;69:413 (Table 1).

VASCULAR MALFORMATIONS Capillary malformations (also known as “port-wine stains”) are slow-flow lesions that may be focal, regional, or diffuse. Clinically, capillary malformations are pale pink to deep red blanching patches that are present at birth and generally permanent. Over time, some lesions, particularly those on the face, may darken, thicken, and become more nodular. Regional and diffuse capillary malformations may be associated with soft tissue or bony overgrowth or undergrowth. Fading macular stains of infancy (also referred to as “angel’s kisses,” “stork bites,” or “salmon patches”) are a subset of capillary malformations located on the glabella, eyelids, forehead, and posterior neck. Unlike the typical vascular malformation, these lesions may fade or disappear entirely after 1 to 2 years of life; however, some lesions, particularly those on the nape of the neck, may persist. Venous malformations (sometimes called “venous angioma” or “cavernous hemangioma”) are slow-flow vascular malformations comprised of irregular, dilated venous channels. Lesions are present at birth, though they may not be clinically evident. Typically, venous malformations present as soft, compressible bluish papules, nodules, or masses that tend to become more prominent with age, dependency, and physical activity (Figure 60-1). Lesions may be confined to the skin and subcutaneous tissue, or may involve deeper structures such as muscle, bone, and viscera. Diminished or stagnant blood flow within ectatic venous channels may lead to production of thrombin and conversion of fibrinogen to fibrin, resulting in chronic localized intravascular coagulation with episodes of localized thrombosis or bleeding.4

FIGURE 60-1. Venous malformation on back of a six-year old boy. Lymphatic malformations consist of irregular, ectatic lymphatic channels, and are classified as macrocystic or microcystic based on the size of the cystic spaces present. Microcystic lesions (formerly called “lymphagioma circumscriptum”) may form clear or hemorrhagic thin-walled vesicles or hyperkeratotic papules at the surface of the skin. Macrocystic lymphatic malformations (formerly referred to as “cystic hygroma”) are usually visible at birth, commonly occur on the neck and axilla, and form large, subcutaneous, compressible masses. Arteriovenous malformations (AVMs) are fast-flow lesions consisting of structurally abnormal arterial and venous vessels directly connected without an intervening capillary bed. Although present at birth, many AVMs may not be apparent until childhood. Early AVMs typically present as pink to red patches on the head or neck and may mimic a capillary malformation or infantile hemangioma. Lesions may have increased warmth, or a palpable thrill. Over time, AVMs may expand, darken, and invade deeper structures, particularly after pregnancy, puberty, trauma, or radiologic or surgical treatment. Late-stage lesions may cause deep destruction with necrosis, ulceration, severe pain, and bleeding. Large AVMs may induce high-output cardiac failure due to increased blood flow. Combined malformations are vascular malformations that include more

than one anomalous vessel type, and are frequently associated with skeletal and soft tissue hypertrophy or hypotrophy. Klippel-Trenaunay syndrome is a slow-flow combined anomaly comprised of abnormal capillary, lymphatic, and venous elements. In contrast, Parkes Weber syndrome is fast-flow combined anomaly characterized by capillary staining with arteriovenous fistulas. Both Klippel-Trenaunay and Parkes Weber syndromes may present with the triad of a capillary stain, venous varicosities, and soft tissue and bony hypertrophy of the lower limb. CLOVES syndrome consists of congenital lipomatous overgrowth (typically, a truncal lipomatous mass), vascular malformations (frequently capillary malformations, lymphatic malformations, or high-flow lesions), epidermal nevi, and scoliosis, skeletal, and spinal anomalies.5

DIAGNOSTIC EVALUATION The assessment and management of a vascular malformation depends on the type, location, and extent of the lesion. Typically, venous malformations and lymphatic malformations can be diagnosed clinically or with the aid of magnetic resonance imaging (MRI). AVMs can usually be diagnosed by ultrasonography or MRI. Infants with a capillary malformation in the distribution of the ophthalmic (V1) branch of the trigeminal nerve should be evaluated for Sturge-Weber syndrome, characterized by a facial capillary malformation, leptomeningeal angiomatosis, and vascular malformations of the choroid of the eye. Clinical manifestations may include seizures, developmental delay, and glaucoma. Further workup should include MRI with and without contrast to assess for leptomeningeal angiomatosis, and an ophthalmologic examination to evaluate for choroidal vascular malformations and glaucoma. Like other congenital midline lesions such as lipomas, tails, or dermal sinuses, capillary malformations in the midline lumbosacral region may warrant further investigation for occult spinal dysraphism. Paraspinal lumbosacral capillary malformations that appear in combination with a second congenital midline skin lesion present a particularly high risk of spinal anomalies.6 Evaluation should include ultrasonography for infants less than 4 months of age, or MRI for children older than 4 months of age. Patients with regional capillary malformations of the lower limb, Parkes

Weber syndrome, or Klippel-Trenaunay syndrome may have overgrowth or undergrowth of the affected leg. Such patients should be evaluated by an orthopedic surgeon for limb length discrepancy around the age of 1 year. Multiple cutaneous venous malformations, particularly on the palms and soles, may be associated with gastrointestinal tract venous malformations in blue rubber bleb nevus syndrome. Clinical manifestations may include anemia from chronic occult gastrointestinal bleeding, abdominal pain, rectal bleeding, melena, or hematemesis. Further work up should include a complete blood count to assess for anemia, as well as imaging studies (such as MRI or computed tomographic scan) to evaluate for gastrointestinal involvement. Multifocal capillary malformations may be associated with fast flow vascular lesions in capillary malformation-arteriovenous malformation (CMAVM), which results from autosomal dominant mutations in RASA1.7 CMAVM typically presents with multiple pink-red, small, round-to-oval macules, some of which have a pale halo. Larger lesions are sometimes fastflow by Doppler exam. Although patients with CM-AVM generally have a benign clinical course, CM-AVMs have rarely been associated with cerebral AVM.8 As a result, further workup with MR/magnetic resonance angiogram (MRA) of the brain may be considered.

MANAGEMENT Capillary malformations may be treated with pulsed dye laser, which selectively targets oxyhemoglobin. The goal of treatment of venous malformations is to prevent disfigurement, functional impairment, pain, and swelling. Conservative management may include compression therapy only, which can limit swelling, alleviate pain, and reduce localized intravascular coagulation.9 Sclerotherapy and surgical excision, alone or in combination, can be considered for more symptomatic lesions. Low molecular weight heparin may improve pain resulting from localized thrombus formation.4 Treatment of lymphatic malformations may be considered to preserve function, limit deformity, and minimize pain and swelling. The primary therapeutic interventions for lymphatic malformations, like venous malformations, are sclerotherapy and surgical excision. Recently, marked

regression of lymphatic malformations has been reported after treatment with oral sildenafil.10 Microcystic lymphatic malformations tend to be less responsive to sclerotherapy, and are sometimes more successfully treated with pulsed dye laser (when hemorrhagic), carbon dioxide laser, and NdYAG laser.11-13 Management of AVMs is challenging. Treatment generally consists of embolization, surgical resection, or a combination of the two; however, rates of recurrence are high, ranging between 85% and 98%.14 The risk of recurrence has been found to be lower following treatment of earlier-stage lesions.14

ADMISSION CRITERIA Certain clinical scenarios require immediate attention and possible inpatient admission for complications of vascular malformations. A patient with Sturge-Weber syndrome and extensive leptomeningeal angiomatosis may require hospitalization for management of seizures or following surgical procedures, such as goniotomy or trabeculotomy, for treatment of glaucoma. Extensive venous malformations may cause localized intravascular coagulopathy, with risk for deep venous thrombosis and pulmonary embolus, particularly perioperatively; inpatient management is recommended. Patients with blue rubber bleb nevus syndrome may require inpatient stabilization or possible surgical intervention for gastrointestinal bleeding, intussusception, volvulus, or infarction. Patients with lymphatic malformations may be hospitalized for bacterial superinfection (which may present as sudden enlargement of the lesion), or less commonly, chylous pleural effusions and chylous ascites leading to respiratory distress. Large AVMs may result in ulceration, pain, bleeding, obstruction of vital structures, and rarely, high-output cardiac failure, which may warrant inpatient admission for endovascular embolization, surgical resection, or management of heart failure. Complications of combined vascular malformations of an extremity (such

as ulceration, pain, bleeding, recurrent cellulitis, deep venous thrombosis, and pulmonary embolism), may require immediate inpatient care. In addition, patients with combined vascular malformation involving the lower limb (such as Klippel-Trenaunay or Parkes Weber syndromes) may be hospitalized following epiphysiodesis for leg length discrepancy. Patients with CLOVES syndrome may be hospitalized following spinal fusion for treatment of scoliosis. Patients with combined vascular anomalies (such as Klippel-Trenaunay, Parkes Weber, or CLOVES syndromes) may be admitted for surgical debulking.

VASCULAR TUMORS Infantile hemangiomas are the most common vascular tumor of infancy, affecting 1% to 2.6% of healthy newborns.1,15 The clinical appearance of these benign tumors of proliferating endothelial cells depends on their location in the skin. Superficial lesions typically present as brightly erythematous lobulated plaques, while deep lesions are bluish to skincolored, compressible subcutaneous plaques or nodules. Combined lesions exhibit both superficial and deep components. Infantile hemangiomas have a life cycle that is both predictable and unique. About 36% to 65% of hemangiomas are present at birth as a premonitory mark, such as a bruise-like lesion, erythematous patch, or area of pallor with or without telangiectasias.16,17 Hemangiomas typically undergo accelerated growth in the first 2 months of life, followed by less rapid growth through the end of infancy, then slow involution over years. Congenital hemangiomas are benign vascular tumors that, unlike infantile hemangiomas, are fully developed at birth and do not exhibit accelerated postnatal growth.18 Two variants of congenital hemangioma have been described: rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH). RICH fully regress during infancy, while NICH tend to grow proportionally with the child and does not regress. Although variable in appearance, congenital hemangiomas are typically light purple to gray with multiple telangiectasias, and sometimes surrounded by a pale halo. Kaposiform hemangioendothelioma (KHE) is a rare infiltrative tumor that

typically appears in infancy and may mimic infantile hemangioma.19 Most commonly, KHE presents as a single, ill-defined, red to purple indurated plaque of the trunk or extremities. The clinical spectrum of KHE is broad, ranging from small superficial cutaneous lesions to large infiltrative lesions with involvement of fascia, muscle, and bone. Tufted angioma (TA) tends to develop in infancy or early childhood. TAs are generally ill-defined, infiltrating, firm, red to violaceous plaques, which may be associated with hyperhidrosis or hypertrichosis.20 Although the clinical course of TA varies, the most typical is slow growth over several months with stabilization in size; spontaneous regression has occasionally been reported.20-23 KHE and TA may overlap both clinically and histologically; some authors believe that these tumors may exist on a continuum. Furthermore, both KHE and TA may be associated with Kasabach Merritt phenomenon (KMP), profound thrombocytopenia and microangiopathic hemolytic anemia resulting from intralesional trapping of platelet and clotting factors. Common presenting features include (1) an enlarging lesion that becomes violaceous, indurated, and ecchymotic, (2) severe thrombocytopenia (frequently 200 mg, is the most common individual inciting agent.4 Drugs causing SJS/TEN with shorter regimens include trimethoprim-sulfamethoxazole and other sulfonamides, aminopenicillins, cephalosporins, and quinolones. Drugs that are often given for longer duration that can cause SJS/TEN include lamotrigine, carbamazepine, phenytoin, phenobarbital, valproic acid, nonsteroidal antiinflammatory drugs (particularly of the oxicam type) and allopurinol. With any of these medications, the highest risk is thought to occur in the first 2 months of treatment.4 It is also very important to recognize that carbamazepine, phenytoin, and phenobarbital have similar molecular structures and therefore a patient who reacts to one of these drugs may react to any of the others, and they should not be substituted for each other given the life-threatening nature of the reaction. Other causes such as infections, certain triggering systemic diseases (such as inflammatory bowel disease), and immunizations are much less common and generally more difficult to prove with the exception of Mycoplasma pneumonia, which is now a well-established cause of SJS. In children, infections (particularly M. pneumonia) are a more commonly identified cause of SJS. Other potentially causal infections include herpes simplex virus (HSV), Mycoplasma tuberculosis, group A streptococci, hepatitis B, EpsteinBarr, and enteroviruses.5,6 Of note, HSV is highly associated with EM, which in the past was thought to be on a spectrum with SJS but is now differentiated as a separate entity (see Differential diagnosis section below). There is compelling evidence to suggest that a genetic susceptibility to SJS/TEN exists; those afflicted have an impaired capacity to detoxify reactive

intermediate drug metabolites.7 HLA alleles have been associated with genetic susceptibility to SJS/TEN and may also play a role in pathogenesis. The HLA-B*1502 allele was first described in cases of carbamazepineinduced SJS/TEN in Han Chinese ancestral Asians. The risk is so high that the FDA recommends checking for HLA-B*1502 in at-risk Asian patients prior to starting carbamazepine.8 Interestingly, although HLA-B*1502 susceptibility has been determined to be population-dependent, other members of the larger HLA family (HLA-B75) have been associated to carbamazepine-induced SJS/TEN among other specific populations.9 Many other possible and/or confirmed HLA susceptibilities have been reported in various populations and with varying drug exposures as well as unique presentations. These include carbamazepine-induced reactions with HLAB*1502, HLA-B*1511, and HLA-B*3101, abacavir-induced reactions with HLA-B*5701, allopurinol-induced reactions with HLA-B*5801, methazolamide-induced reactions with HLA-B*5901, nevirapine-induced reactions with DRB1*0101, oxicam-induced reactions with HLA-A2 and HLA-B12, and sulfonamide-induced reactions with HLA-A29, HLA-B12, and HLA-DR7.9 SJS/TEN presentations appear to be delayed-reaction hypersensitivity reactions. Hypotheses of immunopathogenesis center around T-cell–mediated massive apoptosis in keratinocytes, leading to epidermal necrolysis. Studies suggest possible roles of three pathways: the Fas-FasL interaction, perforin/granzyme B, and granulysin. The particular role of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells is an active area of research. Various cytokines and chemokines are also being identified that may participate in trafficking, proliferation, and regulation of activation.9 Of note, immunocompromised patients, especially those who are HIV positive, are known to be at particular risk for the development of SJS/TEN. The histiologic features of SJS and TEN are full-thickness epidermal necrosis with sparse inflammatory cells. The severe epidermal necrosis is accompanied by incontinence of melanin pigment, colloid bodies, and subepidermal blister formation.10

CLINICAL PRESENTATION SJS/TEN most commonly develops 2 to 8 weeks after drug exposure and is

heralded by a prodrome of nonspecific constitutional symptoms that generally occur 1 to 14 days before the onset of necrotic mucosal or skin lesions. Children with SJS/TEN appear acutely ill. Fever and malaise are universal and are often accompanied by upper respiratory or gastrointestinal symptoms, or both. Skin lesions, which may begin simultaneously or after the onset of mucosal lesions, consist of tender, red to dusky macules that are often targetoid. Lesions generally appear first on the presternal trunk and face, less commonly on the palms or soles. As they spread, the disease may ultimately affect the face, neck, trunk, proximal ends of the extremities, and palms and soles with rapid coalescence (see Figure 65-1). Blistering, often heralded by the development of central graying within the skin lesions, may develop within hours or after several days. Blistering may be limited or consist of widespread epidermal detachment. In the latter case, large areas of raw, bleeding dermis may be seen. Both SJS and TEN are characterized by epidermal detachment in addition to mucosal involvement, although the development of large sheets of epidermal detachment in the absence of mucosal involvement is more characteristic of TEN.11 The frequent presence of overlapping clinical features in a given patient often makes definitive classification difficult. According to a consensus definition for the classification of SJS and TEN, epidermal detachment of 10% or less of total body surface area is classified as SJS, greater than 30% as TEN, and between 10% and 30% as SJS-TEN overlap.10 Other potential systemic complications of SJS/TEN include generalized lymphadenopathy, hepatosplenomegaly, hepatitis, arthritis, and arthralgias. Less common findings are myocarditis, pancreatitis, pulmonary complications (especially pneumonia and pneumothorax), and nephritis.12

FIGURE 65-1. Oxcarbazepine-indueed Stevens-Johnson syndrome. On the day of admission, hemorrhagic crusting of the lips and coalescing erythematous macules on the face and upper part of the trunk were apparent, along with early blister formation. At least two mucosa are involved and most commonly include the intraoral and ocular mucosa but may also include the urethra, anus, vaginal vault, and upper aerodigestive tract. M. pneumonia can lead to typical SJS or more rarely cause an atypical form of SJS that still involves at least two mucous membranes but lacks the classic cutaneous lesions.5,6 Therefore isolated and severe mucositis should always prompt serologic or polymerase chain reaction testing for M. pneumonia, particularly if there is ocular involvement. Classically, hemorrhagic crusts develop on the lips (Figure 651), and painful stomatitis leads to decreased oral intake. The skin of the conjunctivae also sloughs, leading to a purulent conjunctivitis. As the denuded mucosa of the eye attempts to heal, it can form synechea and either cause the lids to adhere to each other or the palpebral conjunctivae to adhere to the bulbar conjunctiva, which can lead to blindness. Genital mucosal involvement is complicated by pain, bleeding, and possible scarring. Respiratory or gastrointestinal involvement may also occur in more severe cases.10,11

DIFFERENTIAL DIAGNOSIS The two childhood entities that are most commonly confused with SJS/TEN are Kawasaki disease (KD) and SSSS. In KD, mucosal involvement consists

of chapped, red lips, without the erosions and hemorrhagic crusts typical of SJS. In addition, the conjunctival injection associated with KD lacks the purulent exudate of SJS. The skin lesions of KD are polymorphous and generally transient, without targetoid lesions or blistering, although superficial peeling of the fingertips and perineum is a characteristic finding seen later in the course of KD (see Chapter 147). SSSS, which usually occurs in infants and children younger than 2 years, is characterized by the onset of widespread, tender erythema (see Chapter 106). Crusting and superficial fissuring of the perioral and periocular skin is common, although mucous membrane involvement is universally absent. Staphylococcal exfoliative toxin selectively hydrolyzes desmoglein 1 (Dsg-1), which is found in all the strata of the skin. However, desmoglein 3 (Dsg-3), which is present in the deeper layers, is able to compensate in these areas (hence the superficial skin involvement of SSSS). The fact that Dsg-3 is found in all the strata of mucous membranes explains the lack of mucosal exfoliation in SSSS.13 While very superficial erosions, which most commonly occur in flexural areas, are a feature of SSSS, they are clinically and histologically distinct from the blistering and deeper skin separation seen in SJS/TEN. Although rare, paraneoplastic pemphigus, which is usually associated with malignancy, can present with mucosal findings identical to those of SJS. Painful, severe oral erosions, often involving the lateral tongue and vermilion, tend to precede a generalized cutaneous eruption of variable morphology. Paraneoplastic pemphigus has a more subacute presentation than SJS and may also involve internal organs such as the lungs, thyroid, kidney, smooth muscle, and gastrointestinal tracts. The malignancy most commonly associated with paraneoplastic pemphigus in children is Castleman disease, followed by lymphoma. Paraneoplastic pemphigus can be diagnosed with a skin biopsy, which shows features distinct from SJS on routine histology, and positive direct and indirect immunofluorescence studies. Grade IV acute graft-versus-host disease and burns can also mimic TEN and should be considered in the appropriate clinical setting. As explained above, EM, which may also have infectious and druginduced etiologies, was previously thought to be on a spectrum with SJS but is now differentiated as a separate entity. Although EM can present with painful acral targetoid papules and plaques that blister as well as oral

ulcerations, EM lacks the involvement of a second mucous membrane, which is characteristic of SJS. In addition, EM tends to have a much better prognosis.

TREATMENT As soon as the diagnosis of SJS/TEN is suspected, any potential drug trigger should be immediately discontinued. Early withdrawal of the causative drug may reduce mortality.14 Supportive therapy is the standard of care for SJS/TEN and includes close monitoring of fluid and electrolyte status, hydration, nutritional support, ophthalmologic care, wound care, and control of pain and infection. If Mycoplasma is the cause, it is not known whether treatment of the underlying infection helps to halt the skin necrosis. Insensible losses are increased as a result of fever and open skin lesions. Oral intake is often limited because of intraoral mucositis, making administration of parenteral fluids with careful monitoring of urine output and electrolytes even more essential. Nutritional support may become necessary when oral intake is inadequate for a prolonged period. Attempts to limit ongoing skin loss should be instituted. Even minor manipulation of intact skin can cause sloughing. Maneuvers to protect fragile skin may include assistance with repositioning, devices to protect against friction and pressure, and assistance with activities of daily living. Use of a controlled-pressure, thermoregulated bed can also be beneficial. Meticulous wound care is of utmost importance. Detached areas and wounds should be treated conservatively, without wide skin debridement unless the skin is entirely necrotic and becoming an infection risk. The blistered skin effectively serves as a natural dressing and may enhance reepitheliazation. Detached areas can be covered with petroleum gauze or nonadhesive biologic dressings. Periorificial erosions and hemorrhagic crusts should be gently cleansed daily and protected with petrolatum or a similar ointment. The mouth should be rinsed several times daily with a solution such as sterile isotonic saline. When the skin begins to heal, denuded areas will often adhere to each other inappropriately and then heal permanently. Care should also be taken to assure that any denuded areas of the oral and genital labia, penis, and perianal areas do not fuse together, by applying petrolatum multiple times per day. Care must also be taken if intubation is

necessary, as more blisters may be induced and the necrotic mucosa can be inadvertently pushed into the tracheobronchial tree. Transfer to an experienced burn unit or intensive care unit may be necessary in order to manage wounds and monitor fluid and electrolyte status. Because sepsis is the principal cause of death, patients should be closely monitored for signs of secondary infection. A complete blood cell count, liver enzyme analysis, urinalysis, and chest radiography should be performed to evaluate for associated visceral complications. The importance of early ophthalmologic consultation cannot be overemphasized because ocular complications, including blindness, are an important potential source of morbidity. The denuded areas will adhere to each other very rapidly and synechae must be cleaved immediately by an experienced ophthalmologist to prevent permanent damage. Amniotic membrane transplantation has been used successfully in the early stages of SJS/TEN, depending on the severity of ocular inflammation, but more controlled studies are warranted.15 There is currently no evidence-based, specific therapy accepted as the standard of care for pharmacologic management of SJS/TEN. Because of the rarity of such disorders and the frequent delay in diagnosis, large, controlled studies are more difficult to organize. The lack of in vitro cell cultures and animal models also makes evaluation of potential treatment modalities more challenging. The literature consists of many scattered case reports and retrospective analyses. Intravenous immunoglobulin (IVIG) has emerged as a potential immunomodulatory therapy for SJS/TEN and has the most data to support its use. Studies have demonstrated arrest in the progression of skin blistering and associated rapid recovery after IVIG infusion (Figure 65-2; also see Figure 65-1).12 IVIG appears to be a useful and safe therapy for children with SJS/TEN and has become the standard of care in many centers.12 Patients with comparable severity of disease were found to have reduced mortality and earlier cessation of further epidermal detachment with IVIG.16 A multicenter retrospective analysis of 14 centers suggested improved survival, and the authors recommended early treatment with high-dose IVIG (1 g/kg/day for 3 days).17 More recently, a Chinese group studied 82 cases and reported that while early corticosteroids appeared to have a benefit, the combination of steroids and IVIG had a greater effect than steroids alone.18

Empirically and based on many of the studies listed above, the typical dose for IVIG is 0.66 to 1 gram/kg/dose, given daily for a total dose of 2 to 3 grams/kg, but it is always advisable to consult with an experienced physician on the final dosage in case a more evidence-based dosage recommendation is available. Of note, there is a small retrospective pediatric case series that failed to show efficacy of IVIG but the patients mostly had SJS.19 As with other therapeutic modalities reported for SJS/TEN, treatment is most effective when initiated as early as possible in the disease course.

FIGURE 65-2. Clinical improvement (hospital day 5) of the patient in Figure 65-1 after four consecutive daily doses of intravenous immunoglobulin. Several treatments, including systemic steroids, plasmapheresis cyclosporine, cyclophosphamide, TNF antagonists, calcineurin inhibitors, plasmapheresis, and N-acetylcysteine, have been reported and variably reported to be beneficial.20 The use of systemic corticosteroids in patients with SJS/TEN has been widely debated and remains controversial. Although some advocate early, short-term use in drug-induced cases, a number of retrospective studies have suggested that systemic corticosteroids may not only fail to improve prognosis but also adversely affect outcome by increasing patient susceptibility to sepsis and gastrointestinal tract hemorrhage. Despite decades of controversy, the efficacy of systemic corticosteroids in patients with SJS/TEN has yet to be demonstrated by large controlled clinical trials.12,21

PROGNOSIS As expected, cases of TEN with the most extensive skin detachment are associated with the highest mortality rates, with large case series pointing to a mortality rate of approximately 30% in such instances. A recent European review of cases showed a 6-week mortality of 23%, whereas the subsequent overall 1-year mortality was 34%, with later deaths associated with severe comorbidities and older age.22 Cases of SJS/TEN triggered by drugs with a long half-life are more likely to result in a fatal outcome. However, with appropriate medical management the prognosis in children is good, with lower mortality and presumed faster re-epithelization than in adults. Late cutaneous complications of SJS/TEN include scarring, dyspigmentation, and fingernail loss and deformity. Large areas of scarring over joints may cause contractures, so physical therapy is an important prophylactic measure for patients at risk. Ocular sequelae are the most common serious cause of morbidity from SJS/TEN. Potential complications include psuedomembrane formation with immobility of the eyelids, symblepharon, entropion, trichiasis, corneal scarring, and permanent visual impairment. Lacrimal scarring with subsequent excessive tearing, anterior uveitis, and panophthalmitis may also occur. Labial, esophageal, and anal strictures, vaginal stenosis, urethral meatal stenosis, and phimosis can occur.21

CONSULTATION Dermatology: Can assist with diagnosis and wound management Ophthalmology: Can help monitor for and prevent ocular complications Plastic surgery: For wound management, acutely and long-term if needed Critical care: When an intensive level of care is required

ADMISSION CRITERIA Patients are managed in the hospital setting because progression of the illness can be swift. Inpatient care centers on: Fluid and electrolyte management and nutritional support

Meticulous care of areas of denuded skin and monitoring for secondary infection Close observation for multiorgan involvement, including respiratory compromise as a result of mucosal injury Coordination of subspecialty services Transfer to a critical care setting is warranted in patients with cardiorespiratory instability or sepsis or if the level of bedside care needed exceeds the capacity of non-intensive care unit staffing. Care in a burn center is often optimal for patients with extensive skin loss.

DISCHARGE CRITERIA Care can be transitioned to the outpatient setting when: Progression of the illness has ceased and the patient has stabilized. Hydration and nutrition can be maintained. Wound care can be managed. Appropriate outpatient follow-up is in place. KEY POINTS 1. Stevens-Johnson syndrome and toxic epidermal necrolysis represent parts of a spectrum of severe idisyncratic drug-related reactions that result in widespread skin breakdown and systemic toxicity. 2. Genetic susceptibility to SJS and TEN have been documented and it is mandatory that patients receiving high-risk drugs be screened for HLA susceptibilities prior to receiving these medications. 3. Common drugs causing these severe drug reactions have included but are not limited to allopurinol, anticonvulsants, and antibiotics, particularly sulfonamides. 4. Upon recognition of SJS or TEN, any potential drug trigger should be immediately discontinued and admission to hospital advised to provide appropriate supportive care and measures to limit further skin barrier disruption.

5. In the hospital setting, sepsis is the most common cause of mortality and patients should be closely monitored for signs of secondary infection.

REFERENCES 1. Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995;131:539-543. 2. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia: report of two cases in children. Am J Dis Child. 1922;24:526-533. 3. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68:355-361. 4. Harr T, French L. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;4:39. 5. Li K, Haber R. Steven-Johnson syndrome without skin lesions (Fuchs syndrome): a literature review of adult cases with Mycoplasma cause. Arch Dermatol. 2012;148:963-964. 6. Ravin KA, Rappaport LD, Zuckerbraun NS, et al. Mycoplasma pneumonia and atypical Stevens-Johnson syndrome: a case series. Pediatrics. 2007;119:e1002-1005. 7. Sullivan JR, Shear NH. The drug hypersensitivity syndrome. What is the pathogenesis? Arch Dermatol. 2001;137:357-364. 8. FDA US Food & Drug Administration. https://www.fda.gov/Drugs/ DrugSafety/. Accessed May 5, 2017. 9. Chung W, Shuen-Iu H. Recent advances in the genetics and immunology of Steven-Johnson Syndrome and toxic epidermal necrolysis. J Dermatol Science. 2012;66:190-196. 10. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96.

11. Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J Invest Dermatol. 1994;102:28S-30S. 12. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin (IVIG) in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: 7 cases and review of the literature. Pediatrics. 2003;112:1430-1436. 13. Bukowski M, Wladyka B, Dubin G. Exfoliative toxins of Staphylococcus aureus. Toxins. 2010;2:1148-1165. 14. Garcia-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136:323-327. 15. Hsu M, Jayaram A, Verner R, et al. Indications and outcomes of amniotic membrane transplantation in the management of acute StevenJohnson Syndrome and toxic epidermal necrolysis: a case-control study. Cornea. 2012;31:1394-1402. 16. Stella M, Clemente A, Bollero D, et al. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS): experience with high-dose intravenous immunoglobulins and topical conservative approach, a retrospective analysis. Burns. 2007;33:452-459. 17. Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139(1):26-32. 18. Chen J, Wang B, Zeng Y, et al. High-dose intravenous immunoglobulins in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis in Chinese patients: a retrospective study of 82 cases. Eur J Dermatol. 2010;20:743-747. 19. Koh MJ, Tay YK. Stevens-Johnson syndrome and toxic epidermal necrolysis in Asian children. J Am Acad Dermatol. 2010;62(1):54-60. 20. Pozzo-Magana BRD, Lazo-Langner A, Carleton B, et al. A systematic review of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Popul Ther Clin Pharmacol. 2011;18:e121-e133.

21. Chave TA, Mortimer NJ, Sladden MJ, et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol. 2005;153:241-253. 22. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013; advance online publication, 7 February 2013; doi:10.1038/jid.2012.510

Skin Disease in Immunosuppressed Hosts

CHAPTER

66

Emily M. Berger and Marissa J. Perman

BACKGROUND A wide variety of cutaneous disorders may affect immunocompromised pediatric patients. Children can be immunocompromised due to an underlying malignancy, immunodeficiency, or secondary to immunosuppressive therapy. Chronic immunosuppressive therapies may be administered for numerous reasons including solid organ transplantation and chronic conditions. In addition, immunosuppression may result from chemotherapeutic treatment regimens for malignancies or conditioning regimens in preparation for bone marrow or stem cell transplantation. The cutaneous disorders associated with immunosuppression range in severity. Even the most banal skin lesions in immunocompromised children can herald life-threatening conditions. Skin biopsies can thus be useful tools in immunosuppressed patients with skin lesions to aid in diagnosis.1 Skin lesions are most frequently a consequence of drug side effects or infection caused by immunosuppression.2,3 Skin disorders affecting immunocompromised patients may occur acutely during high levels of immunosuppression (such as in transplant patients during the early posttransplant period or during periods of acute rejection), while other skin eruptions may be secondary to exposure to various medications. Table 66-1 displays a range of cutaneous lesions seen in immunocompromised patients. TABLE 66-1 Infection Bacterial

Skin Diseases in Immunocompromised Pediatric Patients

Viral Fungal, yeast Other Neoplasia Malignant Skin cancer Post-transplant lymphoproliferative disorder Benign Melanocytic nevi Pyogenic granuloma Medication Side Effects Calcineurin inhibitors Hypertrichosis Gingival hyperplasia Acne vulgaris Corticosteroids Acne vulgaris Striae distensae Cushingoid facies EGFR Inhibitors Acneiform eruptions Paronychia Xerosis Rapamycin Edema Poor wound healing Leukocytoclastic vasculitis Oral aphthous ulcers Voriconazole Photosensitivity Photoaging

Photocarcinogenesis Toxic Erythema of Chemotherapy Mucositis Hyperpigmentation Graft-versus-host disease (GVHD), an important disorder with various cutaneous manifestations, is discussed in Chapter 134.

INFECTIOUS COMPLICATIONS Infections with common and unusual organisms are a complication of immunosuppression. Extensive involvement caused by relatively minor but still problematic skin infections such as tinea corporis, pityriasis (tinea) versicolor, or viral warts is a consequence of long-term immunosuppression.2-4 The most worrisome complication of chronic immunosuppression is the increased risk of life-threatening skin infections that may be associated with significant morbidity The clinical presentation of cutaneous infections caused by a variety of different pathogens is often similar. Prompt evaluation and treatment of these life-threatening infections can reduce morbidity and mortality. Cutaneous lesions suspicious for an infectious process should be biopsied and sent for routine histology, special stains, and tissue culture, as superficial skin cultures are often not sufficient to establish a diagnosis.

BACTERIAL INFECTIONS Bacterial infections such as impetigo, folliculitis, and cellulitis may arise in immunocompromised patients. Moreover, skin infection may herald or coincide with systemic infection with a variety of pathogens. Common pathogens such as Staphylococcus aureus and group A streptococci may be causative agents, but less common pathogens, including gram-negative organisms, may also cause skin disease. Ecthyma gangrenosum is a manifestation of Pseudomonal sepsis that can occur in debilitated and immunocompromised hosts. It begins as an erythematous to purpuric patch that evolves into a hemorrhagic bulla, which progresses to a necrotic ulcer or

eschar. This life-threatening infection must be recognized early and treated promptly (see Chapter 62). Disseminated nocardiosis from a pulmonary source may occur in severely immunocompromised individuals presenting with nonspecific skin lesions (papules and nodules).5,6

FUNGAL INFECTIONS Infections caused by yeasts and molds typically occur when immunosuppression is greatest. In transplant patients, this is often during the first few months after transplantation or when increased immunosuppression is instituted to treat rejection.7-9 The majority of children with cutaneous mold infections have hematologic malignancies, most commonly leukemia or lymphoma. All 18 children in one series were immunocompromised, and most children were severely neutropenic at the time infection was diagnosed.10 Skin lesions may represent primary infection with the potential for dissemination to other organs or metastatic disease from pre-existing systemic organ involvement. Isolated or localized lesions may quickly lead to disseminated infection, which harbors a poor prognosis. Systemic disease caused by a variety of pathogens, including Aspergillus, Fusarium, Alternaria, Paecilomyces, and the mucormycetes may present early as an erythematous patch or nodule that in some cases evolves into an ulcerated, necrotic plaque or multiple erythematous pustules or nodules (Figure 661).11-14 Skin lesions of aspergillosis often present at sites of intravenous catheterization or occlusion by tape or wound dressings.12

FIGURE 66-1. A. Collection of abscesses caused by Rhizopus in a neutropenic child. B. PAS stain demonstrating broad-based, ribbonlike, non-septate hyphae of Rhizopus. (Images used with permission of Dr. Melinda Jen.) Candida species may cause localized skin disease such as intertrigo and folliculitis or Candida sepsis. Candida sepsis may present as erythematous papules or papulopustules, often on the trunk and extremities. Disseminated cryptococcosis presents as nonspecific papules or areas of cellulitis.7,15 Dermatophyte fungus (Trichophyton species) may cause widespread superficial skin infections, including tinea capitis, tinea pedis, and tinea corporis. These common infections are usually not life threatening but may serve as a portal of entry for other pathogens that cause systemic disease. In addition to the above fungi, Trichosporon species—which most commonly cause innocuous superficial infections of the hair in immunocompetent hosts—are a known cause of systemic illness in

immunocompromised patients, especially in those with hematologic malignancy.16 A high index of suspicion is paramount in life-threatening, disseminated infections with Trichosporon spp., as they may present as nonspecific erythematous eruptions.

MYCOBACTERIAL INFECTIONS AND PARASITES Nontuberculous mycobacteria (Mycobacterium kansasii, M. aviumintracellulare, M. fortuitum, M. marinum, M. abscessus, and others) may present as subcutaneous nodules and abscesses.17,18 In addition to these pathogens, parasites such as Leishmania are reported to cause visceral disease and subsequent cutaneous infection in young adults following organ transplantation.19

VIRAL INFECTIONS The risk for herpesvirus infections (herpes simplex virus, varicella zoster virus, cytomegalovirus) is increased in patients with decreased immunity. For example, cutaneous viral infections caused by herpes simplex viruses 1 and 2 may be more extensive in transplant recipients and cause lesions that mimic pressure ulcers. Reactivation of varicella-zoster virus commonly leads to herpes zoster in immunocompromised hosts. Early initiation of antiviral therapy is important to decrease the incidence of cutaneous and visceral dissemination that can result in life-threatening complications.20 The presentation of zoster may not be limited strictly to a dermatomal distribution. Disseminated varicella-zoster virus infection is recognized when more than 20 skin lesions are present outside the affected dermatome or the immediately adjacent dermatome(s). Cytomegalovirus, a common cause of systemic infection in solid organ transplant recipients, may also cause a wide variety of skin lesions, including periorificial ulcers, nodules, and plaques and a diffuse exanthem.21 An increased incidence of herpesvirus infections has been reported in patients taking immunosuppressive medications, especially mycophenolate mofetil, an agent used primarily for prevention of solid organ transplant rejection, as well as off-label use for a variety of inflammatory dermatologic conditions.22 Viral warts caused by human papillomavirus (HPV) are common and

troublesome to immunosuppressed patients. They are often numerous, painful, and unsightly. Moreover, the association of HPV with squamous cell carcinoma is troubling. Verruca vulgaris is especially common in organ transplant recipients and is reported to occur in 13% to 54% of patients.2,3 Warts can occur anywhere on the skin or mucosal surfaces. There is often a history of common viral warts before transplantation, and the prevalence increases over time. Spontaneous regression is uncommon, and treatment is often challenging. Destructive treatments are often used, but these are painful and may be complicated by poor wound healing or infection. Imiquimod, a topical immunomodulator, has been used in adult transplant recipients;23,24 however, its safety and efficacy remain to be determined in pediatric organ transplant recipients. Sinecatechins (Veregen) ointment is a newer agent derived from green tea leaves and is FDA-approved for genital warts. Sinecatechins is thought to have antioxidative properties, but its safety and efficacy in immunocompromised patients has not been studied.25 In immunosuppressed children, molluscum contagiosum can present atypically and in large numbers. Vesicular lesions, papules that lack typical umbilication, and giant nodules in some cases with ulceration have been reported.26 Molluscum occurs in 7% of pediatric organ transplant recipients. These lesions arise in the usual locations including the face, trunk, extremities, and especially the folds, but are often multiple and resistant to conventional treatment.2

NEOPLASIA An increased risk of malignant neoplasms is one of the most concerning consequences of immunosuppression. Chronic immunosuppression causing reduced immune-mediated tumor surveillance is believed to lead to the increased incidence of cancer. An overall three- to fourfold increase in cancer risk is reported.27 Cutaneous cancers (squamous cell, basal cell, and melanoma), post-transplant lymphoproliferative disorder, Kaposi sarcoma, and other sarcomas are commonly reported malignancies.27 Factors increasing the skin cancer incidence in organ transplant recipients, for example, include older patient age, longer duration of immunosuppression, intensity of immunosuppression, ultraviolet light exposure, infection with HPV, and fair skin. Lymphomas, skin and lip carcinomas, sarcomas, and anal

and vulvar carcinomas are the most frequently reported malignant neoplasms in pediatric transplant recipients.28,29 Post-transplant lymphoproliferative disorder may present in the skin as subcutaneous nodules.30 Squamous cell carcinoma is the most common skin cancer in solid organ transplant recipients; there is a 65-fold increase in the overall incidence of squamous cell carcinoma, a 20-fold increase in squamous cell carcinoma of the lip, a 10-fold increase in basal cell carcinoma, and 3- to 4-fold increase in melanoma.27 Squamous cell carcinomas arising in transplant recipients are often multiple, have a younger age of onset than in the general population, and are more aggressive. Pediatric transplant recipients also show increased rates of metastases from skin tumors and increased mortality. In addition to solid organ transplant recipients, patients with hematologic malignancies, bone marrow and stem cell transplant recipients, and patients who received chemotherapy or other therapeutic immunosuppressants have an increased risk of developing skin cancers.31 As a consequence of childhood cancer therapy, several factors lead to secondary cutaneous malignancies including disease-associated immunosuppression, chemotherapy-associated immunosuppression, immunosuppression associated with GVHD prophylaxis in bone marrow transplant recipients, and radiation therapy. Data regarding secondary malignancies as part of the Childhood Cancer Survivor Study from the National Cancer Institute, which surveyed more than 14,000 childhood cancer survivors, noted that children who received radiation therapy for childhood cancer were at 6.3 times higher risk for developing non-melanoma skin cancer than those children who did not receive radiation.32 Malignant melanomas also occurred as secondary malignancies in childhood cancer survivors.32 Owing to this significant increase in skin cancer risk, which may take years to develop, protective strategies should be implemented. Parents and patients need to be counseled about the importance of sun protection, including the use of protective clothing, broad-spectrum sunscreens and lip balms, and behavioral strategies (e.g. avoidance of sun exposure during peak hours). Education should be undertaken before transplant or initiation of cancer therapy and reinforced by physicians and primary care providers. Annual skin examinations are suggested; these should occur more often if suspicious lesions develop. Examining physicians should have a very low threshold for performing skin biopsies of suspicious lesions as skin cancers in

these patients may have an atypical or subtle appearance.

MEDICATION SIDE EFFECTS Acne vulgaris, gingival hyperplasia, striae distensae, and hypertrichosis arise after the immediate transplant period and are cutaneous side effects of immunosuppressive medications. Although these conditions are medically benign, they are disfiguring and adversely affect a patient’s quality of life.2,4 In addition, chemotherapeutics used in cancer treatments, agents used as part of bone marrow transplant conditioning regimens, and antimicrobials given to immunosuppressed children for treatment or prophylaxis of infections, can lead to a wide array of cutaneous reactions. Some of the more common or specific reactions as well as general cutaneous side effects of immunosuppressive agents are addressed in the sections below.

ACNE AND ACNEIFORM ERUPTIONS Several immunosuppressive medications used in transplant recipients and inflammatory disorders contribute to the development of acne, including corticosteroids, cyclosporine, and sirolimus (Figure 66-2). Because combination immunosuppressive therapy is common in transplant patients, it may be difficult to determine the exacerbating drug. Systemic corticosteroids may worsen typical adolescent acne as well as cause “steroid acne.” Steroid acne is characterized by the abrupt onset of monomorphous pink papules on the face and trunk.2 Further evaluation to differentiate this condition from infectious causes of skin lesions may be warranted. Steroid acne improves as corticosteroid doses are reduced. Topical retinoids such as tretinoin cream or gel may be beneficial if active treatment is desired.

FIGURE 66-2. Acne vulgaris in an adolescent transplant recipient. Nodulocystic acne has been described in individuals taking cyclosporine.33 It is less frequently associated with tacrolimus treatment. Tender, draining nodules and cysts characterize this form of acne. Lesions may be very disfiguring, and the course may be complicated by bacterial superinfection.33 The differential diagnosis for this condition includes other infectious causes, but the distribution of lesions on the skin surface and the lack of systemic symptoms are useful to differentiate it from more serious conditions. Nodulocystic acne is difficult to treat in this setting. Patients can be managed with traditional acne therapy, including topical retinoids and antibiotics and systemic antibiotics; however, individuals need to be monitored for medication interactions. There are a few reports of the successful use of the systemic retinoid isotretinoin in young adults who have undergone organ transplantation.33-35 Specific guidelines for isotretinoin use in this population do not exist. The potential for systemic toxicities, including pancreatitis and hyperlipidemia, and early experimental evidence that vitamin A derivatives may increase the likelihood of allograft rejection need to be carefully considered.33-36 It is essential that the dermatologist caring for these individuals work closely with the transplantation team and patient to determine the best course of therapy. Acneiform eruptions are well-known side effects of the epidermal growth factor receptor (EGFR) inhibitors. These chemotherapeutics are employed to counter the increased expression of EGFR involved in a variety of solidorgan cancers. The monoclonal antibody cetuximab and the tyrosine kinase inhibitors gefitinib and erlotinib are the most commonly used EGFR inhibitors. More than half of patients receiving one of these agents experience

papulopustular eruptions that occur in a similar distribution as acne vulgaris.37 A lack of comedones and the presence of pruritus help to distinguish acneiform eruptions due to EGFR inhibitors from acne vulgaris. The onset and severity of an acneiform eruption in a patient treated with an EGFR inhibitor is a good prognostic sign that correlates positively with survival. However, patients can be quite symptomatic from these eruptions and may thus require dose adjustment, delay in treatment, or discontinuation of therapy. Treatment depends on the severity of the eruption and ranges from topical acne therapies including benzoyl peroxide, topical antibiotics (erythromycin, clindamycin, metronidazole), and topical retinoids to oral tetracycline antibiotics or oral retinoids.37 In addition to papulopustular eruptions, EGFR inhibitors have been associated with paronychia (occurring in 10–15% of patients) and xerosis (occurring in 35% of patients).37

GINGIVAL HYPERPLASIA Gingival hyperplasia is commonly seen in individuals receiving cyclosporine and infrequently with tacrolimus administration. It is characterized by thickening of the gingiva and may be widespread or limited to intradental papillae. Gingival hyperplasia can lead to bone and tooth loss. It may improve as cyclosporine is reduced or replaced with another immunosuppressive agent.38 Meticulous oral hygiene is important in the management of gingival hyperplasia. In addition, a 5-day course of azithromycin has been shown to be of benefit in the treatment of gingival hyperplasia in transplant patients taking cyclosporine.39 Surgical intervention is required in rare cases.2

CYCLOSPORINE-INDUCED HYPERTRICHOSIS Cyclosporine-induced hypertrichosis is a common complication, occurring in as many as 69% of children receiving this agent after transplantation.4 It is a dose-dependent effect and improves with the reduction of cyclosporine doses. Parents and patients are very troubled by this complication and may go to great lengths to remove hair. Many modalities are used to treat hypertrichosis, but most are uncomfortable and expensive and do not result in permanent hair removal. Waxing and shaving may be complicated by

folliculitis or local irritation. Electrolysis and laser hair removal are costly and may be painful, making them difficult for younger patients to tolerate. Wendelin et al. reported the successful treatment of cyclosporine-induced hypertrichosis using a low-strength depilatory followed by the application of hydrocortisone to a limited body surface area.40 Patients and their families should be reassured that their appearance will improve, but if treatment is desired, it should be limited to visible areas and a small body surface area.

TOXIC ERYTHEMA OF CHEMOTHERAPY Toxic erythema of chemotherapy is a term described by Bolognia et al. that encompasses a spectrum of previously-described cutaneous side effects associated with chemotherapy administration.41 These reactions are the result of excretion of chemotherapeutic agents through eccrine sweat glands leading to direct toxic insult to these cells. This mechanism explains the most commonly affected cutaneous sites including the palms and soles, intertriginous regions, and other areas of occlusion such as those covered by tape. Agents commonly associated with toxic erythema include cytarabine (AraC), anthracyclines (doxorubicin), 5-fluorouracil and its prodrug capecitabine, taxanes (docetaxel, paclitaxel), and methotrexate. Toxic erythema can present variably. The more common presentations were previously described as palmoplantar erythrodysesthesia, erythematous intertriginous/flexural eruptions, and chemotherapy-associated neutrophilic eccrine hidradenitis. Management of toxic erythema involves a combination of dose reduction strategies and symptomatic management with topical or systemic corticosteroids, vitamin administration (vitamin B6, vitamin E), cool compresses, analgesics, and frequent application of emollients.41

MUCOSITIS Mucositis affects a majority of children undergoing chemotherapy. Painful erosions and ulcerations of the oral cavity and digestive tract occur as the result of chemotherapeutic agents’ effects on rapidly dividing cells of the oral and gastrointestinal systems. Prevention and treatment rely on oral care regimens, monitoring for and prompt treatment of superinfection, antimicrobial rinses (such as chlorhexidine and benzydamine), protective

barriers including sucralfate suspension, and systemic palifermin administration.42 Palifermin is a recombinant keratinocyte growth factor approved by the United States Food and Drug Administration for patients with hematologic malignancies receiving myeloablation in preparation for stem cell transplants. In addition, it is used off-label for the prevention/treatment of mucositis in patients undergoing chemotherapy. Growing literature supports its future use in children. The agent works by affecting the proliferation, differentiation, and migration of epithelial cells in the gastrointestinal system. It is usually administered as 60 μg/kg/day for 3 consecutive days before and after chemotherapy.42 Surveillance for the occurrence of mucositis as well as early and aggressive management of mucositis is paramount, as mucositis has been associated with a negative effect on outcomes in pediatric patients.43

OTHER CUTANEOUS SIDE EFFECTS OF CORTICOSTEROIDS Cushingoid facies is a common side effect of steroid administration and improves as corticosteroid doses are reduced. Striae distensae may be very pronounced, and the severity is not directly proportional to steroid doses. Treatment is unsatisfactory.

CUTANEOUS SIDE EFFECTS OF SIROLIMUS Cutaneous side effects are common in individuals receiving sirolimus, an oral mammalian target of rapamycin (mTOR) inhibitor indicated for the prevention of solid organ transplant recipients. In addition to acneiform eruptions mentioned above, reported mucocutaneous side effects include edema, poor wound healing, leukocytoclastic vasculitis, and oral aphthous ulcers.44 Dose adjustment and topical ultrapotent corticosteroid solution (clobetasol 0.05% applied twice daily) are the main treatments of oral aphthae associated with sirolimus administration.44

VORICONAZOLE-INDUCED PHOTOTOXICITY, PHOTOAGING, AND PHOTOCARCINOGENESIS

Voriconazole is a second-generation triazole antifungal agent frequently employed in the treatment of invasive yeast and mold infections and more recently as antifungal prophylaxis in immunosuppressed patients. There is a well-documented association between voriconazole and photosensitivity, photoaging, and photocarcinogenesis (Figure 66-3).45-47 Exaggerated sunburn response, cheilitis, exfoliative dermatitis, pseudoporphyria cutanea tarda, and lupus-like skin eruptions are associated phototoxicities. Although phototoxic reactions may be reversible upon discontinuation of voriconazole, photoaging and photocarcinogenesis are more chronic issues. Voriconazoleassociated photoaging manifests as erythema, actinic keratoses, and lentigines with striking presentations in pediatric patients. Voriconazole is linked to an increased risk of squamous cell carcinoma as well as malignant melanoma, which are reported to be numerous and aggressive in nature in these patients.45-47 Patients on voriconazole thus warrant close surveillance and early interventions for skin cancers as well as premalignant lesions.

FIGURE 66-3. Photosensitivity and lentigines in an immunosuppressed child on voriconazole. (Image used with permission of Dr. James Treat.) KEY POINTS 1. Children with immune compromise are at significantly greater risk of infectious complications and may suffer from reactions to the medications that are used to reduce immune function in cases of treatment for neoplasia or autoimmune disease. 2. A high index of suspicion should be maintained in cases where skin integrity is compromised in patients with immune compromise, as these can serve as portals for infection and represent incipient infections by bacteria, fungi, viruses, parasites, or mycobacteria.

3. Patients with extensive viral disease may be a marker for underlying immune compromise. For instance, molluscum that are in unusually large number or with unusually large size, may represent underlying immune suppression. 4. Chemotherapy-associated complications are numerous and may manifest in the skin as acneiform eruptions, gingival hyperplasia, toxic erythema (acral areas and intertriginous areas), mucositis, among others. 5. Voriconazole is a known cause of severe photosensitivity and may increase the risk of photocarcinogenesis.

REFERENCES 1. Allen U, Smith CR, Prober CG. The value of skin biopsies in febrile, neutropenic, immunocompromised children. Am J Dis Child. 1986;140:459-461. 2. Euvrard S, Kanitakis J, Cochat P, et al. Skin diseases in children with organ transplants. J Am Acad Dermatol. 2001;44:932-939. 3. Menni S, Beretta D, Piccinno R, Ghio L. Cutaneous and oral lesions in 32 children after renal transplantation. Pediatr Dermatol. 1991;8:194198. 4. Halpert E, Tunnessen WW, Fivush B, Case B. Cutaneous lesions associated with cyclosporine therapy in pediatric renal transplant recipients. J Pediatr. 1991;119:489-491. 5. Kibbler CC. Infections in solid organ transplant recipients. Skin Pharmacol Appl Skin Physiol. 2001;14:332-343. 6. Tsambaos D, Badavanis G. Skin manifestations in solid organ transplant recipients. Skin Pharmacol Appl Skin Physiol. 2001;14:332-343. 7. Hibberd PL, Rubin RH. Clinical aspects of fungal infection in organ transplant recipients. Clin Infect Dis. 1994;19:S33-S40. 8. Hadley S, Karchmer AW. Fungal infections in solid organ transplant recipients. Infect Dis Clin North Am. 1995;9:1045-1074. 9. Pfundstein J. Aspergillus infections among solid organ transplant

recipients: a case study. J Transpl Coord. 1997;7:187-189. 10. Marcoux D, Jafarian F, Joncas V, Buteau C, Kokta V, Moghrabi A. Deep cutaneous fungal infections in immunocompromised children. J Am Acad Dermatol. 2009;61(5):857-864. 11. Boyd AS, Wiser B, Sams HH, King LE. Gangrenous cutaneous mucormycosis in a child with a solid organ transplant: a case report and review of the literature. Pediatr Dermatol. 2003;20:411-415. 12. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am. 2003;17:113-134. 13. Benedict LM, Kusne S, Torre-Cisneros J, Hunt SJ. Primary cutaneous fungal infection after solid-organ transplantation: report of five cases and review. Clin Infect Dis. 1992;15:17-21. 14. Grossman ME, Fithian EC, Behrens C, et al. Primary cutaneous aspergillosis in six leukemic children. J Am Acad Dermatol. 1985;12:313-318. 15. Singh N, Rihs JD, Gayowski T, Yu VL. Cutaneous cryptococcosis mimicking bacterial cellulitis in a liver transplant recipient: case report and review in solid organ transplant recipients. Clin Transplant. 1994;8:365-368. 16. Girmenia C, Pagano L, Martino B, et al. Invasive infections caused by Trichosporon species and Geotrichum capitatum in patients with hematological malignancies: a retrospective multicenter study from Italy and review of the literature. J Clin Microbiol. 2005;43:1818-1828. 17. Patel R, Roberts GD, Keating MR, Paya CV. Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients. Clin Infect Dis. 1994;19:263-273. 18. Farooqui MA, Berenson C, Lohr JW. Mycobacterium marinum infection in a renal transplant recipient. Transplantation. 1999;67:1495-1496. 19. Hernandez-Perez J, Yebra-Bango M, Jimenez-Martinez E, et al. Visceral leishmaniasis (kala-azar) in solid organ transplantation: report of five cases and review. Clin Infect Dis. 1999;29:218-221. 20. Ahmed AM, Brantley JS, Madkan V, Mendoza N, Tyring SK. managing herpes zoster in immunocompromised patients. Herpes. 2007;14:32-36. 21. Wong J, McCracken G, Ronan S, Aronson I. Coexistent cutaneous

Aspergillus and cytomegalovirus infection in a liver transplant recipient. J Am Acad Dermatol. 2001;44:370-372. 22. Orvis AK, Wesson SK, Breza TS Jr, et al. Mycophenolate mofetil in dermatology. J Am Acad Dermatol. 2009;60:183-199. 23. Schmook T, Nindl I, Ulrich C, et al. Viral warts in organ transplant recipients: new aspects in therapy. Br J Dermatol. 2003;149:20-24. 24. Dupin N, Soubrane 0, Escande JP. Eficacite partielle de l’imiquimod sur des verrues plantaires de l’immunodeprime. Ann Dermatol Venereol. 2003;130:210-213. 25. Fougera Pharmaceuticals. Veregen (sinecatechins) ointment, 15% prescribing information. 2012. http://www.veregen.com/pdf/Veregen_ Promotional_4page_PI.pdf. Accessed 20 March 2013. 26. Ozyurek E, Senturk N, Kefeli M, et al. Ulcerating molluscum contagiosum in a boy with relapsed acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2011;33:e114-116. 27. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1-17. 28. Penn I. Posttransplant malignancies in pediatric organ transplant recipients. Transplant Proc. 1994;26:2763-2765. 29. Penn I. De novo malignancies in pediatric organ transplant recipients. Pediatr Transplant. 1998;2:56-63. 30. Schumann KW, Oriba HA, Begfeld WF, et al. Cutaneous presentation of posttransplant lymphoproliferative disorder. J Am Acad Dermatol. 2000;42:923-926. 31. Yokota A, Ozawa S, Masanori T, et al. Secondary solid tumors after allogeneic hematopoietic SCT in Japan. Bone Marrow Transplant. 2012;47:95-100. 32. National Cancer Institute. Late effects of treatment for childhood cancer (PDQ®): subsequent neoplasms. http://www.cancer.gov/cancertopics/ pdq/treatment/lateeffects/HealthProfessional/page2. Accessed 9 March 2013. 33. El-Shahaway MA, Gadallah MF, Massry SG. Acne: a potential side effect of cyclosporine A therapy. Nephron. 1996;72:679-682.

34. Bunker CB, Rustin MHA, Dowd PM. Isotretinoin treatment of severe acne in posttransplant patients taking cyclosporine. J Am Acad Dermatol. 1990;22:693-694. 35. Abel EA. Isotretinoin treatment of severe cystic acne in a heart transplant patient receiving cyclosporine: consideration of drug interactions. J Am Acad Dermatol. 1991;24:511. 36. Floersheim GL, Bollag W. Accelerated rejection of skin homografts by vitamin A acid. Transplantation. 1972;14:564-567. 37. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007;56:317-326. 38. Thorp M, DeMattos A, Bennett W, et al. The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol. Transplantation. 2000;69:1218-1224. 39. Ramalho VL, Ramalho HJ, Cipullo JP, Azoubel R, Burdmann EA. Comparison of azithromycin and oral hygiene program in the treatment of cyclosporine-induced gingival hyperplasia. Ren Fail. 2007;29:265270. 40. Wendelin DS, Mallory GB, Mallory SB. Depilation in a 6-month-old with hypertrichosis: a case report. Pediatr Dermatol. 1999;16:311-313. 41. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59:524-529. 42. Miller MM, Donald DV, Hagemann TM. Prevention and treatment of oral mucositis in children with cancer. J Pediatr Pharmacol Ther. 2012;17:340-350. 43. Cheng KK, Lee V, Li CH, et al. Impact of oral mucositis on short-term clinical outcomes in paediatric and adolescent patients undergoing chemotherapy. Support Care Cancer. 2013; Mar 8 [Epub ahead of print] PMID: 23471538. 44. Campistol JM, de Fijter JW, Flechner SM, et al. mTOR inhibitorassociated dermatologic and mucosal problems. Clin Transplant. 2010;24:149-156. 45. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and

aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:3137 46. Miller DD, Cowen EW, Nguyen JC, McCalmont TH, Fox LP. Melanoma associated with long-term voriconazole therapy. Arch Dermatol. 2010;146:300-304. 47. Frisch S, Askari SK, Beaty SR, Burkemper N. X-linked chronic granulomatous disease with voriconazole-indiced photosensitivity/photoaging reaction. J Drugs Dermatol. 2010;9:562564.

CHAPTER

Epidermolysis Bullosa

67

Benjamin S. Bolser and Kara N. Shah

BACKGROUND Epidermolysis bullosa (EB) refers to a family of rare genodermatoses characterized by an inherited tendency toward recurrent cutaneous and mucosal blistering at sites of mechanical trauma. According to the National Epidermolysis Bullosa Registry, EB affects approximately 12,500 individuals in the United States, with an incidence of 50 new EB cases per 1 million live births annually.1 Historically, EB has been classified into a variety of subtypes based on clinical findings, and a growing number of eponyms and otherwise distinctive EB variants have been described in the literature. The current classification system, however, which was revised in 2008, divides EB into four major types based on the ultrastructural level of blister formation: EB simplex, junctional EB (JEB), dystrophic EB, and Kindler syndrome.2 In general, patients with EB simplex have a milder phenotype, and patients with junctional and dystrophic EB have a more severe phenotype; however, there are particularly severe variants of EB simplex, as well as milder forms of junctional and dystrophic EB. Kindler syndrome is a very rare EB variant characterized by recurrent blistering, photosensitivity, cutaneous atrophy, poikiloderma, and systemic complications due to mucosal blistering. Depending on the particular genotype, the clinical manifestations of EB may range from minimal blistering of the hands and feet to severe, widespread, mutilating blistering that can involve the epithelial mucosa of other organ systems. Although all patients with EB are at risk for complications such as pain, infection, and scarring, those with more severe variants are also at risk for a multitude of chronic morbidities, including nutritional deficiencies and failure to thrive, severe scarring and contractures,

cutaneous squamous cell carcinomas, laryngeal complications, esophageal strictures, and ocular complications that may lead to blindness.3,4 The care of a patient with EB involves a multidisciplinary approach and must incorporate a variety of lifestyle modifications and specialized skin care to minimize disease severity and complications. Some of the acute and chronic complications associated with EB lead to hospitalization for inpatient management. In addition, hospitalists may be involved with the initial presentation of EB in the neonate or young infant. Hospital management of a patient with EB requires a comprehensive understanding of the expected clinical features, severity, and complications based on the type of EB present. For example, when caring for a patient with RDEB, it is imperative to know what is generally considered “normal” to see on physical examination. Interpreting clinical information in an appropriate context is essential for providing the highest level of complex care, especially in patients with more severe types of EB. In addition, as a general hospitalist, it is also vital to remember that individuals with EB are also susceptible to other diseases or conditions that may be seen in the general population. It is therefore important to consider all potential etiologies of the patient’s presenting symptoms when formulating a differential diagnosis and to avoid the temptation to explain every sign and symptom as “part of having EB.”

PATHOPHYSIOLOGY The various subtypes of EB result from mutations in one of over ten known associated genes, all of which encode ultrastructural protein components of the dermal–epidermal junction (Table 67-1). The three most commonly recognized EB types—EB simplex, JEB, and dystrophic EB—involve either intraepidermal, intra-lamina lucida, or sublamina densa blister formation, respectively (Figure 67-1). Kindler syndrome, a rare subtype of EB, involves blister formation involving multiple cleavage planes. Disruption of the integrity of the basement membrane zone or suprabasal cell–cell adhesion desmosomal proteins in affected tissues results in mechanical fragility of the skin and, in some forms of EB, extracutaneous mucosa. Affected patients are predisposed to the development of recurrent blisters, erosions, ulcers, and nonhealing wounds. Inheritance of EB may be either autosomal dominant, as in most forms of EB simplex and in dominant dystrophic EB (DDEB), or

autosomal recessive, as in JEB and RDEB. TABLE 67-1

Classification and Features of Selected Types and Subtypes of Epidermolysis Bullosa (EB)

FIGURE 67-1. Ultrastructural characterization of the level of blister formation in the different forms of epidermolysis bullosa. EB, epidermolysis bullosa–S (simplex); J, junctional; D, dystrophic.

CLINICAL PRESENTATION The hospitalist can most skillfully care for EB patients by understanding the typical presentation and clinical course of each of the different types of EB.

For example, recessive dystrophic EB (RDEB) manifests as severe, chronic, progressive cutaneous and extracutaneous blistering that results in significant risk of scarring and associated complications of the skin, eyes, gastrointestinal tract, genitourinary tract, and respiratory tract as well as chronic pain and failure to thrive, among other concerns. In contrast, patients with DDEB typically manifest chronic, recurrent cutaneous blistering that favors the extremities but have minimal associated risk of extracutaneous complications. A thorough understanding of overall disease severity based on EB type and of the acute and chronic complications associated with each type of EB better equips the hospitalist to provide the most appropriate medical care to affected patients and their families. Skin and mucosal blistering, the cardinal clinical features of EB, may be present at birth, may develop shortly after birth or in early infancy, or may less commonly present later in childhood, adolescence, or young adulthood. It is typically very difficult to reliably predict the type of EB present in a newborn or young infant who develops cutaneous blistering based on clinical examination alone; skin biopsy is generally needed for definitive diagnosis. Onset of cutaneous blistering later in childhood, adolescence, or adulthood is typically seen either with limited forms of EB simplex or with DDEB. EB simplex is characterized by localized or generalized cutaneous blistering without significant involvement of the mucosal epithelia, although superficial erosions involving the oral cavity may be seen. Due to the superficial, intraepidermal localization of blisters to the basal or suprabasal layers, blisters may rupture quickly and present as erosions. Cutaneous blisters associated with EB simplex usually heal without scarring (Figure 672). Milia, though classically associated with dystrophic forms of EB, are also encountered in EB simplex, but with less frequency. Other abnormalities may include dystrophic nails, hypotrichosis, and focal or diffuse keratoderma of the palms and soles. Failure to thrive, constipation, and anemia may be seen in more severely affected patients. Some patients with EB simplex may not present with blistering until later childhood or early adulthood (Figure 67-3). Inheritance is usually autosomal dominant, although rare autosomal recessive subtypes have been reported, including EB simplex with muscular dystrophy. Rare variants of EB simplex include EB simplex with muscular dystrophy and EB simplex with pyloric atresia.

FIGURE 67-2. Erosions of epidermolysis bullosa simplex on the hand of an infant.

FIGURE 67-3. Erosions on an infant with junctional epidermolysis bullosa. JEB typically presents at birth with generalized blistering, although more localized variants may be seen (Figure 67-4). Inheritance is autosomal recessive and blisters form within the basement membrane zone at the level of the lamina lucida. Patients with JEB are at significant risk for extracutaneous involvement of the ocular, gastrointestinal, genitourinary, and respiratory systems, which may result in blistering and stricture formation. Affected patients are therefore at increased risk for nutritional compromise, failure to thrive, anemia, respiratory complications, infection, and sepsis. Associated findings include atrophic scarring, exuberant granulation tissue, dystrophic or absent nails, milia formation, significant dental enamel

hypoplasia with dental caries, and scalp abnormalities. Patients with the more severe subtype, JEB-Herlitz, usually do not survive infancy, whereas those with the non-Herlitz subtype display some clinical improvement with age. JEB with pyloric atresia and laryngo-oculo-cutaneous syndrome are rare, severe variants.

FIGURE 67-4. Bullae and milia on the hand of a patient with dystrophic epidermolysis bullosa. Dystrophic EB involves blister formation below the level of the basement membrane zone within the dermis. Inheritance may be autosomal dominant or autosomal recessive. Dystrophic EB typically presents at birth or during infancy with either localized or generalized blistering. RDEB presents at birth with generalized blistering that results in significant, severe scarring, including progressive scarring of the hands and feet that leads to pseudosyndactyly and flexion contractures (Figure 67-5). Significant systemic involvement of the gastrointestinal, genitourinary, and respiratory tracts, leading to malabsorption, anemia, dysphagia, esophageal strictures, urethral strictures, stridor, tracheolaryngeal stricture, and failure to thrive, among other complications, is the norm. (Table 67-2) Patients with RDEB also have a significant risk of developing squamous cell carcinoma of the skin, corneal ulcerations and scarring, and dental caries. Other complications include cardiomyopathy, glomerulonephritis, chronic renal failure, and osteoporosis. DDEB generally has a milder phenotype, with less significant

systemic involvement and a tendency toward reduced blistering with advancing age. Milia formation and dystrophic or absent nails are commonly seen. Systemic complications such as ocular complications, genitourinary complications, and respiratory tract involvement are not generally seen with DDEB. A rare variant of dystrophic EB is bullous dermolysis of the newborn, which presents at birth with generalized blisters. Although atrophic scarring, nail dystrophy, and milia are commonly seen, blistering typically resolves during infancy and systemic complications, other than excessive caries formation, are not seen.

FIGURE 67-5. Pseudosyndactyly on the hand of a patient with recessive dystrophic epidermolysis bullosa. TABLE 67-2

Differential Diagnosis of Epidermolysis Bullosa in Neonate and Infants

Congenital Disorders Epidermolytic hyperkeratosis Ichthyosis bullosa of Siemens Pachyonychia congenita Incontinentia pigmenti Ankyloblepharon-ectodermal dysplasia-cleft lip syndrome Aplasia cutis congenita Immunobullous Disorders Bullous pemphigoid

Pemphigus vulgaris (includes transplacentally transferred antibodies) Chronic bullous dermatosis of childhood (linear IgA disease of childhood) Epidermolysis acquisita Infectious Diseases Staphylococcal scalded skin syndrome Bullous impetigo Herpes simplex Congenital syphilis (congenital blisters on palms and soles) Other Bullous mastocytosis Traumatic blisters Thermal or chemical burns Kindler syndrome is a very rare autosomal recessive disorder that typically presents at birth with generalized blisters. It is characterized by blister formation involving multiple cleavage planes, generalized skin fragility and blistering, cutaneous atrophy, photosensitivity, and poikiloderma. Systemic complications include esophageal strictures, chronic diarrhea and malabsorption, urethral strictures, gingival hyperplasia, and periodontitis. Patients with Kindler syndrome have an increased risk for the development of mucocutaneous squamous cell carcinoma. Although some subtypes of EB may improve with age, it is generally a chronic disease punctuated by recurrent exacerbations of cutaneous and mucosal blistering and, for patients with junctional and RDEB, both acute and chronic systemic complications. In those with the more severe forms of EB, life expectancy can be significantly reduced as a result of failure to thrive, recurrent infections, laryngeal complications, and sepsis during infancy. Mortality in early adulthood is usually the result of aggressive squamous cell carcinoma. Patients with milder forms of EB may have a normal life expectancy.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of blistering disorders in neonates and infants is extensive and includes other inherited diseases characterized by skin blistering or erosions, infectious diseases, and immunobullous disorders (Table 67-2). Common disorders to be considered include herpes simplex virus infection, staphylococcal scalded skin syndrome, bullous impetigo, traumatic blisters, and child abuse. A general approach to the initial evaluation of a neonate or infant with cutaneous and/or mucosal blistering and suspected EB is presented in Algorithm A (Figure 67-6).

FIGURE 67-6. Algorithm A, Evaluation of the neonate or infant with suspected epidermolysis bullosa.

DIAGNOSTIC EVALUATION Where possible, evaluation of the neonate or infant with cutaneous blistering should be directed by a clinician with expertise in EB given the complexity of diagnosis and prognosis. Proper diagnosis of EB depends on identifying the ultrastructural localization of blister formation in the skin and on excluding other causes of blistering disease.4 A skin biopsy for routine histology may help exclude other blistering diseases; however, use of more specific

diagnostic testing, in particular immunofluorescence mapping (IFM), has replaced the use of routine histology for the diagnosis and classification of the different types of EB. Optimal sensitivity of diagnostic testing by IFM for EB requires sampling of a freshly induced blister in the skin. When EB is suspected, a freshly induced blister can be created by using a pencil eraser held against the skin with moderate pressure and rotated several times with a twisting motion, thus creating a shear force that results in separation of the dermal–epidermal junction, and blister formation. The skin biopsy should be performed at the edge of the blister. Where possible, the specimen(s) should be processed for examination under both light microscopy and IFM of the basement membrane zone in order to facilitate the diagnosis of the type of EB present. Historically, use of transmission EM was commonly used in the diagnostic evaluation of EB; however, the technical expertise required to process and interpret EM with regard to EB is available in only a limited number of laboratories. IFM, which uses a panel of antibodies to basement membrane components and allows the ultrastructural level of the blister to be determined precisely, is more readily available, less expensive, and allows for more rapid results than EM; it may also allow for the detection of relative loss of expression of the affected protein. Specific molecular diagnostic DNA mutation analysis is helpful in confirming a diagnosis of EB and correctly identifying the EB type; however, genotype-phenotype correlation is highly variable and the expense of DNA testing is often prohibitive. Therefore the greatest utility of DNA testing at this time is for consideration for prenatal counseling.

TREATMENT The majority of EB patients requiring hospitalized care are those with severe generalized RDEB, and therefore much of the following discussion pertains to this specific EB patient population. Patients with more severe forms of JEB, in particular JEB-Herlitz, may also require hospitalization, and may suffer from similar complications. RDEB is debilitating and progressive, and results in a perpetual inflammatory state. Directly or indirectly, nearly every organ system is affected. The high degree of morbidity leads to frequent need for hospital care, especially in older children, adolescents, and young adults. Hospitalists should approach patients and families with the understanding

that they may have suffered traumatic healthcare encounters in the past due to an unfortunate lack of familiarity with EB on the part of many healthcare providers, which can result in suboptimal care and iatrogenic complication. Patients and caregivers may therefore be nervous or frightened while in the hospital. The astute hospitalist will gain trust and rapport by first acknowledging that the family may know much more about the disease and also by reassuring the patient, especially if a younger child, that providers will not touch him/her without first explaining what to expect. It can be helpful to ask the patient or the caregiver how to touch, move, or manipulate the patient during an examination in order to minimize pain and discomfort. Finally, it is important to realize that the patient and caregivers are experts in managing the day-to-day dressing changes and skin care. Practicing these behaviors, as well as modeling them to other providers, will increase the chance that patients and families are comfortable, and lessen the chance of undesirable, traumatic experiences. There are no therapies that consistently reduce blister formation in patients with EB. As a chronic, and in some cases multisystem disease, management of patients with EB focuses on the prevention and treatment of skin blistering and infections, pain management, and on careful monitoring for EB-related complications, particularly in patients with JEB and RDEB (see Table 67-3). Although children with EB may be hospitalized for a variety of EB-related complications, they may also be admitted for non-EB indications. The inpatient team should be aware of the myriad complications and issues that may arise with EB patients as well as with general principles of skin and wound care for patients with EB. Additionally, it is important for providers to modify certain hospital interventions such as intravenous catheter placement, intubation, and bladder catheterization in order to prevent iatrogenic damage to the skin or other affected organs. TABLE 67-3

Selected Complications Associated with Recessive Dystrophic and Junctional Epidermolysis Bullosa

System

Complications

Skin, hair, nails

Infection, sepsis, scarring, milia formation, excessive granulation tissue, keratoderma,

alopecia, nail dystrophy, skin cancer (predominantly squamous cell carcinoma, although basal cell carcinoma and melanoma may also be seen) Musculoskeletal Pseudosyndactyly, contractures, osteoporosis, osteopenia, scoliosis, fractures Gastrointestinal

Esophageal strictures, dysphagia, anal stenosis, constipation, malnutrition, failure to thrive, protein losing enteropathy, rectal prolapse, gastroesophageal reflux disease

Ocular

Blepharoconjunctivitis, keratitis, pannus formation, symblepharon, corneal ulceration and scarring, ectropion, lacrimal duct obstruction

Oral

Oral erosions, dental enamel hypoplasia, severe caries, microstomia, ankyloglossia, premature loss of dentition

Genitourinary

Urethral strictures, phimosis, chronic renal failure, urethral diverticuli, ureteral reflux, hydronephrosis, hydroureter, glomerulonephritis, recurrent urinary tract infections

Respiratory

Laryngeal and tracheal strictures, tracheal stenosis, stridor, hoarseness, sudden complete upper airway occlusion

Other

Depression, delayed puberty, developmental delays, cardiomyopathy, anemia, otitis externa, occlusion of the nares

GENERAL SKIN CARE General guidelines for skin care both at home and in the hospital are summarized in Table 67-4. In general, excessive friction, pressure, or

rubbing of the skin is to be avoided where possible to minimize iatrogenic trauma. Vigilance should be maintained for the early detection and management of new blisters and potential complications such as infection. Providers should apply petrolatum or Aquaphor to fingertips of their gloves before contact with the skin. Overheating should be avoided, as it can exacerbate blistering and pruritus. Patients with poor mobility may require airbeds to reduce pressure on the skin. Gentle handing by all caregivers is essential to minimize pain and increased blistering. Soft coverings on infant high chairs and seats can help reduce skin friction. Use of adhesive tape on the skin should be avoided. If tape is necessary, a layer of gauze can be placed first, followed by an overlying layer of tape. Equipment can then be anchored by taping devices down to the already placed tape. Use of a silicone-based foam dressing such as Mepilex or a gentle adhesive tape such as Mepitac, Adaptic touch, or Siltape may be helpful in securing percutaneous catheters and nasogastric feeding tubes (Figure 67-7). G-tube sites may develop local erosions, and placement of a layer of petrolatum gauze, a silicone-based foam dressing such as Mepilex Transfer or contact layer such as Mepitel may minimize complications at these sites (Figure 678).

FIGURE 67-7. Use of a specialized dressing, Mepilex, to protect the skin around a gastrostomy tube.

FIGURE 67-8. Use of a specialized dressing, Mepiform, to safety secure a percutaneous catheter in a patient with recessive dystrophic epidermolysis bullosa. TABLE 67-4

General Care for Infants and Children with Epidermolysis Bullosa

Type of Care Recommendations General skin care

Lift infants by supporting buttocks and head; avoid lifting from under the arms Provide a cool, air-conditioned environment Avoid taking rectal temperatures Take blood pressure readings only when necessary; use soft gauze beneath the blood pressure cuff Use petrolatum gauze under pulse oximetry probes and a hydrogel dressing such as Duoderm under electrocardiogram electrodes Do not use tape to secure dressings or intravenous lines; use gauze or tubular dressings

When tape is necessary, use the “tape-to-tape” method: (1) apply a strip of petrolatum gauze against skin, (2) apply a layer of tape to gauze, (3) fasten equipment to tape, (4) apply tape to underlying tape to anchor equipment Monitor for signs of skin infection Bath care Avoid rubbing the skin vigorously; pat the skin instead Cleanse skin gently with a mild nonsoap cleanser such as Dove or Cetaphil Apply an emollient such as petrolatum twice daily to decrease friction Give weekly baths using dilute bleach or dilute chlorhexidine to help reduce bacterial skin colonization Diet, nutrition, and oral care

For infants: Use soft nipples on bottles and avoid pacifiers For older infants and children: Provide soft, cool foods and teething gels Clean the mouth gently using a soft toothbrush and toothpaste Avoid suctioning the oropharynx Give multivitamins, stool softeners

Bedding and clothing

Use loose-fitting clothing and cloth diapers; avoid elastic Use protective foam or fleece padding on seatbelts and shoes and over elbows and knees Pad mattresses and cribs with foam or fleece For poorly mobile inpatients, use air-cushioned

mattresses to help reduce blisters Wound Clean erosions with saline-soaked gauze care and dressings Decompress blisters by puncturing with a sterile needle; leave blister roof intact where possible as a natural sterile dressing Apply bacitracin or silver sulfadiazine to erosions Apply petrolatum gauze or nonadherent dressing (e.g. Telfa, Mepilex Transfer, Mepitel) Use self-adhering gauze or tubular dressings; avoid tape and adhesive bandages Soak old dressings before removal if there is crusting or if the dressing sticks to the skin A thorough skin evaluation is an important component of the initial assessment of every child with EB who is hospitalized. This evaluation is best coordinated with a regular dressing change. Caregivers for older infants and children typically have an established routine for bathing, removing bandages, and re-dressing wounds, and every effort should be made to allow them to preserve this routine while hospitalized. Provision of appropriate pain control is very important during this process, as it is typically painful and anxiety-provoking for the child as well as the caregivers. Adequate time should be allowed for hospital caregivers to visualize the entire skin surface, noting all blisters and wounds and any associated pain, exudate, odor, increased erythema, and poor healing. For infants and children with generalized blistering, this process may take 1 to 2 hours or more. Periodic reassessment should be made during the hospitalization. Consensus recommendations for wound care for EB patients have been generated.5 General principles of wound care for patients with EB include application of semiocclusive nonadherent dressings, such as petrolatum gauze secured with rolled gauze or tubular dressings or use of specialty wound care products that induce minimal skin trauma.6 Specialty dressings protect denuded areas, aid in re-epithelialization, and minimize discomfort. Newer

products well tolerated by a majority of EB patients utilize silicone-based technology as opposed to traditional adhesives to facilitate dressing security and minimize epidermal stripping. Dressings should be changed once daily or as needed after gentle bathing in warm water with a gentle non-soap cleanser such as Cetaphil. Dressings should never be forcibly removed but should be soaked off in a warm bath or with tap water or saline soaks if they adhere to the wound. Alternatively, use of an adhesive remover such as Coloplast adhesive remover spray or Niltac may be used. For patients admitted with significant cutaneous blistering, whirlpool therapy can help clean and debride wounds. Before new dressings are applied, intact blisters should be decompressed with a sterile needle to prevent them from enlarging, and all wounds should be evaluated for signs of infection and poor wound healing. The roof of the blister should be left intact to provide a natural sterile dressing, which aids in wound healing, prevents infection, and minimizes additional pain and discomfort. Use of emollients such as petrolatum to reduce skin friction and avoidance of vigorous rubbing of the skin are essential. A cool environment also helps minimize blistering. Prolonged use of topical steroids is contraindicated in patients with EB owing to impairment of wound healing. Patients with significant blistering and skin erosions have an impaired skin barrier; therefore medications applied topically may be absorbed to a significant degree. In particular, emollients and medicaments containing salicylic acid, prilocaine or lidocaine, or lactic acid should not be applied to patients with EB or should be used with caution. The choice of wound care dressing depends on the characteristics of the wound, and on any particular patient several different wound care products may need to be utilized.5 Eroded wounds should be covered with a primary dressing such as petrolatum gauze, a contact layer dressing such as Mepitel, or Mepilex foam. Use of a hydrogel dressing such as Duoderm or Intrasite as a primary dressing may aid with associated pruritus and/or pain for some wounds. Exudative wounds are best addressed with a silicone foam dressing such as Mepilex or a lipidocolloid dressing such as Restore as a primary dressing; heavily exudative wounds may benefit from use of a hydrofiber dressing such as Aquacel or an alginate. In wounds with associated eschar, use of a hydrogel such as Duoderm or Intrasite is helpful. Primary dressings may be secured with a secondary dressing such as a nonadherent gauze bandage or a rolled gauze dressing such as Kling or Conform for nonexudative wounds or with an absorbant dressing such as a foam or absorbant

pad for exudative wounds. Use of a tubular gauze dressing such as TubiFast or an elastic net dressing such as Spandage can be used to secure primary and secondary dressings. Interdigitating the fingers and toes using petrolatum gauze may help minimize adhesions or pseudosyndactyly (Figure 67-9).

FIGURE 67-9. Strips of petrolatum gauze are placed between the toes of a patient with recessive dystrophic epidermolysis bullosa to prevent pseudosyndactyly.

INFECTION Chronic skin blistering and ulceration, as well as immunologic suppression as a result of chronic disease and poor nutrition, predispose many of the more severely affected EB patients of all types to infection. Local wound infection and systemic infection account for a significant proportion of hospitalizations of EB patients. Although Staphylococcus aureus and Streptococcus pyogenes are the most commonly isolated organisms, gram-negative bacteria (in particular Pseudomonas aeruginosa), anaerobic bacteria, Candida, and mixed infections can also occur. Most patients with chronic blistering are colonized with a number of different organisms, however, and true infection is uncommon. Critical colonization of a wound with microorganisms can, however, create significant local inflammation and stall wound healing. Any wound that manifests any three of the following criteria should be cultured and treated with a topical antimicrobial agent with consideration for ancillary use of an antimicrobial dressing or bath additive such as bleach or vinegar: a non-healing wound, increasing exudate, presence of friable red tissue, presence of debris, and wound slough, odor, or smell.5 Commonly

used topical antimicrobial agents include mupirocin, Polysporin (bacitracin and polymyxin B), gentamicin, ketoconazole, and medical grade honey. These should be used for short periods of time only and rotated every 1 to 2 months to minimize the development of resistance. Neomycin should be used cautiously due to concern for contact allergic sensitization, and prolonged use of silver sulfadiazine may lead to argyria. Newer dressings that contain nanocrystalline silver or polyhexamethylenebiguinide (PHMB) may be a useful adjunct. Systemic therapy, which should be guided by the results of wound culture for bacterial and fungal organisms, is generally reserved for patients in whom there is evidence of more than superficial colonization. Such judicious antibiotic use prevents the selection of multidrug-resistant organisms, which is a very real possibility given the frequency with which more severely affected EB patients are exposed to antibiotics over their lifetime. The presence of any three of the following criteria indicates a need for systemic antimicrobial therapy: increasing size of the wound, increased temperature of the wound and surrounding skin, exposed bone, new areas of skin breakdown around the wound, erythema and/or edema of the surrounding skin, increasing exudate, and odor or smell.5 Fever and/or other signs and symptoms of more significant infection will guide inpatient management of suspected sepsis (Algorithm B, Figure 67-10). Patients with evidence of Group A streptococcus on wound culture should generally be treated with a systemic antibiotic due to the risk for complications such as sepsis and glomerulonephritis. In patients prone to recurrent skin infections, the use of additives in the bath water may help reduce bacterial overgrowth. Weekly baths in diluted bleach (1 capful of common household bleach per gallon of water; ⅛ to ¼ cup per bathtub of water) or diluted chlorhexidine (10 mL per tubful) may help reduce bacterial skin colonization and thus reduce the risk of infection; dilute formulations of acetic acid (white vinegar diluted 1:10 in tap water) may help reduce the presence of gram-negative organisms in particular.

FIGURE 67-10. Algorithm B, Evaluation of the patient with recessive dystrophic or junctional epidermolysis bullosa and suspected skin infection. Other infections such as abscesses and osteomyelitis can occur, and can be diagnosed in ways similar to any patient without EB. Inflammatory markers such as ESR, CRP, and ferritin levels are chronically elevated; therefore, high values should not be immediately interpreted as indicative of infection. Following the trends of these markers is, however, useful for informing clinical decisions.

ACUTE AND CHRONIC PAIN AND PRURITUS Although all patients with EB experience some pain with cutaneous and other blistering, pain control is a significant concern for patients with more severe forms of EB, in particular RDEB and JEB-Herlitz. At some point in time, almost every severely affected EB patient will require daily use of opiates to address their chronic pain, which unfortunately is often accompanied by acute pain exacerbations. Anxiety plays a substantial role in pain perception, so addition of an anxiolytic may be a useful therapeutic adjunct. Pain and anxiety create significant challenges during dressing changes, bathing, and skin care at home; in the hospital these issues are magnified by the stress of

hospitalization. Pharmacologic options for pain management include topical preparations (morphine gel), traditional medications such as ibuprofen, opiates, or gabapentin, and nontraditional agents such as tricyclic antidepressants and cannabinoids.7 Because there is often difficulty in managing the number of different pain medications needed, as well as their side effects and interactions, the hospitalist should strongly consider involving pain management providers in the care team. Non-pharmacologic interventions such as relaxation and guided imagery have also been successfully used in EB patients.7 An often-overlooked concern is the extreme and chronic pruritus that many patients with EB endure. Although use of antihistamines may be helpful, for many patients the pruritus is so persistent and often resistant to treatment that other medications such as doxepin and ondansetron have been used, with variable results.7

NUTRITION AND HYDRATION A complete nutritional assessment should be performed in all patients with EB who are admitted to the hospital. Useful screening serum laboratory studies include albumin, prealbumin, electrolytes, blood urea nitrogen, liver transaminases, triglycerides, calcium, magnesium, and phosphate. Serum levels of specific vitamins and minerals may also be evaluated as indicated (e.g. vitamin D, zinc, selenium, and carnitine). Careful monitoring of growth parameters in conjunction with dietary assessments to ensure adequate calorie and protein intake is essential for the maintenance of proper growth and nutrition; this is especially important when significant complications such as infection or esophageal strictures are present that result in decreased oral intake and/or increased metabolic demands.8 Careful monitoring of fluid status in EB patients is very important, because patients with significant skin involvement and subsequent loss of skin barrier function can have significant transepidermal water loss and quickly become dehydrated, especially if they are febrile or unable to take in sufficient oral fluids.

ANEMIA

Anemia is common in patients with RDEB and JEB. The anemia associated with EB is multifactorial and recalcitrant to treatment. Patients may require admission for the treatment of significant anemia by administration of intravenous iron preparations or red cell transfusions as part of therapy. Consensus views are to keep hemoglobin concentrations above 8 g/dL. In the setting of poorly healing wounds, maintaining levels of at least 10 g/dL has been shown to benefit wound healing.5 If blood iron levels are adequate, then enteral iron supplementation may be sufficient. However, often iron levels are low from chronic losses, chronic consumption, and poor absorption.3 Enteral iron supplementation becomes difficult in such instances, because intake cannot keep up with losses or GI side effects such as dyspepsia or constipation limit tolerance. For these reasons, periodic intravenous iron infusion becomes necessary. Although intravenous iron dextran and ferric gluconate complex have been successfully used in EB patients, these formulations carry significant risk of adverse events.9 Intravenous iron sucrose seems to have a better safety profile and maintained efficacy when studied in non-EB patients; its use in EB patients therefore seems prudent.10 Consultation with a hematologist for chronic management of anemia is useful.

GASTROINTESTINAL TRACT COMPLICATIONS Gastrointestinal problems that may require hospitalization of the severe RDEB patient include esophageal stricture, poor motility/feeding intolerance, dysmotility, severe constipation/fecal impaction, pyloric atresia, and postoperative care after gastrostomy tube placement.4,11 All EB patients with dysphagia or odynophagia and infants who feed poorly should be evaluated for gastrointestinal dysfunction, including esophageal stricture formation. An upper gastrointestinal radiographic series is indicated to evaluate the anatomy and function of the esophagus. It is crucial to ask the radiologist to include the upper one-third of the esophagus in the images, because this is the typical site of stricture formation, and is not included in routine upper GI imaging. Neonates in whom pyloric atresia is suspected should be evaluated and managed appropriately. Esophageal stricture formation is directly related to mucosal blistering in RDEB and severe JEB-Herlitz; it is best treated with balloon esophageal dilatation.12 Overnight observation may be required for

pain control and/or advancing diet. Dysmotility and constipation most often result from the necessary use of opiates for acute and chronic pain control; anal fissures may contribute to stool withholding as well. Hospital management of dysmotility includes diagnostic workup studies as indicated, and should involve gastroenterology consultation and an individualized treatment plan. Constipation is generally a chronic problem; the home treatment regimen should be continued while in hospital. Severe constipation may require cathartic cleanout and/or manual disimpaction by a surgeon. Important points to note are the following. (1) Digital rectal exam should be avoided unless absolutely necessary, and then should be performed by an experienced provider with excess lubrication. (2) Enemas should be avoided. (3) Nasogastric tube placement, when needed for administration of electrolyte bowel prep solutions, should be performed carefully, with plenty of water-soluble lubricant, and secured with a nonadhesive, frictionless technique, if secure placement is necessary. (4) Although gross abdominal distention is more commonly due to gaseous distention and stool burden, ultrasound imaging to rule out organomegaly should be considered, since physical examination is often limited by patient discomfort. When gastrostomy is indicated for failure to thrive, an open surgical technique can be used, but there are minimally invasive techniques that may result in less pain and fewer complications.13 A patient with a gastrostomy tube may require hospitalization to manage problems at the ostomy site such as skin erosions or granulation tissue formation, local infection, chronic leakage, or surgical revision. These ostomy problems need complex care in the setting of EB, and may require referral to larger centers. Gastroesophageal reflux disease (GERD), while not usually an indication for hospitalization, is not uncommon in patients with RDEB and JEB. Patients should continue any previously prescribed outpatient therapies for GERD or may need symptomatic treatment while hospitalized.

RESPIRATORY TRACT COMPLICATIONS Airway and respiratory problems in EB patients that the hospitalist may encounter are few but significant, and include tracheolaryngeal stenosis or stricture and airway occlusion.4 Patients with EB can also develop bacterial

or viral pneumonia, croup, bronchiolitis, or an upper respiratory infection that may complicate underlying airway disease. Patients with JEB-Herlitz can develop airway-threatening granuloma formation in the supra- and subglottic areas; this causes stenosis and laryngeal webbing. These are most often present in infant. Therefore stridor and other signs or symptoms of upper airway obstruction must be viewed seriously in any patient with the more severe forms of EB, especially junctional type. The upper airway should be evaluated to rule out obstruction, starting with airway x-rays, and when necessary, direct visualization in the operating room by an otorhinolaryngologist. Acute airway obstruction can occur in the more severe types of EB if large enough sheets of oropharyngeal mucosa are sloughed and aspirated such as may occur after trauma, instrumentation, forceful vomiting, or severe coughing. Treatment of upper airway obstruction is based on identification of the cause; if acute, urgent evaluation in the operating room is indicated. Granulation tissue can be cauterized and excised, but tracheostomy is the mainstay of treatment if a safe airway cannot be maintained. Keeping a tracheostomy device in place with tracheostomy ties without injuring the skin is fraught with difficulty in the EB patient. Skin complications associated with a tracheostomy should be ideally be managed jointly by the caregiver, the hospitalist, an EB wound care expert, and ENT surgeon. Lower airway disease is typically related to acute and chronic aspiration. Acute aspiration events, which may lead to pneumonitis, are characterized by similar history and physical findings as are seen in the general pediatric population. Chronic silent aspiration can also be seen, typically as a result of oropharyngeal scarring, which can decrease epiglottic and pharyngeal sensation, causing chronic lung disease over time.

URINARY TRACT COMPLICATIONS Genitourinary tract complications are associated more often with JEB; however, they can also be seen in patients with RDEB. Genitourinary tract complications include hydronephrosis, chronic renal failure, urethral meatal stenosis, and obstruction of the ureteropelvic junction.4 Patients with urinary symptoms, including dysuria, hematuria, or recurrent urinary tract infections, may have a urethral stricture and should be seen by a urologist for a full evaluation of the genitourinary system; this may include imaging studies such as renal ultrasonography and/or a voiding cystourethrogram. In boys, urethral

strictures can occur anywhere along the length of the urethra and can result in a spectrum of clinical manifestations from mild meatal stenosis to complete obliteration of the urethra due to scarring. Surgical dilatation and repair should be attempted with caution. Some patients may require urinary diversion via placement of a suprapubic catheter or in extreme cases, nephrostomy.

MUSCULOSKELETAL COMPLICATIONS Musculoskeletal complications are a major cause of morbidity in patients with RDEB, and include contractures, scoliosis, osteoporosis, and pseudosyndactyly.3 Joint contractures and muscle atrophy from significant pain and blistering are a major cause of morbidity in patients with RDEB and severe JEB. Therefore physical and occupational therapy evaluation is essential in all patients with significant pain and blistering to maintain adequate function, conditioning, and range of motion, in particular during hospitalization. In RDEB, osteopenia and osteoporosis are not uncommon and result from a combination of reduced weight-bearing activity, poor nutrition with low calcium and vitamin D intake and metabolism, and chronic inflammation.3 Osteopenia and osteoporosis may manifest as bone pain of several different clinical presentations. Localized pain may signify a fracture or microfracture. Spine pain may indicate compression fractures of the vertebrae. Diagnosis of spinal fracture is based on clinical findings in combination with typical findings on plain radiographs. Bone scans may be of little use since they are nonspecific, and there are usually multiple areas of inflammation that will lead to confusion and false positive results. Generalized bone pain can result from osteopenia or osteoporosis in the absence of fracture. Lumbar dualenergy x-ray absorptiometry (DXA) scans can be used to quantify low bone mineral density. Severely low scores have been used as markers for treating RDEB patients with IV bisphosphonates.3

OPHTHALMOLOGIC COMPLICATIONS Appropriate eye care for hospitalized EB patients should not be overlooked, as ocular complications related to recurrent erosions and blisters involving

the conjunctivae and cornea are common in patients with JEB-Herlitz and RDEB.4 Patients with ocular manifestations, including pain, discharge, and blepharitis, should undergo a full ophthalmologic examination. Due to the increased risk of corneal abrasion, every consideration should be given to maintaining sufficient moisture of the eyelids and corneas, especially during procedures requiring general anesthesia or sedation. Repeated abrasions lead to corneal scarring and vision loss and increase the risk of corneal ulceration, which also threatens vision. Ointments provide more protection and last longer than aqueous drops; use of these treatments can also be guided by patient and caregiver preference. Ocular antibiotics, analgesics, and cycloplegics may be required to treat corneal erosions.

CARDIOMYOPATHY Dilated cardiomyopathy is associated with RDEB and JEB and its development appears to be related to a complex interplay of several factors, including micronutrient deficiency, transfusion-associated iron overload, and viral myocarditis.14,15 It can pose substantial clinical risks to the affected patient who is physiologically stressed or undergoing general anesthesia. The typical features noted on echocardiogram include dilated cardiomyopathy and aortic root dilatation. Presenting signs and symptoms such as fatigue, exercise intolerance, and malaise may be noted with many other disease processes; therefore cardiomyopathy can be easily overlooked. For this reason, it is recommended that all RDEB patients be evaluated by cardiology consultation with echocardiogram prior to any general anesthesia. Treatment of cardiomyopathy associated with RDEB ranges from active nonintervention to micronutrient supplementation with carnitine and selenium, to use of medications such as beta-receptor antagonists or angiotensinconverting enzyme inhibitors.14

PSYCHOSOCIAL COMPLICATIONS In addition to the significant physical stressors and challenges of living with EB, particularly the more severe forms, psychosocial issues are universal challenges for patients with EB and their caregivers. There are often devastating financial hardships. The parenting challenges of raising a child

with EB can be overwhelming; family and interpersonal relationships are often strained, and separation and divorce of parents is not uncommon. Patients may have anxiety, depression, and thoughts of suicide as a result of chronic pain and other complications. Screening for these issues during admission, and making consultation to behavioral medicine, psychiatry, or social services as appropriate, is an extremely important component of care for this vulnerable population.

CONSULTATION Anesthesiology: Evaluate and manage complicated airways if endotracheal intubation is indicated. Behavioral Medicine/Clinical Psychology: Facilitate use of techniques such as guided imagery or behavioral modification to assist with dressing changes and other painful interventions. Address issues of adherence and behavior. Psychiatry: Evaluate and manage patients with severe depression, anxiety, or suicidal ideation. Child Life: Provide distraction and diversion for painful procedures and dressing changes during hospitalization. Dermatology: Provide initial evaluation of a patient with suspected EB. Coordinate diagnostic testing, including skin biopsy. Provide expertise with regard to the patient’s prognosis. Educate the patient and caregivers on proper wound care and general skin care to maintain skin integrity. The assistance of a wound care specialist such as a wound, ostomy, and continence nurse (WOCN) may also be helpful with regard to management of acute and chronic wound concerns. Gastroenterology: Manage gastrointestinal complications, including chronic constipation, gastroesophageal reflux disease, and dysmotility. Hand Surgery: Perform surgery to improve the dysfunction caused by pseudosyndactyly and contractures of the hand, although the recurrence rate after surgery is high. Infectious Disease: Provide guidance on appropriate antibiotic choices when dealing with multidrug-resistant organisms associated with skin infections. Provide expertise in the evaluation and management of infectious complications such as sepsis or osteomyelitis.

Interventional Radiology (at some institutions): Perform esophageal dilation for symptomatic esophageal strictures. administration, when necessary. Nutrition Therapy: Perform detailed nutritional assessments and prescribe dietary recommendations to ensure that nutritional intake is sufficient to meet metabolic requirements. Provide guidance on appropriate vitamin and other micronutrient supplementation. Ophthalmology: Perform detailed examinations of the eyes and adnexa to identify and manage potential complications, including chronic blepharitis, conjunctivitis, keratitis, corneal scarring, and ectropion. Otolaryngology: Evaluate and manage complicated airways if endotracheal intubation is indicated. Evaluate and manage all cases of suspected airway stenosis and obstruction and when tracheostomy is being considered. Pain Management: Assess and manage concerns related to acute and chronic pain, anxiety, and pruritus. Pediatric Surgery: Manage symptomatic esophageal strictures with esophageal dilation, colonic interposition, or other specialized surgical procedures. Correct pyloric atresia, which requires urgent surgical correction in the neonatal period. Perform gastrostomy tube placement for nutrition and medication administration. Physical Therapy/Occupational Therapy: Perform detailed assessments of musculoskeletal function. Provide recommendations for exercises and other intervention to help maintain strength and coordination and ability to perform activities of daily living. Plastic Surgery: Perform wide resection of aggressive squamous cell carcinoma, which requires careful planning to provide an appropriate closure. Provide expertise in the use of skin grafting and bioengineered skin equivalents, which may be helpful in the management of patients with chronic non-healing wounds. Urology: Provide evaluation and management of phimosis, meatal stenosis, urethral stricture, and other genitourinary issues.

ADMISSION CRITERIA Severe or extensive skin blistering not responsive to outpatient

management. Secondary infection, such as cellulitis, osteomyelitis, or sepsis. Severe malnutrition and failure to thrive. Esophageal strictures that prevent adequate oral intake or cause aspiration. Severe anemia requiring blood transfusion and monitoring for complications. Respiratory compromise in more severe forms of EB (junctional or dystrophic). Acute urinary retention. Perioperative care for surgical management of pseudosyndactyly with mitten-hand deformities or severe contractures that significantly impair function. Non-EB-related medical conditions (e.g. pneumonia, dehydration), or surgical conditions (e.g. appendectomy) for which admission is appropriate. End-of-life palliative care related to metastatic squamous cell carcinoma or other lethal complications.

DISCHARGE CRITERIA Presence of sustained wound healing with no signs or symptoms of infection. Appropriate plan of care regarding the home wound care regimen, including appropriate use of dressings, bathing regimen, and use of any prescribed topical medications. If the assistance of home nursing care is needed, an appropriate schedule of home visits and retention of a nurse with appropriate training in wound care should be arranged. Parents and caregivers demonstrate the appropriate skills required for general skin, stoma, and wound care and are able to recognize the signs of local or systemic infection. Pain is adequately controlled with appropriate bowel regimen in place. Able to receive adequate nutritional support either enterally or parenterally with demonstration of appropriate weight gain for infants. Hemoglobin concentration at least 8 g/dL. No signs or symptoms of respiratory distress such as stridor or chronic cough.

No evidence of urinary retention or other voiding dysfunction. Appropriate follow-up with any subspecialists has been coordinated.

SPECIAL CONSIDERATIONS IATROGENIC INJURY Systemic manifestations of mucosal blistering can affect the gastrointestinal, genitourinary, and respiratory tracts, as well as the eyes in patients with JEB and RDEB. Because of the risk of iatrogenic injury, great care should be taken if children with EB require instrumentation or manipulation of these organ systems. Specific concerns involve complications due to endotracheal intubation or other invasive procedures such as endoscopy, colonoscopy, bronchoscopy, or urinary catheterization. In addition, modification of many common hospital-based procedures is mandatory to minimize the development of unintended injury, such as attachment of identification bracelets to clothing or gowns instead of around the wrist or ankle, where pressure and friction may result in skin blistering.

INTRAVENOUS ACCESS Intravenous catheter placement is often difficult in patients with RDEB and JEB-Herlitz due to the extensive blistering and scarring typically present and the frequency with which intravenous access is required. A skilled vascular access team can assist in obtaining difficult IV access. A percutaneously inserted central catheter (PICC) can be placed if long-term intravenous access is required. Once intravenous access has been placed, it should be adequately secured in a manner that minimizes trauma to the surrounding skin. One technique involves preparing skin at the site with a mild adhesive barrier such as 3M Cavilon No Sting Skin Barrier Spray, which facilitates removal of the dressing at a later date, followed by application of an appropriately-sized square of Mepiform (usually 3 × 3 for a peripheral intravenous catheter, larger for a percutaneously inserted central catheter), having made an opening in the center of the dressing to accommodate the catheter. The Mepiform is used as a “false skin” to which the line is secured using conventional methods, with extreme care to avoid adherence to the patient’s own skin (Figure 67-7).

ANESTHESIA AND PERIOPERATIVE ISSUES Preoperative assessment should include securing IV catheters, screening for and treating anemia, examining mouth opening for potential difficulty with intubation and dental issues, and ensuring that a recent echocardiogram has been performed for all RDEB patients.16 All staff involved in handling and transporting EB patients should be completely briefed on skin fragility and coached on correct techniques for transferring patients to and from beds, examination tables, and wheelchairs, such as the use of a slide sheet or allowing the patient to move themself to the operating table or other location. Use of a foam egg crate mattress pad or other soft covering is recommended if the patient will be positioned on a hard surface. Intraoperative measures to minimize iatrogenic trauma that should be confirmed before the procedure begins include placement of padding under the blood pressure cuff, application of a lubricating ophthalmic ointment to protect the eyes from desiccation, and use of a foam dressing such as Mepilex or petrolatum gauze to protect the face and chin from device-related pressure.3 Anesthesiologists or otolaryngologists with experience in treating EB patients with complicated airways should be consulted for assistance with endotracheal intubation. Their expertise is invaluable in preventing trauma to the upper airway that may result in blistering and scarring. Microstomia and jaw contractures, which are common in patients with RDEB, combined with the fragile mucosa, make it very challenging for even the most skilled anesthesiologist to intubate with minimal trauma to the airway and oropharynx. Endoscopic-assisted intubation is generally recommended in these cases.

BONE MARROW TRANSPLANTATION Hematopoietic stem cell transplantation has been performed on a small number of patients with severe, generalized forms of EB, predominantly RDEB, and is currently performed at a small number of medical centers worldwide. As with all patients who receive stem cell transplantation, there is a significant risk of complications, including medication toxicity, increased risk of infection and other complications of immunosuppression, and graftversus-host disease. Clinicians with expertise in stem cell transplantation should be involved in the care of any patient with EB who is hospitalized for

any indication after transplantation.

REFERRAL TO AN EPIDERMOLYSIS BULLOSA CENTER The level of complex hospital-based medical and/or surgical care required for a patient with EB, in particular RDEB and JEB-Herlitz, may exceed the capacity available at many institutions. In these circumstances, referral to an EB center is recommended in order to ensure that optimal care is provided by the most experienced team of providers and support staff, thus improving outcomes and minimizing potential complications. Specific situations in which transfer should be considered include the presence of significant tracheolaryngeal stenosis, stricture, or occlusion, in particular if a tracheostomy is being considered; clinically significant esophageal strictures requiring esophageal dilatation; and gastrostomy placement. The current EB centers in the United States and Canada are listed in eTable 67-5.

DebRA The Dystrophic EB Research Association of America (DebRA) is a national non-profit organization dedicated to funding research and providing services and programs for those with EB. They provide a large number of programs and services, including educational and other support for families, a wound care product clearinghouse, a national physician referral service, and a family crisis fund. An EB nurse educator is also available to assist patients, families, and providers with EB-related concerns. DebRA maintains a comprehensive website (www.debra.org) which is an excellent resource for clinicians as well.

PREVENTION EB is an inherited blistering disorder that currently has no cure. Preventive care includes the general strategies to minimize skin blistering and prevent infection as detailed above. Use of pharmacologic agents such as phenytoin and tetracyclines has shown some benefit in reducing the frequency and severity of blistering in some patients, but these drugs are not used routinely.

ACKNOWLEDGMENT The authors gratefully acknowledge the assistance of Erin Shaughnessy, MD and Joshua Schaffzin, MD in the preparation of the revisions to this chapter, and of Paul Honig, MD and Albert Yan, MD, who contributed significantly to the content of this chapter for the first edition of the book. KEY POINTS EB is a diverse group of inherited blistering diseases with no cure, some forms of which can result in severe, generalized cutaneous blistering with systemic involvement of extracutaneous mucosa, resulting in significant morbidity and mortality. Four major types of EB have been defined on the basis of their clinical presentation and the ultrastructural level at which the skin blistering occurs: EB simplex, JEB, dystrophic EB, and Kindler syndrome; JEB and RDEB are considered the most severe and carry the highest risk for systemic complications. RDEB and JEB account for the majority of EB patient admissions. Although patients with EB may be hospitalized for non-EB related disease, those with severe disease are frequently admitted for management of extensive blistering, poor wound healing, and/or infectious complications, or for management of systemic complications, in particular of the gastrointestinal, genitourinary, and respiratory tracts, many of which may require surgical intervention. Inpatient care of the patient with EB requires meticulous attention to skin and wound care and modification of routine patient care procedures in order to minimize blistering and iatrogenic complications. Caring for patients with EB requires a multidisciplinary approach involving general pediatrics, dermatology, pain management, ophthalmology, general surgery, plastic surgery, clinical psychology, and nutrition experts. Suspected wound colonization should be cultured and initially

treated with topical antibiotics rather than systemic antibiotics whenever possible. Use of systemic antibiotics should be reserved for deteriorating wounds or when true cellulitis is present. Patients with EB commonly manifest significant psychosocial distress, chronic pain, developmental delays, and other comorbidities common to patients with other chronic, complex diseases.

REFERENCES 1. Fine JD, Bauer EA, Maguire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hospkins University Press; 1999. 2. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008;58(6):931-950. 3. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-384. 4. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-366. 5. Pope E, Lara-Corrales I, Mellerio J, et al. A consensus approach to wound care in epidermolysis bullosa. J Am Acad Dermatol. 2012;67(5):904-917. 6. Schachner L, Feiner A, Camisulli S. Epidermolysis bullosa: management principles for the neonate, infant, and young child. Dermatol Nurs. 2005;17(1):56-59. 7. Goldschneider KR, Lucky AW. Pain management in epidermolysis bullosa. Dermatol Clin. 2010;28(2):273-282, ix.

8. Haynes L. Nutrition for children with epidermolysis bullosa. Dermatol Clin. 2010;28(2):289-301, x. 9. Kuo DJ, Bruckner AL, Jeng MR. Darbepoetin alfa and ferric gluconate ameliorate the anemia associated with recessive dystrophic epidermolysis bullosa. Pediatr Dermatol. 2006;23(6):580-585. 10. Anbu AT, Kemp T, O’Donnell K, Smith PA, Bradbury MG. Low incidence of adverse events following 90-minute and 3-minute infusions of intravenous iron sucrose in children on erythropoietin. Acta Paediatr. 2005;94(12):1738-1741. 11. Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158. 12. Azizkhan RG, Stehr W, Cohen AP, et al. Esophageal strictures in children with recessive dystrophic epidermolysis bullosa: an 11-year experience with fluoroscopically guided balloon dilatation. J Pediatr Surg. 2006;41(1):55-60; discussion 55-60. 13. Stehr W, Farrell MK, Lucky AW, Johnson ND, Racadio JM, Azizkhan RG. Non-endoscopic percutaneous gastrostomy placement in children with recessive dystrophic epidermolysis bullosa. Pediatr Surg Int. 2008;24(3):349-354. 14. Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682. 15. Lara-Corrales I, Mellerio JE, Martinez AE, et al. Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study. Pediatr Dermatol. 2010;27(3):238-243. 16. Goldschneider K, Lucky AW, Mellerio JE, Palisson F, del Carmen Vinuela Miranda M, Azizkhan RG. Perioperative care of patients with epidermolysis bullosa: proceedings of the 5th international symposium on epidermolysis bullosa, Santiago Chile, December 4-6, 2008. PaediatrAnaesth. 2010;20(9):797-804.

SECTION F Endocrinology

CHAPTER

68

Diabetes Mellitus and Hyperglycemia Christine T. Ferrara, Amanda M. Ackermann, and Andrew A. Palladino

BACKGROUND Insulin is produced by beta cells in the islets of Langerhans in the pancreas. Insulin secretion is regulated by glucose influx into the beta cell, which is dependent on the serum glucose level. Insulin acts on target tissues including liver, fat, and muscle to stimulate glucose uptake and inhibit gluconeogenesis, glycogenolysis, lipolysis, and ketogenesis. The prevalence of diabetes mellitus in the United States in youth less than 20 years of age is 0.182%.1 Type 1 diabetes accounts for 85% of these cases, while type 2 diabetes accounts for 12%, and maturity-onset diabetes of the young (MODY) accounts for 1% to 2%. The incidences of type 1 diabetes and type 2 diabetes in children are both increasing, although the United States has seen a particularly striking increase of type 2 diabetes in children and young adults in the past several years.

PATHOPHYSIOLOGY Hyperglycemia results from abnormal insulin production, abnormal insulin action, or both. In type 1 diabetes, autoimmune destruction of beta cells results in an absolute insulin deficiency. Approximately 90% of patients with type 1 diabetes have measurable serum antibodies against islet cells, glutamic acid decarboxylase (GAD), or insulin.2 However, although autoimmunity is an essential component of the pathogenesis of type 1 diabetes, it alone is not sufficient; environmental factors including diet, prenatal influences, infectious exposures, stress, and genetic factors contribute to development of this disease.

Type 2 diabetes is characterized by insulin resistance, often due to obesity, with resulting beta cell dysfunction and glucotoxicity that results in a relative insulin deficiency despite hyperinsulinemia. Although the etiology of type 2 diabetes is multifactorial, there is a stronger genetic component than for type 1 diabetes.2

CLINICAL PRESENTATION Patients with hyperglycemia often have a history of polyuria, polydipsia, polyphagia, weight loss, and/or fatigue. Depending on the duration of illness and the underlying pathophysiology, the patient may or may not have ketosis or acidosis as a consequence of absolute or relative insulin deficiency. Although more common in type 1 diabetes, ketosis and acidosis can also occur in type 2 diabetes. Children with newly diagnosed diabetes may present to the hospital in advanced stages of metabolic decompensation because the symptoms of hyperglycemia were not recognized. Treatment of diabetic ketoacidosis (DKA) in childhood requires strict attention to fluid balance and neurologic status because of the increased risk of cerebral edema in the pediatric population. Early detection of diabetes can reduce these risks.

DIFFERENTIAL DIAGNOSIS The cause of hyperglycemia is not always apparent at initial presentation. The differential diagnosis includes type 1 diabetes, type 2 diabetes, MODY, “stress hyperglycemia” from illness or trauma, pancreatitis, other pancreatic dysfunction (e.g. cystic fibrosis), and drug effect (glucocorticoids, antipsychotics, etc.). Less commonly, hyperglycemia may be seen in the setting of other endocrine disorders such as excess endogenous glucocorticoid, growth hormone, or catecholamine. Type 1 diabetes can also be a component of autoimmune polyendocrine syndrome type 2, which includes autoimmune primary adrenal insufficiency (Addison disease) and autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease). Patients may experience a period of absolute insulin deficiency at the time of diagnosis and present with ketosis with or without acidosis. Younger age at presentation and Caucasian ethnicity is associated with increased

likelihood of type 1 diabetes. Most patients with type 1 diabetes present before the age of 30 years, and for this reason the condition was previously termed “juvenile-onset” diabetes. It is now clear, however, that autoimmune diabetes may develop at any age. Obesity and acanthosis nigricans (thickening and darkening of the skin in flexural areas such as the axillae and posterior of the neck) should raise the possibility that a child has type 2 diabetes, even in the setting of ketoacidosis. These patients typically do not have antibodies against islet cells, GAD, or insulin. This form of diabetes was previously labeled as “adult-onset” diabetes; however, the incidence of type 2 diabetes in the pediatric population is increasing rapidly as childhood obesity has become more prevalent.1,3 MODY is a relatively rare group of disorders of insulin secretion and glucose disposal. They vary in their severity and presentation, and management often differs from that of type 1 and type 2 diabetes. Each is caused by a single gene mutation and is inherited in an autosomal dominant pattern. Insulin resistance and obesity are not features of these disorders.4

DIAGNOSTIC EVALUATION Criteria for the diagnosis of diabetes include a random plasma glucose ≥200 mg/dL or hemoglobin A1c ≥ 6.5% with symptoms of diabetes, or a fasting (at least 8 hours) plasma glucose ≥126 mg/dL, or a 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test using a glucose load of 1.75 grams/kg (up to 75 grams). If an asymptomatic patient is found to have a fasting plasma glucose ≥126 mg/dL or a random plasma glucose ≥200 mg/dL as part of screening labs, these should be repeated on a second day to confirm these results. However, if a patient with signs and symptoms of diabetes including polyuria, polydipsia, or weight loss is found to have a random glucose of ≥200 mg/dL, no further testing is needed for diagnosis.5

HYPERGLYCEMIC STATES Patients with diabetes can present various hyperglycemic states, each with its own diagnostic criteria and management. The various ways in which diabetes can present are described below; the management will be discussed later.

Hyperglycemia with Ketoacidosis DKA is defined by a glucose ≥200 mg/dL, venous pH 330 mOsm, venous pH >7.3, HCO3 >15 mM, and absent to small ketonuria or ketonemia. It is often accompanied by hypernatremia, significant dehydration, and altered mental status.6,7 Admission to an ICU is indicated due to increased risk of cerebral edema and stroke in these patients even in comparison to DKA. Mixed Hyperglycemic Hyperosmolar State and Ketoacidosis Mixed hyperglycemic hyperosmolar state and ketoacidosis, defined by glucose >600 mg/dL, serum osmolality >320 mOsm, venous pH 4 mL/kg/hr); such losses include urine, vomiting, and Kussmaul respirations. Potassium Total body potassium is depleted in DKA and should be added to the intravenous fluids as soon as the following criteria have been met: serum potassium is 1200 mg/dL, serum osmolality >300 mOsm), the therapeutic goals should be adjusted to replace the fluid deficit over a period of 48 to 72 hours, and after an initial period of rehydration, to lower the blood glucose by 50 mg/dL/hr. Continued Monitoring and Reevaluation After initial therapy for DKA has been instituted, monitor blood pH and electrolytes every 1 to 2

hours until the patient is improving (pH >7.3 or bicarbonate >15 mM) and then every 2 to 4 hours. Check serum glucose levels every hour via finger stick (or laboratory glucose if too high for the glucose monitor). Neurologic status should be evaluated every 1 to 2 hours. Urine output should be recorded and overall input and output reviewed frequently. A flow sheet is extremely helpful to track changes in fluid balance, vital signs, electrolytes, urine ketones, and blood sugar. It is important to note that serum ketones and urine ketones may not exactly coincide; however, urine ketones are often used to track improvement in DKA.6 Complications Complications associated with DKA resuscitation include hypoglycemia, hypokalemia, hypophosphatemia, hypocalcemia, hypernatremia, fluid overload with edema, acute respiratory distress syndrome, and symptomatic cerebral edema. Cerebral edema is the leading cause of death in DKA with a mortality rate of 21% to 24%. The incidence of cerebral edema is generally reported as less than 1%.6 Patients at particularly high risk include those younger than 5 years of age and those with severe acidosis, severe dehydration, and high serum osmolarity.9 Symptoms of cerebral edema include any change in sensorium, headache, increased drowsiness, deepening coma, and cranial nerve abnormalities. Cushing’s triad (increased blood pressure, decreased heart rate, irregular respirations) may be seen in the setting of increased intracranial pressure, which is a neurosurgical emergency. It is important to have mannitol or hypertonic saline available when a patient is admitted with DKA in the event that symptomatic cerebral edema develops. Case reports have shown possible beneficial effects of mannitol or hypertonic saline. Intravenous mannitol should be given (0.25–0.5g/kg over 20 minutes) in patients with signs of cerebral edema and impending respiratory failure. If there is no initial response, it should be repeated in 2 hours. Hypertonic saline (3%) (5 mL/kg over 30 minutes), may be a reasonable alternative to mannitol if there is concern for hypotension (and cerebral hypoperfusion) due to an osmotic diuresis that could be seen with mannitol administration. Intubation and ventilation may be necessary in severe DKA. Mild hypercapnea, however, should be tolerated, as aggressive hyperventilation has been associated with poor outcomes in DKA-related cerebral edema.6 Transition to Subcutaneous Insulin The criteria for switching from an intravenous insulin infusion to subcutaneous insulin injections include the

ability to tolerate oral intake, a normal mental status, and resolved acidosis (bicarbonate ≥15 mM or pH ≥7.3). The first dose of subcutaneous insulin should be given 15 to 60 minutes (15–30 minutes with rapid acting, 30–60 minutes with regular insulin) before stopping the intravenous infusion to allow sufficient time for absorption. It is optimal to convert to a subcutaneous regimen just before a meal. For patients in DKA, it is convenient, when possible, to give long-acting basal insulin while still on infusions in order to help with the transition to subcutaneous insulin. A typical starting daily dose of insulin for a patient with type 1 diabetes is between 0.4 and 1 units/kg/day, but the dose and type of subcutaneous insulin varies by institution and should be taken into consideration when planning a regimen (Table 68-1). Treatment needs to be individualized for each patient and should be discussed with a pediatric endocrinologist. Patients with previously diagnosed diabetes can usually be started on their home insulin regimen. TABLE 68-1

Type of Insulin

Insulin Preparations Available for Subcutaneous Therapy Onset of Action

Peak Action

Duration of Action

15 min

45 min

3–5 hr

30 min

2–5 hr

5–8 hr

Intermediate NPH acting

1–3 hr

6–12 hr

10–12 hr

Long acting

Glargine (Lantus)

4–6 hr

None

24 hr

Detemir

4–6 hr

Dose-

24 hr

Name

Rapid acting Lispro (Humalog) Aspart (NovoLog) Apidra (Glulisine) Short acting

Regular

(Levemir)

dependent

Patients with a new diagnosis of type 2 diabetes who present with a hemoglobin A1c of ≥8.5% will likely be initiated on insulin therapy and require initial insulin doses of at least 1 unit/kg/day, as they will demonstrate mild to severe insulin resistance. Metformin can also be used in patients 10 years of age and older, provided they do not have significant kidney or liver dysfunction. This medication improves insulin sensitivity, which should, over time, decrease their insulin requirement.

TREATMENT OF THE HYPERGLYCEMIC HYPEROSMOLAR STATE A hyperglycemic hyperosmolar state may be seen in type 1 diabetes, although it is more common in type 2 diabetes. Management of this disorder is outside the scope of this chapter and should involve the ICU team. It is important to know, however, that the underlying pathophysiology involves severe dehydration and requires that adequate fluid administration precede insulin administration to avoid cardiovascular collapse.8

TREATMENT OF HYPERGLYCEMIA WITHOUT ACIDOSIS If the initial workup reveals only hyperglycemia or hyperglycemia with mild to moderate ketosis, it may be possible to manage the patient with oral rehydration and subcutaneous insulin therapy. This approach is not appropriate in patients with hyperosmolality, nausea or vomiting, or another issue precluding oral intake. Electrolyte imbalance is less frequently seen and can usually be corrected with oral therapy. The approach to insulin management is similar to that described in the previous section.

ADMISSION AND DISCHARGE CRITERIA ADMISSION CRITERIA Hyperglycemia accompanied by ketosis and acidosis

Altered mental status Any patient receiving insulin who is unable to tolerate sufficient oral intake to prevent hypoglycemia and dehydration Pediatric patients with newly diagnosed diabetes requiring initiation of insulin therapy if intensive education is not immediately available on an outpatient basis

DISCHARGE CRITERIA Normal electrolytes and hydration status Ability to tolerate oral intake It is not necessary to obtain perfect glucose control before discharge; insulin doses will require adjustments after discharge and on an ongoing basis For a patient being discharged on insulin therapy, it is necessary to ensure that the family has been educated regarding the following: Definition and pathophysiology of the different types of diabetes Insulin action Signs and symptoms of hypoglycemia Treatment of hypoglycemia and use of glucagon Proper technique in using the glucometer Proper technique in drawing up and administering insulin Consequences of poor glycemic control Follow-up should be arranged with a pediatric endocrinologist as an outpatient

CONSULTATIONS Pediatric endocrinology Possible: pediatric critical care, pediatric neurosurgery

SPECIAL CONSIDERATIONS COMORBIDITIES

Patients with type 1 diabetes are at increased risk for other autoimmune disorders such as hypothyroidism and celiac disease. Patients with type 2 diabetes are at increased risk for non-alcoholic steatohepatitis and dyslipidemia. Patients with known diabetes should have screening for these comorbidities, in addition to assessment of urine microalbumin to detect nephropathy and ophthalmology exam to detect retinopathy.

PREVENTION Prevention of type 1 diabetes is currently being studied at three levels. Primary prevention aims to prevent development of autoantibodies that could lead to type 1 diabetes by means of diet modifications and antigen-specific vaccines. Secondary prevention aims to prevent beta cell destruction in patients who already have developed autoantibodies. Tertiary prevention aims to preserve beta cell function in patients already diagnosed with type 1 diabetes via immunomodulators.10 Prevention of type 2 diabetes involves lifestyle modifications such as dietary alterations and increased exercise to induce weight loss. Bariatric surgery can also prevent progression of and reverse metabolic syndrome and type 2 diabetes, although such procedures are controversial in children.11

NEW THERAPIES Several new drugs are approved for use in adults with type 2 diabetes that may prove beneficial to the pediatric population as well. First are the injectable agents (exenatide and liraglutide), which are modeled after the human incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is secreted in response to food intake and has multiple effects on the stomach, liver, pancreas, and brain. The next new class of drugs for treatment of type 2 diabetes are inhibitors of dipeptidyl-peptidase-4 (DPP-4), the enzyme that inactivates GLP-1. Third, pramlintide, a synthetic amylin analogue, has been shown to decrease glucagon secretion and delay gastric emptying, resulting in less glycemic excursion and facilitating weight reduction without causing hypoglycemia.11 Investigational therapies for type 1 diabetes include closed-loop insulin delivery systems, immunomodulators, improved islet transplantation

techniques, and stem cell differentiation.10 KEY POINTS Hyperglycemia often presents in the inpatient setting and may be a result of type 1 (autoimmune) diabetes mellitus, type 2 diabetes mellitus, illness, sepsis, or drug effects. History of polyuria, polydipsia, polyphagia, and weight loss should be noted. The presence or absence of ketosis and acidosis at initial presentation does not necessarily differentiate type 1 from type 2 diabetes. If ketosis is present, it suggests an absolute insulin deficiency at that time. Physical examination should focus on vital signs, neurologic status, and clinical signs of dehydration during initial evaluation of a patient with hyperglycemia. Initial laboratory evaluation should include venous or arterial blood gas, electrolytes, CO2, BUN, and creatinine, liver enzymes, insulin, C-peptide, hemoglobin A1c, GAD-65 antibodies, islet cell antibodies, and insulin autoantibodies. Urine should be assessed for the presence of glucose and ketones. In patients with significant electrolyte abnormalities, an ECG should be obtained. Management of patients with DKA is individualized and aimed at correcting the underlying insulin deficiency, ketosis, and acidosis, as well as replacing the fluid deficit over a 48-hour period or longer if clinically indicated.

BOX 68.1. Corrected Sodium and Estimated Serum Osmolality Calculations in DKA corrected sodium = measured sodium + [1.6 × (serum glucose– 100)/100]

REFERENCES 1. SEARCH for Diabetes in Youth Study Group. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510-1518. 2. Alemzadeh R, Ali O. Diabetes mellitus in children. In: Kliegman RM, Stanton BF, St. Gemel III JW, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:1968-1997. 3. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364-382. 4. Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ. 2011;837-842. 5. Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186-212. 6. Wolfsdorf J, Craig ME, Daneman D, et al. ISPAD clinical practice consensus guidelines 2009 compendium: diabetic ketoacidosis in children and adolescents with diabetes. Pediatr Diabetes. 2009;10(Suppl 12):118-133. 7. Zeitler P, Haqq A, Rosenbloom A, Glaser N. Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr. 2011;158(1):9-14. 8. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344(4):264269. 9. Rewers A. Current controversies in treatment and prevention of diabetic ketoacidosis. Adv Pediatr. 2010;57(1):247-267. 10. Majidi S, Maahs DM. Update on care of children with type 1 diabetes. Adv Pediatr. 2012;59(1):303-327. 11. Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: new and future developments in treatment. Lancet. 2011;378(9786):182-197.

CHAPTER

69

Disorders of Thyroid Hormone Katherine Lord and Andrew A. Palladino

BACKGROUND Thyroid hormone has many effects on the human body. It plays an essential role in growth and development, thermogenesis, oxygen consumption, and the metabolism of carbohydrates, lipids, and proteins. Although thyroid hormone is essential for the normal function of many tissues, thyroid dysfunction is frequently insidious and may be missed. The hypothalamic-pituitary-thyroid axis is finely tuned to maintain stable levels of thyroid hormone in the body. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and stimulates the production and secretion of thyroid-stimulating hormone (TSH) by the anterior pituitary gland.1 Through binding of the thyroid-stimulating hormone receptor (TSHR), TSH leads to production and release of the thyroid hormones, thyroxine (T4) and triiodothyroxine (T3), as well as thyroid cell growth. Thyroid hormones feedback on the anterior pituitary and hypothalamus, decreasing secretion of TSH and TRH, respectively, allowing for tight regulation of thyroid hormone concentrations. The predominant form of hormone secreted by the thyroid is T4, which then undergoes peripheral conversion to T3 by types I and III deiodinases. T3, the metabolically active hormone, and exerts its effects by binding nuclear receptors and influencing DNA transcription. T4 may also be converted into the inactive reverse T3 (rT3) by deiodinase type III. Increased rT3 is commonly seen in the fetus and in severely ill patients.1 The majority of thyroid hormone circulates bound to thyroid-binding globulin (TBG) and to a lesser extent, other serum proteins. The remainder circulates unbound (free) and is metabolically active. Estrogen decreases TBG clearance, leading to higher levels of total thyroid hormone. As a result, oral contraceptive pill use or pregnancy will lead to elevated total T4 levels,

but the free amount of thyroid hormone remains normal. The maturity level of the hypothalamic-pituitary-thyroid axis must be considered to correctly interpret thyroid function tests in newborns and children. At birth, an acute surge in TSH occurs in response to exposure to the cold extrauterine environment, resulting in a rise in T4 and T3 levels. TSH remains elevated for 3 to 5 days after birth while the T4 and T3 levels gradually decline over the first 2 to 4 weeks of life.2 During childhood, there is a progressive decrease in TSH and thyroid hormone levels until approximately age 15 to 16 years, when adult levels are reached (Table 691). TABLE 69-1

Normal Values for Thyroid Function Tests

Age

Reverse T4 Free T4 T3 T3 TSH (μU/mL) (μg/dL) (ng/dL) (ng/dL) (ng/dL)

Premature infants (26– 32 wk): 3–4 days of life

0.8–6.9 (2.3)

Full-term infants: 1–3 days of life

2.6–14.0 0.4–2.8 (6.4) (1.5)

24–132 (65)

8.2–20.0 (14.6)

89–405 (273)

90–250+

Full-term infants: 3–7 days of life

1.3–16.0 (4.9)

6.0–15.9 2.0–4.9 (12.0) (3.5)

91–300 (190)

1–12 mo of life

0.9–7.7 (2.9)

6.1–14.9 0.9–2.6 (9.8) (1.6)

82–250 (175)

Prepubertal

0.6–5.5 (1.9)

1–3 yr: 0.8–2.2 6.8–13.5 (1.6) (9.3)

119–218 10–50 (168)

3–10 yr: 5.5–12.8 (8.6) Pubertal

0.5–4.8 (1.6)

4.9–13.0 0.8–2.3 (8.0) (1.5)

80–185 (116)

10–50

Source: Data from Esoterix. TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine. *Range of values, with mean in parentheses. †Levels

decline to the adult range by 1 wk of life.

CLINICAL PRESENTATION HYPOTHYROIDISM Congenital Hypothyroidism Congenital hypothyroidism, defined as thyroid hormone deficiency present at birth, occurs in approximately 1:2000 to 1:4000 newborns and is one of the leading causes of preventable intellectual disability.2 The clinical manifestations are often subtle and usually not present at birth. Symptoms include lethargy, difficulty feeding, constipation, a hoarse cry, and prolonged jaundice. Physical examination may show a wide posterior fontanel, macroglossia, coarse facies, umbilical hernia, and hypotonia. Placental transfer of maternal thyroid hormone protects the developing fetus.3 Due to newborn screening, infants are usually identified before they develop clinical signs or symptoms of hypothyroidism. Acquired Hypothyroidism Hashimoto thyroiditis or autoimmune hypothyroidism is the most common cause of acquired hypothyroidism in children. The presentation is variable as the child may be euthyroid, hypothyroid, or transiently hyperthyroid at diagnosis. Children may complain of neck swelling, fatigue, constipation, cold intolerance, and in pubertal girls, menstrual irregularities. 70% to 80% of children with hypothyroidism will present with a goiter, which is typically symmetric and nontender.4 Other exam findings include bradycardia, proximal muscle weakness, delayed deep tendon reflexes, and growth failure (Figure 69-1). Hypothyroidism produces poor linear growth with preservation of normal weight gain, and these children may be relatively overweight for their height, but contrary to popular

belief, hypothyroidism generally does not cause obesity.

FIGURE 69-1. Growth chart demonstrating growth failure from undiagnosed hypothyroidism. Although weight remains relatively stable, linear growth slows significantly and the girl eventually has declining height percentiles. Catch-up growth occurs with initiation of levothyroxine treatment (arrow). (Developed by the National Center for

Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion; 2000. http://www.cdc.gov/ growthcharts.) Autoimmune hypothyroidism has a female predominance (2:1) and 40% to 50% of patients will have a positive family history of autoimmune thyroid disease.4 It can be associated with other autoimmune disorders, including type 1 diabetes mellitus, primary adrenal insufficiency (Addison disease), and celiac disease. Autoimmune thyroiditis is also more common in patients with certain chromosomal disorders, such as Down syndrome and Turner syndrome.

HYPERTHYROIDISM Neonatal Hyperthyroidism Neonatal thyrotoxicosis (neonatal Graves disease) is a rare disorder, occurring in only 1% to 1.4% of pregnancies affected by maternal Graves disease (autoimmune hyperthyroidism).5 It is most commonly due to transplacental passage of TSH receptor-stimulating antibodies from a mother with Graves disease, leading to increased thyroid hormone production in the fetus. The hyperthyroidism persists until the maternal antibodies are cleared from the infant’s circulation, which can take up to 3 to 4 months. Thyrotoxicosis may be suspected due to fetal tachycardia and intrauterine growth restriction. Clinical symptoms in the neonate are variable and may not occur until several days after birth due to antithyroid medications taken by the mother during pregnancy. Neonates may present with irritability, tachycardia, jaundice, poor weight gain, and exophthalmos.5 Affected infants need to be admitted to a neonatal intensive care unit for close monitoring of vital signs and frequent testing of thyroid labs, as neonatal hyperthyroidism can result in high-output cardiac failure and even death. A pediatric endocrinologist should be consulted immediately if neonatal hyperthyroidism is suspected. Untreated infants that survive may develop advanced bone age, craniosynostosis, and intellectual disability. Graves Disease The most common cause of hyperthyroidism in children is Graves disease (autoimmune hyperthyroidism), occurring in 1:10,000 children in the United States.6 There is a female predominance and peak incidence is during adolescence. Graves disease is an autoimmune disorder in

which antibodies against the TSH receptor (also known as thyroidstimulating immunoglobulins) cause the overproduction and secretion of thyroid hormone. The symptoms are often insidious and the rarity of the disorder and its nonspecific symptoms often result in a delay in diagnosis. Children may present with fatigue, weight loss, palpitations, increased bowel movements, irritability, and difficulty sleeping. Parents may report that their child has deteriorating school performance and decreased concentration.6 On examination, the thyroid is generally diffusely enlarged, and the patient may have tachycardia, hypertension, hyperreflexia, and a fine tremor. Ophthalmopathy (thyroid eye disease) may occur in children, but less commonly than in adults. Thyroid storm in children is extremely rare, but is a medical emergency. It consists of acute hyperthermia, tachycardia, and encephalopathy in a patient with hyperthyroidism. Heart failure can result from the tachycardia. Thyroid storm may be precipitated by infection, surgery, or noncompliance with antithyroid medications.

DIFFERENTIAL DIAGNOSIS HYPOTHYROIDISM Congenital Hypothyroidism Congenital hypothyroidism can be permanent or transient and is classified as primary, due to an inherent defect of the thyroid gland or thyroid hormone production or secretion, or secondary (central), due to defects in the pituitary/hypothalamus. Eighty-five percent of primary congenital hypothyroidism is caused by thyroid gland dysgenesis.2 The gland may be ectopically located, hypoplastic, or absent. In some parts of the world, iodine deficiency is an important cause of congenital hypothyroidism; however, this condition is almost nonexistent in the United States. Isolated TSH deficiency is very rare and central congenital hypothyroidism occurs more commonly in the presence of other pituitary deficits. The presence of midline defects, micropenis, and/or hypoglycemia in a neonate suggests the possibility of hypopituitarism, which could be due to anatomical defects of the pituitary or septo-optic dysplasia, a disorder in which pituitary deficiencies may also occur later in life. Transient congenital hypothyroidism is rare, but can be caused antithyroid medications taken by the mother during pregnancy that cross the

placenta, inhibiting fetal thyroid hormone production. Generally, neonatal hypothyroidism induced by maternal medication resolves within 1 to 2 weeks. Other causes of transient congenital hypothyroidism include iodine deficiency or excess in the mother, pre- or postnatal exposure to iodine, and maternal TSH receptor-blocking antibodies that cross the placenta and block thyroid hormone production in the fetus/neonate.2 Acquired Hypothyroidism Acquired hypothyroidism is also classified as primary or secondary. Hashimoto, or autoimmune, hypothyroidism, is the most common cause of primary acquired hypothyroidism. Other causes include radiation to the neck, commonly used in the treatment of certain types of lymphoma, and surgical resection of the thyroid gland for treatment of Graves disease or thyroid cancer. Certain medications can also induce hypothyroidism.7 Drugs that down-regulate the release of TSH from the pituitary include glucocorticoids and dopamine. Glucocorticoids also appear to inhibit the peripheral conversion of T4 to T3. Drugs that affect thyroid hormone synthesis and release include amiodarone and iodine, and lithium. Although iodine is essential for proper thyroid function, large amounts can block the release of preformed thyroid hormone and the synthesis of new hormone (the Wolff–Chaikoff effect). Hypothyroidism is seen in infants or children who receive large amounts of cutaneous iodine for surgical procedures or those receiving amiodarone, which contains significant amounts of iodine. Lithium carbonate, used to treat psychiatric disorders, inhibits thyroid hormone release. Antiepileptic medications, particularly phenytoin and carbamazepine, increase hepatic metabolism of thyroxine, which can result in low levels of total T4 with normal TSH and T3 levels. Central hypothyroidism should be suspected in children with a history of central nervous system disease, such as hydrocephalus, hemorrhage, brain tumor, or meningitis, or central nervous system malformations. In any patient with central hypothyroidism, it is important that other pituitary hormone deficiencies be investigated, such as deficiencies of adrenocorticotropic hormone, growth hormone, gonadotropins, and vasopressin. Nonthyroidal illness (NTI), also known as sick euthyroid syndrome, is seen in severely ill patients and in states of starvation.1 Patients will commonly have low or normal TSH, low total T4 and T3, and normal or high free T4 levels. Multiple mechanisms may give rise to these changes, including suppression of TSH secretion by cytokines and decreased

peripheral conversion of T4 to T3.8 Reverse T3 (rT3) levels are generally elevated, because conversion of T4 to rT3 is not impaired, and the degradation of rT3 is reduced. NTI is thought to be a protective adaptive response aimed at decreasing metabolism and preserving energy stores during stress. There is no clear evidence that treatment of NTI with thyroid hormone replacement improves outcomes.

HYPERTHYROIDISM In addition to Graves disease, other causes of hyperthyroidism in childhood and adolescence include autonomously functioning thyroid nodules, infections of the thyroid. and McCune–Albright syndrome. Hashimoto thyroiditis may have a hyperthyroid phase during destruction of the thyroid gland resulting in release of pre-formed thyroid hormone and transient hyperthyroidism. Drugs that can cause hyperthyroidism include amiodarone, iodine, and intentional or accidental ingestion of levothyroxine.5

DIAGNOSTIC EVALUATION HYPOTHYROIDISM An elevated serum TSH in the presence of low T4 levels is consistent with primary hypothyroidism. In subclinical primary hypothyroidism, there will be a mildly elevated TSH with normal T4 levels. In contrast, a child with central hypothyroidism can have a low, normal, or even elevated TSH combined with low T4 levels. Congenital Hypothyroidism The vast majority of infants with congenital hypothyroidism are identified through newborn screening programs in countries with such programs. The newborn screen is based on the measurement of T4 or TSH (or both) in a dried blood filter paper sample obtained between 2 and 4 days of life (or at discharge from the hospital).3 There are advantages and disadvantages to either a T4 or TSH screening approach. If T4 is measured, infants with a T4 level below a specific cutoff point have their TSH measured as well. This method can miss subclinical hypothyroidism (normal T4 but elevated TSH levels). Primary screening with TSH has a higher false-positive rate owing to the early screening (before 2

days of life) and it also misses infants with central hypothyroidism. When the newborn screen reports abnormal thyroid tests, the infant should be seen and examined immediately and serum confirmatory testing should be obtained. The newborn screen should not be repeated for confirmation as that can result in delayed treatment.3 Thyroid function testing should include TSH and free T4 or total T4 combined with a measure of binding proteins, such as a T3 resin uptake. Once the diagnosis of hypothyroidism is confirmed, additional diagnostic tests can be performed in order to determine its etiology. A technetium scan can establish whether there is any thyroid tissue or an ectopic or hypoplastic thyroid. A scan with normal uptake suggests dyshormonogenesis. Obtaining the technetium scan should not delay the initiation of treatment, because the scan can still be performed within the first several days of levothyroxine therapy. A thyroid ultrasound study is noninvasive and is easier to obtain, but is generally not as accurate the technetium scan in detecting an ectopic gland. Controversy exists as to whether or not these additional tests are necessary in the diagnosis of congenital hypothyroidism, and the American Academy of Pediatric guidelines classify them as optional.3 Low thyroid hormone in the setting of a low or normal TSH level is suggestive of central hypothyroidism and hypopituitarism. An infant with this presentation should be monitored carefully for hypoglycemia and must undergo evaluation of the other pituitary hormones. It is particularly crucial to identify if there is central adrenal insufficiency, and if detected, cortisol must be adequately replaced prior to initiating thyroid hormone replacement. Thyroid hormone supplementation increases cortisol clearance from the circulation and could precipitate cardiovascular collapse and adrenal crisis in patients with adrenal insufficiency. Acquired Hypothyroidism Evaluation of older children with suspected acquired hypothyroidism should include a serum TSH with a total and free T4. Antithyroid peroxidase and antithyroglobulin antibodies can be obtained to confirm the diagnosis of autoimmune hypothyroidism. Thyroid imaging in acquired hypothyroidism is not usually warranted unless a nodule is present. Low total T4 levels with a normal TSH can be seen with familial thyroidbinding globulin deficiency, an X-linked recessive condition.7 The free T4 level should be normal in TBG deficiency, and treatment is not indicated. Children with the diagnosis of acquired central hypothyroidism must have

assessment of the other pituitary hormones and require an MRI of the brain and pituitary to rule out a mass.

HYPERTHYROIDISM Low TSH and elevated T4 and T3 levels are consistent with primary hyperthyroidism. The initial laboratory tests should include serum TSH, free or total T4, and total T3 levels. Measurements of thyroid-stimulating immunoglobulins and TSH receptor antibodies should be obtained to confirm the diagnosis of Graves disease. An I-123 scan may be necessary to distinguish Hashimoto thyroiditis from Graves, given overlap in the antibody profiles.6 Hashimoto thyroiditis and Graves can also be distinguished clinically if exophthalmos is present (seen in Graves). In the setting of Graves disease, imaging of the thyroid gland is generally not indicated. However, if a nodule is present or there is an asymmetric gland, a thyroid ultrasound should be obtained.

MANAGEMENT HYPOTHYROIDISM Congenital Hypothyroidism The goal of treatment for congenital hypothyroidism is to adequately replace thyroid hormone as early as possible to maximize the chances for normal neurologic development. Neurodevelopmental outcomes are inversely related to age at diagnosis and start of treatment. Levothyroxine (T4) is the accepted treatment. The starting dose is generally 10 to 15 μg/kg (usually 37.5–50 μg/day) in one daily dose.2 However, it has been shown that term infants receiving a dose of 50 μg/day had better neurologic outcomes compared to those receiving 37.5 μg/day.9 The goal of treatment is to normalize the T4 level as quickly as possible, recognizing that the TSH will take longer to normalize. Overtreatment with levothyroxine can lead to advanced bone age and craniosynostosis. For infants with a late diagnosis of congenital hypothyroidism who have been hypothyroid for 2 to 3 months, it is advisable to work up to a full replacement dose over 1 to 2 weeks to avoid precipitating rapid mobilization of fluid. Levothyroxine should be given as a crushed tablet in a small amount of

formula, breast milk, or water. Liquid preparations and suspensions of levothyroxine should be avoided, because they are unstable and do not provide reliable dosing. During the first three years of life, the T4 level should be kept in the upper half of the reference range. The AAP recommends clinical and biochemical monitoring at 2 to 4 weeks following levothyroxine initiation; every 1 to 2 months during the first 6 months of life; every 3 to 4 months between 6 months and 3 years old; then every 6 to 12 months until completion of growth.2 Given the risk of neurologic damage, careful and ongoing counseling of the parents is essential to limit noncompliance, which is the most common cause of an elevated TSH while receiving treatment. Acquired Hypothyroidism The treatment for primary or central acquired hypothyroidism is levothyroxine, which is dosed based on weight and age (Table 69-2). As with congenital hypothyroidism, suspensions of levothyroxine should be avoided. For younger children, tablets may be crushed and mixed with a small amount of liquid or food. Although absorption of levothyroxine is greatest on an empty stomach, dosing at a mealtime is often easiest for families. Any decrease in absorption that comes from taking it with a meal can be compensated with a higher dose. Iron, calcium supplements, and soy products decrease the absorption of levothyroxine and should be administered at a different time. TABLE 69-2

Levothyroxine Dosing

Age

Oral Dose*

0–3 months

10–15 μg/kg/day

3–6 months

8–10 μg/kg/day

6–12 months

6–8 μg/kg/day

1–5 years

5–6 μg/kg/day

6–12 years

4–5 μg/kg/day

> 12 years

2–3 μg/kg/day

Postpubertal/adult

1.7 μg/kg/day or 100–200 μg/day (average adult dose)

*Intravenous dose is 50% of oral dose

The goal of treatment is to keep the TSH and T4 within the normal range. Elevated TSH and T4 levels in a patient treated for primary hypothyroidism should raise the suspicion for noncompliance with a recent effort to conceal their noncompliance by taking multiple doses at one time. T4 is monitored in patients with central hypothyroidism. Treatment of subclinical hypothyroidism and NTI remains controversial. In patients with subclinical hypothyroidism, many practitioners treat with levothyroxine when the TSH rises above 10 mIU/L. There is no evidence to support the treatment of NTI in children and adolescents and it should not be done unless under the guidance of a pediatric endocrinologist.

HYPERTHYROIDISM Neonatal Hyperthyroidism Given the risk of cardiac failure and death, treatment for neonatal thyrotoxicosis should be initiated as soon as possible. The antithyroid medications methimazole and propylthiouracil (PTU) block the production of thyroid hormone.5 PTU (5 to 10 mg/kg/day) has the additional benefit of blocking the conversion of T4 to T3 and is available in a liquid preparation. However, given the association of PTU and severe liver failure, methimazole (0.5–1 mg/kg/day) is now the first-line agent for treatment of neonatal hyperthyroidism. PTU may need to be used if a compounded suspension of methimazole cannot be obtained. Propranolol (1– 2 mg/kg/day) should be administered to treat tachycardia. In severe cases, a saturated potassium iodide solution (SSKI 1 drop/day) or Lugol iodide solution (1–3 drops/day) may be used to decrease thyroid hormone production.5 Frequent monitoring of thyroid levels is essential. As the TSH receptor-stimulating antibodies are cleared from the infant’s circulation, the antithyroid medications and propranolol can be weaned and are typically discontinued after 3 to 4 months once the TSI is no longer detectable. Graves Disease The first-line treatment for Graves disease in children and adolescents is antithyroid drug therapy with methimazole (0.5 to 1 mg/kg/day or 15–20 mg/day).6 As with neonatal Graves disease, use of PTU (5 to 10

mg/kg/day) is now generally avoided due to the association with liver failure. These medications inhibit thyroid hormone formation but not its release, so it may take a number of weeks until circulating thyroid hormone levels begin to decrease. A beta-blocker such as propranolol (1–2 mg/kg/day) or atenolol (0.5–1.2 mg/kg/day) may be added to control tachycardia and ameliorate symptoms while the antithyroid medications take effect. Thyroid levels, including TSH, T4, and T3, should be checked 4 to 6 weeks after starting therapy, then every 2 to 3 months once on a stable dose.6 Severe side effects of methimazole include agranulocytosis, hepatitis, and Stevens–Johnson syndrome. Routine monitoring of complete blood cell counts and liver function tests are generally not indicated. Children with ophthalmyopathy should be referred to a pediatric ophthalmologist. Remission rates for Graves disease are lower in children (30%) than in adults (50%).6 Given the difficulty of maintaining compliance and the risk of side effects from antithyroid drug therapy, definitive therapy can be pursued if remission is not achieved within 12 to 24 months or sooner if methimazole cannot be tolerated. With the goal of inducing a hypothyroid state, definitive therapy consists of either radioiodine ablation or surgical removal of the thyroid gland. Radioiodine ablation is a safe and effective treatment in children, with long-term studies showing no evidence of decreased fertility or increase rates of malignancy. Thyroidectomy is generally recommended for younger children (< 10 years), those with large glands, or those with severe eye disease.6 Treatment of thyroid storm may include propranolol (2 to 3 mg/kg per day, divided every 6 hours) to control the tachycardia, dexamethasone (1 to 2 mg every 6 hours) to reduce conversion of T4 to T3, and intravenous sodium iodide (125 to 250 mg/day) or Lugol solution (concentrated iodide; 5 drops by mouth every 8 hours) to decrease the release of thyroid hormone from the thyroid gland. Methimazole (0.6 to 0.7 mg/kg per day) or PTU (6 to 10 mg/kg per day; maximum 200 to 300 mg/day) should be started, although the effect will not be seen for several days.

ADMISSION AND DISCHARGE CRITERIA ADMISSION CRITERIA

Neonatal thyrotoxicosis Thyroid storm Congenital hypothyroidism or severe hypothyroidism in an older child if there is any suspicion that the family is not administering the medication properly

DISCHARGE CRITERIA Resolution of acute symptoms of neonatal thyrotoxicosis or thyroid storm and improving thyroid function tests on medication. For any child with thyroid disease, the family must understand proper dosing and administration of medication, and thyroid function tests should be improving.

CONSULTATION Most often, thyroid disorders are diagnosed and managed in the outpatient setting. However, if thyroid function tests are obtained on a hospitalized patient, a pediatric endocrinologist should be consulted to interpret the results, because interpretation of such tests obtained during periods of illness can be challenging. A pediatric endocrinologist should always be consulted for patients with possible thyroid storm or infants with suspected neonatal thyrotoxicosis.

SPECIAL CONSIDERATIONS PREVENTION Congenital hypothyroidism is a preventable cause of intellectual disability, with earlier recognition and treatment initiation leading to better neurologic outcomes. Therefore it is essential that infants have timely follow-up of their newborn screens and rapid referral for evaluation if their screens are positive for thyroid dysfunction. KEY POINTS

Congenital hypothyroidism is a preventable cause of intellectual disability, and early initiation of treatment with levothyroxine improves neurodevelopmental outcomes. Autoimmune hypothyroidism is the most common cause of acquired hypothyroidism. Neonatal hyperthyroidism is a rare but potential fatal disorder which requires close monitoring and rapid initiation of treatment. Methimazole is the first-line agent for treating Graves disease. PTU is no longer recommended, given its association with severe liver failure. Illness may produce thyroid abnormalities, known as nonthyroidal illness; there is no evidence to support treating this condition in children.

REFERENCES 1. Fisher DA, Grueters A. Thyroid disorders in childhood and adolescence. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2008:227-253. 2. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010;5:1-22. 3. AAP. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006;117(6):2290-2303. 4. De Vries L, Bulvik S, Philip M. Chronic autoimmune thyroiditis in children and adolescents: at presentation and long-term follow-up. Arch Dis Child. 2009;94:33-37. 5. Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am. 1998;27(1):1998. 6. Bauer AJ. Approach to the pediatric patient with Graves disease: when is definitive therapy warranted? J Clin Endocrinol Metab. 2011;96(3):580-588. 7. Counts D, Varma SK. Hypothyroidism in children. Pediatr Rev. 2009;30(7):251-258.

8. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205:1-13. 9. Selva KA, Harper A, Downs A, et al. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr. 2005;147(6):775-780.

CHAPTER

70

Disorders of Pituitary Function Rachana Shah

BACKGROUND The pituitary gland is comprised of two parts with distinct origins. The anterior pituitary is derived embryonically from Rathke’s pouch of oral ectoderm, while the posterior pituitary is of neuroectoderm origin. The pituitary gland regulates endocrine target organs, such as the adrenal gland, ovary, testis, and thyroid gland. Disorders of the pituitary and hypothalamus may therefore result in disruption of any of these hypothalamic-pituitary– target organ axes. Abnormalities in end-organ hormone release caused by pituitary dysfunction are considered “secondary,” and those caused by a hypothalamic abnormality are considered “tertiary.” For example, abnormal thyroid function caused by a decrease in pituitary thyroid stimulated hormone is considered “secondary hypothyroidism” while hypothyroidism due to deficient thyrotropin-releasing factor from the hypothalamus is “tertiary hypothyroidism.” Failure of growth and failure of sexual maturation are two common presentations of hypothalamic-pituitary disease in the pediatric population. Pituitary disorders may be genetic or acquired. The hypothalamus secretes releasing factors that travel via the portal circulation to the anterior pituitary gland and include growth-hormone releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin releasing hormone (GnRH). These factors stimulate or inhibit release of the six peptide hormones produced by the five distinct cell types of the anterior pituitary gland: growth hormone (GH) from somatotropes, prolactin by lactotropes, thyroid-stimulating hormone (TSH) from the thyrotropes, adrenocorticotropic hormone (ACTH) via corticotropes, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH), secreted by gonadotropes.

The posterior pituitary gland releases arginine vasopressin, also known as antidiuretic hormone (ADH), and oxytocin. The neurons that produce vasopressin originate in the paraventricular and supraoptic nuclei of the hypothalamus. For this reason, diabetes insipidus (DI) can occur with hypothalamic disease, but may not always occur with pituitary disease, even if the stalk has been transected (depending on the level of transection).

CLINICAL PRESENTATION GENETIC CAUSES OF PITUITARY HORMONE DEFICIENCY Several genetic causes of multiple pituitary hormone deficiency have been described (see online eTable 70-1), including mutations in transcription factors integral to the embryonic development of the pituitary. However, known genetic defects still explain less than 20% of hypopituitarism in humans. Congenital malformations involving the midline of the central nervous system (CNS) are associated with pituitary deficiencies. Midline defects elsewhere may alert clinicians to screen for pituitary deficiency (i.e. single central incisor, cleft lip and palate, tracheo-esophageal fistula, omphalocele and gastroschisis, and extrophy of the bladder). In the newborn, pituitary deficiency may present as hypoglycemia (due to GH and/or ACTH deficiency), micropenis (combination of GH and gonadotropin deficiency), or hyperbilirubinemia. Septo-optic-dysplasia, with optic nerve hypoplasia, is often associated with pituitary deficiencies as is holoprosencephaly and absence of the septum pellucidum. Findings on magnetic resonance imaging may include a small or absent anterior pituitary gland, an absent or ectopic posterior pituitary “bright spot,” or a transected pituitary stalk.1

ACQUIRED CAUSES OF PITUITARY HORMONE DEFICIENCY Mass-occupying lesions in the hypothalamic area may result in disruption of pituitary function. Tumors such as craniopharyngioma and, less commonly, germinoma and astrocytoma may first present during childhood with growth failure, DI, or visual complaints (or any combination of these). Even in cases when the tumor does not cause loss of pituitary function, surgery may render

these children with panhypopituitarism. Hypothalamic hamartomas and pineal tumors are associated with precocious pubertal development during childhood. Pituitary adenomas are rare in childhood and may or may not actively produce peptide hormones. When active, they most often secrete prolactin (50%) or GH (20%).2 Langerhans cell histiocytosis is a rare disorder that most often presents with DI, but it may also affect the production of other pituitary hormones. Inflammatory, postinfectious, and traumatic lesions of the CNS may cause hypopituitarism as well. CNS irradiation predisposes to the loss of pituitary function, depending on the dose received. Higher doses may precipitate precocious pubertal development. Clinical signs directly related to pituitary deficiency in children include poor linear growth (GH deficiency), fatigue and malaise (TSH and ACTH deficiency), delayed pubertal development, amenorrhea, or sexual dysfunction (LH and FSH deficiency), hypotension or hypoglycemia (ACTH deficiency). Inability to regulate temperature, appetite, thirst, and vital signs may be seen in hypothalamic dysfunction. Indirect signs of central nervous system lesions, including headaches, vision changes, and other neurological disturbances, may be seen.

ANTERIOR PITUITARY HORMONE DEFICIENCY DIAGNOSTIC EVALUATION Diagnosis of anterior pituitary dysfunction typically requires a combination of random hormone measurements and stimulation tests with known secretagogues specific for the pituitary hormone in question. TSH deficiency can be diagnosed by observing low thyroid hormone (T4) with low or inappropriately normal TSH levels (distinguished from primary hypothyroidism in which TSH is elevated). Random GH measurements can be diagnostic in the newborn period prior to establishment of the diurnal and pulsatile secretion pattern at 2 to 4 weeks of life. Levels greater than 20 ng/mL are unequivocally sufficient. After this point, or when the diagnosis is not clear, stimulation tests must be performed. Commonly used secretagogues include arginine, clonidine, and glucagon;

insulin-induced hypoglycemia was considered a gold standard but is rarely used due to safety concerns. Stimulated growth hormone peaks >10 ng/mL are normal. Diagnosis of gonadotropin deficiency can be made in the first 6 months for males and before 2 to 3 years of life for females, when the gonadotropin axis is active by measuring random LH and FSH.3 Otherwise diagnosis is generally left until pubertal age. Secondary or tertiary adrenal insufficiency is diagnosed by observing ACTH and cortisol rise after administration of CRH (1 ug/kg intravenously). Samples for ACTH and cortisol are drawn at baseline and 30, 45, 60, and 120 min after CRH. Normal: Basal ACTH increases 2- to 4-fold after CRH; peak cortisol >19 μg/dL Secondary adrenal insufficiency: Basal ACTH 300 mOsm/kg H2O and/or the serum sodium is >145 mmol/L. With DI, urine osmolality will not rise above 600 mOsm/kg despite high serum osmolality or hypernatremia. Plasma ADH level should be sent at the end of the test to help distinguish central DI (low/absent ADH) from nephrogenic DI (normal levels). Once ADH level is sent, administer desmopressin (1 mg) subcutaneously and continue following urine osmolality and volume for an additional 2 hours. After 2 hours of administering DDAVP, a rise in urine osmolality over (often 50% above baseline) confers a diagnosis of central diabetes insipidus, whereas a rise of less than 10% above baseline confers a diagnosis of nephrogenic diabetes insipidus.6 Once the diagnosis of diabetes insipidus is established, two methods can be used as guides for fluid management:

Method 1: Give maintenance intravenous fluids as normal saline (NS) or ½NS. Replace urine output in excess of 4 mL/kg/hr with D5W or D5/ ¼NS, depending on the serum sodium level. Method 2: Give intravenous fluids for insensible loss of 400 to 600 mL/m2/day as NS or ½NS. Replace all urine output with D5W or D5/ ¼NS, depending on the serum sodium level. The second method ensures that the fluids will be adjusted for urine output and protects against overhydration if a change in the patient’s status is anticipated. Serum glucose needs to be monitored closely with both methods because patients may become hyperglycemic, which can worsen the polyuria. For glucose levels higher than 250 mg/dL, an insulin drip may be required (starting dose, 0.03 U/kg/hr).

TREATMENT Treatment with ADH can be initiated if serum sodium is greater than 145 mEq/L and serum osmolality is greater than 195 mOsm. The dose should be titrated according to the patient’s response to the initial dose. The most flexible regimen is an aqueous pitressin drip. Its extremely short half-life enables rapid changes in dose. Aqueous pitressin as an intravenous drip: Aqueous pitressin is manufactured as 20 U = 1 mL. Add 0.1 mL to 20 mL NS, and then add 5 mL of that solution to 500 mL NS so that 1 mL = 1 mU aqueous pitressin. The usual starting dose is 0.10 mU/kg/hr. The dose can be adjusted every 30 minutes until the desired trend in serum sodium is noted. Doses higher than 0.8 mU/kg/hr are not likely to increase the antidiuretic effect. Subcutaneous aqueous pitressin (20 U/mL) can also be used. It has a half-life of 3 to 6 hours. The suggested starting dose is 0.05 to 0.1 U/kg per dose subcutaneously (SC) Examples: 1 U SC every 4 to 6 hours for infants

2.5 U SC every 4 to 6 hours for toddlers 5 U SC every 4 to 6 hours for children Maximum of 10 U SC every 4 to 6 hours for adults. Parenteral desmopressin acetate (DDAVP) (0.1 mL = 0.4 μg) has a half-life of 6 to 12 hours (or longer). The suggested starting dose is 0.01 to 0.03 μg/kg per dose intravenously (IV) or SC daily or twice daily Examples: 0.05 mL SC or IV every 12 hours for infants 0.1 mL SC or IV every 12 hours for toddlers 0.15 mL SC or IV every 12 hours for children Up to 0.5 mL SC or IV every 12 hours for adults Nasal DDAVP (0.1 mL = 10 μg) has a half-life of 6 to 24 hours. Nasal dose of 5 to 20 μg/day (0.05 to 0.2 mL) divided twice daily or daily as needed 1 spray = 10 μg or 0.1 mL = 10 μg The nasal dose is 10 times the parenteral dose in micrograms Oral DDAVP (0.1- and 0.2-mg tablets) Dose of 0.025 to 0.4 mg orally every 8 to 24 hours

IMPORTANT CONSIDERATIONS DI may be transient. Posttraumatic or postoperative DI may be followed by the syndrome of inappropriate ADH secretion (SIADH), which may be followed by recurrence of DI (triphasic pattern of DI/SIADH/DI). Avoid hyponatremia, which can exacerbate posttraumatic cerebral edema. In general, always start with the lowest recommended dose of DDAVP or aqueous pitressin and adjust the dosage as necessary based on ongoing laboratory evaluations.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an uncommon cause of hyponatremia in the inpatient setting. Hyponatremia (Na 150 beats/min) Decreased urine output (parental report) * Subset of items included in a 4-point scoring system.

ANCILLARY STUDIES The majority of children with uncomplicated dehydration do not require laboratory testing. A decreased serum bicarbonate concentration is often associated with dehydration; however, this usually reflects the ketoacidosis that accompanies fasting. The measurement of serum bicarbonate may be a useful adjunct if the diagnosis is unclear, but by itself, it does not determine the need for hospitalization.2 Measurement of serum electrolytes is indicated for children with severe dehydration or those with risk factors for hypo- or hypernatremia (see Chapter 74). Blood glucose should be measured when intravenous therapy is chosen over oral treatment, because glucosecontaining fluids are not routinely used in initial parenteral therapy unless there is documented hypoglycemia.

TREATMENT ORAL REHYDRATION THERAPY Oral rehydration therapy (ORT) is recommended by the American Academy of Pediatrics and the World Health Organization (WHO) as the treatment of choice for mildly and moderately dehydrated patients.3,4 Contraindications to ORT include shock or suspected acute abdomen. Vomiting itself is not a contraindication to a trial of ORT. Because ORT can be instituted rapidly and treatment failure is typically apparent early on, it is reasonable to start with ORT and if it is unsuccessful, progress to intravenous fluids (Figure 73-1). However, if ORT has already been attempted without success, initial parenteral therapy may be appropriate.

FIGURE 73-1. Algorithm for the treatment of dehydration. GI, gastrointestinal; IV, intravenous line; ORT, oral rehydration therapy. ORT uses the sodium-glucose cotransport mechanism to passively absorb water across the intestinal mucosa. Hence, the oral rehydration solution (ORS) should have the correct sodium-to-glucose ratio,5 which is optimally 1:1. Rehydralyte and the WHO ORS packets are examples of appropriate solutions for the rehydration phase of treatment. The WHO ORS has a 1:1 ratio, whereas Rehydralyte has a 1:2 ratio. Maintenance solutions, such as Pedialyte, are acceptable alternatives for mildly and moderately dehydrated patients. The ratio of sodium to glucose in Pedialyte is 1:3. The proper procedure for administering ORT is shown in Figure 73-1. The aim is to replace fluid losses over 4 to 6 hours. When vomiting is a prominent part of the clinical picture, administration of small, frequent aliquots is necessary. Ongoing assessment, including serial weight measurement, is necessary to

evaluate the progress of treatment. ORT failure is defined as progression of signs of dehydration, failure to replace the deficit over 8 hours, or the presence of intractable vomiting. Once patients are better able to tolerate oral intake, the normal diet can be reintroduced. If the gastroenteritis is severe, the brush border of the small bowel may be injured, causing a temporary secondary lactase deficiency. Lactose-free milk may be recommended for 48 hours to 1 week, depending on the severity of diarrhea, but lactose restriction is not a routine recommendation in most children. Despite the recommendations and evidence that ORT is as effective as intravenous fluids for mild and moderate dehydration, in North America, especially the United States, ORT is underused in cases for which it is indicated.6 Fluids may also be administered in children via the nasogastric tube. This is especially helpful in infants and younger children who may voluntarily withhold from drinking in the setting of illness. In children with mild-tomoderate dehydration, oral rehydration solution may be administered as a continuous bolus of 50 to 100 mL/kg over a 4-hour period. Maintenance fluids may also be provided in this manner at similar rates to expected IV fluid administration. Co-administration of ondansetron may be indicated in infants with emesis. Rapid nasogastric hydration has been found to be equally effective and to have fewer complications than rapid intravenous hydration in children with mild-to-moderate dehydration.7,8

INTRAVENOUS FLUID THERAPY Intravenous fluid therapy is needed when ORT fails or is contraindicated. The usual approach is to administer 20 mL/kg aliquots of isotonic fluid (e.g. normal saline) over 20 to 60 minutes, with frequent reexamination to determine the need for additional bolus administration. After bolus therapy has been administered, intravenous fluids can be administered at a rate calculated to replace the entire deficit over a 24- to 48-hour period (see Chapter 74). Alternatively, for children with isonatremic dehydration, it is reasonable to provide this additional fluid in the form of 5% dextrose with ¼ to ½ normal saline at a rate of 1.5 to 2 times maintenance to account for ongoing losses until intravenous therapy is no longer needed. Intravenous

fluids may be discontinued when clinical signs are improving and the patient is able to take sufficient oral fluids to meet maintenance needs and ongoing losses.

SUBCUTANEOUS REHYDRATION THERAPY A renewed interest in subcutaneous rehydration has recently come about due to the advent of a recombinant human hyaluronidase enzyme. The hyaluronidase enzyme is administered under the skin and allows fluids to be administered and rapidly absorbed into the vascular system through the capillary beds. Although this method is not common practice now, there are years of experience with the use of subcutaneous hydration in children in the era prior to intravenous rehydration therapy. There are a few recent industrysponsored clinical trials that show ease of use and safety of the subcutaneous method with recombinant hyaluronidase.9,10 Subcutaneous therapy may be an option for mildly and moderately dehydrated children who fail ORT and need short-term isotonic fluids. It has also been found clinically to be useful as a bridge for providing fluids to a patient who will ultimately need an intravenous line but has poor access due to the dehydration.

ANTIEMETICS Traditionally, the routine use of antiemetics was discouraged in pediatric patients owing to the side effects of the commonly used drugs (i.e. promethazine, prochlorperazine, etc.). However, ondansetron, which selectively blocks serotonin 5-HT3 receptors, has an acceptable side effect profile. Approximately 80% of these receptors are located in the emetic center in the brain. Ondansetron can be administered either orally or intravenously, but it should be instituted early in the rehydration phase in patients with persistent vomiting. Several studies have shown that ondansetron reduces emesis in patients with viral gastroenteritis.11,12 Although a majority of patients stop vomiting with routine rehydration measures alone, these studies found that 20% more patients stop vomiting after ondansetron administration. Patients who are more ill may derive an additional benefit. The orally disintegrating tablet is easy to use and has been used extensively in children.

ADMISSION CRITERIA Inability to tolerate ORT due to persistent vomiting, high stool output, or inability to cooperate, requiring ongoing intravenous fluid therapy. Signs or symptoms of severe dehydration (>10% loss of body weight). Significant electrolyte abnormalities (see Chapter 74).

DISCHARGE CRITERIA Ability to maintain hydration status orally. Correction of abnormal electrolyte status. KEY POINTS Dehydration is one of the most common reasons for hospitalization in children. ORT is the treatment of choice for mildly and moderately dehydrated patients. Intravenous fluid therapy is needed when ORT fails or is contraindicated. Ondansetron appears to reduce emesis in patients with viral gastroenteritis.

SUGGESTED READINGS Centers for Disease Control and Prevention. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR. 2003;52:1-16. Gorelick MH, Shaw KN, Murphy KO. Validity and reliability of clinical signs in the diagnosis of dehydration in children. Pediatrics. 1997;99:e6. Spandorfer PR, Alessandrini EA, Joffe M, et al. Oral vs intravenous rehydration of moderately dehydrated children: A randomized controlled trial. Pediatrics. 2005;115:295-301. Spandorfer, PR, Mace, SE, Okada, PJ, et al. A randomized clinical trial of recombinant human hyaluronidase facilitated subcutaneous versus

intravenous rehydration in mild to moderately dehydrated children in the emergency department. Clin Therap. 2012;34(11):2232-2245. Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA. 2004;291:2746-2754. The Treatment of Diarrhoea: A Manual for Physicians and Other Senior Health Workers. 3rd ed. WHO/CDD/SER/80.2. Geneva: World Health Organization, Division of Diarrhoeal and Acute Respiratory Disease Control.

REFERENCES 1. Gorelick MH, Shaw KN, Murphy KO. Validity and reliability of clinical signs in the diagnosis of dehydration in children. Pediatrics. 1997;99:e6. 2. Wathen JE, MacKenzie T, Bothner JP. Usefulness of the serum electrolyte panel in the management of pediatric dehydration treated with intravenously administered fluids. Pediatrics 2004;114:1227-1234. 3. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Practice parameter: the management of acute gastroenteritis in young children. Pediatrics. 1996;97:424. 4. The Treatment of Diarrhoea: A Manual for Physicians and Other Senior Health Workers. 3rd ed. WHO/CDD/SER/80.2. Geneva: World Health Organization, Division of Diarrhoeal and Acute Respiratory Disease Control. 5. Centers for Disease Control and Prevention. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR. 2003;52:1-16. 6. Freedman SB, Sivabalasundaram V, Bohn V, Powell EC, Johnson DW, Boutis K. The treatment of pediatric gastroenteritis: a comparative analysis of pediatric emergency physicians’ practice patterns. Acad Emerg Med 2011;18(1):38-45. 7. Nager AL, Wang VJ. Comparison of nasogastric and intravenous methods of rehydration in pediatric patients with acute dehydration. Pediatrics. 2002;109(4):566-572

8. Fonseca BK, Holdgate A, Craig JC. Enteral vs intravenous rehydration therapy for children with gastroenteritis, a meta-analysis of randomized controlled trials. Arch Pediatr Adolesc Med. 2004;158:483-490. 9. Spandorfer, PR. Subcutaneous hydration: updating a traditional technique. Pediatr Emerg Care. 2011;27(3):230-236. 10. Allen CH, Etzwiler LS, Miller MK, et al. Recombinant human hyaluronidase-enabled subcutaneous pediatric rehydration. Pediatrics. 2009;124(5):e858-e867. 11. Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron for gastroenteritis in a pediatric emergency department. N Engl J Med. 2006;354:1698-1705. 12. Reeves JJ, Shannon MW, Fleisher GR. Ondansetron decreases vomiting associated with acute gastroenteritis: a randomized, controlled trial. Pediatrics. 2002;109:e62.

CHAPTER

74

Fluid and Electrolyte Therapy Daniel T. Coghlin

PHYSIOLOGY OF WATER AND ELECTROLYTE REGULATION DISTRIBUTION OF WATER, CATIONS, AND ANIONS Total body water is distributed as follows: two-thirds in the intracellular space and one-third in the extracellular space. Seventy-five percent of the water in the extracellular space is located interstitially, while the remaining 25% is located intravascularly. For the extracellular fluid (ECF) space, sodium is the primary cation, while chloride and bicarbonate are the primary anions. For the intracellular fluid (ICF), potassium is the primary cation, while phosphate is the primary anion.

TONICITY, OSMOLALITY, AND SODIUM CONCENTRATION The tonicity (the measurement of osmotic pressure) of body fluids is tightly regulated within a physiologic range (osmolality of 275–290 mOsm/kg). While the body actually regulates tonicity, labwork measures osmolality (the concentration of solution, in terms of number of solute particles per kilogram). High osmolality (what is measured in a lab) does not always mean high tonicity. For example, urea, ethanol, methanol, and ethylene glycol freely cross cell membranes, so there is no water shift and no change in cell volume. In this case, tonicity is not affected, but osmolality is. Tonicity and osmolality align so closely in most situations, however, that these terms are used interchangeably in this chapter. Sodium concentration is the dominant factor in serum osmolality, as shown by the following estimation:

Osmolality = 2 [Na+] +BUN (mg/dL)/2.8 + glucose (mg/dL)/18 The two principal regulatory factors that maintain osmolality (and indirectly, the sodium concentration) in the normal range are antidiuretic hormone (ADH) and thirst.

REGULATORY MECHANISMS Antidiuretic Hormone ADH is the main determinant of free water excretion. It is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. Hypertonicity triggers its release, causing resorption of water by the kidney’s collecting tubules. ADH release is also triggered by hypovolemia (via volume receptors in the carotid sinuses), but not as powerfully. Other stimuli for ADH release include CNS disorders, meningitis, postoperative state, malignancies, pneumonia, pain, and stress (resulting in the syndrome of inappropriate antidiuretic hormone [SIADH]). When ADH is present, urine osmolality ranges from 300 to 1200 mOsm/kg, and urine specific gravity is >1.010. When ADH is absent, urine osmolality ranges from 50 to 80 mOsm/kg, and urine specific gravity is 10 but 20 kg

1500 mL + 20 mL/kg†

60 mL + 1 mL/kg

*This additional amount for the weight >10 kg only. †

This additional amount for the weight >20 kg only.

MAINTENANCE SODIUM AND POTASSIUM REQUIREMENTS The Holliday-Segar method refers only to water requirements and does not take into consideration electrolyte losses and needs. In healthy children, most electrolyte loss is through urine. An average of 3 mEq of Na+ and 2 mEq of K+ is lost for every 100 kcal of energy expended or 100 mL of maintenance fluid required per 24 hours. Estimations of 3 mEq/kg/day of Na+ per day and 2 mEq/kg/day of K+ are not as accurate. Alternatively, one can estimate electrolyte requirements by body surface area (BSA): BSA (m2) = Height (cm) × Weight (kg)/3600 Using the BSA method, the electrolyte requirements are as follows: Na+ = 30 to 50 mEq/m2/day K+ = 30 to 40 mEq/m2/day Cl− = 30 mEq/m2/day

FLUID DEFICITS The fluid deficit is the volume of fluids needed for a hypovolemic patient to become euvolemic. The fluid deficit calculation is as follows: Well weight − ill weight = kg of fluid lost (remember that 1kg = 1L of fluid

lost). If you don’t have a well weight, use Table 74-2 to estimate the patient’s degree of dehydration, as discussed in Chapter 73. TABLE 74-2

Example: Isonatremic Dehydration

A 7-year-old boy is admitted with a 2-day history of vomiting and diarrhea. He is estimated to be 7% dehydrated and vomited all attempts at oral rehydration in the emergency department. He was given a 20-mL/kg bolus of IV normal saline prior to transfer to the inpatient unit. His weight is 23 kg and his serum sodium level is 139 mEq/L.

Water

Sodium

Calculation Result Calculation Result Maintenance 1st 10 kg = 100 mL/kg

10 kg × 100 mL/kg = 1000 mL

2nd 10 kg = 50 mL/kg

10 kg × 50 mL/kg = 500 mL

>20 kg = 20 mL/kg

3 kg × 20 mL/kg = 30 mL

Total Fluid Deficit = weight × % dehydration × 1000 mL/kg or

23 kg × 0.07 × 1000 mL/kg

1560 mL

1560 mL × 3 mEq/100 mL

47 mEq

1610 mL

—

—

= (normal wt − dehydrated wt) × 1000 mL/kg ECF Na+ Deficit = 0.6 × total fluid deficit × 140 mEq/L

—

—

1.61 L × 0.6 × 135 140 mEq/L mEq

No sodium derangement

—

—

—

—

Total Requirements

—

3170 mL

—

182 mEq

Previous Replacement

23 kg × 20 mL/kg

–460 mL

0.46 L × 154 mEq/L

–71 mEq

Balance of Requirements

3170 mL − 460 mL

2710 mL

182 mEq − 71 mEq

111 mEq

Concentration of Saline Solution

111 mEq ÷ 2.71 L

41 mEq/L

Correction for Sodium Derangement

Note: numbers that are in bold are specific for the patient data provided in the example. Maintenance: This boy’s maintenance water needs for the first 24 hours are 100 mL/kg for his first 10 kg of body weight (1000 mL) plus 50 mL/kg for the second 10 kg of body weight (500 mL) plus 20 mL/kg for the last 3 kg of body weight, which yields a total of 1560 mL. Only a current weight is available for this child but provides a sufficiently close approximation of his normal body weight to be used in these calculations. His daily maintenance sodium needs are 3 mEq for each 100 mL of water, or 47 mEq. Total Fluid Deficit: This child’s weight loss is used to approximate his total fluid loss. Since he is estimated to be 7% dehydrated, the weight loss can be calculated by multiplying his body weight by the estimated percent of dehydration (23 kg × 0.07). Since each kilogram of weight loss is equivalent to 1000 mL, the total fluid loss would be 1610 mL.

ECF Sodium Deficit: The sodium content of this total fluid deficit is based on the proportion of the fluid that is made up by the extracellular fluid (ECF), which is 60% of the total. The sodium concentration is normally 140 mEq/L; therefore the sodium content in the total fluid deficit is found by multiplying this concentration by the volume of ECF deficit (1.61 L × 0.6), which yields 135 mEq. Correction for Sodium Derangement: Since this child is isonatremic, no additional water or sodium deficits beyond that already approximated above are expected. Total Requirements: The total water requirements are equal to the sum of the maintenance (1560 mL) and volume of the total fluid deficit (1610 mL), which is 3170 mL. The total sodium requirements are the maintenance sodium needs (47 mEq) plus the amount of sodium in the ECF deficit volume (135 mEq), which is 182 mEq. Previous Replacement/Balance of Requirements: This boy received a bolus of 20 mL/kg of normal saline, which provided some portion of his total water and sodium needs. The total volume of water in this saline bolus is equal to the total volume (23 kg × 20 mL/kg = 460 mL = 0.46 L). Since the concentration of normal saline solution is 154 mEq/L, the amount of sodium in that volume is 71 mEq (= 0.46 L × 154 mEq/L). These amounts of water and sodium are subtracted from the total requirements, which leaves the balances of 2710 mL of water and 111 mEq of sodium. Concentration of Saline Solution: An appropriate concentration of intravenous saline would be 111 mEq of sodium in 2710 mL (2.71 L) of water, or 41 mEq/L. Since normal saline is 154 mEq/L, this would be proportional to approximately ¼ normal saline solution (41 mEq/L ÷ 154 mEq/L = 0.27 ≈ ¼.) Concentration of Potassium Solution: The potassium needs are estimated by multiplying the daily maintenance potassium needs (2 mEq/100 mL) by the maintenance daily fluid requirements (1560 mL), which would be 31 mEq. This amount should be added to the balance of fluids that he will receive in the first day (2710 mL, or 2.71 L), which is equivalent to 11 mEq/L (31 mEq ÷ 2.71 L). A standard or “stock” solution that contains 10 or 20 mEq/L KCI can be used. Potassium should not be added routinely to an intravenous solution if renal failure is suspected. Calculate the Hourly Rate and Add Glucose: The hourly rate at which the fluids should be delivered is calculated by dividing the balance of the fluids needed in the first day (2710 mL) by 24 hours, or 113 mL/hour for the first 24 hours. To provide some caloric support and to deliver a more isotonic fluid through the vein, the saline is provided in a 5% dextrose solution. Answer: D5/¼ NS + 20 mEq/L KCI at 113 mL/hour (or D5/¼ NS + 10 mEq/L KCI at 113 mL/hour).

ELECTROLYTE DEFICITS Sodium deficit calculation: [Liters of fluid lost] × [Percent from extracellular fluid*] × [measured Na+] = Sodium deficit *In cases of acute dehydration, use 0.8. In cases of chronic dehydration,

use 0.6. In acute dehydration (3 days or less), most of the fluid loss is from the extracellular space (80% extracellular, 20% intracellular). In chronic dehydration (longer than a 3-day period), there is greater intracellular fluid loss (60% extracellular, 40% intracellular). Intracellular fluid will move into the extracellular space, particularly the interstitial space, to make up for the loss of fluid in that space. Osmotic shifts will start to occur, making rapid fluid replacement more dangerous. In this case, fluid replacement should be slower and more controlled.

SUMMARY OF THE PHYSIOLOGIC APPROACH Combine the fluid deficit and electrolyte deficits to the maintenance requirements to determine the total amount of fluid and electrolytes that need to be replaced in 24 hours. Using that total volume and the total amounts of sodium and potassium needed, calculate the concentration of sodium and potassium for the patient’s intravenous fluids. Then, calclulate the hourly rate to administer that total volume over 24 hours. See Table 74-3 for an example that uses this approach to calculate a patient’s fluid needs. In addition, replace ongoing fluid losses 1:1 with the appropriate solution (Table 74-4). TABLE 74-3

Electrolyte Content of Various Fluids

Site

Na+ (mEq/L)

K+ (mEq/L)

Cl− (mEq/L)

HCO3− (mEq/L)

Gastric

20–80

5–30

100–140

0

Small intestine

100–140

5–25

90–135

0

Ileostomy

45–135

3–15

20–115

110

Diarrhea

50–100

5–80

10–110

15–50

TABLE 74-4

Example: Hypovolemic Hyponatremia

Note: numbers that are in bold are specific for the patient data provided in the example. Maintenance: This child’s maintenance water needs for the first 24 hours are 100 mL/kg for each of her 9 kg of body weight, or 900 mL. Her maintenance sodium needs for this time period are 3 mEq for each 100 mL of water, or 27 mEq. Total Fluid Deficit: Her total fluid deficit is calculated by the difference between her preillness weight (9 kg) and her weight at the time she presented with dehydration (8 kg), which is 1 kg. This indicates that she is 11% dehydrated, i.e. 1 kg is 11% of her pre-illness weight (9 kg). If a pre-illness weight were not available, estimates of degree of dehydration would be made based on physical findings (see Chapter 57). Since each 1000 mL weighs 1 kg, her total fluid deficit is 1000 mL. ECF Sodium Deficit: The sodium content of this total fluid deficit is based on the proportion made up by her extracellular fluid (ECF) compartment, which is 60% of the total fluid deficit. The sodium concentration in the ECF is normally 140 mEq/L; therefore this little girl’s estimated sodium deficit is the product of her ECF deficit (expressed in liters) and the normal sodium concentration, or 84 mEq. Correction for Sodium Derangement: However, this child is hyponatremic; therefore she has an additional sodium deficit, beyond that already approximated above. The additional sodium deficit is estimated by the difference between her current serum sodium level and her desired serum sodium level for her whole body ECF compartment. The whole body ECF volume is 60% of the total body weight. Rather than target a complete correction of her serum sodium level, a desired sodium level 12 mEq/L higher than her current level, or 134 mEq/L, is used. Therefore, the sodium deficit is calculated by multiplying her ECF volume (body weight × 0.6) by the difference between her desired and current serum sodium level. For this example the sodium deficit would be 65 mEq. Total Requirements: The maintenance water (900 mL) and total fluid deficit (1000 mL) are added to determine the total water requirements for the first 24 hours (1900 mL). The total sodium requirements are the sum of the maintenance sodium needs (27 mEq), the amount of sodium in the ECF deficit (84 mEq), and the additional sodium deficit due to her hyponatremia (65 mEq), which is 176 mEq. Previous Replacement/Balance of Requirements: However, her initial resuscitation included 20 mL/kg of normal saline. This provided her with 180 mL of water and 28 mEq of

sodium, which are subtracted from the total needs. This leaves the balances of water and sodium needed in the first 24 hours of 1720 mL and 148 mEq, respectively. Concentration of Saline Solution: If a saline solution containing the proportions of salt and water from the balance of requirements were prepared, it would yield a saline concentration of 79 mEq/L. Since normal saline is 154 mEq/L, this would be approximately equivalent to a ½ normal saline solution. Concentration of Potassium Solution: The potassium needs are approximated by multiplying the daily maintenance potassium needs (2 mEq/100 mL each day) by the maintenance fluid requirements (900 mL), which yields 18 mEq/day. This amount should be added to the balance of fluids that she will receive in the first 24 hours (1720 mL, or 1.72 L), which is equivalent to 10 mEq/L (18 mEq ÷ 1.72 L = 10 mEq/L). Potassium should not be added routinely to intravenous solutions if renal failure is suspected. Calculate the Hourly Rate and Add Glucose: To provide some caloric support and to deliver a more isotonic fluid through the vein, the saline is provided in a 5% dextrose solution. The total volume should be delivered over 24 hours, so one would divide 1720 mL by 24 hours to provide a rate of 72 mL/hour. Answer: D5/½ NS + 10 mEq/L KCI to run at 72 mL/hour. For patients with hyponatremia secondary to excessive renal sodium loss, the underlying disorder should be corrected if possible. Mineralocorticoid supplementation should be given for deficient states such as congenital adrenal hyperplasia. Long-term oral sodium supplementation is often needed if the underlying defects cannot be completely corrected.

EMPIRIC APPROACH TO FLUID DECISIONS ENTERAL FLUID THERAPY Oral rehydration is the best first therapy in uncomplicated mild and moderate dehydration (see Chapter 73). Compared with IV therapy, there is increased risk of paralytic ileus and more treatment failures, but no difference in weight gain, duration of diarrhea, or total fluid intake at 6 hours, and a shorter length of stay.8 Parents generally prefer IV therapy over nasogastric hydration, however.9,10

RATE OF RESUSCITATION OF ACUTE HYPOVOLEMIA Traditional recommendations regarding the time frame to fully correct moderate to severe hypovolemic dehydration from gastroenteritis have ranged from 24 to 48 hours.11,12 However, evidence from studies of oral or nasogastric rehydration therapy13 and from the emergency department setting14,15 demonstrates that a more rapid initial correction of hypovolemia

using at least 20 mL/kg of isotonic crystalloid is safe and beneficial. Generally, this initial rapid correction involves boluses given over 5 to 10 minutes in urgent/emergent situations, and up to 20 to 30 minutes if less urgent. Controversy remains over rapid intravenous fluid resuscitation beyond 20 to 40 mL/kg.11,14,15 Holliday argues for more aggressive initial fluid resuscitation of the extracellular space, akin to volume repletion with severe burns (which calls for 4 mL/kg per percent of that is burned, the first half which administered over the first 8 hours). However, care must be taken to avoid dangerous complications from rapid fluids shifts in certain clinical conditions (such as hypernatremia, hyponatremia, diabetic ketoacidosis, severe illness with severe anemia, and cardiac or renal failure).16 Development of crackles or hepatomegaly may indicate that the patient’s cardiorespiratory status is not tolerating rapid fluid therapy.

HYPOTONIC VERSUS ISOTONIC INTRAVENOUS FLUIDS Use of the traditional Holliday-Segar method typically results in choosing hypotonic fluids (0.2 normal saline [NS] or 0.5 NS). Over the past 10 years, however, there has been considerable focus in the medical literature about an alternative approach to IV fluid selection, shifting away from physiologic calculations and toward outcomes. In particular, this newer approach eschews hypotonic IV fluids in order to minimize the chance of cerebral edema and brain herniation, rare but devastating iatrogenic complications of unrecognized severe hyponatremia.17 There is now solid evidence that the use of hypotonic fluids for maintenance in the pediatric settings causes sodium concentration to drop significantly lower than isotonic fluid use does.18-24 The evidence is particularly strong in the postsurgical and intensive care population, who carry higher risk for SIADH. Some authors have cautioned against use of isotonic fluids as a strategy to mitigate harm from SIADH, considering that the treatment for SIADH is fluid restriction, not changing the sodium concentration of the fluids.25,26 Studies examining routine reduction of maintenance rates have failed to document reduced rates of hyponatremia, however.20,21 Critics of routine isotonic saline at maintenance rates also raise concern that this approach provides excessive sodium chloride, setting up

edema and potentially exacerbating acidosis by causing hyperchloremic acidosis.27 To date, the most important potential benefit of isotonic saline at maintenance rates—reduced rates of cerebral edema and herniation—has not been demonstrated. Given the rarity of this outcome, however, only extremely large, likely retrospective database studies would have the power to answer this question.

VALUE OF INITIAL CHEMISTRY PANEL WHEN TREATING DEHYDRATION WITH INTRAVENOUS FLUIDS One investigation of the utility of obtaining a chemistry panel found that 10% of these results altered clinical management in the emergency department setting (due to hypoglycemia, hypokalemia, hypernatremia, or severe acidosis).28 This investigation also found the treating physicians did not reliably predict which children would have clinically significant electrolyte abnormalities (58% sensitivity).

BOTTOM LINE SUMMARY Two schools of thought remain. Empiricists’ take Do not use hypotonic saline (especially not 0.2 NS) at maintenance rates. Live with the edema and perhaps a prolongation of acidosis from chloride overload. The benefit of lower rates of hyponatremia (and by extension less risk of iatrogenic cerebral edema and herniation) are worth this tradeoff. If there is a clinical condition that alters or might alter fluid balance, then monitor clinical status carefully, including serum sodium. Convert to oral fluid hydration as soon as clinically allowable. Purists’ take Fluid selection requires careful thought, not an algorithm. Using established physiologic methods, calculate maintenance rates and electrolyte needs. If clinical risk for SIADH or other clinical condition that requires adjustment of the Holliday-Segar method, then monitor clinical condition carefully, including serum sodium. Mitigate elevated ADH levels by rapid correction of extracellular fluid hypovolemia with isotonic fluids. If there is a clinical condition that alters or might alter fluid balance, then

monitor clinical status carefully, including serum sodium. Convert to oral fluid hydration as soon as clinically allowable.

ELECTROLYTE DISORDERS HYPONATREMIA (TOO MUCH WATER, COMPARED WITH SODIUM) Background Hyponatremia is defined as serum sodium less than 135 mEq/L. Hyponatremia is usually caused by sodium loss in excess of free water loss. It is important to note that the serum sodium concentration does not accurately reflect total body sodium; rather, hyponatremia reflects a relative excess of free water. To determine the cause and treatment of hyponatremia, three factors are most important: the patient’s volume status, urine sodium, and urine osmolality. Before beginning therapy it is important to determine whether true (hypotonic) hyponatremia is present. Pseudohyponatremia exists when serum is either isotonic (as in severe hyperlipidemia or hyperproteinemia) or hypertonic (as in hyperglycemia). In isotonic pseudohyponatremia caused by hyperlipidemia or hyperproteinemia, the volume of lipid or protein displaces plasma water so that a smaller volume of sodium-containing plasma is measured. In hypertonic or “dilutional” hyponatremia, hyperglycemia causes intracellular fluid to shift into the vascular space such that a decrease in serum Na+ of 1.6 mEq/L occurs for every 100-mg/dL elevation in serum glucose (e.g. a serum glucose concentration of 800 results in a sodium concentration of 124: 800 − 100 = 700, 1.6 × 7 = 11, 135 − 11 = 124).29 True hyponatremia (Na+ 0.5 to 1 mEq/L/h) may lead to osmotic demyelination syndrome (formerly called central pontine myelinolysis), characterized by a persistent “locked in” neurologic state.30 Diagnostic Evaluation Volume status is diagnosed from either known weight change or clinical criteria, as discussed above. In determining the cause of hyponatremia, supportive lab data include the urine osmolarity and urine sodium concentration. Hyponatremia with hypovolemia is characterized by urine osmolality greater than 100 mOsm/kg (not maximally dilute). If urine Na+ is less than 20 mEq/L, hyponatremia is due to extrarenal losses such as vomiting and diarrhea. If urine Na+ is greater than 20 mEq/L, renal losses are occurring as a result of diuretics, mineralocorticoid deficiency, saltlosing nephropathy, bicarbonaturia, ketonuria, or osmotic diuresis. In euvolemic hyponatremia due to SIADH, urine osmolality is greater than 100 mOsm/kg and urine Na+ is greater than 20 mEq/L. Euvolemic hyponatremia with urine osmolality less than 100 mOsm/kg is due to water intoxication. When there is hyponatermia with edema, urine osmolality is greater than 100 mOsm/kg. In renal failure, urinary sodium is >20 mEq/L. In cases of decreased cardiac output (congestive heart failure) or decreased oncotic pressure (cirrhosis or nephrotic syndrome), the urinary sodium is 40 mEq/L. Hypokalemia

Management • Hyperkalemia If there is hyperkalemia ≥6.5, a significant arrhythmia, or widened QRS, the patient should be placed on a cardiorespiratory monitor and transferred to an ICU setting. Immediately discontinue any potassium intake and start the following treatments, listed in order of priority: 1. Cardiac membrane excitability can be decreased by infusing 10% calcium gluconate, 0.5 to 1 mL/kg intravenously (60–100 mg/kg per dose, maximum of 3000 mg)38 peripherally; or calcium chloride, 20 mg/kg (20 mg/kg per dose, maximum 2000 mg)37 through a central venous line, not to exceed 100 mg/min. 2. Potassium can be shifted from the extracellular to the intracellular space by: a. Infusing 0.1 U/kg of insulin with dextrose 0.5 to 1 g/kg (e.g. 2–4 mL/kg of 25% dextrose). b. Infusing NaHCO3, 1 to 2 mEq/kg per dose intravenously. This works

best in the presence of metabolic acidosis. 3. Potassium can be removed from the body by: a. Sodium polystyrene sulfonate (Kayexalate) with sorbitol (1 g/kg per dose) orally or per rectum.37 b. Diuresis if the patient has normal renal function by a combination of an NS bolus, 10 to 20 mL/kg per dose, and furosemide, 0.5 to 1 mg/kg per dose intravenously. c. Hemodialysis or peritoneal dialysis can also be used in patients with renal failure or severe poisoning.39 One center has described success with a standardized combination of calcium gluconate, insulin, glucose, and sodium acetate via central access in treating hyperkalemia.40 Treatment of hypokalemia is potassium repletion. For symptomatic, severe hypokalemia, use 0.25 to 0.5 mEq/kg/dose (maximum dose: 40 mEq) to infuse at 0.25 mEq/kg/hour (maximum dose/rate: 1 mEq/kg/hour).37 If infusions of >40 mEq/L are needed, patients should be monitored in an ICU setting and a central line should be used for administration. The concentration should not exceed 0.1 mEq/mL in a peripheral line and 0.2 mEq/mL in a central line. Enteral replacement (oral or via nasogastric tube) can supplement repletion efforts, or in less severe settings can be used instead. For hypokalemia in the face of metabolic acidosis, potassium may be given as phosphate or acetate, whereas with metabolic alkalosis it is given as KCl.2,41 For patients with ongoing and severe potassium losses, such as patients with Bartter syndrome, repletion doses may need to be increased. Hypokalemia

ADMISSION AND DISCHARGE CRITERIA Any patient with a significant electrolyte abnormality should be admitted, especially if the cause of the abnormality is unclear. Discharge is contingent on correction of the abnormal electrolyte status and presence of a treatment plan to maintain normal electrolyte status after discharge.

CONSULTATION Given the myriad of disease states that can lead to electrolyte disturbances, the hospitalist may consult with several specialists, including renal, endocrine, or critical care colleagues, to assist in the management of these patients, especially if the electrolyte derangements are severe.

REFERENCES 1. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics. 1957;19(5):823-832. 2. Finberg L, Kravath RE, Hellerstein S. Water and Electrolytes in Pediatrics:Physiology, Pathology, and Treatment. 2nd ed. Philadelphia, PA: Saunders; 1993. 3. Holliday M. The evolution of therapy for dehydration: should deficit therapy still be taught? Pediatrics. 1996;98(2 Pt 1):171-177. 4. Winters RW. Principles of pediatric fluid therapy. 2nd ed. Boston, MA: Little, Brown; 1982. 5. Feld LG, Kaskel FJ, Schoeneman MJ. The approach to fluid and electrolyte therapy in pediatrics. Adv Pediatr. 1988;35:497-535. 6. Arieff AI, DeFronzo RA. Fluid, Electrolyte, and Acid-Base Disorders. 2nd ed. New York: Churchill Livingstone; 1995:877-904. 7. Roberts KB. Fluid and electrolytes: parenteral fluid therapy. Pediatr Rev. 2001;22(11):380-387. 8. Hartling L, Bellemare S, Wiebe N, Russell K, Klassen TP, Craig W. Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children. Cochrane Database Syst Rev. 2006(3):CD004390. 9. Freedman SB, Keating LE, Rumatir M, Schuh S. Health care provider and caregiver preferences regarding nasogastric and intravenous rehydration. Pediatrics. 2012;130(6):e1504-e1511. 10. Karpas A, Finkelstein M, Reid S. Parental preference for rehydration method for children in the emergency department. Pediatr Emerg Care. 2009;25(5):301-306.

11. Holliday MA, Friedman AL, Wassner SJ. Extracellular fluid restoration in dehydration: a critique of rapid versus slow. Pediatr Nephrol. 1999;13(4):292-297. 12. Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA. 2004;291(22):2746-2754. 13. Powell CV, Priestley SJ, Young S, Heine RG. Randomized clinical trial of rapid versus 24-hour rehydration for children with acute gastroenteritis. Pediatrics. 2011;128(4):e771-e778. 14. Freedman SB, Parkin PC, Willan AR, Schuh S. Rapid versus standard intravenous rehydration in paediatric gastroenteritis: pragmatic blinded randomised clinical trial. BMJ. 2011;343:d6976. 15. Nager AL, Wang VJ. Comparison of ultrarapid and rapid intravenous hydration in pediatric patients with dehydration. Am J Emerg Med. 2010;28(2):123-129. 16. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495. 17. Moritz ML, Ayus JC. Prevention of hospital-acquired hyponatremia: a case for using isotonic saline. Pediatrics. 2003;111(2):227-230. 18. Choong K, Kho ME, Menon K, Bohn D. Hypotonic versus isotonic saline in hospitalised children: a systematic review. Arch Dis Child. 2006;91(10):828-835. 19. Neville KA, Verge CF, Rosenberg AR, O’Meara MW, Walker JL. Isotonic is better than hypotonic saline for intravenous rehydration of children with gastroenteritis: a prospective randomised study. Arch Dis Child. 2006;91(3):226-232. 20. Yung M, Keeley S. Randomised controlled trial of intravenous maintenance fluids. J Paediatr Child Health. 2009;45(1-2):9-14. 21. Neville KA, Sandeman DJ, Rubinstein A, Henry GM, McGlynn M, Walker JL. Prevention of hyponatremia during maintenance intravenous fluid administration: a prospective randomized study of fluid type versus fluid rate. J Pediatr. 2010;156(2):313-319; e311-e312. 22. Montanana PA, Modesto i Alapont V, Ocon AP, Lopez PO, Lopez Prats JL, Toledo Parreno JD. The use of isotonic fluid as maintenance therapy

prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study. Pediatr Crit Care Med. 2008;9(6):589-597. 23. Rey C, Los-Arcos M, Hernandez A, Sanchez A, Diaz JJ, Lopez-Herce J. Hypotonic versus isotonic maintenance fluids in critically ill children: a multicenter prospective randomized study. Acta Paediatr. 2011;100(8):1138-1143. 24. Coulthard MG, Long DA, Ullman AJ, Ware RS. A randomised controlled trial of Hartmann’s solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients. Arch Dis Child. 2012;97(6):491-496. 25. Holliday MA, Ray PE, Friedman AL. Fluid therapy for children: facts, fashions and questions. Arch Dis Child. 2007;92(6):546-550. 26. Roberts KB. Hospital-acquired hyponatremia is associated with excessive administration of intravenous maintenance fluid. Pediatrics. 2004;114(6):1743-1744; author reply 1744-1745. 27. Burdett E, Roche AM, Mythen MG. Hyperchloremic acidosis: pathophysiology and clinical impact. Transfus Altern Transfus Med. 2003;5(4):424-430. 28. Wathen JE, MacKenzie T, Bothner JP. Usefulness of the serum electrolyte panel in the management of pediatric dehydration treated with intravenously administered fluids. Pediatrics. 2004;114(5):12271234. 29. Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev. 2002;23(11):371-380. 30. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. New Engl J Med. 1986;314(24):1535-1542. 31. Sarnaik AP, Meert K, Hackbarth R, Fleischmann L. Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med. 1991;19(6):758-762. 32. Keating JP, Schears GJ, Dodge PR. Oral water intoxication in infants. An American epidemic. Am J Dis Child. 1991;145(9):985-990. 33. Rose BD: Hyperosmolal states-hypernatremia. In: Clinical Physiology of Acid-Base and Electrolyte Disorders. 4th ed. New York: McGraw-Hill,

Health Professions Division; 1994:695-736. 34. Finberg L. Hypernatremic (hypertonic) dehydration in infants. N Engl J Med. 1973;289(4):196-198. 35. Saborio P, Tipton GA, Chan JC. Diabetes insipidus. Ped Rev. 2000;21(4):122-129; quiz 129. 36. Leung AK, Robson WL, Halperin ML. Polyuria in childhood. Clin Pediatr. 1991;30(11):634-640. 37. Lexi-Comp Inc., American Pharmacists Association. Pediatric & neonatal dosage handbook. Lexi Comp’s Drug Reference Handbooks. Hudson, Ohio and Washington, DC: LexiComp; American Pharmacists Association: v. 38. Hegenbarth MA. Preparing for pediatric emergencies: drugs to consider. Pediatrics. 2008;121(2):433-443. 39. Fuhrman BP. Pediatric Critical Care. 4th ed. Philadelphia, PA: Elsevier Saunders; 2011. 40. Janjua HS, Mahan JD, Patel HP, Mentser M, Schwaderer AL. Continuous infusion of a standard combination solution in the management of hyperkalemia. Nephrol Dialysis Transplant. 2011;26(8):2503-2508. 41. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York: McGraw-Hill, Medical Pub. Division; 2001.

SECTION H Gastroenterology and Nutrition

CHAPTER

75

Biliary Disease Amethyst C. Kurbegov

BACKGROUND The biliary tree includes the ducts that drain bile from the liver and coalesce into the right and left hepatic ducts, the cystic duct and gallbladder, and the common bile duct that drains bile from the gallbladder through the pancreas and into the duodenum. Biliary tract diseases can present at any age and have become increasingly recognized in pediatric practice as diagnostic tests have improved. Some diseases of the biliary system are associated with liver disease and others are specific to the biliary tract alone. In addition, some biliary diseases present at specific ages in children while others can develop at any time from early infancy through adulthood.

PATHOPHYSIOLOGY The primary pathologic processes of biliary tract disease fall into two categories, obstructive or inflammatory. Obstruction diminishes flow of bile from the liver into the duodenum with resultant pressure in the biliary system (leading to pain, jaundice, and potentially pancreatitis), fat malabsorption (from poor micelle formation in the gut), and potential infection (from gut flora contamination of the static bile fluid in the biliary tree). Hepatic inflammation and damage may result if biliary obstruction or inflammation is not relieved or treated. Obstruction is most often from gallstones but may also occur as a result of anatomic abnormalities or scar formation. Chronic inflammation of the biliary tree, whether in the large ducts draining the liver and gallbladder or in the small ducts within the liver, can lead to scarring and obstruction of bile flow. Inflammatory processes are most often autoimmune in nature but can

be due to chronic infections or genetic diseases. They are often insidious and unrecognized until significant biliary damage has occurred and large duct obstruction develops. Finally, the gallbladder itself can be poorly functional in storing and/or evacuating bile, which can lead to more subtle, subacute reductions in bile flow and chronic pain from gallbladder distention and inflammation.

CLINICAL PRESENTATION Jaundice is the primary sign of biliary disease, indicating significant obstruction to bile flow. Jaundice typically prompts medical evaluation that leads to the diagnosis of biliary disease. Complete or near-complete obstruction of bile flow can result in acholic stools that are light yellow to clay in color. For infants in diapers, stools may occasionally have a hint of pigment on the exterior surface due to sloughing of enteric cells or staining from bile-pigmented urine. Once this layer is removed, however, the claycolored stool inside is apparent.1 Careful attention is required when evaluating jaundice in neonates as approximately 60% of term neonates and 80% of preterm infants develop physiologic jaundice in the first days of life.2 This can lead to complacency and delays in diagnosing more serious liver and biliary diseases that present in early infancy. Any infant with new or persistent jaundice beyond the first 2 weeks of life requires further evaluation that includes measurement of fractionated serum bilirubin. Physiologic jaundice, breast milk jaundice, and hemolytic diseases are all associated with unconjugated hyperbilirubinemia; in contrast, extrahepatic biliary atresia (EHBA) and other cholestatic hepatobiliary diseases of the newborn result in an elevated conjugated bilirubin.1,3 A conjugated or “direct” bilirubin >2.0 mg/dL or 20% of the total bilirubin is considered the threshold definition of cholestasis and requires prompt and aggressive evaluation and management in any young infant.4,3 Biliary disease may present with poor growth and weight gain as a consequence of inadequate bile salts in the intestinal lumen, which leads to poor micelle formation and fat malabsorption. In addition, symptoms or physical findings indicative of fat-soluble vitamin deficiencies may be found. Specific findings include hemorrhage or hematoma (vitamin K deficiency), rickets (vitamin D deficiency), night blindness and corneal xerophthalmia

(vitamin A deficiency), and peripheral neuropathy (vitamin E deficiency).5 While older children with biliary disease can present with jaundice, they often have other symptoms indicating biliary obstruction or inflammation, especially right upper quadrant to epigastric pain, right shoulder referred pain from diaphragmatic irritation, postprandial pain or nausea (particularly with high-fat foods), vomiting, light-colored stools, or dark urine. Fever, if present, may suggest superimposed infection. Signs of biliary disease include a positive Murphy sign (right upper quadrant tenderness during inspiration), scleral icterus and jaundice, epigastric tenderness if pancreatitis is present, and right upper quadrant mass. Subacute biliary disease such as acalculus cholangitis or biliary dyskinesia can present gradually with persistent and worsening right upper quadrant pain and tenderness and often nausea or vomiting with high-fat foods, but no fever or jaundice. Systemic illnesses such as scarlet fever, Kawasaki disease, and leptospirosis can lead to hydrops of the gallbladder, with subsequent findings of right upper quadrant pain (93%) and mass (55%) along with evidence of broader acute systemic disease.6 In patients with infection of the biliary tree (cholangitis), Charcot’s triad of fever, right upper quadrant pain, and jaundice may be seen.1,6 Bacterial cholangitis can progress to bacteremia and sepsis, especially if obstruction is present. Hepatosplenomegaly is not typically associated with primary biliary tract conditions. However, the cholestasis of chronic biliary disease can result in hepatocellular injury, which may ultimately lead to liver fibrosis and portal hypertension. Thus the presence of hepatosplenomegaly in the context of biliary disease likely indicates the presence of advanced chronic disease and progressive liver dysfunction.

DIFFERENTIAL DIAGNOSIS As with many diseases in pediatrics, the differential diagnosis of biliary disease in children is best categorized by age of presentation (Table 75-1). Metabolic, congenital endocrinologic, and genetic disorders are more likely to present in the neonatal and infant population, while gallbladder dysfunction and cholelithiasis are more typically found in older children and adolescents. Anatomic abnormalities often present in infancy, such as biliary atresia, which must be recognized within the first 2 months of life for optimal

management, but may present later. Choledochal cysts, for example, can become apparent at any age, from birth to old age, with variable presentation from acute ascending cholangitis to chronic obstruction from biliary ductal carcinoma, a consequence of unresected choledochal cysts.7 Finally, biliary involvement of acute systemic processes such as Kawaski syndrome with gallbladder hydrops or graft-versus-host disease following bone marrow transplant must be considered within the specific context of the child’s health. TABLE 75-1

Differential Diagnosis of Biliary Tract Disease by Age

Infancy Biliary atresia Choledochal cyst Gallstone, gallbladder sludge Spontaneous perforation of common bile duct Bile duct paucity Syndromic (Alagille syndrome) Nonsyndromic Hypothyroidism Panhypopituitarism Congenital infection Cystic fibrosis Childhood Gallstone Choledochal cyst Cholangitis Acalculous cholecystitis Biliary dyskinesia Hydrops of gallbladder Primary sclerosing cholangitis Common bile duct stricture

Malignancy Biliary helminthiasis Graft-versus-host disease

DIAGNOSTIC EVALUATION Although the evaluation for possible biliary tract disease should be tailored to the individual patient, the initial steps are usually similar (Table 75-2). Thereafter, certain studies may be selected on the basis of clinical suspicion, feasibility, and invasiveness. Evaluation of neonates and young infants with jaundice should be prompt and efficient, because timely intervention is required if biliary atresia is found. Management of conditions detected during diagnostic evaluation is addressed in the discussions of each specific diagnosis. TABLE 75-2

Evaluation of Suspected Biliary Tract Disease

All Patients History and physical examination Laboratory studies Fractionated bilirubin Aspartate transaminase, alanine transaminase, γglutamyltransferase, alkaline phosphatase Albumin, prothrombin time/INR Complete blood count, blood culture (in presence of fever) Abdominal ultrasonography Further Options Hepatobiliary iminodiacetic acid scan (HIDA) Liver biopsy Sweat test Endoscopic retrograde cholangiopancreatography Magnetic resonance cholangiopancreatography

Genetic and metabolic testing Thyroid function tests Congenital infection tests (urine CMV PCR or culture, TORCH titers) The first and most fundamental step in evaluating jaundice is the fractionation of the serum bilirubin.3 Biliary tract disease is associated with elevation of direct or conjugated bilirubin, as opposed to the elevated indirect or unconjugated bilirubin found in various hemolytic and abnormal liver conjugating conditions such as breast milk jaundice and Crigler-Najjar syndrome. An elevated conjugated bilirubin is associated with obstruction of bile flow through or from the liver due to either congenital or acquired lesions. Conditions of hepatic dysfunction can also be associated with elevated bilirubin without extrahepatic obstruction, such as occurs in viral hepatitis or gram-negative rod sepsis, which causes intracellular disruption of the bile flow. Various genetic and endocrinologic syndromes, such as progressive familial intrahepatic cholestasis or panhypopituitarism, may also interrupt or impede normal bile production and flow without involving frank ductal obstruction. In addition to a fractionated bilirubin, a broader laboratory assessment of liver inflammation and function should be pursued in all patients with suspected biliary disease. These include alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, gammaglutamyltransferase (GGT), total protein, and albumin levels and prothrombin time (PT)/INR. ALT and AST are markers of hepatocyte inflammation and breakdown and may be elevated if biliary tract disease is severe enough to generate secondary inflammation in the liver. Alkaline phosphatase and GGT are more specific for the biliary tract than are AST and ALT, and they are usually elevated, possibly 10 times normal or more, with acute obstruction or inflammation of the biliary tree.8,9,10 Albumin and protime (PT) are indicators of liver synthetic function and are less likely to be abnormal in an acute biliary process. Although not common, liver failure can be seen with some biliary tract diseases, including biliary atresia and unrelieved acute obstruction such as untreated common bile duct cholelithiasis.3,11 In patients with fever, a complete blood count and blood culture should be obtained, given the possibility of cholangitis and subsequent bacteremia.

Ultrasonography is the most useful imaging study for assessing biliary tract disease.12,13 A carefully performed ultrasound study can detect stones in the gallbladder, common bile duct, or elsewhere in the biliary tree. Dilatation of bile ducts, either intra- or extrahepatic, can indicate obstruction. Congenital malformations of the biliary tree, primarily choledochal cysts, are typically detected by ultrasonography. Although biliary atresia cannot be definitely diagnosed by ultrasonography, an absent gallbladder or the presence of a “triangular cord” in the porta hepatitis is suggestive.13-15 Conversely, it is important to note that the presence of a gallbladder does not rule out biliary atresia. Finally, abdominal ultrasonography allows the evaluation of other abdominal organs that can be affected by or associated with biliary disease, such as gallstone pancreatitis or polysplenia associated with the embryonic form of biliary atresia. For a young infant presenting with cholestasis, the initial evaluation should include the blood work discussed earlier and ultrasonography. The presence of a choledochal cyst should lead to surgical consultation for repair. If such a definitive finding is absent, further investigation to rule out biliary atresia should be undertaken, particularly in patients with acholic stools. A hepatobiliary scintigram (HIDA scan) can be performed to look for excretion of the radioactive tracer from the liver into the gut, which would confirm the patency of the biliary tree.13 Lack of excretion into the gut may mean that biliary atresia is present. This study is not available at all institutions, however, and an abnormal study does not always distinguish extrahepatic obstruction from intrahepatic causes of cholestasis, such as Alagille syndrome or cystic fibrosis. A liver biopsy is helpful in these patients to distinguish among several causes of jaundice, including neonatal hepatitis, bile duct paucity syndromes such as Alagille, and extrahepatic biliary atresia (which is characterized by bile duct proliferation on biopsy).1,3 Due to the possible overlap in the appearance of these cholestatic conditions on biopsy, if there is ongoing clinical concern for biliary atresia, surgical consultation for an intraoperative cholangiogram should be obtained. The cholangiogram is the most definitive study for biliary atresia. Some major pediatric centers have used endoscopic retrograde cholangiopancreatography (ERCP) to define biliary anatomy in neonates and infants with good results, but so far intraoperative cholangiogram remains the standard of care.16 A few other studies may be appropriate in selected patients. Since

hypothyroidism, either alone or in conjunction with panhypopituitarism, can stunt intrahepatic bile duct formation, jaundiced infants should have thyroid function tests performed.17,18 Infants with cystic fibrosis can also develop jaundice due to thick, inspissated bile plugging of both intra- and extrahepatic bile ducts, so patients in this age group should have their newborn screen tests for cystic fibrosis reviewed and a skin sweat test performed if there is any lingering question of cystic fibrosis.19,20 Older children presenting with jaundice, abdominal pain, and elevated GGT or alkaline phosphatase are most likely to have acute obstruction of the biliary tree with gallstones, hematoma from trauma, or previously unrecognized anatomic abnormality such as a choledochal cyst. In the absence of gallstones or other obvious obstruction seen by ultrasound, the child may be suffering from primary sclerosing cholangitis, an autoimmune condition of the biliary tree. This condition requires imaging with either ERCP or magnetic resonance cholangiopancreatography (MRCP) to show the characteristic areas of alternating stricture and dilation, giving the intrahepatic and extrahepatic ducts a beaded appearance (Figure 75-1).21,22 Characteristic findings are also present on liver biopsy. A history of inflammatory bowel disease, particularly ulcerative colitis, in the patient or the family should raise the suspicion for primary sclerosing cholangitis and lead to consultation with a pediatric gastroenterologist or hepatologist for a full evaluation.

FIGURE 75-1. Type 1 choledochal cyst (arrow) in an 11-month-old girl. Magnetic resonance cholangiopancreatography maximum intensity projection reveals cystic dilation of the common bile duct without abnormality of the intrahepatic duct. (Image used with permission from the Children’s Hospital Colorado Department of Radiology and reviewed by Christina J. White, DO and Laura Z. Fenton, MD.)

SPECIFIC DISEASES AND THEIR MANAGEMENT This section discusses in greater depth the pathophysiology and management of those biliary diseases most likely to be encountered by the pediatric hospitalist. Biliary atresia and choledochal cysts are typically diagnosed in infancy, although the latter may rarely present in older children and adults. Cholelithiasis, cholangitis, biliary dyskinesia, gallbladder hydrops, and primary sclerosing cholangitis are more likely to be found in older children and adolescents, although infants may develop cholelithiasis, particularly if treated with parenteral nutrition in the neonatal period.

BILIARY ATRESIA Biliary atresia is the most common cause of chronic cholestasis in infants,

accounting for 40% to 50% of all cases of neonatal cholestasis, and occurring in 1 in 8000 to 12,000 births. It is the leading indication for pediatric liver transplantation worldwide.23,3,24 In this condition, all or part of the extrahepatic bile ducts are destroyed or absent, leading to early cholestasis and rapidly progressive liver disease. Fifteen percent to 20% of cases are an embryonic form and thus usually associated with other congenital anomalies such as heterotaxy syndrome and polyspenia. The remaining 80% to 85% of cases are acquired, resulting from an inflammatory process in the intra-and extrahepatic bile ducts that destroys and scars the bile ducts. The etiology for this inflammation is still not fully understood, although it may be an autoimmune response to early viral infection in the infant.25 Without surgical correction, death occurs in the first 1 to 2 years of life from liver failure; even with therapy, timing and surgical expertise are crucial to patient outcome. Typical presenting symptoms of biliary atresia include prolonged neonatal jaundice and acholic stools; testing for biliary atresia should be considered for any infant with jaundice beyond the first 14 days of life. The physical examination reveals jaundice and possibly malnutrition due to fat malabsorption from inadequate bile secretion into the stools. Laboratory studies reveal an elevated conjugated bilirubin, and liver enzymes are often mildly elevated. The GGT and alkaline phosphatase are also often disproportionately elevated compared to the AST and ALT. Abdominal ultrasonography frequently fails to identify a gallbladder, although the presence of a gallbladder does not rule out biliary atresia. Radioisotope studies with technetium cholescintigraphy (HIDA scan) can be helpful in distinguishing between neonatal hepatitis and biliary atresia as causes of jaundice. Classically, tracer is taken up well by the liver but is not excreted into the bowel in biliary atresia, whereas the opposite is true in neonatal hepatitis and other nonobstructive lesions. Excretion of the tracer makes biliary atresia very unlikely, but other causes of chronic cholestasis, such as cystic fibrosis, Alagille syndrome, and α-1-antitrypsin deficiency, may also have non-excretion of tracer, so an abnormal study by itself is not diagnostic of biliary atresia.1,3,13,12 The definitive diagnosis of biliary atresia is made by liver biopsy and/or intraoperative cholangiogram. Liver biopsy shows proliferation of intrahepatic bile ductules, diffuse cholestasis, and often fibrosis without the degree of hepatocyte inflammation seen in neonatal hepatitis.3,26 If the biopsy

is suggestive of obstruction, an intraoperative cholangiogram should be performed before surgical correction to confirm the diagnosis and determine the degree of anatomic involvement. When suspicion of biliary atresia is high, proceeding directly to operative cholangiogram and open liver biopsy should be considered. A Kasai procedure (hepatoportoenterostomy) should follow cholangiogram if biliary atresia is confirmed. The goal of this surgery is to reestablish bile flow from the remaining patent ductules in the liver to a jejunal limb attached to the porta hepatis via a Roux-en-Y anastomosis. The timing of surgery is crucial, with correction before 60 days of life vastly improving outcome. The procedure is initially successful in approximately 80% to 90% of patients if it is performed during this time frame by an experienced surgeon in a center with significant numbers of biliary atresia patients. The success rate drops to less than 20% in patients 90 days of age or older at the time of surgery.1,3 Establishment of good bile flow immediately after surgery predicts a good outcome, but progressive liver disease and fibrosis usually still occurs after surgery. Overall, 50% of children with biliary atresia, despite Kasai procedure, require liver transplantation in the first 2 years of life, and 80% of children with biliary atresia will require transplantation before adulthood.1,27 Transplantation is not pursued at the time of diagnosis due to neonatal size and the possibility of long-term success with hepatoportoenterostomy alone. Following this procedure, children’s survival and outcome with transplantation is greatly improved owing to their growth and improved nutritional status during the months and years of functional bile flow.28

CHOLEDOCHAL CYSTS Choledochal cysts are congenital cystic dilations of the biliary tree; they may be extrahepatic, intrahepatic, or both. The incidence of cysts varies worldwide, occurring in about 1 in 13,000 to 15,000 births in Western countries but as frequently as 1 in 1000 births in Japan. There is a 4:1 female predominance. Patients usually present in infancy but may occasionally present as late as adulthood, and unrecognized malformations may develop malignant cholangiocarcinoma in adulthood.7,9 Cysts are diagnosed in up to 2% of infants presenting with obstructive jaundice.3 The cysts are categorized

into five major groups (I–V) according to the Todani classification, and the majority (60%–90%) are type I cysts characterized by diffuse dilatation of the hepatic and common bile duct without intrahepatic involvement.29 Patients with choledochal cysts most commonly present with jaundice, although vague right upper quadrant pain, cholangitis, and rarely, recurrent pancreatitis may also be present. The classic triad of intermittent abdominal pain, jaundice, and right upper quadrant mass is found relatively infrequently, studies reporting this presentation in only 5% to 20% of patients.6,9,30 Studies comparing pediatric and adult presentations find jaundice to be much more common in children, particularly those presenting under 2 years of age, while pain is the most common symptom in adults. Cholangitis (fever and biliary infection) may occur in a third of patients.30,7,6 Infants present similarly to those with biliary atresia, including jaundice and acholic stools. Diagnosis is usually made by ultrasonography, and ERCP or intraoperative cholangiogram reveals the full anatomy and presence of intrahepatic disease, as occurs in types IV and V.12 Preoperative MRCP can provide an adequate assessment of the lesion, although primarily in older children or adults.22,31,32 Treatment consists of complete surgical excision of the cyst and creation of a Roux-en-Y choledochojejunostomy proximal to the most distal lesion.9,3 The goals of surgery are good bile drainage and complete cyst removal to reduce the risk of future malignancy. Biliary adenocarcinoma rates are 20 times higher in patients with choledochal cysts than in the general population, and carcinoma has been reported between 10% and 26% of patients left with residual cystic tissue after surgery.30,33,34 With successful radical excision of the cyst and Roux-en-Y formation, now often done laparoscopically, longterm outcomes are excellent. However, patients should be followed by a pediatric gastroenterologist after surgery to monitor for recurrent cholangitis, pancreatitis, and malignancy.33,30

CHOLELITHIASIS Cholelithiasis, or stone formation in the gallbladder, a frequent condition in adults, occurs in up to 10% of the adult population of North America.35,36 The incidence and prevalence in children are less well studied, but the prevalence in North American and western European children has been on

the rise over the last 30 years.37 Cholelithiasis in children is frequently associated with known predisposing conditions such as obesity, hemolytic disease, ileal disease, total parenteral nutrition (TPN), prolonged fasting, and pregnancy, although some studies show that up to half of infants and a quarter of older children with gallstones have no identifiable underlying condition.37 A recent study comparing normal/underweight children to obese children found a two- to threefold increase in gallstones in moderate to extremely overweight boys and a five- to eightfold increase in gallstone rates for moderate to extremely overweight girls. Girls who took oral contraceptives were at further increased risk compared to their similar-weight counterparts.38 Children of Hispanic ethnicity have higher rates of gallstone formation than Caucasian or black children, particularly if obesity is present.39,40 Pigmented stones are most common in children younger than 6 years and in patients with hemolytic processes, while cholesterol stones predominate in school-age children and adolescents. Infants with symptomatic cholelithiasis present with jaundice, sepsis, or abdominal pain, although asymptomatic gallstones may be identified incidentally, particularly in infants requiring prolonged fasting and support with TPN. Epigastric and right upper quadrant abdominal pain, vomiting, and jaundice are common presenting symptoms in older children and adolescents, and pancreatitis may be a complication of gallstones in 5% to 10% of patients.6,11 Laboratory studies may be normal in asymptomatic patients, but liver enzymes, GGT, alkaline phosphatase, and conjugated bilirubin may all be elevated in the presence of ductal obstruction from a dislodged stone or infection. Ultrasonography is the best initial study for identifying both gallstones and dilation of the biliary tree.12,13 Stones and sludge may be identified in the gallbladder, and a thickened gallbladder wall indicates inflammation or infection. Asymptomatic or “silent” stones found incidentally generally do not require therapy. In adults, long-term follow-up studies have shown that less than 5% of patients with silent stones require non-elective cholecystectomy.41 Longitudinal studies of children with silent stones have not been completed, but a recent, large retrospective study of children identified with gallstones by ultrasound found that 50% of the children were asymptomatic, and only 3% of these patients later developed symptoms that necessitated surgery. Infants with stones were usually asymptomatic (81%), and 16% of older children and

34% of infants with silent stones showed resolution of their cholelithiasis upon follow-up imaging.42 Dissolution of cholesterol stones less than 2 cm in size with ursodeoxycholic acid has been effective in 60% of adult patients, although the recurrence rate of stones after cessation of therapy is 10% per year.43 Pediatric patients with hemolytic diseases are at particular risk for gallstone formation, with 30% to 60% of patients with sickle cell disease developing stones in the first 14 years of life.11,42 These patients may require ERCP to accurately identify common bile duct stones, and it is generally recommended they undergo cholecystectomy for gallstones even when asymptomatic due to high risk for obstruction, cholecystitis (gallbladder infection), and pancreatitis from stone passage.42,44 Patients with hemolytic disease, particularly sickle cell disease, may continue to form biliary tree stones even several years after cholecystectomy that may cause clinically significant common bile duct obstruction.45,46 For symptomatic gallstones, the definitive therapy is cholecystectomy, usually done laparoscopically. In acute cholecystitis, urgent or even emergent gallbladder removal may be warranted, but in those patients without infection or obstruction, surgery can usually be delayed for a few days to a month or more to allow for convenient timing.11 Laparoscopic cholecystectomy has been proven safe and effective in children and is the standard of care surgical approach to gallbladder removal. For uncomplicated, planned cases, it can often be done with discharge in 24 hours or even as an outpatient day procedure.47 Acute cholecystitis, or infection of the gallbladder, is usually associated with cholelithiasis and cystic duct obstruction. It presents with right upper quadrant pain, fever, and vomiting, and approximately half of patients are jaundiced.6,11 Treatment includes intravenous antibiotics with gram-negative and anaerobic bacterial coverage, fluid resuscitation, and urgent cholecystectomy. In addition to cholecystitis, other acute complications of gallstone passage can include obstructive hepatitis and/or pancreatitis. Hepatitis typically resolves once the obstruction is relieved. Pancreatitis may develop in children with gallstone passage via the common bile duct, and this can result with or without persistent biliary obstruction. Gallstone pancreatitis is an indication for cholecystectomy, and recent pediatric series show that cholecystectomy, either on its own or with ERCP if necessary, is best

performed during the initial hospitalization for pancreatitis rather than waiting until a later date. Delay in surgery can be associated with development of further biliary complications, including repeat pancreatitis or cholecystitis, prior to the set date of future surgery.48 For stones obstructing the common bile duct (choledocholithiasis), therapeutic ERCP has become popular in both children and adolescents. The procedure is often combined with sphincterotomy of the sphincter of Odi to allow balloon clearance for extrication of stones from the common bile duct.37,49 ERCP is safe in children and has been performed safely by experienced practitioners for a variety of indications in children of all ages, even younger than 1 year. Complication rates are typically around 4% and can include post-ERCP pancreatitis, bleeding, infection, and biliary or duodenal hematoma or perforation.49,50,16 Whether ERCP is required in patients with suspected common bile duct stones prior to or along with cholecystectomy remains controversial. Some authors argue for intraoperative cholangiography and bile duct exploration by surgeons at the time of cholecystectomy, reserving ERCP for patients whose duct cannot be cleared at the time of surgery.51,52 Not all centers have an endoscopist skilled in ERCP in children, and in such circumstances an intraoperative procedure may be preferable to therapeutic ERCP.

CHOLANGITIS AND CHOLECYSTITIS Cholangitis is a bacterial infection of the biliary tree, encompassing the extraor intrahepatic ducts or both. Cholecystitis is infection of the gallbladder without involvement of the ducts leading to or from it. Patients at risk for bacterial cholangitis are those with biliary tree anomalies and those with acute biliary obstruction. Patients with choledochal cysts, cholelithiasis, biliary atresia following a Kasai portoenterostomy, or strictures of the biliary tree (e.g. primary sclerosing cholangitis) are all at risk for cholangitis. Charcot’s triad of right upper quadrant abdominal pain, fever, and jaundice is common in older children and adults, and infants may present with fever and acholic stools as well as jaundice. Up to half of patients with bacterial cholangitis have positive blood cultures, and in those cases, cultures can help direct and narrow antibiotic choices. The most common bacteria identified on both blood and biliary fluid

cultures are Escherichia coli, Klebsiella spp., Bacteroides spp., enterocci, Enterobacter spp., and Pseudomonas spp.53-55 Mixed infections with both aerobic and anaerobic bacteria commonly occur. Therapy includes relief of obstruction if it exists, fluid resuscitation, and intravenous antibiotics. Traditionally, a penicillin and aminoglycoside have been used, but recent resistance patterns of bacteria cultured from bile suggest that piperacillintazobactam may be used as a first-line single agent and meropenem or imipenem should be used for more severe cases.54,53 Duration of antibiotic therapy is usually 21 days, although the entire course need not always be parenteral. Oral alternatives include amoxicillin-clavulanate or the combination of ciprofloxacin and metronidazole. In patients with biliary obstruction, the timing of decompression depends on the stability of the patient. Toxic patients often need emergent endoscopic or operative decompression, whereas most stable patients can wait until they are afebrile for 24 to 48 hours before undergoing therapeutic interventions.56 Therapy usually involves ERCP with removal of a stone or stenting of a stricture. In patients with cholelithiasis, a cholecystectomy should be performed once the patient has recovered from the acute illness. Duration of antibiotic administration following ERCP and decompression has been debated, although some studies have shown no significant difference in outcomes when adult patients were treated with intravenous antibiotics for either 2, 3, or 5 or more days, provided the patient was doing well and had defervesced after surgery.57,58 The key criteria in these studies was resolution of fever for discontinuation of antibiotics with observation another 24 to 72 hours after antibiotics stopped to confirm no return of infection.

ACALCULOUS CHOLYCYSTITIS Acalculous cholecystitis is an acute distention and inflammation of the gallbladder in the absence of gallstones and is typically due to infection or systemic illness. Prolonged fasting and TPN use, episodic ischemia, and the use of opiates in critically ill or postoperative patients may contribute to its development, resulting from gallbladder stasis and bacterial infection in these circumstances.11 Several systemic illnesses have been associated with acalculous cholecystitis, including streptococcal and gram-negative sepsis, leptospirosis, Rocky Mountain spotted fever, typhoid fever, ascariasis, and

Giardia lamblia infection. Parasitic, candidal, and viral infections have been identified in immunocopromised patients.11,59-62 Anatomically, the cystic duct that drains the gallbladder is narrowed due to a congenital anomaly, edema, or lymph node compression; this leads to inadequate drainage of the gallbladder and subsequent bile stasis and infection. Clinically, patients present with right upper quadrant abdominal pain, nausea, vomiting, and possibly fever, and may have a palpable gallbladder on examination. Diagnosis of acalculous cholecystitis is most often made via ultrasonography and nuclear medicine imaging.12,63,64 Increased gallbladder wall thickness on ultrasonography is an inconsistent finding, and may be due to other systemic causes of hypoalbuminemia, inflammation, or edema, but progressive thickening of the wall in serial examinations may be suggestive.65,66 Other ultrasound findings include an absence of calculi, gallbladder distention, and poor contraction in response to cholecystokinin (CCK), although these can also be seen in hydrops of the gallbladder. Radioisotope studies with technetium cholescintigraphy, using the hepatic iminodiacetic acid or HIDA scan, are sensitive for detecting cystic duct obstruction that is suggestive of acalculous cholyesystitis.12,63 Findings on HIDA scan include good hepatic uptake and intestinal excretion of isotope without gallbladder filling. In the event of gallbladder perforation, tracer extrudes into the abdominal cavity. HIDA scan has come to largely replace ultrasound as the most reliable way to confirm acalculous cholecystitis, but ultrasound is needed initially to confirm the absence of gallstones or obstruction. Thus, in the correct clinical setting, ultrasound should be followed by HIDA scan for further investigation of symptoms. Therapy for acalculous cholecystitis includes treatment of any underlying condition, intravenous antibiotics, and surgical removal of the gallbladder.11,64 Cholecystectomy is frequently necessary to avoid progression to gallbladder necrosis and possible perforation with bile peritonitis.

BILIARY DYSKINESIA Biliary dyskinesia describes the abnormal or absent motion of the gallbladder to contract and expel bile when stimulated by gastrointestinal hormonal signals, particularly CCK. This dysfunction has become increasingly

recognized as a cause of chronic abdominal pain in children. Pain is typically chronic, often postprandial, localized to the right upper quadrant to epigastric region, and frequently associated with nausea and/or vomiting.67,68 Acute symptoms such as fever or jaundice or hematemesis are absent. Symptoms often are similar to those of peptic disease, and distinguishing between these two diagnoses can at times be challenging. Diagnosis is classically based upon the demonstration of no cholelithiasis or biliary obstruction on abdominal ultrasound plus an abnormal gallbladder ejection fraction on HIDA scan with CCK stimulation. A low ejection fraction, usually defined as less than 35% but in some studies as low as 15% and some as high as 40%, indicates abnormal contraction by the gallbladder and ostensibly, inadequate delivery of bile to the intestinal tract. Many patients will have pain when CCK is injected during HIDA scan to stimulate gallbladder contraction, and the ability of this induced pain to replicate the chronic complaints can suggest a gallbladder source of symptoms. Treatment of biliary dyskinesia is typically considered surgical with cholecystectomy. Some surgeons prefer upper endoscopy to be performed prior to surgery to confirm that peptic ulcer disease is not the cause of pain and nausea/vomiting, but recent studies have not found routine esophagogastroduodenoscopy to be necessary unless symptoms are out of the ordinary.69 Response rates to cholecystectomy vary by study reports, with some groups reporting greater than 90% of children with resolution or significant improvement of symptoms and other groups reporting 70% to 77% resolution.67-70 Histopathology of the removed gallbladder often shows some degree of chronic inflammation, studies reporting anywhere from 40% to 88% of gallbladders with chronic inflammation. Of note, those studies with higher rates of response to surgery typically found higher rates of inflammation on their pathological specimens, thus likely showing a more specifically selected patient population for surgery.68,69

HYDROPS OF THE GALLBLADDER Hydrops is the acute distention and poor contractility of the gallbladder without concomitant inflammation, obstruction, or infection of the organ. It is distinguished from chronic biliary dyskinesia by more acute presentation and a pronounced degree of gallbladder distention, rather than strictly abnormal

contractility. The lack of gallstones, infection, or anatomic abnormality of the biliary system also distinguishes this condition from several of those previously mentioned.71 It is associated with several systemic illnesses, including Kawasaki syndrome, in which it is found in up to 20% of patients.72,73 Other associated conditions include staphylococcal or streptococcal infection, leptospirosis, sepsis, TPN administration, and mesenteric adenitis (often with a preceding viral syndrome).74,75 Hydrops is a self-limited condition that usually does not require surgical intervention. Symptoms and signs often include right upper quadrant to epigastric abdominal pain and tenderness, vomiting, and sometimes a palpable mass in the right upper quadrant, in addition to those symptoms associated with the underlying disease. Ultrasonography reveals a markedly distended, acalculous, and unthickened gallbladder with no other biliary tree dilatation. Serial examinations can confirm a return to normal size and function. The rare need for surgery arises only if hydrops has led to insufficient gallbladder perfusion, with subsequent gangrene or perforation of the organ. Failure of the hydrops to resolve may also warrant surgical investigation to reliably distinguish hydrops from acalculous cholecystitis, although HIDA scan showing good uptake by the distended gallbladder would point toward hydrops. Overall, most cases resolve with no surgical intervention as the underlying systemic inflammatory disease resolves.

PRIMARY SCLEROSING CHOLANGITIS Primary sclerosing cholangitis (PSC) is an autoimmune disease of the biliary tree that results in progressive scarring of both the intra- and extrahepatic bile ducts.1 The disease is typically silent unless acute cholangitis develops from a scarred, obstructed area of the bile ducts, or if end stage liver disease develops. GGT and alkaline phosphatase levels are typically elevated, often out of proportion to other liver enzyme and bilirubin elevations. Diagnosis is made through biliary imaging, either through ERCP or MRCP, which shows alternate stricturing and dilatation of affected portions of the biliary ducts. The disease is often associated with inflammatory bowel disease, and it can present as an “overlap syndrome” with autoimmune hepatitis, a phenomenon more common in children than adults with PSC.76 Children with overlap syndrome may respond well to immunosuppressive therapy; however, biliary

tract inflammation may continue to progress and ultimately lead to liver cirrhosis regardless of therapy.

ADMISSION AND DISCHARGE CRITERIA ADMISSION CRITERIA Hospitalization of a child with biliary disease may be indicated for the following reasons: Infant with direct hyperbilirubinemia (evaluate for biliary atresia, choledochal cyst, or other anatomic, endocrinologic, or genetic causes of jaundice). Jaundice accompanied by fever (intravenous antibiotics for treatment of cholangitis and evaluation of underlying cause of infection). Biliary tree obstruction (surgical or endoscopic relief of obstruction). Biliary tree anomaly in the presence of jaundice or fever (intravenous antibiotics and surgical correction of anomaly). Evidence of liver failure (vitamin K administration, intensive support and monitoring, correction of underlying cause, evaluation for liver transplant at tertiary center).

DISCHARGE CRITERIA Overall, patients may be discharged when the diagnosis has been established or when serious or life-threatening disorders are treated or no longer being considered. Further diagnostic evaluation may proceed after discharge if appropriate, such as genetic or metabolic testing, hemolytic evaluation, or serial radiologic studies. Treatment should be completed or should be able to be continued or completed after discharge, such as completion of antibiotics or scheduled outpatient surgery. Appropriate ongoing monitoring and followup should be in place prior to discharge. Many biliary disorders will need follow-up by pediatric gastroenterology, pediatric surgery, or both.

CONSULTATION Subspecialty consultation is appropriate in the following circumstances:

Hepatosplenomegaly: Pediatric gastroenterology Biliary tree anomaly: Pediatric surgery and pediatric gastroenterology Obstructive cholelithiasis: Pediatric surgery and pediatric gastroenterology Biliary dyskinesia: Pediatric surgery Liver inflammation or synthetic dysfunction: Pediatric gastroenterology Cystic fibrosis: Pediatric pulmonology and pediatric gastroenterology Hormonal deficiencies (thyroid, growth hormone, cortisol): Pediatric endocrinology Dysmorphism or associated congenital anomalies: Pediatric genetics and pediatric gastroenterology Gallstones with hemolysis: Pediatric hematologist and pediatric surgeon KEY POINTS Diseases of the biliary tract range from those that need urgent surgical correction, such as biliary atresia or obstructed and septic cholangitis, to genetic conditions that require lifelong subspecialist management. Jaundice, abdominal pain (often localized to the right upper quadrant), and fever are the most frequent presenting signs of biliary disease, and a basic evaluation includes a complete blood count, fractionated bilirubin, hepatic enzymes including GGT, liver function tests, and abdominal ultrasonography. The basic evaluation often indicates whether the disease is a primary liver disorder or a primary biliary tract disease. Infants with suspected biliary atresia warrant transfer to a pediatric hepatology center for prompt evaluation and treatment of their jaundice, including performance of a Kasai procedure by a pediatric surgeon experienced in the operation. Biliary tract disease, particularly gallstones and gallbladder dysfunction, have increased with the rising incidence of obesity in children and adolescents in Western societies. Therapeutic ERCP has gained importance in the acute management of obstructive gallstones in the pediatric population, and children with gallstones often warrant ERCP management of acute obstruction followed by surgical cholecystectomy.

Laparoscopic cholecystectomy has become a safe, frequently performed, and effective procedure in children for the treatment of gallstones, biliary dyskinesia, cholangitis, and acalculous cholangitis. Children with evidence of hepatic synthetic failure, regardless of cause, should be transferred to a pediatric hepatology center for emergent evaluation and management.

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to 1989. J Pediatr Surg. 1990;24(10):1076-1080. 24. Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr. 2006;148(4):467-474. 25. Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2012;32(4):307-316. 26. Russo P, Magee JC, Boitnott J, et al. Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterol Hepatol. 2011;9(4):357-362. 27. Lykavieris P, Chardot C, Sokhn M, Gauthier F, Valayer J, Bernard O. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology. 2005;41(2):366-371. 28. DeRusso PA, Ye W, Shepherd R, et al. Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia Research Consortium. Hepatology. 2007;46(5):1632-1638. 29. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile duct cysts: classification, operative procedures, and review of thirtyseven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134(2):263-269. 30. de Vries JS, de Vries S, Aronson DC, et al. Choledochal cysts: age of presentation, symptoms, and late complications related to Todani’s classification. J Pediatr Surg. 2002;37(11):1568-1573. 31. Irie H, Honda H, Jimi M. Value of MR cholangiopancreatography in evaluating choledochal cysts. AJR Am J Roentgenol. 1998;171(5):13811385. 32. Murphy AJ, Axt JR, Crapp SJ, Martin CA, Crane GL, Lovvorn HN 3rd. Concordance of imaging modalities and cost minimization in the diagnosis of pediatric choledochal cysts. Pediatr Surg Int. 2012;28(6):615-621. 33. Cho MJ, Hwang S, Lee YJ, et al. Surgical experience of 204 cases of adult choledochal cyst disease over 14 years. World J Surg. 2011;35(5):1094-1102. 34. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma.

Hepatology. 2011;54(1):173-184. 35. Ruhl CE, Everhart JE. Gallstone disease is associated with increased mortality in the United States. Gastroenterology. 2011;140(2):508-516. 36. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham Study. J Chronic Dis. 1966;19(3):273-292. 37. Svensson J, Makin E. Gallstone disease in children. Semin Pediatr Surg. 2012;21(3):255-265. 38. Koebnick C, Smith N, Black MH, et al. Pediatric obesity and gallstone disease. J Pediatr Gastroenterol Nutr. 2012;55(3):328-333. 39. Ma MH, Bai HX, Park AJ, et al. Risk factors associated with biliary pancreatitis in children. J Pediatr Gastroenterol Nutr. 2012;54(5):651656. 40. Mehta S, Lopez ME, Chumpitazi BP, Mazziotti MV, Brandt ML, Fishman DS. Clinical characteristics and risk factors for symptomatic pediatric gallbladder disease. Pediatrics. 2012;129(1):e82-e88. 41. Gracie WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Engl J Med. 1982;307(13):798-800. 42. Bogue CO, Murphy AJ, Gerstle JT, Moineddin R, Daneman A. Risk factors, complications, and outcomes of gallstones in children: a singlecenter review. J Pediatr Gastroenterol Nutr. 2010;50(3):303-308. 43. O’Donnell LD, Heaton KW. Recurrence and re-recurrence of gall stones after medical dissolution: a longterm follow up. Gut. 1988;29(5):655658. 44. Al-Salem AH, Issa H. Laparoscopic cholecystectomy in children with sickle cell anemia and the role of ERCP. Surg Laparosc Endosc Percutan Tech. 2012;22(2):139-142. 45. Amoako MO, Casella JF, Strouse JJ. High rates of recurrent biliary tract obstruction in children with sickle cell disease. 65. 2013;60(4):650-652. 46. Vicari P, Gil MV, Cavalheiro Rde C, Figueiredo MS. Multiple primary choledocholithiasis in sickle cell disease. Intern Med. 2008;47(24):21692170. 47. Jawaheer G, Evans K, Marcus R. Day-case laparoscopic cholecystectomy in childhood: outcomes from a clinical care pathway.

Eur J Pediatr Surg. 2013;23(1):57-62. 48. Knott EM, Gasior AC, Bikhchandani J, Cunningham JP, St Peter SD. Surgical management of gallstone pancreatitis in children. J Laparoendosc Adv Surg Tech A. 2012;22(5):501-504. 49. Otto AK, Neal MD, Slivka AN, Kane TD. An appraisal of endoscopic retrograde cholangiopancreatography (ERCP) for pancreaticobiliary disease in children: our institutional experience in 231 cases. Surg Endosc. 2011;25(8):2536-2540. 50. Vegting IL, Tabbers MM, Taminiau JA, Aronson DC, Benninga MA, Rauws EA. Is endoscopic retrograde cholangiopancreatography valuable and safe in children of all ages? J Pediatr Gastroenterol Nutr. 2009;48(1):66-71. 51. Short SS, Frykman PK, Nguyen N, Liu Q, Berel D, Wang KS. Laparoscopic common bile duct exploration in children is associated with decreased cost and length of stay: results of a two-center analysis. J Pediatr Surg. 2013;48(1):215-220. 52. Waldhausen JH, Graham DD, Tapper D. Routine intraoperative cholangiography during laparoscopic cholecystectomy minimizes unnecessary endoscopic retrograde cholangiopancreatography in children. J Pediatr Surg. 2001;36(6):881-884. 53. Kaya M, Beştaş R, Bacalan F, Bacaksız F, Arslan EG, Kaplan MA. Microbial profile and antibiotic sensitivity pattern in bile cultures from endoscopic retrograde cholangiography patients. World J Gastroenterol. 2012;18(27):3585-3589. 54. Karpel E, Madej A, Bułdak Ł, et al. Bile bacterial flora and its in vitro resistance pattern in patients with acute cholangitis resulting from choledocholithiasis. Scand J Gastroenterol. 2011;46(7-8):925-930. 55. Ecoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D. Bacterial cholangitis after surgery for biliary atresia. J Pediatr. 1987;111(6 Pt 1):824-829. 56. Mosler, P. Diagnosis and management of acute cholangitis. Curr Gastroenterol Rep. 2011;13(2):166-172. 57. Kogure H, Tsujino T, Yamamoto K, et al. Fever-based antibiotic therapy for acute cholangitis following successful endoscopic biliary drainage. J

Gastroenterol. 2011;46(12):1411-1417. 58. van Lent AU, Bartelsman JF, Tytgat GN, Speelman P, Prins JM. Duration of antibiotic therapy for cholangitis after successful endoscopic drainage of the biliary tract. Gastrointest Endosc. 2002;55(4):518-522. 59. Walker DH, Lesesne HR, Varma VA, Thacker WC. Rocky Mountain spotted fever mimicking acute cholecystitis. Arch Intern Med. 1985;145(12):2194-2196. 60. Khan FY, Elouzi EB, Asif M. Acute acalculous cholecystitis complicating typhoid fever in an adult patient: a case report and review of the literature. Travel Med Infect Dis. 2009;7(4):203-206. 61. Peison B, Benisch B. Acute acalculous cholecystitis secondary to Candida albicans. N J Med. 1996;93(4):39-42. 62. Liu KJ, Atten MJ, Donahue PE. Cholestasis in patients with acquired immunodeficiency syndrome: a surgeon’s perspective. Am Surg. 1997;63(6):519-524. 63. Swayne, LC. Acute acalculous cholecystitis: sensitivity in detection using technetium-99m iminodiacetic acid cholescintigraphy. Radiology. 1986;160(1):33-38. 64. Huffman JL, Schenker S. Acute acalculous cholecystitis: a review. Clin Gastroenterol Hepatol. 2010;8(1):15-22. 65. Patriquin HB, DiPietro M, Barber FE, Teele RL. Sonography of thickened gallbladder wall: causes in children. AJR Am J Roentgenol. 1983;141(1):57-60. 66. Jeffrey RB Jr, Sommer FG. Follow-up sonography in suspected acalculous cholecystitis: preliminary clinical experience. J Ultrasound Med. 1993;12(4):183-187. 67. Kaye AJ, Jatla M, Mattei P, Kelly J, Nance ML. Use of laparoscopic cholecystectomy for biliary dyskinesia in the child. J Pediatr Surg. 2008;43(6):1057-1059. 68. Siddiqui S, Newbrough S, Alterman D, Anderson A, Kennedy A Jr. Efficacy of laparoscopic cholecystectomy in the pediatric population. J Pediatr Surg. 2008;43(1):109-113. 69. Hofeldt M, Richmond B, Huffman K, Nestor J, Maxwell D. Laparoscopic cholecystectomy for treatment of biliary dyskinesia is safe

and effective in the pediatric population. Am Surg. 2008;74(11):10691072. 70. Carney DE, Kokoska ER, Grosfeld JL, et al. Predictors of successful outcome after cholecystectomy for biliary dyskinesia. J Pediatr Surg. 2004;39(6):813-816. 71. Rumley TO, Rodgers BM. Hydrops of the gallbladder in children. J Pediatr Surg. 1983;18(2):138-140. 72. Slovis TL, Hight DW, Philippart AI, Dubois RS. Sonography in the diagnosis and management of hydrops of the gallbladder in children with mucocutaneous lymph node syndrome. Pediatrics. 1980;65(4):789-794. 73. Suddleson EA, Reid B, Woolley MM, Takahashi M. Hydrops of the gallbladder associated with Kawasaki syndrome. J Pediatr Surg. 1987;22(10):956-959. 74. RG, Strauss. Scarlet fever with hydrops of the gallbladder. Pediatrics. 1969;44(5):741-745. 75. Bloom RA, Swain VA. Non-calculous distension of the gall-bladder in childhood. Arch Dis Child. 1966;41(219):503-508. 76. Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008;14(21):3360-3367.

Constipation

CHAPTER

76

Michelle W. Parker

BACKGROUND Constipation is a common pediatric disorder, with studies citing a prevalence up to 30% with a median of 9% of children;1 however, in special patient populations such as children with cerebral palsy, prevalence is much higher.2 It was the principal diagnosis in 52/10,000 hospital discharges for patients 3 years

1.0/day

Constipation can occur at any age but is particularly common in toddlers and elementary school–age children. In most studies, no significant gender-

specific prevalence difference has been reported.1 The causes of constipation can be divided into anatomic, physiologic, and functional (Table 76-2). Anatomic causes of constipation include Hirschsprung disease, imperforate anus, and bowel obstruction. Physiologic causes include a number of processes that alter bowel motility, such as hypothyroidism and spinal cord defects. Functional constipation, which results from voluntary stool withholding, is the most common cause of constipation (90%–97% of cases) and is often a self-perpetuating condition that starts with an episode of pain on defecation, a battle over toilet training, or toilet phobia.1,4,5,7,9,10 Functional constipation may progress to encopresis, which is either voluntary or involuntary fecal incontinence in a child at least 4 years of age. It can involve leakage of stool around more distal, firm fecal impaction and is thought to result from chronic constipation secondary to functional fecal retention. TABLE 76-2

Differential Diagnosis of Constipation

Functional Toilet phobia Coercive toilet training School bathroom avoidance Sexual abuse Anatomic Hirschsprung disease Imperforate anus Anal stenosis Anteriorly displaced anus Bowel obstruction, pseudo-obstruction Tethered cord Physiologic Hypothyroidism Hypercalcemia Diabetes mellitus

Cystic fibrosis Bowel motility disorders Spinal cord abnormalities Neuropathic conditions Drugs (opiates, anticholinergics, lead, iron, antidepressants) Poor fluid or fiber intake Depression Connective tissue disorders (scleroderma, systemic lupus erythematosus, Ehlers-Danlos syndrome) Infant botulism Indications for hospitalization include failure of outpatient management to resolve excessive stool burden or inability to maintain adequate intake due to associated vomiting or abdominal pain.

CLINICAL PRESENTATION Constipation does not always present with the obvious history of infrequent or hard stools. Children may have regular, even daily, bowel movements but incomplete evacuation leading to progressive stool retention. The presenting complaint is often abdominal pain, which may be intermittently severe but is typically low grade and difficult for the child to describe. The location of the pain is usually periumbilical, and on examination there may be tenderness but usually no rebound or guarding. Other manifestations of constipation include diarrhea as with encopresis, also abdominal distention, anorexia, flatulence, dyschezia, blood-streaked stools, nausea, and vomiting, and constipation can even progress to bowel obstruction.

DIFFERENTIAL DIAGNOSIS Constipation is often diagnosed easily and with specificity by the presence of infrequent or hard stools. However, there is a large differential diagnosis of underlying disorders that can lead to constipation (see Table 76-2). Although functional constipation is the most common type, it is important to keep other

disorders in mind, especially in children with complex medical needs, recurrent constipation, or new onset of constipation.

DIAGNOSIS AND EVALUATION The diagnosis and evaluation of constipation rests on a thorough history and physical examination. History alone may differentiate those children with an organic cause of constipation from those with functional constipation (Table 76-3). Besides stool consistency and frequency, the history should include time to passage of the first meconium stool, age at onset of symptoms, details of toilet training, urinary retention or incontinence and associated symptoms of rectal pain and bleeding, abdominal pain, and stool incontinence. An evaluation of other constitutional symptoms, such as fevers, weight loss, and nausea should also be considered for those who have an acute or subacute onset of symptoms and those with severe enough symptoms to require hospitalization, as they may suggest an underlying organic disorder. A history of delayed passage of the first stool beyond 48 hours of life raises the suspicion of Hirschsprung disease, as would a longstanding family or personal history of constipation. A history of stool withholding or of constipation associated with toilet training or toilet phobia is strongly suggestive of functional constipation. TABLE 76-3

Historical Factors of Importance in the Evaluation of Constipation

Historical Factor

Special Significance

Constipation history Timing of first stool in neonatal period

Delay suggestive of Hirschsprung disease

Quality of stool Frequency of stool Duration of symptoms

Sudden onset may indicate nonfunctional causes

Family history Hirschsprung disease Other causes of constipation

Identify potentially inherited predisposition to constipation

Other systemic disease (e.g. thyroid, cystic fibrosis, inflammatory bowel disease) Diet Amount of fluid

May identify contributors to constipation or trigger suggestions for dietary modifications

Amount of fiber General nutrition Recently weaned off formula Social Toilet training New school Family or social stressors

Absence of these may raise concern for non-functional causes of constipation Alternately, treatment of contributing behavioral concerns may be helpful achieving long-term therapeutic success

Sexual abuse History of withholding behavior Toilet phobia Medications, ingestions, or exposures Narcotic use or ingestion Any other ingestions

May suggest medication-induced

constipation Previous medication for constipation Lead exposure

Toxicity may lead to constipation

Associated symptoms Abdominal pain Nausea Vomiting Weight loss

Suggestive of non-functional cause

Diarrhea

May indicate encopresis

Pain with defecation Blood in stool Fever General medical history Neuropathic disorder

Suggestive of non-functional cause Positive history may suggest underlying physiologic reason for constipation

Cerebral palsy Spina bifida A careful and thorough physical examination can help identify underlying disorders. For all children with constipation, there may or may not be abdominal distension present or palpable stool in the abdomen. For children with functional constipation, a large rectal impaction may be found on digital rectal examination, but the remainder of the physical examination should be normal, including normoactive bowel sounds and no significant focal tenderness. Hirschsprung disease may be suggested by an empty, nondistended rectum or by expulsion of gas and stool following a digital rectal examination. Inspection of the anus may reveal imperforate anus or anal

stenosis, and fissures may be detected in those with a complaint of bloody stools. Bowel obstruction, which can be caused by constipation or can lead to constipation, should be associated with abdominal distension along with persistent vomiting and inability to tolerate food or liquids, and auscultation may reveal tinkling or hypoactive bowel sounds. On neurologic examination, deep tendon reflexes may be sluggish in hypercalcemia and hypothyroidism, or hyperreflexic in spinal cord abnormalities. Lower extremity weakness or an absent anal wink are suggestive of a neurologic cause of constipation. Examination of the lumbosacral area of the spine may reveal a hairy patch, sinus tract, or other midline defect which could suggest spina bifida. If the examination is limited by body habitus or the diagnosis is still in doubt, a simple flat-plate abdominal radiograph to look for a moderate to large stool can be diagnostic (Figure 76-1). Laboratory studies or additional imaging are necessary only if based on the history or physical examination there is concern about an underlying organic cause of the constipation. To evaluate anatomic concerns, abdominal radiograph may be diagnostic. Contrast enema or rectal biopsy looking for an aganglionic colon done in consultation with a pediatric gastroenterologist or surgeon may be considered for diagnosis of Hirschsprung disease or other motility disorders. CT scan may be needed to diagnose bowel obstruction and would necessitate the involvement of a pediatric surgeon. Laboratory studies may include thyroid function tests (thyroxine and thyroid-stimulating hormone) looking for hypothyroidism, calcium, glucose, lead level, celiac screening (anti-tissue transglutaminase antibodies and total serum IgA), and cow-milk protein allergy testing (by specific IgE or skin prick testing) can be considered when concerns exist for underlying pathology, but their routine use for functional constipation is not supported by the evidence.8 If the patient presents with abdominal pain or urinary complaints, a urinalysis and urine culture may be indicated, because constipation significantly increases the risk of a urinary tract infection. A sweat test to rule out the possibility of cystic fibrosis may be considered, especially in the presence of accompanying failure to thrive or pulmonary symptoms. Spinal magnetic resonance imaging and colonic transit time may be warranted if there is concern about an occult spinal abnormality or neuropathy.

FIGURE 76-1. Abdominal radiograph showing stool burden with fecal impaction.

COURSE OF ILLNESS Constipation is frequently a chronic problem that requires long-term followup and management. In the inpatient setting, acute impaction can often be relieved and the patient discharged home in 1 to 2 days. However, maintenance therapy with stool softeners may be indicated for months, along with behavioral and toileting modification. Long-term complications are generally related to loss of normal colonic size and tone and the development of encopresis. In severe cases, chronic anorexia and failure to thrive can also result. Also, psychosocial functioning can be severely affected in children with chronic constipation, leading to poor self-esteem, poor school performance, and family stress and conflict.5,9

TREATMENT

Most patients with a clear diagnosis of functional constipation can be managed without hospitalization if close outpatient follow-up is available. After the initial diagnosis and initiation of therapy, reassessment of the frequency and character of stools and observation for new symptoms or findings are necessary. Patients should be followed at regular intervals until the child is having regular soft stools with no evidence of stool withholding or fecal soiling. The successful treatment of functional constipation and encopresis requires a multipronged approach. Acutely, the child may require disimpaction (Table 76-4). Although either the oral or the rectal route have been shown to be equally effective,11 the rectal route is faster and is sometimes preferred for hospitalized patients. For these patients, disimpaction is often initiated by the administration of enemas, which can be repeated as needed until no hard stool is present in defecation or rectal effluent. The patient should be adequately hydrated prior to initiation of therapy to avoid sudden shifts in fluids and electrolytes. Recommended enemas include bisacodyl, saline, docusate, sodium phosphate, or mineral oil. Soapsuds, water, or magnesium enemas should not be used because of the potential risk of electrolyte imbalance.4 Evaluation of serum electrolytes should be considered after two enema administrations, as rare but serious adverse events stemming from hyperphosphatemia, hypernatremia, and hypocalcemia related to sodium phosphate enemas have been reported.12,13 Often, more proximal stool must be evacuated via an oral (or nasogastric) polyethylene glycol-electrolyte solution at a dose of 25 mL/kg/hour until effluent is clear. Rarely, stool is impacted to such a severe degree that the impaction is refractory to pharmacologic therapy. In this case, manual disimpaction should be considered and is often done in consultation with pediatric surgery and under anesthesia for young patients to maximize cooperation and minimize discomfort to the patient. TABLE 76-4

Method Enemas

Disimpaction Guidelines Dosage

Comments and Side Effects

Bisacodyl

2–10 y: 5 mg

Rare electrolyte abnormalities include metabolic acidosis or alkalosis, hypocalcemia

>10 y: 5–10 mg Docusate

2–1 y: 6 mL/kg

Mineral oil

2–11 y: 30–60 mL

Not for use in patients with renal insufficiency, colitis or megacolon

>11 y: 60–150 mL Glycerin suppository

12 mo: 1–3 mL/kg/day

Comments and Side Effects Do not use in children younger than 12 mo or in those at risk of aspiration Can cause anal leakage Long-term use (>1–2 y) can cause fat-soluble vitamin deficiency

Polyethylene Osmotic

0.8 g/kg/day of

Preferred

glycol 3350

laxative

powder starting maintenance dose, adjusted to medication clinical response; each 17-g dose should be dissolved in 4–8 oz of liquid

Magnesium hydroxide (milk of magnesia)

Osmotic laxative

12 y: Start with as needed to 2 tablets or 10– maximum doses, 15 mL as follows: 2–6 y: 1 tablet, or 3.75 mL syrup twice a day

7–12 y: 2 tablets, or 7.5 mL syrup twice a day ≥12 y: 4 tablets or 15 mL twice a day Can cause abdominal cramps Bisacodyl oral

Bisacodyl rectal

Stimulant laxative

Stimulant laxative

≤12 y: 5–10 mg daily

Do not use for more than 1 wk

>12 y: 5–15 mg daily

Can cause abdominal cramping

6 mo–2 y: 5 mg suppository daily

Do not use for more than 1 wk

3–11 y: 5–10 mg suppository daily

Can cause abdominal cramping

≥12 y: 10 mg suppository daily Lactulose

Osmotic laxative

Children: 1–2 g/kg/day Adults: 15–30 mL/day, increased to 60 mL/day in 1–2 divided doses if necessary

Can cause abdominal cramping and flatulence

Counseling and education should include promotion of adequate fluid

intake as well as a healthy diet, which includes whole grains, fruits, and vegetables.4 Additionally, if functional constipation is the diagnosis, behavioral factors must be addressed. Families should be instructed to initiate regular toileting times and durations. On average, a child should be put on the toilet for 5 to 10 minutes once or twice a day, ideally after meals. With younger or smaller children, use of a footstool may allow proper foot support to permit 90 degrees of hip and knee flexion.5 Children should not be punished if they fail to produce stool, but they should be encouraged to attempt to do so. The purpose of regular toileting routines is to resensitize the body to the gastrocolic reflex, and parents should explicitly be told not to make this process a source of anxiety for the child. Children with severe emotional disorders or psychological avoidance of stool production may benefit from psychological evaluation and therapy. Children younger than 1 year with functional constipation should be managed more carefully. For this age group, emphasis is placed on increased intake of fluids and modest consumption of juices containing sorbitol (prune, pear, or apple). Pharmacologic treatment may include lactulose. Although enemas should generally be avoided, rectal glycerin suppositories may be helpful for rectal disimpaction. Additionally, infants in this young age group should have careful consideration of possible underlying conditions contributing to constipation.

CONSULTATION Subspecialty consultation should be considered if the initial workup raises concern for any of the following: Chronic or refractory constipation, possible bowel motility disorder: Gastroenterology Hirschsprung disease, bowel obstruction, acute abdomen: General surgery Hypothyroidism: Endocrinology Spinal dysraphism, spina bifida, neuromuscular disorders: Neurology Severe toilet phobia: Psychiatry

ADMISSION CRITERIA

Hospitalization is indicated for any of the following reasons: Unclear cause, with concern about potentially life-threatening conditions or those that require presumptive inpatient evaluation and treatment (e.g. cystic fibrosis, bowel obstruction). Severe abdominal pain. Nasogastric electrolyte solution administration for bowel cleanout. Persistent vomiting or inability to tolerate oral intake. Lack of appropriate outpatient support or follow-up.

DISCHARGE CRITERIA Successful evacuation of stool. Ability to tolerate oral or enteral fluids and nutrition. Stable or resolving symptoms and issues that the family can manage at home. Reliable outpatient follow-up with primary pediatrician and, if indicated, pediatric gastroenterologist or other specialist.

PREVENTION Eating a well-balanced diet with plenty of fruits, vegetables, and water can help prevent constipation, as can regular physical activity. Most important, hospitalization can usually be prevented by educating parents about the importance of appropriate toileting regimens. It is also important to deal with any behavioral issues early, before severe constipation and encopresis result. Special consideration should be given to children with cerebral palsy, other neuromuscular disorders, or severe medical problems. These children are at greater risk for the development of constipation because of their relative inactivity, decreased muscle use and tone, and low-fiber diets. Therefore, efforts should be made to prevent constipation in these children by the routine use of stool softeners and maintenance therapy, and physicians should increase this therapy or begin disimpaction promptly if stools become more infrequent or hard. KEY POINTS

Constipation can present with infrequent passage of hard stool and a variety of other symptoms, including abdominal pain, abdominal distention, pain with defecation, and nausea. Frequent liquid stools from encopresis may lead the family to report diarrhea. Functional constipation may require hospitalization if symptoms are severe or require close monitoring or intervention, and postdischarge follow-up is critical for preventing repeat episodes. Recent advances in pharmacotherapy, such as tegaserod (Zelnorm), a serotonin 5-HT4 receptor agonist, and other new promotility agents, show promise in the management of constipation. Continuing research on the pathophysiology of impaired colonic transit may shed more light on the underlying cause of idiopathic constipation.

SUGGESTED READINGS Baker S, Liptak G, Colletti R, et al. Constipation in infants and children: evaluation and treatment. J Pediatr Gastroenterol Nutr. 1999;29:612-626. Loening-Baucke V. Prevalence, symptoms and outcome of constipation in infants and toddlers. J Pediatr 2005;146:359-363. Rahhal R UA. Functional constipation. In: Kleinman R, ed. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker; 2008:675-682. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527-1537. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr. 2014;58(2):258-274.

REFERENCES 1. van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol. 2006;101(10):2401-2409. 2. Veugelers R, Benninga MA, Calis EA, et al. Prevalence and clinical presentation of constipation in children with severe generalized cerebral palsy. Devel Med Child Neurol. 2010;52(9):e216-e221. 3. Sethi S, Mikami S, Leclair J, et al. Inpatient burden of constipation in the United States: an analysis of national trends in the United States from 1997 to 2010. Am J Gastroenterol. 2014;109(2):250-256. 4. Baker SS, Liptak GS, Colletti RB, et al. Constipation in infants and children: evaluation and treatment. A medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 1999;29(5):612-626. 5. Liacouras CA, Piccoli DA. Constipation and irritable bowel syndrome. In: Pediatric Gastroenterology. 1st ed. Philadelphia, PA: Mosby/Elsevier; 2008:30-41. 6. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527-1537. 7. Rahhal R UA. Functional constipation. In: Kleinman R, ed. Walker’s Pediatric Gastrointestinal Disease. 5th ed. Hamilton, Ontario: BC Decker; 2008:675-682. 8. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr. 2014;58(2):258-274. 9. Phatak U PD. Constipation. In: Bishop WP, ed. Pediatric Practice Gastroenterology. 1st ed. New York, NY: McGraw Hill; 2010. 10. Loening-Baucke V. Prevalence, symptoms and outcome of constipation in infants and toddlers. J Pediatr. 2005;146(3):359-363. 11. Bekkali NL, van den Berg MM, Dijkgraaf MG, et al. Rectal fecal impaction treatment in childhood constipation: enemas versus high doses

oral PEG. Pediatrics. 2009;124(6):e1108-e1115. 12. Ladenhauf HN, Stundner O, Spreitzhofer F, Deluggi S. Severe hyperphosphatemia after administration of sodium-phosphate containing laxatives in children: case series and systematic review of literature. Pediatr Surg Int. 2012;28(8):805-814. 13. Mendoza J, Legido J, Rubio S, Gisbert JP. Systematic review: the adverse effects of sodium phosphate enema. Aliment Pharmacol Ther. 2007;26(1):9-20.

CHAPTER

77

Dyspepsia Oren L. Koslowe and Denesh K. Chitkara

BACKGROUND Children often experience epigastric discomfort or dyspepsia either as a presenting symptom or during hospitalization. The challenge to the hospitalist is to identify the cause or causes based on typically vague complaints, a wide differential, generally indirect examination of the affected area, and laboratory and radiographic evaluations that are nonspecific and rarely diagnostic.

CLINICAL PRESENTATION Nausea, vomiting, heartburn, regurgitation, early satiety, postprandial abdominal bloating or distention, excess gas with or without belching or flatulence, queasiness, fullness, and retching are all common presentations of gastric dysfunction. These symptoms overlap with the discussions of other disorders such as abdominal pain, gastrointestinal (GI) bleeding, failure to thrive, and feeding issues. Dyspepsia is defined as chronic or recurrent pain or discomfort in the upper abdomen (above the umbilicus), with discomfort being a subjective sensation that may include fullness and early satiety.1-3 These symptoms are typically to the exclusion of “heartburn” or a burning sensation in the retrosternal region, which is generally presumed to be gastroesophageal reflux disease (GERD).3 In one study of children at a tertiary center evaluated for unexplained recurrent abdominal pain, 15.9% met criteria for functional dyspepsia, a term applied to dyspeptic symptoms absent other identifiable disease.4 The timing of symptoms is often helpful in determining the presence of

underlying disease. Pain attributable to gastric ulceration often peaks when the stomach is empty, whereas pain associated with functional dyspepsia usually develops immediately after eating and may linger for hours.

DIFFERENTIAL DIAGNOSIS Many disorders can cause dyspepsia, including functional, mucosal, and anatomic abnormalities of the stomach or extragastric GI system. In addition, extra-GI disorders, such as genitourinary or psychiatric dysfunction, can have prominent dyspeptic symptoms (Table 77-1). TABLE 77-1

Differential Diagnosis for Dyspepsia

Functional disorders Functional dyspepsia GERD-predominant symptoms Rumination syndrome Aerophagia Postviral gastroparesis Abdominal migraine Inflammatory or mucosal disorders GERD Helicobacter pylori gastritis Peptic ulcer NSAID ulcer Eosinophilic gastroenteritis Infection: Giardia, Blastocystis hominis, Dientamoeba fragilis Bacterial overgrowth Inflammatory bowel disease (Crohn disease) Ménétrier disease Varioliform gastritis Celiac disease Lactose or carbohydrate malabsorption or intolerance

Henoch-Schönlein purpura Anatomic disorders Malrotation with or without volvulus Duodenal web Psychiatric disorders Psychogenic vomiting Depression Somatization Anxiety Panic disorders Conversion reactions Anorexia nervosa Other disorders Chronic pancreatitis Chronic hepatitis Ureteropelvic junction obstruction Biliary dyskinesia Intestinal pseudo-obstruction Lymphoma, carcinoma GERD, gastroesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory drug.

DIAGNOSIS AND EVALUATION The broad differential diagnosis and the subjective nature of these symptoms can present a challenge, and a standard approach or algorithm for evaluation is difficult to establish. Certainly a timeline as well as any type of symptom journal that the patient or family can provide is helpful. Initial questions should include duration of symptoms, antecedent infection or antibiotic use, degree of disability associated with symptoms, medication history, and measures—effective and ineffective—taken thus far to address the symptoms. If symptom severity has dictated hospitalization it is generally incumbent on the hospitalist to begin some investigation, but it should be measured. A reasonable initial laboratory workup might include a complete

blood count, inflammatory markers (erythrocyte sedimentation rate or Creactive protein), chemistry profile (including liver and renal function tests), pancreatic enzymes, (amylase, lipase) stool testing for ova and parasites, urinalysis, and screening for Helicobacter pylori. While screening for H. pylori is the most likely to yield a positive result in this setting, the practitioner should be aware that a positive H. pylori screen does not necessarily mean the source for the symptoms has been identified. As guidelines for diagnosis and treatment of H. pylori in children evolve, further consultation with a gastroenterologist or infectious disease specialist may be indicated to determine the most effective means of diagnosis and therapy.5 Noninvasive tests for H. pylori including a 13C urea breath test and a stool antigen test are currently recommended to be obtained after therapy to confirm eradication.5 The combination of the history, physical findings, and laboratory results may indicate the need for further evaluation into conditions including inflammatory bowel disease (IBD), H. pylori gastroenteritis, eosinophilic gastroenteritis, chronic hepatitis, chronic renal disease, or parasitic infection. Further evaluation should proceed in a stepwise fashion and may include radiographic imaging or endoscopy. Ultrasonography, upper GI series, or computed tomography should be considered where there is particular suspicion for pancreatitis, obstruction, or renal disease. Hydrogen breath tests may be a useful diagnostic tool for the evaluation of clinically suspected bacterial overgrowth and lactose or carbohydrate malabsorption, but these are rarely indicated in the inpatient setting. An upper endoscopy should be strongly considered in patients with symptoms including weight loss, recurrent vomiting, hematemesis, anemia, and dysphagia. It should be relayed to the patient and family that an upper endoscopy in the setting of dyspepsia is generally a diagnostic and not a therapeutic procedure, that the yield is low,6 and that negative findings are still helpful in management. Patients with severe chronic symptoms without identifiable disease may require evaluation of motility of the stomach and small intestine by GI transit or emptying studies, barostat to investigate gastric accommodation or visceral sensation, or manometry to better delineate motor abnormalities. A psychosocial evaluation may also be warranted, as children with chronic dyspeptic symptoms are at risk for depression and functional impairment.7

TREATMENT Treatment should be directed at the specific disorder if one is identified. Frequently, however, no obvious cause is found, yet the patient has persistent symptoms. In this case a diagnosis of functional dyspepsia is generally made and empiric management is often warranted (Table 77-2). The most effective means of therapy is avoidance of triggers where they can be identified. Again, symptoms in this setting are chronic and patients should be afforded the opportunity to properly identify triggers. Beyond that, empiric management usually begins with anti-secretory therapy—H2 receptor antagonists or proton pump inhibitors,1-3,8 though symptom journals and relaxation exercises should begin as well.9 Prokinetic agents are often subsequently considered.2 TABLE 77-2

Management and Therapeutic Options for Dyspepsia

Diet Timing of meals Small, frequent meals Solid vs. liquid diet Low FODMAP (Fermentable Oligo-, Di-, Mono-saccharides and Polyols) Pharmacology H2 agonists (e.g. famotidine, ranitidine) Proton pump inhibitors (e.g. omeprazole, esomeprazole, lansoprazole, pantoprazole) Prokinetic agents (e.g. metoclopramide, erythromycin, tegaserod) Serotonin antagonist (cyproheptadine) Neutraceuticals (e.g. ginger, Iberogast) Serotonin-1 agonists (e.g. sumatriptan, buspirone) Tricyclic antidepressants (e.g. amitriptyline) Surgery Fundoplication for GERD (may exacerbate ulcer-like and

dysmotility-like dyspepsia) Gastrostomy or jejunostomy for nutritional supplementation Alternative therapy Guided imagery Hypnotherapy Behavioral therapy Psychotherapy Acupuncture For patients who test positive for H. pylori, treatment should be directed specifically at this infection. There are many regimens to treat H. pylori, but a 14-day course of amoxicillin, clarithromycin, and a proton pump inhibitor is a good first choice in children.5 The pharmacologic choices for dysmotility symptoms are relatively limited. Prokinetic agents may be considered in patients with predominant symptoms of fullness, bloating, or early satiety. Metoclopramide (a central and peripheral dopamine-2 antagonist) has been used for treating nausea, fullness, and bloating but its use has been limited by neurologic side effects. A low dose of erythromycin (a motilin agonist) increases gastric emptying but also decreases gastric accommodation, so it may increase dyspeptic symptoms in some patients. In addition, erythromycin has a high occurrence of tachyphylaxis (diminishing response to successive doses) after 3 to 4 weeks of therapy.10 The nonpharmacologic therapies listed in Table 77-2 are often the most helpful and should be included in treatment plans. Conservative measures such as changes in diet (e.g. reducing fat, avoiding caffeine and carbonated beverages, decreasing meal size) and in the timing of meals (e.g. eating breakfast, avoiding bedtime snacks) may be especially helpful in patients with dysmotility symptoms. Off-label use of other medications including cyproheptadine, and neutraceuticals such as ginger have become increasingly popular given their noted benefits in studies and their favorable side-effect profile.9,11 The idea of modifying the gut microbiota for clinical benefit has been applied more often to irritable bowel syndrome (IBS), but given the clinical overlap of symptoms between functional dyspepsia and IBS, attempts to manipulate the microbiota will

likely be utilized with increasing frequency for dyspepsia as well. This may include probiotics, antibiotics effective primarily in the intestine, such as rifaximin, and dietary changes (e.g. low FODMAP [fermentable oligosaccharides, disaccharides, monosaccharides, and polyols] diets, shortchain carbohydrates, and sugars that are poorly absorbed by the small intestine).12 If symptoms persist after a trial of at least 4 weeks of therapy, a change in treatment should be considered. Failure of multiple therapies is usually an indication for endoscopy if not previously performed. Additionally, in patients with functional dyspepsia that is resistant to therapy, the diagnosis should be reevaluated periodically. Should persistence of symptoms ultimately result in transit and manometric studies as mentioned above that are abnormal, placement of gastric electrical simulation devices may be considered and have been used effectively in limited numbers.13 The role for tricyclic antidepressants (TCAs), which seem to relieve visceral hyperalgesia, is unclear. However, administered in low doses, they tend to be very well tolerated and effective in some patients.14 It is important to discuss that the time to symptom benefit with any of these medications may be prolonged, especially with TCAs. In the short term, once any identifiable conditions have been addressed, the focus should be on symptom management, even in the absence of resolution, with return to baseline activities in spite of lingering symptoms as quickly as possible.

CONSULTATION Evaluation for chronic symptoms should initially occur in the outpatient setting, but when they are identified in the inpatient setting input from pediatric gastroenterologists may be helpful in providing management advice, addressing patient and parent concerns, and establishing outpatient follow-up.

ADMISSION CRITERIA Persistent vomiting, severe abdominal pain, hematemesis, bilious emesis, dehydration, persistent weight loss, and significant hematochezia or melena all indicate the need for inpatient evaluation and management.

DISCHARGE CRITERIA Once patients are able to tolerate adequate oral intake, the remainder of the evaluation can usually be completed on an outpatient basis. It is important to ensure adequate follow-up, as these problems are often chronic and require long-term management. KEY POINTS Dyspepsia can represent gastric, intestinal, or extra-GI disorders. Symptomatic relief is often warranted and can be initiated before completion of the diagnostic evaluation. Gastric acid blockade and prokinetic agents, as well as modification of the diet, are standard elements of empirical therapy. Upper endoscopy should be considered in dyspeptic patients presenting with weight loss, recurrent vomiting, bleeding, anemia, dysphagia, or jaundice, patients taking NSAIDs, and patients with severe or persistent symptoms. Further studies on the impact of neutraceuticals and manipulation of the gut microbiota on dyspeptic symptoms.

SUGGESTED READINGS Chitkara DK, Delgado-Aros S, Bredenoord AJ, et al. Functional dyspepsia, upper gastrointestinal symptoms, and transit in children. J Pediatr. 2003;143:609-613. Perez ME, Youssef NN. Dyspepsia in childhood and adolescence: insights and treatment considerations. Curr Gastroenterol Rep. 2007;9(6):447-455.

REFERENCES 1. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;130(5):1466-1479.

2. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527-1537. 3. Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol. 2005;100(10):2324-2337. 4. Walker LS, Lipani TA, Greene JW, et al. Recurrent abdominal pain: symptom subtypes based on the Rome II Criteria for pediatric functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2004;38(2):187-191. 5. Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53(2):230-243. 6. Tam YH, Chan KW, To KF, et al. Impact of pediatric Rome III criteria of functional dyspepsia on the diagnostic yield of upper endoscopy and predictors for a positive endoscopic finding. J Pediatr Gastroenterol Nutr. 2011;52(4):387-391. 7. Rippel SW, Acra S, Correa H, Vaezi M, Di Lorenzo C, Walker LS. Pediatric patients with dyspepsia have chronic symptoms, anxiety, and lower quality of life as adolescents and adults. Gastroenterology. 2012;142(4):754-761. 8. Ford AC, Moayyedi P. Current guidelines for dyspepsia management. Dig Dis. 2008;26(3):225-230. 9. Perez ME, Youssef NN. Dyspepsia in childhood and adolescence: insights and treatment considerations. Curr Gastroenterol Rep. 2007;9(6):447-455. 10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17(5):643-653. 11. Rodriguez L, Diaz J, Nurko S. Safety and efficacy of cyproheptadine for treating dyspeptic symptoms in children. J Pediatr. 2013;163(1):261267. 12. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-176. 13. Teich S, Mousa HM, Punati J, Di Lorenzo C. Efficacy of permanent gastric electrical stimulation for the treatment of gastroparesis and

functional dyspepsia in children and adolescents. J Pediatr Surg. 2013;48(1):178-183. 14. Teitelbaum JE, Arora R. Long-term efficacy of low-dose tricyclic antidepressants for children with functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2011;53(3):260-264.

CHAPTER

78

Disorders of Gastric Emptying Richard J. Noel

BACKGROUND AND PATHOPHYSIOLOGY Passage of the alimentary bolus from the stomach to the duodenum constitutes an important anatomical and functional transition point in the digestive process. The stomach functions as both a digestive organ and a temporary reservoir for the alimentary bolus. The stomach can be divided into a proximal half that functions as a reservoir, and via receptive relaxation, can accommodate changes in volume from the fasted to the postprandial state. Contractions in this region, together with the chemical action of hydrochloric acid and pepsin, further digest the triturated bolus. Weak contractions propel the bolus towards the antrum, where stronger contractions are coordinated with the duodenum and result in progressive emptying of the stomach across the pylorus. The rate of emptying is influenced by the physical nature of the meal, with liquids emptying more rapidly than solids, and foods with lower caloric density emptying more rapidly than foods with higher caloric density. Abnormal gastric emptying into the duodenum may result in symptoms that require hospitalization for supportive care, diagnostic procedures, and therapeutic procedures. To simplify this review, the terms gastroparesis and dumping are utilized for delayed and accelerated gastric emptying, respectively. More detail is provided regarding hypertrophic pyloric stenosis (HPS), a common disorder of gastric emptying in infants.

CLINICAL PRESENTATION Based on history alone, it is difficult to differentiate disorders of delayed from those of accelerated gastric emptying. Furthermore, as in many pediatric

disorders, a child’s description of symptomatology may not be accurate or medically useful, and the presenting symptom may not be more specific than a “feeding disorder.” Gastroparesis may present with vomiting that prompts consideration of small bowel obstruction. However, the typical symptoms are more vague and may include nausea, epigastric fullness, early satiety, pyrosis, and belching. Typically, vomiting does not occur during or immediately after ingesting a meal, which is a pattern more suggestive of rumination syndrome. Rapid gastric emptying may result in nausea, vomiting, epigastric fullness, and early satiety. Rapid emptying may also result in the classic dumping syndrome in a minority of patients, characterized by pallor, diaphoresis, or syncope. The etiology of this syndrome is thought to be rapid release of hyperosmolar fluid into the small bowel and resultant fluid shifts into the bowel. Patients have subsequent disordered glycemia, characterized by initial hyperglycemia, followed by hypoglycemia resulting from persistent elevated insulin levels when substrate absorption from the intestine rapidly declines.

DIFFERENTIAL DIAGNOSIS Delayed gastric emptying has many potential causes (Table 78-1). TABLE 78-1

Differential Diagnosis of Delayed Gastric Emptying

Anatomic Obstruction

Hypertrophic pyloric stenosis Antral or duodenal webs Ectopic pancreatic tissue Antral polyp Hyperplastic gastric folds Duodenogastric intussusception Bezoar

Metabolic or electrolyte

Hypothyroidism

disturbance

Hypokalemia Acidosis

Medications

Opioids Anticholinergics Antidepressants

Neuromuscular dysfunction

CNS* disease Post-vagotomy CIPO* Autonomic dysfunction Visceral myopathy SLE* Myotonic dystrophy

Malnutrition / Eating disorder

Anorexia nervosa Bulemia

Infectious disease

Viral Bacterial toxins

Idiopathic

Idiopathic

Differential Diagnosis of Accelerated Gastric Emptying Post-Surgical

Fundoplication Pyloric operative procedures Partial gastrectomy (proximal or distal)

Vagotomy CNS, Central nervous system; CIPO, Chronic idiopathic pseudoobstruction; SLE, Systemic lupus erythematosus

GASTROPARESIS Gastric outlet obstructions must be considered in the diagnosis of gastroparesis, particularly in younger children who may have the initial presentation of a congenital or acquired anatomical anomaly. Most common among these is hypertrophic pyloric stenosis (HPS),1 which occurs at an annual incidence of 2 to 5 cases per 1000 infants and is the most common condition requiring operative correction in young infants. Infants typically present with “projectile” vomiting and variable degrees of toxicity depending on hydration and nutrition. Less impressive is the vomiting that may be seen with antral and duodenal webs. These are fenestrated, mucosal diaphragms that obstruct gastric outflow as a function of the fenestration diameter.2 Less commonly, outlet obstruction may occur in association with ectopic pancreatic tissue,3 pyloric duplication cysts,4 polypoid tissue,5 or intermittent duodenogastric intussusception.6 Lastly, hyperplastic gastric folds have been known to obstruct antral outflow; conditions such as lymphocytic gastritis or viral infection (Menetrier disease) may result in such changes.7 Bezoars, when of sufficient size, may result in partial gastric outlet obstruction and delayed gastric emptying.8 These may include lactobezoars, trichobezoars, pharmacobezoars, and phytobezoars. Theoretically, large bezoars may also cause dumping if their main effect is a decrease in fundic compliance. Metabolic problems may also result in ineffective gastric emptying. Hypothyroidism decreases antroduodenal motility that resolves upon treatment that restores the euthyroid state.9 Other metabolic abnormalities such as acid–base and electrolyte disturbances, by interacting with the gastrointestinal neuromuscular components, may result in impaired motility and delayed gastric emptying. This must be considered in settings such as diabetes mellitus or renal insufficiency.10 Note that metabolic alterations such as hypokalemia may be aggravated by recurrent vomiting, as may be found in hypertrophic pyloric stenosis, producing a vicious cycle of worsening gastric function. Various types of medications cause a relative gastroparesis. Medications

that may be used in hospital wards and operating rooms have profound untoward effects on the ability of the stomach to empty promptly. These may include opiates,11 anticholinergics (imipramine),12 and tricyclic antidepressants.13 Case reports and animal studies have also implicated benzodiazepines, anesthetics (propofol),14 and chemotherapy medications (cisplatin).15 Diseases primarily affecting the neuromuscular components of the gastrointestinal tract obviously may have a profound effect on gastric emptying. These might include primary central nervous system disease, vagotomy (planned or inadvertent), visceral myopathy, autonomic dysfunction (Riley-Day syndrome), systemic lupus erythematosus (SLE), myotonic dystrophy, or chronic idiopathic pseudoobstruction (CIPO). Mitochondrial disorders may frequently present with gastroparesis or a degree of dysmotility.16 Anorexia nervosa and bulimia are frequently associated with a secondary gastroparesis that responds to improved nutrition and weight gain.17 Infectious diseases that result in gastroparesis include viral gastritis and exposure to endotoxin from gram-negative bacteria.18 Duodenal tuberculosis causing obstructive poor gastric emptying has been reported.19

DUMPING SYNDROME Dumping syndrome is most commonly seen in post-surgical states where the normal proximal compliance or distal tone of the stomach has been affected. In children, the most likely procedure by far to result in dumping syndrome is fundoplication.20 Pyloroplasty is occasionally performed with a fundoplication, potentially resulting in more severe dumping.

DIAGNOSIS AND EVALUATION Symptoms may not be very specific, especially in young children. In patients with recurrent, forceful vomiting, understanding the specific frequency, amounts, and contents of the emesis is critical toward determining if the case involves small bowel obstruction rather than a problem of gastric emptying. HPS has a unique demographic profile that suggests a predilection for firstborn males; however, this may be a demographic artifact and it is likely

that the incidence of HPS is sporadic. Also associated with HPS is prenatal or early postnatal exposure to erythromycin.21, 22 Infants in whom prostaglandin E1 has been infused for maintenance of a patent ductus arteriosus are susceptible to developing obstructing antral hypertrophy.23 Any history of intra-abdominal or thoracic operative procedures where vagal injury could have occurred is relevant toward diagnosing altered gastric emptying. Physical examination should focus on determination of clinical hydration and general toxicity of the patient. Specific to HPS is the palpable mass that may be noticed along with strong, ineffective peristaltic gastric contractions. Palpation of this mass may be facilitated by sham feeding the infant with liquid that is then aspirated via nasogastric suction. Laboratory evaluation (see Table 78-2) should address potential etiologies of recurrent vomiting, if applicable. These may include a complete hepatic panel with pancreatic enzymes. A hemogram should be performed to assess for anemia. A complete electrolyte panel is critical toward the diagnosis of metabolic disturbances that may either cause or be exacerbated by (e.g. hypochloremic, hypokalemic, metabolic alkalosis) dysfunctional gastric emptying. In cases where dumping is suspected, a glucose tolerance test or a hydrogen breath test may be diagnostic. TABLE 78-2

Diagnostic Modalities for Disorders of Gastric Emptying

Laboratory studies

Electrolyte panel Hemogram Hepatic panel Pancreatic enzymes Glucose tolerance tests

Radiographic studies

Upper gastrointestinal series Abdominal ultrasound Scintigraphy gastric emptying scan

Endoscopy

Diagnostic Therapeutic

Motility studies

Antroduodenal manometry Electrogastrography

Operative procedures

As indicated

Radiographic studies may be the most illustrative toward forming a diagnosis. An upper gastrointestinal series has been shown to be the most cost-effective study in the vomiting infant and has the added benefit of diagnosing anomalous rotation and obstruction of the small bowel.1 When the index of suspicion is high for HPS, an ultrasound may help determine if specific diagnostic criteria for length of the pyloric channel and thickness of the muscle have been met.24 In non-emergent situations, radionuclide studies may provide an objective metric of gastric emptying.25 Studies of liquid emptying are performed in infants, whereas studies of liquid and solid emptying are more useful in older children and adults. Endoscopy may be performed to assess for mucosal inflammation from infection and may also be therapeutic in conditions where tissue masses (ectopic pancreas or polyps) impede antroduodenal outflow. Endoscopy may also be utilized to place catheters utilized for antroduodenal motility studies that may be useful in diagnosing primary motility disorders26 or for the injection of botulinum toxin into the pyloric musculature of a patient with gastroparesis.27 While not widely available, electrogastrography may be performed to ultimately diagnose primary disorders of gastric pacing; this technique has been utilized to demonstrate the therapeutic efficacy of supplemental thyroxin in hypothyroid adults9; however, the value of this diagnostic test in discriminating between patients with gastric versus nongastric etiologies of nausea and vomiting is unclear.

MANAGEMENT Clinical management should be directed toward three parameters:

1. Fluid and electrolytes 2. Nutrition 3. Diagnosis and definitive treatment, where applicable

FLUID AND ELECTROLYTES Both impaired and accelerated gastric emptying may result in marked alterations and fluid status and electrolytes. The recurrent vomiting seen in HPS causes loss of sodium, potassium, and chloride that can lead to hypochloremic metabolic alkalosis. This is accentuated by the paradoxical aciduria that results from renal mechanisms to retain sodium and intravascular fluid. Metabolic alterations may be profound and must be corrected prior to exposure to general anesthetics and performance of operative procedures. Patients with severe dumping syndrome may also present with intravascular fluid depletion and hypoglycemia. The former is the result of rapid passage of hyper-osmolar fluid into the small bowel. The latter is due to overcompensation to early hyperglycemia.

NUTRITION Nutritional management can often be the primary focus of treatment since only the more severe cases of gastroparesis present with profound malnutrition. In the event that definitive treatment is not available or indicated, symptomatic improvement can often be achieved with use of small frequent meals, and/or with liquid supplements which may be better tolerated since liquids will still empty faster. If such modifications to intragastric feeding are not successful, the stomach may be bypassed with placement of a nasojejunal tube (although with vomiting the tube may be displaced), a surgical jejunostomy, or parenterally via an intravenous catheter.

MEDICATIONS Pharmacologic options for treatment of gastroparesis are relatively limited and inconsistent in their efficacy. Drugs that function as 5HT-4 receptor agonists (cisapride, tegaserod), dopamine-2 receptor antagonists (domperidone, metoclopramide), and motilin receptor agonists (erythromycin), have been considered when prokinetic effects on the

gastrointestinal tract are sought. However, to date, the agents that target these signaling pathways have had limited success due to low response rates and/or side effects.28-30 Agonism of 5HT-4 receptors in the digestive tract results in prokinetic effects beneficial in treating gastrointestinal motility problems; however, the same 5HT-4 receptors are found in the cardiac atria where agonism may result in arrhythmia, perhaps due to prolongation of the QT interval. Cisapride and tegaserod were both removed from the market due to concerns for cardiovascular effects. Dopamine antagonists have also had problems; domperidone has never been approved for use in the United States and metoclopramide, while still available, carries a “black box label” warning of the potential for tardive dyskinesia, and should not be used chronically. Erythromycin is available and does not have safety issues; however, it may not have sustainable effects due to tachyphylaxis.31 The outcome of medical treatment appears to be inversely related to patient age, with a larger fraction of infants resolving their gastroparesis when compared to children and adolescents.32

OPERATIVE MANAGEMENT Attention should be directed toward identifying the specific etiology of the gastric emptying problem, as some require prompt operative or metabolic intervention, while others require less specific, chronic management. The Ramstedt pyloromyotomy is the current standard of surgical management of hypertrophic pyloric stenosis and is the most frequently performed operative procedure on infants.33 Endoscopic balloon dilatation of the pyloric channel34 and medical therapy with intravenous atropine35 have also been described in the literature but are not considered to be the standard of care in most cases of HPS.

DUMPING SYNDROME While the more severe cases of dumping syndrome will present with dramatic glycemic alterations, toxic appearance, and syncope, presentation may be limited to more subtle signs, including irritability with feeding, and retching. Dumping syndrome should always be considered in children with feeding disorders who have had a fundoplication. A contrast study via gastrostomy or

nasogastric tube can quantify the volume of liquid the stomach will hold prior to emptying—in this situation, feedings should not exceed the volume demonstrated by the contrast study. Treatment of dumping syndrome may be considered chronic, as it involves long-term dietary changes with smaller, more frequent feedings and limited simple carbohydrates. For more severe dumping syndrome symptoms, use of octreotide (somatostatin) has been shown to provide marked relief in adults.36 Additionally, adding acarbose, starch, or glucomannan to the diet may reduce osmotic load and symptoms.37,38

ADMISSION AND DISCHARGE CRITERIA ADMISSION CRITERIA Toxic appearance or signs of severe dehydration on physical examination. Malnutrition apparent on physical examination or laboratory analysis. Screening studies indicating possible necessity for operative procedures.

DISCHARGE CRITERIA No requirement for supportive care. Resolved surgical issues. Outpatient plan of care.

CONSULTATION General pediatric surgery, depending on results of physical examination and results of screening radiographic studies. Gastroenterology if endoscopy or long-term nutritional management are required. Any of neurology, nephrology, endocrinology, infectious disease depending on any specific underlying diagnosis.

PREVENTION

The most effective prevention for disorders of gastric emptying is careful consideration of operative procedures that impair gastric function; most prominent among these is the fundoplication. In some patients, a feeding jejunostomy may provide similar airway protection to a fundoplication with decreased morbidity. Knowledge of medication side effects that could play a role in a patient’s symptoms is also of importance. KEY POINTS Disorders of gastric emptying may present with symptoms of a severity that merit hospitalization. The differential diagnosis includes inborn, acquired, and iatrogenic etiologies. Management is directed at both supportive care and direct operative intervention when applicable. Drug development continues to search for 5HT-4 agonists with selective gastrointestinal effects that lack detrimental cardiac effects.39 Aprepitant, a neurokinin 1 receptor antagonist, is currently available for the treatment of nausea—in adults, it has been effective for the treatment of gastroparesis-related nausea,40 but pediatric studies have not been carried out. Gastric pacing with implanted stimulators has also shown promise in adults with postoperative or diabetic gastroparesis, improving nausea without a discrete prokinetic effect.41,42 Pediatric studies are pending.

REFERENCES 1. Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology. 2003;227:319-331. 2. Noel RJ, Glock MS, Pranikoff T, et al. Nonobstructive antral web: an unusual cause of excessive crying in an infant. J Pediatr Gastroenterol Nutr. 2000;31:439-441. 3. Ormarsson OT, Haugen SE, Juul I. Gastric outlet obstruction caused by

heterotopic pancreas. Eur J Pediatr Surg. 2003;13:410-413. 4. Patel MP, Meisheri IV, Waingankar VS, et al. Duplication cyst of the pylorus–a rare cause of gastric outlet obstruction in the newborn. J Postgrad Med. 1997;43:43-45. 5. Wakhlu A, Sharma AK. Gastric outlet obstruction due to solitary gastric polyp in a neonate. Indian Pediatr. 1994;31:1299-1300. 6. Osuntokun B, Falcone R, Alonso M, et al. Duodenogastric intussusception: a rare cause of gastric outlet obstruction. J Pediatr Gastroenterol Nutr. 2004;39:299-301. 7. Morinville V, Bernard C, Forget S. Foveolar hyperplasia secondary to cow’s milk protein hypersensitivity presenting with clinical features of pyloric stenosis. J Pediatr Surg. 2004;39:E29-E31. 8. DuBose TMt, Southgate WM, Hill JG. Lactobezoars: a patient series and literature review. Clin Pediatr (Phila). 2001;40:603-606. 9. Gunsar F, Yilmaz S, Bor S, et al. Effect of hypo- and hyperthyroidism on gastric myoelectrical activity. Dig Dis Sci. 2003;48:706-712. 10. Ravelli AM. Gastrointestinal function in chronic renal failure. Pediatr Nephrol. 1995;9:756-762. 11. Asai T. Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids. Arzneimittelforschung. 1998;48:802805. 12. Bridges JW, Dent JG, Johnson P. The effects of some pharmacologically active amines on the rate of gastric emptying in rats. Life Sci. 1976;18:97-107. 13. Woodhouse KW, Bateman DN. Delayed gastric emptying with dothiepin. Hum Toxicol. 1985;4:67-70. 14. Inada T, Asai T, Yamada M, et al. Propofol and midazolam inhibit gastric emptying and gastrointestinal transit in mice. Anesth Analg. 2004;99:1102-1106, Table of Contents. 15. Sharma SS, Gupta YK. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale). J Ethnopharmacol. 1998;62:49-55. 16. Bhardwaj J, Wan DQ, Koenig MK, et al. Impaired gastric emptying and small bowel transit in children with mitochondrial disorders. J Pediatr

Gastroenterol Nutr. 2012;55:194-199. 17. Benini L, Todesco T, Dalle Grave R, et al. Gastric emptying in patients with restricting and binge/purging subtypes of anorexia nervosa. Am J Gastroenterol. 2004;99:1448-1454. 18. Spates ST, Cullen JJ, Ephgrave KS, et al. Effect of endotoxin on canine colonic motility and transit. J Gastrointest Surg. 1998;2:391-398. 19. Moirangthem GS, Singh NS, Bhattacharya KN, et al. Gastric outlet obstruction due to duodenal tuberculosis: a case report. Int Surg. 2001;86:132-134. 20. Di Lorenzo C, Orenstein S. Fundoplication: friend or foe? J Pediatr Gastroenterol Nutr. 2002;34:117-124. 21. Cooper WO, Griffin MR, Arbogast P, et al. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med. 2002;156:647-650. 22. Cooper WO, Ray WA, Griffin MR. Prenatal prescription of macrolide antibiotics and infantile hypertrophic pyloric stenosis. Obstet Gynecol. 2002;100:101-106. 23. Peled N, Dagan O, Babyn P, et al. Gastric-outlet obstruction induced by prostaglandin therapy in neonates. N Engl J Med. 1992;327:505-510. 24. Spinelli C, Bertocchini A, Massimetti M, et al. Muscle thickness in infants hypertrophic pyloric stenosis. Pediatr Med Chir. 2003;25:148150. 25. Mariani G, Boni G, Barreca M, et al. Radionuclide gastroesophageal motor studies. J Nucl Med. 2004;45:1004-1028. 26. Zangen T, Ciarla C, Zangen S, et al. Gastrointestinal motility and sensory abnormalities may contribute to food refusal in medically fragile toddlers. J Pediatr Gastroenterol Nutr. 2003;37:287-293. 27. Rodriguez L, Rosen R, Manfredi M, et al. Endoscopic intrapyloric injection of botulinum toxin A in the treatment of children with gastroparesis: a retrospective, open-label study. Gastrointest Endosc. 2012;75:302-309. 28. Tonini M, De Ponti F, Di Nucci A, et al. Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther. 1999;13:1585-1591.

29. Drolet B, Rousseau G, Daleau P, et al. Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders. Circulation. 2000;102:1883-1885. 30. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:10891096. 31. Dhir R, Richter JE. Erythromycin in the short- and long-term control of dyspepsia symptoms in patients with gastroparesis. J Clin Gastroenterol. 2004;38:237-242. 32. Rodriguez L, Irani K, Jiang H, et al. Clinical presentation, response to therapy, and outcome of gastroparesis in children. J Pediatr Gastroenterol Nutr. 2012;55:185-190. 33. Fujimoto T, Segawa O, Lane GJ, et al. Laparoscopic surgery in newborn infants. Surg Endosc. 1999;13:773-777. 34. Khoshoo V, Noel RA, LaGarde D, et al. Endoscopic balloon dilatation of failed pyloromyotomy in young infants. J Pediatr Gastroenterol Nutr. 1996;23:447-451. 35. Kawahara H, Imura K, Nishikawa M, et al. Intravenous atropine treatment in infantile hypertrophic pyloric stenosis. Arch Dis Child. 2002;87:71-74. 36. Scarpignato C. The place of octreotide in the medical management of the dumping syndrome. Digestion. 1996;57(Suppl 1):114-118. 37. Zung A, Zadik Z. Acarbose treatment of infant dumping syndrome: extensive study of glucose dynamics and long-term follow-up. J Pediatr Endocrinol Metab. 2003;16:907-915. 38. Kneepkens CM, Fernandes J, Vonk RJ. Dumping syndrome in children. Diagnosis and effect of glucomannan on glucose tolerance and absorption. Acta Paediatr Scand. 1988;77:279-286. 39. Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012;35:745-767. 40. Fahler J, Wall GC, Leman BI. Gastroparesis-associated refractory nausea treated with aprepitant. Ann Pharmacother. 2012;46:e38. 41. Lin Z, Sarosiek I, Forster J, et al. Two-channel gastric pacing in patients

with diabetic gastroparesis. Neurogastroenterol Motil. 2011;23:912e396. 42. Li FY, Jiang LS, Cheng JQ, et al. Clinical application prospects of gastric pacing for treating postoperative gastric motility disorders. J Gastroenterol Hepatol. 2007;22:2055-2059.

Liver Failure

CHAPTER

79

Scott A. Elisofon

BACKGROUND Liver failure, or hepatic failure, is a clinical condition that results from significant hepatocyte dysfunction or death. It differs from hepatitis in that patients must have uncorrectable coagulopathy in addition to hepatocyte injury, with or without encephalopathy. Hepatic failure is an acute process and should be differentiated from the acute decompensation of chronic liver disease. The strict criteria for acute or fulminant liver failure in adults include encephalopathy, coagulopathy, and evidence of hepatic dysfunction without prior evidence of liver disease, occurring within 8 weeks of the first symptoms of illness. Because encephalopathy is uncommon and difficult to identify in infants and young children, most clinicians use uncorrectable coagulopathy and hepatic dysfunction as clinical criteria for liver failure in this age group. Recognition of hepatic failure and its associated metabolic disturbances (Table 79-1) is crucial so that supportive therapy can be provided until recovery, or liver transplantation. Hepatic failure accounts for up to 15% of pediatric liver transplants in the United States each year. TABLE 79-1

Complications of Acute Hepatic Failure

Metabolic Hypoglycemia Hypokalemia Hypophosphatemia Hyponatremia

Neurologic Encephalopathy Cerebral edema Intracranial hemorrhage Acid–base imbalance Respiratory alkalosis Metabolic acidosis Hematologic Coagulopathy Disseminated intravascular coagulation Aplastic anemia Multiorgan dysfunction Gastrointestinal hemorrhage Ascites Pancreatitis Renal failure (hepatorenal syndrome) Shock Sepsis Respiratory failure Pulmonary hemorrhage Source: Modified with permission from Squires R. Liver failure. In: Rudolph CD, Rudolph AM, Hostetter MK, et al. eds. Rudolph’s Pediatrics. 21st ed. New York: McGraw-Hill; 2002:1513.

CLINICAL PRESENTATION NEONATES AND INFANTS Neonates and young infants can present with a range of symptoms, depending on the disease. Some infants are quite ill immediately after birth with coagulopathy and acidosis. This presentation is highly suggestive of hypoxic or ischemic injury, neonatal hemochromatosis, neonatal enteroviral infection, or some other intrauterine or perinatal insult. Laboratory tests may reveal elevated transaminases in the high hundreds to thousands (suggestive

of ischemia) and hyperbilirubinemia. Hypoglycemia may also be present. Clinical symptoms suggestive of sepsis, including hypotension and poor perfusion, may occur. Encephalopathy is recognizable in only one-third of these infants.1 Infants with neonatal hemochromatosis have intrauterine growth retardation, coagulopathy, hypoalbuminemia, ascites, mild transaminase elevation, and varying degrees of renal insufficiency.

CHILDREN AND ADOLESCENTS Children with acute hepatic failure also may present with a wide variety of symptoms. Those with infectious hepatitis may have fever, malaise, nausea, jaundice, and right upper quadrant pain. They may have been recently discharged from the emergency department or physician’s office with a diagnosis of hepatitis and elevated transaminases, jaundice, and a normal prothrombin time (PT). Many children improve (especially those with hepatitis A), but some return with rapidly worsening jaundice, and signs of coagulopathy such as petechiae, bruising, or bleeding. Mental status changes with encephalopathy may include reversal of the day–night sleep cycle, uncooperative behavior, delirium, stupor, or coma. The physical examination may reveal a shrunken liver. Patients with hypoxic or drug- or toxin-related injury may present with very high transaminase levels. Metabolic diseases typically present with high transaminase levels and hypoglycemia. Wilson disease presenting as acute hepatic failure is often accompanied by Coombs-negative hemolytic anemia.

DIFFERENTIAL DIAGNOSIS It is important to distinguish acute liver failure from acute hepatitis. The former involves an uncorrectable coagulopathy, with or without encephalopathy. The majority of patients who present clinically with hepatitis —elevated alanine transaminase (ALT), with or without jaundice, usually have normal synthetic function (normal PT, albumin)—but this condition can quickly progress to acute liver failure. The causes of acute hepatitis are therefore almost identical to those of acute liver failure. They include infections, metabolic and autoimmune diseases, and toxic injuries (Table 792). Infectious hepatitis is most frequently viral, with hepatitis A and Epstein-

Barr virus being the most common. In the United States, hepatitis B and C are uncommon causes of acute hepatitis in children.2 TABLE 79-2

Cause Infectious

Causes of Acute Hepatic Failure in Children Perinatal Period

Infancy

Childhood

Herpes simplex virus

Hepatitis A

Hepatitis A

Echovirus

Hepatitis B

Hepatitis B

Adenovirus

Epstein-Barr virus Hepatitis D

Hepatitis B

Non-A-E hepatitis Epstein-Barr virus Non-A-E hepatitis

Metabolic

Tyrosinemia

Tyrosinemia

Wilson disease

Galactosemia

Hereditary fructose intolerance

Autoimmune hepatitis

Neonatal Fatty acid hemochromatosis oxidation defects Mitochondrial disorders Autoimmune hepatitis Toxic

Medications

Medications

Herbs

Herbs

Miscellaneous Congenital heart disease

Congenital heart disease

Ischemia

Cardiac surgery

Cardiac surgery

Budd-Chiari syndrome

Severe asphyxia

Severe asphyxia

Malignancy

In addition to those with acute liver injury, patients with underlying liver disease may present with increasing transaminases, jaundice, and coagulopathy, with or without encephalopathy. This is referred to as an acute decompensation of chronic liver disease. Diseases that involve significant liver fibrosis, such as α1-antitrypsin deficiency, autoimmune hepatitis, primary sclerosing cholangitis, and Wilson disease, can present in this fashion. These patients need to be evaluated thoroughly, because many have clinical findings that are similar to those in acute liver failure. In addition, many have portal hypertension with thrombocytopenia. These two conditions can contribute to a higher risk of bleeding from esophageal varices, portal hypertensive gastropathy, or mucosal surfaces. In most cases of hepatic failure in children, the cause is unknown. The most common identifiable causes are infections, toxins (including drugs), metabolic diseases, and vascular or cardiac disease. Infections and toxins, especially acetaminophen, are thought to account for a large proportion of cases in the United States.3,4 Natural herbs, such as pennyroyal and kava, can also cause acute liver failure. The causes of fulminant hepatic failure are age dependent, as outlined in Table 79-2.

DIAGNOSTIC EVALUATION Liver failure presents differently according to age and cause. A careful history is always important to determine a time course of symptoms; identify exposures, such as infections, chemicals, or drugs; and uncover a family history of liver disease. In the case of ill infants, questions should focus on maternal infections (hepatitis B, human immunodeficiency virus, herpes simplex virus, enterovirus) and a family history of genetic or metabolic

diseases. The physical examination may direct the physician to specific investigations. Splenomegaly, ascites, or cutaneous spider angiomas suggest worsening of underlying chronic liver disease. Splenomegaly also may be present in acute processes, such as atypical viral infections or vascular events (e.g. hepatic vein thrombosis), but it is usually more suggestive of portal hypertension from chronic liver disease. Skin vesicles suggest systemic infection with agents such as herpes simplex virus. The liver may be enlarged, normal, or shrunken; a shrunken liver indicates significant hepatic necrosis. If Wilson disease is suspected, the patient should undergo a slitlamp ophthalmic examination to identify Kayser-Fleischer rings. All patients should undergo careful monitoring of liver synthetic and metabolic function (Table 79-3). Patients with hepatic failure usually have a PT greater than 18 to 20 seconds (international normalized ratio [INR] >1.5 to 2). Transaminases may be quite elevated, but the degree of hyperbilirubinemia can be more variable. TABLE 79-3

Test

Laboratory Evaluation in Acute Hepatic Failure Description

Hematology Complete blood count with platelets; differential; PT, PTT, INR Chemistry

AST, ALT, bilirubin (total, direct), alkaline phosphatase, GGTP, total protein, albumin, glucose, blood urea nitrogen, creatinine, electrolytes, ammonia

Infectious evaluation

HAV, HBV, HCV, Epstein-Barr virus Herpes simplex culture, fluorescent antibody of scraped vesicle or PCR (neonates) Enteroviral PCR (neonates) Maternal hepatitis B serologies (neonates)

Other studies Neonates Ferritin, lactate, pyruvate, plasma amino acids, urine and succinylacetone (tyrosinemia), urine organic acids, infants urine ketones, urine-reducing substances (galactosemia) Children

Antinuclear, anti-smooth muscle, anti-liver-kidney microsomal antibody; copper, ceruloplasmin, 24-hr urine copper, toxicology screen, acetaminophen level

ALT, Alanine transaminase; AST, Aspartate transaminase; GGTP, γ-glutamyl transpeptidase; HAV, Hepatitis A virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; INR, International normalized ratio; PT, Prothrombin time; PTT, Partial thromboplastin time; PCR, Polymerase chain reaction.

Ultrasonography of the abdomen with Doppler interrogation of the vessels can provide information about the size and consistency of the liver, patency of the biliary tree, presence of ascites, and patency of the hepatic veins to rule out hepatic vein thrombosis (Budd-Chiari syndrome).

MANAGEMENT Patients with isolated transaminase elevation and jaundice with no other signs of acute hepatic failure can be managed as outpatients with close follow-up. Any patient with dehydration secondary to vomiting or poor oral intake should be admitted for hydration, and any child with coagulopathy or mental status changes should be admitted and rapidly transferred to a tertiary center that has a pediatric intensive care unit and liver transplantation service. Most children who develop hepatic failure are extremely ill and require careful monitoring, often in an intensive care setting. Children may remain confused or slightly drowsy but have the potential to rapidly develop worsening encephalopathy, including coma. Children with early encephalopathy (within 7 days) after the first laboratory evidence of liver disease have a better prognosis than do patients with late encephalopathy.5 Close monitoring of mental status is crucial, because advanced stages of encephalopathy (stupor or coma) are associated with higher mortality. The cause of liver failure is important in terms of prognosis. Patients with acetaminophen overdose, autoimmune hepatitis, or hepatitis A virus infection

have a much higher survival rate than do those with hepatitis B or liver failure with an unknown cause. Mortality is usually due to the complications of hepatic failure. Cerebral herniation secondary to cerebral edema is the most common cause of death in children. Infection, either bacterial or fungal, is also a significant cause. Bleeding, especially gastrointestinal, is less common in children than adults, unless there is underlying chronic liver disease with esophageal or gastric varices from portal hypertension. In some cases, with or without specific therapy, the INR and mental status begin to improve as transaminase values decrease. However, falling transaminases with a rising INR and bilirubin suggest worsening hepatic necrosis and may indicate the need for liver transplantation. Even with a known cause of liver failure, many cases are irreversible at the time of diagnosis. Treatment remains mostly supportive. The key concepts in management are correction of metabolic abnormalities and prevention of potentially lethal complications such as bleeding, multiorgan failure, and cerebral edema. Major treatment strategies include the following: All noncritical medications and herbal supplements should be considered as possible causes or aggravating factors and discontinued. Patients with known acetaminophen ingestion should receive N-acetylcysteine. Infants with suspected galactosemia should have galactose-containing formulas withheld. If hypoxia or ischemia from cardiac surgery or cardiac insult is suspected, prompt support of perfusion and maintenance of normal blood pressure and oxygenation are crucial. Metabolic abnormalities, such as hypoglycemia, hypokalemia, and hypophosphatemia, should be corrected. Many children require infusions of 10% dextrose to remain euglycemic. Once dehydration is corrected, fluids should be restricted to approximately 75% maintenance to prevent fluid overload or contribution to cerebral edema. Renal function and urine output should be closely monitored. Coagulopathy should be treated initially with vitamin K, 1 mg/year of age up to 10 mg parenterally each day for 3 days. Products to improve clotting (fresh frozen plasma, cryoprecipitate, platelets) should be given only for significant bleeding or for prevention of bleeding during invasive procedures, because excess blood products can contribute to fluid

overload, and artificial correction of INR can make clinical assessment difficult. If the patient is having significant gastrointestinal bleeding and has evidence of portal hypertension (splenomegaly, ascites, spider angiomas), octreotide should be considered. Frequent neurologic examinations are warranted to detect encephalopathy. Sedatives, such as benzodiazepines, should be avoided because they can alter the patient’s mental status examination. Enteral lactulose may be used if fluid status is stable and electrolytes are normal. Blood counts must be monitored closely, because some children with acute hepatic failure develop aplastic anemia. Bone marrow failure may present at the onset of the acute liver disease, develop as the liver is improving, or even after a liver transplant. Patients should receive intravenous gastric acid suppressants to prevent gastrointestinal bleeding. Patients with hepatic failure are susceptible to bacterial infections. A sepsis evaluation should be performed and antibiotics provided if the patient develops fever or other clinical signs of infection, such as hypotension. Any infant or child with suspected herpes simplex virus infection should receive intravenous acyclovir. Some medications should be avoided, and others require dose adjustment in patients with significant liver injury. Consultation with a clinical pharmacist may be useful to determine appropriate medication dosages. Administration of N-acetylcysteine for non–acetaminophen-induced liver failure is not recommended, as studies in children have not shown the same benefit as in adults with liver failure.6,7

ADMISSION CRITERIA Dehydration or the inability to tolerate liquids by mouth. Encephalopathy or any mental status changes. Coagulopathy. Bleeding complications (most importantly, gastrointestinal bleeding).

DISCHARGE CRITERIA Steadily improving coagulopathy.

Normal mental status. Improving transaminases and bilirubin.

CONSULTATION Children with acute hepatitis should be seen by a pediatric gastroenterologist or hepatologist. If the child develops acute liver failure, the child should be immediately transferred to a tertiary referral center that has a liver transplant program.

SPECIAL CONSIDERATIONS PREVENTION There is no single preventive strategy for acute hepatic failure. All infants should be immunized for hepatitis B, and all children older than 1 year of age should be immunized for hepatitis A. If a virus is suspected, all caretakers should wear protective gowns, gloves, and masks. Any prescription or overthe-counter medication should be considered potentially hepatotoxic and discontinued promptly if evidence of significant hepatic dysfunction develops. KEY POINTS The majority of cases of acute liver failure have no identifiable cause. Infants or children with liver failure present with abnormal transaminases, jaundice, uncorrectable coagulopathy, and possibly mental status changes or hypoglycemia. Management of liver failure is largely supportive, including correction of metabolic disturbances, attention to coagulopathy, and rapid referral to tertiary care center for further evaluation and treatment. At this time, N-acetylcysteine should only be used for acetaminophen-induced liver injury.

REFERENCES 1. Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH. Characterization and outcomes of young infants with acute liver failure. J Pediatr. 2011;159(5):813-818 e811. 2. Centers for Disease and Control and Prevention. Surveillance for Acute Viral Hepatitis—United States, 2007. MMWR Morb Mortal Wkly Rep. 2009;58(SS-3). 3. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148(5):652-658. 4. Alonso EM, Squires RH, Whitington PF. Acute liver failure in children. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3rd ed. New York, NY: Cambridge University Press; 2007:71-96. 5. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273-275. 6. Squires RH, Dhawan A, Alonso E, et al. Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebocontrolled clinical trial. Hepatology. 2013;57(4):1542-1549. 7. Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856-864, 864 e851.

CHAPTER

80

Inflammatory Bowel Disease Michael C. Stephens and Subra Kugathasan

BACKGROUND Crohn’s disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are idiopathic, lifelong, destructive chronic inflammatory conditions of the gastrointestinal tract which typically manifest during late childhood and adolescence.1 The burden of these chronic relapsing diseases and their devastating effects imposed on affected children and teenagers may be considerable. IBD is divided into CD and UC based on clinical characteristics, although 5% to 24 % of patients do not clearly fit into either category and are termed inflammatory bowel disease–unspecified (IBD-U).2 Chronic inflammation in CD can involve any part of the gastrointestinal tract and is characterized by discontinuous inflammation with intervening areas of normal mucosa (skip lesions) and transmural inflammation, which can result in fistulae, perforations, and strictures. Finding of noncaseating granulomas histologically in the mucosal biopsies are hallmark of CD. Intestinal involvement of UC is limited to the colon and typically begins distally in the rectum and extends proximally. Inflammation in UC is superficial. The etiopathogenesis of IBD has been linked to a combination of genetic and environmental factors, but the exact cause remains elusive.3 Current thinking suggests patients with a genetically determined predisposition develop an immune-mediated response to an environmental trigger or intestinal microbial dysbiosis, which leads to chronic dysregulated inflammation.4 The early discovery of several genes, including CARD15 and the OCTN cation transporter associated with CD lends support to this hypothesis.5-7 Subsequent advances in the genetics of IBD have implicated many genes representing several aspects of intestinal homeostasis including

maintenance of the epithelial barrier, immune surveillance, neutrophil dysfunction, defects in innate immunity, and intracellular processes (e.g. autophagy, oxidative stress, carbohydrate metabolism).8 This highlights the fact that IBD represents a heterogeneous group of diseases beyond the clinical phenotypes of CD versus UC. Population-based studies suggest that IBD is unevenly distributed throughout the world, with the highest disease rates occurring in Western countries.9 Epidemiologic surveys have also suggested that IBD incidence rates have changed over the second half of the twentieth century, gradually increasing for both UC and CD.10-12 Recently an epidemiological study was completed which evaluated all children in Wisconsin with a new diagnosis of IBD over an 8-year period.13 The incidence of IBD was 9.5 per 100,000 in children under 18 years of age. The incidence of IBD was noted to be equal among all ethnic groups. Children from sparsely as well as densely populated counties were also equally affected. Over a 4-year period of follow-up, 17% of children with CD and 13% of those with UC required surgery. This epidemiologic data highlights the importance for pediatric hospitalists to be knowledgeable in the care of children with IBD.

CLINICAL PRESENTATION Patients with IBD can present with a diverse constellation of signs and symptoms. The clinical presentation of CD varies with the anatomic location(s) of involvement.1,14 In UC the clinical presentation typically is more predictable since intestinal involvement is limited to the colon. In both conditions, the severity of inflammation usually, but not always, correlates with the severity of the clinical presentation. It is likely that a primary care provider taking care of adolescents will be faced with a diagnosis of IBD one to three times a year, and a busy hospital-based pediatric gastroenterology practice will diagnose as many as one case per week.15 Recognition of the various clinical presentations of IBD can aid in early diagnosis and initiation of therapy. Symptoms in the patient presenting with IBD can include abdominal pain, hematochezia, diarrhea, anorexia, nausea, weight loss, fatigue, and oral ulcerations.14,16 Signs can include abdominal tenderness, perianal skin tags or fistulae, other fistulae, delayed puberty, iron deficiency anemia,

hypoalbuminemia, and signs of extra-intestinal complications. Laboratory tests frequently include an elevated ESR and C-reactive protein. IBD is a systemic disease with many extra-intestinal manifestations (Table 80-1). TABLE 80-1

Extra-Intestinal Manifestations of IBD

Skin Erythema nodosum Pyoderma gangrenosum Perianal disease Joints Arthlagia Arthritis Ankylosing spondylitis Eye Uveitis Episcleritis Conjunctivitis Liver Primary sclerosing cholangitis Hepatitis Cholelithiasis Bone Osteoporosis Mouth Cheilitis Stomatitis Aphthous ulcerations

Blood Iron deficiency anemia Anemia of chronic disease Thrombocytosis Autoimmune hemolytic anemia Vascular Vasculitis Thrombosis Kidney Nephrolithiasis Obstructive hydronephrosis Enterovesical fistula Urinary tract infection Amyloidosis Pancreas Pancreatitis Lung Pulmonary vasculitis Fibrosing alveolitis Growth Delayed growth Delayed puberty

DIFFERENTIAL DIAGNOSIS The evaluation of a patient with possible IBD should be based on clinical suspicion and initial laboratory testing that usually will indicate if definitive endoscopic and/or radiologic procedures are necessary. Stool studies to exclude intestinal infections that can cause diarrhea and rectal bleeding such as Salmonella, Shigella, Campylobacter, Yersinia, Escherichia coli 0157/H7, and Clostridia difficile are imperative. Other diagnostic considerations in adolescents with abdominal pain and rectal bleeding include HenochSchonlein purpura,17 Behçet’s disease18 (considered a form of IBD but beyond the scope of this chapter), hemolytic–uremic syndrome,19 or systemic vasculitis. When an abdominal abscess is found during the investigation of abdominal pain, in addition to CD, a perforated appendix, trauma and gynecologic diseases must be considered.

DIAGNOSIS AND EVALUATION The diagnosis of IBD is usually confirmed by a combination of clinical observations and laboratory, radiographic, endoscopic, and histological findings.1 A detailed history and physical examination remain the most important aspects in the evaluation of a child with abdominal pain. The most appropriate diagnostic approach often includes complete blood count, ESR, CRP, albumin, and stool specimens to rule out bacterial and protozoal pathogens. Endoscopic examinations (upper endoscopy and colonoscopy) with mucosal biopsies to directly examine the mucosa are key components to confirm the diagnosis (Figure 80-1). An upper GI series with small bowel follow through is the primary tool for evaluation of the jejunum and proximal ileum. However, in the hospitalized patient, a CT scan20 may be an important early step to rule out other important diseases such as appendicitis, and can reveal signs that may suggest CD21 (e.g. “creeping fat” in the mesentery). Other tests that have been useful in selected patients who may have occult small bowel CD include enteroclysis, MRI (enterography), and WBC scanning.22-24 Capsule endoscopy may prove to be the most sensitive way to assess the small bowel.25-27 The use of capsule endoscopy requires careful consideration, because there is a risk of impaction of the instrument in patients with narrowing of the intestines, which could necessitate surgery.

This is a particularly important issue in the smaller child. Table 80-2 describes the suggested initial diagnostic evaluation in child with suspected IBD. A commercial serologic panel has been added to the armamentarium of the laboratory evaluation of patients with suspected IBD28,29 (pANCA, ASCA, and OmpC). This panel may be a useful adjunct to conventional laboratory tests, but it has not replaced the need for definitive examinations such as endoscopy or radiologic evaluations.

FIGURE 80-1. Photos from a colonoscopy showing (a) a normal appearing colon and (b) a colon from a patient with severe ulcerative colitis, which reveals serpiginous deep ulcerations along with pseudopolyps as a result of chronic inflammation.

TABLE 80-2

Diagnostic Evaluation of the Child with Suspected IBD

Laboratory studies CBC with differential, reticulocyte count Sedimentation rate Total protein, albumin Aminotransferases, alkaline phosphatase, bilirubin Serum iron, ferritin Stool cultures For bacteria (including E. coli 0157/H7) C. difficile Stools for ova and parasites Radiological Upper GI series with small bowel follow through Abdominal and pelvic MRE scan or CT scan, if abscess is suspected WBC scan, if small bowel disease is suspected Endoscopy Upper endoscopy, colonoscopy, ileoscopy, and biopsies Video-capsule endoscopy (Pillcam) MRE, magnetic resonance enterogram

MANAGEMENT Initial management of the patient hospitalized with IBD must be tailored to the degree of illness the patient is exhibiting. Primary interventions should be directed toward stabilizing the patient and ensuring emergent surgical intervention is not required while the evaluation proceeds. Intravenous fluids and/or transfusions may be required in the dehydrated or anemic patient. Careful attention to hydration status is critical in the patient with significant hypoalbuminemia. When appendicitis or other surgical emergencies are considered in the differential diagnosis, it is prudent to withhold oral intake

and administer IV broad-spectrum antibiotics that cover intestinal flora (e.g. ampicillin + aminoglycoside + metronidazole). In less ill patients, oral intake can be permitted while the evaluation proceeds. Diet may need to be tailored to the patients’ individual needs. Patients with upper intestinal CD can have a secondary disaccharidase deficiency30 and require a low-carbohydrate/lactose-free diet. In patients with significant intestinal narrowing either from inflammation or stricture, a liquid diet may be better tolerated.31,32 Careful attention to nutritional status is important in managing IBD in children. Quantifying caloric intake can help the physician determine the best intervention.33,34 Enteral nutrition is preferable to parenteral but the route is dictated by the degree of illness. Advances in medical therapy have revolutionized the management of IBD and have reduced the need for hospitalization.35 As with any chronic disease, a cooperative approach between the subspecialist and primary care physician is critical. Since there is no cure for IBD, the goal of therapy is to induce and maintain sustained remission from disease activity. Corticosteroids are typically reserved only for brief, acute therapy to control symptoms, and are avoided for maintenance therapy because of their long-term side effects and lack of long-term efficacy.36-38 In the United States, corticosteroids are frequently used to alleviate symptoms in the hospitalized patient presenting with IBD or with an acute flare in the known patient. Budesonide, a newer generation corticosteroid that may have fewer adverse effects is effective in CD involving the distal ileum and proximal colon.39 Nutritional therapy, using exclusive elemental or polymeric formula often administrated by nasogastric tube as the primary source of nutrition, has been shown to reduce inflammation and is the front-line therapy of choice in many Canadian and European IBD centers.33,34,40 Because children tend to oppose the use of liquid diet as an exclusive source, and daily use of nasogastric tube, this treatment modality has not gained as much popularity in the United States. Surgical management remains an important component of IBD therapy. Colectomy must be considered in the patient with colitis unresponsive to medical management, steroid-dependent or longstanding disease, given the risk of malignancy.41 Emergent colectomy can be necessary in patients who develop toxic megacolon. The patient with severe colitis is at increased risk of developing toxic megacolon following a colonoscopy. Surgery may be required in patients with CD who develop strictures, fistulae, abscesses, and

intestinal perforation. There is a high risk of recurrence following surgery for CD and medical therapy should not be discontinued following a surgically created state of remission.42

SPECIFIC GUIDANCE REGARDING CHILDREN WITH ACUTE SEVERE COLITIS Until recently, there was some controversy and a lack of guidance about the timing of second-line rescue medical therapy and/or surgical intervention in children hospitalized with severe colitis. Guidelines for the care of a child with acute severe colitis were published in 2011 and outline the most appropriate strategy for managing hospitalized patients.43 If the hospitalization represents the patient’s initial presentation of IBD, an appropriate workup is required and needs to be tailored to the individual patient’s ability to tolerate the evaluation (e.g. sigmoidoscopy vs. colonoscopy in a severely colitic child). On admission, exclusion of infection by stool culture and testing for Clostridium difficile is essential even in patients with known IBD. Caregivers should monitor the patient’s clinical progress using common clinical indices (frequent monitoring of vital signs, stool output and hydration status, CBC, electrolytes, albumin, CRP) and should calculate a daily Pediatric Ulcerative Colitis Disease Activity Index (PUCAI).44 The elements of the PUCAI are outlined in Table 80-3, and a score of at least 65 points represents severe colitis (moderate 35–60, mild 10– 30, and remission 8

0 5 10 15

Nocturnal bowel movements No Yes

0 10

Activity level No limitation of activity Occasional limitation Severely restricted activity

0 5 10

The PUCAI can be used to monitor the patient’s response to therapy. Initial rescue therapy is typically IV corticosteroids but in some cases an antiTNF agent may be chosen (for example, when it is anticipated the patient will need anti-TNF therapy for maintenance). Early planning for second-line therapy should be automatic and will allow the patient and family to be prepared for this possibility. In patients whose PUCAI remains greater than 45 at day 3 this planning should be already in progress, anticipating a second intervention at day 5. This includes considering a sigmoidoscopy to exclude cytomegalovirus (CMV) colitis, appropriate screening for second-line therapy (e.g. testing for tuberculosis in patients for whom anti-TNF therapy is

being considered) and consultation with a surgeon if not already done. If the patient’s PUCAI is >65 points at day five, the planned second-line intervention should be undertaken. Medical options under these circumstances are anti-TNF or calcineurin inhibitors. Patients who are started on calcineurin inhibitors should receive prophylaxis for Pneumocystis species. Colectomy is an alternative option at this point to a second medical therapy, and should have been discussed with the family in planning for this scenario. If a second medical intervention is employed, persistently severe disease warrants colectomy at day 11–14. A third medical therapy is NOT recommended. Delaying surgery to optimize nutritional status is likewise not recommended under these circumstances.

THROMBOSIS Adult guidelines recommend prophylaxis for thrombosis in patients hospitalized with IBD.45 The 2011 pediatric guidelines do not recommend prophylaxis in children, citing a lack of evidence demonstrating a favorable benefit-to-risk ratio.43 A recent publication by Zitomersky et al. demonstrated that children with IBD have an increased risk of thrombosis and recommended a risk stratification approach using prophylaxis in a subgroup of higher risk patients.46

MEDICATION SIDE EFFECTS Many maintenance therapies are available and it is important to be familiar with the side effects and toxicities associated with them. Table 80-4 provides a partial list of the common agents and their side effects. Options include 5aminosalicylate (5-ASA) agents such as mesalamine, antibiotics such as metronidazole, immunomodulating agents including thiopurines (azathioprine or 6-mercaptopurine), methotrexate, infliximab (a monoclonal antibody that binds free and receptor bound TNF-α), cyclosporine, tacrolimus, and mycophenolate. The 5-ASA agents provide sustained remission in only a minority of patients,47,48 primarily mild to moderate UC. The thiopurine analogues (azathioprine or 6-mercaptopurine) are frequently used for maintenance of remission.49 Common side effects of thiopurines include bone marrow suppression, hepatotoxicity, pancreatitis, and

hypersensitivity.50 It has been recognized that patients with genetic polymorphisms in thiopurine methyltransferase can be at greater risk for bone marrow suppression.51 Testing for thiopurine methyltransferase (TPMT) insufficiency is now the accepted standard of practice prior to starting a thiopurine. Patients taking immunomodulating medications may be at increased risk for infections or malignancy.52,53 In addition to the commonly known side effects, the hospitalist should be aware that immunosuppressive medications may mask the presentation of significant intra-abdominal infection or sepsis. Patients may initially present with minimal symptoms and even a benign exam, so clinical suspicion is important and the threshold to image must be low in these situations. TABLE 80-4

Common Side Effects/Adverse Reactions to IBD Drugs

5-Aminosalicylates

Allergic reactions Interstitial nephritis Colitis exacerbation Agranulocytosis

Corticosteroids

Adrenal suppression Cushingoid features Diabetes Hypertension Osteoporosis Cataracts Mood effects Growth retardation

Thiopurines (6-mercaptopurine, azathioprine)

Bone marrow suppression Hepatitis Pancreatitis Allergic reactions

Methotrexate

Bone marrow suppression

Hepatitis Nausea Anti-TNF biologics Infliximab Adalimumab Certolizumab Golimumab

Infusion reactions Autoantibody formation Antibodies against the medication Invasive infections Reactivation of quiescent tuberculosis Lupus-like reaction CNS vasculitis

Metronidazole

Neuropathy Yeast infections Coated tongue

Cyclosporine

Renal toxicity Anaphylaxis Seizures Hypertension Hirsutism Gum hyperplasia

SUGGESTED ADMISSION CRITERIA Indications for hospitalization include: Unexplainable fever with worsening abdominal symptoms. Signs of intestinal obstruction or unclear diagnosis and/or alternate considerations may require surgery or IV antibiotics or other therapy best started in an inpatient setting. Active disease refractory to outpatient oral therapy. Significant gastrointestinal blood loss leading to anemia with potential

need for transfusion. Inability to maintain hydration orally.

SUGGESTED DISCHARGE CRITERIA Ability to tolerate oral/ng diet and maintain hydration and positive nutritional balance. Stable or improving signs and symptoms of active disease (e.g. hemoglobin, stool output). Reliable outpatient follow-up and family able to manage therapy and recovery at home.

THE FUTURE OF IBD Despite the use of anti-inflammatory and immunomodulatory therapies, investigators continue to look for the ideal IBD therapy. Such therapies should be very effective in inducing remission as well as prevention of relapses, while exerting minimal toxicity. Newer therapies are aimed at either selectively blocking detrimental mucosal immune responses and/or decreasing the levels of luminal antigens. The successful introduction of biological therapies, such as monoclonal antibodies against TNF-α, have opened a new field of research and possibilities. Infliximab is an example of this novel approach that has been shown to be very effective in CD. New humanized agents are being designed to target the production of cytokines, adhesion molecules, and the modulation of tissue architecture. Similar to trials for multiple sclerosis, bone marrow ablation, and stem cell transplantation for severe CD is being studied as well. The challenge and hope for the future remains the development of treatments that can alter the natural history of the disease.

SUGGESTED READINGS Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol. 2001;96:21692176. Escher JC, Taminiau JA, Nieuwenhuis EE, Buller HA, Grand RJ. Treatment

of inflammatory bowel disease in childhood: best available evidence. Inflamm Bowel Dis. 2003;9:34-58. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115:182-205. Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. Growth and clinical course of children with Crohn’s disease. Gut. 1993;34:939-943. Griffiths, et al. Inflammatory bowel disease. In: Walker WA, et al., eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Hamilton, Ontario: B.C. Decker, 2000:613-651. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146:35-40. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998;115:813-821. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr. 2003;143:525-531. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417429. Shashinder H, Integlia MJ, Grand RJ. Clinical Manifestations of Pediatric Inflammatory Bowel Disease. Sanders; 2000.

REFERENCES 1. Shashinder H, Integlia MJ, Grand RJ. Clinical manifestations of pediatric inflammatory bowel disease. In: Inflammatory Bowel Disease. 5th ed. Philadelphia, PA: Sanders; 2000. 2. Geboes K, De Hertogh G. Indeterminate colitis. Inflamm Bowel Dis. 2003;9(5):324-331. 3. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115(1):182-205. 4. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347(6):417-429.

5. Cho JH. The Nod2 gene in Crohn’s disease: implications for future research into the genetics and immunology of Crohn’s disease. Inflamm Bowel Dis. 2001;7(3):271-275. 6. Stoll M, et al. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet. 2004;36(5):476-480. 7. Peltekova VD, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004;36(5):471475. 8. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307-317. 9. Binder V. Epidemiology of IBD during the twentieth century: an integrated view. Best Pract Res Clin Gastroenterol 2004;18(3):463-479. 10. Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of inflammatory bowel disease within the United States. Gastroenterology. 1991;100(1):143-149. 11. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut. 1989;30(5):618-622. 12. Calkins BM, Mendeloff AI. Epidemiology of inflammatory bowel disease. Epidemiol Rev. 1986;8:60-91. 13. Adamiak T, et al. Incidence, clinical characteristics, and natural history of pediatric IBD in Wisconsin: a population-based epidemiological study. Inflamm Bowel Dis. 2013;19(6):1218-1223. 14. Kugathasan S, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr. 2003;143(4):525-531. 15. Fish D, Kugathasan S. Inflammatory bowel disease. Adolesc Med Clin. 2004;15(1):67-90, ix. 16. Heyman MB, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146(1):35-40. 17. Ballinger S. Henoch-Schonlein purpura. Curr Opin Rheumatol.

2003;15(5):591-594. 18. Kasahara Y, et al. Intestinal involvement in Behcet’s disease: review of 136 surgical cases in the Japanese literature. Dis Colon Rectum. 1981;24(2):103-106. 19. Del Beccaro MA, et al. Outbreak of Escherichia coli O157:H7 hemorrhagic colitis and hemolytic uremic syndrome: effect on use of a pediatric emergency department. Ann Emerg Med. 1995;26(5):598-603. 20. Johnson GL, Johnson PT, Fishman EK. CT evaluation of the acute abdomen: bowel pathology spectrum of disease. Crit Rev Diagn Imaging. 1996;37(3):163-190. 21. Siegel MJ, Evans SJ, Balfe DM. Small bowel disease in children: diagnosis with CT. Radiology. 1988;169(1):127-130. 22. Antes G. Enteroclysis in children with Crohn’s disease. Eur Radiol. 2001;11(11):2341-2342. 23. Charron M. Pediatric inflammatory bowel disease imaged with Tc-99m white blood cells. Clin Nucl Med. 2000;25(9):708-715. 24. Guidi L, et al. Clinical correlations of small bowel CT and contrast radiology findings in Crohn’s disease. Eur Rev Med Pharmacol Sci. 2004;8(5):215-217. 25. Kornbluth A, Legnani P, and Lewis BS. Video capsule endoscopy in inflammatory bowel disease: past, present, and future. Inflamm Bowel Dis. 2004;10(3):278-285. 26. Seidman EG, Sant’Anna AM, Dirks MH. Potential applications of wireless capsule endoscopy in the pediatric age group. Gastrointest Endosc Clin N Am. 2004;14(1):207-217. 27. Mow WS, et al. Initial experience with wireless capsule enteroscopy in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2004;2(1):31-40. 28. Dubinsky MC, et al. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol. 2001;96(3):758-765. 29. Ruemmele FM, et al. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology. 1998;115(4):822-829.

30. Pfefferkorn MD, et al. Lactase deficiency: not more common in pediatric patients with inflammatory bowel disease than in patients with chronic abdominal pain. J Pediatr Gastroenterol Nutr. 2002;35(3):339-343. 31. Sakurai T, et al. Short-term efficacy of enteral nutrition in the treatment of active Crohn’s disease: a randomized, controlled trial comparing nutrient formulas. JPEN J Parenter Enteral Nutr. 2002;26(2):98-103. 32. Korelitz BI. The role of liquid diet in the management of small bowel Crohn’s disease. Inflamm Bowel Dis. 2000;6(1):66-67; discussion 68-69. 33. Forbes A. Review article: Crohn’s disease–the role of nutritional therapy. Aliment Pharmacol Ther. 2002;16(Suppl 4):48-52. 34. Griffiths AM. Enteral nutrition in children. Nestle Nutr Workshop Ser Clin Perform Prog. 1999;2:171-83; discussion 183-186. 35. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology. 2004;126(2):402-413. 36. Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. Growth and clinical course of children with Crohn’s disease. Gut. 1993;34(7):939-493. 37. Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf. 2000;23(5):429-448. 38. Tripathi RC, Kipp MA, Tripathi BJ, et al. Ocular toxicity of prednisone in pediatric patients with inflammatory bowel disease. Lens Eye Toxic Res. 1992;9(3-4):469-482. 39. Kundhal P, Zachos M, Holmes JL, Griffiths AM. Controlled ileal release budesonide in pediatric Crohn disease: efficacy and effect on growth. J Pediatr Gastroenterol Nutr. 2001;33(1):75-80. 40. Ruemmele FM, Roy CC, Levy E, Seidman EG. Nutrition as primary therapy in pediatric Crohn’s disease: fact or fantasy? J Pediatr. 2000;136(3):285-291. 41. Escher JC, Taminiau JA, Nieuwenhuis EE, Büller HA, Grand RJ. Treatment of inflammatory bowel disease in childhood: best available evidence. Inflamm Bowel Dis. 2003;9(1):34-58. 42. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol.

2001;96(7):2169-2176. 43. Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol. 2011;106(4):574-588. 44. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133(2):423-432. 45. Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology. 2014. 46. Zitomersky NL, Levine AE, Atkinson BJ, et al. Risk factors, morbidity, and treatment of thrombosis in children and young adults with active inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2013;57(3):343-347. 47. Sutherland LR. Prevention of relapse of Crohn’s disease. Inflamm Bowel Dis. 2000;6(4):321-328; discussion 329. 48. Sutherland L, Parker CE, Feagan BG, MacDonald JK. Oral 5aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2002; (4): CD000544. 49. Markowitz J, Grancher K, Kohn N, Daum F. Immunomodulatory therapy for pediatric inflammatory bowel disease: changing patterns of use, 1990-2000. Am J Gastroenterol. 2002;97(4):928-932. 50. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998;115(4):813-821. 51. Paerregaard A, Schmiegelow K. Monitoring azathioprine metabolite levels and thiopurine methyl transferase (TPMT) activity in children with inflammatory bowel disease. Scand J Gastroenterol. 2002;37(3):371-372. 52. Markowitz JF. Therapeutic efficacy and safety of 6-mercaptopurine and azathioprine in patients with Crohn’s disease. Rev Gastroenterol Disord. 2003;3(Suppl 1):S23-S29.

53. Kirschner B. Malignancy and aneuploidy: prevention and early detection. Inflamm Bowel Dis. 1998;4(3):216-220.

CHAPTER

Malnutrition

81

Jennifer Maniscalco

BACKGROUND Malnutrition refers to disorder of nutritional status from either a deficiency or excess (i.e. imbalance) of energy, protein, and/or other nutrients that lead to adverse effects on tissue and body form and function as well as adverse clinical outcomes.1 Malnutrition therefore includes undernutrition, overweight, and obesity. Despite significant advances in prevention and treatment worldwide, malnutrition continues to have a substantial negative impact on child morbidity and mortality.2 The prevalence of undernutrition among hospitalized children in the United States and other resource-rich countries may be as high as 50%, but it varies considerably by age and disease state.3-6 The presence of undernutrition, overweight, and obesity among hospitalized children has also been associated with an increased risk of adverse clinical events, prolonged length of stay, and increased hospital charges and costs.3-7 This chapter addresses undernutrition, focusing on problems relating to inpatient care. Chapter 23 addresses failure to thrive.

PATHOPHYSIOLOGY Pediatric undernutrition is defined as an imbalance between nutrient requirement and intake, resulting in cumulative deficits of energy, protein, or micronutrients that may negatively affect growth, development, and other outcomes.6 Undernutrition is often related to environmental or behavioral factors. However, many hospitalized children have illness-related malnutrition, with one or more conditions directly resulting in a nutrient imbalance. This occurs as a result of decreased nutrient intake, altered utilization, excessive nutrient losses, or increased nutrient requirements not

matched by intake.6 Furthermore, illness-related malnutrition is often associated with an inflammatory component, which may increase nutrient requirements and promote a nutrient-wasting catabolic state. The presence and severity of the inflammatory state may also impair the effectiveness of therapeutic nutrition interventions. Secondary complications include compromised immune function, impairments of gastrointestinal (GI) tract function, suboptimal response to medical or surgical therapy, and abnormal cognitive and behavioral development.3,6

CLINICAL PRESENTATION AND CLASSIFICATION Physical examination findings in children with malnutrition are variable and related to the chronicity, severity, and type of nutrient imbalance. Table 81-1 lists some of the findings associated with deficiencies of both macro- and micronutrients. Excessive intake of nutrients from overfeeding or unbalanced dietary intake can also result in abnormal physical examination findings, such as increased subcutaneous fat. Abnormal growth ultimately occurs in all patients with ongoing undernutrition, and in some cases it may be the only objective marker of poor nutritional status. Careful anthropometric measurements can assess growth cross-sectionally (e.g. triceps skinfold thickness) or longitudinally (length or height). TABLE 81-1

Physical Examination Findings Associated with Macro- and Micronutrient Deficiencies

Finding

Nutrient Deficiency

General Short stature

Calorie

Decreased subcutaneous fat

Calorie

Muscle wasting

Protein, calorie

Muscle tenderness

Thiamine, biotin

Edema, ascites

Protein, thiamine

Hepatosplenomegaly

Protein

Hair Alopecia or sparse hair

Protein, zinc, biotin, copper

Easy pluckability

Protein

Flag signs (bands of light and dark hair)

Protein

Skin Follicular hyperkeratosis

Vitamins A, C

Dermatitis

Niacin, zinc, biotin, vitamin B6

Poor wound healing

Protein, zinc, vitamins A and C

Dry, xerosis

Essential fatty acids

Petechiae, purpura

Vitamins C, K

Nails Koilonychia (spoon shaped)

Iron

Transverse ridging

Protein

Dry, brittle

Essential fatty acids

Eyes Xerophthalmia, Bitot spots (conjunctival spots), night blindness

Vitamin A

Angular palpebritis

Riboflavin

Oropharynx Dental caries

Fluoride

Cheilosis

Riboflavin, niacin, vitamin B6

Glossitis

Riboflavin, niacin, pyridoxine, folate, vitamin B12

Angular stomatitis

Riboflavin, niacin, iron, vitamins B6 and B12

Hypogeusia (reduced ability to taste)

Zinc

Bleeding gums

Vitamin C

Bone Craniotabes, rachitic rosary, bowing Vitamin D of legs Bone tenderness

Vitamin C

Nervous system Neuropathy (weakness, paresthesias)

Niacin, thiamine, copper, vitamins B6, B12, and E

Dementia

Niacin

Seizures

Vitamin B6

Miscellaneous Goiter

Iodine

Historically, physical findings and anthropometry have been used to divide patients with malnutrition into two broad categories: marasmus and

kwashiorkor.8 Marasmus develops after chronic and severe calorie deprivation, resulting in weight loss and marked wasting of fat and muscle stores. Because visceral protein stores are generally preserved, edema does not develop. Although both height and weight measurements are abnormally low, weight is often decreased out of proportion to height. Kwashiorkor develops in acute or chronic situations when protein deficits exceed caloric deficits. Decreased visceral protein stores result in muscle wasting, edema, and changes in the skin and hair. Although some degree of growth failure is likely, weight may appear normal for height due to fluid retention. More recently, the term protein–energy malnutrition has been used to describe states of malnutrition in which there are interrelated deficiencies in carbohydrates, proteins, and fat, as well as vitamins, minerals, and trace elements. As a consequence of these multinutrient imbalances, children may have a combination of physical signs.

DIAGNOSIS AND EVALUATION Nutrition screening can identify individuals who are malnourished or at risk for malnutrition to determine whether a more detailed assessment of nutrition is indicated.3 Several formal screening tools have been studied and validated in hospitalized pediatric patients, and risk factors for malnutrition have been identified (Table 81-2).5,6 The presence of one or more of these risk factors should prompt a comprehensive evaluation using the history, physical examination, anthropometric measurements, and laboratory data to define nutritional status and develop a proper nutrition care plan. TABLE 81-2

Risk Factors for Malnutrition

Recent unintentional weight loss of >10% Weight 20% over or under ideal body weight No oral intake for >7 days Any medical condition resulting in the following: Inadequate intake (e.g. oromotor or swallowing dysfunction, anorexia) Malabsorption (e.g. cystic fibrosis, short gut syndrome)

Increased metabolic needs (e.g. CHD, BPD, trauma, burns) Protracted nutrient losses (e.g. vomiting, diarrhea, skin wounds) Medications with catabolic properties (e.g. steroids, chemotherapy) BPD, bronchopulmonary dysplasia; CHD, congenital heart disease.

The medical history should include use of any dietary supplements, a careful recall diet history, and a detailed psychosocial history. Special emphasis should be placed on conditions or medications that impair the ability to ingest and absorb food or that might result in high metabolic demands. The dietary history should focus on the type and preparation of food or formula, the amount and frequency of feedings, and the route of feeding. Prospectively, a 3- to 5-day diet diary can provide an objective and accurate method of assessing dietary intake in the home setting and may be an important part of discharge recommendations. Important psychosocial factors include adequacy of resources to purchase, store, and prepare food; level of parental knowledge and skills; drug and alcohol use or mental illness among caregivers; and potential child abuse or neglect. A thorough physical examination and precise anthropometric measurements provide convenient and noninvasive methods for evaluating both acute and chronic nutritional status. Basic measurements include weight, height (for children aged 2 years or older) or recumbent length (for those younger than 2 years), and head circumference (children younger than 2 years). Body mass index (BMI) is the best measure of adiposity and is commonly used to define underweight, overweight, and obesity in children older than 2 years. It is calculated by the following formula:

The use of published charts as reference standards for growth varies by the age and condition of the child. For children up to 2 years of age who are measured in the supine position for length, use of the 2006 World Health Organization (WHO) charts is recommended.9 For children and adolescents aged 2 to 20 years who are measured with a standing height, the 2000 Centers for Disease Control and Prevention charts are recommended.10 Reference values for children with special health care needs are also available. Experts

recommend using z scores, which express in standard deviation units how far a child’s measurements are from the mean of the population reference standard.6 The weight-for-height value is the ratio of the patient’s actual weight to the ideal weight for the patient’s height. When acute medical conditions result in short-term nutritional deprivation, the body weight is depleted out of proportion to height (or length), and the weight-for-height value is low. Conversely, chronic malnutrition affects both weight gain and linear growth, resulting in a small child with a body weight that is more proportional to height (or length). The Waterlow criteria use the weight-for-height value and a similar measure, the height-for-age value, to differentiate and classify acute and chronic malnutrition (Table 81-3).11 Chronic malnutrition is often characterized by a height-for-age that is less than −2 z scores.6 TABLE 81-3

Waterlow Criteria for the Classification of Malnutrition

Acute Malnutrition (Weight for Height, % Category Median)

Chronic Malnutrition (Height for Age, % Median)

Normal

>90

>95

Mild

80–90

90–95

Moderate

70–80

85–90

Severe

5 nuclear lobes). Folic acid is naturally found in fruits and vegetables and cow’s milk, and deficiency is normally limited to those patients with selfimposed dietary restrictions (e.g. consumption of only unfortified goat’s milk or a diet devoid of fruits and vegetables). Serum or RBC folate levels can be assayed; the latter is less susceptible to short-term fluctuation and more reflective of tissue stores. Vitamin B12 is present in animal products, so a dietary basis for vitamin B12 deficiency is usually limited to strict vegans. Vitamin B12 and folate deficiencies can also result from malabsorption. In contrast to folate, however, vitamin B12 absorption depends on the activity of a gastric-derived cofactor (intrinsic factor); therefore, vitamin B12 deficiency can be due to a lack of intrinsic factor (e.g. pernicious anemia) rather than simple dietary deficiency or malabsorption. It is important to establish that vitamin B12 is the cause of the megaloblastic anemia, because irreversible neuropathy often accompanies vitamin B12 deficiency, making timely diagnosis and treatment critical.

DISORDERS OF RED CELL DESTRUCTION: THE HEMOLYTIC ANEMIAS Hemolytic anemias result from the accelerated destruction of RBCs and should be suspected when there are signs of hemolysis such as jaundice, hyperbilirubinemia, organomegaly, dark urine, and reticulocytosis. RBCs normally survive for 4 months, so any cause of premature destruction can result in anemia, particularly when bone marrow production fails to keep pace with the destructive process. Hemolytic anemias result from factors

either intrinsic or extrinsic to the RBC. In general, intrinsic defects are inherited, whereas extrinsic causes are usually acquired. Inherited hemolytic anemias can be caused by defects in the erythrocyte membrane (e.g. spherocytosis), defects in globin genes (e.g. sickle cell anemia, thalassemia, unstable hemoglobin), or defects in RBC metabolism (e.g. pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency). A directed family history is critical in the workup of patients with hemolytic anemias since family members will often share a history of anemia or side effects of anemia. The primary causes of extrinsic destruction of RBC in children are immune-mediated; these include autoimmune hemolytic anemia and alloimmune hemolytic anemia (hemolytic disease of the newborn). Microangiopathy can also result in significant anemia; these include typical and atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation.

INHERITED HEMOLYTIC ANEMIAS Hemoglobinopathies Many abnormal hemoglobin variants result in premature destruction of the RBC by relative insolubility and precipitation of hemoglobin in the red cell cytoplasm. Hemoglobin precipitation somehow leads to less deformable RBC membranes, resulting in accelerated splenic clearance of the affected cells. Hemoglobin defects can result from either unbalanced expression of α- and β-globin genes (thalassemias) or mutations of the globin genes themselves (e.g. sickle cell, hemoglobin C, hemoglobin E, unstable hemoglobins). Although abnormal RBC morphology is a common finding in hemoglobinopathy, hemoglobin evaluation by electrophoresis, sequencing, and other tests, along with Heinz body testing (which detects hemoglobin precipitation in RBCs), is the preferred method of diagnosing this group of hemolytic anemias. Certain hemoglobin disorders such as α-thalassemia trait are difficult to detect even by electrophoresis. Other than the detection of a small amount of Bart’s hemoglobin at birth, electrophoresis is virtually normal in those with silent α-thalassemia trait and carriers, and these individuals are usually diagnosed by genetics or by sequencing the α-globin loci. Consideration should be paid to children with genetic origins in parts of the world with a high incidence of thalassemia. Sickle cell disease and some thalassemias are diagnosed via standard newborn screening of children in the United States; however, the less

common thalassemias may not be detected. In addition, children born in locations without newborn screening may present with undiagnosed sickle cell disease or thalassemia. Owing to its high incidence and special management considerations, sickle cell anemia is discussed separately. Abnormalities of the Red Blood Cell Membrane The most common genetic RBC membrane abnormality is hereditary spherocytosis, which is usually inherited dominantly and results from defects in membrane proteins that bridge the actin cytoskeleton and the phospholipid bilayer.24 Defective membrane–protein interactions lead to the loss of small segments of the lipid membrane, resulting in spherocytic red cells that have lost their biconcave discoid shape and have an increased mean corpuscular hemoglobin concentration. Spherocytic cells are less deformable and are cleared rapidly by the spleen, resulting in a much-shortened life span. Patients with hereditary spherocytosis usually have mild chronic hyperbilirubinemia and splenomegaly. Hereditary spherocytosis patients are normally wellcompensated but are also susceptible to aplastic crises, worsening anemia with infection and gallstones. The disease is diagnosed by osmotic fragility testing because the cells are unusually sensitive to lysis in hypotonic solutions. Important points for the hospitalist are that the osmotic fragility test may be falsely negative in very young infants, and that infants with hereditary spherocytosis may require transfusions early in the first year of life because of hemolysis and a poor early marrow response. Other membrane abnormalities associated with hemolysis include hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis. Disorders of Red Blood Cell Metabolism To survive normally, the RBC must be replete with the enzymes needed for adenosine triphosphate (ATP) generation and reduced nicotinamide adenine dinucleotide phosphate (NADPH) production. Defective enzymes of the hexose monophosphate shunt or Embden-Meyerhof pathway can result in anemia by limiting the RBCs energy or antioxidant capabilities, shortening their life span in the circulation. The most common abnormality is glucose-6-phosphate dehydrogenase (G6PD) deficiency. The enzyme G6PD protects the RBC from oxidative damage. Cells deficient in G6PD are susceptible to injury from oxidant drugs, infection, acidosis, and fava bean ingestion. The most likely presentation of this disorder to a hospitalist would be a boy of Mediterranean or Asian descent who develops acute hemolysis marked by

jaundice, dark urine, and anemia. The “A” variant of G6PD, common in African-Americans (1 in 10 males is thought to be affected), is mild and usually does not result in severe hemolysis. G6PD deficiency should be suspected in the setting of prolonged jaundice in the neonatal period after alloimmune hemolysis has been ruled out by a normal Coombs test. Supravital staining for Heinz bodies (to detect precipitated hemoglobin) may be positive. G6PD testing can be performed, although the results may be falsely normal soon after a hemolytic event owing to selective hemolysis of cells with the lowest G6PD levels and increased G6PD levels in abundant reticulocytes. Inheritance of pyruvate kinase deficiency, the second most common enzymopathy, is autosomal recessive. Pyruvate kinase deficiency can result in severe anemia, with reticulocytosis and splenomegaly. In general, the management of patients with enzymopathies is supportive (chronic folic acid supplementation), with an emphasis on the avoidance of known oxidative stressors (e.g. medications, foods, environmental exposure). Treatment of Inherited Hemolytic Anemias In general, treatment of inherited hemolytic anemias is dictated by the severity of the anemia, the nature of the defect, and its clinical consequences. Patients with mild anemia can be observed, whereas those with severe anemia may require chronic transfusions or splenectomy. In general, patients with chronic hemolytic anemias require only supportive care (e.g. folic acid supplementation) to facilitate chronic compensatory reticulocytosis. These children generally do well clinically unless an intercurrent illness slows bone marrow production of new RBCs. Parvovirus B19, the causative agent of erythema infectiosum (fifth disease), replicates in RBC precursors and can almost completely shut down erythropoiesis from 1 to 2 weeks, leading to aplastic crisis in children with hemolytic anemias. Often, RBC transfusion is required to maintain homeostasis until erythropoiesis recovers from the infection (typically within 1 month). In general, it is appropriate to involve hematology subspecialists in the diagnosis and long-term management of patients with inherited hemolytic anemias.

ACQUIRED HEMOLYTIC ANEMIAS Immune-Mediated Hemolytic Anemias Immune-mediated hemolytic anemias are common causes of acquired anemia in the pediatric population. By definition, antibody is produced against one or more antigens on the

surface of RBCs, promoting premature destruction by opsonization and subsequent erythrocyte removal by the reticuloendothelial system or by complement-mediated lysis of RBCs in the bloodstream.25,26 Antibodies may come from the patient (in which case the process is known as autoimmune hemolytic anemia [AIHA]) or from another source (alloimmune hemolytic anemia), such as occurs in hemolytic disease of the newborn. Unlike hemolytic disease of the newborn, which is invariably caused by transplacental maternal immunoglobulin (IgG) and is a problem only in utero and in the newborn period, AIHA can affect patients of any age and can be caused by either IgM or IgG. Patients with AIHA often relate a history of previous viral or viral-like illness preceding the development of fatigue and pallor. The presentation of AIHA is usually sudden and may include symptoms of severe anemia. A history of dark urine suggests acute intravascular hemolysis and argues for complement-mediated red cell lysis (see later). Jaundiced sclerae or pruritus suggests hyperbilirubinemia. Mild splenomegaly is occasionally present. AIHA can result in intravascular or extravascular hemolysis. Intravascular hemolysis is complement mediated and caused by IgM or complement-fixing IgG directed against RBC antigens, resulting in lysis of RBCs directly in the plasma and leading to jaundice or hyperbilirubinemia, elevated lactate dehydrogenase, and low haptoglobin. In contrast, extravascular hemolysis is typically mediated by IgG without complementfixing characteristics. Extravascular hemolysis may result in little or no increase in lactate dehydrogenase and bilirubin, presumably because RBCs are destroyed in the phagocytic cells of the reticuloendothelial system rather than in the plasma itself. Laboratory evaluation of AIHA reveals a moderate to severe anemia with a brisk reticulocytosis. However, it is important to note that the reticulocyte count may be unexpectedly low if the reactive antibody also results in clearance of young RBCs. Review of the peripheral blood smear may show spherocytosis, polychromasia, and RBC clumping. Urinalysis may show hemoglobinuria in the absence of hematuria. Direct Coombs testing (which tests for antibody bound to the patient’s RBCs) is almost always positive in AIHA. Indirect Coombs testing, which tests for free anti-erythrocyte antibody in the patient’s serum, usually detects alloantibodies but may be positive in AIHA when the antibody titer exceeds antigen binding; this can help define which isotype and RBC antigen are involved. If multiple cell lineages are depressed or Coombs testing is

negative, examination of the bone marrow should be considered to rule out leukemia or aplastic anemia. Primary AIHA can be divided into three types based on the nature, thermal reactivity, and amplitude of the implicated antibody. In warm-reactive AIHA, antibody (usually IgG) binds RBC antigens at 37°C, resulting in opsonization and removal by the reticuloendothelial system. Warm-reactive IgG typically binds common RBC protein antigens, which explains why blood bank testing often demonstrates a pan-reactive pattern. Warm-reactive AIHA tends to behave in a more chronic fashion than cold agglutinin disease and may warrant a more long-term treatment approach. Warm-Reactive Autoimmune Hemolytic Anemia

In paroxysmal cold hemoglobinuria (PCH), complement-fixing IgG autoantibody binds RBCs at low temperatures (usually in the extremities in vivo) and then causes complement-dependent intravascular hemolysis at warm temperatures (in central, warmer parts of the body). PCH sometimes follows infection with Mycoplasma pneumoniae or other atypical organisms. Testing for the cold-reactive (Donath-Landsteiner) antibody of PCH is performed by maintaining freshly drawn venous blood at 37°C until it is intentionally cooled in the laboratory, permitting antibody binding (if the patient’s blood is not kept warm until separation of plasma from RBCs, the antibody may be cleared by binding RBCs in the collection tube, leaving none free to be detected). Erythrocyte–antibody complexes are then warmed, inducing complement activation and hemolysis. Paroxysmal Cold Hemoglobinuria

In cold agglutinin disease, antibody (usually IgM) binds erythrocyte antigens (typically red cell surface polysaccharides) and fixes complement at temperatures below 37°C. In this manner, IgM efficiently results in intravascular hemolysis. Because IgM inefficiently binds antigen at 37°C, unbound antibody can frequently be detected in the plasma. Cold agglutinin AIHA is usually a self-limited process and typically does not respond well to immunosuppressive therapy. Cold Agglutinin Disease

Although great progress has been made in reducing the incidence of severe hemolytic disease of the newborn caused by Rh incompatibility between parents, hemolytic disease of the newborn caused by ABO mismatch and mismatch related to minor red cell antigen systems still occurs, as does classic hemolytic disease of the newborn, particularly in Hemolytic Disease of the Newborn

the later pregnancies of sensitized women. Much of the initial management occurs prenatally or in the NICU—including intrauterine transfusions, and exchange transfusions for hyperbilirubinemia as well as administration of immunoglobulin to slow the immune mediated destruction. Despite perinatal management, these infants are susceptible to persistent anemia due to the persistence of maternally derived antibodies to their red cells in the infants’ circulation. Hemolysis may continue for several months postnatally. The developing red cells in the bone marrow are also often subject to hemolysis. Infants may require from 1 to 4 transfusions after discharge home from the hospital because of repeated drops in the hemoglobin level. Typically this process declines to a clinically insignificant level within a few weeks, but for some babies this can persist for up to 4 months of age. A careful history is one key to diagnosis, being sure to ask about mother’s Rh status, administration of RhoGam, the performance of prenatal procedures, and prior affected pregnancies. The anemia is normocytic, and some spherocytes can be seen on the smear. The direct antiglobulin test is positive. There may be reticulocytopenia. The decision to transfuse rests on the infant’s response to the anemia, as well as the rate of fall of the hemoglobin and the reticulocyte count. Microangiopathic Hemolytic Anemia The hallmark of microangiopathy is the finding of schistocytes (red cell fragments) on peripheral blood smear analysis. Infection and sepsis can result in microangiopathy through uncontrolled fibrinogenesis and consequent physical disruption of RBCs by shearing forces that occur when blood circulates through vessels clogged with fibrin strands. RBC destruction in this setting can be severe and may be accompanied by thrombocytopenia and coagulation factor consumption, resulting in disseminated intravascular coagulation (DIC). These patients are typically quite ill and often have multiorgan pathology in addition to hemolytic anemia. Microangiopathic anemia also occurs with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS and TTP exist on a continuum and have in common decreased activity of von Willebrand protease (ADAMTS13). HUS is far more common in the pediatric population and typically results from infection with enteric bacteria, classically Escherichia coli 0157:H7, which expresses the Shiga toxin that directly interferes with ADAMTS13.27 Atypical HUS (aHUS) is due to one of several

inherited or acquired disorders of the complement system. The complementinactivating humanized monoclonal antibody eculizumab, which was FDAapproved for the treatment of paroxysmal nocturnal hemoglobinuria, has been used to successfully treat aHUS.28-30 The clinical syndrome of HUS together with neurologic symptoms suggests TTP27,31 and justifies prompt treatment with plasma infusion and plasmapheresis and possibly eculizumab.32 Regardless of degree of thrombocytopenia, platelet transfusions are contraindicated. If HUS or TTP is suspected, prompt consultation with hematology and nephrology should be obtained. Treatment of Acquired Hemolytic Anemias Treatment of hemolytic anemias due to extrinsic defects is normally directed toward the underlying problem resulting in hemolysis. Severe anemia may justify RBC transfusion, although the underlying pathophysiologic mechanism will likely destroy the newly transfused cells as well as the patient’s own RBCs. Transfusion of other blood products may also be beneficial; however, platelet transfusion should be avoided when TTP is a consideration, given the increased risk of thrombosis. The appropriate treatment of AIHA depends on the degree of hemolysis and resulting anemia. Children with mild anemia associated with postinfectious antibody development can usually be observed without transfusion. However, children with severe anemia or anemia with physiologic consequences should be promptly transfused with erythrocytes. Determination of the antigenic target of the autoantibody can be helpful in the selection of compatible blood for transfusion. If time permits, blood bank personnel should select the most compatible (or least incompatible) blood available, but emergent transfusion should not be delayed for this purpose.33 Transfusion in this challenging situation can be facilitated by direct clinicianblood bank interaction. Because incompatible transfused erythrocytes may be rapidly hemolysed, multiple transfusions are often required until more definitive therapy can be instituted. Children with cold-reactive antibodies should avoid cold exposure, and blood should be administered with the use of a blood warmer. AIHA is often responsive to immunosuppression, and systemic corticosteroids are particularly effective for patients with warmreactive IgG.34 For life-threatening hemolysis, treatment with methylprednisolone (1–2 mg/kg per day intravenously every 6 hours) should be initiated promptly.

Response to therapy is characterized by increasingly stable hemoglobin, decreasing reticulocytosis, and diminishing requirement for transfusion. After stabilization, prednisone 1 to 2 mg/kg per day can be substituted for methylprednisolone, and based on response, gradually tapered over several weeks to months. To avoid the side effects of chronic steroid treatment, highdose therapy should not continue for more than several days, and in the absence of a response, alternative treatments should be considered. Intravenous immunoglobulin has been used to treat AIHA with occasional success, but it should be considered a second-line treatment. Intravenous immunoglobulin may have some efficacy in a limited number of warmreactive AIHA patients.35 Exchange transfusion or plasmapheresis has limited efficacy in AIHA, although plasmapheresis may be marginally more effective for IgM- than IgG-based disease. Splenectomy may be considered for refractory IgG-dependent chronic extravascular hemolysis. Other immunosuppressive drugs such as cyclophosphamide, 6-mercaptopurine, 6thioguanine, azathioprine, and cyclosporine A may serve as steroid-sparing agents for children with chronic AIHA. For refractory autoimmune cytopenias there has been increasing use of antibody-mediated immune suppression. For example, rituximab (anti-CD20 monoclonal antibody) has proven effective for a subset of children with chronic or refractory AIHA.36 Treatment with any of these immunosuppressive agents should be in consultation with a hematology or immunology specialist.

ADMISSION CRITERIA Severe anemia complicated by physiologic changes. Ongoing hemolytic process that requires monitoring and possible transfusion. Anemia associated with severe neutropenia or thrombocytopenia. Lack of appropriate follow-up.

DISCHARGE CRITERIA Absence of physiologic manifestations of anemia. No evidence of excessive ongoing hemolysis. Reliable outpatient follow-up with a pediatric practitioner to evaluate for a

durable response to treatment and for recurrence of anemia. Communication of the inpatient treatment, laboratory values at the time of discharge, and pending laboratory studies is critical for appropriate posthospital care. Follow-up with a hematology or oncology specialist is necessary for children with ongoing hemolysis, unclear diagnoses, bone marrow failure syndromes, or possible neoplastic processes.

CONSULTATION Hematology or oncology consultation should be obtained in cases of unclear diagnosis, persistent or refractory anemia, requirement for bone marrow examination, concern about bone marrow failure syndromes, possible need for immunosuppressive therapy, or blast forms seen on the peripheral blood smear. Such specialists should also be consulted during the diagnostic workup before transfusion and for the long-term management of patients with chronic or refractory anemia. Transfusion medicine specialists can be of assistance when there is a need for plasmapheresis or exchange transfusion, there are difficulties in blood crossmatching due to autoantibody production, or a determination of autoantibody specificity is required. They will typically work in conjunction with a pediatric hematologist. KEY POINTS The clinical syndrome of anemia can have diverse causes. Anemia of inflammation is common in hospitalized children and may coexist with other cause of anemia. The evaluation of anemia is best performed in a systematic and stepwise fashion. Children with mild anemia are most appropriately evaluated in the outpatient setting. However, children with severe anemia, especially when the cause is uncertain, may require hospitalization for evaluation and treatment. Hospitalization allows the close monitoring of physiologic indicators (heart and respiratory rate) and blood counts, affording the ability to

respond rapidly to changes. Severe anemia, especially with signs of cardiovascular compromise, should be treated with blood transfusion to enhance oxygen carrying capacity and reverse the associated physiologic changes. It is important to note that transfusion of blood products complicates subsequent laboratory testing by infusing donor cells and plasma. Thus it is critical to collect samples for laboratory investigation before transfusion, which probably justifies consultation with a hematologist. Better understanding of the mutations causing intrinsic hemolytic anemias, together with improvements in gene delivery to hematopoietic stem cells, will result in curative treatments. The clinical application of hepcidin testing may facilitate the evaluation of anemia of inflammation, and targeting of hepcidin may alter treatment of this common condition.

SUGGESTED READINGS Ball SE, Gordon-Smith EC. Failure of red cell production. In: Lilleyman J, Hann I, Blanchette V, eds. Pediatric Hematology. London: Churchill Livingstone; 1999:65-81. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Orkin SH, Nathan DG, Ginsberg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: Saunders Elsevier; 2009:455-466. Grace RF, Lux SE. Disorders of the erythrocyte membrane. In: Orkin SH, Nathan DG, Ginsberg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia, Saunders Elsevier; 2009:661-836. Ware RE. Autoimmune hemolytic anemia. In: Orkin SH, Nathan DG, Ginsberg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: Saunders Elsevier; 2009:613-658.

REFERENCES

1. Brugnara C, Oski F, Nathan DG. Diagnostic approach to the anemic patient. In: Orkin SH, Nathan DG, Ginsberg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: Saunders Elsevier; 2009:455-466. 2. Kwiatkowski JL, West TB, Heidary N, et al. Severe iron deficiency anemia in young children. J Pediatr. 1999;135:514-516. 3. Cetinkaya F, Yildirmak Y, Kutluk G. Severe iron-deficiency anemia among hospitalized young children in an urban hospital. Pediatr Hematol Oncol. 2005;22:77-81. 4. Traxler SG, Benjamin JT. The incidence, treatment, and follow-up of iron deficiency in a tertiary care pediatric clinic. Clin Pediatr (Phila). 2005;44:333-337. 5. Ballin A, Lotan A, Serour F, et al. Anemia of acute infection in hospitalized children-no evidence of hemolysis. J Pediatr Hematol Oncol. 2009;31:750-752. 6. Bhaskaram P, Madhavan Nair K, Balakrishna N, et al. Serum transferrin receptor in children with respiratory infections. Eur J Clin Nutr. 2003;57:75-80. 7. Dallman PR, Siimes MA. Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr. 1979;94:26-31. 8. Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277:973-976. 9. Brugnara C. Iron deficiency and erythropoesis: new diagnostic approaches. Clin Chemistry. 2003;49:1573-1578. 10. Ullrich C, Wu A, Armsby C, et al. Screening healthy infants for iron deficiency using reticulocyte hemoglobin content. JAMA. 2005;294:924930. 11. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21:378-382. 12. Singh A, Patel T, Hertel J, et al. Safety of ferumoxytol in patients with anemia and CKD. Am J Kidney Dis. 2008;52:907-915. 13. Hassan N, Cahill J, Rajasekaran S, Kovey K. Ferumoxytol infusion in pediatric patients with gastrointestinal disorders: first case series. Ann

Pharmacother. 2011;45:e63. 14. Crary SE, Hall K, Buchanan GR. Intravenous iron sucrose for children with iron deficiency failing to respond to oral iron therapy. Pediatr Blood Cancer. 2011;56:615-619. 15. Abshire TC. The anemia of inflammation. A common cause of childhood anemia. Pediatr Clin North Am. 1996;43:623-637. 16. Agarwal N, Prchal JT. Anemia of chronic disease (anemia of inflammation). Acta Haematol. 2009;122:103-108. 17. Abshire TC, Reeves JD. Anemia of acute inflammation in children. J Pediatr. 1983;103:868-871. 18. Jansson LT, Kling S, Dallman PR. Anemia in children with acute infections seen in a primary care pediatric outpatient clinic. Pediatr Infect Dis. 1986;5:424-427. 19. Eichelbronner O, Sibbald WJ, Chin-Yee IH. Intermittent flow increases endotoxin-induced adhesion of human erythrocytes to vascular endothelial cells. Intensive Care Med. 2003;29:709-714. 20. Frede S, Fandrey J, Pagel H, et al. Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats. Am J Physiol. 1997;273:R1067-1071. 21. van Iperen CE, Gaillard CA, Kraaijenhagen RJ, et al. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med. 2000;28:2773-2778. 22. Pels LP, Van de Vijver E, Waalkens HJ, et al. Slow hematological recovery in children with IBD-associated anemia in cases of “expectant management.” J Pediatr Gastroenterol Nutr. 2010;51:708-713. 23. Ganz T. Molecular pathogenesis of anemia of chronic disease. Pediatr Blood Cancer. 2006;46:554-557. 24. Gallagher PG, Forget BG, Lux SE. Disorders of the erythrocyte membrane. In: Nathan DG, Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: WB Saunders; 1998:544-664. 25. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002;69:258-271. 26. Ware RE, Rosse WF. Autoimmune hemolytic anemia. In: Nathan DG,

Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: WB Saunders; 1998:499-522. 27. Tsai HM, Chandler WL, Sarode R, et al. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res. 2001;49:653-659. 28. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolyticuremic syndrome. N Engl J Med. 2009;360:544-546. 29. Nurnberger J, Philipp T, Witzke O, et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:542-544. 30. Loirat C, Saland J, Bitzan M. Management of hemolytic uremic syndrome. Presse Med. 2012;41:e115-135. 31. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med. 1998;339:1578-1584. 32. Furlan M, Robles R, Morselli B, et al. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura. Thromb Haemost. 1999;81:8-13. 33. Petz LD. A physician’s guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol. 2004;124:712-716. 34. King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Semin Hematol. 2005;42:131-136. 35. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993;44:237-242. 36. Zecca M, Nobili B, Ramenghi U, et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood. 2003;101:3857-3861.

Management of Sickle Cell Disease

CHAPTER

89

Matthew M. Heeney and Venée N. Tubman

BACKGROUND Sickle cell disease (SCD) is an inherited hemolytic anemia that affects approximately 100,000 persons in the United States, mostly in the AfricanAmerican population. It is responsible for lifelong medical complications in most affected individuals. Complications of SCD can be divided into those that are acute and those that are the result of the chronic repetitive vasoocclusion of target organ systems (Table 89-1). This chapter focuses on the acute complications that the hospitalist is likely to encounter. TABLE 89-1

Medical Complications of Sickle Cell Disease

Acute Vaso-occlusive

Dactylitis (hand foot syndrome) Splenic sequestration Priapism Pain crises Acute chest syndrome Stroke/Cerebrovascular accident

Non–Vaso-occlusive

Cholelithiasis/Cholecystitis Aplastic Crisis

Bacteremia Chronic Constitutional

Decreased stamina

Cardiovascular

Pulmonary hypertension Cardiomegaly

Renal

Hyposthenuria Hematuria Nocturnal enuresis

Eyes

Proliferative retinopathy

Lungs

Chronic lung disease

Skin

Leg ulcers

Musculoskeletal

Osteonecrosis Avascular necrosis

Endocrine

Growth failure Delayed puberty

Neurologic

Learning disability Motor deficits

Psychiatric

Poor self-image Depression

PATHOPHYSIOLOGY SCD refers to a group of hemolytic anemias in which hemoglobin S (HbS) is present in either a homozygous state (HbSS) or in a compound heterozygous

state, as when combined with hemoglobin C (HbSC) or hemoglobin betathalassemia (HbS-beta thalassemia). The HbS mutation is the result of an amino acid substitution (valine is substituted for glutamic acid at position 6) in the beta globin of the hemoglobin heterotetramer. The mutation creates a hydrophobic region that, in the deoxygenated state, facilitates a non-covalent polymerization of HbS molecules into rigid strands. These HbS polymers damage the erythrocyte membrane and change the rheology of the erythrocyte in circulation, causing erythrocyte dehydration hemolytic anemia and vaso-occlusion.

CLINICAL PRESENTATION The National Institutes of Health recommends that all infants be screened in the neonatal period for SCD1 and all 50 states and the District of Columbia perform universal screening for SCD.2 For this reason, most children with SCD are identified early and medical management is started even before the usual age of presentation. Because the sickle mutation affects beta globin, a component of adult hemoglobin rather than fetal hemoglobin (HbF), affected infants are usually asymptomatic for the first 6 months of life. Anemia and complications from SCD usually present toward the end of the first year of life, after the physiologic switch from fetal to adult hemoglobin. Despite newborn screening and early identification, cases of previously undiagnosed SCD presenting with a medical complication do occur, and the clinician is advised to consider SCD in the differential of patients with nonimmune hemolytic anemia. Although affected patients typically have moderate or severe anemia with hemoglobin values ranging from 7 to 9 g/dL, they generally are not overly symptomatic (e.g. weakness, fatigue) since the anemia is chronic and physiologically compensated. As the result of a markedly shortened red cell survival time, bone marrow production of new erythrocytes is brisk, as indicated by chronically elevated reticulocyte counts (usually 10% to 20%). Patients will often be slightly icteric due to chronic hemolysis, and may have splenomegaly and skull bone deformities due to extramedullary hematopoiesis.

HEALTH MAINTENANCE

Infants diagnosed by newborn screening should be referred to pediatric hematologists for confirmation of the diagnosis, parental education, genetic counseling, and long-term follow-up. Routine health maintenance visits to a pediatric hematologist are scheduled for every 3 months in the first 2 years of life, then every 6 months until 4 to 5 years of age, and annually thereafter. More frequent visits may be required for patients with increased educational needs, accumulated complications, and therapeutic monitoring (e.g. hydroxyurea and/or chronic transfusion therapy). “Well visits” allow the practitioner to obtain baseline clinical, laboratory, and radiological data that is important in the event of an acute complication and affords the opportunity for education and anticipatory guidance.

COMPLICATIONS AND MANAGEMENT Acute and chronic complications are an important part of the management of SCD (Table 89-1). Although the hematologist manages conditions associated with chronic disease, the generalist may need to consider these complications and their impact when called upon to evaluate children with SCD. The discussion below focuses on the acute complications.

FEVER Patients with SCD develop impaired spleen function in the first year of life and are functionally asplenic by 2 years of age. They are therefore at risk for invasive and overwhelming infections. Prior to the introduction of routine vaccination in many countries, encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) were a significant threat.3,4 Though less frequent now, pneumococcus remains a common cause of sepsis. Antibiotic prophylaxis should be initiated when the diagnosis of SCD is made (Table 89-2). Children with SCD should receive a complete routine immunization schedule, including Haemophilus influenzae type b series (Hib), pneumococcal conjugate vaccine (Prevnar [PCV13]) series, and a pneumococcal polysaccharide vaccine (Pneumovax [PPV23]) at age 2 with a booster 3 to 5 years later, to decrease the risk of bacteremia. Influenza vaccine should be administered to all sickle cell patients annually and the meningococcal polysaccharide vaccine should be administered to

patients 2 years of age and older.4 TABLE 89-2

Antibiotic Prophylaxis

Age

Antibiotic Dose*

Birth– 3 years

Penicillin VK 12 5mg PO BID

3 Penicillin VK 250 mg PO BID years– 5 years >5 years

Discontinue, except in the circumstance of previous surgical splenectomy, after which antibiotic prophylaxis should be continued indefinitely.

*Erythromycin can be substituted in patients with penicillin allergies.

Even with antibiotic prophylaxis and complete immunizations, all sickle cell patients should be considered high-risk for bacteremia and overwhelming sepsis. Prompt evaluation and empiric treatment of febrile SCD patients is necessary to reduce both mortality and morbidity of sepsis. Children with an obvious source of infection (e.g. otitis, gastroenteritis) should still receive full evaluation and appropriate empiric treatment until bacteremia has been excluded. The key to the proper management of febrile SCD patients (or any asplenic patient) involves rapid triage and assessment with administration of empiric parenteral antibiotics within 1 hour of presentation. The focused history, physical examination, and laboratory evaluation, including blood cultures, should be done promptly. If the patient has a central line or implanted port, blood cultures must be drawn off this line. Additional peripherally obtained cultures are not necessary. A chest radiograph is recommended for most patients, especially those with tachypnea, cough, hypoxemia, or thoracic pain, and considered for history of asthma or recurrent acute chest syndrome (ACS). Urinalysis and urine culture are recommended for all males 6 cm, and are often accompanied by tenderness, erythema, and fever. On the other hand, children with acute bilateral cervical lymphadenitis usually have self-limited, systemic viral infections caused by viruses such as

EBV and cytomegalovirus. Inflammatory changes such as tenderness and erythema associated with these infections are typically mild when compared to cases of lymphadenitis caused by bacteria. Therefore the term lymphadenopathy is sometimes used in these situations instead of lymphadenitis, indicating a simple, reactive enlargement of the lymph nodes in response to regional infection or inflammation. Fever and other associated viral symptoms such as sore throat, rash, hepatomegaly, or splenomegaly may be present and aid in diagnosis. These infections are more typical of patients in the preschool to adolescent age range. Subacute or chronic lymphadenitis usually has a more indolent course, worsening over a period of several weeks. Presentation varies depending on the inciting agent, with Bartonella henselae and mycobacterial organisms being two of the most common infectious causes. Infection with B. henslae, also known as cat-scratch disease, causes tender lymphadenopathy measuring over 4 cm, usually in a regional distribution and often involving nodes in the axilla or cervical areas. Symptoms begin anywhere from 5 days to 2 months after inoculation, classically after being scratched by cats or kittens. Sometimes a papule or pustule can be seen at the site of inoculation. Lymphadenopathy persists for several weeks, but usually will diminish in size by 6 weeks unless suppurative complications occur. Associated symptoms of fever, malaise, and headache often occur, but typically resolve prior to the onset of lymphadenitis. Mycobacterial causes of chronic lymphadenitis can be due either to Mycobacterium tuberculosis or nontuberculous mycobacterium. Nontuberculous infections usually occur in young children and typically result from an environmental exposure, as organisms are ubiquitous in soil. Mycobacterial infections of the neck are sometimes referred to as “scrofula.” Such infections are typically localized to a unilateral lymph node and have an insidious onset with gradual increase in size over several weeks. The majority of involved nodes are under 3 cm in size and other symptoms such as pain, fever, and erythema tend to be less common. Overlying skin may change from pink to a violaceous discoloration. Untreated cases may resolve, but there is a risk of spontaneous drainage with sinus tract formation.25 Clinical signs of nontuberculous mycobacterial adenitis are often very similar to those of M. tuberculosis.

DIFFERENTIAL DIAGNOSIS The differential for possible causes of enlarged cervical lymph nodes is quite broad, with other infectious etiologies often to blame. In addition to the common etiologies discussed above, there are many other infectious agents to consider when evaluating children with enlarged lymph nodes. A comprehensive listing can be found in Table 100-2. While infiltration of inflammatory cells is a major cause of enlarged lymph nodes, infiltration by neoplastic cells is also possible and is an important diagnosis to consider. In these cases, enlarged nodes are often painless, firm, and fixed to adjacent tissues. While not specific to neoplastic disease, lymphadenopathy related to malignancy may be found in the posterior cervical or supraclavicular areas. Additionally, some congenital malformations in the neck can be mistaken for lymphadenitis, particularly if they become secondarily infected. These lesions include thyroglossal duct cysts (midline defect), branchial cleft cysts (anterior along the cervical chain), and cystic hygromas (located posteriorly, above the clavicles). Other causes include medications (phenytoin or carbamazepine) and systemic illnesses such as Kawasaki disease, histiocytosis, Castleman disease, Kikuchi-Fujimoto disease, sarcoidosis, Kimura disease, and PFAPA. TABLE 100-2

Infectious Causes of Cervical Lymphadenitis

Bacteria

Viral

Other

Anaerobes

Adenovirus

Aspergillus fumigatus

Actinomyces israelii

Cytomegalovirus

Candida spp.

Bartonella henselae

Enterovirus

Coccidiomycosis

Brucella spp.

Epstein-Barr virus

Cryptococcus neoformans

Corynebacterium diphtheriae

Human herpesvirus 6, 7, or 8

Histoplasma capsulatum

Francisella tularensis

Human

Leptospira

immunodeficiency virus

interrogans

Group A Streptococcus

Herpes simplex virus

Orientia tsutsugamushi

Group B Streptococcus

Influenza

Toxoplasma gondii

Mycobacterium tuberculosis

Parvovirus B19

Treponema pallidum

Mycoplasma pneumonia

Rhinovirus

Nocardia spp.

Rubella virus

Nontuberculous mycobacterium Pasturella multocida Staphylococcus aureus Yersinia spp.

DIAGNOSTIC EVALUATION The evaluation of cervical lymphadenitis should be guided by the initial presenting history and exam findings. As discussed previously, attention to pertinent exposure history and determination of whether the onset of lymphadenitis has been acute or chronic, and unilateral or bilateral, will help limit the likely causes and focus the diagnostic evaluation. An acutely inflamed solitary nodule in an otherwise well-appearing child may not require any further workup, as the most likely cause would be a localized bacterial infection with either S. aureus or GABHS. If fluctuance of the affected node is appreciated on exam, needle aspiration can be not only

therapeutic, but also helpful in identifying an etiology. Aspirated fluid can be sent for Gram stain and acid-fast bacillus stain as well as bacterial (aerobic and anaerobic), fungal, and mycobacterial culture. Blood culture is not indicated routinely, but should be obtained if the child is febrile and illappearing. B. henselae can be detected by serologic studies. Cat owners may have “low-level” positive titers (1:32 or 1:64), so repeating the titers 2 weeks later to document an increase in IgG may be helpful to confirm the diagnosis. Lymph node tissue specimens can be sent for B. henselae PCR, a test offered by many commercial laboratories. For children with persistent or severe symptoms, further workup can be considered including complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hepatic function panel, tuberculin skin test and other serologic testing for specific pathogens as indicated by history and exam. Imaging of the neck with either ultrasound or CT can be useful in guiding surgical management, detecting the extent of infection, and identifying the presence of a drainable fluid collection. If the diagnosis continues to remains in question and symptoms are persistent or worsening, an excisional lymph node biopsy can be done to help evaluate further for malignancy or other infectious causes.

MANAGEMENT Management of cervical adenopathy depends on what is deemed as the most likely underlying etiology. Patients with uncomplicated bilateral lymphadenitis that is thought to be secondary to a viral infection require supportive care and observation only. Children who have acute onset of unilateral lymphadenitis and are thought to have a bacterial etiology will require treatment with antibiotics. Recommendations for initial antibiotic coverage may vary based on local resistance patterns, but it needs to offer adequate coverage of both S. aureus and GABHS. Because methicillin-resistant S. aureus (MRSA) is prevalent in most areas in the United States, clindamycin is reasonable empiric therapy. Areas with low MRSA prevalence may use cefazolin, oxacillin, or nafcillin for the hospitalized child. Trimethoprim-sulfamethoxazole also provides good coverage for MRSA; however, it does not offer sufficient activity against GABHS and may be associated with uncultured treatment failures in

some patients with skin and soft tissue infections.26 Other options are available to treat MRSA, such as linezolid, vancomycin and quinupristindalfopristin, but consultation with an infectious disease specialist may be advisable before prescribing these antibiotics. If the patient’s symptoms are associated with periodontal disease, an infection with anaerobic bacteria should be suspected and treatment begun with either amoxicillin-clavulanic acid, ampicillin-sulbactam, or clindamycin. Symptomatic improvement is usually seen within 48 to 72 hours after starting treatment, but it may take up to 6 weeks for the enlarged node to completely resolve. When an abscess is seen on imaging or palpable on exam, treatment with either incision and drainage or needle aspiration can be therapeutic. In patients with nontuberculous mycobacterial infection, excisional biopsy is the most effective therapy, but is often accompanied by antimicrobial therapy. For B. henslae, surgical drainage is rarely necessary, and some argue that no treatment is necessary at all due to the self-limited course of the infection. If treatment is desired, azithromycin, rifampin, or trimethoprimsulfamethoxazole can be used. In a small, randomized trial of children with B. henselae lymphadenitis, azithromycin treatment for 5 days was associated with an 80% reduction in lymph node volume measured at 30 days in ~50% of those treated and 3 g/dL and pleural–serum ratio >0.5

Amylase

If concern for pancreatic disease or esophageal rupture

Cholesterol

If >60 mg/dL and pleural fluid–cholesterol

ratio >0.3, indicative of exudate Cytology

To exclude malignancy

Chylomicrons, triglycerides

Along with cholesterol if chylothorax suspected

*Aerobic and anaerobic; consider mycobacterial and fungal. LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PMN, polymorphonuclear neutrophils; PPE, parapneumonic effusion; TB, tuberculosis.

ADMISSION AND DISCHARGE CRITERIA Although the majority of children with community-acquired pneumonia are successfully managed in the outpatient setting, pneumonia remains one of the most common indications for pediatric hospitalization in the United States.6 A tool to predict severe pneumonia outcomes was recently developed which may inform site of care and other management decisions but requires further validation prior to implementation.177 Ill appearance, moderate to severe respiratory distress with or without hypoxia, and inability to eat are common reasons necessitating hospitalization for children with pneumonia. Potential barriers to effective home care should also be considered. Children with severe respiratory distress and impending respiratory failure or hemodynamic instability require admission to a pediatric critical care unit. Children may be discharged once responding appropriately to therapeutic interventions, typically within 1 to 3 days.

CONSULTATION Most children hospitalized with pneumonia improve quickly with appropriate antimicrobial therapy and supportive care under the direction of a pediatric care team that includes nursing, pharmacy, and respiratory care staff, and a generalist physician. Access to pediatric critical care services is paramount. When available, ancillary support services such as social work and child life can be an excellent resource. Subspecialty consultation may be beneficial for children with selected comorbidities, significant complications, or disease that is not responding to typical therapies, or in children with recurrent infections. Infectious disease specialists may assist with antimicrobial

management or evaluation for underlying immunodeficiency in a child with non-responding pneumonia or frequent infections; pulmonary specialists can help with the evaluation of recurrent pneumonia in a single location indicative of an underlying structural or functional abnormality, those with significant respiratory comorbidity, or in children who require bronchoscopy, such as a child with non-responding pneumonia; general surgery or interventional radiology consultation is appropriate for children requiring intervention for local complications such as parapneumonia effusion or empyema.

PERTUSSIS BACKGROUND Epidemiology Pertussis is an acute infectious disease caused by the bacterium Bordetella pertussis. Outbreaks of pertussis were described as early as the 15th century, but the causative bacterium was not isolated until 1906. Pertussis is also called whooping cough, which is descriptive of the high-pitched inspiratory noise (“whoop”) made by infected children. Pertussis was one of the most common childhood diseases in the 20th century and a major cause of childhood mortality in the U.S. There were more than 200,000 cases of pertussis reported annually before pertussis vaccine became available in the 1940s. With the advent of widespread vaccination in the United States, the incidence had decreased more than 80% compared with the pre-vaccine era; fewer than 2000 cases were reported in 1975. However, increasing rates of non-medical or personal belief vaccine exemptions to school immunization requirements have contributed to increasing rates of pertussis through frequent outbreaks.178 In 2014, there were >30,000 cases of pertussis in the United States, with >8000 in the state of California.179 Secondary attack rates among unvaccinated people range from 50% to 100%, depending on proximity to the infected person. In a study of pediatric pertussis hospitalizations, family members were the source in nearly 75% of cases; daycare contacts accounted for 3% of cases.180 The highest case rates and mortality occur in infants 6 years: Fluency and word finding: See Image 121-1. Naming: See Image 121-2. Reading: Stop; See the dog run; Little children like to play outdoors. Repetition: a. Stop. b. Stop and go c. If it rains we play inside. d. The President lives in Washington.

IMAGE 121-1. Describe what is happening in the picture.

IMAGE 121-2. Name these items. 0

No aphasia, normal

1

Mild to moderate aphasia; some loss of fluency or facility in comprehension

2

Severe aphasia; all communication is through fragmentary expression

3

Mute, global aphasia; no usable speech of auditory

comprehension. 10 Dysarthria

Use reading and repetition items from Item 9. 0

Normal

1

Mild to moderate; patient slurs at least some words

2

Severe; patient’s speech is so slurred as to be unintelligible

11 0 Extinction/Inattention 1

2 Total Score

No abnormality Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities Profound hemi-inattention to more than one modality Mild stroke 16

NEUROIMAGING (Table 121-4) AIS Acute AIS in children can sometimes be diagnosed on head CT as a typical wedge-shaped area of hypodensity involving both cortex and subcortical white matter (Figure 121-2A). Head CT is often more quickly and cheaply obtained than MRI in children but may not demonstrate infarction in the hyperacute setting.29,30 Therefore a normal head CT rules out a hemorrhage but should not be reassuring when a child presents with a possible stroke. Instead, an MRI should be obtained rapidly (when possible and safe) to definitively make or rule out the diagnosis of AIS. MRI with diffusion-weighted sequences is the gold standard for the diagnosis of AIS in

children because it better delineates parenchymal abnormalities, including non-ischemic lesions that clinically mimic AIS. In addition, MR angiography (MRA) of the brain and neck should be obtained in all children in whom AIS is suspected given that many have intracranial vasculopathy or dissection as the etiology for their stroke. Imaging of the vertebrobasilar arteries is particularly high-yield when neurological symptoms localize to the posterior circulation (ataxia, vertigo, cranial nerve dysfunction, nausea, or vomiting) or AIS is diagnosed on MRI in the cerebellum, brainstem, and/or occipital lobes). In performing an acute MRI, one should always be aware that braces can obscure MR imaging and should be removed urgently prior to an MR whenever possible. TABLE 121-4

Stroke Investigations

Alternatively, CT and CT angiography (CTA) can be performed to confirm an AIS in patients who have contraindications or who are too medically unstable to undergo MRI/MRA. CT/CTA may also be utilized when MR imaging is not available or will be delayed due to need for anesthesia or lack of local resources. CTA can be done at the same time as the CT, is performed quickly (95% in postpubertal patients)

Typically a relapsing course

Pain with eye movement

Transverse myelitis (TM)

Periaqueductal, corpus callosum, and periventricular white matter often involved

Must have ON and TM

extending over 3 cord segments (longitudinally extensive myelitis)

and/or CSF CSF WBC often very elevated (can be >100 cells)

Brain lesions, if present, tend to occur in the hypothalamic region or midbrain CSF, cerebrospinal fluid; Gd, gadolinium; IgG, immunoglobulin; WBC, white blood cells

TABLE 122-2

Differential Diagnosis of Demyelinating Disease

Diagnostic Category

Characteristic Clinical Features

Additional Investigations

Infectious/periinfectious Bacterial, viral, fungal, or parasitic infections, such as: Herpes virus (HSV, VZV, CMV) EBV Mycoplasma Enterovirus Neuroborreliosis HIV Neurosyphilis Tuberculosis (TB) JC virus

Fever Meningsmus Rash (such as petechiae in bacterial meningitis or vesicles in herpes viruses) Systemic evidence of infection Alteration in mental status

Blood and CSF cell counts and cultures PCR testing for infection in CSF TB testing Fungal culture

HTLV-1 Hepatitis A, B, and C Cryptococcus Rheumatologic Primary CNS angiitis Sarcoidosis Sjogren syndrome System lupus erythematosus Bechet syndrome Anticardiolipin or antiphospholipid antibody syndrome

Persistent and prominent headache

ESR, ANA profile ACE level Antiphospholipid Systemic evidence of and anticardiolipin vasculitis (not antibodies required) MRA of head Note: Clinical, Cerebral laboratory, and angiography radiographic evidence Brain biopsy of systemic disease may be absent in CNS vasculitis

Malignancy CNS lymphoma Glioma

History of prior malignancy and/or chemotherapy

Blood smear

Systemic symptoms (weight loss, night sweats, fever)

Brain biopsy

CSF cytology

Note: With CNS lymphoma, symptoms may improve with administration of steroids Neuroimmune disorders Anti-NMDA receptor encephalitis

Encephalopathy Vital sign instability Movement

Anti-NMDA receptor antibody from CSF and blood

abnormalities

Abdominal ultrasound in Psychiatric symptoms females; testicular ultrasound in males (evaluate for teratoma) Consider other paraneoplastic antibody testing (based on clinical symptomatology) Macrophage activation syndromes

History of similarly affected sibling

Serum ferritin and triglycerides

Systemic signs of liver, skin, renal, or bone marrow involvement

Soluble IL-2 receptor level

Persistent fever Metabolic or Symptomatic mitochondrial disease worsening with fever Pre-existing progressive neurologic deterioration, developmental delay, or cognitive dysfunction

Blood, CSF, and bone marrow evaluation for hemophagocytosis Serum and CSF lactate/pyruvate MR spectroscopy Consider plasma amino acids, urine organic acids, ammonia, acylcarnitine profile

Vascular Cerebral Autosomal Dominant Arteriopathy with Subcortical Infracts and Leukoencephalopathy (CADASIL)

Prominent headaches NOTCH3 genetic testing Cognitive and psychiatric symptoms are common Family history of migraines, early onset dementia, and strokes

Source: Data from Banwell B. Acute disseminated encephalomyelitis. In: Lisak R, Truong D, Carroll W, Bhidayasiri R, eds. International Neurology. Wiley-Blackwell; 2009:381-385; and Waldman AT, Shumski MJ, Tennekoon GI. Acquired demyelinating syndromes of the central nervous system. In: Abend NS, Helfaer MA, eds. Pediatric Critical Care. Demos Medical; 2012.

DIAGNOSTIC EVALUATION The evaluation of a child with acute neurologic symptoms begins with a detailed history that includes information about the timing and duration of symptoms. Although a thorough neurologic examination should be performed to help localize neurologic dysfunction, asymptomatic inflammation (lesions that do not cause symptoms or findings on exam) is also common in these disorders. Similarly, a normal sensory or ophthalmologic examination does not preclude the possibility of CNS demyelinating lesions. Therefore extensive imaging (brain, cervical and thoracic spine) is often indicated, even without symptoms or examination findings that specifically localize to these areas of the CNS. Though magnetic resonance imaging (MRI) is required to determine the extent of CNS inflammation, computed tomography (CT) of the brain may be performed acutely if there are signs of elevated intracranial pressure, altered mental status, or new focal neurologic deficits. In all children with suspected CNS inflammation, cerebrospinal fluid (CSF) analysis should be considered. In addition to obtaining CSF cell count, protein, glucose, Gram stain and culture, and other clinically indicated tests (i.e. for infectious etiologies), and evaluation for immunoglobulin synthesis within the CNS should be performed. The intrathecal synthesis of immunoglobulins is a hallmark of CNS inflammation but not specific to

demyelinating diseases. To interpret these studies, CSF and blood should be drawn at the same time and sent for an oligoclonal band profile, which includes a qualitative test to visualize the oligoclonal bands through isoelectric focusing as well as quantitative measures of these immunoglobulins through an immunoglobulin G (IgG) index and IgG synthesis rate.

MANAGEMENT In severe cases, acute demyelination may be life threatening and can impair respiration (especially if upper cervical cord or brainstem lesions are present). As a result, assessment of vital signs is a key part of the initial management of any patient with acute demyelination. Airway, breathing, and circulation should be assessed and respiratory support should be quickly obtained if needed. It is not always possible at the onset of CNS inflammation to determine the diagnosis. For example, inflammation of the optic nerves causing visual loss (ON, described below) may occur without any other clinical or radiographic neurologic findings (termed a clinically isolated syndrome) or may be a feature of ADEM, MS, or NMO. Therefore acute therapy, targeting the CNS inflammation, is similar at presentation regardless of diagnosis. Most clinicians initiate a short course of corticosteroids to reduce inflammation. Other therapies include intravenous immunoglobulin or plasma exchange in severe or refractory cases.

CORTICOSTEROIDS Though the optimal dose has not been established for pediatric patients, most clinicians prescribe 20 to 30 mg/kg/day (with a maximum of 1000 mg/day) of intravenous methylprednisolone for 3 to 5 days for initial treatment of an acquired demyelinating syndrome requiring hospitalization. The use of a steroid taper is physician-dependent.7 If symptoms resolve after intravenous treatment, additional treatment with oral prednisone may not required. For children with improvement but ongoing deficits, oral prednisone, starting at a dose of 1 mg/kg/day (max of 60 mg), can subsequently be administered and tapered over a few weeks.8,9

Often treatment with corticosteroids is delayed due to concern for infection. Of note, corticosteroids are often used to treat patients with Haemophilus influenzae type b and pneumococcal meningitis, and have been safely given in severe case of herpes encephalitis.10 Therefore delaying treatment with corticosteroids due to concern for infection may not be necessary and is under further investigation. While steroids may be safe even in the presence of a viral or bacterial CNS infection, corticosteroids are contraindicated in fungal infections. When administering high-dose corticosteroids, it is important to remember to also treat with an H2 blocker or a proton pump inhibitor for gastrointestinal prophylaxis. Other less common side effects of corticosteroids to consider include hyperglycemia, hypertension, psychiatric symptoms (anxiety, psychosis), insomnia, and weight gain. Avascular necrosis can also occur and has been reported in a patient treated with corticosteroids for less than 1 month.11

INTRAVENOUS IMMUNOGLOBULIN Intravenous immunoglobulin (IVIg) has been reported to be effective in some children with acquired demyelinating syndromes who do not respond to corticosteroids, or in some patients who experience recurrence of neurological deficits upon corticosteroid withdrawal. The typical dose administered is 2 g/kg divided over 2 to 5 days, though faster infusions can be safely used.

PLASMA EXCHANGE For patients with acquired demyelinating syndromes and severe neurologic deficits who fail to demonstrate clinical improvement by the third to fifth day of corticosteroid treatment, or children with life-threatening demyelination or paralysis at onset, plasma exchange (PE) should be considered.9,12 A typical PE regimen consists of 5 to 7 exchanges over a 2-week period.

REHABILITATION Physiatrists and physical, occupational, and speech therapists play a major

role in the recovery of patients with CNS inflammation and should be consulted as early as appropriate during an admission. Some children will require transfer to a rehabilitation facility after discharge from the acute care setting, depending upon their clinical recovery. In summary, acquired demyelinating syndromes occur in children and often require hospitalization at symptom onset to fully evaluate the CNS and exclude alternative diagnoses. Treatment of CNS inflammation is often initiated before all of the diagnostic studies are obtained in the inpatient setting. The prototypical acquired demyelinating syndromes are described in more detail below.

ACUTE DISSEMINATED ENCEPHALOMYELITIS Approximately 25% of all children with an acquired demyelinating syndrome will manifest with ADEM, which is defined by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) as a clinical CNS event with a presumed inflammatory cause characterized by polyfocal neurologic deficits and encephalopathy not explained by fever or systemic illness.13 Though ADEM is typically a monophasic (isolated illness followed by recovery and no recurrence) pediatric disorder, multiphasic forms have been reported. Rarely, an ADEM-like initial attack can be the first presentation of a chronic demyelinating disorder, such as MS or NMO.

CLINICAL PRESENTATION In order to meet consensus criteria for ADEM, a patient must present with encephalopathy, which can be manifested by behavioral change, profound irritability, or altered consciousness (including coma), and polyfocal neurologic deficits.13,14 Prodromal systemic symptoms such as fever, headache, and malaise can occur in the days prior to the onset of neurologic symptoms. The initial symptoms of ADEM may occur spontaneously without antecedent illness, but more typically begin within days to weeks of a febrile illness of presumed viral etiology. Upper respiratory tract infections are the most commonly reported preceding illnesses, followed by gastrointestinal infection, and then nonspecific febrile illnesses.14 Once neurologic symptoms begin, the clinical course progresses quickly and patients typically develop

maximal symptoms over the following 3 to 5 days.14 Neurologic symptoms in ADEM can vary and correspond to the sites of CNS inflammation in a particular patient. The most common neurologic features in ADEM include upper motor neuron symptoms (such as weakness, increased tone, and hyperreflexia), followed by ataxia and cranial nerve palsies.

DIFFERENTIAL DIAGNOSIS In a patient with encephalopathy and neurologic symptoms, with or without a recent fever or illness, investigations are initially directed toward excluding active CNS infections and evaluating for recent viral exposures. The presence of fever, meningismus, rash, or systemic illness should raise suspicion for an infectious process rather than ADEM, although it may often be difficult to differentiate infections from post-infectious disorders if the neurologic symptoms coincide with the fever and systemic illness. Other symptoms and signs are particularly relevant, such as pain over a dermatome (with or without vesicular lesions), which may be caused by herpes infections. Adenopathy is present in cat-scratch disease and other infections. A patient presenting with encephalopathy and psychiatric symptoms or a movement disorder should raise concern for anti-NMDA-R encephalitis.

DIAGNOSTIC EVALUATION A lymphocytic CSF pleocytosis (>10 cell/μL) and/or elevation of CSF protein is present in more than half of cases of ADEM. Oligoclonal bands detected in CSF but not detected in concurrent serum are rare but have been reported to be present acutely in up to 19% of patients with ADEM.2,15,16 Presence of CSF oligoclonal bands in this population is nonspecific, as intrathecal immunoglobulins can also be seen with CNS infection, but it is still recommended as part of the diagnostic evaluation in patients presenting with ADEM.7

MRI FEATURES Radiologically, ADEM is typically characterized by multifocal T2/FLAIR

hyperintense lesions in both the white and gray matter of the brain and spinal cord. Lesions are typically large with poorly demarcated margins. Visible lesions in the deep gray matter (thalamus and basal ganglia) are frequently noted. Typical radiologic features of ADEM are demonstrated in Figure 1221. Though ADEM is thought to be an acute disorder, it is rare for all lesions to enhance with gadolinium, and some patients have no enhancing lesions.17 Meningeal enhancement, the presence of completely ring-enhanced lesions,18 and lesions that are persistently T1 hypointense are uncommon in ADEM and suggest alternative diagnoses.

FIGURE 122-1. Common radiologic features of ADEM: (a) axial and (b) coronal fluid-attenuated inversion recovery (FLAIR) images demonstrating typical radiologic features of ADEM. Lesions are typically large, asymmetric, and have poorly demarcated borders. Deep gray lesions are often visualized (arrow).

MANAGEMENT Treatment is based on the severity of neurologic symptoms. If the encephalopathy and polyfocal symptoms have resolved by the time of medical evaluation, acute treatment may not be necessary. For children with neurologic deficits, intravenous corticosteroids should be initiated. Typically, intravenous methylprednisolone is given for 3 to 5 days, during which time clinical improvement often occurs. An oral prednisone taper may be used subsequently if there is improvement but some persistent neurologic deficits

remain. If the symptoms do not improve with intravenous steroids or children have life-threatening demyelination at onset, plasma exchange can be considered. IVIg has been reported to be effective in some children with ADEM who do not respond fully to corticosteroids, or in some patients who seem to experience recurrence of neurological deficits upon corticosteroid withdrawal. Additional details can be found in the Treatment section above. Although rare, some children with ADEM experience fulminant, lifethreatening cerebral edema refractory to conventional medical management. In these cases, decompressive craniectomy may lead to rapid improvement and an improved outcome. Survival has been reported with combination treatment using corticosteroids, plasma exchange, and decompressive craniectomy if needed in such cases.

PROGNOSIS While the acute phase of ADEM can be severe and children are often illappearing, the prognosis of ADEM is generally favorable and the majority patients with ADEM recover fully. The average time to complete recovery ranges between 1 and 6 months, though patients typically show some improvement within a few days of starting treatment. Despite the favorable prognosis, minor residual deficits have been reported in up to 20% to 30% of children.9,14 Residual deficits depend on the clinical sites involved, with the most common residual deficits including motor dysfunction, visual and cognitive impairment, behavioral problems, and seizures.18,19 Although ADEM is typically monophasic, a child may rarely experience a second ADEM-like attack. According to the most recent IPMSSG consensus criteria, multiphasic ADEM can be diagnosed if a patient experiences two attacks consistent with ADEM separated by at least 3 months. The second attack may be characterized by new symptoms or recurrence of prior symptoms. Should a patient have a third event, the diagnosis is no longer consistent with ADEM and investigations into a more chronic inflammatory disorder should be pursued.13

CLINICALLY ISOLATED SYNDROME

As defined by the IPMSSG, clinically isolated syndrome (CIS) represents an initial event of CNS inflammation characterized by either monofocal or polyfocal neurologic dysfunction.13 In contrast to ADEM, encephalopathy is not a clinical feature in CIS and should not be present unless the brainstem is involved. CIS is a heterogeneous clinical syndrome and symptoms reflect the involved areas in the CNS. The two most common clinically isolated syndromes, ON and transverse myelitis, are described below.3 Visual disturbances and spinal cord disease can also be seen in ADEM, MS, and NMO; therefore it is important to determine whether the patient meets criteria for these alternate diagnoses. This often requires comprehensive imaging of the brain and spine for asymptomatic lesions. In other words, a patient presenting with a first clinical attack may actually have MS if the 2010 McDonald criteria are fulfilled (see MS section below).20

OPTIC NEURITIS ON is an acute inflammatory demyelinating event in which the anterior visual pathway (optic nerve and/or chiasm) is affected. ON can be either unilateral or bilateral. Additionally, ON can occur either in insolation, or in the context of diffuse demyelination (as part of an attack of ADEM, MS, or NMO). Clinical Presentation ON is typically associated with a disturbance in vision or decreased visual acuity, reduced color vision, decreased depth perception, and sometimes visual field defects.21 See Table 122-3 for a summary of the ophthalmologic findings in ON. Eye pain is also typically reported with ON, and generally worsens with eye movement. Disc swelling can occur in ON but it is not a required feature since its visualization depends on the site of optic nerve inflammation. If the inflammation occurs at the junction between the retina and optic nerve, disc swelling may be seen on funduscopic examination. However, if the inflammation affects the posterior optic nerve, disc swelling is not typically visible, and the term retrobulbar ON is preferred. TABLE 122-3

Ophthalmologic Findings in Optic Neuritis Method

Test

Bedside Tests

Ophthalmologic Tests Findings

Visual acuity Near card

Snellen or Decreased visual equivalent distance acuity ranging eye charts from subtle deficits (such as 20/40) to severe visual loss (no light perception).

Color vision

Red desaturation

Ishihara color plates

Dyschromatopsia (difficulty with color vision).

Visual fields

Confrontational testing

Perimetry testing

Visual field defect (especially central scotoma).

Afferent pupillary defect

Swinging Swinging flashlight flashlight test: test the examiner swings a light back and forth from one pupil to the other, and observes the size of the pupils as the patient gazes straight ahead

Funduscopic Undilated exam

Dilated

Normally, both the illuminated and nonilluminated pupil will constrict. In cases of optic neuritis, when light is moved away from the unaffected eye and toward the affected eye, the non-illuminated pupil will dilate from its prior constricted state. Normal in

examination

with an examination with ophthalmoscope indirect and direct visualization of the optic nerve

retrobulbar optic neuritis, or disc edema is present in papillitis.

Differential Diagnosis ON can occur as an isolated inflammatory event, but can also manifest as part of other inflammatory disorders such as MS, NMO, ADEM, or chronic relapsing inflammatory optic neuropathy (CRION). Presence of other clinical features (myelopathy, encephalopathy, relapsing course, or poor response to therapy) can help to differentiate these entities. Neuroretinitis, characterized by vision loss, optic disc swelling, and macular exudate, often occurs in the setting of infection and must be considered in the differential of inflammatory ON. Cat-scratch disease, caused by Bartonella henselae, is a common cause of neuroretinitis. Another common cause of optic neuropathy in the pediatric population is Lyme disease, caused by Borrelia burgdorferi, which should be investigated in the appropriate clinical context.22 Leber hereditary optic neuropathy is a mitochondrial disorder that should be considered in patients presenting with bilateral subacute, painless vision loss. Vision loss typically progresses over weeks to months, and final visual acuity is less than 20/200 in both eyes. This disorder is most commonly diagnosed in males between the ages of 15 and 35 years.23 Diagnostic Evaluation • CSF Analysis CSF analysis is not always obtained in cases of isolated ON.7 When done acutely, a lymphocytic pleocytosis has been reported in about 33% to 50% of patients, and CSF protein and glucose are usually normal.21,24 The presence of oligoclonal bands has been reported in patients with ON and can be predictive of a diagnosis of MS, especially when seen in conjunction with an abnormal brain MRI.25 MRI of the orbits may be obtained to confirm a diagnosis of ON, and typically reveals optic nerve swelling, T2/FLAIR hyperintensity, and/or contrast enhancement of the optic nerve (Figure 122-2). In a study of 36 children with ON followed prospectively, neuroimaging of the optic nerve was found to be abnormal in 55% of the cohort.24 Imaging

FIGURE 122-2. Optic Neuritis - Typical radiologic features of Optic Neuritis: axial T2 weighted image (upper image) showing enlargement and increased signal (arrow). Axial T1 post-contrast image (lower image) demonstrating enhancement of the intraorbital left optic nerve (arrow). In cases of ON, a brain MRI can lead to the confirmation of an MS diagnosis if asymptomatic brain lesions are present thereby demonstrate dissemination in time and space20 (see Prognosis section below). Inflammation of the optic chiasm seen on a brain or orbit MRI should also raise suspicion for NMO. Similarly, an MRI of the C- and T-spine can also be helpful, as they may reveal lesions suspicious for MS or NMO. Management In adults, the Optic Neuritis Treatment Trial has shown that treatment does not affect the long-term recovery of visual function (acuity) in ON.26 In this trial, the visual acuity at the conclusion of the study was favorable regardless of whether a subject received IV methylprednisolone, oral prednisone, or placebo. However, treatment with IV steroids has been shown to increase the rate of visual recovery in patients with ON.27 In addition, the use of oral steroids (specifically prednisone 1 mg/kg/day) in adults was associated with an increased risk of ON relapse. Therefore many neurologists and ophthalmologists still administer IV methylprednisolone for 3 days, often followed by a taper over 1 to 2 weeks. Prognosis In pediatric patients with monophasic ON, visual recovery is typically excellent. The majority (76%–80%) of patients regain visual acuity of better than 20/40 in the affected eye.26,28 Of note, many children in these studies received IV methylprednisolone.24 Though ON can be isolated and monophasic, it can also be the initial

presentation of a chronic demyelinating disorder, such as MS or NMO. Studies have shown that the presence of one of more clinically silent white matter lesions (outside the optic nerve) on brain imaging is strongly associated with a subsequent MS diagnosis.24 Children without additional clinically silent white matter lesions at onset are at very low risk for MS as well.4,24,29,30 ON is also a major criterion for NMO (discussed below). The visual deficits in NMO may not recover as readily as seen in monophasic ON. Finally, isolated ON (without brain or spinal cord lesions) can also rarely recur and is termed either sequential or recurrent ON depending on the affected eye and timing of relapse.

TRANSVERSE MYELITIS Transverse myelitis is an inflammatory demyelinating disorder characterized by acute or subacute motor, sensory, and/or autonomic spinal cord dysfunction. Diagnostic criteria established by the Transverse Myelitis Consortium Working Group in 2002 require the presence of spinal cord inflammation, as evidence by CSF pleocytosis, elevated IgG index, or gadolinium enhancement on spine MRI, with the exclusion of CNS infection, compressive myelopathy, or another underlying disease process that may account for symptoms (such as connective tissue disease or vascular malformations).31 Like ON, transverse myelitis can occur as a clinically isolated syndrome in which only spinal cord signs and symptoms occur, or can occur in the context of another demyelinating disease in which there may be brain and/or optic nerve involvement as well. Clinical Presentation Symptoms that suggest spinal cord inflammation include acute respiratory failure, bowel or bladder dysfunction, weakness involving the legs and/or arms, and a Lhermitte sign (an electrical sensation that extends down the spine and is often elicited by forward flexion of the neck) with the absence of cortical signs (visual field deficits, aphasia, or neglect). In addition, positive sensory symptoms (tingling, burning) or sensory loss/numbness are common in patients with transverse myelitis. Symptoms typically progress over days, and most patients reach their clinical nadir between 2 and 10 days after their first clinical symptom.32,33 In terms of motor dysfunction, while flaccidity and depressed reflexes are typically present initially, this evolves into spasticity and hyperreflexia over the course

of about 1 week. In patients with inflammatory transverse myelitis, a sensory level (rostral border of sensory loss) may be detected on neurologic examination. In one case series, the sensory level was detected most commonly at a thoracic level.33 Additional findings on exam may include extremity weakness, sensory dysfunction, (vibration, light touch, or temperature discrimination), and abnormal reflexes (may be depressed acutely or brisk if few days into the course). Differential Diagnosis When a patient presents with suspected spinal cord pathology, a careful history and examination are urgently needed to determine the extent of neurologic injury, risk factors, and time course. First, a compressive lesion must be excluded. This is considered a neurologic emergency for which prompt imaging is required (see below). Compressive lesions can be caused by herniated discs, neoplasms, and other causes. A history of trauma or malignancy raises concern for a herniated disc or metastasis, respectively. Pathologic vertebral fractures or spondylolisthesis have also caused compressive lesions. Guillain-Barré syndrome (GBS), an acute polyneuropathy, is another important entity to consider in the differential of transverse myelitis and can sometimes be differentiated by a history of ascending weakness and lower extremity pain. Reflexes are often absent or depressed with GBS. CSF sampling (looking for elevated protein without an accompanying pleocytosis) and electromyography can help to confirm this diagnosis. The timing of symptoms should also be noted and can help to differentiate transverse myelitis from other disorders. As described above, symptoms in inflammatory transverse myelitis progress over days, typically 2 to 10 days. In contrast, an ischemic process nadirs over several hours. The presence of fever, rash, meningismus, adenopathy, and active systemic infections are worrisome for an infectious etiology rather than an inflammatory process. The differential for infectious etiologies affecting the CNS is similar to other disorders and outlined in Table 122-2. Diagnostic Evaluation • CSF Analysis A CSF pleocytosis or abnormal CSF protein is reported in more than half of children with transverse myelitis. In one study of 47 pediatric patients with transverse myelitis, the mean CSF WBC was 137 ± 67 cells/mm3 and the mean CSF protein was 173 ±75

mg/dL.33 It is uncommon for oligoclonal bands to be present in the CSF in cases of isolated transverse myelitis and have been reported in less than 5% of cases. In fact, the presence of CSF oligoclonal bands should raise suspicion for another process such as MS, and further investigation should be pursued. An MRI of the spine is typically notable for T2 signal abnormality in either the thoracic or cervical levels of the spinal cord in transverse myelitis. Lesions can be small or longitudinally extensive (≥3 spinal segments) and there may be more than one lesion present (See Figure 122-3). One case series reported that the average number of spinal cord segments spanned for an acute transverse myelitis lesion was six.33 Of note, longitudinally extensive cord lesions are also sometimes seen in cases of ADEM or NMO. Gadolinium enhancement of spinal cord lesions is also common in transverse myelitis and has been reported in up to 74% of cases.33 Imaging

FIGURE 122-3. Sagittal T2 weighted images demonstrating short segment versus (left, small bracket) longitudinally extensive (right, large bracket) myelitis. Rarely, the spine MRI in transverse myelitis can be normal. In these cases, clinical symptoms and CSF findings are used to make the diagnosis. Management When the diagnosis of transverse myelitis is suspected, prompt treatment with corticosteroids should be initiated (see Treatment section). If symptoms are severe or do not improve with steroids, early

initiation of plasma exchange should be considered. In severe cases unresponsive to steroids and plasma exchange, immunosuppressive therapies such as cyclophosphamide can be used. Prognosis The prognosis with acute transverse myelitis is variable, and many children require intensive rehabilitation and ongoing support for activities of daily living at follow-up. Studies have reported that up to 40% of children surviving transverse myelitis remain wheelchair-dependent, 80% are left with residual bladder symptoms (30% of whom remain catheterdependent), and 27% require assistance for tasks of daily living.33 Pain and sensory symptoms may also persist with transverse myelitis. Depending on the severity of symptoms, evaluation by pain management specialists may be necessary. Clinical factors that have been associated with better functional outcome include shorter time to diagnosis, absence of complete paraplegia, and a lower sensory level found on examination.34 Young age at onset, requirement of respiratory support during the acute illness, and higher CSF WBC counts have all been shown to predict worse functional outcome in follow-up. In terms of prognostic radiologic features, Pidcock et al reported that the presence of T1 hypointensity at onset correlated with worse ambulation outcome.33 Although transverse myelitis is most commonly isolated and monophasic, it can also be the first presentation of a more chronic process such as MS or NMO. A number of studies have shown that with a normal brain MRI, likelihood of an MS diagnosis after the initial attack of transverse myelitis is low. Longitudinally extensive cord lesions should prompt consideration of NMO, especially if there is optic nerve or brainstem/hypothalamic involvement on MRI.

MULTIPLE SCLEROSIS MS is a chronic demyelinating disease resulting in multiple areas of CNS inflammation in both children and adults. Using the 2010 revised McDonald criteria, a diagnosis of MS is confirmed after at least two clinical “MS-like” (non-encephalopathic) events separated by at least 30 days and involving different areas of the CNS (known as dissemination in time and space). Alternatively, a diagnosis of MS can be made at the time of a first clinical

demyelinating “MS-like” event if a patient’s MRI shows radiographic evidence of lesions that are disseminated in time and space using specific criteria.13,20 As other diseases may clinically or radiologically mimic MS, it is imperative that an appropriate diagnostic workup be initiated to exclude these disorders in the correct clinical context (see differential diagnosis section and Table 122-1).

CLINICAL PRESENTATION MS is characterized by transient neurologic symptoms, lasting days to weeks, due to areas of focal inflammatory demyelination in the CNS. Presenting manifestations are heterogeneous, reflecting the regions of the CNS that are involved. While ON and sensory symptoms are the most common initial presentations, other symptoms such as weakness or hemiparesis, ataxia, diplopia (secondary to an isolated intranuclear ophthalmoplegia or other cranial nerve palsy), and bladder or bowel dysfunction can also herald onset of this disease.

DIFFERENTIAL DIAGNOSIS In children, MS is almost exclusively relapsing-remitting (defined as attacks of neurologic dysfunction followed by periods in which symptoms either partially or completely improve without accrual of disability). Therefore the diagnosis should be questioned in any patient who presents with progressive neurologic symptoms from onset. Additionally, seizures and encephalopathy (in the absence of a brainstem lesion) are uncommon in pediatric MS.

DIAGNOSTIC EVALUATION CSF analysis A lymphocytic pleocytosis has been reported in about twothirds of children with MS, though a CSF WBC count greater than 50 is uncommon.35 CSF protein may be elevated but this is not a requirement. Oligoclonal bands, which are a key diagnostic feature in adult MS, are less commonly seen in young children with MS. Studies have reported positive oligoclonal bands in 40% to 90% of pediatric patients,36 with some

variability explained by different methodology of oligoclonal band detection. Imaging MS lesions are hyperintense on T2-weighted or FLAIR sequences and most commonly found in the periventricular white matter, corpus callosum, junctions of the gray–white matter (juxtacortical areas), and the spinal cord. “Dawson fingers” are a radiographic feature depicting demyelinating plaques through the corpus callosum, arranged at right angles to the ventricle, along medullary veins (callososeptal location) (Figure 1224). Lesions that are chronically hypointense on T1 sequences are termed “black holes” and are associated with areas of severe white matter destruction and axonal loss.37

FIGURE 122-4. “Dawson’s fingers” – A common radiologic feature of MS: (left) axial FLAIR image illustrating typical periventricular sharply demarcated ovoid lesions, (right) sagittal FLAIR image depicting Dawson’s fingers extending from the corpus callosum, arranged at right angles to the ventricle. Figure 122-5 compares and contrasts radiologic features of MS and ADEM. When trying to radiologically distinguish MS from ADEM, features such T1 hypointense lesions, periventricular lesion location, and absence of bilateral diffuse lesions38 have been found to be more consistent and predictive of MS.

FIGURE 122-5. ADEM vs. MS - Contrasting radiographic features of ADEM and MS: (left) axial FLAIR image demonstrating typical brain lesions in ADEM, which tend to be large with ill-defined borders (closed arrow). Involvement of the deep gray nuclei is commonly seen (open arrow). (Right) Axial FLAIR image demonstrating the typical MRI appearance of MS, which is characterized by multifocal ovoid lesions that have sharper borders and are primarily in the periventricular (arrow) and subcortical white matter.

MANAGEMENT Similar to the other acquired demyelinating syndromes, intravenous corticosteroids are typically used to treat moderate to severe neurologic symptoms. Acute treatment is thought to hasten clinical recovery of neurologic symptoms but has not been shown in adults to impact disease course or prognosis.39 Therefore an expert panel has stated that not all attacks require acute therapy. Instead, the decision to initiate impatient treatment is based on the severity of symptoms. After the diagnosis of MS is confirmed, a patient will be started on disease-modifying therapy; typically interferon beta (Avonex, Betaseron, Extavia, and Rebif) and glatiramer acetate (Copaxone) in the outpatient setting. These medications are given by injection (intramuscular for Avonex, all others are subcutaneous) and are not on hospital formularies. For established MS patients who are hospitalized for an MS flare, they must bring

their own medication from home. Natalizumab (Tysabri) has also been used in the pediatric population and is given intravenously every 28 days. There are significant risks with this medication, namely progressive multifocal leukoencephalopathy (PML). PML has been reported in adults receiving natalizumab, especially those with exposure to natalizumab over 2 years, John Cunningham (JC) virus (a polyoma virus) positivity, and a history of immunosuppression. Given the risk of PML, natalizumab can only be given through certified centers familiar with the infusion protocol.

PROGNOSIS Neurologic recovery after MS flares is typically more complete in children as compared to adults.40 As compared with adult patients, the relapse rate in children with MS is higher (1.12–2.76 in children vs. 0.3–1.78 in adults),41,42 and most patients will experience a second clinical event within a year of their first attack. Children typically accrue physical disability more slowly as compared to adults. One longitudinal study reported the median time from initial attack to secondary progression was 28 years, which is about 10 years longer than the average time reported for time to irreversible disability in adult MS patients.42

NEUROMYELITIS OPTICA NMO is a demyelinating disorder that is most commonly characterized by repeated attacks on the spinal cord and optic nerves. According to the most recent consensus criteria, a diagnosis of NMO requires at least one episode of ON and one episode of acute myelitis as major criteria, and either a longitudinally extensive cord lesion (≥3 spinal segments) or anti-aquaporin-4 antibody (NMO-IgG) seropositive status (discussed below).13,43 Of note, patients who are found to have a positive anti-aquaporin-4 antibody but do not meet all of the clinical criteria for NMO are considered to have an NMOspectrum disorder.

CLINICAL FEATURES ON occurs at disease onset in about half of pediatric patients with NMO and

about 15% of patients present with bilateral ON.33 Isolated transverse myelitis, which often is longitudinally extensive, is the presenting episode in about one-quarter of patients with NMO and simultaneous ON and transverse myelitis is found in about 9% of patients at onset.6 In NMO, attacks are usually severe and can result is permanent motor and visual dysfunction.44 Additionally, symptoms such as hiccups, nausea, and vomiting are often reported in patients with NMO and are usually referable to lesions involving the periaqueductal gray, an area rich in aquaporin 4.

DIFFERENTIAL DIAGNOSIS Similar to the other acute demyelinating syndromes, infectious, metabolic, and systemic rheumatologic diseases must be considered (Table 122-2). Though recovery from clinical exacerbations may not be as complete or rapid in NMO as it is in MS, the diagnosis of NMO should still be questioned in any patient who presents with progressive neurologic symptoms from onset.

DIAGNOSTIC EVALUATION NMO-IgG NMO-IgG is considered a pathogenic autoantibody and biomarker for NMO that selectively binds aquaporin 4, a protein that is highly expressed in the astrocytic foot processes that forms a component of the blood–brain barrier. The antibody can be identified in both serum and CSF of NMO patients but is not currently required for diagnosis if the clinical criteria for NMO are met. In one study of a cohort of pediatric patients with clinically diagnosed NMO, 78% of children with relapsing NMO were found to be seropositive and only 12.5% of patients with monophasic NMO were found to have the NMO autoantibody.45 Serological testing for NMO-IgG has high specificity and has become more sensitive in recent years. Tests using recombinant aquaporin 4 antigen–based assays are preferred over tissue-based immunofluorescence.46 CSF Analysis A CSF lymphocytic or neutrophil predominant leukocytosis and/or elevated CSF protein are present in more than 50% of patients with NMO. In addition, it is not uncommon to have a CSF pleocytosis of more than 50 WBC per mm3 in NMO. In fact, the CSF WBC may be several

hundred or even reach 1000. Unlike with MS, oligoclonal bands are rare and are only reported in about 6% of cases.5 Imaging With NMO, spine MRI commonly shows longitudinally extensive lesions spanning multiple cord segments. Brain imaging can vary from being normal without evidence of demyelination to showing large tumefactive supratentorial lesions. Most commonly, brain lesions in NMO tend to involve the brainstem and hypothalamic regions. Acutely, the MRI of the optic nerve in NMO patients may show nerve swelling with enhancement, which then later evolves to optic nerve atrophy.

MANAGEMENT To date, there have been no randomized controlled trials for the acute or chronic treatment of pediatric NMO. As a result, treatment recommendations are based on expert consensus and observational reports. Management of an acute NMO attack is similar to treatment of any acute demyelinating flare (see Management section above) and begins with administration of high-dose intravenous corticosteroids. In contrast to the other disorders, early PE is recommended by some practitioners. Similarly, immune suppression may be initiated early. In terms of long-term treatment, chronic immunosuppression is currently prescribed for relapsing NMO to prevent ongoing attacks and disability accrual. A number of long-term treatments have been used for NMO including daily low-dose prednisone, mycophenolate mofetil, azathioprine, and rituximab, a monoclonal antibody to the CD 20 antigen found on B cells, with variable success.

PROGNOSIS While NMO can be monophasic (requiring a single event of simultaneous ON and transverse myelitis without recurrent episodes of demyelination), 90% of patients have a relapsing course, with the diagnosis being confirmed at a time after the initial attack of isolated transverse myelitis or ON. As compared with MS flares, recovery from NMO attacks is poor and patients can accrue permanent disability from each attack. Similar to MS, adults and children with NMO have been reported to have long-term cognitive sequelae

that include memory, processing, and language dysfunction.47 DEMYELINATING DISEASE WORKUP: KEY POINTS Brain MRI is always necessary in an acquired demyelinating syndrome as it delineates the extent of inflammation and can help prognosticate risk for MS diagnosis in CIS (especially cases of ON or transverse myelitis). If clinical symptoms are referable to the spinal cord, spine MRI is warranted. Typically, the entire cord can be visualized with just a cervical and thoracic spine MRI. If CSF analysis is performed, oligoclonal bands should always be sent when considering a demyelinating etiology. A paired serum sample, which should ideally be collected at the same time, must also be sent within 48 hours. Screening labs for other systemic inflammatory diseases (see Table 122-2) should be considered and sent in the appropriate clinical context (i.e. other systemic symptoms present). Patients with demyelination may rarely have normal imaging and CSF studies at presentation. If the clinical level of suspicion remains high for demyelination, these studies should be repeated in 5 to 7 days, as the inflammation detected by these tests may lag behind the clinical symptoms.

ADMISSION CRITERIA Patient has persistent neurologic symptoms with or without clear etiology. Diagnostic workup should be tailored based on patient history and presenting symptoms. Intravenous therapy is required acutely due to the severity of symptoms.

DISCHARGE CRITERIA The patient is medically stable and has started to experience improvement of symptoms.

No further IV therapy is required. If the severity of neurologic symptoms does not warrant an inpatient admission for rehabilitation and the clinical course is improving without the need for escalating of therapy, the patient may be discharged.

CONSULTATION Input from a neurologist is generally warranted to advise on diagnostic testing and appropriate treatment of all patients admitted with a demyelinating disease. Outpatient neurologic follow-up will be required whether the disease is monophasic or chronic. If a patient is diagnosed with MS or NMO, the patient will need to be started on immunomodulatory therapy by a neurologist, which is often done in the outpatient setting after discharge from the hospital. If a patient presents with visual dysfunction, an evaluation by an ophthalmologist or a neuro-ophthalmologist is also likely indicated. KEY POINTS Visual or sensory disturbances are often the initial presenting symptoms of demyelination in the pediatric population. Therefore practitioners should have a high index of suspicion when evaluating children with blurry or altered vision or paresthesias. The neurologic exam may be normal in children with isolated sensory or visual symptoms, and diagnostic imaging may still be warranted. When considering a demyelinating etiology based on symptoms, MRI of the brain, optic nerves, and cervical and thoracic spine may reveal pathology. Imaging should primarily be directed by presumed localization of symptomatology. Corticosteroids are first-line therapy for demyelination and their initiation should not be delayed unless there is a high suspicion for underlying CNS infection (especially fungal). Early referral to neurology can help guide evaluation and management of demyelinating disorders.

SUGGESTED READINGS Banwell, B. Acute disseminated encephalomyelitis. In: Lisak R, Truong D, Carroll W, Bhidayasiri R eds. International Neurology. Wiley-Blackwell; 2009:381-385. Waldman AT, Shumski MJ, Tennekoon GI. Acquired demyelinating syndromes of the central nervous system. In: Abend NS, Helfaer MA eds. Pediatric Critical Care. Demos Medical; 2012.

REFERENCES 1. Murthy SN, Faden HS, Cohen ME, Bakshi R. Acute disseminated encephalomyelitis in children. Pediatrics. 2002;110 (2 Pt 1):e21. 2. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59(8):1224-1231. 3. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology. 2009;72(3):232-239. 4. Waldman AT, Stull LB, Galetta SL, et al. Pediatric optic neuritis and risk of multiple sclerosis: meta-analysis of observational studies. J AAPOS. 2011;15(5):441-446. 5. Lotze TE, Northrop JL, Hutton GJ, et al. Spectrum of pediatric neuromyelitis optica. Pediatrics. 2008;122(5):e1039-1047. 6. McKeon A, Lennon VA, Lotze T, et al. CNS aquaporin-4 autoimmunity in children. Neurology. 2008;71(2):93-100. 7. Waldman AT, Gorman MP, Rensel MR. Management of pediatric central nervous system demyelinating disorders: consensus of United States neurologists. J Child Neurol. 2011;26(6):675-682. 8. Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology. 2001;56(10):1308-1312. 9. Pohl D, Tenembaum S. Treatment of acute disseminated encephalomyelitis. Curr Treat Options Neurol. 2012;14(3):264-275.

10. Payne ET, Rutka JT, Ho TK, et al. Treatment leading to dramatic recovery in acute hemorrhagic leukoencephalitis. J Child Neurol. 2007;22(1):109-113. 11. Richards RN. Short-term corticosteroids and avascular necrosis: medical and legal realities. Cutis. 2007;80(4):343-348. 12. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300. 13. Krupp LB, Tardieu M, Amato MP, et al., International Pediatric Multiple Sclerosis Study Group. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revision to the 2007 definitions. Mult Scler. 2013;19(10):1261-2167. 14. Tenembaum SN. Acute disseminated encephalomyelitis. Handb Clin Neurol. 2013;112:1253-1262. 15. Dale RC, Brilot F. Biomarkers of inflammatory and autoimmune central nervous system disorders. Curr Opin Pediatr. 2010;22:718-725. 16. Pohl D, Hennemuth I, von Kries R, et al. Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey. Eur J Pediatr. 2007;166:405-412. 17. Verhey LH, Branson HM, Shroff MM, et al., Canadian Pediatric Demyelinating Disease Network. MRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective national cohort study. Lancet Neurol. 2011;10(12):10651073. 18. Tenembaum S, Chitnis T, Ness J, Hahn JS, International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007;68(16 Suppl 2):S23-36. 19. Dale RC, de Sousa C, Chong WK, et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain/ 2000;123 (12):2407-2422. 20. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol.

2011;69(2):292-302. 21. Liu, GT, Volpe NJ, Galetta SL. In: Gabbedy R ed. NeuroOphthalmology: Diagnosis and Management. 2nd ed. Saunders Elsevier; 2010;131-143. 22. Costello F. Inflammatory optic neuropathies. CONTINUUM: Lifelong Learning in Neurology. 2014;20(4):816-837. 23. Van Stavern G. Metabolic, hereditary, traumatic, and neoplastic optic neuritis. CONTINUUM: Lifelong Learning in Neurology. 2014;20(4):877-906. 24. Wilejto M, Shroff M, Buncic JR, et al. The clinical features, MRI findings, and outcome of optic neuritis in children. Neurology. 2006;67(2):258-262. 25. Cole SR, Beck RW, Moke PS, et al. The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. The Optic Neuritis Study Group. Neurology. 1998;51(3):885-887. 26. Beck RW, Cleary PA. Optic neuritis treatment trial. One-year follow-up results. Arch Ophthalmol. 1993;111(6):773-773. 27. Beck RW, Cleary PA, Anderson MM, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581-588. 28. Brady KM, Brar AS, Lee AG, et al. Optic neuritis in children: clinical features and visual outcome. J AAPOS. 1999;3(2):98-103. 29. Alper, G. Wang L. Demyelinating optic neuritis in children. J Child Neurol. 2009;24(1):45-48. 30. Bonhomme GR, Waldman AT, Balcer LJ, et al. Pediatric optic neuritis: brain MRI abnormalities and risk of multiple sclerosis. Neurology. 2009;72:881-885. 31. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59(4):499-505. 32. Kerr DA, Krishnan C, Pidcock F. Acute transverse myelitis. In: Singer HS, Kossoff EH, Hartman AL, Crawford TO eds. Treatment of Pediatric Neurologic Disorders. Boca Raton, FL: Taylor and Francis; 2005:445451. 33. Pidcock FS, Krishnan C, Crawford TO, et al. Acute transverse myelitis

in childhood: center-based analysis of 47 cases. Neurology. 2007;68(18):1474-1480. 34. Defresne P, Hollenberg H, Husson B, et al. Acute transverse myelitis in children: clinical course and prognostic factors. J Child Neurol. 2003;18(6):401-406. 35. Pohl D, Rostasy K, Reiber H, et al. CSF characteristics in early-onset multiple sclerosis. Neurology. 2004;63(10):1966-1967. 36. Ness JM, Chabas D, Sadovnick AD, et al., International Pediatric MS Study Group. Clinical features of children and adolescents with multiple sclerosis. Neurology. 2007;68(16 Suppl 2):S37-45. 37. van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology. 1998;50(5):1282-1288. 38. Callen DJ, Shroff MM, Branson HM, et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology. 2009;72(11):968-973. 39. Ciccone A, Beretta S, Brusaferri F, Galea, I, Protti A, Spreafico C. Corticosteroids for the long-term treatment in multiple sclerosis. Cochrane Database Syst Rev. 2008; (1): CD006264. 40. Fay AJ, Mowry EM, Strober J, Waubant E. Relapse severity and recovery in early pediatric multiple sclerosis. Mult Scler. 2012;18(7):1008-1012. 41. Gorman MP, Healy BC, Polgar-Turcsanyi M, Chitnis T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol. 2009;66(1):54-59. 42. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356(25):2603-2613. 43. Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489. 44. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53(5):1107-1114. 45. Banwell, B, Tenembaum S, Lennon VA, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology.

2008;70(5):344-352. 46. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostaus and disability outcome in neuromyelitis optica. Neurology. 2013;81(14):1197-1204. 47. Blanc F, Zephir H, Lebrun C, et al. Cognitive functions in neuromyelitis optica. Arch Neurol. 2008;65:84-88.

SECTION N Newborn Medicine

CHAPTER

123

Delivery Room Medicine Kelley Shultz

BACKGROUND In order for a normal transition from fetal to newborn physiology to occur, a complicated and well-orchestrated sequence of physiologic changes must transpire. While the majority of newborns transition from fetal to postnatal circulation without significant difficulty, it is estimated that 10% require some degree of resuscitation in the delivery room and about 1% require significant resuscitation.1 Birth asphyxia accounts for approximately 23% of the 4 million neonatal deaths per year.1 Delays in establishing effective cardiorespiratory function may increase the risk for hypoxic-ischemic cerebral injury, pulmonary hypertension, and systemic organ dysfunction. Some of these injuries may be preventable with prompt resuscitation. However, some of these outcomes are related to events or exposures that precede the birth process, such as prenatal injuries, abnormal development, and insults to the intrauterine environment.

PATHOPHYSIOLOGY The adaptation from intrauterine life to extrauterine life starts during the process of labor.2 Labor not only increases oxygen consumption in the transitioning fetus but also causes brief periods of asphyxia during contractions as umbilical venous blood flow is briefly interrupted. The fetus tolerates this interruption in blood flow because fetal tissue beds have greater resistance to acidosis than adult tissue beds do. The fetus responds to bradycardia with the “diving reflex” whereby blood preferentially flows to the brain, heart, and adrenal glands. Finally, the fetus is capable of switching to anaerobic sugar production, provided that liver glycogen stores are

adequate. During labor and delivery, catecholamine levels surge and increase lung fluid resorption, release of surfactant, and stimulation of gluconeogenesis. This surge also helps direct blood flow to vital organs such as the heart and brain. With clamping of the umbilical cord, the low-resistance placental circuit is removed from the newborn’s circulation. Systemic blood pressure increases, and transition to the postnatal circulation begins.2 As a newly born infant takes the first few breaths, negative intrathoracic pressure is generated, which helps the lungs expand and become filled with air. Alveolar oxygenation increases as air replaces the fetal lung fluid. The negative intrathoracic pressure, however, is countered by lung compliance, lung fluid viscosity, and surface tension forces. Because these factors need to be overcome to establish adequate alveolar expansion, the infant must take deep enough breaths to create the large transpulmonary pressure initially required after birth. Surfactant, a phospholipid-protein complex that is produced by type II pneumocytes and is deposited along the alveolar surfaces, also helps counteract alveolar surface tension and promote alveolar stability. As a result of the increasing effect of surfactant, less transpulmonary pressure is needed for subsequent breaths, and functional residual capacity is soon established. Pulmonary blood flow increases as the lungs expand, and pulmonary vascular resistance declines under the influence of oxygen-mediated relaxation of the pulmonary arterioles. This increase in pulmonary blood flow in turn allows the patent foramen ovale and the patent ductus arteriosus to functionally close, thereby allowing further blood flow to the lungs. The postnatal circulation is now that of a low-resistance pulmonary circuit and high-resistance systemic circuit, and the lungs assume the responsibility of gas exchange and oxygenation.2 Asphyxia is defined as failure of gas exchange leading to a combination of hypoxemia, hypercapnia, and metabolic acidemia. If adequate ventilation and pulmonary perfusion are not rapidly established, a progressive cycle of worsening hypoxemia, hypercapnia, and metabolic acidemia ensues. Initially, blood flow to the brain and heart is preserved, whereas blood flow to the intestines, kidneys, muscles, and skin is sacrificed. However, maintenance of blood flow, even to vital organs, cannot be sustained endlessly. Ultimately, ongoing ischemia, hypoxia, and acidosis result in myocardial dysfunction and impaired cardiac output. Inadequate blood flow, perfusion, and tissue

oxygenation result in brain injury, multiorgan injury, and even death.

CLINICAL PRESENTATION Clinical signs and symptoms of disrupted fetal-to-neonatal transition include cyanosis, bradycardia, hypotension, decreased peripheral perfusion, depressed respiratory drive, and poor muscle tone. Apgar scoring is an objective method of quantifying the infant’s status and to convey information about response to resuscitation, depicted in Table 123-1. The newborn is assessed at 1 and 5 minutes, and if the 5-minute score remains less than 7, additional scores should be assigned every 5 minutes for up to 20 minutes.1 Because resuscitation must be initiated before a 1-minute score is assigned, Apgar scores should not be used to determine need for resuscitation or to guide steps of resuscitation. However, changes in Apgar scores at sequential time points after birth can reflect how well the infant is responding to resuscitation. TABLE 123-1

Apgar Scoring Score of 0

Score of 1

Score of 2

Skin color/ Blue or pale Blue at Complexion all over extremities Pink body (acrocyanosis)

No cyanosis Body and extremities pink

Pulse rate

Absent

36.5°C and 97.7°F and 60%) or respiratory support such as mechanical ventilation. PPHN is one of the more serious conditions that presents with respiratory distress, but others must also be considered. A newborn exhibiting prolonged, significant respiratory distress or requiring a high level of respiratory support may be suffering from neonatal sepsis, pneumonia, pneumothorax, respiratory distress syndrome, or

cardiac disease. TABLE 127-1

Causes of Respiratory Distress in the Newborn

Structural and anatomic Diaphragmatic hernia Choanal atresia Tracheomalacia Laryngomalacia Tracheoesophageal fistula Vocal cord paralysis Excessive nasal secretions Pulmonary Transient tachypnea of the newborn Respiratory distress syndrome Meconium aspiration syndrome Persistent pulmonary hypertension of the newborn Pulmonary hypoplasia Pneumothorax Neonatal pneumonia Pulmonary cysts Infectious Neonatal pneumonia Sepsis Systemic Metabolic acidosis Hypothermia Encephalopathy Cardiac Congenital heart disease

Significant cardiac malformations causing respiratory distress can be differentiated from TTN and other causes of respiratory distress. The initial evaluation should include auscultation for the existence of a pathologic murmur. Chest radiography may also be useful to assess for cardiomegaly or vascular congestion/differentiating these disorders. In infants with significant cyanotic cardiac lesions, blood is shunted away from the lungs through the lesion. Therefore, when these infants receive exogenous oxygen, their oxygen saturation or arterial oxygen tension improves only minimally (or not at all). Measurements of upper and lower extremity blood pressures may reveal a difference between the two, suggestive of coarctation of the aorta. In the presence of critical lung disease or a more subtle cardiac lesion, echocardiography may be necessary to detect or confirm a diagnosis.

DIAGNOSTIC EVALUATION TTN is a clinical diagnosis. PPHN is also suggested by the clinical presentation, but further diagnostic testing is usually performed to confirm the diagnosis and or assess the severity. The initial evaluation may include a blood gas, a complete blood count (CBC) and a chest radiograph. If there are clinical features (e.g. temperature instability, lethargy) or risk factors (e.g. maternal fever, chorioamnionitis, untreated or incompletely treated maternal group B streptococcal colonization) for infection, appropriate cultures should also be obtained. In addition, measurement of C-reactive protein (CRP) levels may be helpful, although these results may be unreliable when obtained shortly after birth if there has been insufficient time for an inflammatory response to occur. In TTN, an arterial blood gas evaluation reveals a mild respiratory acidosis due to mild hypoxemia and hypercapnia; the complete blood count and C-reactive protein are typically normal. On chest radiographs, classic findings of TTN include prominent central markings suggestive of vascular engorgement, moderate cardiomegaly, increased lung volume, and increased anteroposterior chest diameter.1 Among a cohort of 2824 consecutively born infants, ~4% had a clinical picture consistent with TTN but a normal chest radiograph.9 This finding suggests that TTN can occur despite normal chest findings. Unless the infant’s clinical symptoms suggest more serious disease, other studies are usually not necessary.

In PPHN, chest radiographs typically reveal a normal or slightly enlarged heart. The arterial blood gas evaluation reflects a low oxygen tension for the inspired oxygen content; carbon dioxide levels may be normal if there is no parenchymal lung disease. The presence of a gradient between preductal and postductal oxygen saturation may also be helpful in the diagnosis (see earlier). However, to diagnose PPHN definitively, an echocardiogram must be obtained to exclude structural heart lesions as the cause of the severe hypoxemia. In PPHN, the echocardiogram reveals normal structural anatomy with evidence of increased right ventricular pressure and right-to-left shunting.

MANAGEMENT Management of TTN is supportive. Although an infant exhibiting mild tachypnea can usually be observed for a few hours in the newborn nursery, significant tachypnea (>60 to 80 bpm) prevents oral feeding and necessitates transfer to a higher level of care for initiation of intravenous fluids and monitoring. In selected situations, an orogastric or nasogastric tube can be placed for assistance with feeding, but only after determining that the infant is unlikely to require ventilatory support. Because of concerns about gastroesophageal reflux and aspiration, infants with respiratory rates greater than 90 to 100 breaths per minute should not receive oral or gastric feedings. However, placement of an orogastric or nasogastric tube for stomach decompression may be helpful to maximize lung volume expansion. Supplemental oxygen may be needed, and nasal continuous positive airway pressure may be required for infants exhibiting persistent and significant work of breathing. Although some have proposed that furosemide may be useful in the treatment of TTN, studies have not confirmed that it has any role. Whenever there is concern about PPHN, the infant should be placed on 100% oxygen and transferred to a neonatal intensive care unit. While awaiting transfer, any metabolic abnormalities should be corrected, including metabolic acidosis (although the use of alkalizing agents is controversial), hypoglycemia, hypothermia, hypovolemia, anemia, and hypocalcemia.

ADMISSION AND DISCHARGE CRITERIA

CRITERIA FOR TRANSFER TO A NEONATAL INTENSIVE CARE UNIT Suspected or proven PPHN Respiratory distress requiring supplemental oxygen Significant tachypnea (>60 to 80 bpm) that requires frequent reassessment or precludes oral feeding Prolonged tachypnea (>4 to 6 hours) Respiratory distress that may require the administration of continuous positive airway pressure or other ventilatory support Suspected or proven infection Suspected or proven cardiac disease Respiratory distress for which there is an unclear diagnosis

CRITERIA FOR DISCHARGE IN THE SETTING OF TRANSIENT TACHYPNEA OF THE NEWBORN Resolved respiratory distress No exogenous oxygen requirement for at least 12 to 24 hours Able to feed adequately by mouth Reliable outpatient follow-up

CRITERIA FOR DISCHARGE IN THE SETTING OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN Management and discharge criteria determined by the neonatologist

CONSULTATION Consultation with a pediatric cardiologist should be considered in persistent pulmonary hypertension. KEY POINTS

TTN is a common cause of neonatal respiratory distress that usually presents in the first few hours of life with tachypnea, mild cyanosis, and mildly increased work of breathing. TTN is a clinical diagnosis but may require diagnostic tests to exclude other causes of respiratory distress, based on a history of risk factors and typical findings on chest radiographs. TTN has a benign and self-limited course, and treatment is supportive. PPHN usually occurs in term or near-term infants and presents with severe cyanosis and tachypnea. The findings on chest radiographs depend on the presence of associated lung disease. For any infant suspected of having PPHN, an echocardiogram is required to exclude structural heart defects as the cause of hypoxemia. PPHN is a life-threatening condition that requires management in an intensive care setting.

REFERENCES 1. Avery ME, Gatewood OB, Brumley G. Transient tachypnea of newborn. Am J Dis Child. 1966;111:380-385. 2. Fiori H, Henn R, Baldisserotto M, et al. Evaluation of surfactant function at birth determined by the stable microbubble test in term and near term infants with respiratory distress. Eur J Pediatr. 2004;163:443448. 3. Tutdibi E, Hospes B, Landmann E, et al. Transient tachypnea of the newborn (TTN): a role for polymorphisms of surfactant protein B (SPB) encoding gene? Klin Paediatr. 2003;215:248-252. 4. Levine EM, Ghai V, Barton JJ, Strom CM. Mode of delivery and risk of respiratory diseases in newborns. Obstet Gynecol. 2001;97:439-442. 5. Tita AT, Landon MB, Spong CY, et al. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med. 2009;360:111. 6. Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO:

focus on PPHN. Semin Perinatol. 2005;29:8-14. 7. Konduri GG. New approaches for persistent pulmonary hypertension of newborn. Clin Perinatol. 2004;31:591-611. 8. Dakshinamurti S. Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn. Pediatr Pulmonol. 2005;39:492-503. 9. Agrawal V, David RJ, Harris VJ. Classification of acute respiratory disorders of all newborns in a tertiary care center. J Natl Med Assoc. 2003;95:585-595.

CHAPTER

128

Congenital and Perinatal Infections Neera Goyal

CONGENITAL INFECTIONS BACKGROUND Congenital infections acquired in utero are a significant cause of neonatal mortality and childhood morbidity. The original concept of the TORCH acronym was to group five infections with similar presentations: toxoplasmosis, “other” (traditionally referring to syphilis), rubella, cytomegalovirus (CMV), and herpesvirus. However, recent additions have expanded the scope of this term to include infections such as human immunodeficiency virus (HIV), enteroviruses, parvovirus B19, and varicella. The incidence of TORCH infections in the United States is variable, ranging from 0.7% for CMV, the most common congenital viral infection, to ≤1 in 10,000 for rare infections such as rubella and toxoplasmosis. A high index of suspicion for congenital infection and awareness of the prominent features of the most common etiologies will help to facilitate early diagnosis and management. Pathophysiology Transplacental spread and invasion of the bloodstream after maternal infection is the primary route for intrauterine infection, though it is also possible for the fetus to be infected by extension from adjacent infections of the peritoneum and the genitalia during the birth process or during invasive procedures such as fetal monitoring and intrauterine transfusion.1 In order for the maternal immune system to tolerate pregnancy, the placenta serves as a protective barrier that shields the fetus from maternal humoral and cell-mediated immune activity. Without immunologic mechanisms necessary to eradicate an infecting organism, the fetus is

susceptible to infection, and a state of immunologic tolerance is often established. The fetus is particularly vulnerable during the first trimester of pregnancy, when the most complex events in embryogenesis occur, including development of sensory organs such as the eyes and ears. The outcome of fetal infection depends on several factors, including gestational age at the time of infection, organism virulence, degree of associated placental damage, and maternal disease severity.1 Primary infection is also likely to have more significant effects on the fetus than recurrent infection. Infection during the first few weeks of gestation may cause embryonal death and resorption, prior to recognition of pregnancy. Spontaneous abortion and stillbirth are among the earliest recognizable effects of fetal infection after 6 to 8 weeks of pregnancy. In infants who are live-born, effects of fetal infection may present as preterm birth, intrauterine growth restriction (IUGR), congenital anomalies, or local or systemic signs of infection. Alternatively, fetal infection may present in live-born infants as the complete absence of any clinical signs of disease, with abnormalities becoming obvious only as the child develops and fails to reach appropriate physiologic or developmental milestones.

CLINICAL PRESENTATION Intrauterine infection with CMV, herpes simplex virus (HSV), syphilis, rubella, toxoplasmosis, and enterovirus may present in the neonatal period with signs of widely disseminated disease caused by microbial invasion and proliferation over weeks or months prior to delivery.1 In such infants it can be difficult to determine whether infection was acquired in utero, intrapartum, or postpartum. However, if the onset of clinical symptoms after birth occurs within the minimal incubation period for the disease, it is likely that infection was acquired before delivery. Cytomegalovirus Congenital CMV infection may present at birth with generalized petechiae, direct hyperbilirubinemia, hepatosplenomegaly, purpuric rash, microcephaly, seizures, focal or general neurologic deficits, retinitis, and intracranial calcifications (usually periventricular) (Figure 1281A). However, 90% of infants with congenital CMV infection are asymptomatic at birth, and most cases are undetected prior to discharge from the birth hospital. Infants who are symptomatic at birth are at highest risk of

long-term neurological sequelae, including sensorineural hearing loss, mental retardation, cerebral palsy, and vision impairment. However, approximately 10% to 15% of asymptomatic, infected infants will also experience later, long-term adverse neurological outcomes.2

FIGURE 128-1. Intracranial calcifications in infants with congenital infection. A. Head ultrasound of an infant with congenital cytomegalovirus infection, note periventricular distribution. B. Head computed tomography in an infant with congenital toxoplasma infection, note scattered or generalized distribution. (Reproduced with permission from Shah SS, Ludwig S. Symptom-Based Diagnosis in Pediatrics. New York: McGraw-Hill Education; 2014:153, figure 6-2;

477, figure 19-3, toxoplasma.) Herpes Simplex Virus Intrauterine infection with HSV is rare (approximately 1 in 300,000 deliveries), compared with the vast majority of neonatal HSV infections which result from exposure during delivery. Intrauterine HSV transmission is highest during the first 20 weeks of pregnancy, resulting in abortion, stillbirth, and congenital anomalies in infants who survive.3 Perinatal mortality is high, and infected infants usually have clinical abnormalities identified at birth. Typical presentation is a triad of clinical findings: cutaneous manifestations (i.e. scarring, active lesions, hypo- and hyperpigmentation, aplasia cutis, and/or an erythematous macular exanthem), ophthalmologic findings (i.e. micro-opthalmia, retinal dysplasia, optic atrophy, and/or chorioretinitis), and neurologic involvement (i.e. microcephaly, encephalomalacia, hydranencephaly, and/or intracranial calcification).3 Clinical presentation for infants infected with HSV during delivery can be divided into three categories, each associated with different outcomes and manifestations. Neonates with infection confined to the skin, eyes, and mucosa (SEM) comprise about 45% of most case series, most often presenting with cutaneous or mucosal vesicular lesions.4 By definition, infants in this category have no central nervous system (CNS) or visceral organ involvement, although systemic therapy is required to prevent further disease progression. Infants with SEM HSV disease often have recurrent cutaneous outbreaks in early childhood. The second category is HSV infection with CNS involvement, comprising 30% of cases.4 CNS disease can present with lethargy, poor feeding, or seizures, with or without cutaneous lesions. Morbidity with CNS involvement is higher with HSV-2 than HSV-1 infection, with potential long-term sequelae including developmental delay, epilepsy, blindness, and cognitive disabilities. Relapses of CNS infection may also occur during childhood, further increasing morbidity. Disseminated HIV infection is the third category and occurs in 25% of cases. Mortality risk is highest for these infants (approximately 30%), as it is associated with multiorgan dysfunction. Clinical presentation can be indistinguishable from bacterial sepsis.4 Syphilis Congenital syphilis results from fetal infection with the spirochete Treponema pallidum via transplacental transmission. In recent years, the rate

of congenital syphilis in the United States has increased, now affecting 10 per 100,000 births.5 Untreated syphilis during pregnancy results in fetal or neonatal death in up to 40% of cases. Infected live-born infants are often asymptomatic, with only severe cases clinically apparent at birth. Untreated asymptomatic infants can subsequently develop severe sequelae in the first few weeks, months, or years of life. Early presentation of congenital syphilis, manifesting within the first few months to first year of life, can include hepatosplenomegaly, jaundice, lymphadenopathy, meningoencephalitis, chorioretinitis, and mucocutaneous findings such as maculopapular erythema, bullae, and desquamation. Infants may fail to thrive and have a characteristic mucopurulent or blood-stained nasal discharge causing “snuffles.” Osteochondritis of the long bones and ribs may cause pseudoparalysis of the limbs with characteristic radiologic changes. Late presentation of congenital syphilis, manifesting after the first 1 to 2 years of life, can include gummatous ulcers of the nose, septum, or hard palate; periosteal lesions resulting in saber shins and frontal and parietal bossing; juvenile paresis and tabes secondary to neurosyphilis; optic atrophy and interstitial keratitis; and progressive sensorineural deafness. Dental abnormalities include Hutchinson incisors (small, widely spaced, peg-shaped, notched upper incisors with thin discolored enamel), hypoplastic enamel, and mulberry molars. “Hutchinson triad” is a pathognomonic constellation of findings that consist of interstitial keratitis, Hutchinson teeth, and sensorineural hearing loss. Toxoplasmosis Toxoplasma gondii is a protozoan parasite transmittable through contact with cat feces or consumption of contaminated foods, such as meat containing infective tissue cysts or unwashed produce from contaminated soil. The risk of transplacental infection is lower (10% to 25%) when maternal infection occurs in the first trimester compared with the third trimester (60% to 90%). However, severe sequelae, including stillbirth and neonatal death, are more likely when infection is acquired in the first trimester. Overall risk of congenital infection from acute prenatal infection ranges from approximately 20% to 50%. Most neonates with congenital toxoplasmosis are asymptomatic; however, clinical presentation can include hepatosplenomegaly, lymphadenopathy, maculopapular rash, jaundice, anemia, and thrombocytopenia. A classic triad of clinical findings associated with this disease is chorioretinitis with intracranial calcifications (typically

generalized) (Figure 128-1B) and hydrocephalus. Enteroviruses Enteroviruses are small, single-stranded RNA viruses belonging to the Picornaviridae family. Congenital enterovirus infection often presents with a maternal history of viral illness including fever, respiratory concerns, or abdominal symptoms preceding or immediately following delivery. There may also be a history of viral symptoms in other family members. Signs of infection in neonates may include temperature instability, irritability, lethargy, jaundice, emesis, abdominal distension, diarrhea, respiratory distress, and macular or maculopapular rash. Most affected neonates have mild disease, however, a small percentage develop severe sequelae including meningoencephalitis, myocarditis, pneumonia, hepatitis, and coagulopathy. Myocarditis in particular confers high-mortality risk for affected infants and has special diagnostic significance for enterovirus infection. Rubella Since licensure of live attenuated rubella vaccines in the late 1960s, the number of reported US cases of congenital rubella infection has declined dramatically to 20 mg/dL.1 A systematic approach to the detection and management of hyperbilirubinemia in newborns is therefore critical for prevention. While kernicterus in the United States is a rare condition, with an estimated incidence of 1.5 per 100,000 full-term newborns, the diagnosis of hyperbilirubinemia is far more common, affecting over 15% of full-term infants and nearly 60% of preterm infants in the first 30 days of life.2 Hyperbilirubinemia is the most common neonatal condition requiring extension of the newborn hospital stay or readmission to the hospital after newborn discharge.3

PATHOPHYSIOLOGY Bilirubin is a breakdown product of heme, which is contained primarily in hemoglobin but also in myoglobin and cytochromes. Microsomal heme oxygenase catabolizes heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase. The resulting unconjugated biliruibin is a non-polar, lipid-soluble molecule that is transported to the liver in plasma bound to albumin. In the endoplasmic reticulum of the hepatocytes, bilirubin uridine diphosphate glucuronosyl transferase (UDPGT) conjugates bilirubin with glucuronic acid. Conjugated bilirubin is a polar, water-soluble molecule that is excreted from the hepatocyte to the bile canaliculi, through the biliary tree,

and into the duodenum. In the colon, bacterial β-glucuronidase converts conjugated bilirubin to urobilinogen. A small amount of urobilinogen is absorbed and returned to the liver (enterohepatic circulation) or excreted by the kidneys. The rest is converted to stercobilin and excreted in the feces. Hyperbilirubinemia is classified as either conjugated or unconjugated (also known as direct or indirect, referring to the van den Bergh reaction used to measure bilirubin). Unconjugated hyperbilirubinemia is caused by increased production, decreased hepatic uptake or metabolism, or increased enterohepatic circulation of bilirubin. Newborn infants are particularly susceptible to unconjugated hyperbilirubinemia because, compared with adults; they have more red cells with a higher turnover and a shorter life span, and a limited ability to conjugate bilirubin. Newborn bilirubin levels typically peak on days 3 to 5 of life at about 5 to 6 mg/dL and then decrease over the next few weeks to adult levels. Exaggerated physiologic jaundice occurs at values above this threshold (7 to 17 mg/dL). Bilirubin levels higher than 17 mg/dL are not generally considered physiologic, and a cause of pathologic jaundice should be sought.4 Conjugated hyperbilirubinemia can occur with hepatocellular or cholestatic disease that causes a decreased secretion of bilirubin into the canaliculi or decreased drainage through the biliary tree. Unconjugated bilirubin that exceeds the binding threshold of albumin (maximum of 8.2 mg bilirubin per gram of albumin) enters the brain and deposits primarily in neurons in the basal ganglia, hippocampus, cerebellum, and brainstem nuclei for oculomotor function and hearing. Bilirubin’s neurotoxicity is mediated through a variety of mechanisms, including impaired mitochondrial function, DNA and protein synthesis, and synaptic transmission. Factors that increase bilirubin neurotoxicity include the concentration of bilirubin and the duration of exposure to it, albumin levels, and conditions that increase blood-brain barrier permeability (e.g. infection, acidosis, hyperoxia, sepsis, prematurity, hyperosmolarity).5

CLINICAL PRESENTATION Jaundice, the yellow discoloration of the skin and sclerae, may be present at birth or appear any time in the first month of life. It generally starts on the face and spreads down the body in a cephalocaudal progression.

Unconjugated bilirubin in the skin appears bright yellow or orange, whereas conjugated bilirubin appears more greenish or muddy yellow; these may be difficult to detect in darker-skinned infants. The extent of cephalocaudal jaundice progression has a poor overall accuracy for predicting risk of significant hyperbilirubinemia, and therefore should not be used to estimate bilirubin level; however, complete absence of jaundice is helpful in predicting which infants will not develop significant hyperbilirubinemia.6 Infants who are jaundiced secondary to insufficient milk intake may also be dehydrated, appear lethargic, and have significant weight loss (>10% of birth weight), dry mucous membranes, poor capillary refill, sunken eyes and fontanelle, and poor skin turgor. Signs of acute bilirubin encephalopathy usually appear 2 to 5 days after birth but may occur any time during the neonatal period. In the early phase, infants display lethargy, hypotonia, and poor ability to suck. In the intermediate phase, infants have stupor, irritability, and hypertonia (retrocollis-opisthotonos) alternating with drowsiness and hypotonia. They may also develop a fever and high-pitched cry. Infants who reach the late phase may have increased retrocollis-opisthotonos, cessation of feeding, bicycling movements, inconsolable irritability and crying, seizures, fever, and coma. Many of these infants die, and the survivors are likely to have severe kernicteric sequelae, even after intensive treatment. The rate of progression of clinical signs depends on the rate of bilirubin rise, duration of hyperbilirubinemia, host susceptibility, and presence of comorbidities.5 Infants who survive acute bilirubin encephalopathy may have kernicteric sequelae such as extrapyramidal movement disorders (dystonia and athetosis), gaze abnormalities (especially upward gaze), auditory disturbances (especially sensorineural hearing loss with central processing disorders or auditory neuropathy), and enamel dysplasia of the deciduous teeth. Cognitive deficits are unusual. Earlier reports of mental retardation in children with kernicterus probably reflected an inability to accurately assess intelligence in children with hearing, communication, and coordination problems.

DIFFERENTIAL DIAGNOSIS The distinction between physiologic jaundice and pathologic jaundice relates to the timing, rate of rise, and extent of hyperbilirubinemia, as some of the

same causes of physiologic jaundice (e.g. large red blood cell mass, decreased capacity for bilirubin conjugation, increased enterohepatic circulation) can also result in pathologic jaundice. Jaundice appearing in the first 24 hours of life and bilirubin levels that exceed 17 mg/dL or rise more than 5 mg/dL per day should be considered pathologic, and a specific cause should be sought. Direct bilirubin fractions greater than 10% of the total bilirubin should also be considered abnormal. The differential diagnosis for pathologic jaundice is extensive (Table 130-1). Processes that lead to increased bilirubin production include isoimmune hemolysis (due to ABO, Rh, or other minor blood group incompatibility), extravascular hemolysis (cephalohematoma and skin bruising), polycythemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Genetic and metabolic disorders resulting in decreased uptake, storage, or metabolism of bilirubin include Crigler-Najjar syndrome (I or II), Gilbert syndrome, Lucey-Driscoll syndrome, hypothyroidism, and hypopituitarism. These rare disorders should be considered when bilirubin levels are greater than 10 mg/dL beyond the first week of life. Processes that result in increased enterohepatic circulation, such as breastfeeding and intestinal obstruction, may also cause pathologic jaundice. Breastfeeding is one of the strongest risk factors for significant hyperbilirubinemia. Infants who are breastfed have higher average peak bilirubin levels than do formulafed infants. The hyperbilirubinemia observed with breastfeeding is likely multifactorial in origin. Decreased milk intake before maternal milk production is established results in dehydration, which hemoconcentrates bilirubin. Poor milk intake results in fewer bowel movements, which in turn increases the enterohepatic circulation of bilirubin. TABLE 130-1

Differential Diagnosis of Pathologic Jaundice

Finding

Diagnosis

Unconjugated hyperbilirubinemia Increased production

Isoimmune hemolysis (ABO, Rh, other)

Cephalohematoma Ecchymoses Sepsis Polycythemia Congenital hemolytic anemias (spherocytosis, elliptocytosis, pyknocytosis) Erythrocyte enzyme defects (G6PD, pyruvate kinase, hexokinase) Medicines (vitamin K, maternal oxytocin) Decreased uptake, storage, or metabolism

Crigler-Najjar syndrome (I or II) Gilbert syndrome Lucey-Driscoll syndrome Hypothyroidism or hypopituitarism Sepsis Hepatitis Congestive heart failure Hypoxia Acidosis

Increased enterohepatic circulation

Breastfeeding jaundice Breast milk jaundice Intestinal obstruction (ileal atresia, Hirschsprung disease, cystic fibrosis)

Conjugated hyperbilirubinemia

Sepsis Extrahepatic biliary atresia Intrahepatic cholestasis Metabolic disorders Congenital viral infections

G6PD, glucose-6-phosphate dehydrogenase.

Breastfeeding jaundice, which occurs in the first week of life, should be distinguished from breast milk jaundice, which refers to the jaundice that persists beyond the first week of life in approximately 2% of breastfed infants. With breast milk jaundice, bilirubin levels can rise as high as 10 to 30 mg/dL in the second to third week and then decrease, but jaundice may persist for up to 10 weeks. Discontinuation of breastfeeding and substitution of formula for 1 to 2 days results in a rapid and sustained decline in serum bilirubin, but this is generally not recommended unless bilirubin levels approach treatment thresholds. The cause of breast milk jaundice is not known with certainty, although β-glucuronidase (resulting in deconjugation of bilirubin and increased enterohepatic circulation) and other factors in breast milk that might interfere with bilirubin conjugation (e.g. pregnanediol and free fatty acids) have been implicated as potential causes. Causes of conjugated hyperbilirubinemia include extrahepatic biliary atresia, intrahepatic cholestasis, metabolic disorders, urinary tract infections, and congenital viral infections.

DIAGNOSTIC EVALUATION RISK ASSESSMENT AND SCREENING The 2004 American Academy of Pediatrics (AAP) Clinical Practice Guideline recommended that all newborn infants ≥35 weeks gestation be assessed before discharge for the risk of developing severe hyperbilirubinemia using either clinical risk factors or bilirubin measurement or both.7 Clinical risk factors for severe hyperbilirubinemia include lower gestational age, exclusive breastfeeding, isoimmune or other hemolytic

disease, East Asian ancestry, cephalohematoma or significant bruising, and previous sibling with significant jaundice;2,7-9 evaluation of such risk factors may help guide timing of follow-up as well as need for additional clinical and laboratory evaluation. However, more recent literature has suggested that combining evaluation of clinical risk factors with bilirubin measurement improves prediction of hyperbilirubinemia risk compared with either bilirubin measurement or clinical risk assessment alone.8,9 Therefore, 2009 recommendations of an AAP-convened panel of experts are to perform universal screening with predischarge bilirubin measurement and to interpret risk for hyperbilirubinemia using the hour-specific bilirubin nomogram depicted in Figure 130-1 in combination with clinical risk factors.8,10 In fact, a recent study demonstrated that combining hour-specific bilirubin measurement and only one clinical risk factor—gestational age—was equally predictive of hyperbilirubinemia risk compared with combining hour-specific bilirubin measurement and multiple clinical risk factors.9

FIGURE 130-1. Hour-specific bilirubin nomogram for predischarge risk assessment. (Reproduced with permission from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hourspecific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103:6-14. © 1999 by the AAP.)

In addition to universal predischarge screening, bilirubin measurement should be obtained for infants who are jaundiced in the first 24 hours after birth or for those who appear excessively jaundiced for their age in hours at any point during hospitalization. As above, these levels can be interpreted using the hour-specific bilirubin nomogram in Figure 130-1, which quantifies risk for severe hyperbilirubinemia on an age-adjusted percentile basis.10

TRANSCUTANEOUS VERSUS TOTAL SERUM BILIRUBIN MEASUREMENT Total serum bilirubin (TSB) measured in a clinical laboratory is considered the gold standard for bilirubin measurement; however, interlaboratory variability in this measurement may result in inaccuracies. Clinicians should be aware of the method of testing used by their clinical laboratory, as the Vitros method in particular has been shown to result in higher bilirubin values compared with traditional methods.11 The Vitros method will generally report total, conjugated and unconjugated bilirubin levels, while traditional methods measure and report total, direct, and indirect bilirubin levels. Various devices are available for transcutaneous bilirubin (TcB) measurement, which should be measured over the sternum. Transcutaneous bilirubinometers operate by transmitting light that penetrates the blanched skin and transilluminates the subcutaneous tissues. The scattered light returns through a fiber optic filament, and the yellowness of the reflected light is measured in a spectrophotometric module and converted into an estimate of the TSB concentration. Values generally correlate within 2 to 3 mg/d of TSB values, although there is some evidence that transcutaneous instruments are less accurate at higher bilirubin levels (>15 mg/dL) or for infants with darker skin. In addition, there may be inconsistencies in performances across instruments, and quality control is essential to ensure proper function and accuracy. Advantages of TcB measurement include noninvasive testing, instantaneous information, and the possibility of performing multiple measurements over a single day.12 Either TSB or TcB measurement (interchangeably) is recommended for screening in the 2004 AAP hyperbilirubinemia guidelines. However, if

bilirubin levels are documented as ≥15 mg/dL or rising rapidly, confirmation with TSB measurement is recommended. TSB values should also be measured once infants begin phototherapy, as TcB measurement may falsely underestimate total bilirubin in this setting.

ADDITIONAL LABORATORY STUDIES As part of routine prenatal care, maternal blood type should be determined; if the mother has not had prenatal blood typing or is Rh-negative, the infant’s cord blood should be tested for blood type and Rh (D). Testing of infant cord blood for blood type and direct (Coombs) antibody when the maternal blood is group O, Rh-positive is an option but not routinely recommended, as long as appropriate surveillance and follow-up for hyperbilirubinemia are performed. Infants whose TSB levels are rising rapidly (crossing percentiles) or who require phototherapy should have fractionated (conjugated and unconjugated) bilirubin levels checked, as well as blood type, Coombs test, complete blood count (CBC) and smear, reticulocyte count, and G6PD levels (if available), to evaluate for hemolysis and congenital red blood cell membrane defects. Infants with elevated direct bilirubin levels should have urinalysis and urine culture to rule out urinary tract infection. Infants who are jaundiced beyond 2 weeks of age should have total and direct bilirubin levels measured and should undergo evaluation for the cause of cholestasis if the direct bilirubin level is elevated. The results of the newborn screen can be used to evaluate for congenital hypothyroidism and galactosemia as causes of jaundice.

MANAGEMENT PHOTOTHERAPY Hour-specific bilirubin thresholds for initiating phototherapy and exchange transfusion have been recommended by the AAP (Figure 130-2 and Figure 130-3, respectively). Clinicians should use the TSB, not the indirect (or unconjugated) fraction, in applying these treatment guidelines. Treatment thresholds are dependent on the infant’s gestational age, appearance (well versus ill), and other clinical risk factors, all of which modify the infant’s susceptibility to bilirubin neurotoxicity.

FIGURE 130-2. Guidelines for phototherapy in hospitalized infants of 35 or more weeks gestation. G6PD, glucose-6-phosphate dehydrogenase; TSB, total serum bilirubin. (Reproduced with permission from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. © 2004 by the AAP.)

FIGURE 130-3. Guidelines for exchange transfusion in infants 35 or more weeks gestation. B/A, bilirubin-albumin; G6PD, glucose-6phosphate dehydrogenase; TSB, total serum bilirubin. (From American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316.) Phototherapy achieves reduction of hyperbilirubinemia by two mechanisms: (1) reversible photoisomerization of the nonpolar native unconjugated 4Z, 15Z-bilirubin into the polar configurational isomer 4Z, 15E-bilirubin, which is excreted in the bile without need for conjugation; and (2) irreversible conversion of native unconjugated bilirubin into the structural isomer lumirubin, which is excreted by the kidneys. Phototherapy must contain light in the blue range (420 to 470 nm) and be of sufficient intensity to efficiently reduce hyperbilirubinemia. The AAP recommends that hospitals use intensive phototherapy light of at least 30 μW/cm2/nm measured by a radiometer at the infant’s skin directly below the center of the unit. Intensive phototherapy can be expected to decrease the initial bilirubin level by 30% to 40% in the first 24 hours, with the most significant drop in the first 4 to 6

hours. For infants who are discharged after birth and then readmitted, phototherapy should be continued until the TSB is less than 13 to 14 mg/dL. Though uncommon, rebound hyperbilirubinemia requiring another course of phototherapy can occur, particularly in infants with hemolytic disease or those in whom phototherapy was initiated early and discontinued before 3 to 4 days of life. Discharge from the hospital need not be delayed because of the potential for rebound bilirubin; however, these infants should have a followup bilirubin measurement within 24 hours after discontinuation of phototherapy.

EXCHANGE TRANSFUSION Exchange transfusion is the last therapeutic resort if the TSB level does not decrease despite intensive phototherapy or if an infant presents with signs of acute bilirubin encephalopathy. When the TSB level exceeds the recommended threshold for exchange transfusion, intensive phototherapy should be administered, the TSB measurement should be repeated every 2 to 3 hours, preparations for exchange transfusion should be made, and exchange transfusion should be performed if the TSB remains above the recommended threshold after 6 hours of intensive phototherapy. The bilirubin-to-albumin ratio can also be used, together with TSB level, as an additional risk factor in determining the need for exchange transfusion (Table 130-2). For infants with isoimmune hemolytic disease whose TSB is rising despite intensive phototherapy or whose TSB is within 2 to 3 mg/dL of the exchange level, intravenous gamma globulin (0.5 to 1 g/kg over 2 hours) should be administered, because it has been shown to reduce the need for exchange transfusion in these infants. TABLE 130-2

Bilirubin-Albumin Ratio as an Additional Risk Factor When Considering Exchange Transfusion

Risk Category

Total Serum Bilirubin (mg/dl)to-Albumin (g/dL) Ratio

Infants

wk

8.0

Infants to wk and well or wk if higher risk or with isoimmune hemolytic disease or G6PD deficiency

7.2

Infants to wk if higher risk or with isoimmune hemolytic disease or G6PD deficiency

6.8

Source: Data from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316 G6PD, glucose-6-phosphate dehydrogenase.

FOLLOW-UP Appropriate and timely follow-up should always be provided, as even for infants with a low predischarge TSB or TcB level the risk of subsequent hyperbilirubinemia is not zero.13 Infants discharged before 24 hours, between 24 and 47.9 hours, and between 48 and 72 hours should be seen by age 72 hours, 96 hours, and 120 hours, respectively. Earlier or more frequent followup may be needed for infants who have elevated hour-specific bilirubin values or clinical risk factors for hyperbilirubinemia. If an infant’s predischarge bilirubin level remains in, or is crossing percentile tracks into, the high-risk zone and appropriate follow-up cannot be assured, a clinician may opt to delay discharge until the bilirubin trajectory is elucidated and a decision can be made about the need for phototherapy or discharge home.

ADMISSION AND DISCHARGE CRITERIA Jaundiced infants who require intensive phototherapy, exchange transfusion, or management of dehydration should be admitted to the hospital. Infants with profound dehydration or with bilirubin levels approaching or exceeding exchange transfusion thresholds should be admitted to a neonatal intensive care facility, if available. Infants with mild to moderate dehydration and bilirubin levels requiring phototherapy alone can be monitored and treated in

a pediatric inpatient ward or newborn nursery setting. Infants who are discharged and then readmitted should receive phototherapy until the TSB is less than 13 to 14 mg/dL. For infants treated during the initial birth hospitalization, the TSB thresholds for discontinuing phototherapy are less clear, but reducing the TSB level below the 40th percentile can be used as a treatment goal. Before discharge, infants must be well hydrated and feeding well, with frequent wet diapers and stools. For breastfed infants, particularly those whose jaundice can be attributed to lactation or breastfeeding problems, both the parents and the healthcare providers must be confident that the infant will have an adequate milk supply through either lactation interventions (e.g. pumping) or supplemental feedings.

SPECIAL CONSIDERATIONS PREVENTION A hospital-based approach to primary prevention of severe hyperbilirubinemia includes the establishment of standing protocols for nurses’ assessment of jaundice, including measurement of TcB and TSB levels, without requiring a physician’s order (similar to the protocols in place for measuring serum glucose levels). Checklists or reminders should prompt providers to consider risk factors and age at discharge, as well as laboratory test results that guide appropriate follow-up. Educational materials concerning the identification of jaundice should be provided to parents. KEY POINTS Universal bilirubin screening, when combined with clinical risk assessment and targeted follow-up, is the most effective method of identifying infants at high or low risk for development of severe hyperbilirubinemia. Gestational age as a clinical risk factor has a strong impact on prediction of severe hyperbilirubinemia, with risk decreasing continuously with each additional week of maturity. TSB or TcB measurement and interpretation using the hourspecific nomogram provides an immediate and quantitative

method to assess degree of hyperbilirubinemia and the need for additional surveillance and testing. Initiation of phototherapy or exchange transfusion should be guided using TSB levels and the AAP hour-specific bilirubin nomogram thresholds. Timely follow-up to ensure hyperbilirubinemia surveillance should be provided for all newborns, including those with a low predischarge TSB or TcB level.

REFERENCES 1. Ip S, Chung M, Kulig J, O’Brien R, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;114(1):e130-e153. 2. Burke BL, Robbins JM, Bird TM, et al. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988-2005. Pediatrics. 2009;123(2):524-532. 3. Owens PL, Thompson J, Elixhauser A, Ryan K. Care of Children and Adolescents in U.S. Hospitals. HCUP Fact Book No. 4; AHRQ Publication No. 04-0004. Rockville, MD: Agency for Healthcare Research and Quality; 2003. ISBN 1-58763-137-7. 4. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344:581-590. 5. Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia: WB Saunders; 2001. 6. Keren R, Tremont K, Luan X, Cnaan A. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94:F317-F322. 7. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. 8. Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant > or =35 weeks’ gestation: an update with clarifications.

Pediatrics. 2009;124(4):1193-1198. 9. Bhutani VK, Stark AR, Lazzeroni LC, et al. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr. 2013;162(3):477-482. 10. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103:6-14. 11. Burgos AE, Flaherman VJ, Newman TB. Screening and follow-up for neonatal hyperbilirubinemia: a review. Clin Pediatrics. 2012;51(1):7-16. 12. Maisels MJ. Transcutaneous bilirubin measurements: an opportunity to enhance laboratory utilization and improve patient care. Clin Chem. 2012;58(10):1395-1396. 13. Bromiker R, Bin-Nun A, Schimmel M, Hammerman C, Kaplan M. Neonatal hyperbilirubinemia in the low-intermediate-risk category on the bilirubin nomogram Pediatrics. 2012;130;e470-e475.

CHAPTER

131

Neonatal Abstinence Syndrome Kathy E. Wedig

BACKGROUND Approximately 4.4% of women of childbearing years use illicit drugs or abuse prescription medications, including marijuana, cocaine, hallucinogens, heroin, sedatives, painkillers, and stimulants.1 Infants born to mothers who habitually use opioids (heroin, methadone, morphine, buprenorphine, meperidine, or codeine) can have physical manifestations of opiate withdrawal, termed neonatal abstinence syndrome (NAS). In recent years, the number of infants diagnosed with NAS nationally has increased significantly,2 likely in part due to more liberal use of prescription opiates during pregnancy.3 Although NAS refers specifically to opiate withdrawal, similar symptoms can occur in infants with intrauterine exposure to other drugs.

PATHOPHYSIOLOGY Placental passage to the fetus will vary depending on pharmacokinetic properties of each drug. Highly lipophilic drugs with a relatively low molecular weight are more likely to equilibrate rapidly between maternal and fetal circulation. They may then accumulate in the fetus due to renal and metabolic immaturity. Manifestations of withdrawal after delivery of the infant depend on various factors, including specific drug properties, dose and frequency of exposure, infant metabolism, and the interval between last exposure to the drug and delivery. Withdrawal is generally a function of the drug’s half-life; with a longer half-life being associated with later onset of withdrawal and potentially decreased likelihood of NAS. Maternal polysubstance use can potentiate or delay neonatal withdrawal

symptoms. Infants of mothers who use narcotics and also smoke cigarettes may have heightened symptoms of NAS. Opiate use combined with sedative use during pregnancy may mask infant withdrawal symptoms for up to 2 weeks. Another factor known to cause delayed or protracted infant withdrawal is prolonged maternal use of high-dose methadone; complete withdrawal for these infants may take up to 4 months.4

CLINICAL PRESENTATION Nearly all infants with chronic intrauterine exposure to opioids have some symptoms of NAS, and 25% require pharmacologic intervention.4 Infants born to mothers who use opiates usually present with symptoms within the first 72 to 96 hours of life. Withdrawal symptoms can be classified into three areas: central nervous system (CNS), autonomic nervous system, and gastrointestinal (GI) symptoms (see Table 131-1). Skin excoriation on the buttocks (due to excessive stooling) and the elbows and knees (due to friction burns secondary to tremors) is also well described. Additionally, infants with intrauterine opiate exposure are at increased risk of reduced fetal growth parameters, prematurity, and low birth weight. TABLE 131-1

Symptoms of Neonatal Abstinence Syndrome

Central nervous system Irritability Jitteriness Tremors Excessive crying High-pitched cry Hyperreflexia Sleep disturbance Seizures Autonomic nervous system Hyperthermia

Excessive sweating Mottling Tachypnea Nasal congestion Sneezing Hiccupping Yawning Gastrointestinal system Hyperplasia Excessive sucking Suck-swallow incoordination Vomiting Diarrhea Poor weight gain Mild NAS symptoms may persist until age 4 months, even after successful medical management.5 Sleep may continue to be disorganized, and hyperreflexia and hypertonia may continue, but tremor and jitteriness usually resolve earlier. GI disturbances such as loose stools, emesis, and colic also tend to resolve later in the withdrawal process. An increased incidence of sudden infant death syndrome has been reported in this population. In addition, there is a higher incidence of child abuse, possibly associated with maternal isolation, poor parenting preparation and skills, increased infant irritability, and the stresses of ongoing maternal drug use or recovery.5 Long-term effects of opioid withdrawal are not clearly defined. In many infants the withdrawal hypertonia changes to post-withdrawal hypotonia. Eye abnormalities such as esotropia, opsoclonus, and nystagmus have been described. There is some evidence that intrauterine opiate exposure leads to problems such as attention-deficit hyperactivity disorder, cognitive deficits, and poorly developed organizational and adaptive skills, although these behaviors may be related to home and social environment rather than drug exposure.6

DIFFERENTIAL DIAGNOSIS Careful consideration needs to be given to the differential diagnosis of NAS. An infant should not be treated for narcotic withdrawal if exposure cannot be confirmed. The differential diagnosis of NAS in an infant less than 2 weeks of age can include electrolyte abnormalities (e.g. hypoglycemia, hypomagnesemia, hypercalcemia, hypocalcemia) or neonatal hyperthyroidism. Infantile colic, formula intolerance, or severe gastroesophageal reflux may present with symptoms similar to NAS. Infants exposed in utero to large amounts of caffeine, antidepressants,7 nicotine, or alcohol may also present with NAS-like symptoms.

DIAGNOSTIC EVALUATION In the case of known intrauterine exposure to opiates or other illicit drugs, urine and meconium or umbilical cord toxicology screens are indicated. This testing may detect polysubstance use that might not have been revealed in the maternal history. If an infant presents with symptoms consistent with NAS and there is no reported history of maternal drug use, maternal drug use is still a possibility. If the mother abstained from drug use just before delivery, both she and her infant may have negative urine toxicology screens in the peripartum period. In the presence of a negative urine screen, a meconium or cord screen may be helpful in defining in utero exposure to narcotics and risk for NAS. If maternal drug abuse is verified, it is important to test the mother for sexually transmitted diseases, such as human immunodeficiency virus, hepatitis B, hepatitis C, syphilis, gonorrhea, and chlamydia, because of their higher risk for infection. For infants with symptoms concerning for NAS but who have a negative maternal history and negative toxicology studies, maternal history should be explored for the presence of intrauterine growth retardation during pregnancy, nicotine use, caffeine in large quantities, antidepressant medications, or alcohol abuse. These infants should also be screened for electrolyte abnormalities and hyperthyroidism.

MANAGEMENT

NAS SCORING To assess the severity of NAS and determine the need for medical intervention, it is important to use a tool that is objective, is reproducible, and has low inter-observer variability. Multiple assessments performed over time are more informative than a single assessment performed at one point in time. While multiple NAS scoring systems are available to determine severity of withdrawal and to guide pharmacologic treatment, Finnegan’s system— initially published in 1975 and updated in 1986—remains the most comprehensive and widely used scoring tool for infants with NAS8 (see Figure 131-1).

FIGURE 131-1. Example of Finnegan scoring form for neonatal

abstinence syndrome. (Reproduced with permission from Finnegan LP, Kaltenbach K. The assessment and management of neonatal abstinence syndrome. In: Hoekelman R and Nelson N, eds. Primary Pediatric Care. 2nd ed. St. Louis, MO: Mosby; 1992:1367-1378. Copyright © Elsevier.)

NON-PHARMACOLOGIC TREATMENT Initial intervention for NAS is supportive care, which may suffice for mild withdrawal symptoms. This includes keeping the infant tightly swaddled in a dimly lit, quiet environment, with minimal interruptions between feedings. Infants should be able to determine their own feeding schedule and quantity as long as adequate intake is maintained. Parents can be taught how to minimize external disturbances and help with the infant’s care by allowing them to do as many feedings as possible and reinforcing basic parenting skills in the nursery. Infants should have frequent diaper changes for loose stools and a barrier medication should be used to prevent or treat diaper rash. Social services should be involved as soon as an infant with NAS is identified or when infant drug exposure is confirmed without NAS symptoms. Social services can assess parenting behavior and the safety of the home environment and help assure that mothers are in a recovery program. Child protective services should be informed of the intrauterine exposure to narcotics and should determine appropriate social services follow-up for the infant. Infants with NAS are at high risk for developmental and behavioral problems, and arrangements for early intervention and follow-up are indicated for these infants. Nutrition must be carefully monitored during and after the initial hospital stay. For mothers in a recovery program and drug-free, breastfeeding is recommended unless there are other contraindications (i.e. HIV infection).9 Methadone does cross into breast milk, thus breastfeeding with methadone exposure is considered safe and may be associated with a shorter period of treatment for NAS.10 Adjunctive nutritional therapy includes using a high calorie formula (22 to 27 kcal/oz) for infants showing poor weight gain and hypoallergenic formula for infants with continued watery stools. Irritability and poor feeding may require use of gavage feedings until neurologic symptoms of NAS

improve. Vomiting may warrant a workup for gastroesophageal reflux and possible treatment for gastroesophageal reflux disease to decrease hyperirritability.

PHARMACOLOGIC TREATMENT Pharmacologic intervention is recommended in moderately to severely affected infants to achieve symptomatic relief and adequate weight gain. For infants whose mothers used only opiates during pregnancy, opiates (rather than benzodiazepines or phenobarbital) are recommended as single agent treatment for NAS for an infant, as they will improve CNS, GI, and autonomic nervous system symptoms.11,12 Neonatal opiate solution (NOS) is an aqueous solution containing 0.4 mg/mL of morphine sulfate. The starting dosage for NOS is 0.2 to 0.5 mg/kg per day orally, divided into 6 to 8 doses, depending on the frequency of feedings. This initial dosage is continued for 48 to 72 hours to stabilize the infant. An NAS scoring tool such as the one depicted in Figure 131-1 can be used to help guide the weaning process. If the infant responds with improved feeding, sleeping, and comfort and reduced GI symptoms the NOS dosage can be decreased by 10% every 24 to 48 hours, as long as the symptoms remain under control. If the initial dosage does not significantly improve the infant’s symptoms, it can be increased by 10% until treatment goals are met. Maximum dosing of 1 to 2 mg/kg per day has been used. Although methadone as treatment for NAS has not been prospectively compared to morphine, it is used commonly, with dosages of 0.05 to 0.1 mg/kg orally every 6 hours. Infants can be weaned by 0.01 mg/kg/dose every 24 hours as long as average Finnegan scores are less than 8. Since 2002, buprenorphine, a partial narcotic agonist, has been approved for sublingual use as treatment for narcotic withdrawal, at doses of 13.2 to 39 ug/day divided into 3 doses.13 Buprenorphine is best used in neonates born to mothers who used buprenorphine during pregnancy. Phenobarbital can be considered as an adjunctive therapy with morphine or methadone in infants who have refractory NAS symptoms.12 Adjunctive therapy with phenobarbital should be considered with NOS doses higher than 1 mg/kg per day. Another option for adjunctive therapy is clonidine, which decreases adrenergic responses of withdrawal.12

ADMISSION AND DISCHARGE CRITERIA Admission to the hospital is indicated for: Infants born to mothers with known opiate or other illicit drug use. These infants should remain hospitalized for a minimum of 72 to 96 hours to observe for symptoms of moderate to severe NAS and to allow proper social services intervention to ensure the safety of the home before discharge. Infants without known in utero drug exposure but exhibiting symptoms consistent with NAS. These infants should be observed for at least 48 hours, and appropriate studies should be performed. Infants with known in utero drug exposure who have been discharged from the nursery after the initial observation period and then develop symptoms of significant NAS or have dehydration, persistent emesis, failure to thrive, CNS disorganization, or seizures. Discharge from the hospital is appropriate when: The infant is no longer receiving opiate medication for at least 48 hours without reemergence of moderate or severe symptoms. The infant achieves adequate oral intake and consistent weight gain. Social services personnel have contacted the local child protective agency, and an appropriate primary caregiver and safe home environment for the infant have been assured. Close medical, developmental and social follow-up is ensured.

SPECIAL CONSIDERATIONS PREVENTION Prevention of intrauterine drug exposure and NAS requires both medical and socioeconomic interventions, including increased access to and promotion of healthcare and drug abuse therapy during pregnancy. Although universal drug screening of all pregnant women is optimal and nonprejudicial, each institution should at least develop objective criteria to screen for illicit drug use in pregnant women at the time of delivery. Pregnant women using heroin or oxycodone are encouraged to enter a

methadone maintenance program to avoid complications associated with ongoing heroin use. For women using buprenorphine during pregnancy, drug substitution therapy may be more difficult because of the possibility of withdrawal. Women requiring narcotic replacement therapy during pregnancy need close postpartum follow-up. Ongoing psychological support and services should be provided in a nonjudgmental setting. KEY POINTS Each hospital should consider adopting an objective policy for maternal drug screening to avoid discriminatory practices and to allow rapid detection and management of neonatal drug exposure. An infant urine toxicology screen should be obtained if maternal results are not available. If the maternal toxicology screen is positive, infant cord or meconium toxicology screens should be sent to detect other drug exposures during pregnancy. A NAS screening tool should be initiated at 24 hours of age in exposed infants, with observation in the hospital for 72 to 96 hours, depending on the specific exposure. A social services consult should be obtained to determine safest home placement. Initial care of infants with NAS includes appropriate nutritional support, skin care, and an environment appropriate to the infant’s state. Replacement medication is indicated for those with severe NAS symptoms. Appropriate medical and developmental follow-up should be ensured at discharge.

REFERENCES 1. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-41, HHS Publication No. (SMA)

11-4658. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011. 2. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA. 2012;307:1934-1940. 3. Hudak ML, Tan RC, American Academy of Pediatrics (AAP) Committee on Drugs and AAP Committee on Fetus and Newborn. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560. 4. Kandall SR. Treatment strategies for drug-exposed neonates. Clin Perinatol. 1999;26(1):231-243. 5. Lipsitz P. A proposed narcotic withdrawal score for use with newborn infants. Clin Pediatr. 1975;14(6):592-594. 6. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome following methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320-2331. 7. Martinez A, Partridge JC, Taeusch HW. Perinatal substance abuse. In: Taeusch HW, Ballard RA, Gleason CA, eds. Avery’s Diseases of the Newborn. Philadelphia: Elsevier Saunders; 2004:106-126. 8. Finnegan LP. Neonatal abstinence syndrome. In: Nelson NM, ed. Current Therapy in Neonatal-Perinatal Medicine. 2nd ed. Philadelphia: BC Decker; 1990:314-320. 9. Jansson LM, Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #21: guidelines for breastfeeding and the drugdependent woman. Breastfeed Med. 2009;4(4):225-228. 10. Jansson LM, Choo R, Velez ML, et al. Methadone maintenance and breastfeeding in the neonatal period. Pediatrics. 2008;121(1):106-114. 11. Osborn DA, Cole MJ, Jeffery HE. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst Rev. 2010; (10):CD002059. 12. Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence syndrome. J Perinatol. 2011;31(11): 692-701. 13. Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treatment of the neonatal abstinence syndrome: a randomized trial. Pediatrics. 2008;122(3):e601-e607.

SECTION O Oncology

CHAPTER

132

Childhood Cancer Barbara Degar and Michael Isakoff

BACKGROUND Childhood cancer is rare, with only approximately 10,000 new cases diagnosed each year in the United States. Nonetheless, cancer is the leading cause of disease-related mortality in children younger than 15 years of age.1 Pediatricians and general practitioners commonly encounter children with vague symptoms that could signal an undiagnosed cancer. The challenge is to identify those children who warrant an evaluation for malignancy. This chapter reviews the typical presentations of the most common pediatric hematologic and solid tumors and provides guidelines for the initial diagnostic evaluation. A review of current therapies and expected outcomes is beyond the scope of this chapter. However, it can be broadly stated that the majority of children diagnosed with cancer can be cured of their disease with currently available treatment. Cancer results from the uncontrolled proliferation of a clonal cell population, and can arise in essentially any cell type or organ. In general, children with cancer present with symptoms related to the location and extent of the tumor. Cancers cause symptoms by invading or obstructing tissues locally or by spreading to distant sites, leading to pain, organ dysfunction, or both. During childhood, the incidence of specific malignancies varies dramatically with age. The most common types of cancer in children are hematologic malignancies (i.e. leukemias, lymphomas), brain tumors, and extracranial solid tumors, including sarcomas and embryonal tumors.

CAUSE Because childhood cancer is rare and heterogeneous, the elucidation of its

causes is extremely challenging. Certain factors are associated with an increased risk of some types of childhood cancer. For example, in utero exposure to ionizing radiation leads to about a 1.5-fold increased risk of lymphoblastic leukemia.2 External beam radiation, sometimes used to treat patients with solid tumors, is associated with an increased risk of osteosarcoma within the radiation field. Patients with Down syndrome have a 10- to 20-fold increased risk of developing leukemia.3 Several other genetic syndromes are also associated with an increased risk of developing cancer, including neurofibromatosis, Beckwith-Wiedemann syndrome, and LiFraumeni syndrome (Table 132-1). However, in the vast majority of children with cancer, no predisposing factors are identified. TABLE 132-1

Common Childhood Genetic Syndromes and Associated Malignancies

Genetic Syndrome

Associated Malignancy

Trisomy 21 (Down syndrome)

ALL, AML

Ataxia-telangiectasia

ALL

Familial monosomy 7

AML

Neurofibromatosis type 1

ALL, AML, optic glioma, rhabdomyosarcoma

Tuberous sclerosis

Brain tumors

Beckwith-Wiedemann syndrome

Wilms tumor, hepatoblastoma

Li-Fraumeni syndrome

Osteosarcoma, rhabdomyosarcoma, retinoblastoma

Nevus basal cell carcinoma syndrome

Medulloblastoma, rhabdomyosarcoma, basal cell carcinoma

Klinefelter syndrome

Dysgerminoma

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia.

INCIDENCE The incidence of childhood cancer is highest in the first year of life, declines until about age 9 years, and then gradually increases into adulthood. The peak rates of specific childhood malignancies occur at different ages. In a child with suspected cancer, the age at presentation has a major impact on the differential diagnosis. Leukemia accounts for approximately one-third of cancers diagnosed in childhood. In contrast to adults, acute lymphoblastic leukemia (ALL) occurs relatively more commonly than acute myeloid leukemia (AML). In fact, ALL is the most common specific childhood malignancy, representing approximately 20% of cancers diagnosed in children younger than 15 years. The peak age at diagnosis of childhood ALL is 2 to 3 years. White children are about two times more likely than black children to be diagnosed with ALL, and boys are affected slightly more commonly than girls. In contrast, the incidence of AML peaks in the first year of life, subsequently decreases, and then gradually increases late in childhood and throughout adulthood. Chronic leukemias are distinctly uncommon in childhood. Chronic myeloid leukemia accounts for only about 3% to 5% of childhood leukemia cases and chronic lymphoid leukemia does not typically occur in children. NonHodgkin lymphoma (NHL) accounts for 3% of cancers diagnosed in children, and Hodgkin lymphoma accounts for about 5%. Brain tumors are a diverse group of malignant neoplasms that, taken together, account for approximately 30% of childhood cancers. Among pediatric solid tumors that originate outside the central nervous system, neuroblastoma is the most common, representing 8% of childhood cancers, primarily affecting children younger than 5 years. Wilms tumor accounts for 6% of childhood cancers and also occurs primarily in those younger than 5 years. The bone sarcomas, including osteosarcoma and Ewing sarcoma, together represent 5% of childhood cancers. These tumors generally affect older children, with the highest incidence in adolescence and young adulthood.

HEMATOLOGIC MALIGNANCIES

LEUKEMIA Clinical Presentation and Differential Diagnosis ALL arises as a consequence of malignant transformation of lymphocyte precursors in the bone marrow or lymphoid organs.4 AML is an analogous process involving malignant transformation of myeloid progenitors.5 The presentation of newonset leukemia may be dramatic, insidious, or rarely even asymptomatic, with an incidental finding of leukemia blasts on peripheral blood smear. Often, the differential diagnosis includes benign conditions, such as acute viral infection (e.g. Epstein-Barr virus), aplastic anemia, hemophagocytic syndrome, and other rare congenital disorders (Table 132-2). TABLE 132-2

Differential Diagnosis of Childhood Acute Lymphoblastic Leukemia

Noncancer diagnoses Infectious mononucleosis Juvenile rheumatoid arthritis Systemic lupus erythematosuss Pertussis Immune thrombocytopenic purpura Aplastic anemia Malignant diagnoses* Neuroblastoma Retinoblastoma Rhabdomyosarcoma Ewing sarcoma *With small, round, blue cell morphology similar to acute lymphoblastic leukemia.

Children with new-onset acute leukemia usually present with symptoms caused by the impaired production of normal blood cells, owing to the proliferation of leukemia cells in the bone marrow. Fatigue, pallor, and fever are common presenting symptoms. Decreased numbers of normal white blood cells lead to an increased risk of serious infection. Bruising and petechiae may be present due to thrombocytopenia. Concomitant

coagulopathy may magnify the risk of serious bleeding, especially in certain leukemia subtypes. Patients may complain of bone pain or present with limp or refusal to walk related to bone marrow infiltration and expansion. Leukemia cells may infiltrate organs such as the lymph nodes, liver, or spleen, resulting in lymphadenopathy or hepatosplenomegaly. Leukemia cells may form solid masses, such as in the anterior mediastinum, leading to tracheal or vascular compression. Uncommonly, new-onset leukemia involves the central nervous system, testes, skin, gingivae, and eyes. Children with very large numbers of circulating malignant cells (white blood cell counts >200,000/μL) may experience symptoms of hyperleukocytosis with ocular, neurologic or respiratory symptoms (see Chapter 133). Hyperleukocytosis occurs in patients with AML at relatively lower white blood cell counts than in ALL. Diagnostic Evaluation and Management When leukemia is suspected, immediate evaluation is warranted, beginning with a complete blood count. The white blood cell count may be low, normal, or elevated. Leukemia blasts may be seen in the peripheral blood smear. Anemia with reticulocytopenia and thrombocytopenia are usually present but of variable severity. When leukemia is strongly suspected, it is important to assess renal function and serum electrolytes, including calcium, phosphate, and uric acid. Patients with a large, rapidly proliferating leukemia burden may present with features of acute tumor lysis syndrome (see Chapter 133) even before the initiation of cytotoxic therapy. Liver function tests should also be performed because marked elevation of lactate dehydrogenase is often seen and hyperbilirubinemia may be present. Coagulation studies should be obtained, and coagulation abnormalities should be corrected before high-risk invasive procedures are attempted, including lumbar puncture and central line placement. Blood cultures should be obtained from patients presenting with fever, and empirical antibiotics should be strongly considered, especially if the neutrophil count is low. A blood sample should be sent to the blood bank in preparation for red blood cell or platelet transfusion. A screening chest radiograph is also recommended. Intravenous access should be established and the patient should be hospitalized for completion of the diagnostic evaluation and initiation of therapy. Further diagnostic workup should then be performed under the direction of a hematologist/oncologist. Expert evaluation of the peripheral blood smear

is often informative (Figure 132-1). When circulating blasts are present, flow cytometry of peripheral blood may establish the diagnosis. Examination of the bone marrow is needed to complete the evaluation of morphology, flow cytometry, and cytogenetic and molecular analysis. These studies have become increasingly important for risk stratification in patients with ALL and AML. In most cases, assessment of the cerebrospinal fluid by lumbar puncture is performed to document the presence or absence of leukemic involvement. At the time of the initial staging lumbar puncture, chemotherapy should be instilled directly into the spinal fluid. Diagnostic lumbar puncture without intrathecal chemotherapy is strongly discouraged.

FIGURE 132-1. Bone marrow smears demonstrating characteristic morphology in (A) acute lymphoblastic leukemia (ALL), (B) acute promyelocytic leukemia (APL) and (C) acute myeloid leukemia (AML) with monoblastic differentiation. A normal lymphocyte is marked with an arrow in each panel for size comparison. (Photos used with permission of Marian Harris, MD.)

LYMPHOMA NON-HODGKIN LYMPHOMA Clinical Presentation and Differential Diagnosis Several different subtypes of NHL occur in childhood,6 the most frequently encountered types demonstrating high-grade histology and aggressive behavior. Lymphoblastic lymphoma is a malignant lymphoma that is indistinguishable from ALL except that the extent of bone marrow involvement is, by definition, less than 25%. Most cases of lymphoblastic lymphoma are of precursor T-cell origin. Children with lymphoblastic lymphoma often present with an anterior

mediastinal mass (Figure 132-2). Compression of the airway or vascular structures at or below the thoracic inlet can lead to orthopnea or superior vena cava syndrome. Diagnosis is made by means of biopsy of involved tissue. When a mass is present in the anterior mediastinum, biopsy requires extreme caution owing to the high risk of anesthesia in the setting of tracheal compression.

FIGURE 132-2. Chest X-ray demonstrating a medastinal mass in a patient with lymphoblastic lymphoma. Burkitt lymphoma is a high-grade malignancy of mature B-cell origin. In the United States, the disease occurs in a sporadic form, with the majority of tumors presenting in the abdomen. Bone marrow or central nervous system involvement is relatively uncommon and is associated with a less favorable prognosis.7 Because of the extremely rapid growth rate of this tumor, patients are at high risk for the development of hyperuricemia and acute tumor lysis syndrome at presentation and after initiation of treatment. Large-cell lymphomas may be of B-cell, T-cell, or null-cell origin. These tumors arise most commonly in the lymph nodes of the mediastinum and abdomen but may arise in or spread to skin, bone, and soft tissues. Diagnostic Evaluation and Management The same laboratory assessment described above for leukemia, including measurement of electrolytes, creatinine, and uric acid, is recommended for all patients with suspected or confirmed NHL. Diagnosis depends on histopathologic

examination of tumor tissue. Sufficient biopsy material should be obtained so that specialized flow cytometric and molecular studies can be performed. These studies may demonstrate specific molecular characteristics that define certain tumor types, such as rearrangement of the MYC oncogene in Burkitt lymphoma. Computed tomography (CT) of the chest, abdomen, and pelvis, fluorodeoxyglucose positron emission tomography (FDG-PET) scan and examination of the bone marrow and cerebrospinal fluid are usually performed to determine the stage of the disease. Because systemic therapy is necessary in nearly all cases of lymphoma, an aggressive attempt at complete surgical resection is usually not warranted.

HODGKIN LYMPHOMA Clinical Presentation and Differential Diagnosis Hodgkin lymphoma is a relatively indolent malignancy that most commonly arises in the neck and is characterized by slowly progressive nodal enlargement and spread of tumor to contiguous lymph node groups over time.8 Involved lymph nodes are usually nontender and may have a firm, rubbery, or matted texture on physical examination. Mediastinal involvement is common and may be demonstrated on chest radiographs. Uncommonly, bulky tumors in the mediastinum may be associated with vascular compression and symptoms of superior vena cava syndrome. Widespread nodal involvement, as well as extranodal spread of tumor to the liver, lung, cortical bone, and bone marrow, occurs in advanced stages of the disease. Some patients, especially those with extensive disease, may experience systemic symptoms, termed “B” symptoms, such as fevers, night sweats, and weight loss. For unclear reasons, occasional patients present with generalized pruritus. Nonspecific markers of inflammation, including the erythrocyte sedimentation rate and C-reactive protein, are often elevated at diagnosis and may be used as markers of response to therapy and as early indicators of recurrence. Diagnostic Evaluation and Management Under most circumstances, the diagnostic evaluation of a patient with suspected Hodgkin lymphoma may be safely completed in the outpatient setting once respiratory insufficiency, hemodynamic instability, and metabolic derangement have been ruled out. Many children are referred for excisional node biopsy after a course of oral antibiotics for presumed lymphadenitis is ineffective. Once the diagnosis of

Hodgkin lymphoma is established by biopsy of involved tissue, a staging evaluation is performed under the direction of the treating oncologist. Radiographic studies, including CT scan of the neck through pelvis and FDG-PET scan are usually obtained. Bone marrow aspiration/biopsy for staging is reserved for patients with B symptoms or advanced-stage disease.

BRAIN TUMORS Central nervous system tumors are a diverse group of neoplasms that occur in the brain, brainstem, spinal cord, or ependymal lining of the ventricles. Most brain tumors in children are primary tumors, whereas brain metastases of extra-axial tumors commonly occur in adults. Pediatric brain tumors can be broadly classified as tumors of glial origin and those of primitive neuroectodermal cell origin. Tumors of glial origin can arise anywhere within the craniospinal axis and are of variable grade. Specific diagnoses in this group range from low-grade astrocytomas to high-grade glioblastoma multiforme and ependymoma.9,10 The neuroectodermal tumors presumably arise from primitive undifferentiated cells in the central nervous system. Tumors with this histology that arise in the cerebellum are called medulloblastomas.11

CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS Depending on their location, pediatric brain tumors come to medical attention because of signs and symptoms of increased intracranial pressure or because of the development of focal neurologic signs. Infratentorial tumors account for more than half of all pediatric brain tumors. Commonly, infratentorial tumors obstruct the flow of cerebrospinal fluid, leading to headache and vomiting (characteristically without nausea, especially in the morning). As symptoms of elevated intracranial pressure progress, patients may experience severe headache, intractable emesis, visual disturbances, abnormal eye movements, and eventually altered mental status. Infants may demonstrate bulging of the anterior fontanelle. Children with cerebellar tumors may demonstrate nystagmus and ataxia. Supratentorial tumors sometimes cause symptoms of increased intracranial pressure but more commonly come to

medical attention because of focal seizures, hemiparesis, or visual changes. Vague personality changes, ranging from lethargy to irritability, may be noted (Table 132-3). TABLE 132-3

Location

Tumors Affecting the Central Nervous System Specific Tumor Types

Supratentorial Low-grade gliomas hemispheric • Pilocytic • Fibrillary High-grade glioma Mixed neuronal-glial • Neoplasms • Ganglioglioma Ependymoma Choroid plexus tumors Primitive Neuroectodermal Tumor

Presenting Signs and Symptoms

Comments

Varies with site • Hemiparesis • Hemisensory deficits • Seizure • Hemianopsia

Outcome for these tumors usually improved by extensive resection

Supratentorial Chiasmatic/hypothalamic Vision deficits midline glioma Diencephalic Craniopharyngioma syndrome Germinoma/malignant Neuroendocrine germ cell tumors symptoms Pineoblastoma Hydrocephalus Primitive Parinaud neuroectodermal tumor syndrome Infratentorial

Medulloblastoma Cerebellar astrocytoma Ependymoma

Cranial nerve palsies Cerebellar

Germinoma and germ cell tumors require biopsy as treatment usually just chemotherapy, not surgery

Diffuse malignant brainstem glioma Benign focal brainstem glioma

signs • Ataxia • Dysmetria Brainstem signs • Weakness • Unsteady gait Increased intracranial pressure

For the general practitioner, a broad differential should be considered when evaluating neurologic symptoms. Patients who present with headache and emesis may have a nonmalignant infectious condition, such as a systemic viral gastroenteritis or viral meningitis. However, more serious infections such as encephalitis or bacterial meningitis could present similarly. In addition, for some presenting symptoms, such as focal neurologic deficits or extremity weakness, seizure disorder or stroke are possible.

DIAGNOSTIC EVALUATION AND MANAGEMENT Imaging of the brain is usually the first step in the evaluation of a patient with a suspected brain tumor. A CT scan may be obtained emergently to look for a mass or associated findings such as hydrocephalus or cerebral edema. However, magnetic resonance imaging (MRI) is the preferred study for the diagnosis and follow-up of pediatric brain tumors because it is more sensitive than CT and does not expose the child to ionizing radiation. In the setting of increased intracranial pressure, lumbar puncture should not be performed because it may precipitate fatal herniation of the cerebellar tonsils. When a brain tumor is suspected, the patient should be referred to a pediatric neurosurgeon, preferably one who collaborates with an experienced multidisciplinary team that includes a pediatric oncologist, neurologist, and radiation oncologist. Depending on the size, appearance, and location of the tumor, biopsy, subtotal resection, or complete resection may be undertaken. Sometimes biopsy is not recommended because the radiographic appearance of the tumor is characteristic or because its location makes biopsy extremely risky. Patients with optic pathway gliomas (especially those known to have

neurofibromatosis) and diffuse intrinsic pontine gliomas are usually not subjected to biopsy. Beyond surgery, therapeutic options for many types of brain tumors include chemotherapy, radiation, or both, depending on the tumor grade and histology. Some low-grade tumors may not require therapy if they are not causing symptoms and are stable in size.

EXTRACRANIAL SOLID TUMORS CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS Children with solid tumors may present with a range of signs and symptoms, depending on the size, location, and site of origin of the tumor. In children, malignant solid tumors most often arise in the abdomen, and less commonly in the thorax, extremities, and head and neck. Abdominal tumors come to medical attention because of abdominal pain, distention, vomiting, or change in bowel or bladder habits. An abdominal mass may be detected incidentally during routine child care or may come to medical attention when an individual without daily contact with the child notices abdominal distention. Abdominal masses may be difficult to palpate, especially in toddlers. Because most abdominal masses in children represent malignant disease, expedited evaluation is warranted. In most cases, abdominal ultrasonography is the first study performed to confirm the presence of the mass and to begin to formulate a differential diagnosis. Once a mass is confirmed, the child should be referred to a pediatric oncologist or pediatric surgeon for further evaluation (Table 132-4). TABLE 132-4

Benign and Malignant Abdominal/Pelvic Masses

Location

Benign

Malignant

Hepatic

Adenoma Hemangioma Storage disease Hamartoma

Hepatoblastoma Hepatocellular carcinoma Sarcoma Metastatic disease

Infectious

Leukemia

Kidney/Adrenal

Hydronephrosis Cycts Renal vein thrombosis Adrenal hemorrhage

Wilms tumor Renal cell carcinoma Rhabdoid tumor Neuroblastoma Pheochromocytoma

Gastrointestinal

Torsion/duplication Gastrointestinal stromal Feces (constipation) tumor Lymphoma Hernia Abscess Appendicitis

Pancreas

Trauma Pseudocyst

Pancreaticoblastoma

Ovary

Torsion Cyst Immature teratoma

Lymphoma Germ cell tumor Sex cord/stromal tumor Carcinoma

Bladder/Prostate Duplication Cyst

Rhabdomyosarcoma

Thoracic tumors can emanate from the chest wall or originate in any compartment of the mediastinum. Patients may complain of pain or show signs of respiratory compromise with coughing, wheezing, or shortness of breath. Apical lung or mediastinal tumors may lead to Horner syndrome (unilateral ptosis, miosis, and anhidrosis). A chest radiograph is the initial study of choice. Extremity tumors are usually accompanied by pain. Soft tissue swelling with or without a palpable mass may be present. A history of trauma or athletic injury to the extremity is frequently reported. Again, plain films are obtained initially. Additional studies such as ultrasonography, CT, or MRI

can help narrow the differential diagnosis and direct further diagnostic evaluation.

NEUROBLASTOMA Clinical Presentation and Differential Diagnosis Neuroblastoma is the most common extracranial solid tumor in children. It is a diverse disease, ranging from a localized tumor with benign behavior to disseminated disease with extremely aggressive features. Neuroblastoma arises from primitive neural crest elements that exist throughout the body.12 Most tumors arise in the abdomen, especially in the adrenal gland (Figure 132-3); thoracic tumors also occur, especially in infants. Infants with thoracic tumors may present with incidental findings on chest radiographs or with respiratory distress, wheezing, or facial swelling. Thoracic and retroperitoneal tumors may extend into the spinal canal and lead to spinal cord compression. In these cases, diagnostic evaluation and initiation of treatment must be expedited to minimize the risk of irreversible spinal cord injury. Neuroblastoma may disseminate to cortical bone, bone marrow, liver, or skin (cutaneous involvement is characteristic of infants with metastatic disease). Patients with disseminated disease experience bone pain, irritability, fatigue, pallor, bruising, and fevers. Spread of neuroblastoma to the orbital bones may lead to proptosis and orbital discoloration, a characteristic sign referred to as “raccoon eyes.”

FIGURE 132-3. CT scan of a patient with a retroperitoneal mass demonstrating the typical calcifications seen in neuroblastoma.

Occasionally, neuroblastoma is associated with paraneoplastic syndromes. Secretion of vasoactive intestinal peptide and catecholamines by the tumor may lead to secretory diarrhea and hypertension, respectively. Up to 5% of children with neuroblastoma develop opsoclonus-myoclonus syndrome (“dancing eyes, dancing feet”) secondary to autoantibodies against neural tissue. Diagnostic Evaluation and Management Blood tests in children with disseminated neuroblastoma may demonstrate cytopenias as a consequence of bone marrow infiltration. The peripheral blood may show show myelophthisic features, including “teardrop” forms. Blood levels of lactate dehydrogenase and ferritin may be elevated. Elevated levels of the catecholamines vanillylmandelic acid and homovanillic acid are detectable in the urine in the majority of cases and support the diagnosis of neuroblastoma. Histopathologic examination of the primary tumor or of a metastatic focus is necessary to establish the diagnosis. When neuroblastoma is suspected, sufficient biopsy tissue should be obtained for analysis of MYC-N, ploidy, and cytogenetics, if possible. Evaluation for metastatic disease with CT, bone scan, I-131 metaiodobenzylguanidine (MIBG) imaging, and bone marrow aspirates and biopsies is usually indicated. If there is intraspinal extension of tumor, spinal MRI may be recommended to assess the risk to the spinal cord.

RENAL TUMORS Clinical Presentation and Differential Diagnosis The majority of primary renal tumors in children are Wilms tumor; however, several other histologic types do occur.13 A small but significant fraction of renal tumors occurs in children with congenital anomalies. Abdominal distention, without other symptoms, is the most common presenting feature. Abdominal pain may result from stretching of the renal capsule. Occasionally, patients come to medical attention because of rapid abdominal enlargement and signs of anemia due to intratumoral hemorrhage or tumor rupture. In extreme cases, sudden hemorrhagic shock can occur. Gross or microscopic hematuria may be present, and moderate to severe hypertension is commonly seen. Diagnostic Evaluation and Management Abdominal ultrasonography is useful to confirm the presence of a renal mass and may suggest the renal origin of the tumor. CT with contrast may demonstrate the characteristic

“claw sign” of preserved renal parenchyma adjacent to the tumor (Figure 132-4). The contralateral kidney should also be evaluated, because bilateral tumors do occur. Wilms tumor characteristically metastasizes via the renal vein into the inferior vena cava and to the lungs. Doppler ultrasonography of the venous system and a chest radiograph (or chest CT scan) are important for staging the tumor and planning therapy. When feasible, up-front nephrectomy is recommended for unilateral tumors that do not extend into the renal vein. However, in some circumstances preoperative chemotherapy is preferred.

FIGURE 132-4. CT scan of a patient with a Wilms tumor demonstrating the characteristic “claw sign” of preserved renal parenchyma (arrow).

BONE TUMORS Clinical Presentation and Differential Diagnosis Osteosarcoma is the most common primary malignant bone tumor in children and adolescents,14 followed by Ewing sarcoma.15 Children older than 10 years are affected more

frequently than are younger children. Both types of tumors can arise in any bone, but Ewing sarcoma is relatively more likely to involve the axial skeleton and can arise in soft tissues. A hallmark of bone malignancy is “deep,” unrelenting pain that occurs at night and is poorly controlled with analgesics. Typically, these tumors grow relatively slowly, and the pain is chronic and progressive. Pain, swelling, and limitation of range of motion associated with the tumor may be attributed to a sports injury or to trauma for some time before medical attention is sought. Pathologic fracture may precipitate the diagnosis. X-ray typically demonstrates a destructive bone lesion (Figure 132-5). In patients with disseminated Ewing sarcoma, systemic symptoms such as fever, malaise, and weight loss sometimes occur.

FIGURE 132-5. X-ray of a tibia demonstrating an osteosarcoma with a classic “sunburst” pattern (arrow). Diagnostic Evaluation and Management Blood work is usually normal in patients with bone tumors, but alkaline phosphatase or lactate dehydrogenase is elevated in some cases. Metastatic disease to the lungs and other bones may be present at diagnosis or may develop later. Unlike osteosarcoma, Ewing sarcoma can metastasize to the bone marrow. If a primary bone tumor is suspected, referral to an orthopedic surgeon with experience in the surgical management of bone malignancies is strongly encouraged. In most cases, percutaneous biopsy is performed to establish the diagnosis. Surgical resection, or in some cases radiation therapy to the primary tumor, is often delayed until a course of systemic chemotherapy has

been administered.

OTHER EMBRYONAL TUMORS A variety of other solid tumors of embryonal origin occur in children, including rhabdomyosarcoma, hepatoblastoma, retinoblastoma, and germ cell tumors. The clinical manifestations correspond to the location and extent of the tumor. Rhabdomyosarcoma is a soft tissue sarcoma with histologic features of primitive muscle development.16 It can arise anywhere in the body, but the most common sites are the head and neck, genitourinary tract, and extremities; chest wall tumors also occur. In advanced stages, rhabdomyosarcoma can spread to the lungs, bones, and bone marrow. Hepatoblastoma is a primary tumor of the liver that occurs almost exclusively in children younger than 2 years. Abdominal distention is the most common presenting symptom. In most cases, serum levels of αfetoprotein are elevated. Children with a history of low birth weight and those with Beckwith-Wiedemann syndrome are at increased risk for the development of this tumor.17 Retinoblastoma is an uncommon tumor of retinal origin that occurs in young children.18 Retinoblastoma was the first cancer to be linked to a specific genetic defect—namely, mutation of the RB gene on chromosome 13. Individuals with inherited or acquired constitutional mutations involving this genetic locus are at high risk of developing multiple and bilateral tumors. Unilateral (i.e. nongermline) retinoblastoma accounts for about 60% of cases and is associated with a slightly older median age at diagnosis. The most common presenting sign of retinoblastoma is leukokoria, or loss of the normal red retinal reflex. If the tumor is large, it may manifest as a painful red eye. Germ cell tumors are a heterogeneous group of malignant tumors of several different histologic types that, taken together, account for only about 1% of cancers in children. These tumors develop from primordial germ cells that migrate during embryogenesis from the yolk sac to the gonads. Therefore these tumors may arise in gonadal or extragonadal (usually midline) sites. A mass in the abdomen or pelvis or in the male testis is the usual presenting complaint. Adolescent boys may be reluctant to complain about testicular

enlargement, and some patients present with surprisingly large tumors discovered during a thorough physical examination. Several serum markers may be elevated in patients with germ cell tumors, including α-fetoprotein, βhuman chorionic gonadotropin, lactate dehydrogenase, and placental alkaline phosphatase. When serum markers are elevated at diagnosis, they may be useful for following response to therapy and identifying disease recurrence.

CONSULTATION AND ADMISSION AND DISCHARGE CRITERIA All patients with newly diagnosed leukemia should be admitted to a hospital experienced in the management of children with cancer. Patients with a new diagnosis of a solid tumor can be evaluated on an outpatient basis as long as pain is controlled and there is no evidence of superior vena cava syndrome, spinal cord compression, respiratory distress, bleeding, or metabolic derangement. The initial management of all childhood cancers is directed by a pediatric hematology-oncology team, with the consultation of other appropriate specialists. The primary care provider’s support and involvement are needed for the optimal care of the patient and his or her family. Discharge criteria are determined by the type of cancer and by the recommendations of the hematology-oncology team and involved subspecialists. KEY POINTS Childhood cancer is a rare disease, and the cause is usually unknown. The majority of children diagnosed with cancer will be cured of their disease. The most common childhood malignancy is acute lymphoblastic leukemia. The most common pediatric solid tumor is neuroblastoma. Osteosarcoma is the most common primary malignant bone tumor. Treatment regimens vary according to diagnosis, staging, and

histopathologic and cytogenetic studies. Dramatic progress has been made in elucidating the molecular basis of various types of cancer. The ability to rapidly amplify and sequence disease-associated genes and detect specific chromosomal translocations has enhanced diagnostic precision, risk stratification, and early detection of residual and recurrent disease. These molecular techniques will continue to evolve and gain clinical applications. The preliminary cloning of the human genome and other technologic advances have led to the development of microarrays, which are powerful tools that can screen the expression of thousands of genes in a single procedure. Analogous techniques for detecting disease-associated changes on the protein level are under development.

REFERENCES 1. Ries LAG EM, Kosary CL, Hankey BF, et al. eds. SEER Cancer Statistics Review, 1975-2001. 2004. 2. Wakeford R. The risk of childhood leukaemia following exposure to ionising radiation-a review. J Radiol Protect. 2013;33(1):1-25. 3. Robison LL. Down syndrome and leukemia. Leukemia. 1992;(6 Suppl 1):5-7. 4. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166-178. 5. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood. 2012;120(16):3187-3205. 6. Cairo M, Raetz, E, Lim, MS, Davenport, V, Perkins, SL. Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future. Pediatr Blood Cancer. 2005;45(6):753-769. 7. Patte C, Auperin A, Michon J, et al. The Societe Francaise d’Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy

tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood. 2001;97(11):3370-3379. 8. Sandlund JT, Hudson MM. Hematology: treatment strategies for pediatric Hodgkin lymphoma. Nature Rev Clin Oncol. 2010;7(5):243244. 9. Watson GA KR, Wisoff JH. Multidisciplanry management of pediatric low-grade gliomas. Semin Radiat Oncol. 2001;11(2):152-162. 10. Finlay J, Zacharoulis, S. The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: a historical - and futuristic - perspective. J Neurooncol. 2005;75(3):253-266. 11. Jakacki R. Treatment strategies for high-risk medulloblastoma and supratentorial primitive neuroectodermal tumors. Review of the literature. J Neurosurg. 2005;102(1 Suppl):44-52. 12. Maris JM. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr. 2005;17(1):7-13. 13. Shamberger R. Pediatric renal tumors. Semin Surg Oncol. 1999;16(2):105-120. 14. Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9(4):422-441. 15. Grier HE. The Ewing family of tumors. Ewing’s sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am. 1997;44(4):991-1004. 16. Meyer WH, Spunt SL. Soft tissue sarcomas of childhood. Cancer Treat Rev. 2004;30(3):269-280. 17. Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood Cancer. 2012;59(5):776-779. 18. Lohmann DR, Gallie BL. Retinoblastoma. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP eds. Seattle, WA: GeneReviews; 1993.

CHAPTER

133

Oncologic Emergencies Andrew E. Place

INTRODUCTION Early recognition, prevention, and treatment of oncological emergencies improves clinical outcomes. Both at initial presentation and during treatment, pediatric cancer patients can develop acute, severe, and life-threatening conditions (Table 133-1). This chapter reviews the presentation and management of the most commonly encountered emergent conditions seen in pediatric cancer patients. The pediatric hospitalist should be able to identify at-risk patients, adopt preventive strategies, recognize clinical deterioration, and initiate prompt treatment of these emergencies. TABLE 133-1

Pediatric Oncologic Emergencies

Metabolic emergencies Tumor lysis syndrome Hyperuricemia Hyperkalemia Hyperphosphatemia/hypocalcemia Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic emergencies Hyperleukocytosis, leukostasis Hemorrhage and DIC Thrombosis Infectious and inflammatory emergencies Febrile neutropenia

Septicemia, shock Neutropenic enterocolitis Pancreatitis Mechanical emergencies Superior vena cava syndrome, superior mediastinal syndrome Pleural and pericardial effusions Cardiac tamponade Neurologic emergencies Spinal cord compression Increased intracranial pressure Pain Altered mental status Malignant hypertension Seizure When a new diagnosis of cancer or an oncologic emergency is suspected, a pediatric oncologist should be consulted to aid in the initial diagnostic evaluation and therapeutic management. Pediatric cancer patients benefit from rapid referral to a tertiary care center with a subspecialty pediatric oncology program. Ideal treatment of some oncologic emergencies will involve the initiation of chemotherapy or radiation therapy, which must be done at a facility experienced in the administration of these modalities in children and adolescents.

METABOLIC EMERGENCIES TUMOR LYSIS SYNDROME The rapid release of the intracellular contents of tumor cells into the plasma can cause significant metabolic derangements that can progress to multiorgan failure and death. The laboratory abnormalities most often associated with this tumor lysis syndrome (TLS) include hyperuricema, hyperphosphatemia, hyperkalemia, and hypocalcemia. There are no strict criteria defining TLS, but recently it has been proposed that TLS can be categorized into

“laboratory” and “clinical” entities, the former being defined by simultaneous presence of two or more electrolyte abnormalities and the latter by the presence of renal dysfunction, seizures, cardiac dysrhythmia, or multiorgan system failure.1 TLS is most commonly encountered shortly after initiation of therapy for malignancies with high tumor burden. TLS can also be identified prior to the initiation of therapy, especially in tumors with high cellular proliferation such as acute lymphoblastic leukemia (ALL) or Burkitt lymphoma. Recently, TLS management guidelines based on risk stratification have been proposed.2,3 High-risk clinical features include diagnoses of acute myelogenous leukemia (AML), ALL and advanced stage non-Hodgkin lymphoma (NHL), WBC count greater than 100,000 cells/mm3, elevated lactate dehydrogenase (LDH), presence of renal dysfunction, or multiple electrolyte abnormalities (Table 133-2). Incorporation of these guidelines into prospective pediatric studies may lead to further improvement in TLS prevention and treatment. Rapid identification of at-risk patients should expedite the initiation of prophylactic strategies to avoid complications of TLS (Table 133-3). TABLE 133-2

TLS: Risk-Stratified Prophylaxis Strategies Low Risk

AML

WBC 100 mL/m2/hr and specific gravity 10 mg/dL and include lethargy, nausea, vomiting, uric acid calculi, hematuria, oliguria, anuria

Hyperhydration

Implement seizure precautions

Allopurinol or rasburicase (see Table 133-4)

ECG, electrocardiogram.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can develop as a side effect of certain chemotherapeutics or can be associated with intracranial malignancies and infections such as pneumonia. The resulting hyponatremia can be clinically significant and require intervention. While fluid restriction is the mainstay of therapy, this can compromise the hydration strategies utilized around certain chemotherapy regimes or clinical scenarios. For instance, in patients receiving hyperhydration for prevention of TLS or to aid clearance of methotrexate, fluid restriction may be contraindicated. Consultation with a pediatric oncologist is recommended in

these cases.

HEMATOLOGIC EMERGENCIES HYPERLEUKOCYTOSIS The initial presentation of childhood ALL or acute myelogenous leukemia (AML) can be complicated by the presence of a very elevated circulating blast count. Hyperleukocytosis is defined as a WBC greater than 100,000 cells/mm3 and can be seen in both ALL and AML. Hyperleukocytosis is more commonly seen in ALL, but clinical evidence of vascular obstruction by blasts (leukostasis) is more commonly encountered in patients with AML. Hyperleukocytosis increases blood viscosity, which can ultimately result in leukostasis, small vessel obstruction, and decreased perfusion. The circulatory anatomy of the brain and lungs puts these organs at particular risk of developing life-threatening complications. Classic presenting symptoms of pulmonary leukocytosis include hypoxia, tachypnea, and respiratory distress. Chest x-rays are generally not useful in the diagnosis of leukostasis, but when they are performed, they may demonstrate bilateral “whiteout” of the lung fields, sometimes prompting an incorrect diagnosis of pneumonia. Chest imaging is not informative and should not be used to diagnose leukostasis. Central nervous system (CNS) manifestations of cerebral leukostasis may be subtle, so a thorough neurologic exam is essential. Common signs or symptoms include headache or somnolence, but altered metal status, seizure, or comas are also possible. Less common presentations of leukostasis include renal dysfunction, cardiac ischemia, priapism, and dactylitis. Close monitoring of patients presenting with hyperleukocytosis is important, as leukostasis is diagnosed clinically rather than by laboratory or imaging assessment. Critical goals in the initial management of a patient with hyperleukocytosis include reduction of blood viscosity and initiation of TLS prevention. Administration of intravenous fluids aids both of these goals and should be promptly initiated. While patients with leukemia can present with exceptional anemia, red cell transfusions should be avoided if possible, because increasing the hematocrit will directly increase blood viscosity. Early consultation with a pediatric oncologist is critical, as initiation of hydroxyurea or induction chemotherapy should be started as soon as possible.

Cytoreduction by leukapheresis or exchange transfusion can be considered as alternative methods to decrease blood viscosity, but is controversial. Generally, these procedures are considered when peripheral blood WBC count is greater than 100,000 cells/mm3 in AML or greater than 300 to 500,000 cells/mm3 in ALL. However, these are typically offered only to patients whose chemotherapy is delayed and who are symptomatic of leukostasis. There are no studies comparing the use of leukapheresis to initiation of chemotherapy in pediatric patients with hyperleukocytosis or leukostasis. In addition, in cases where hyperleukocytosis is accompanied by coagulopathy (see below) or septic shock, leukapheresis may be unsafe. As a result, there are no uniformly accepted criteria supporting the use of leukapheresis or exchange transfusion in children with hyperleukocytosis. Leukapheresis should be initiated on a case-by-case basis after consultation with a pediatric oncologist. Considering the complexities of preparing for leukapheresis (e.g. catheter placement, blood product administration, and critical care support), the local blood bank and/or apheresis team should be quickly notified of any patient being considered for this procedure.

HEMORRHAGE AND DISSEMINATED INTRAVASCULAR COAGULATION Severe thrombocytopenia is commonly seen in pediatric oncology patients, either as a result of direct invasion of the bone marrow by cancer cells or as a consequence of cancer therapy. Abnormal bleeding associated with thrombocytopenia typically presents with either petechiae or spontaneous mucosal bleeding, such as epistaxis. Less commonly, more severe bleeding such as intracranial hemorrhage or gastrointestinal bleeding can occur. Transfusing asymptomatic patients when their platelet count is below a specific threshold can prevent thrombocytopenia-related bleeding. Typically, this platelet count threshold is between 10,000 and 30,000 platelets/mm3, but is variable among different centers and in certain clinical situations. Hemorrhage in cancer patients can also occur because of acquired coagulation factor deficiency that occurs as a result of disseminated intravascular coagulation (DIC) or secondary to specific chemotherapeutics such as asparaginase, which blocks production of numerous coagulation factors. DIC in oncology patients is most commonly encountered when these

patients are experiencing overwhelming infections, such as sepsis. However, certain subtypes of childhood AML, especially acute promyelocytic leukemia (APML), can present with life-threatening DIC prior to or immediately after initiation of therapy. The management of DIC in the setting of sepsis in the oncology patient is similar to non-oncology patients, with emphasis on fibrinogen and coagulation factor replacement through the administration of cryoprecipitate and fresh frozen plasma (FFP), respectively. In the case of APML-associated DIC, initiation of appropriate chemotherapy should be expedited, in addition to supportive administration of FFP and cryoprecipitate. L-Asparaginase, a chemotherapeutic commonly used in the treatment of childhood ALL and AML, depletes asparagine, which starves tumor cells of this essential amino acid. Unfortunately, asparagine depletion also reduces the production of numerous coagulation factors, predisposing these patients to both hemorrhage and thrombosis. A detailed explanation of the management of blood product support in cases of severe hemorrhage and DIC is outside the scope of this chapter and may be found elsewhere in this text. However, the pediatric hospitalist should be knowledgeable about transfusion management strategies that are particular to the pediatric oncology patient. In general, transfusions of blood products should be minimized as much as possible to avoid the development of alloimmunization, transfusion reactions, infections, and iron overload. The transfusion thresholds for platelets and red blood cells vary by center but should always be tailored to the particular clinical scenario (Table 133-6). TABLE 133-6

Transfusions in the Oncology Patient

It is common for family members of a newly diagnosed pediatric oncology patient to request direct donation of blood products for their loved one. This practice should be discouraged for two reasons. First, directly donated blood products have not been shown to be safer than anonymously donated blood products. Second, oncology patients may at some point need an allogeneic hematopoietic stem cell transplant, and exposure to familial human lymphocyte antigens may increase the risk of graft rejection and poor outcome.

THROMBOSIS Risk of thrombosis is increased in pediatric cancer patients for numerous reasons. The most common risk factor in children is the presence of an indwelling central venous catheter. As mentioned earlier, certain medications, such as L-asparaginase, increase the risk of thrombosis through depletion of the coagulation factors like antithrombin III (ATIII), plasminogen, protein C, and protein S. Mechanical compression of large veins by tumor can also result in thrombosis. Other risk factors for thrombosis in the cancer setting include sepsis, prolonged immobility, and the underlying inflammatory state

intrinsic to malignancy. Presenting symptoms of thrombosis are related to location and may include extremity or facial swelling. When occurring in the cerebral venous sinuses, patients can present with headache, seizures, or other neurological manifestations. Central venous line (CVL)-associated thrombosis can present with line malfunction. Pulmonary embolism should be considered in patients with respiratory distress, chest pain, hypoxia, syncope, or with sustained tachycardia of unclear etiology. Once identified by appropriate imaging, the management of venous thrombosis must be tailored with consideration of thrombus location (superficial vs. deep vein thrombosis), provocative triggers (CVL vs. mass), type/duration of chemotherapy, and age of the child (ambulating vs. toddling), as these factors will influence the type and duration of anticoagulation as well as supportive care. For instance, during periods of chemotherapy-induced severe thrombocytopenia, anticoagulation may be reduced or discontinued. Furthermore, patients receiving anticoagulation with enoxaparin may need frequent repletion of ATIII in order to achieve therapeutic levels of enoxaparin; this is especially relevant if they are receiving L-asparaginase, which is known to inhibit ATIII synthesis. While thrombosis in pediatric oncology patients is not uncommon, it is rarely associated with an underlying hypercoagulability syndrome (e.g. Factor V Leiden). The involvement of a pediatric hematologist is encouraged to help guide therapy and to determine the need for a hypercoagulability evaluation.

FEVER AND NEUTROPENIA BACKGROUND Neutropenia is a common side effect of chemotherapy administered to children, particularly alkylating agents, anthracyclines, and cytarabine. In contrast to thrombocytopenia and anemia, which can be treated with the transfusion of blood products, neutropenia resolves only after recovery of bone marrow function. While the transfusion of donor granulocytes is possible, this practice is controversial without clear clinical benefit. Severe neutropenia is commonly encountered in pediatric oncology patients and can lead to the development of life-threatening bacterial and fungal infections. The febrile and neutropenic patient is a true emergency, as overwhelming

sepsis and death can occur in a matter of hours if appropriate interventions are not emergently implemented. Recently, new fever and neutropenia guidelines have been published by the Infectious Diseases Society of America and the International Pediatric Fever and Neutropenia Guideline Panel.7,8 Common definitions used in these guidelines are presented in Table 133-7. The guidelines stress the importance of utilizing risk stratification in determining treatment strategies. However, there are still no universally accepted pediatric criteria to categorize neutropenic patients at low or high risk of developing severe infections. As a result, many institutions adopt specific algorithms that differentiate risk based on neutrophil count, clinical status, malignancy, and chemotherapy most recently given. What follows are general approaches to the neutropenic patient at high risk for serious infections. TABLE 133-7

Clinical Feature

Fever and Neutropenia: Definitions and Initial Laboratory Assessment Definition

Fever

• Single temperature greater than 38.3° C, or • Temperature greater than 38° C lasting more that 1 hour, or obtained twice within 12–24 hours

Neutropenia

ANC 50% have been shown to tolerate anesthesia well.11-13 In extreme circumstances, such as impending respiratory failure, implementation of empiric antineoplastic therapy must be considered prior to obtaining tissue for diagnosis. Strategies employed in this scenario include initiation of steroids, chemotherapy, or radiation therapy. In these situations, a pediatric oncologist should always be involved. Some malignancies, such as lymphoma, may have an exceptional response to empiric therapy with rapid resolution of both AMM size and symptoms. Such a response may make biopsy more challenging or infeasible, thus jeopardizing the ability to make an accurate pathological diagnosis.

SUPERIOR VENA CAVA SYNDROME/SUPERIOR MEDIASTINAL SYNDROME SVC syndrome classically presents with upper extremity swelling and/or facial plethora resulting from decreased venous return from the head and upper extremities. Rarely, SVC syndrome is associated with cardiogenic shock or signs of increased intracranial pressure. SVC syndrome can also be caused by an occlusive thrombus resulting from the placement of an indwelling catheter into venous structures already narrowed by the mediastinal mass. One must also be careful with fluid administration in patients presenting with significant vascular compromise from anterior mediastinal masses. The increased intrathoracic pressure or direct

compression of the right atrium from the tumor may make these patients particularly pre-load sensitive; hypovolemia in these patients may precipitate cardiopulmonary arrest secondary to poor cardiac output. On the other hand, hyperhydration may worsen symptoms of SVC syndrome, increasing upper extremity and facial swelling. As in the case of severe tracheal compression, antineoplastic therapy should be urgently initiated.

NEUROLOGIC EMERGENCIES SPINAL CORD COMPRESSION Rapid identification of spinal cord compression in the pediatric oncology patient is necessary in order to avoid permanent neurological disability. Spinal cord compression is most commonly encountered in solid tumors such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, metastatic CNS tumors, lymphoma, and AML-related chloromas. Spinal cord compression can be associated with both advanced stage metastatic disease or at initial presentation. The presenting signs are dependent upon the location and severity of cord compression, but can include back pain, weakness, loss of bladder/bowel function, and changes in sensation. Clinicians must remain vigilant and be on the lookout for spinal cord compression lest the diagnosis be missed. In patients who are very young, for whom the neurologic exam is difficult to interpret, or for patients who are otherwise very ill, new findings consistent with spinal cord compression may be overlooked. The workup of suspected spinal cord compression should be expedited as a medical emergency requiring a multidisciplinary approach, beginning with an efficient, thorough neurological examination followed by MRI of the spine. If cord compression is strongly suspected based on known areas of disease or clinical presentation, IV dexamethasone (1–2 mg/kg over 30 minutes) may be administered prior to imaging. If imaging confirms cord compression, an emergent consultation with neurosurgery, radiation oncology, and pediatric oncology should be obtained in order to decide whether surgery, chemotherapy, or radiation therapy should be emergently initiated.14,15

INCREASED INTRACRANIAL PRESSURE

The presence of an expanding intracranial mass or hydrocephalus can result in increased intracranial pressure (ICP) that can progress to uncal herniation. Intracranial malignancies can cause increased ICP by means of either mass effect or an obstructive hydrocephalus, depending on location. Increased ICP can also be caused by thrombosis, infarction, infection, or hemorrhage. Finally, malfunction of an indwelling ventriculoperitoneal (VP) shunt can cause elevated ICP. Presenting symptoms of increased ICP include headache, nausea, emesis, and visual complaints. On physical examination, cranial nerve abnormalities (including papilledema), deficits in strength and sensation, and altered mental status may be encountered. Cushing’s triad of bradycardia, hypertension, and respiratory irregularities must be recognized immediately, as they herald impending herniation. A rapid evaluation of the patient with suspected increased ICP must occur concurrently with consideration of starting therapy. Imaging of the brain is most rapidly obtained with a CT scan. CT is able to identify the presence of increased ICP, impending cerebral herniation, and hemorrhage. MRI has the advantage of obtaining superior anatomical detail compared to CT, especially in the posterior fossa, and can be used initially if available, or after initial evaluation with CT. Patients with an indwelling ventricular shunt or Ommaya reservoir should have a radiographic shunt series performed and be referred for emergency neurosurgical consultation. For emergent therapy, IV mannitol can be administered as a 25% solution at a dose of 0.25 to 1 g/kg over 30 minutes. IV dexamethasone may also be indicated, and can be administered at a dose of 1 to 2 mg/kg IV over 30 minutes. Once intubated, hyperventilation with a goal PCO2 to 30–35 mmHg can be effective in the management of increased ICP. Early discussion with neurosurgery and critical care consultants will help optimize patient care.

PAIN EMERGENCIES Despite favorable long-term outcomes in many forms of pediatric cancer, pain, whether acute or chronic, remains a significant clinical challenge. Patients can experience pain as a presenting symptom at time of diagnosis (e.g. bone pain with osteosarcoma), as a side effect of therapy (e.g. mucositis pain) or as a sign of tumor progression (e.g. gastrointestinal obstruction).

Controlling pain in patients with advanced-stage disease or at end of life is particularly challenging. Unfortunately, there is evidence that pain and other discomfort at the end of life is often undertreated;16 however, recent studies indicate that patterns of end-of-life care are improving.17 A full discussion of palliative care can be found elsewhere in this text, but the pediatric hospitalist should be familiar with strategies to control pain in patients with advancedstage disease or those approaching end of life. Severe pain in these patients is a medical emergency and should be approached with urgency. In general, severe pain should be treated with a multidisciplinary approach, including pharmacologic interventions as well as nonpharmacologic integrative therapies.18 Initial interventions need to be closely monitored so as to capture pain control as quickly as possible. Advanced-stage oncology patients are likely to require rapid escalation of opioids or doses of opioids that are significantly larger than typically administered to opioid-naïve patients. Adequate pain control is determined by the amount of relief or comfort acceptable to the patient, not by the cumulative dosages of analgesics. The pediatric hospitalist should become familiar with institution-specific algorithms and policies around rapid escalation of opioids. In addition to opioids, non-opioid analgesics (e.g. acetaminophen) and integrative approaches (e.g. massage, music therapy, biofeedback) should be maximized. Not uncommonly, patients may require adjuvant therapies (e.g. anticonvulsants, benzodiazepines, dissociative agents) or more invasive approaches such placement of epidural catheters or nerve blocks. Palliative care expertise is invaluable in these settings and can assist the pediatric hospitalist in optimizing comfort at end of life.

ALTERED MENTAL STATUS Altered mental status in an oncology patient has a broad differential ranging from relatively benign causes to etiologies that are truly life threatening. The hospitalist should be familiar with this differential, as it will help guide a rapid assessment (Table 133-10). TABLE 133-10

Etiologies of Altered Mental Status in the Oncology Patient

Tumor Primary CNS tumor Metastatic CNS tumor Leukemic or carcinomatous meningitis Hyperleukocytosis CNS infection Meningitis Viral encephalitis Brain abscess Cerebrovascular accident Ischemic or hemorrhagic stroke Sagittal venous sinus thrombosis Metabolic derangements Hyponatremia Hypo/hyperglycemia Hypomagnesemia Uremia Hypo/hyperthyroidism Increased intracranial pressure Tumor All-trans-retinoic acid

Cytotoxic chemotherapy Methotrexate Cyarabine Ifosphamide Supportive care medications Opioids Benzodiazepines Gabapentin Anticonvulsants Antidepressants Antihistamines Dronabinol Psychiatric conditions Adjustment disorders Depression Anxiety “ICU psychosis” Cardiopulmonary insufficiency Hypoxia Hypercarbia Hypotension Seizure/postictal state

KEY POINTS Overall, outcomes for childhood malignancies are superior to those seen in adults despite the relative rarity of pediatric cancer. However, expected and unexpected complications of

the underlying malignancy and its treatment influence both morbidity and mortality. A pediatric hospitalist must recognize patients who are at risk for developing oncologic emergencies and implement appropriate preventive strategies when available. A pediatric hospitalist must recognize the most common oncologic emergencies and be knowledgeable about appropriate emergency management. Although early consultation with a pediatric oncologist is critical to the management of pediatric oncologic emergencies, treatment often needs to be initiated by the hospitalist. Institution-specific treatment algorithms for these emergencies exist at many pediatric hospitals and should be readily available for review. A thorough but efficient history and physical examination are critical to ensure that appropriate radiographic and laboratory studies are obtained. Novel targeted antineoplastic therapies with fewer side effects are actively being studied in pediatric clinical trials. It is hoped that these therapies will decrease the toxicity associated with the classic cytotoxic agents, yet reproduce or improve upon patient outcomes. These targeted therapies will have their own idiosyncratic side effects, and the pediatric hospitalist will be expected to be familiar with these as newer agents are incorporated into standard therapy. Improved genomic profiling of both the pediatric patient and their tumor will identify patients with both favorable and unfavorable prognoses. Risk stratification on the basis of genomic profiling will allow for personalized tailoring of therapeutic regimens aimed to decrease short- and long-term treatment-associated toxicity while improving survival.

SUGGESTED READINGS

Fisher MJ, Rheingold SR. Oncologic emergencies. In: Pizzo P, Poplack D eds. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2011:11251151 Mullen E, Whangbo J, Vrooman L. Oncologic emergencies. In: Orkin S, Fisher D, Look A eds. Oncology of Infancy and Childhood. 1st ed. Philadelphia, PA: Elsevier; 2009:1121-1143. Ullrich C, Berde C, Billett A. Symptom management in children with cancer. In: Orkin S, Fisher D, Look A eds. Oncology of Infancy and Childhood. 1st ed. Philadelphia, PA: Elsevier; 2009:1204-1220.

REFERENCES 1. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127(1):3-11. 2. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149(4):578-586. 3. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844-1854. 4. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97(10):2998-3003. 5. Holdsworth MT, Nguyen P. Role of i.v. allopurinol and rasburicase in tumor lysis syndrome. AJHP. 2003;60(21):2213-2222; quiz 2223-2214. 6. Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol. 2001;19(3):697-704. 7. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-93.

8. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(35):4427-4438. 9. Azizkhan RG, Dudgeon DL, Buck JR, et al. Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg. 1985;20(6):816-822. 10. Hammer GB. Anaesthetic management for the child with a mediastinal mass. Paediatr Anaesth. 2004;14(1):95-97. 11. Perger L, Lee EY, Shamberger RC. Management of children and adolescents with a critical airway due to compression by an anterior mediastinal mass. J Pediatr Surg. 2008;43(11):1990-1997. 12. Shamberger RC. Preanesthetic evaluation of children with anterior mediastinal masses. Semin Pediatr Surg. 1999;8(2):61-68. 13. Shamberger RC, Holzman RS, Griscom NT, Tarbell NJ, Weinstein HJ. CT quantitation of tracheal cross-sectional area as a guide to the surgical and anesthetic management of children with anterior mediastinal masses. J Pediatr Surg. 1991;26(2):138-142. 14. Lewis DW, Packer RJ, Raney B, Rak IW, Belasco J, Lange B. Incidence, presentation, and outcome of spinal cord disease in children with systemic cancer. Pediatrics. 1986;78(3):438-443. 15. Pollono D, Tomarchia S, Drut R, Ibanez O, Ferreyra M, Cedola J. Spinal cord compression: a review of 70 pediatric patients. Pediatr Hematol Oncol. 2003;20(6):457-466. 16. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med. 2000;342(5):326-333. 17. Wolfe J, Hammel JF, Edwards KE, et al. Easing of suffering in children with cancer at the end of life: is care changing? J Clin Oncol. 2008;26(10):1717-1723. 18. Friedrichsdorf SJ. Pain management in children with advanced cancer and during end-of-life care. Pediatr Hematol Oncol. 2010;27(4):257261.

CHAPTER

134

Hematopoietic Stem Cell Transplant Christine N. Duncan

INTRODUCTION Thousands of hematopoietic stem cell transplants (HSCT) are performed in children and adolescents annually in the United States. HSCT is being used to treat a growing number of indications including malignancies, nonmalignant hematologic diseases, immunologic disorders, inborn errors of metabolism, and autoimmune disorders (Table 134-1). HSCT is not the first line of therapy for many of these diseases, but is reserved for patients for whom first-line therapy is not sufficient or is ineffective. While most pediatric transplants are performed at tertiary care centers, post-transplant patients receive a portion of their care in community hospitals and local oncologists’ offices. It is important for the pediatric hospitalist to have a general understanding of the medical issues facing HSCT patients who may present to their emergency departments or get admitted to inpatient units. TABLE 134-1

Examples of Pediatric Diseases Treated with Stem Cell Transplant

High-Risk Hematoloic Malignancies

Solid Tumors

Acute myelogenous leukemia

Neuroblastoma

Acute lymphoblastic leukemia

Burkitt lymphoma

Chronic myelogenous leukemia

Wilms tumor

Juvenile myelomonocytic leukemia

Certain brain tumors

Hodgkin and non-Hodgkin lymphoma Bone Marrow Failure Syndromes

Immunodeficiencies

Aplastic anemia

Severe combined immunodeficiency

Swachmann Diamond syndrome

Chronic granulomatous disease

Fanconi anemia

Wiskott-Aldrich syndrome

Diamond-Blackfan anemia

X-linked lymphproliferative disease

Hematologic Disorders

Metabolic and Inherited Disorders

Sickle cell anemia

Lysosomal storage diseases

Thalassemia major

Osteopetrosis

Hemophagocytic lymphohistiocytosis

Niemann-Pick disease Lysosomal storage diseases Adrenoleukodystrophy

BACKGROUND HSCT is the process of replacing diseased or dysfunctional bone marrow with stem cells capable of restoring normal hematopoietic function. The three main types of HSCT are autologous, allogeneic, and syngeneic. In autologous HSCT, stem cells are collected from the patient and stored until the time of infusion. Autologous transplant has the advantages of being readily available for current and future transplants if needed, eliminating the risk of graftversus-host disease (GVHD), more rapid immune reconstitution, and lower short-term mortality rates.1 High-dose chemotherapy followed by autologous

stem cell infusion (often called rescue) is used to treat children with some high-stage or relapsed solid tumors, and is employed in gene therapy transplants.2 In allogeneic HSCT, stem cells are collected from another person and infused into the patient following conditioning with chemotherapy and/or radiation. A syngeneic HSCT is a transplant using the patient’s identical twin sibling as a donor. The benefits of allogeneic transplants are that there is no risk of residual tumor cells in the graft, the stem cells have not been potentially damaged by prior therapy, and the cells may exhibit a graftversus-leukemia effect.3 Disadvantages include the risk of GVHD, less flexible timing of donation, the need for immunosuppression following engraftment, slower immune reconstitution with increased risk of infection, and greater overall morbidity and mortality. Human leukocyte antigen (HLA) typing is performed to determine the suitability of potential allogeneic donors. HLAs are genetic markers found on the surface of white blood cells. The genetic composition of these antigens, located on the short arm of chromosome six, is determined from a blood test or buccal swab of the recipient and the potential donor.4 HLAs are inherited, making siblings more likely than unrelated donors or parents to have similar typing. There is an approximate 25% chance of two siblings having matching HLA typing.5 The closer the HLA match between the donor and the recipient, the lower the risk of GVHD and better overall survival. Allogeneic donors may be related to the patient or found through an unrelated donor search. Related donors have the advantages of being more closely HLA-matched, are typically readily available for donation, and have lower risk of GVHD and higher survival rates. Unfortunately, only 30% of individuals needing an allogeneic HSCT have a suitably matched sibling.5,6 Unrelated allogeneic donors may be less readily available than related donors, may be unavailable for potential future transplants, are less well matched, and are associated with an increased risk of GVHD. The National Marrow Donation Program (NMDP) is a nonprofit organization in the United States that anonymously matches unrelated stem cell transplant recipients and donors.7 Using the NMDP and similar organizations, a suitable stem cell source can be found for approximately 80% of Caucasians with a transplantable disorder.8 However, African-

Americans and Hispanics have a less than 30% chance of finding a wellmatched, unrelated bone marrow or peripheral blood stem cell (PBSC) donor.8 Alternative donor sources, including umbilical cord blood and haploidentical transplants, are needed for many of these patients. Sources of stem cells include bone marrow, peripheral blood, and umbilical cord blood (UCB). Bone marrow and umbilical cord blood are rich in stem cells and are the most commonly used stem cell sources for pediatric HSCT. Bone marrow is typically collected under anesthesia and requires no physical pre-donation preparation of the donor. Bone marrow donors undergo confirmatory HLA typing, health assessment, and infectious screening prior to being approved to donate. The process of identifying and clearing a bone marrow donor takes weeks to months. UCB is removed via cannulation or drainage following delivery of the infant.9 The blood is stored frozen in public banks as an anonymous donation or in private banks for use by the family. The risk of GVHD is lower with UCB compared with bone marrow or PBSCs. UCB units that are matched at fewer HLA loci have equivalent GVHD risk compared to the other stem cell sources.10 This has increased the ability to find a suitable stem cell source for patients for whom fully matched unrelated bone marrow or PBSC donors are not found in international registries.11 Another advantage is the rapid availability of the stem cell product. Clinical challenges with the use of UCB is that the stem cell yield is limited to what is collected at birth, a single unit may not be adequate for adults or large children, there may be lack of complete medical follow-up on the child who donated the UCB, and there is a slower immune reconstitution compared to other stem cell sources.5 Peripheral blood has a low concentration of circulating stem cells.12 Chemotherapy or stimulating factors are used to mobilize stem cells from the bone marrow into the peripheral circulation. Chemotherapy with or without stimulating factors is commonly given to autologous donors prior to PBSC collection as part of treatment of their underlying disease. Granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colonystimulating factor (GM-CSF) are given to allogeneic PBSC donors prior to collection.13 PBSCs are removed via apheresis through large peripheral intravenous access or central venous line. For young sibling donors, the need for large intravenous access can preclude the collection of PBSCs. Advantages of using PBSCs are more rapid neutrophil and immune recovery,

potentially greater graft-versus-leukemia effect, and the collection procedure is less invasive on the donor. The primary disadvantage of using PBSC is the greater risk of GVHD. In pediatrics the use of PBSC is associated with greater GVHD and increased mortality, and no decrease in relapse rate.14 PBSC is not a favored stem cell source in pediatrics because of higher mortality rates without improvement in relapse rates.

TRANSPLANT PROCEDURE Prior to receiving stem cells patients receive a conditioning regimen of chemotherapy or chemotherapy with radiation. Patients are admitted to the hospital for conditioning and typically remain hospitalized until neutrophil engraftment, though some centers allow discharge prior to engraftment following autologous stem cell infusion. The purposes of conditioning are to create marrow space for the transplanted cells, eliminate diseased marrow cells when applicable, and remove host lymphocytes capable of rejecting the transplanted cells. The specific conditioning protocol used depends on the disease being treated and the practices of the transplanting institution. Commonly used myeloablative conditioning regimens include one or more of the following: cyclophosphamide, total body irradiation, busulfan, treosulfan, carboplatin, melphalan, and carumustine. Toxicities common to many conditioning regimens are myelosuppression, nausea, emesis, mucositis (inflammation, irritation, and ulceration of gastrointestinal mucosal cells), alopecia, increased risk of infection, organ dysfunction, and infertility. A detailed discussion of specific conditioning agents and their toxicities is beyond the scope of this chapter. Patients receive supportive care in the forms of blood product transfusions, anti-emetics, analgesia, nutritional supplementation, antimicrobial agents, and other therapies targeted at individual toxicities. Select groups of patients receive growth factors (G-CSF or GM-CSF) following the stem cell infusion. Once conditioning is completed stem cells are infused through a central venous line. This can be done by manual injection or by a pump similar to a blood transfusion. The day that the stem cells are infused is called “day zero.” The days prior to day zero are referred to as “minus” days and the days following the transplant are referred to as “plus” days. For example, the day

prior to stem cell infusion is considered day minus one, and the day following transplant is day plus one. The time from stem cell infusion to engraftment (defined as an absolute neutrophil count of 500/mm3 for three consecutive days) can be a medically complex period. Patients are at risk for significant complications in addition to the expected toxicities of the conditioning and GVHD prevention regimen. Patients are profoundly immunosuppressed and at risk for severe, potentially life-threatening infections. They commonly experience mucositis requiring narcotic analgesia. Nausea and emesis remain a significant problem during this period, exacerbated by mucositis and the paralytic effects of narcotics on the gastrointestinal tract. Other less common, but important medical issues during this period are veno-occlusive disease of the liver, organ dysfunction and failure, noninfectious pulmonary complications, and life-threatening bleeding. Discharge criteria vary across institutions. However, discharge typically occurs following engraftment, once all acute medical issues resolve and the child tolerates enteral medications and is able to maintain an adequate hydration status at home. After hospital discharge, patients require close monitoring and are seen frequently in an outpatient HSCT clinic. The frequency of visits is dictated by the patient’s condition and decreases as he or she improves. Patients are followed annually for an indefinite period to monitor for post-HSCT late effects.

GRAFT-VERSUS-HOST DISEASE GVHD is a significant cause of morbidity and mortality in HSCT patients. It can present with either subtle or fulminant symptoms at any time following transplant. It is important that the pediatric hospitalist caring for HSCT patients has an understanding of the disease and its varied presentations. GVHD is a T-cell-mediated immunoreactive process in which donor cells react against recipient cells. Tissue damage is caused by direct cytolysis and by the effects of inflammatory cytokines such as TNF-α, IL-6, and IL-10.15 Acute GVHD is an inflammatory process and commonly occurs in the first 100 days after transplant. While chronic GVHD may have elements of inflammation, it is also characterized by scarring and fibrosis. Chronic GVHD typically occurs after day (+)100. Risk factors for both acute and chronic GVHD are HLA mismatch between the host and the donor, the type

of GVHD prophylaxis used, the use of PBSC as the stem cell source, increased age of donor and recipient, parity in female donors, and the presence of T-lymphocytes in the stem cell infusion.16,17 Additional risk factors described for chronic GVHD are previous acute GVHD, female donors, and the use of total body irradiation during conditioning.18 Acute and chronic GVHD differ not only in time of onset, but also in presentation. The skin and gastrointestinal system are frequently affected systems in both diseases. The rash seen in acute GVHD can have many different appearances. Acute skin GVHD often first appears as tender, erythematous patches on the palms, soles, occiput, posterior neck, or face. The patient may develop diffuse erythroderma. Severe skin GVHD can blister and ulcerate. Chronic skin GVHD commonly involves larger areas and presents with a dry, pruritic rash, which can progress to sclerodermatous changes. Extensive sclerodermatous GVHD may impair joint mobility and adversely affect quality of life and survival. Oral changes are also seen in both acute and chronic GVHD. Oral changes may include ulcerative lesions, lichenoid patches, mucoceles, and fibrotic bands. Patients with chronic oral GVHD may develop sicca syndrome with severely dry mouth with the potential for salivary gland atrophy. The presence of GVHD is associated with increased risk of secondary malignancies, and patients should be followed by an oral medicine specialist familiar with oral cancers.19 Acute gastrointestinal (GI) GVHD can affect any portion of the GI tract as well as the liver. The gold standard diagnostic tool is biopsy revealing cellular necrosis, glandular dropout, and apoptosis.20 However, the condition is often diagnosed clinically. Anorexia, nausea, emesis, and abdominal pain are symptoms of upper GI GVHD. Lower GI GVHD presents with profuse, watery or bloody diarrhea, abdominal cramping, and anorexia. Severe lower tract GI GVHD may present with ileus. Abnormalities of cholestasis are the hallmarks of hepatic acute and chronic GVHD, though transaminitis may be observed. Chronic GI GVHD is less common than acute. It presents with similar symptoms as acute (diarrhea, abdominal pain, nausea, emesis, weight loss, dysphagia, and early satiety). Histologically, chronic GVHD appears more fibrotic with crypt distortion. Other signs and symptoms of acute and chronic GVHD are listed in Table 134-2.

TABLE 134-2

Signs and Symptoms of Graft-VersusHost Disease

Acute Erythematous rash on palms, soles, occiput, face and posterior neck Bullous skin eruption with peeling skin Oral ulceration and inflammation Nausea, vomiting Anorexia, weight loss Profuse diarrhea, may be bloody Liver function abnormalities Jaundice Chronic Dry, pruritic diffuse rash Sclerodermatous skin changes with contractures Sicca syndrome (dry skin, dry eyes) with possible tooth decay and corneal ulceration Dysphagia Abdominal pain Hyperbilirubinemia or transaminitis Premature graying of hair Patchy alopecia Immune dysfunction Bronchiolitis obliterans with organizing pneumonia Genital or urinary stricture All patients undergoing allogeneic stem cell transplant receive GVHD prophylaxis. Immune modulation may include T-cell depletion of the stem cell product or the use of immunosuppressive medications. Methotrexate, calcineurin inhibitors, mycophenylate mofetil, rapamycin, and corticosteroid are commonly used prophylactic agents. The regimen used depends on the patient’s risk factors for GVHD and the practices of the transplanting institution. Allogenic stem cell transplant patients remain on

immunosuppressive drug therapy for months following HSCT, even with no evidence of acute of chronic GVHD. Immunosuppressive drugs are tapered off over a period of weeks to months determined by the clinical situation. Corticosteroid therapy is first-line treatment for acute and chronic GVHD. Additional and second-line therapies are directed at specific symptoms, and practices differ between institutions. Patients with evidence of GVHD may remain on immunosuppressive therapy for years. In these cases the clinician attempts to maintain the patient on the lowest dose of therapy that controls the patient’s disease. In addition to immunosuppressive therapy these patients receive prophylactic antiviral, antifungal, and antibacterial prophylaxis. All patients with chronic GVHD should be considered functionally asplenic and receive appropriate therapy when febrile. Additionally, the patient should receive regular screening for long-term complications of immunosuppression and of GVHD. This should include routine evaluation by oral medicine and dermatologic specialists familiar with GVHD and secondary cancers. In addition, patients should undergo screening for skeletal, endocrinologic, cardiac, pulmonary, ophthalmologic, and reproductive health. Infection is a significant cause of morbidity and mortality in HSCT patients. Profound immunosuppression, breakdown of the GI mucosa, indwelling central lines, and disruption of skin integrity contribute to the infectious risk for patients during the acute transplant hospitalizaton. During the HSCT hospitalization, patients are placed on infectious prophylaxis and are isolated either in a hospital room or on the transplant floor, depending on air filtration and hospital policy. Bacterial, fungal, and viral prophylaxis are commonly given, and specific agents used differ between institutions. Trimethoprim-sulfamethoxazole or other agent for pneumocystis coverage is mandatory for all patients.

FEVER Fever and symptoms of potential infection during the inpatient hospitalization and post-transplant period warrant evaluation. Patients presenting to an emergency department should be moved to a private examination room as soon as possible. Patients should not spend time in a waiting room due to the risk of acquiring infections through exposure to patients with infections in the waiting room. “Reverse” precautions should be observed (i.e. care provider wears a mask, protective gown, and gloves). All febrile HSCT patients

require a meticulous physical exam. Special attention should be given to the skin, perirectal tissue, neurologic exam, and CVL site, when applicable. Rectal temperatures and rectal examinations should not be performed because of the risk of introducing infection. Blood cultures should be drawn from all central venous lines, or peripherally if lines are no longer present. Lumbar puncture in not routinely indicated for febrile HSCT patients unless specific signs or symptoms consistent with meningitis or encephalitis are present. A chest radiograph is recommended for any patient with respiratory symptoms. Broad-spectrum antibiotics should be started as soon as possible, with a goal of within 60 minutes of presentation. The start of antimicrobial therapy should not be delayed for diagnostic procedures including blood culture or lumbar puncture if there is difficulty obtaining the sample. Hospital admission for febrile HSCT patients depends on the time since transplant, degree of immunosuppression, and the presence of post-transplant complications. Most allogeneic transplant recipients within a year of their transplant will need to be admitted for any episode of fever, particularly if remaining on immunosuppressive drugs. Hospitalization and the choice of antimicrobial therapy should be discussed with the HSCT team.

VACCINATION Autologous and allogeneic HSCT recipients lose immunologic memory responses to most vaccinations. Thus patients need to be revaccinated after transplant. The timing of revaccination differs among transplant institutions, though there are international recommendations from multiple organizations.21 Clinicians evaluating HSCT transplant patients should be aware of the patient’s vaccination status and remain alert for unusual infections. Live vaccines should be avoided in any patient receiving immunosuppression and for a minimum of 2 years after transplant.

MEDICATION ISSUES HSCT patients are frequently on multiple medications which may interact with other drugs, including immunosuppressants, antimicrobials, and antiepileptics. Because of the potential for drug interaction it is important to review medication lists with a pharmacist or other credible source before adding a new agent. This is also important when considering a dose change

of a medication a patient is already taking. In addition to interacting with other drugs, some common medications are known to cause decreased blood counts due to either marrow suppression or peripheral destruction. These drugs should be avoided if possible. The primary transplant team can provide assistance in choosing appropriate medications for these patients.

CONCLUSION Patients who have undergone stem cell transplantation often are cared for in local community settings after their transplant. Pediatric hospitalists may be involved in the evaluation and treatment of these patients for both routine and acute post-transplant issues. Therefore it is essential to have insight into the particular risks of this group of patients. It must be recognized that this group of patients is at heightened risk for common and uncommon infections, and always require prompt and thorough evaluation and initiation of treatment. Communication with the patient’s transplant center is crucial. The hospitalist needs to be informed of the patient’s often complex history, and pediatric hospitalists should discuss management decisions with the primary transplant center. HSCT is a rapidly changing field. The focus of much clinical development is on reducing the toxicity of the transplant process. This includes but is not limited to developing and improving nonablative transplants, creating less immunosuppressive treatment strategies for GVHD, and decreasing the length of hospitalization. These and other developments would enable transplants to be extended to more diverse patient populations.

REFERENCES 1. Saba N, Abraham R, Keating A. Overview of autologous stem cell transplantation. Crit Rev Oncol Hematol. 2000;36:27-48. 2. Johns A. Overview of bone marrow and stem cell transplantation. J Intraven Nurs. 1998;21:356-360. 3. Busca A, Amoroso A, Miniero R. Bone marrow transplantation from unrelated volunteer donors. An overview. Panminerva Med. 1997;39:71-77.

4. McCluskey J, Peh CA. The human leucocyte antigens and clinical medicine: an overview. Rev Immunogenet. 1999;1:3-20. 5. Cutler C, Ballen KK. Improving outcomes in umbilical cord blood transplantation: state of the art. Blood Rev. 2012;26:241-246. 6. Pidala J, Kim J, Schell M, et al. Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization. Bone Marrow Transplant. 2013;48:346-350. 7. Perkins HA, Hansen JA. The U.S. National Marrow Donor Program. Am J Pediatr Hematol Oncol. 1994;16:30-34. 8. Laver JH, Hulsey TC, Jones JP, Gautreaux M, Barredo JC, Abboud MR. Assessment of barriers to bone marrow donation by unrelated AfricanAmerican potential donors. Biol Blood Marrow Transplant. 2001;7:458. 9. Brunstein CG, Wagner JE. Umbilical cord blood transplantation and banking. Annu Rev Med. 2006;57:403-417. 10. Wagner JE, Gluckman E. Umbilical cord blood transplantation: the first 20 years. Semin Hematol. 2010;47:3-12. 11. Barker JN, Byam CE, Kernan NA, et al. Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant. 2010;16:15411548. 12. Arai S, Klingemann HG. Hematopoietic stem cell transplantation: bone marrow vs. mobilized peripheral blood. Arch Med Res. 2003;34:545553. 13. Cottler-Fox MH, Lapidot T, Petit I, et al. Stem cell mobilization. Hematology Am Soc Hematol Educ Program. 2003:419-437. 14. Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol. 2004;22:4872-4880. 15. Blazar BR, Murphy WJ. Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD). Philos Trans R Soc Lond B

Biol Sci. 2005;360:1747-1767. 16. Ferrara JL, Yanik G. Acute graft versus host disease: pathophysiology, risk factors, and prevention strategies. Clin Adv Hematol Oncol. 2005;3:415-419, 28. 17. Martin PJ, Carpenter PA, Sanders JE, Flowers ME. Diagnosis and clinical management of chronic graft-versus-host disease. Int J Hematol. 2004;79:221-228. 18. Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant. 1998;21(Suppl 2):S45-49. 19. Mawardi H, Elad S, Correa ME, et al. Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes. Bone Marrow Transplant. 2011;46:884-891. 20. Akpek G, Chinratanalab W, Lee LA, et al. Gastrointestinal involvement in chronic graft-versus-host disease: a clinicopathologic study. Biol Blood Marrow Transplant. 2003;9:46-51. 21. Hilgendorf I, Freund M, Jilg W, et al. Vaccination of allogeneic haematopoietic stem cell transplant recipients: report from the international consensus conference on clinical practice in chronic GVHD. Vaccine. 2011;29:2825-2833.

SECTION P Psychiatry

CHAPTER

135

Depression and Physical Illness Harsh K. Trivedi and Katherine A.S. Gallagher

BACKGROUND Children and adolescents hospitalized for the treatment of physical illness often have feelings of sadness, frustration, or irritability that represent a normal response to their experience. Common factors impacting a child’s ability to cope include disruption of routine, separation from family and peers, uncertainty regarding diagnosis and prognosis, pain related to the illness or its treatment, and fear of the illness or its sequelae. When the sadness becomes pervasive and is associated with cognitive or physiologic symptoms, however, a depressive disorder must be considered. It is incumbent on the hospitalist to distinguish normal feelings of sadness from a depressive disorder and to implement treatment when necessary. Chronically ill children are at increased risk for developing depressive, anxiety, and eating disorders.1-5 Clinical depression has been reported to increase the risk of poor physical health in the future6 and has been associated with poor adherence to treatment regimens,7 reduced immune function,8 increased disease severity, and death due to nonadherence.9 Emerging data suggest that depression in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) is associated with declining CD4 counts, accelerated disease progression, and increased mortality.10 In addition, suicidal ideation and suicide attempts are tragic consequences of depression that increases with the onset of puberty.11 Depressive disorders cause significant suffering on the part of the child and family and are generally highly treatable once they are recognized. The purpose of this chapter is to provide the pediatric hospitalist with a framework for understanding the diagnosis and treatment of depressive disorders in children and adolescents with physical illness.

PATHOPHYSIOLOGY While multiple theories exist regarding the pathophysiology of depression (Table 135-1), conclusive evidence of its etiology is still uncertain. The Diagnostic and Statistical Manual (DSM) bases the diagnosis of depression on a cluster of symptoms. As the DSM is atheoretical by design, it is important to note that patients who may look similar phenotypically for depression may indeed have different etiological mechanisms for their depression. As such, simply making a diagnosis of depression does not indicate the pathophysiological mechanism or the optimal treatment regimen. TABLE 135-1

Pathophysiological Hypotheses of Depression12

Mechanism

Comments

Genetic vulnerability

Based upon evidence from twin studies

Altered HPA axis activity

Based upon effects of stress as a risk factor

Monoamine deficiency

Based upon mechanism of action of medication treatments

Brain region dysfunction

Based upon stimulation of specific brain regions reproducing antidepressant effects

Neurotoxic and neurotrophic processes

Based upon concept of “kindling” and brain volume loss over course of depressive illness

Reduced GABAergic activity

Based upon evidence from magnetic resonance spectroscopy and postmortem studies

Glutamate dysregulation

Based upon mechanism of action of medication treatments

Circadian rhythm impairment

Based upon circadian rhythm changes having antidepressant effects

Additional factors further complicate the diagnosis of depression. First, the term depression is ambiguous and has many connotations. It may be used to describe a transient mood state or one of several clinical syndromes of varying severity. Second, because symptoms of depressive disorders are subject to developmental variation, they may present differently depending on the child’s stage of development.11 Third, because medical and nursing staff often view depression as a normal and understandable response to a chronic, terminal, or disfiguring illness, psychiatric evaluation and treatment may not be pursued.12 Fourth, patients and families may be resistant to exploring the possibility of a depressive disorder because of the perceived stigma of a psychiatric diagnosis. Last, the diagnosis of depression is made on the basis of a constellation of psychological and somatic symptoms. As somatic symptoms are commonly seen in physical illness, it is often difficult to determine whether the symptoms are related to the physical illness or to a depressive disorder.

CLINICAL PRESENTATION The symptoms of depressive disorders can be divided into two general realms: psychological and somatic. Psychological symptoms include dysphoric mood, anhedonia (loss of interest in usual, pleasurable activities), feelings of helplessness or hopelessness, feelings of guilt or worthlessness, loss of self-esteem, decreased ability to concentrate, and thoughts of suicide. Somatic symptoms of depression include fatigue, sleep disturbance (insomnia or hypersomnia), appetite changes (decrease or increase), and motor restlessness or retardation (see Chapter 137 for a discussion of somatic symptom and related disorders). The hospitalist should focus on the psychological symptoms because of the frequent overlap between somatic symptoms of depression and symptoms of the physical illness. The presentation of depression depends on the child’s stage of development, and depression in children may manifest differently from depression in adolescents. Signs of depression in children (or in older children with developmental delay) may include feelings of sadness, a

depressed appearance, somatic complaints (most commonly stomachaches and headaches), separation anxiety, low self-esteem, social withdrawal, academic decline, sleep or appetite disturbances, decreased concentration, and suicidal thoughts.11 In adolescents, depression frequently presents with an irritable rather than a depressed mood. Additional symptoms commonly associated with depression in adolescents include behavioral disturbances, motor hyperactivity, feelings of being unloved, self-deprecation, tearfulness, hopelessness, low self-esteem, hypersomnia, lethargy, anhedonia, weight gain, decreased concentration, declining school performance, psychomotor retardation, feelings of being misunderstood, and suicidal ideation. Adolescents frequently do not recognize their symptoms as being part of a depressive disorder and may not report them unless specifically asked.11 The hospitalist should consider the diagnosis of depression in patients who report feelings of sadness or who appear sad or withdrawn, in patients who exhibit oppositional behavior (e.g. refusal to participate in self-care or nonadherence to a treatment plan), or in patients with a history of other psychiatric disorders (e.g. anxiety, bipolar disorder, substance abuse). Studies have estimated that 40% to 70% of adolescents with depressive disorders also meet the criteria for at least one other psychiatric disorder.11

DIFFERENTIAL DIAGNOSIS The next step is to determine into which diagnostic category the patient’s symptoms best fit. Depressive symptoms in hospitalized children and adolescents typically fall into one of three categories, although overlap is common: adjustment disorder with depressed mood (situational depression), depressive disorder related to a general medical condition or substance, and primary psychiatric disorders, such as major depressive episode or dysthymia (persistent depressive disorder). Adjustment disorder with depressed mood (situational depression) involves symptoms such as depressed mood, tearfulness, or feelings of hopelessness that arise in response to an identifiable stressor. Illness, hospitalization, and medical or surgical procedures are the stressors typically identified in hospitalized children. Patients frequently appear sad and tearful and may not be motivated to participate in their treatment regimens. They

may describe feeling overwhelmed by their illness or its treatments and may report feeling hopelessness or fear that they will never leave the hospital. Depressive symptoms typically resolve when the stressor is removed and the patient is able to resume his or her usual routine following discharge from the hospital. Certain medical conditions, medications, and drugs of abuse may be associated with depressive symptoms and should be considered in the differential diagnosis of depression (Table 135-2). TABLE 135-2

Common Medical and Pharmacologic Causes of Depression

Source: Adapted from Wise MG, Rundell JR. Concise Guide to Consultation Psychiatry. Washington, DC: American Psychiatric Press; 1988.

A mood disorder due to a general medical condition refers to a significant and persistent disturbance in mood that is the direct physiologic effect of a medical condition. A substance-induced mood disorder is the direct effect of a medication or drug of abuse. In both disorders, symptoms may range from depressed mood or anhedonia to multiple psychological and somatic symptoms of depression. A clue to the diagnosis is a temporal relationship between the onset, exacerbation, or remission of the mood disturbance and the medical disorder, medication, or drug of abuse.13,14 Primary psychiatric disorders such as major depressive episode and dysthymic disorder (persistent depressive disorder) should also be considered

in the differential diagnosis of depressive symptoms. A major depressive episode is an acute episode (at least 2 weeks) of pervasive sadness or anhedonia in conjunction with four or more other symptoms of depression such as poor appetite, weight loss, poor sleep, poor concentration, loss of energy or recurrent thoughts of death. The patient must experience significant distress or functional impairment (e.g. decline in social or academic performance), and the symptoms cannot be the direct physiologic effects of a medical condition or substance (e.g. medication, drug of abuse).15 Dysthymic disorder (persistent depressive disorder) refers to a chronically depressed or irritable mood most of the time for at least 1 year (2 years in adults), with any remission in symptoms lasting less than 2 months, in conjunction with two or more of the following symptoms: insomnia or hypersomnia, poor or excessive appetite, decreased energy, poor concentration, low self-esteem, and feelings of helplessness. The symptoms must cause significant distress or functional impairment and cannot be the direct physiologic effects of a medical condition or substance.15 Primary psychiatric disorders are more common in patients with a history of previous depressive episodes or a family history of depression.

DIAGNOSTIC EVALUATION When the hospitalist suspects depression, psychiatric consultation should be obtained if available. If unavailable, the hospitalist should complete the assessment as follows. The first step is to meet with the patient and his or her parents or guardians to obtain the following information: past individual and family psychiatric histories, description of academic performance and peer relations, and drug or alcohol use. In addition, the hospitalist should inquire about current and past psychosocial stressors, perform a mental status examination, and screen for the psychological and somatic symptoms of depression. These symptoms can be remembered using the mnemonic SIGECAPS, which refers to a prescription one might write for a depressed person (sig.: energy capsules). Each letter refers to one of the diagnostic criteria for a major or clinical depressive episode (Table 135-3).15,16 TABLE 135-3

SIGECAPS: A Mnemonic for Symptoms of Depressive Disorders

S Sleep

Insomnia or hypersomnia*

I

Loss of interest or pleasure in activities (anhedonia)

Interests

G Guilt

Excessive guilt, worthlessness,* hopelessness*

E Energy

Loss of energy or fatigue*

C Concentration Decreased ability to concentrate* A Appetite

Appetite disturbance (decreased or increased)*

P Psychomotor

Psychomotor retardation or agitation

S Suicidality

Suicidal thoughts or plans; feeling that life is not worth living

Source: Data from Wise MG, Rundell JR. Concise Guide to Consultation Psychiatry. Washington, DC: American Psychiatric Press, 1988; and Carlat DJ. The psychiatric review of symptoms: a screening tool for family physicians. Am Fam Physician. 1998;58:1617-1624. SIG: E CAPS (prescribe energy capsules). *To meet the criteria for a major depressive episode, a patient must have four of the above symptoms, in addition to depressed mood or anhedonia, for at least 2 weeks. To meet the criteria for dysthymic disorder, a patient must have two of the six symptoms marked with an asterisk, in addition to a depressed or irritable mood for at least 1 year (2 years in adults).

Elements of the psychiatric history that should be elicited from both the patient and the family include current and past histories of psychiatric disorders, treatments, and medications. A personal or family history of depression predisposes children and adolescents to develop a primary depressive disorder in the face of the stress of illness and hospitalization.14,17 The mental status examination should focus on evidence of the presence of mood dysphoria, suicidal ideation, and thought disorder (e.g. hallucinations, delusions). It is important for the hospitalist to meet with the patient and parents separately for part of the evaluation to encourage full reporting of symptoms and concerns. If they are interviewed together, the patient or parents may not feel comfortable speaking freely and may withhold valuable diagnostic information. The evaluation should include the following: Onset, severity, and duration of symptoms.

Functioning in various domains (e.g. family, school, peers). Burden of suffering imposed by the symptoms (e.g. depth of distress, difficulty coping). Presence or absence of suicidal ideation. Together, these factors help determine the type and level of depression.11 The hospitalist should obtain collateral information from as many sources as possible. Teachers, guidance counselors, and therapists may provide helpful information about the patient’s mood and level of functioning outside the hospital. Within the hospital, nurses and child life specialists may provide valuable information about the patient’s symptoms and level of functioning throughout the course of each day. Assessments of the patient’s mood at different points during the day may also assist in making the diagnosis. For example, a patient who presents with a depressed mood and withdrawn behavior during morning rounds but who appears cheerful and engaged when observed in the playroom later in the day is less likely to be suffering from clinical depression than is a patient whose depressive symptoms persist without change over the course of several days. It is important to recognize that suicidal ideation and suicide attempts may be tragic consequences of depression in children and adolescents. If there is any concern about suicide, a risk assessment should be conducted to determine the history of previous suicide attempts, family history of suicide, exposure to family violence or abuse, level of impulsivity, accessibility to lethal agents, and presence of comorbid psychiatric disorders. For those patients deemed to be at risk for suicide, constant observation in the form of a one-to-one sitter should be implemented to monitor the patient around the clock until the patient is no longer a suicide risk or is transferred to a psychiatric hospital (see Chapter 136, Assessment and Management of the Suicidal Patient).

MANAGEMENT The management of depression in hospitalized children and adolescents varies, depending on the cause. It requires both an acute intervention in the hospital and a plan for follow-up after discharge, if necessary. If available, a psychiatric consultant can be helpful in guiding the initial evaluation and diagnosis and creating a treatment plan appropriate to the child’s

developmental level that incorporates the patient and his or her family, medical and nursing staff, social workers, and child life specialists. The symptoms of depression in patients with situational depression (adjustment disorder with depressed mood) are frequently related to unexpressed anxiety or fears about the illness and its treatment, feeling “out of control,” and disruption of routine. In these cases, patients typically respond well to a combination of psychosocial and behavioral interventions, and antidepressant therapy is usually not necessary.17 Psychosocial interventions are designed to help the patient and family better understand the medical condition and its treatment and to facilitate coping with the illness and hospitalization. For example, the psychiatric consultant can help explain medical issues and treatments to children in a developmentally appropriate manner to encourage feelings of mastery and control. Supportive therapy may include engaging younger children in therapeutic play with medical toys and dolls or having older patients create a scrapbook or a mood journal to cope with their feelings related to the illness and hospitalization.18 Validating a child’s experience of sadness, fear, or anxiety may be an important component of supportive therapy. Parents should be encouraged to bring special items from home (e.g. favorite blanket, toys, pictures) to help the child feel more comfortable in the hospital. If possible, the child’s teacher should be informed of the hospitalization to help facilitate contact between the patient and friends at school. Contact with other patients can provide peer support and help the child understand that he or she is not alone. Children and adolescents may benefit from cognitive behavioral therapy (CBT) to help them cope with depressive symptoms.18 Therapeutic goals involve working with children and parents to identify and restructure negative cognitions, develop adaptive, approach-oriented coping strategies, and increase active, positively-reinforcing patterns of behavior. For instance, children with depression and inflammatory bowel disease who received a course of CBT showed improvements in depressive symptoms, perceived control, and functioning.19 The Treatment for Adolescents with Depression Study demonstrated that combining CBT with antidepressant medication may be preferable to monotherapy when treating adolescents with major depression.20 Parents also play an important role in treatment of child and adolescent depression, and parent-focused sessions are components of some

CBT interventions.21 Behavioral activation (BA), another treatment for depression, aims to increase positive environmental reinforcement in order to provide opportunities for reward and mastery experiences. For chronically ill children, increased mastery may provide a greater sense of control. BA is well validated for use with adults, and preliminary research suggests that it may improve depressive symptoms and increase hopefulness among adolescents with depression.22 Creating a daily routine can allow a medicallyhospitalized child a greater sense of control and predictability during a stressful and often uncertain time. Sticker charts or other reward systems can be helpful implements for promoting BA, such that children can receive rewards for medical and other important goals during the hospitalization. Distraction and engagement in pleasurable activities, in the form of movies, visitors, and crafts projects, may also be components of BA interventions and can be helpful in alleviating depressive symptoms. Ongoing pain may be another contributor to depression. The importance of adequately treating pain cannot be overstated. Behavioral therapies such as hypnosis, relaxation, and guided imagery can be helpful adjuncts in the management of both acute and chronic pain. Children and adolescents with mood disorder due to a general medical condition or substance generally improve with treatment of the underlying medical condition or removal of the substance causing the depressive symptoms (medication or drug of abuse). These patients may also benefit from the psychosocial and behavioral interventions previously described. If psychosocial and behavioral interventions fail, or if the patient’s symptoms are severe (e.g. major depressive disorder), a trial of an antidepressant medication should be considered. It is important to note that there are no controlled studies addressing the use of antidepressants in children or adolescents with physical illnesses. As most antidepressants take weeks to reach maximal efficacy, the formation of a treatment alliance with the patient and parents is crucial. Before treatment begins, a meeting should be held at which the specific target symptoms are defined and the risks, benefits, and goals of treatment are delineated. It is imperative to inform the patient and parents about side effects, dosage schedule, lag in therapeutic efficacy, and danger of overdose for each agent prescribed.18 Following discharge from the hospital, the parents should be responsible for storing and

administering these medications to minimize the risk of overdose. In addition, it is important to establish outpatient psychiatric follow-up in order to assess efficacy and monitor side effects of new medications. The choice of medication depends on several variables, including the patient’s concomitant medical or psychiatric condition, potential drug interactions with other medications, and medication side effects.23 For example, an antidepressant such as mirtazapine, with the primary side effects of appetite stimulation and weight gain, would not be the first choice for a patient with diabetes. It is important to keep in mind that certain antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors) are metabolized by the cytochrome P-450 enzyme system and may interfere with the metabolism of other medications.17 Selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment for depressive disorders. A review of evidence-based SSRI treatments in children and adolescents is provided in Table 135-4.24 While non-SSRI treatments of depression (such as bupropion, venlafaxine, mirtazapine, and duloxetine) are used, it is recommended that a psychiatric consult be ordered when considering non-SSRI treatments in youth or when considering the treatment in youth who have failed first-line agents. A discussion of such treatments is beyond the scope of this chapter and is available in other sources.23,25 TABLE 135-4

Selective Serotonin Reuptake Inhibitors26

Source: Data from Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.

Citalopram (Celexa) and escitalopram (Lexapro) have very little cytochrome P-450 activity and therefore less potential for drug–drug interactions. Although baseline laboratory testing is not required, it is prudent to obtain liver function tests and a complete blood count with differential and platelets before initiating therapy.24 Initial adverse effects of SSRIs may include nausea, dizziness, drowsiness, insomnia, nervousness, behavioral activation, and memory problems. These symptoms typically abate within the first few weeks of treatment and may be minimized by starting with a low dose and slowly increasing the dosage as tolerated. Longer-term adverse effects of SSRIs may include weight gain or loss, sexual dysfunction, and an amotivational syndrome characterized by the development of apathy, indifference, amotivation, or disinhibition.18 In

addition, the hospitalist should be aware of a potentially lethal condition of serotonergic hyperstimulation known as the serotonin syndrome, which can be produced by the concurrent use of drugs that enhance central nervous system serotonin (e.g. linezolid [Zyvox], voriconazole [Vfend]). Common clinical features include altered mental status, diaphoresis, myoclonus, diarrhea, tremors, shivering, restlessness, and hyperreflexia. The FDA issued a public health advisory requiring that antidepressant labels carry a black box warning informing patients of an increased risk of suicidal thoughts and behaviors among children and adolescents taking these medications. These potential risks should be discussed with patients and their families as part of the informed consent process,25 and balanced against clinical need. Patients who are started on antidepressant therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. If antidepressant treatment is initiated during a hospitalization, parents should be counseled to take responsibility for storing and administering these medications to minimize the risk of overdose after discharge from the hospital. In addition, it is important to establish outpatient psychiatric follow-up in order to assess efficacy and monitor side effects of new medications. Families and caregivers should be advised of the need for close observation and communication with the prescriber.26 Table 135-4 provides a list of SSRIs and dosage guidelines. Currently, recommendations for weight-based dosing are not available. Stimulants have been used with success in the treatment of depression in adults with physical illnesses and should be considered in children and adolescents. Although these agents are approved for use in youngsters with attention-deficit hyperactivity disorder, there have been no controlled studies addressing their use in the treatment of depression in the pediatric population. Studies in medically ill adults have demonstrated improvement in depressive symptoms, including mood, appetite, and energy level. Stimulants generally have a rapid onset of action (often within days) and are relatively safe, with a short half-life. Side effects may include insomnia, agitation, anxiety, confusion, and paranoia. Stimulants should be used with caution in patients with tic disorders and Tourette disorder, because they may exacerbate tics.3,27,28 A comprehensive follow-up treatment plan should be developed for the patient and family before discharge. This may include referrals to mental

health providers for outpatient psychotherapy, pharmacotherapy, family therapy, or group therapy. For children and adolescents with severe depression or suicidal ideation, transfer to an inpatient psychiatric unit or enrollment in a partial hospital program may be warranted.18 If available, at this stage of treatment, a mental health professional should be involved to assist in assessment and disposition planning.

ADMISSION AND DISCHARGE CRITERIA Most hospitalized children who are experiencing depressive symptoms are admitted for medical reasons, therefore in most cases discharge criteria will depend upon sufficient stabilization or improvement in the medical condition that prompted admission. Psychiatric admission criteria are an imminent danger to self or others, often due to suicidal or homicidal ideation or due to severe behavioral dysregulation likely to result in harm to others. Such determinations are best made via a psychiatric consultation. Discharge criteria for children who are medically hospitalized and have ongoing psychiatric concerns will depend upon availability of appropriate psychiatric care. These children commonly require inpatient or residential psychiatric care. In these cases, children are usually actively suicidal, very recently suicidal, actively or very recently exhibiting dangerous and aggressive behavior, or pose an imminent threat to themselves or others. Occasionally a partial hospitalization program in which children receive day treatment and return home in the evenings may be appropriate, such as in the case of major depression that significantly impairs functioning but with no active or recently active suicidal ideation. When available, a mental health professional can be helpful in evaluating and securing appropriate psychiatric disposition.

CONSULTATION Mental health services should be incorporated into the patient’s care when depressive symptoms are recognized. Psychiatrists can provide guidance for diagnosis and treatment and help organize the multidisciplinary mental health team. Input from these specialists also assists the medical team members. The mental health team may provide guidance for proper interactions with the

patient and family and insights into the interactions between depression and medical illness. They are also helpful in establishing continued mental health support after discharge from the hospital.

SPECIAL CONSIDERATIONS The diagnosis and treatment of depression in medically ill children is complex. While hospitalists can often appropriately diagnose youth and begin first-line psychotherapeutic or psychopharmacological interventions, it is important to involve a psychiatric consultation for more difficult cases. This is particularly true for cases where there is concern regarding potential for imminent harm or likelihood of needing further inpatient psychiatric treatment after medical stabilization. In some of these situations, parents insist that they should be able to take their child home and can watch them 24 hours a day if necessary to maintain their safety. In such cases, if there is concern that a child may pose danger to self or others, the appropriate disposition is to an inpatient unit.

PREVENTION Pediatric depression is burdensome for affected children and families as well as the healthcare system, particularly given its association with chronic illness, and can be difficult to treat. Therefore researchers have evaluated the potential for secondary and tertiary prevention, with results suggesting that evidence-based programs may be effective in preventing depression among at-risk children, such as those with a family history of affective disorders, exposure to violence, or social isolation.29 Besides being evidence-based, common factors of effective prevention programs include manualized treatment, comprehensive training for providers implementing the protocols and adherence to the manuals, and be based on cognitive-behavioral or interpersonal therapeutic approaches. Most prevention programs also work within the family environment to reduce adverse interactions and improve family functioning, which may further reduce risk of depression.29

REFERENCES

1. Burke P. Depression in pediatric illness. Behav Modif. 1991;15:486-500. 2. Canning EH, Kelleher K. Performance of screening tools for mental health problems in chronically ill children. Arch Pediatr Adolesc Med. 1994;148:272-277. 3. Katon WJ. Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Soc Biol Psychiatry. 2003;54:216-226. 4. Vitulano LA. Psychosocial issues for children and adolescents with chronic illness: Self-esteem, school functioning and sports participation. Child Adolesc Psychiatr Clin North Am. 2003;12:585-592. 5. Kashani JH, Venzke R, Milar EA. Depression in children admitted to hospital for orthopaedic procedures. Br J Psychiatry. 1981;138:21-25. 6. Cohen P, Pine DS, Must A, et al. Prospective associations between somatic illness and mental illness from childhood to adulthood. Am J Epidemiol. 1998;147:232-239. 7. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med. 2000;160:3278-3284. 8. Leonard B. Stress, depression and the activation of the immune system. World J Biol Psychiatry. 2000;1:17-25. 9. Shemesh E, Bartell A, Newcorn J. Assessment and treatment of depression in medically ill children. Curr Psychiatry Rep. 2002;4:88-92. 10. Evans DL, Charney DS. Mood disorders and medical illness: a major public health problem. Biol Psychiatry. 2003;54:177-180. 11. Beasley PJ, Beardslee WR. Depression in the adolescent patient. Adolesc Med State Art Rev. 1998;9:351-362. 12. Neese JB. Depression in the general hospital. Nurs Clin North Am. 1991;26:613-622. 13. Sutor B, Rummans TA, Jowsey SG, et al. Major depression in medically ill patients. Mayo Clin Proc. 1998;73:329-337. 14. Rush JA, Keller MB, Bauer MS, et al. Mood disorders. In: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:317-393.

15. Carlat DJ. The psychiatric review of symptoms: a screening tool for family physicians. Am Fam Physician. 1998;58:1617-1624. 16. Wise MJ, Rundell JR. Effective psychiatric consultation. In Hales RE ed. Concise Guide to Consultation Psychiatry. Washington, DC: American Psychiatric Press; 1994:1-10. 17. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 1998;37(Suppl 10):63S-83S. 18. Clark MS, Jansen KL, Cloy JA. Treatment of childhood and adolescent depression. Am Fam Physician. 2012;85(5):442-448. 19. Szigethy E, Kenney E, Carpenter J, et al. Cognitive-behavioral therapy for adolescents with inflammatory bowel disease and subsyndromal depression. J Am Acad Child Adolesc Psychiatry. 2007;46(10):12901298. 20. Treatment for Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy and their combination for adolescents with depression: treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. 21. Wells KC, Albano AM. Parent involvement in CBT treatment of adolescent depression: experiences in the treatment for adolescents with depression study (TADS). Cogn Behav Pract. 2005;12(2):209-220. 22. Ritschel LA, Ramirez CL, Jones M, Craighead WE. Behavioral activation for depressed teens: a pilot study. Cogn Behav Pract. 2011;18:281-299. 23. Birmaher B, Brent D. Depressive disorders. In: Martin A, Scahill L, Charney DS, Leckman J eds. Pediatric Psychopharmacology: Principles and Practice. New York: Oxford University Press; 2003:466-483. 24. Choe CJ, Emslie GJ, Mayes TL. Depression. In: Trivedi HK, Cheng K eds. Psychopharmacology. Child Adolesc Psychiatr Clin North Am. 2012;21(4):807-829. 25. Trivedi HK, Kershner JD. Practical Child and Adolescent Psychiatry for Pediatrics and Primary Care. Cambridge: Hogrefe and Huber; 2009. 26. Pappadopulos EA, Tate Guelzow B, Wong C, et al. A review of the

growing evidence base for pediatric psychopharmacology. Child Adolesc Psychiatr Clin North Am. 2004;13:817-855. 27. Masand P, Pickett P, Murray G. Psychostimulants for secondary depression in medical illness. Psychosomatics. 1991;32:203-208. 28. Beliles K, Stoudemire A. Psychopharmacologic treatment of depression in the medically ill. Psychosomatics. 1998;39:S2-S19. 29. Gladstone TRG, Beardslee WR. The prevention of depression in children and adolescents: a review. Can J Psychiatry. 2009;54(4):212221.

CHAPTER

136

Assessment and Management of the Suicidal Patient Robert L. Kitts and Patricia I. Ibeziako

BACKGROUND Suicide is the second leading cause of death among all youth in the United States between 10 and 24 years old.1 Suicide rates have increased almost steadily from 1999 through 2014 for both males and females of all ages between 10–74 years old. The percent increase in suicide rates for females was greatest for those aged 10–14 years.2 A review of youth suicides in 2014 revealed the greatest number and percentage of death was among youth age 15 to 24 years old, with 5079 youths in this age group having died from suicide as compared with 425 children age 10–14 years.1 Males continue to have higher rates of suicide, with 18.2% of male youth between 15 and 24 years old committing suicide in 2014 compared with 4.6% of females in the same age group.2 The most common means of suicide among youth 10 to 14 years old in 2010 were suffocation (56.1% males/77% females), firearms (37.8% males/13.8% females), and poisoning (2.8% males/5.7% females).3 The most common means of suicide among youth 15 to 24 years old were firearms (48.9% males/24.4% females), suffocation (37.4% males/49.9% females), and poisoning (6.2% males/16.8% females).3 More recent data from 2014 shows that overall, percentages of suicides in the United States involving suffocation (including hanging and strangulation) increased from 1999–2014, while suicides by firearm and poisoning decreased.2 Nonfatal suicide attempts are more prevalent than suicides, with ranges between 5% and 8% of youths annually.4 It is estimated that there is one completed suicide per 100 to 200 suicide attempts among youth between 15

and 24 years old, which is a greater ratio than for adults.5 Results from the 2015 national Youth Risk Behavior Surveillance (YRBS) indicated that 17.7% of high school students nationwide had seriously considered attempting suicide in the past year, 14.6% had made a plan about how they would attempt suicide and 8.6% had attempted suicide one or more times during the 12 months before the survey.6 Suicidal ideation and attempts were higher among females than males and greater in Hispanic females than black or white females.6 With numbers and prevalence this high it is important that pediatricians are not only aware of the issue of suicide, but feel competent in helping address this problem. This includes screening for suicidality in youth (many youth may not open up about suicidal ideation unless directly asked), conducting an adequate suicide assessment, and knowing how to acutely manage patients who are suicidal or have had a suicide attempt.7-9

PATHOPHYSIOLOGY Understanding Suicidality: Biological, Psychological, and Social Etiological Factors An increase in both suicide and suicide attempts is seen with adolescence.3,7,10 This increase is likely attributed to biological, psychological, and social factors that influence each other. Adolescent brains are still developing, including the frontal lobes and neural circuits involved in emotional and cognitive regulation.11 Therefore cognition and executive functioning are not fully matured and may be manifested by a narrow view of options when faced with challenges, impaired decision making, increased impulsivity, and increased emotional dysregulation.10-13 Suicidality has been associated with novelty-seeking and risk-taking behaviors in adolescents, which may be influenced by age-related differences in the reward system (nucleus accumbens) and executive functioning (prefrontal cortex), and imbalance in dopamine–serotonin activity (dopamine input to prefrontal cortex greater than serotonin input).11,14 There are far less neurobiological studies of adolescent suicide than there are of adult suicide.15 Few but significant postmortem adolescent brain studies compared with controls provide preliminary evidence suggesting that adolescents who commit suicide have lower than normal phosphoinositide-

phospholipase C, protein kinase A activity, transcription factor CREB protein, BDNF protein, and gene expression in the prefrontal cortex. They also have lower than normal full-length tyrosine kinase B receptors, gene expression, and protein kinase C activity in the prefrontal cortex and hippocampus.15 The most common biological system related to suicidality is the serotonergic system, as evidenced by postmortem findings, serotonin receptor abnormalities on platelets, metabolite levels, and candidate gene association studies relating to the serotonergic system.14 Findings include postmortem brains of adolescents who have committed suicide having higher than normal 5HT2A receptor binding and gene expression in the prefrontal cortex and hippocampus, and negative correlation between plasma serotonin levels and the severity of suicidal behavior.14 Additional biological difference has been seen in the hypothalamic-pituitary-adrenal axis, adrenergic system, and growth hormone secretion.14 Accumulating evidence is also showing the impact of adverse childhood experiences on some of the biological systems noted above, including epigenetic effects and impact on stress response systems.16-18 One of the most relevant biological factors to play a role in adolescent suicidality is the increase in psychiatric disorders associated with increased suicide, including mood disorders, anxiety disorders (especially females), substance use disorders, disruptive behavior disorders (especially males), and psychotic disorders.19-22 However, adoption studies suggest that there is a genetic susceptibility to suicide that is partially independent of the presence of a psychiatric disorder.14 Additional biological factors may include hormonal changes, physical changes, and sleep disturbance.7,11,23 Psychologically, adolescents are more vulnerable as they begin to develop their sense of self (e.g. personal and sexual identity). They may move from a more predictable and validating supportive system (i.e. family) to one that is less so (i.e. peers) while they strive to be more independent. This developmental process may preclude them from utilizing their adult supports and promote internalization and maladaptive coping (e.g. substance use, self-injurious behaviors). This also accompanies an increased exposure to potential social stressors, including bullying, alienation, negative romantic and sexual experiences, and increased academic pressure and other

responsibilities (e.g. finding a job). High-risk behaviors (e.g. sexual activity and substance use) associated with adolescence may result in negative consequences such as dropping out of school, getting pregnant, being sexually assaulted, or contracting a sexually transmitted disease.10,24 It is not uncommon that a suicide attempt or suicide is preceded by a stressful life event.7 Additionally, youth are more impressionable than adults and have been shown to be more influenced by media, and susceptible to cluster suicides.9 How all of these biological, psychological, and social factors influence one other (e.g. in which direction and to what degree) is not entirely clear. Another issue to consider is why the suicide rate for adolescents 15 to 19 years old increased by 300% (particularly males) from 1950 to 1990, decreased by about 35% from 1990 to 2003, and more recently has begun to rise.3,9,25 Changes in treatment (e.g. introduction of antidepressants and impact of the black box warning), access to means (e.g. guns, hanging, overdose), family and community structure (e.g. dispersal of families and reduced sense of community), and culture (e.g. internet and media content) are just some of the factors to consider when trying to understand this issue.7,21 What we do know is that adolescents are biologically and psychologically more vulnerable as they move into a period of increased social stressors that they may not be prepared to handle in a healthy manner.

CLINICAL PRESENTATION Clinical presentation may vary in regard to setting, source, and level of concern. Suicidal youth may present in the emergency, outpatient, and inpatient settings. According to the 2015 YRBS, 2.8% of ninth to twelfth grade students nationwide made a suicide attempt that resulted in an injury, poisoning, or overdose that had to be treated by a doctor or nurse in the 12 month period prior to the survey.6 Pediatric emergency department (ED) visits for mental health concerns are increasing at a faster rate than ED visits related to other medical illnesses.26 The total proportion of pediatric patients admitted to a general medical inpatient setting from the ED for mental health problems is also increasing.8 The source of information may vary and include the patient, caregivers,

schools, or other clinical providers. For example, a patient admitted after a motor vehicle accident, who becomes quadriplegic, states, “I’d rather die than be like this.” Or a 10-year-old who is sick may make suicidal statements, such as “If this pain doesn’t go away, I’ll kill myself.” Some patients may be brought into the ED for a school-mandated evaluation because they were overheard making statements in class regarding self-harm. Concerns may arise based on other factors, such as prior history (e.g. prior suicide attempts or recent discharge from an inpatient psychiatric facility) or while conducting a physical exam (e.g. cutting marks on forearms). These presentations may also vary in severity from low concern (e.g. an isolated suicidal statement in reaction to a transient stressor) to high (e.g. patient brought to the ED after a severe suicide attempt). However, there are times when the level of severity is less clear (e.g. caregivers are not concerned, but school is very concerned about patient’s suicidal statements or patient brought into the ED after taking 14 stimulant tablets, claiming that it was just to get high and not to hurt self). Regardless of setting, source, and level of concern, a suicide assessment is indicated. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) recommends obtaining psychological consultation to assess immediate risk of all patients admitted for medical treatment following a suicide attempt.27 If a patient has not had a suicide attempt but there is still concern regarding suicidality, a mental health consultation should also be obtained. However, there are often circumstances where a mental health consultant is not readily available, therefore pediatricians should be prepared to conduct suicide assessments.

EVALUATION RISK ASSESSMENT Knowing and routinely asking about risk factors for youth suicide will help guide more thorough but efficient assessments (e.g. know what to look for and ask directly about) and promote better screening and determination of level of risk. Some of the most serious risk factors for youth suicide are prior suicide attempts, access to firearms/means, family/friends who completed suicide (particularly if recent), and certain psychiatric disorders as noted above.7,9,21 Approximately a third of those who have died by suicide have

had a prior suicide attempt.7 It is estimated that over 80% to 90% of youth who have committed suicide met criteria for a psychiatric disorder, with up to 70% of youth having multiple comorbid disorders.7,9,19,21 Please refer to Table 136-1 for a more comprehensive list of risk factors. TABLE 136-1

Risk Factors for Child and Adolescent Suicide Attempts and Suicide

Biological • Mental illness: including mood disorders, psychotic disorders, substance use disorders, anxiety disorders, disruptive behavior disorders, eating disorder, and cluster B personality disorders (antisocial, borderline, histrionic, and narcissistic) • Gender: females (suicide attempts) and males (suicide) • Age: 16 and above • Parental psychopathology • Family history of completed suicides • Chronic medical conditions Psychological • Prior suicide attempts • Impulsivity, risk-taking behaviors, aggression • Impaired decision making • Perceptions of hopelessness • Poor self-esteem and self-confidence • Self-injurious behaviors, particularly ones that warrant medical attention and in locations such as head, neck, and genital areas • Sexual orientation or gender identity conflicts • Immature or maladaptive coping (e.g. internalizing, self-injury, substance use) • Negative thinking pattern • Childhood adversities/trauma Social (includes potential precipitants) • Access to means (e.g. guns and lethal medication) • Friend who completed suicide • Contagion behavior (locally or through the media)

• Runaway, homeless • Coming from a non-intact family • Poor family communication and lower parental monitoring • Interpersonal conflict, unrelenting discord, including family discord • Dropping out of school or period of absence from school • Difficulties in school or even just perception that their academic performance is poor, which is independent of intelligence • Disconnect from major support systems (school, work, family); lives alone • Loss (e.g. loss of caregiver to death or divorce) • Shameful event • Bullying (both bully and being bullied) • Legal and disciplinary problems Source: Data from Kitts RL, Goldman S. Education and depression. Child Adolesc Psychiatr Clin N Am. 2012;21(2):421-446. Additional references: AACAP 2001;7 Bridge 2006;21 Bridge 2012;13 Brodsky 2008,16 Fleischmann 2005;19 Steele 2007.22

SUICIDE ASSESSMENT When conducting suicide assessments, it is important to approach and interact with the patient in a manner that promotes open and honest disclosure. The following simple tips may be helpful in doing so by giving patients a sense that the clinician is invested in their wellbeing and is willing to listen:7,9 Interview the patient separately from their caregiver(s) Sit down and avoid coming across as rushed Avoid doing the assessment with a large number of clinicians present; try to limit it to two or three individuals Discuss confidentiality and its limitations (i.e. duty to report when safety is a concern) Be direct with questions; adolescents have been shown to be more forthcoming about personal questions, including suicidality and risk factors, when directly asked rather than waiting for them to bring it up with more open-ended questions (e.g. “Anything else?”)

When a patient presents with a suicide attempt, it is important to assess the severity, as this helps determine the level of future risk (i.e. the more the severe attempt, the more at risk). This requires carefully reviewing the aspects of a suicide attempt as you would with any presenting problem. Things to inquire about in the assessment of severity include the following:7,21 Timing of attempt (e.g. attempt that occurred within 24 hours being more concerning than a reported attempt that occurred 2 months ago) Medical lethality of attempt (e.g. hanging necessitating admission to the intensive care unit vs. ingestion of a few pills with no acute medical instability or monitoring) Patient’s suicidal intent as indicated by: Belief about intent (e.g. taking a handful of pills with the belief that it would lead to death) Preparation before attempt (e.g researching on line, saving up pills several days or weeks before the attempt vs. impulsively ingesting pills from medicine cabinet at home) Chance of discovery or rescue (e.g. making the attempt when at home alone vs. in front of peers or family) Communication (e.g. presence of suicide note, text, voice message, or social media message) Reason for the suicide attempt/temporally related stressors and whether those reasons/stressors still exist at the time of the assessment (those with highest suicidal intent reported wanting to permanently escape a psychologically painful situation21) Mental status at time of attempt (e.g. intoxicated/under the influence of drugs and not fully aware of actions vs. calm and logical) Mood and functioning (school, social, personal) for the month prior to attempt Reaction to being saved (e.g. relieved; apathetic/hopeless; angry that plan failed) Frequency, intensity, and duration of suicidal ideations before and after attempt (transient vs. recurrent, persistent thoughts) Patient’s ability to problem-solve regarding alternative strategies to suicide; coping style

Signs and symptoms of impulsivity, aggression, and impulsive aggression Presence of future-oriented goals For the rest of the history, it is important to inquire about the following:7 Psychiatric review of systems: mood, anxiety, psychosis, substance use disorders Psychiatric history: prior suicide attempts or self-injurious behaviors (inquire about time of occurrence, lethality, and precipitants); trauma history; presence of active treatment (medications or therapy); prior psychiatric hospitalizations Family psychiatric history: family history of suicide attempt or completion Medical history: acute or chronic medical issues as a potential source of stress or medical means to hurt self (e.g. potential to mismanage insulin) Social history: quality of home, peer, and school environment; presence of support system; potential shaming event or sources of stress; issues with sexual attraction/orientation; access to weapons It is important to review the above areas with the caregiver(s) as well to ensure the patient’s report is consistent.7,9 Patients may minimize symptoms, especially to avoid psychiatric hospitalization. If inconsistencies arise, ask about a history of manipulation and lying. It is also important to assess the following: Quality of the relationship between patient and caregiver(s) Whether suicide attempt was a surprise to the caregiver (e.g. would they be able to predict and prevent another attempt?) Red flags that were present before the attempt (e.g. patient become more isolative, stopped hanging out with friends, showered less) What caregivers are thinking about in regard to next steps of treatment (e.g. do they want to bring patient home immediately after medical stabilization or are they open to psychiatric treatment?) to assist in the preparation for management and delivery of recommendations Caregivers’ level of concern and insight regarding clinical presentation (e.g. caregivers who does not understand the severity of the attempt/current risk) Concerns regarding patient being aggressive and/or an elopement risk

It is important to conduct a mental status examination in addition to the physical examination. Key components that should be included are the following:7 Quality of interaction and patient’s reliability as a historian (difficulty establishing rapport and alliance; inconsistencies in the history) Signs of acute intoxication or delirium (e.g. agitated, confused, lethargic, disoriented) Signs of psychomotor agitation or psychomotor retardation Signs of self-injurious behavior (e.g. scars on forearm) Mood and affect during the assessment Presence of psychotic features (responding to internal stimuli) Obtaining collateral information from outpatient mental health providers if applicable is helpful, especially when caregivers’ and patients’ reports are inconsistent.7,9 Patients who present with suicidal ideation in the absence of a suicide attempt should also have a thorough suicide assessment. This includes review of the following: Recent suicidal thoughts (how, when, where, and why) Presence of a suicide plan (active vs. passive ideation; e.g. “sometimes I wish I would just go to sleep and not wake up”) Desire/intent to act on thoughts Frequency and pervasiveness of thoughts Triggers that precede thoughts Any preparation for suicide Extent to which patient has tried to act on thoughts (e.g. went to the ledge of a bridge but did not jump off, tied a noose around the neck but released it) Motivating factors that prevent acting on suicide thoughts (e.g. concern for family) Recent worsened mood (e.g. increased anger, sadness, irritability) Communication of thoughts to anyone else (e.g. close friend, posting on social media) Ability of patient to engage in any safety planning Presence of acute or chronic stressors; likelihood of stressors being

resolved Patient’s coping and problem-solving abilities/style Presence of any mental health disorder and any active mental health treatment Comfort level of caregiver(s), and/or other providers for a discharge plan to home Presence of other red flags (e.g. decline in academic, social, and/or personal functioning; dramatic change in personality; giving away of property; little to no future planning; increase in reckless behaviors)

MANAGEMENT If the patient is an imminent danger to self and awaiting inpatient psychiatric placement in the ED or on the medical floor, it will be important to implement the following immediate steps to optimize safety: Environment: Removal of any means to hurt self, including cords that could be used to hang self, sharp objects (e.g. cutlery), insulin pumps, unnecessary items in the room that can be impulsively ingested, etc. Personal items: Should be searched for any potential objects that may be used to hurt self. Sitter: Placement of a 1:1 staff sitter may be necessary so that patient cannot attempt to hurt self when alone in the room. Family members should not be used in lieu of staff sitters at any time. Security: Any concern for elopement risk or aggressive behavior may warrant presence of security personnel to ensure safety of patient and others. Maintain sitter and/or security until an inpatient psychiatric placement can be secured. Caregivers: Support and educate caregivers as to the rationale for the management plan and steps taken toward safety. Transparency and empathy can go a long way to comfort distressed caregivers. The treatment goal for a pediatrician is not necessarily treating suicidality, but ensuring immediate safety and appropriate level of mental health treatment. Pediatricians should be aware that as the gatekeepers, the experience of how the mental health referral is made can potentially influence the patient and family’s adherence with the referral.7

Psychopharmacology and psychotherapy are important components of treatment for mental disorders associated with suicidality and should be tailored to a youths’ particular need.7 Evidence-based treatments include cognitive behavioral therapy (CBT), interpersonal therapy (IPT), dialectical behavioral therapy (DBT), and family therapy.7 Evidence- and consensusderived guidelines and an associated toolkit have been developed for the assessment and management of adolescent depression in primary care settings.27,28 Concerns about the use of antidepressants and suicidality led to the 2004 Food and Drug Administration (FDA) black box warning for all antidepressants regarding an increase in suicidal thoughts and behaviors (4% vs. 2% on placebo) in patients younger than 25 years. No suicides occurred in any of the studies leading to the FDA black box warning, and more recent studies indicate that benefits of using antidepressants—particularly in combination with CBT—to treat children and adolescents with a major depressive disorder outweigh the risks.29-34 Recommended monitoring guidelines for starting antidepressant treatment in the outpatient setting in children and adolescents include weekly visits for the first 4 weeks, every other week for the following 4 weeks, then monthly and as clinically indicated thereafter.9

ADMISSION AND DISCHARGE CRITERIA Different levels of psychiatric care from least restrictive to most restrictive include outpatient treatment (which may include intensive outpatient care/wraparound services), partial hospitalization, acute residential treatment program, and inpatient psychiatric hospitalization. If the patient is deemed an imminent danger to self based on immediate clinical presentation (e.g. after a significant suicide attempt or endorsing active suicidal ideation with a plan), admission to an inpatient psychiatric facility is warranted. Although there are no randomized controlled studies regarding the outcome of psychiatric hospitalization, this is the safest and most reasonable course of action to save the life of these patients.7,9 Potential complications when trying to facilitate a transfer to a psychiatric facility include the following scenarios: Inpatient psychiatric hospitalization is warranted, but neither caregivers

nor patient want to go: First, explore reasons caregivers are resistant and try to address; consider involving a provider (within or outside of the hospital) who has a therapeutic alliance with the family. If these do not yield positive results, commitment to a psychiatric hospital for involuntary hospitalization may be necessary. It would be important to know applicable state laws regarding criteria for psychiatric commitment, including at what age patients can consent to and refuse treatment; consulting with the hospital’s legal, risk management services is advisable in these circumstances. Consultation with child protection services may also be indicated if there are concerns for medical neglect due to caregiver’s refusal to pursue appropriate care. One caregiver agrees to psychiatric hospitalization but the other does not: Explore reason(s) the caregiver is against the plan and attempt to resolve. If caregivers are divorced but have joint legal custody, one caregiver may be able consent to the psychiatric treatment. Factors that help determine whether a patient is at low risk of suicide and can be safely discharged home include the following:7 Although suicidal ideation is present, it is not pervasive and there is no evidence of a plan or desire to act on it. Absence of major risk factors for suicide. Absence of acute precipitants and ongoing stressors. Patient appears insightful and expresses a genuine desire to get help. Identification of healthy coping and solutions to acute stressors or potential precipitants of future suicidal ideation or behavior. Patient has an adequate mental health outpatient plan in place that matches the severity of the presentation and there appear to be no barriers to treatment. Identification of reliable supports; i.e. patient would be discharged to a supportive, stable home environment that could provide monitoring, and ensure follow-up care with mental health services. Safety plan and measures are in place prior to discharge (e.g. removal of weapons/guns, medications locked up, toxic household items removed, alcohol removed because of its disinhibiting effects). (Evidence indicates that unless discussed, caregivers will not take such precautions on their own.)7

Caregivers are receptive to education on signs and symptoms to look for and how to proceed if concerns arise (e.g. call 911, local emergency department, or mental health crisis number). Patient, caregiver(s), collateral (e.g. therapist and school), and current clinical providers (pediatrician and psychiatric consultant) are all in agreement that patient is safe to go home with discharge plan. (Of note, there is no evidence to support the use of “no-suicide” contracts with patients.)7

CONSULTATION Request a psychiatry consultation to assist with further management. If such a service does not exist, contact the hospital’s department of psychiatry for assistance. Consult with toxicology if any concerns for overdose are present; if not available, consider contacting poison control. Minimal labs to obtain include a urine toxicology screen for drugs of abuse, urine pregnancy test in post-pubertal females, and a serum toxicology screen if there is a suspected or known ingestion (e.g. acetaminophen and salicylate levels). If there are concerns for psychotropic and other medication ingestion, obtaining an ECG may be indicated to assess for cardiac effects from the ingestion.

PREVENTION Pediatricians are encountering increasing amounts of mental illness in their practices. Most patients who have committed suicide have had contact with a healthcare provider within a year—predominantly within 3 months—of seeing them.4,35 The American Academy of Child and Adolescent Psychiatry and American Academy of Pediatrics recommend that pediatricians take steps to help reduce the incidence of youth suicide by screening for depression and suicidal ideation and behavior.7-9 Improvement of primary care physician recognition of depression and suicide risk has been shown to decrease suicide rates.35 JCAHO, in their 2010 Sentinel Event Alert, acknowledged that suicide has ranked in the top five most frequently reported events to the Joint Commission since 1995.36 They recommended being able to identify

immediate suicide risk and that all patients who demonstrate concerning behaviors be screened for suicide, including acute signs of depression, anxiety, agitation, delirium, and dementia; medical or psychological problems that significantly impact judgment (e.g. acute drug intoxication); and chronic pain or other debilitating problems.36 They recommend providing suicide screening in the ED and screening for depression in all patients who are admitted to the hospital.36 Additionally, the American Academy of Pediatrics and American College of Emergency Physicians recognize the need for brief, easy to administer suicide screens in hospitals.8 Brief screens have been studied to promote standard use among busy pediatricians in different settings. A brief standardized screening for suicidal adolescents using two questions has been shown to be effective in increasing identification of those with suicidal ideation in pediatric primary care practices without overburdening their referral resource.37 The Ask SuicideScreening Questions is a four-question screening instrument with high sensitivity and negative predictive value that can identify the risk for suicide in patients presenting to pediatric emergency departments.4 Suicide scales are useful for screening, but cannot substitute a clinical assessment.7 Anyone who presents with a positive screen should receive a more through suicide assessment. Facilitating a connection with the appropriate treatment, advocating for increased access to mental health treatment, and supporting and educating caregivers are all very important. For pediatricians in the outpatient setting, it would be important to have an outpatient plan if a patient were to present in the outpatient setting with imminent suicidal risk. Such a plan would include how to get the patient safely to the ED, including means of organizing transport and monitoring the patient. An ambulance should be utilized to ensure the patient arrives safely at the recommended facility. A list of relevant numbers should be easily available in the office, including local hospitals with psychiatric units, mental health agencies, crisis hotlines, and crisis intervention centers.9 KEY POINTS Suicide has remained in the top three leading causes of death for youth in the United States for several decades. Adolescents are biologically and psychologically more

vulnerable to suicide and suicide attempts. Some of the most serious risk factors for youth suicide are prior suicide attempts, access to firearms/means, family/friends who completed suicide, and presence of certain psychiatric disorders. Pediatricians can take steps to help reduce the incidence of youth suicide by screening for depression and suicidal ideation and behavior, and facilitating access to mental health treatment.

REFERENCES 1. Center for Disease Control and Prevention. Suicide: Data Sources. https://www.cdc.gov/violenceprevention/suicide/statistics/index.html. Accessed May 2017. 2. Center for Disease Control and Prevention. National Center for Health Statistics Data Brief No. 241. April 2016. https://www.cdc.gov/nchs/ products/databriefs/db241.htm Accessed May 2017. 3. Centers for Disease Control and Prevention. Injury prevention & control: data & statistics. Web-based Injury Statistics Query and Reporting System (WISQARS). http://www.cdc.gov/injury/wisqars/ index.html. Accessed February 2013. 4. Horowitz LM, Bridge JA, Teach SJ, et al. Ask Suicide-Screening Questions (ASQ) - a brief instrument for the pediatric emergency department. Arch Pediatr Adolesc Med. 2012;166(12):1170-1176. 5. Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE eds. Reducing Suicide: a National Imperative. Washington DC: National Academy Press; 2012. 6. Kann L, McManus T, Harris WA, et al. Youth risk behavior surveillance —United States, 2015. MMWR Surveill Summ. 2016;65(No. SS-6):1174. 7. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry. 2001;40(7 Suppl):24S-51S.

8. Dolan MA, Fein JA; Committee on Pediatric Emergency Medicine. Pediatric and adolescent mental health emergencies in the emergency medical services system. Pediatrics. 2011;127(5):e1356-1366. 9. Shain BN; Committee on Adolescence. Suicide and suicide attempts in adolescents. Pediatrics. 2007;120(3):669-676. 10. Spirito A, Esposito-Smythers C. Attempted and completed suicide in adolescence. Annu Rev Clin Psychol. 2006;2:237-266. 11. Weir JM, Zakama A, Rao U. Development risk 1: depression and the developing brain. Child Adolesc Psychiatr Clin N Am. 2012;21(2):237259. 12. Bell CC, et al. Affect regulation and prevention of risky behaviors. JAMA. 2010;304(5):565-566. 13. Bridge JA, McBee-Strayer SM, Cannon EA, et al. Impaired decision making in adolescent suicide attempters. J Am Acad Child Adolesc Psychiatry. 2012;51(4):394-403. 14. Zalsman G. Genetics of suicidal behavior in children and adolescents. In: Dwivedi Y ed. The Neurobiological Basis of Suicide. Boca Raton, FL: CRC Press; 2012:Chapter 14. https://www.ncbi.nlm.nih.gov/ pubmed/23035284. 15. Pandey GN, Dwivedi Y. Neurobiology of teenage suicide. In: Dwivedi Y ed. The Neurobiological Basis of Suicide. Boca Raton, FL: CRC Press; 2012:Chapter 15. https://www.ncbi.nlm.nih.gov/books/ NBK107198. 16. Brodsky BS, Stanley BS. Adverse childhood experiences and suicidal behavior. Psychiatr Clin N Am. 2008;31:223-235. 17. Chatzittofis A, Nordstrom P, Hellstrom C, et al. CSF 5-H1AA, cortisol and DHEAS levels in suicide attempters. Eur Neuropsychopharmacol. 2013;23(10):1280-1287. 18. Zhang TY, Labonte B, Wen XL, Turecki G, Meaney M. Epigentic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacol Rev. 2013;38:111-123. 19. Fleischmann A, Bertolote JM, Belfer M, Beautrais A. Completed suicide and psychiatric diagnoses in young people: a critical examination of the

evidence. Am J Orthopsychiatry. 2005;75(4):676-683. 20. Cooper J, et al. Suicide after deliberate self-harm: a 4-year cohort study. Am J Psychiatry. 2005;162:297-303. 21. Bridge JA, Goldstein TR, Brent DA. Adolescent suicide and suicidal behavior. J Child Psychol Psychiatry. 2006;47(3-4):372-394. 22. Steele MM, Doey T. Suicidal behavior in children and adolescents. Part 1: Etiology and risk factors. Can J Psychiatry. 2007;52(1):21-33. 23. Clarke G, Harvery AG. The complex role of sleep in adolescent depression. Child Adolesc Psychiatr Clin N Am. 2012;21(2):385-400. 24. Kitts RL, Goldman S. Education and depression. Child Adolesc Psychiatr Clin N Am. 2012;21(2):421-446. 25. Grupp-Phelan J, McGuire L, Husky MM, Olfson M. A randomized controlled trial to engage in care of adolescent emergency department patients with mental health problems that increase suicide risk. Pediatr Emerg Care. 2012;28(12):1263-1268. 26. Horowitz LM, Ballard ED, Pao M. Suicide screening in schools, primary care and emergency departments. Curr Opin Pediatr. 2009;21:620-627. 27. Zuckerbrot RA, Cheung AH, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): I. Identification, assessment, and initial management. Pediatrics. 2007;120:1299-1232. 28. Cheung AH, Zuckerbrot RA, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): II. Treatment and ongoing management. Pediatrics. 2007;120:1313-1316. 29. Bridge JA, Ivengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683-1696. 30. Gibbons RD, Hur K, Bhaumik DK, et al. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006;163(11):1898-1904. 31. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363. 32. March JS, Vitiello BB. Clinical message from the treatment for

adolescents with depression study (TADS). Am J Psychiatry. 2009;166(10):1118-1123. 33. Meyer RE, Salzman C, Youngstrom EA, et al. Suicidality and risk of suicide—definition, drug safety concerns, and a necessary target for drug development: a brief report. J Clin Psychiatry. 2010;71(8):1040-1046. 34. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepres- sant prescription rates in Japan, 1999-2003. J Clin Psychiatry. 2007;68(6):908-916. 35. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA. 2005;292(16):2064. 36. The Joint Commission. A follow-up report on preventing suicide: focus on medical/surgical units and the emergency department. Sentinel Event Alert. 2010;46:1-4. 37. Wintersteen MB. Standardized screening for suicidal adolescents in primary care. Pediatrics. 2010;125(5):938-944.

CHAPTER

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Conversion and Pain Disorders Ashley K. Storrs and Patricia I. Ibeziako

BACKGROUND The assessment and management of children and adolescents who present with medically unexplained symptoms or symptoms in excess of what would be expected for a particular medical illness can be difficult task. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), illnesses previously referred to as somatoform disorders are defined as somatic symptom and related disorders.1 These disorders are classified on the basis of distressing somatic symptoms and excessive thoughts, feelings, or behaviors in relation to these symptoms. Somatic symptom and related disorders form a continuum that can range from pain to disabling neurological symptoms. The physical symptoms are not explained better by another mental illness, are spontaneous in nature, and are not contrived by the child or adolescent.2 In addition, a medical condition if present does not fully account for the level of impairment the child is displaying.2 In early childhood, the most common somatic symptoms are recurrent abdominal pain and headaches, while older children tend to experience neurological symptoms, insomnia, and fatigue.2 The symptoms can be severe, recurrent, and impairing. Impairment often involves withdrawal and avoidance of everyday responsibilities and stresses.3 As a result, the child and family may have contact with multiple medical providers with the expectation of medical treatment.3 The diagnosis and management of somatic symptom and related disorder often present significant challenges to primary care clinicians and pediatric subspecialists.4 The pediatrician trying to formulate an understanding of these symptoms without multidisciplinary support may feel poorly prepared and

have little time to assess or treat the somatic concerns.5 Somatic symptom and related disorders comprise a small but important number of costly medical visits that increase exposure to unnecessary medical tests and procedures6 because of the fear that an organic etiology will be missed.3 This patient population is more likely to present to pediatricians than to psychiatrists, and they disproportionately consume health resources by overutilizing the emergency department, inpatient, and consultation services, and may seek multiple health providers in pursuit of a medical etiology.3,7,8 To understand the multiple factors that can contribute to the development of somatic symptoms, it is critical to keep in mind the biological, psychological, developmental, and sociocultural factors in the child’s life.

PATHOPHYSIOLOGY: CONVERSION DISORDER BIOLOGICAL FACTORS According to the DSM-5, conversion disorder, also known as functional neurological symptom disorder, is one of the somatic symptom and related disorders and is characterized by clinically significant distress leading to impairment in functioning due to a deficit affecting voluntary motor and sensory functioning. The symptoms cannot be better accounted for by another medical condition or mental illness.2 Hyperactivity of the anterior cingulate cortex has been found in patients with conversion disorder, along with either increased or decreased activity of the dorsolateral prefrontal cortex.9 Patients with non-epileptic seizures have increased activity of neurobiological stress systems with lower heart rate variability at baseline and during recovery from an induced stress condition.10,11 Decreased heart rate variability is associated with increased arousal and poor emotion regulation.12 Patients with conversion disorders also have increased diurnal cortisol levels that were not explained by depression, medication, smoking, current seizures, or group differences in sympathetic nervous system activity when compared to controls.13

PSYCHOLOGICAL AND SOCIAL FACTORS Psychological factors that can contribute to the etiology of conversion

disorder include attachment, environmental stress, family discord, trauma as well as culture. In several studies, insecure-avoidant attachment behavior was associated14 with a predisposition for increased complaints of physical symptoms, whereas secure attachment correlated with health-maintaining behaviors.15 There is often a model for the patient’s symptoms such as a parent or family member. In a study of conversion disorder, a significant proportion of patients had family members who reported having medical conditions with similar presentations.14 There are times that the patient may be their own symptom model; a common example of this is children with epilepsy who also have pseudoseizures.2 Recent family stress, unresolved grief reactions, and family psychopathology occur at a higher frequency in cases of conversion symptoms.16 External environmental factors such as school stress or change in family situation and internal factors such as coping deficits or poor behavioral selfcontrol are common in children presenting with conversion disorder.14 Common school stressors in this patient population include bullying, fear of exams, extracurricular activities, as well as beginning the new school year.14,17 Family dysfunction and less support within the family system are common in children with conversion disorders. A transition within the family system such as death of a family member, birth of a sibling, parental divorce, physical punishment by parents, and an increase in the number of arguments between parents have all been linked to conversion symptoms.14,17 Conversion symptoms sometimes do not immediately follow a specific stressor, but instead can occur months or years later. One study showed that children with non-epileptic seizures had significantly higher life events and stress scores the preceding year compared to the seizure group and control group.17 Conversion disorder presents differently in various cultures. The use of nonverbal body language as a way of communication or expression of self in response to interpersonal conflicts may represent a culturally determined and socially learned behavior.4 Emerging literature indicates the risk of conversion disorder may be higher in adolescents who have anxiety related to sexual behaviors, sexual orientation, or gender identity.18 The adolescent may struggle with communicating their internal turmoil due to fear of parental rejection, peer

isolation, stigmatization, and victimization.

CLINICAL PRESENTATION It is estimated that 17% to 30% of patients referred to comprehensive epilepsy centers have non-epileptic seizures.7 Studies indicate that episodic loss of consciousness, typically syncope or non-epileptic seizures, and motor functioning, typically abnormal gait or the inability to walk, are the most frequently reported symptoms of conversion disorder in childhood.4 Conversion disorder may be accompanied by “la belle indifference,” which is an attitude of disinterest by the patient despite the serious symptoms experienced.2 Early diagnosis can prevent symptom fixation and the performance of expensive and sometimes painful invasive procedures.

DIFFERENTIAL DIAGNOSIS When evaluating a child with conversion symptoms it is important to keep in mind other medical causes that may lead to the same presentation. Thus it is important to consider temporal lobe epilepsy, tumors of the central nervous system, multiple sclerosis, and myopathies. The pediatrician should keep in mind that the presence of a conversion disorder does not exclude the possibility of a physical condition in the same patient.19 Apart from conversion disorder, other psychiatric disorders may cause similar presentations such depression, anxiety, factitious disorder, and malingering. Factitious disorder involves the intentional production of physical or psychological symptoms or signs to assume the sick role. External incentives for the behavior such as economic gain or avoiding legal responsibility are absent.1 Malingering occurs when patients intentionally produce false or exaggerated physical or psychological symptoms and are motivated by external incentives such as avoiding work, financial compensation, or obtaining drugs.1 The disorders of falsification are generally described in adults, although some cases in older children and adolescents have been reported.20 It is not uncommon for depression in children to present as somatic symptoms. Acute stress disorder and symptoms of post-traumatic stress disorder can present with symptoms similar to that of conversion disorder.19 Conversion symptoms can occur within other somatic

symptom disorders with a combination of pain and gastrointestinal, sexual, and pseudoneurologic symptoms.

DIAGNOSTIC EVALUTION Early diagnosis is important because it avoids unnecessary hospitalization and investigations that result in an economic burden for the family, clinicians, and health system.4 Video-EEG monitoring remains the gold standard in diagnosing non-epileptic seizures. EEG monitoring also helps parents to understand the emotional non-electrical nature of these episodes, as the episodes occur in the absence of electrical activity on the EEG.21 The use of provocative testing to confirm a diagnosis of non-epileptic seizures is very controversial. The most common method is injecting a placebo, typically saline, that has been described to the patient as an anticonvulsant agent. Proponents of these techniques believe the gains include decreased healthcare cost, shorter time to diagnosis, and the avoidance of adverse effects of use of antiepileptic drugs. Arguments against provocative testing cite ethical concerns of using deception and the damage it may cause the physicianpatient relationship.11 Other neuroimaging studies and lumbar puncture with CSF analysis may be indicated in certain types of conversion disorders, although avoiding invasive procedures when possible is preferred. For all types of conversion disorders, a psychiatric evaluation should be conducted in addition to the medical work-up, to assess for biopsychosocial contributing and risk factors that would inform the diagnosis and treatment plan.

PATHOPHYSIOLOGY: PAIN DISORDER BIOLOGICAL FACTORS According to the DSM-5, pain disorders have been reclassified as somatic symptom disorders with predominant pain, and should be suspected when there are excessive thoughts, feelings, or behaviors in relation to pain symptoms, an intense preoccupation with the pain, and resultant disruption of daily life.2 The reactivity and recovery of the nervous system during time of stress can influence the experience of pain.22 Children with recurrent

abdominal pain (RAP) exhibit a lower threshold to internal and external pain cues of painful stimuli.19 In addition, when there is a strong expectation of pain, the anterior insular cortex is activated in proportion to this expectation. Thus the preactivation will predict the subjective intensity of subsequent pain stimulus.23 In studies of long-term pain, including migraine and tension type headache, there appears to be progressive loss of gray matter density in brain structures involved in registering pain such as the somatosensory cortex, anterior cingulate cortex, and insula. Also, there is loss of gray matter density in structures such as the dorsolateral and medial orbital prefrontal cortex and periaqueductal gray region of the brainstem involved in inhibiting the pain signal.23

PSYCHOLOGICAL FACTORS Psychological factors related to pain include temperament, attention biases toward system-related stimuli, and coping strategies that are developed and used by the child.22 Subjective representations of pain can occur as a result of emotional states, thoughts, beliefs, intentions, suggestions, injuries to social or attachment relationships, memories of past injuries, and the emotional state of others.24 Negative emotions such as sadness, fear, or anger can significantly influence how the brain processes pain and can increase the degree of pain felt by the child.24 A recent meta-analysis shows that internalizing symptoms, as measured by parents and self report, is approximately six times more likely to occur in children with recurrent abdominal pain than matched healthy controls.25 Attachment-based theoretical perspectives of pain have portrayed insecurely attached individuals as having a greater risk of developing chronic pain, being less able to internally manage the distress associated with pain and access and maintain external supports and form a consistent therapeutic alliance. This same patient population perceives more negative intent, evokes more negative responses, and may sabotage therapeutic efforts from health professionals. Thus insecure attachment is a risk factor to the adjustment to pain, and patients with this attachment type have poor outcomes from a range of treatment interventions.26 Positive or negative reinforcement of acute pain behavior, such as

inactivity or pain medication, may cause a chronic problem.27 Somatization is a learned behavior that may begin because the experience of having a somatic complaint is more acceptable or more noticed in some households than the expression of strong emotions such as anxiety, fear, or anger. In such an environment, a child may repeatedly garner minimal attention for emotional distress, but obtain more attention and sympathy for physical symptoms that can accompany a disturbed emotional state.3 Pain behaviors may also be reinforced by the surrounding environment in the form of increased concern or interest from a family member or from a highly regarded physician.27 While pain behaviors are being reinforced, healthier behaviors may result in negative consequences, such as decreased attention. These types of responses can decrease the probability that the well behavior will be repeated in the future.27

SOCIAL FACTORS Social factors include environmental stressors, especially chronic stress, and parental functioning.22 Campo et al. found that mothers of children with functional abdominal pain had poorer health-related quality of life in areas including physical and social functioning, bodily pain, and mental health than mothers of children with no pain in the control group.28 Mothers of children with functional abdominal pain were also significantly more likely to have made ten or more ambulatory health visits during the previous 6 months than mothers of children in the control group.28 Children with chronic pain symptoms often live with family members who complain of similar physical symptoms3 and a parent’s response to a child’s pain as well as ongoing daily stressors have been shown to exacerbate and maintain pain symptoms.16 Increased medical diagnoses, hospitalizations, being female, having problems in school, and parental stress over their own pain were predictive of increased somatic symptoms over 6 years in a pediatric population.16

CLINICAL PRESENTATION Pain is the leading symptom in up to 70% of patients presenting with physical complaints that cannot be fully explained by any medical disease.15 Chronic

pain without an identifiable organic basis occurs in 4% to 15% of the normative adolescent population and represents a substantial proportion of referrals to adolescent medicine and rheumatology clinics.29 RAP is defined as intermittent pain with full recovery between episodes, lasting more than 3 months, and it is the most common recurrent pain complaint of childhood. Studies indicate that RAP affects 8% to 25% of school-age children ages 9 to 12 years old.25 The prevalence of recurrent abdominal pain increases with age into adolescence, with an equal gender ratio in early childhood and symptom reporting by girls predominating by late childhood.30 Headaches have been reported to affect 20% to 55% of all children, with 10% of teenagers reporting frequent headaches, chest pain, nausea, and fatigue.2 Multiple studies have found a strong relationship between pain and anxiety disorders in children. It is increasingly held that recurrent abdominal pain and anxiety disorders may share a common risk factor or are different aspects of a single causal process.30 Generalized anxiety disorder, specific phobia, social phobia, and separation anxiety disorder have all been associated with RAP.30 Four studies completed structured diagnostic interviews with children diagnosed with RAP and found the prevalence of anxiety disorders to be between 42% and 85%.25 Studies show that parents of children with RAP rated their children higher on scales than healthy children for measures of anxiety, affective problems, and somatic symptoms.25 Anxiety disorders have been associated with children with chronic daily headaches.31 RAP is strongly associated with depressive symptoms, other pain syndromes such as headache, limb pain, or chest pain as well as other somatic symptoms such as fatigue, dizziness, weakness, and numbness.30 One study found 43% of the children with RAP in their sample had depression, compared 8% of the controls.30 Reflex sympathetic dystrophy or complex regional pain syndrome is defined as pain that spreads along a dermatomal pattern beyond the location of the initial injury and is usually accompanied by autonomic dysfunction, movement deficits, dystrophy, and edema.32 Children with this syndrome have been shown to have elevated risk of somatic symptoms and emotional distress, particularly anxiety.32

DIFFERENTIAL DIAGNOSIS When assessing a child with pain symptoms it is important to evaluate any potential medical illnesses that may contribute to their pain. Other disorders such as depression and anxiety may present with pain symptoms, but the mood disorder typically tends to be more significant. Younger children may be affected with Factious disorder imposed on another. Although factitious disorders or malingering are less common in the pediatric age group, it is important to keep these diagnoses as a possibility on the differential.

DIAGNOSTIC EVALUATION Invasive procedures are more frequently performed in patients with somatic symptom disorders with predominant pain than in patients with nociceptive or neuropathic pain.15 Many children with RAP may go through potentially risky and possibly unnecessary hospitalizations, tests, and procedures, placing a heavy burden on the medical community.25 Thus it is very important to diagnose and intervene early. The clinical interview should include a careful assessment of the psychological and social stressors that may be contributing to their pain as well as a thorough family psychiatric and pain history. The evaluation should provide the clinical team with a biopsychosocial explanation of the child’s symptoms, which will inform the treatment plan.22 The history of prior episodes of pain should be included in the assessment, in addition to the child’s social and academic functioning, other physical symptoms, coping strategies, consequences, and family functioning.22 A clinician can further assess a child’s pain by using a structured pain assessment tool that is developmentally appropriate for the child in addition to having the child complete a pain diary.22 The physical examination will find that the child’s symptoms may be anatomically inconsistent or in excess of what would be expected from the physical findings. If there are physical findings, it is most likely because of pathological changes from immobilization.19

MANAGEMENT PSYCHOEDUCATION

Psychoeducation and the management of children and families with somatic symptoms can be extremely challenging. The pediatrician must convey an understanding that the patient’s pain is real.2 Psychoeducation can be directed at understanding and adhering to a treatment regimen, clarifying when to worry about symptoms, enhancing communication and collaboration with treating professionals, and using problem-solving coping techniques. As part of discussing the mind–body connection, it is helpful to use examples that incorporate themes in everyday language to allow the parent to better understand the connection between emotions and the body. A common example is that when someone experiences “butterflies in their stomach,” it can be related to anxiety. It has been found that showing respect for a patient’s own perception of illness and allocating enough time for communicating the diagnosis are critical with treating this patient population.33 Families often worry about abandonment by the physician after a diagnosis of a somatic symptom and related disorder; however, scheduled follow-up visits with their pediatrician and other specialists are important in order for the family to continue to have investment in treatment.34 In some cases, reassurance and the suggestion from the pediatrician that the symptom will improve is helpful; however, in many instances a message of implied feigning may be heard by the patient,35 thus pediatricians should recognize their own responses to the family’s resistance and reluctance to stop the medical workup.2 Even if they disagree with their physicians, many families can accept treatment recommendations if they are assured regularly scheduled follow-up visits with their pediatrician.2 It is important to focus on reducing dysfunction by utilizing a multidisciplinary rehabilitation approach.

REHABILITATION MODEL The main approach to treatment is based on the rehabilitation model. Goals are to reduce symptoms, improve normal functioning, enhance coping, and prevent secondary disabilities. The implementation of interventions that simultaneously target “body and mind” can facilitate the family’s acceptance of the psychological aspect of the treatment.24 The child becomes an active participant by using intensive physical and occupational therapy to help restore their functioning. Participation in these services should be combined

with encouraging the parents to view their child as capable and strong as well as using a behavioral modification program that has incentives when improvements in functioning are shown.22 A gradual return to school with a structured plan to address obstacles and support can be effective.36 In a study of treatment for children with non-epileptic seizures where six of the children were symptom-free after 3 to 6 months and eight experienced more than 50% reduction in the frequency of the symptoms, the treatment involved shifting the focus of the parents from organic to psychosocial explanation of symptoms, while encouraging the child and parents to resume normal activities.17 A critical element to this model is that parents should ignore or reduce attention to sick role behavior, use problem-solving coping techniques when the child struggles and family counseling to enhance parental competence to resolve family crises.17

COGNITIVE BEHAVIORAL THERAPY Cognitive behavioral therapy (CBT) techniques can encourage participation in routine activities through gradual exposure, while discussing the links between physical and psychological pain.3 A study found that patients with psychogenic non-epileptic seizures treated with CBT had a mean seizure frequency that decreased from intervention to completion as well as an improvement in their quality of life, psychosocial functioning, anxiety, depression, and somatic symptoms.37 Participants in a randomized control trial that examined CBT versus enhanced usual care found that participants in the CBT group had an improvement their social functioning, physical functioning, bodily pain, and vitality, less worry about their illness, and improvement in physical symptoms.38

ADDITIONAL TECHNIQUES Techniques such as hypnosis and biofeedback have been helpful in treating somatic symptom and related disorders. There is conflicting evidence of how effective hypnosis is as a means of treatment in this patient population, as there have been no randomized control studies in the pediatric population. Even so, there has been some evidence in the adult population that hypnosis alone or in the form of self-hypnosis using relaxation techniques have

resulted in improved in symptoms such as back pain, headache, and emotional arousal.39

PHARMACOLOGIC MANAGEMENT There is a paucity of randomized, controlled trials investigating the use of psychotropic medication in the management of somatic symptoms in the pediatric population. One open-trial study of 25 children with recurrent abdominal pain found that 84% responded to a trial of Citalopram.40 The interpretation of these results was limited by the small sample size and methodology. A child who does not respond to intensive treatment should be evaluated for the possibility of comorbid disorders such as a mood disorder, anxiety disorder, and substance use disorder, which should be identified and treated to assure a successful outcome.2

ADMISSION AND DISCHARGE CRITERIA Studies have suggested that the treatment of patients on medical-psychiatric units leads to a decrease in healthcare utilization and an appropriate increase in psychiatric interventions.41 If the frequency and duration of the episodes are unchanged or escalate, then psychiatric admission may be indicated for further evaluation and continued acute intervention.36 Also, if the child has declined significantly in their social and academic functioning as evidenced by their inability to complete a normal routine of going to school, completing extracurricular activities, and taking care of their activities of daily living, they may require a psychiatric admission to receive more intense treatment. In the treatment of somatic symptom and related disorders, it is helpful to establish realistic goals that emphasize improvements in functioning rather than the expectation that symptoms can be completely resolved.42 A child will be ready for discharge from the hospital and not need psychiatric admission if they demonstrate functional improvement with regard to eating, drinking, and ability to complete their activities of daily living with minimal support/supervision.

CONSULTATION

If somatization is suspected, psychiatric consultation should be included early in the evaluation process.42 The psychiatrist should start seeing the child shortly after their medical admission, in parallel with the medical workup.36 It is helpful for the pediatrician to frame the consultation as a routine part of a comprehensive assessment to evaluate stress, as it can be connected with current physical symptoms.42 Multidisciplinary management includes the child mental health clinician, pediatric neurologist, pain specialists, physical therapy, social work, occupational therapy, child life/activity therapist, and school personnel. It is important for physical and occupational therapy to be involved, because although symptoms can be self-limited, they may persist and can be associated with chronic sequelae such as contractures2 in patients with conversion and pain disorders with decreased mobility.

PREVENTION Given the chronicity of symptoms in some children, early identification of risk factors and prevention of further impairment and more disabling symptoms can be critical to the overall course of their illness. Early intervention and recognition have been reported to be associated with a good prognosis.4 The longer the duration of presenting symptoms, the more likely the child will have a relapse of symptoms. Short-term treatment goals are to stop or significantly decrease the frequency and duration of symptoms, limit medical interventions, and return the child to normal daily activities.36 It is integral to involve and educate school personnel regarding any social or educational factors that may be potential risk factors in order to help the school create a safe environment for the child’s optimal functioning.36 KEY POINTS Conversion and pain disorders are extremely common in the pediatric hospital setting. It is critical to include biological, psychological, developmental, and social factors when assessing a child with somatic symptoms because this formulation will inform the treatment plan. The psychiatrist should start evaluating the child shortly after

admission in conjunction with the medical workup. A multidisciplinary team approach is integral to providing this patient population with comprehensive care by also including social work, child life, nursing, physical therapy, and occupational therapy. It is important to emphasize the rehabilitation model with a focus on the connection between the body and mind.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (DSM V). Washington, DC: American Psychiatric Association; 2013. 2. Silber TJ. Somatization disorders: diagnosis, treatment and prognosis. Pediatr Rev. 2011;32:56-64. 3. Garralda ME. Unexplained physical complaints. Child Adolesc Psychiatr Clin N Am. 2010;19:199-209, vii. 4. Coskun M, Zoroglu S. Long-lasting conversion disorder and hospitalization in a young girl: importance of early recognition and intervention. Turk J Pediatr. 2009;51:282-286. 5. Spratt EG, Thomas SG. Pediatric case study and review: is it a conversion disorder? Int J Psychiatry Med. 2008;38:185-193. 6. Walker LS, Beck JE, Garber J, et al. Children’s Somatization Inventory: psychometric properties of the revised form (CSI-24). J Pediatr Psychol. 2009;34:430-440. 7. Thompson NC, Osorio I, Hunter EE. Nonepileptic seizures: reframing the diagnosis. Perspect Psychiatric Care. 2005;41(2):71-78. 8. Sumathipala A, Siribaddana S, Hewege S, et al. Understanding the explanatory model of the patient on their medically unexplained symptoms and its implications on treatment development research: a Sri Lanka Study. BMC Psychiatry. 2008;8:54. 9. Cloninger CR and Dokucu, ME. Somatoform and dissociative disorders. In: Fatemi SH, Clayton PJ eds. The Medical Basis of Psychiatry. 3rd ed.

Humana Press; 2008:190-191. 10. Kozlowska K, Scher S, Williams LM. Patterns of emotional-cognitive functioning in pediatric conversion patients: implications for the conceptualization of conversion disorders. Psychosomat Med. 2011;73(9):775-788. 11. Siket MS, Merchant RC. Psychogenic seizures: a review and description of pitfalls in their acute diagnosis and management in the emergency department. Emerg Med Clin N Am. 2011;29:73-81. 12. Bakvis P, Roelofs K, Kuyk J, et al. Trauma, stress, and preconscious threat processing in patients with psychogenic nonepilieptic seizures. Epilepsia. 2009;50:1001-1011. 13. Bakvis P, Spinhoven P, Giltay EJ, et al. Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures. Epilepsia. 2009;51:752-759. 14. Teo WY, Choong CT. Neurological presentations of conversion disorders in a group of Singapore children. Pediatr Int. 2008;50:533536. 15. Nickel R, Ademmer K, Egle UT. Manualized psychodynamic interactional group therapy for the treatment of somatoform pain disorders. Bull Menninger Clin. 2010;74:219-237. 16. Bursch B, Lester P, Jiang L, et al. Psychosocial predictors of somatic symptoms in adolescents of parents with HIV: a six year longitudinal study. AIDS Care. 2008;20:667-676. 17. Chinta SS, Malhi P, Singhi P, Prabhakar S. Clinical and psychosocial characteristics of children with nonepileptic seizures. Ann Indian Acad Neurol. 2008;11(3):159-163. 18. Johnson KB, Harris C, Forstein M, Joffe A. Adolescent conversion disorder and the importance of competence discussing sexual orientation. Clin Pediatr. 2010;49:491-494. 19. Ibeziako PI, DeMaso DR. The somatoform disorders. In: Klykylo WM, Kay JL, eds. Clinical Child Psychiatry. 3rd ed. West Sussex, England: Wiley. 2012;26:458-474. 20. Libow J. Beyond collusion: active illness falsification. Child Abuse Neglect. 2002;26:525-536.

21. Bujoreanu IS, Ibeziako PI, DeMaso DR. Psychiatric concerns in pediatric epilepsy. Child Adolesc Psychiatr Clin N Am. 2010:371-386. 22. Bursch B. Pediatric pain. In: Shaw RH, DeMaso DR eds. Textbook of Pediatric Psychosomatic Medicine: Mental Health Consultation with Physically Ill Children. Washington DC: American Psychiatric Press; 2010:141-154. 23. Borkum JM. Chronic headaches and the neurobiology of somatization. Curr Pain Headache Rep. 2010;14:55-61. 24. Kozlowska K, Rose D, Khan R, MA, Kram S, Lane L, Collins J. A conceptual model and practice framework for managing chronic pain in children and adolescents. Harvard Rev Psychiatry. 2008;16:136-150. 25. Dufton LM, Dunn MJ, Compas BE. Anxiety and somatic complaints in children with recurrent abdominal pain and anxiety disorders. J Pediatr Psychol. 2009;34:176-186. 26. Meredith PJ, Ownsworth T, Strong J. A review of the evidence linking adult attachment theory and chronic pain: presenting a conceptual model. Clin Psychol Rev. 2008;28:407-409. 27. Stiles TC, Wright D. Cognitive behavioral treatment of chronic pain conditions. Nordic J Psychiatry. 2008;62(Suppl 47):30-36. 28. Campo JV, Bridge J, Lucas A, Savorelli S. Physical and emotional health of mothers of youth with functional abdominal pain. Arch Pediatr Adolesc Med. 2007;161(2):131-137. 29. Griffin A, Christie D. Taking the psycho out of psychosomatic: using systemic approaches in a pediatric setting for the treatment of adolescents with unexplained psychical symptoms. Clin Child Psychol Psychiatry. 2008;13:531-542. 30. Campo JV, Bridge J, Ehmann M, et al. Recurrent abdominal pain, anxiety, and depression in primary care. Pediatrics. 2004;113:817-824. 31. Seshia SS, Phillips DF, von Baeyer CL. Childhood chronic daily headache: a biopsychosocial perspective. Devel Med Child Neurol. 2008;50:541-545. 32. Cruz N, O’Reilly J, Slomine BS, Salorio CF. Emotional and neuropsychological profiles of children with complex regional pain syndrome type-I in an inpatient rehabilitation setting. Clin J Pain.

2011;27(1):27-34. 33. Karterud HN, Knizek BL, Nakken KO. Changing the diagnosis from epilepsy to PNES: patients’ experiences and understanding of their new diagnosis. Seizure. 2010;19:40-46. 34. Ibeziako PI, Bujoreanu S. Approach to psychosomatic illness in adolescents. Curr Opin Pediatr. 2011;4:384-389. 35. Kanaan RA, Armstrong D, Wessely SC. Neurologists’ understanding and management of conversion disorder. J Neurol Neurosurg Psychiatry. 2011;82:961-966. 36. Plioplys S, Asato MR, Bursch B, et al. Multidisciplinary management of pediatric nonepileptic seizures. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1491-1495. 37. LaFrance WC Jr, Miller IW, Ryan CE, et al. Cognitive behavioral therapy for psychogenic non-epileptic seizures. Epilepsy Behav. 2009;14(4):591-596. 38. Schroder A, Rehfeld E, Ornbol E, Sharpe M, et al. Cognitivebehavioural group treatment for a range of functional somatic syndromes: randomised trial. Br J Psychiatry. 2012;200(6):499-507. 39. Shaw R. Somatoform Disorder. In: Shaw RH, DeMaso DR eds. Textbook of Pediatric Psychosomatic Medicine: Mental Health Consultation with Physically Ill Children. Washington DC: American Psychiatric Press; 2010:121-139. 40. Campo JV, Perel J, Lucas A, et al. Citalopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders: an exploratory study. J Am Acad Child Adolesc Psychiatry. 2004;43:12341242. 41. Leue C, Driessen G, Strik JJ, et al. Managing complex patients on a medical psychiatric unit: an observational study of university hospital costs associated with medical service use, length of stay and psychiatric intervention. J Psychosomat Res. 2010;68:295-302. 42. Shaw RJ, DeMaso DR. Somatoform disorder. In: Shaw RJ, DeMaso DR eds. Clinical Manual of Pediatric Psychosomatic Medicine. American Psychiatric Publishing; 2006:143-168.

CHAPTER

138

Agitation Colleen A. Ryan and Michael L. Trieu

BACKGROUND Episodes of acute agitation in children and adolescents can range from a state of unrest and anxiety with low frustration tolerance to a state of fear, anger, and/or pain expressed through verbal or physical aggression. An episode of agitation can pose a significant safety risk to the agitated youth, nearby patients, family members, and hospital staff. Thus identifying an episode of acute agitation at its earliest stage is desirable. There are nonpharmacological and pharmacological interventions that can be used to reduce agitation. If there is imminent risk of harm to self and/or others, and there is no less restrictive intervention available to prevent or interrupt harm, medication and/or physical restraints are indicated. This chapter discusses the assessment, management, and prevention of acute agitation in the pediatric population.

ETIOLOGY Agitation and aggression can have biological and/or psychosocial contributors. Accordingly, a thorough clinical evaluation in the context of both a medical and social history, and treatment of identified contributing factors, is required for all agitated patients.1 Risk factors for acute agitation include a recent history of agitation, impaired cognitive functioning/brain injury, delirium, recent psychosocial stressors and loss, substance use/withdrawal, specific medication side effects (psychotropic medications, steroids, etc.), a prior history of violence or assault as a victim and/or perpetrator, a prior history of physical restraint, acute medical illness, pain, worsening of a chronic medical condition, and

various psychiatric and developmental disorders (Figure 138-1). Agitation can occur in multiple psychiatric conditions, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), bipolar disorder, autism spectrum disorders, agitated unipolar depression, impulse control disorders, disruptive behavior disorders, childhood psychosis, and developmental disorders. Agitation is not a marker for a specific diagnosis; rather, agitation manifests across multiple psychiatric disorders and is often indicative of illness severity. It is unclear whether agitation is the same across psychiatric disorders in quality, cause, and treatment response.2

FIGURE 138-1. Risk identification algorithm.

Multiple studies support the characterization of two subtypes of aggression: impulsive aggression (IA) and planned aggression (PA). Epidemiological research shows differences between IA and PA in both antecedent events and developmental trajectories (IA is associated with poor peer relationships, inadequate problem-solving skills, and a history of physical abuse; PA is associated with aggressive role models who positively value violent behavior). Animal studies indicate that IA and PA are linked to different patterns of brain activation.2 The orbitofrontal cortex, medial prefrontal cortex, hypothalamus, and amygdala are proposed brain systems involved in the modulation of aggression and impulsivity. Behavioral and pharmacological interventions can be effective in reducing aggressive behavior, regardless of subtype, although IA is often more amenable to pharmacological interventions.3 Much of the information presented in this chapter relates to the impulsive subtype of aggression, which is referred to as acute agitation.

CLINICAL PRESENTATION Agitation consists of a psychological state (anxiety, anger, etc.) and a motoric state (excessive motor activity, restlessness, etc.). Agitation can develop through a series of stages, with each stage characterized by a certain psychological and motoric state. Initial agitation may present as anxiety, noted by an increase or change of behavior, such as rocking, crying, pacing, minimal eye contact, tense posturing, excessive worry, and ruminative fear. Anxiety may evolve into a state of defensiveness, oppositionality, verbal intimidation, and aggressive posturing. At this stage, the patient often challenges limits and authority, refuses initial attempts at redirection, makes excessive and unrealistic demands, uses inappropriate language, and begins to loose rational control. With further escalation, the agitated patient may act out through physical assaultiveness, property destruction, and self-injury. Aggression is defined as behavior that has the potential (and often the intention) to damage an inanimate object or harm a living being.4 As noted above, aggression has been divided into two subtypes. IA is unplanned, overt, and often reactive aggression in which the aggressor perceives the outcome of the aggressive act as negative with negative accompanying emotions, such as guilt, regret, and fear. PA is covert, often deliberate, “predatory” or

instrumental aggression in which the aggressor perceives the outcome of the aggressive act as positive, with positive accompanying emotions such as heightened interest, satisfaction, and happiness.2

DIFFERENTIAL DIAGNOSES Youth with aggressive behaviors require systemic diagnostic evaluation and thorough review of medical, family, social, and psychiatric history. Agitation may present in many types of central nervous system (CNS) disorders, including epilepsy (particularly temporal lobe seizures), delirium/encephalopathy, brain injury, and CNS infections and tumors. Certain endocrinologic diseases, including diabetes and hyperthyroidism, are also associated with aggressive behavior. Substance intoxication and withdrawal, and side effects of certain medications, including corticosteroids, antihistamines, benzodiazepines, antidepressants, and antipsychotics, can induce episodes of agitation. Pain can precipitate agitation in children and adolescents.5 As previously discussed, aggression is a common phenotype in multiple psychiatric disorders. Aggression is most frequently seen in disruptive behavior disorders, including oppositional defiant disorder (ODD), ADHD, and conduct disorder. In psychiatric disorders, aggression can occur from cognitive and perceptual disturbances, as seen in psychotic and autism spectrum disorders, and mental retardation; from affective states, witnessed in mania and mixed bipolar disorder, unipolar depression, trauma disorders, and ADHD; and from premeditated aggression to achieve an acquired goal or effect, noted in conduct disorder, narcissistic personality disorder, and antisocial personality disorder.5 Developmental disorders, including mental retardation and autism spectrum disorders, increase risk of agitation in youth. This increased risk is related to primary deficits in planning, impulse control, and affective regulation and secondary factors related to frequent psychiatric comorbidities and increased vulnerability to CNS insults related to metabolic, infectious, and medication side effects, and other organic and iatrogenic causes.

DIAGNOSTIC EVALUATION

For all patient encounters, risk factors for acute agitation should be assessed. If multiple risk factors are identified, especially a history of violence in a similar situational or illness-related context, a preventative behavioral response plan should be devised. A behavioral response plan should identify potential triggers for agitation, effective behavioral interventions, and effects of previous medications on agitation, both effective and adverse. Figure 1381 details a useful assessment checklist for determining agitation risk in a new patient encounter. Aggressive behavior in youth requires a systemic diagnostic evaluation, with in-depth interviews of the patient, family, school personnel, outpatient providers, and probation personnel if present. A psychiatric, medical, relational, behavioral, academic, family, and violence history should be attained, with focus on a detailed description of aggression in terms of duration, frequency, predictability, and severity of symptoms. A journal of aggressive events, describing the antecedents and consequences of each episode of agitation, is often useful. Although this evaluation may be too comprehensive for the acute medical setting, it may be required for full understanding and treatment of aggression and agitation. When evaluating an acutely agitated patient, the severity of agitation should be assessed immediately (Figure 138-2). One can classify the level of agitation as mild, moderate, or severe. Mild agitation can be defined as the patient experiencing excessive worries/fears, the patient responding to calming interventions, the clinician feeling in control, and the patient agreeing to take medication as indicated. Moderate agitation can be defined as the patient expressing verbal aggression, the patient not responding to deescalation interventions, the clinician feeling worried, and the patient agreeing to take medication. Severe agitation can be defined as the patient exhibiting physical aggression or engaging in destruction of property, an explosive situation, the clinician feeling alarmed, imminent danger to self/others is present, and the patient refusing medication. Patient factors must be considered, such as the presence of a psychiatric and/or medical diagnosis, history of agitated episodes, likelihood of substance abuse/ingestion, recent medication history, and recent diagnostic tests (labs, electrocardiogram [ECG], etc.). Additionally, scales, such as the Modified Overt Aggression Scale, have been found to be useful in assessing and monitoring the frequency, severity, change, and character of agitated episodes.2

FIGURE 138-2. Agitation severity determination and agitation management algorithm.

MANAGEMENT There are nonpharmacological de-escalation techniques (Figure 138-3) that should be implemented in all agitation events. A conscious effort should be made to not take anger personally when assessing a child or adolescent who is acutely agitated, regardless of the nature of their behavior. Clearly

introducing oneself to the patient is important. Use simple, unambiguous language, in a soft, calm voice, with slow motor movements, when attempting to explain the steps of de-escalation and treatment. Depending on the situation, it may be best not to speak directly to the agitated patient, but rather to their parent or family member. At times, it is useful for the clinician to recruit trusted and calming family members into the process of deescalation. With some patients, decreased external stimuli is most helpful, and not speaking at all in the presence of the patient is indicated. Reassuring the child and/or parent that the goal is to keep him/her safe is important. Explaining the treatment plan to the child and how the team may be able to honor his/her reasonable requests may be indicated. Making an effort to understand the child’s goals and linking cooperation with safety planning to these goals is often helpful. Offering food or drink can be a very useful calming intervention. Reducing environmental stimulation (e.g. reduce lighting and number of people) is usually very helpful. Increasing environmental safety is important by removal of access to breakable objects and equipment. Attempting to find things for the child to control by offering distracting toys, ordering meals, and/or using sensory modalities is also important. Patients experiencing/who have experienced acute agitation ideally should be moved to a single room.

FIGURE 138-3. Common de-escalation techniques. When de-escalation techniques are unsuccessful or inappropriate due to level of risk of harm to self and others, medication and physical restraints are

warranted (though as last resort) to protect the patient and others (Figure 1382). Medication restraint is defined as the one-time administration of medication, either by mouth or injection, to calm an agitated patient in an emergent situation. Medication restraint is not the first-line default treatment for agitation; rather, medication is utilized with the intent to control a patient’s behavior and/or limit freedom of movement due to imminent danger to self and/or others which may result in severe injury and/or death without intervention. Medication restraint is a deviation from the patient’s existing treatment plan and can be involuntary. A medication that is used as part of the patient’s existing medical or psychiatric treatment and is administered within the standard dose indicated for that patient’s condition is not considered restraint. Medication restraint should not be used for staff convenience or as a method of discipline or retaliation. It is to be administered by trained staff following guidelines set forth by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) standards.1 Classes of medication to be considered in the treatment of acute pediatric agitation include α-agonists, antihistamines, benzodiazepines, and antipsychotics. Patients should be given the option of taking oral medication first and should only be given medication intramuscularly (IM) or intravenous (IV) if necessary and clinically warranted (such as patients with severe agitation, dangerousness to self and others, oral medication refusal, delirium, impaired level of consciousness, etc.). Antipsychotic medications are recommended for use in the management of moderate to severe agitation. Haloperidol, risperidone, and olanzapine are the recommended medications for use in a treatment-naïve pediatric patient experiencing severe agitation. An advantage of haloperidol is that it can be given IV, though this type of dosing is associated with an increased risk of QTc prolongation and should be administered only in an intensive care unit (ICU) setting with ECG monitoring. Risperidone can be administered in oral tablet, liquid, and oral disintegrating tablet (ODT) preparations; olanzapine is available in oral, ODT, and IM forms. The advantage of olanzapine and risperidone is that they have a more favorable short-term side effect profile than haloperidol. Important to note is that children and adolescents are more susceptible than the general population to neuroleptic malignant syndrome and extrapyramidal symptoms.6 Medication choice should not default to the

clinician’s familiarity, but rather be based on individual characteristics of the patient, any previous history of antipsychotic use or neuroleptic malignant syndrome, and review of the risks and benefits of a particular agent.7 Diphenhydramine can be administered with an antipsychotic medication to prevent/treat extrapyramidal symptoms and/or acute dystonias, although it should be used with caution. The most common side effects of diphenhydramine are anticholinergic side effects such as dry mouth, dizziness, constipation, urinary retention, dry skin, flushing, and exacerbation of reactive airway disease. In addition, it can cause a paradoxical reaction, manifesting in increased agitation and disinhibition. Benzodiazepines (e.g. lorazepam) are commonly used to manage acute agitation. The main side effects are sedation and respiratory depression. Paradoxical reactions similar to ones observed with antihistamines are quite common in children and other special populations. One should be especially cautious in giving this medication to children with autism spectrum or pervasive developmental disorders, developmental delay, learning disorders, or other neurological disorders. Due to high frequency of paradoxical responses, patients and parents/guardians should be asked about any previous treatments with antihistamines and benzodiazepines. If a primary anxiety disorder is suspected, one should first utilize a benzodiazepine medication. Clonidine for mild agitation could be considered in patients who are already prescribed this medication and/or in those who carry a diagnosis of disruptive behavior disorder or a developmental disorder. Manual physical restraint is indicated to prevent clear, imminent harm to the patient and others. Manual restraint use minimizes harm done to and by the restrained person, implying that the force of restraint is less injurious to all concerned than the restrained person’s behavior. Manual physical restraint is generally defined as bodily restriction through the use of physical (the physical hold) or mechanical (use of soft leather straps, etc.) holding. It is considered four-point restraint when legs and arms are restricted from movement, five-point when either head or torso is also restricted from movement, and so on. Manual physical restraint should be used for children aged 12 and under, as mechanical holding is contraindicated in this population. Nursing staff may initiate a physical restraint, but a physician must assess the patient in person within 1 hour of restraint initiation. A restraint order lasts only 1 hour. If the patient requires physical restraint for more than 1 hour, the physician must reassess the patient to evaluate the need

for continued restraint. It is important for physicians to examine the restrained patient, not only to minimize restraint use (as physical restraints can be uncomfortable and shameful to the patient) but also to ensure the patient’s physical wellbeing. Restraint-related deaths, especially in the prone position, are rare but have occurred, again emphasizing the use of physical restraint only as a method of last resort. A psychiatric “code” should be designed to alert a hospital behavioral response team to a psychiatric emergency. A group of clinicians (ideally mental health specialists) familiar with the management of acute agitation should be the designated behavioral response team, or psychiatric “code team.” When an episode of acute agitation occurs on the medical floor or emergency department, this behavioral response team is notified and should respond promptly and effectively to the psychiatric crisis.

EPISODE CRITERIA An episode of agitation has ended when the patient demonstrates a decrease in physical and emotional energy and has regained rational control. This reduction in energy is noted by a decrease in restlessness, agitation, and verbal and physical aggression. The patient may begin to apologize, cry, request space, attempt to rest or sleep, or engage in a nonthreatening activity. The de-escalated patient shows the increasing ability to re-establish communication with staff and others. The de-escalated patient is considered calm and cooperative. Sedation should not be the desired endpoint for an episode of pediatric agitation. Following resolution of an episode of agitation, it is recommended that the physicians and staff involved in the episode review the event through an event debrief. Identifying risk factors, precipitating events, triggers, helpful and unhelpful interventions, and episode duration and quality, is indicated. The responsible physician should document an updated assessment of the patient, including vital signs, extrapyramidal side effects or other medication side effects if medications were used, physical injuries, ECG, and other interventions as necessary. A revised treatment plan should reflect identified triggers, pharmacological and behavioral interventions, preventative measures, and other information gathered from the event debrief. Nursing staff are also encouraged to document their review of the event and add to the patient’s plan of care the goal to eliminate restraint use (if restraints have

been utilized).

CONSULTATION For all pediatric patients seen in an emergency department or admitted to the hospital, an evaluation of risk factors for agitation is recommended. Psychiatry consultation services, if available, are recommended for all patients with who have experienced moderate or severe agitation, especially if medication or physical restraint was utilized. Addressing any potential worries regarding an existing medical condition and clarifying the treatment plan for that condition is recommended. There should be a development of a preventative behavioral and pharmacological response plan if multiple risk factors are present or events warrant further intervention. Psychiatry consultation services or a behavioral specialist can assist in the creation of a response plan. It is important to utilize any available supports such as family members, child life services, sensory interventions with occupational therapist input. The use of a behavioral response team to psychiatric crises or “code” is also recommended, as mentioned above.

SPECIAL CONSIDERATIONS PHARMACOLOGIC CONSIDERATIONS Once medication for acute agitation is administered to a patient, it is recommended that they be assessed at least every 15 minutes until the episode of agitation has ended. Assessment of the patient’s mental status and vital signs is recommended, along with monitoring the development of extrapyramidal side effects (e.g. akathisia, dystonic reactions) and respiratory depression. The clinician must be aware of the rare, but previously reported, serious adverse side effect of neuroleptic malignant syndrome (cardinal features of tachycardia, fever, elevated white blood cell count and creatine kinase, confusion) and monitor youth, particularly males, with psychosis and females with affective disorders, treated with antipsychotics. Of those pediatric cases of neuroleptic malignant symptoms that have been reported, deaths and permanent medical sequelae have been associated with firstgeneration (typical) antipsychotics but not with second-generation (atypical) antipsychotics.8 When clinically appropriate, obtain an ECG to assess QT

interval, as antipsychotics may prolong QTc interval. Pediatric patients experiencing acute agitation should be offered the choice of taking medication by mouth for all levels of agitation. Medication considerations to take orally for acute agitation include lorazepam, risperidone, haloperidol, and clonidine, all of which are available in an oral liquid form (Figure 138-2). Both first- and second-generation antipsychotics have evidence supporting their utilization for acute agitation. To date, neither type has been proven superior to the other. However, each medication has its own individual side effects, which should be considered for each patient. It should be noted that the pediatric population is more at risk than the general population for developing extrapyramidal symptoms, acute dystonic reactions, and neuroleptic malignant syndrome, and thus symptoms of these should be monitored carefully.6 Medications utilized for acute situations are ideally ordered after obtaining parental (or legal guardian) permission; however, in an emergency situation antipsychotics for acute agitation may be administered without parental (or legal guardian) consent when there is imminent danger to self and/or others. KEY POINTS Acute agitation in children and adolescents is a pediatric emergency which should be assessed and managed immediately. This should include obtaining psychiatric consultation (if available) and calling a hospital psychiatric code if danger to the patient or others is imminent. Behavioral and pharmacologic interventions are available to manage and reduce episodes of agitation. There are no published investigation trials comparing various medication options for treatment of agitation in children and adolescent population but there is evidence to support the use of certain classes of medications to manage acute agitation. Goals of treatment for pediatric agitation with medication are to promote safety for the patient, providers, and environment, and to help the patient achieve a state of calmness.

REFERENCES 1. Sonnier L, Barztnan D. Pharmacologic management of acutely agitated pediatric patients. Pediatr Drugs. 2011;13(1):1-10. 2. Jensen PS, Youngstrom EA, Steiner H, et al. Consensus report on impulsive aggression as a symptom across diagnostic categories in child psychiatry: implications for medication studies. J Am Acad Child Adolesc Psychiatry. 2007;46(3):309-322. 3. Anderson SL. Neurobiology of aggression and impulsivity. Presented at Boston Children’s Hospital Psychopharmacology Seminar, December 3, 2010; Boston, MA. 4. Schur SB, Sikich L, Findling RL, et al. Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY): part I a review. J Am Acad Child Adolesc Psychiatry. 2003;42(2):132-144. 5. Turgay A. Aggression and disruptive behavior disorders in children and adolescents. Exp Rev Neurotherapeut. 2004;4(4):623-632. 6. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008;47(1):9-20. 7. Hilt RJ, Woodward TA. Agitation treatment for pediatric emergency patients. J Am Acad Child Adolesc Psychiatry. 2008;47(2):132-138. 8. Neuhut R, Lindenmayer JP, Silva R. Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol. 2009;19(4):415-422.

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139

New-Onset Psychosis Georgina Garcia

BACKGROUND Psychosis is a cluster of symptoms used to define specific psychiatric disorders. Psychotic symptoms include hallucinations, delusions, or disorganization of thoughts and behavior. Children, adolescents, and adults can present with these symptoms in the context of depression, bipolar disorder, schizophrenia, substance use/abuse, delirium, and post-traumatic stress disorder (PTSD). Few studies have examined hallucination and delusion phenomenology in children, thereby making diagnosis and prevalence difficult to assess. Schizophrenia is estimated to impact 1% of the population, with a peak onset in late adolescence.1 Early-onset schizophrenia (EOS), before 18 years of age, is rare and is estimated to occur in less than 4% of all cases of schizophrenia, and has a poor prognosis.2,3 Psychotic symptoms can also be present in other mood disorders in children and adolescents. According to the National Comorbidity Survey Replication-Adolescent Supplement, the lifetime prevalence of mood disorders in adolescents is 14.3%.4 It is estimated that 20% of pediatric patients diagnosed with bipolar type I will have symptoms of psychosis during a mood episode.5 Regardless of the psychiatric diagnosis, hallucinations and delusions are present within the general population and appear to be associated with worse health function, higher incidence of depression, and higher likelihood of diagnosis and treatment for a psychiatric disorder.6

CLINICAL PRESENTATION Children with psychosis may present with cognitive abnormalities, emotional

difficulties, and changes in social functioning (Table 139-1).3 Studies indicate that premorbid social and emotional function is lower in patients who later on develop schizophrenia or schizoaffective disorder as opposed to mood disorders with psychotic features.7 In children and adolescents there is often a prodromal period during which there is a decline in social, emotional, and academic function that predates the onset of psychosis by a period of weeks to months. Changes in social functioning due to new-onset psychosis may present with disruptive behaviors, social withdrawal, or difficulties with peer relationships. TABLE 139-1

Symptoms Associated with Psychosis

Symptom

Clinical Presentations

Delusions

Fixed false belief without supporting evidence • Paranoid delusions • Delusions of reference • Somatic delusions • Delusions of grandeur

Hallucinations

Sensory perception in the absence of a stimulus (e.g. visual, auditory, tactile, olfactory, gustatory)

Disorganized Looseness of associations, “word salad,” clanging, speech/thinking echolalia, neologisms Disorganized or catatonic behavior

Motor disharmony, bizarre postures, stereotypies, stupor, extreme rigidity, negative symptoms, waxy flexibility

Negative symptoms

Alogia, avolition, affective flattening

Cognitive manifestations of psychosis include distortions of thoughts to the extent of hallucinations or delusions. Hallucinations are false sensory perceptions in the absence of evidence of stimuli. In children, hallucinations are most frequently auditory in nature.3 David et al. reported the following

rates of hallucinations in childhood schizophrenia: auditory (95%), visual (80%), olfactory (30%), and somatosensory/tactile (61%).8 Delusions represent distorted or fixed beliefs held by the person that are not substantiated by evidence. Delusions can be impacted by the patient’s interpretation of their environment as well as their cultural and religious beliefs. Systematized delusions (e.g. persecution) are rare in children less than 12 years of age and become more common in the adolescent period.3 Patients presenting with new-onset psychosis can also present with alterations in their mood. Children can present as irritable, angry, or elevated (e.g. mania with psychosis). Negative symptoms may be present such as apathy, flat/blunted affect, and paucity of speech. Mood symptoms may change rapidly for patients and manifest in mood-congruent or -incongruent hallucinations or delusions. For example, a patient with a depressed mood may have mood-congruent hallucinations of voices speaking in a derogatory way about him/her, while having delusions of persecution by peers. Speech and language may also be impacted by an altered cognitive state. In addition to hallucinations and delusions, patients with psychosis may respond to questions in a disorganized or nonsensical fashion. At times their dialogue may include perseveration on topics, neologisms, or stereotypies (e.g. echolalia, clanging). Behaviors may be congruent with the thought processes and patients may exhibit a regression of behaviors, bizarre behaviors, and other motoric disturbances. Patients may exhibit compulsions that are in response to hallucinations or delusions (e.g. checking behaviors). Catatonia represents the most extreme presentation of negative symptoms including mutism, immobility, and avolition. Classical catatonia represents severe bradykinesia with unusual properties such as waxy flexibility and stereotypies of the hand or other parts of the body. Conversely, agitated catatonia can present with extreme psychomotor agitation without identified purpose of their actions.

DIFFERENTIAL DIAGNOSIS Psychosis can present differently based on a combination of factors including the etiology as well as the developmental stage that the child is in. Early childhood psychosis is a very rare disorder, making it important to rule out any medical or toxic causes of mental status changes with psychosis (Table

139-2). Children should be assessed for seizures, delirium, central nervous system lesions (e.g. tumors), neurodegenerative disorders (e.g. Rett syndrome), infectious diseases (e.g. bacterial or viral meningitis), or ingestion or exposure to toxins (e.g. medications, household chemicals). TABLE 139-2

Abbreviated List of Medical Causes of Mental Status Changes with Psychosis Causes of Mental Status Changes +/Psychotic Features

Central nervous system

Epilepsy Hydrocephalus Lesions Intracranial tumors Huntington disease Dementia

Nutritional

Malnourishment Pellagra (vitamin B3 deficiency) Pernicious anemia (vitamin B12 deficiency) Thiamine

Endocrine

Adrenocortical insufficiency (Addison disease) Adrenocortical excess (Cushing syndrome) Hyperparathyroidism Hyperthyroidism Diabetes

Metabolic

Hypoxia Porphyrias Homocystinuria Hepatolenticular degeneration (Wilson disease) Hartnup disease

Electrolyte imbalances Hepatic or renal failure Infectious

Cerebral cysts or abscesses Encephalitis Neurosyphilis HIV encephalopathy Infection/sepsis

Autoimmune Anti-NMDA receptor encephalitis Rheumatic fever Addison disease Multiple sclerosis Systemic lupus erythematosis Vascular

Myocardial infarction Sagittal vein thrombosis Subarachnoid hemorrhage Hypertensive crisis

Toxins

Arsenic, bismuth, bromine, carbon monoxide, copper, lead, magnesium, manganese, mercury, thallium, pesticides

Drugs

Drugs of abuse: alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, opioids, sedatives (in use and withdrawal states) Therapeutic drugs: almost all classes

Providers should complete a careful medical review of organ systems of the patient to assist in identifying reversible causes of mental status changes. Patients with recent infections, surgeries, or medication changes would be at an increased risk for delirium. Delirium is the diagnosis for anyone who is suffering from a reversible toxic or metabolic derangement that is impacting a person’s mental status. Children suffering from delirium may present with

social and emotional regression, withdrawal, mood symptoms (e.g. anxiety, depression), hallucinations, delusions, and sensory misperceptions. Ten percent of children referred to pediatric consultation services for evaluation are eventually diagnosed with delirium due to the significant symptom overlap between psychotic disorders and delirium.9 Providers should be cautious when assessing any patient with a sudden onset of mental status changes under these circumstances. The hallmark of delirium is the waxing and waning of consciousness and cognition throughout the day. Psychotic symptoms also wax and wane in delirium, which generally is not the case in schizophrenia or mood disorders. Carefully identifying and understanding the onset of symptoms is useful in the diagnosis of new-onset psychosis. More acute onset of symptoms suggests a possible physical insult to the body or nervous system. Concurrent physiologic findings (e.g. fever, hypertension) also suggest physical etiologies. An insidious onset may be more consistent with a psychiatric diagnosis. There is a prodromal period associated with schizophrenia that is characterized by a reduction in functioning across social domains. Concurrent or premorbid mood symptoms may help differentiate mood disorder with psychotic features from schizophrenia. Hallucinations are reported frequently in the pediatric population even in the absence of a psychiatric diagnosis.8 Children at different developmental stages can present with hyperactivity, aggression, tearfulness, or regression in response to internal stimulation. There should be a careful assessment of a child’s level of social, emotional, and language function prior to the onset of symptoms prior to any diagnosis. Children with impaired receptive or expressive language or social capacity can present with disruptive and/or bizarre behavior in an effort to express their wishes or desires. These behaviors can easily be misinterpreted as signs of a psychotic disorder. For example, children with autism spectrum disorder with concrete thinking and limited expressive abilities may make statements that seem delusional or psychotic when observed out of context from their baseline level of functioning. Comorbid anxiety disorders can also mask or exacerbate behaviors (e.g. obsessive compulsive disorder) in a way that appear psychotic when reviewed in isolation. For these reasons, a careful assessment should include comorbid Axis I diagnoses, developmental stage, and social/emotional capacity.

DIAGNOSIS AND EVALUATION At this time, there is no definitive diagnostic test or laboratory analysis for psychosis. The purpose of a complete physical exam and diagnostic tests is to assess for any medical causes of psychotic symptoms and/or exacerbating factors (e.g. depression with superimposed delirium). Practitioners should initially complete a thorough history and physical examination of the patient. The exam should include a neurologic assessment or neurology consultation to rule out any organic etiologies. Any physical changes or medication changes should carefully be reviewed for their possible contribution to the patient’s presentation. A urine toxicology screening is crucial for the assessment of any intentional or accidental exposure or ingestion of a toxic substance. Some substances are often not included in standard toxicology screens such as amphetamine salt compounds, inhalants, synthetic marijuana, prescription opioids, and hallucinogens (e.g. phencyclidine [PCP]). If any of these substances are suspected, providers should request that additional toxicology panels be ordered. Additional medical testing may include electrolytes, complete blood counts, thyroid function tests, ceruloplasmin, erythrocyte sedimentation rate, renal function, liver function, antinuclear factor antibodies, and a pregnancy test. Neuroimaging may be useful to rule out any intracranial tumors or lesions. Although children with the first onset of psychosis have been shown to have loss of grey matter in the frontal lobes and enlarged ventricles, these findings are hard to generalize into clinical practice.10 Similarly, a lumbar puncture may be indicated to assess for changes in cerebral spinal fluid (CSF) pressure or signs of an infection. Recently there has been the identification of an autoimmune disorder called anti-NMDA receptor encephalitis, which can present as a sudden onset of mental status changes with psychosis in youth.11 If there is a suspicion of anti-NMDA receptor encephalitis, providers should consider sending off either blood or CSF for analysis of anti-NMDA receptor antibodies. Although there have been advancements in genetics, there is limited clinical usefulness in the addition of any genetic testing in assisting with the diagnosis of psychosis unless there is concern for a genetic disorder with psychotic features (e.g. Huntington disease). Clinicians should assess the rationale for genetic studies on a case-by-case basis.

RISK FACTORS Patients and their past history should be carefully reviewed for any risk factors that would make them more susceptible to psychosis. In addition to a family history of psychiatric disorders, several environmental exposures have been identified as risk factors associated with the development of schizophrenia. A patient’s prenatal and perinatal history should be reviewed carefully, as obstetric complications (e.g. maternal hypertension, prenatal exposure to analgesics, or maternal–fetal blood incompatibility), prenatal nutrition, and prenatal maternal stress have been found to increase the odds of developing schizophrenia.12 Patients with premorbid neurological disorders should also be assessed carefully, as they may pose an increased risk for schizophrenia. One metaanalysis in patients with epilepsy found a prevalence rate of 1.3% in patients with schizophrenia.12 Acquired brain injury (ABI) has also been indicated in the development of psychotic disorders. It has been hypothesized that antiNMDA receptor encephalitis may also be a risk factor for schizophrenia, as its initial presentation can include seizures, dyskinesias, and catatonia.12 Patients with autism have symptoms of social withdrawal (e.g. isolation, mutism), risk for catatonia, seizures, and disorganized thinking or behavior and have been explored as a population that may have an increased risk for psychotic disorders.13 Childhood adversity and trauma have also been identified as possibly playing a role in the development of schizophrenia and psychotic symptoms.12,14,15 It is very important to assess for trauma to include sexual trauma, physical trauma, emotional trauma (e.g. bullying), physical abuse, emotional abuse, neglect, or exposure to domestic violence. These factors appear to work synergistically to increase the risk for schizophrenia.12 In assessing adolescents with new onset of psychosis, it is imperative to review their substance use history. One meta-analysis review reported that cannabis users have a 2- to 2.9-fold increase in risk of developing schizophrenia.16 It appears that cannabis use confers a vulnerability to psychotic disorders that is mediated by both the duration and the amount used by the individual. It is estimated that between 8% and 15% of all schizophrenia can be attributed to cannabis use.17,18

MANAGEMENT Psychosis is a rare and complex disorder. Patients presenting with symptoms of psychosis in a medical setting are often experiencing extreme positive or negative symptoms. Urgent management of these patients most often occurs when patients are experiencing significant positive symptoms such as auditory hallucinations, delusions, or disorganization. Depending on the content and severity of the hallucinations or delusions, patients can present as confused, agitated, aggressive, or threatening. Patients presenting with extreme negative symptoms may present with withdrawal, psychomotor retardation, and flattening of affect. The decision to initiate medication is based on the risk-versus-benefit assessment of the clinician. Patients at an imminent risk of harming themselves or others without intervention should be considered for acute medication management. Patients who appear to be worsening or progressing with their cognitive decline may also be considered for initiating treatment. Initiating psychotropic medication should take into account multiple factors including the patient’s past medical history, allergies to medications, prior trials of psychotropic medications (e.g. antihistamines, benzodiazepines), and other risk factors for side effects. Antipsychotics are the first line of medications for the treatment of schizophrenia in children (Table 139-3).19,20 Patients should be carefully assessed for any cardiac conditions or movement disorders prior to initiation of medications. If possible, it is recommended that at a minimum an electrocardiogram be done or a past one reviewed prior to initiation of an antipsychotic due to the risk of prolongation of the Qtc interval. A patient who has had paradoxical responses to either antihistamines or benzodiazepines should be given alternative medications to calm him/her down. TABLE 139-3

First- and Second-Generation Antipsychotics in Children and Adolescents Medication

FDA approved

Indication(s) Children

Firstgeneration

Haloperidol

≥4 yrs

Schizophrenia Tourette syndrome Behavioral problems

Perphenazine

≥12 yrs

Schizophrenia

Chlorpromazine ≥12 yrs

Schizophrenia, bipolar, behavioral problems Schizophrenia

Loxapine

≥12 yrs

Schizophrenia

Thioridazine

≥12 yrs

Schizophrenia

Thiothixene

≥12 yrs

Agitation

Droperidol

≥2 yrs

Tourette syndrome

Pimozide

≥12 yrs

Fluphenazine Molindone* Secondgeneration

Risperidone

Olanzapine

Adolescents 13–17 yrs

Schizophrenia

Adolescents 10–17 yrs

Bipolar

Children 5–16 yrs

Irritability w/autism

Adolescents

Schizophrenia,

Quetiapine

Aripiprazole

13–17 yrs

bipolar

Adolescents 13–17 yrs

Schizophrenia

Adolescents 10–17 yrs

Bipolar

Adolescents 13–17 yrs

Schizophrenia

Adolescents 10–17 yrs

Bipolar

Ziprasidone Asenapine Paliperidone Clozapine Iloperidone *Molindone is no longer available in the United States.

In addition to the medical and psychiatric factors listed above, providers should take into consideration the route of administration of medications. Patients who are acutely agitated and will not take tablets by mouth may require an injectable medication. Many first-generation (typical) and secondgeneration (atypical) medications come in the injectable form and may be considered for use. Unfortunately, due to the limited use of first-generation antipsychotics, most are not easily available in hospital formularies, so providers will have to identify what medications are available. Of the typical medications, haloperidol is the most commonly available antipsychotic. Olanzapine and ziprasidone are the only atypical medications available in the intramuscular formulation. Ziprasidone may not be a first choice because it has been found to be ineffective in a double-blind placebo controlled trial in children with schizophrenia.19 Ziprasidone may also be avoided due to the finding of prolonged Qtc in several trials.21 Risperidone and olanzapine are both available in an orally disintegrating tablet that can be used when a

patient is able to cooperate with administration of the medication. Patients should be carefully monitored for the development of side effects and treated appropriately (Table 139-4). Some of the most acute side effects are those related to the extrapyramidal system. In the acute phase, patients can present with acute dystonias, torticollis, or oculogyric crisis. Subacutely, patients can present with akathesia, restlessness, or bradykinesia. Chronic use of antipsychotics can cause tardive dyskinesias, involuntary repetitive movements usually involving the small muscles of the face. Neuroleptic malignant syndrome (NMS) can also occur in rare instances and presents with fever, autonomic dysregulation, and muscle rigidity after administration of an antipsychotic. Patients can be administered benztropine or diphenhydramine concurrently with antipsychotics to reduce the risk of extrapyramidal symptoms. TABLE 139-4

Side Effect

Significant Side Effects Associated with Antipsychotic Use Clinical Presentation

Treatment and Management

Extrapyramidal Dystonia side effects Akathesia Tardive dyskinesia Bradykinesia/drug induced Parkinsonism

Antihistamines (Diphenhydramine, benztropine) Benzodiazepines Amantadine Propranolol Naloxone Switching antipsychotic agents

Neuroleptic malignant syndrome

Symptom management (cooling blankets, antiypretics, fluids) Medications (dantrolene, amantadine, bromocriptine)

Muscle rigidity Autonomic dysregulation Fever Mental status

changes Elevated creatine phosphokinase (CPK)

Electroconvulsive therapy

Cardiac abnormalities

QTc prolongation* Torsades de pointes

Discontinuation/or reduction of antipsychotic

Metabolic syndrome

Obesity Glucose metabolism impairment Dyslipidemia

Weight loss/management Metformin Discontinuation or switching antipsychotics

*Black box warning for sudden cardiac death.

Patients should also be monitored at initiation of antipsychotic use to assess for any cardiac abnormalities. Specifically, patients should be assessed for any history of syncope, cardiac disease, and family history of cardiac disease or sudden cardiac death. Patients initiating antipsychotic treatment should have a baseline electrocardiogram to assess for any prolongation of the Qtc interval. Antipsychotic use has been associated with difficulties in ventricular repolarization resulting in Qtc prolongation and potential for causing torsades de pointes. There is an increased risk of Qtc prolongation with dose escalation as well as with IV administration of haloperidol.22 After initiation, patients should be monitored, taking into consideration any concurrent medical factors impacting Qtc interval (e.g. electrolyte imbalances, concurrent serotonin reuptake inhibitor administration, or Qtc prolonging medications). Although metabolic abnormalities generally take a period of time to manifest themselves, it is important to take medication side effect profile into consideration, as the course of schizophrenia is chronic and often unremitting. Metabolic syndrome is defined as abnormalities in lipid profile, weight gain, and insulin regulation associated with antipsychotic use. At this time, there is no clear mechanism identified that causes the constellation of symptoms associated with metabolic syndrome, but it is clear from multiple

studies in children that there are differential effects of different medications.23,24 Olanzapine is the one medication that in multiple studies has been associated with more negative effects on weight, lipids, and glucose tolerance and is often avoided in the pediatric population as a maintenance medication.24-26 Additional common side effects of antipsychotics include sedation, insomnia, orthostatic hypotension, rash, and sialorrhea. Patients should also be monitored for blood dyscrasias and hepatic injury, especially if initiated on clozapine. Due to the myriad of side effects, care should be given to provide psychoeducation throughout the treatment process to parents, who may be overwhelmed and have difficulties comprehending the disease and the medications their children may be treated with.

CONSULTATION When feasible, all patients admitted to a medical facility identified as having a new-onset or ongoing psychiatric disorder should be referred for a psychiatric consultation. Many institutions have psychiatric consultation services that may consist of psychologists and psychiatrists. Ideally, the patient should be seen with a provider with a background in pediatric psychology/psychiatry. The consultation can assist in the diagnostic assessment of the patient by clarifying the patient’s premorbid psychological and social functioning as well as current level of functioning. Consultants can assist with management if the patient is at risk of harm to themselves or others due to their level of disorganization or psychosis. This may include acute psychotropic management of agitation using antipsychotics, benzodiazepines, or antihistamines. Consultants can provide support and guidance to the medical staff, child life specialist, and nurses caring for the patient. Recommendations made for the patient may include a structured day with a schedule of activities, 1:1 supervision for safety or observation, physical therapy for assistance with resolving dystonias or catatonia, and the teaching of distraction or relaxation techniques. In the instance of a new onset of psychosis, the consultation team may provide valuable psychoeducation for the family and patient. This could include information about the diagnostic impressions, types of behavioral and

medication treatment, and levels of care (e.g. outpatient, partial hospitalization, and inpatient hospitalization). The consultant can provide referrals for the required levels of psychiatric care for the patient. Depending on the structure of the institution, the consulting team may collaborate with the social work team to provide ongoing social and emotional support for the family throughout this process.

ADMISSION CRITERIA Patients for whom there is a concern for psychosis should be medically admitted initially to complete any relevant diagnostic tests and to rule out any medical or toxic causes of their mental status changes. During this time they should be carefully observed in the hospital for any changes due to a general medical condition or intoxication. If there is concern about trauma or abuse, the admission would allow providers to observe the patient out of his/her home environment. Once a complete medical workup has been completed, if the patient’s mental status remains the same and there is a high suspicion of an ongoing psychiatric process he/she should be considered for an inpatient psychiatric hospitalization. Appropriate reasons for an inpatient admission include new onset of psychotic disorder, diagnostic assessment and clarification, initiation of behavioral treatment, initiation or adjustment of psychotropic medication, inability to care for self (e.g. poor intake), or at risk to self or others (e.g. suicidal or homicidal ideation).

DISCHARGE CRITERIA Patients who are considered medically stable may be considered medically cleared for discharge to further psychiatric care. If there is a concern about the patient’s ability to care for himself/herself due to poor safety awareness, nutritional status, or other medical concerns (e.g. comorbid epilepsy) he/she may require transfer to a facility with both medical and psychiatric capacity. Patients who do not have medical needs but are impaired significantly and require more intense psychiatric treatment(s) may be referred for inpatient psychiatric care. Patients who are functioning close to their baseline but require initiation or intensive daily psychiatric treatment may be referred

to a partial hospitalization. This requires that the patient and family be comfortable with the patient returning home for part of the day and to sleep at night. If over the course of the patient’s medical hospitalization the patient has returned close to or at their baseline mental status, providers may consider discharge to home with supports. This would most likely be feasible in a patient with a longstanding history of psychiatric treatment who already has a therapist and psychiatrist in the community. Providers may also coordinate with additional in-home supports, family therapy, and school-based supports that may allow the patient to return safely to the community.

REFERENCES 1. Vyas NS, Gogtay N. Treatment of early onset schizophrenia: recent trends, challenges and future considerations. Front Psychiatry. 2012;3:29. 2. Pagsberg AK. Schizophrenia spectrum and other psychotic disorders. Eur Child Adolesc Psychiatry. 2013;22(Suppl 1):3-9. 3. Remschmidt H, Theisen F. Early-onset schizophrenia. Neuropsychobiology. 2012;66(1):63-69. 4. Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49(10):980-989. 5. Sala R, Axelson D, Birmaher B. Phenomenology, longitudinal course, and outcome of children and adolescents with bipolar spectrum disorders. Child Adolesc Psychiatric Clin N Am. 2009;18(2):273-289, vii. 6. Nuevo R, Van Os J, Arango C, Chatterji S, Ayuso-Mateos JL. Evidence for the early clinical relevance of hallucinatory-delusional states in the general population. Acta Psychiatr Scand. 2013;127(6):482-493. 7. Tarbox SI, Brown LH, Haas GL. Diagnostic specificity of poor premorbid adjustment: comparison of schizophrenia, schizoaffective disorder, and mood disorder with psychotic features. Schizophr Res.

2012;141(1):91-97. 8. David CN, Greenstein D, Clasen L, et al. Childhood onset schizophrenia: high rate of visual hallucinations. J Am Acad Child Adolesc Psychiatry. 2011;50(7):681-686; e683. 9. Hatherill S, Flisher AJ. Delirium in children and adolescents: a systematic review of the literature. J Psychosomat Res. 2010;68(4):337344. 10. Arango C, et al. Progressive brain changes in children with first-episode psychosis. arch gen psychiatry. 2012;69(1):16-26. 11. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098. 12. Clarke MC, Kelleher I, Clancy M, Cannon M. Predicting risk and the emergence of schizophrenia. Psychiatric Clin N Am. 2012;35(3):585612. 13. Gadow KD. Association of schizophrenia spectrum and autism spectrum disorder (ASD) symptoms in children with ASD and clinic controls. Res Devel Disabil. 2013;34(4):1289-1299. 14. Matheson SL, Shepherd AM, Pinchbeck RM, Laurens KR, Carr VJ. Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol Med. 2013;43(2):225-238. 15. Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophren Bull. 2012;38(4):661-671. 16. Casadio P, Fernandes C, Murray RM, Di Forti M. Cannabis use in young people: the risk for schizophrenia. Neurosci Biobehav Rev. 2011;35(8):1779-1787. 17. Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophren Bull. 2005;31(3):608-612. 18. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-328. 19. Carlisle LL, McClellan J. Psychopharmacology of schizophrenia in

children and adolescents. Pediatr Clin N Am. 2011;58(1):205-218; xii. 20. Kendall T, Hollis C, Stafford M, Taylor C. Recognition and management of psychosis and schizophrenia in children and young people: summary of NICE guidance. BMJ. 2013;346:f150. 21. Garcia G, Logan GE, Gonzalez-Heydrich J. Management of psychotropic medication side effects in children and adolescents. Child Adolesc Psychiatric Clin N Am. 2012;21(4):713-738. 22. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013;54(1):1-13. 23. Maayan L, Correll CU. Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol. 2011;21(6):517-535. 24. Correll CU. Multiple antipsychotic use associated with metabolic and cardiovascular adverse events in children and adolescents. Evid Based Ment Health. 2009;12(3):93. 25. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2012;8(2):114-126. 26. Correll CU. Monitoring and management of antipsychotic-related metabolic and endocrine adverse events in pediatric patients. Int Rev Psychiatry. 2008;20(2):195-201.

SECTION Q Pulmonology

CHAPTER

140

Apparent Life-Threatening Event, Infant Apnea, and Pediatric Obstructive Sleep Apnea Syndrome Craig C. DeWolfe, Angela M. Statile, and Aaron S. Chidekel

BACKGROUND Infants are often brought for urgent or emergent medical assessment owing to abnormal breathing patterns or worrisome respiratory episodes. Often the episode resolves before the patient arrives for initial evaluation and does not recur. However, some infants with respiratory episodes have significant underlying medical conditions or even life-threatening events. Many infants with both types of episodes are hospitalized for monitoring, diagnostic testing, and management despite a stable appearance at presentation, while others are able to be managed as outpatients. There is wide variation in the evaluation and management of these episodes. This chapter addresses presentations suggestive of apparent life-threatening events (ALTEs) and briefly discusses central apnea of neonates and young infants. It also examines pediatric obstructive sleep apnea.

APPARENT LIFE-THREATENING EVENT Apparent life-threatening event (ALTE) refers to a complex set of symptoms that presents unexpectedly in an infant, are of concern to the observer, and cannot be easily characterized by the healthcare provider.1,2 Approximately 1% of infants have an ALTE which prompts admission. The most common age at presentation ranges from 6 to 10 weeks.3-7 Many other events may occur during infancy, yet not be appreciated or raise concern for the

caregiver. For example, in one large longitudinal cohort study of infants on home cardiorespiratory monitors, 43% of healthy term infants had at least one 20-second apneic episode over a 3-month period.8 In a separate study, over 5% of parents recalled seeing an apnea of that duration.7 The pediatric hospitalist may be asked to clarify the features of the presentation, stabilize the infant, and reassure the caregivers. If admission is considered, the hospitalist must diagnose and treat the precipitating cause (if one is determined), educate the caregivers, and render a disposition.

BACKGROUND In September 1986, the National Institutes of Health (NIH) convened an expert panel to review the literature and discuss the relationship of infantile apnea, ALTE, and sudden infant death syndrome (SIDS). These experts standardized the definition of ALTE by describing it as “an episode that is frightening to the observer and that is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.” NIH also proposed eliminating the terms “near miss SIDS” and “aborted crib death” because no causal link could be found between ALTE and SIDS.1 The relationship among ALTE, infant apnea, and SIDS is still unclear, and there is increasing evidence that these disorders are unrelated.3,8,9 Owing to the breadth of the definition, ALTE has been attributed to everything from normal physiologic events to life-threatening illnesses.5,10,11 Therefore, it must be stressed that the symptoms of ALTE may represent a normal physiologic occurrence and be of no clinical significance. Although most ALTEs are benign, healthcare providers must be able to distinguish events that are frightening, potentially clinically significant, and truly life threatening.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION The potential underlying abnormalities of ALTE are myriad; therefore the pathophysiology depends on the underlying condition. A partial listing of diagnoses is provided in Table 140-1, and a detailed discussion of the

pathophysiology for each condition is found within the corresponding section of this text. TABLE 140-1

Differential Diagnosis of Apparent LifeThreatening Events, with Estimates of Frequency

Gastrointestinal: 34% Gastroesophageal reflux Gastroenteritis Dysphagia Surgical abdomen Laryngeal chemoreflex apnea Vomiting Neurologic: 17% Seizure Intracranial hemorrhage Central apnea or hypoventilation syndromes Hydrocephalus Brain tumor Vasovagal reflex Meningitis, encephalitis Myopathy Congenital malformation of the brainstem Respiratory: 11% Respiratory syncytial virus Pertussis Aspiration pneumonia Foreign body Other lower or upper respiratory tract infections Otolaryngologic: 4% Laryngomalacia

Subglottic stenosis Cardiac: 1% Cardiac arrhythmia (prolonged Q-Tc) Congenital heart disease Cardiomyopathy Myocarditis Metabolic or endocrine: 1% Electrolyte disturbance Hypoglycemia Inborn error of metabolism Other infections: 2% Sepsis Urinary tract infection Child maltreatment syndromes: 1% to 2% Shaken baby syndrome Intentional suffocation Munchausen syndrome by proxy Other: 6% Physiologic event (periodic breathing, acrocyanosis) Breath-holding spell Accidental suffocation strangulation in bed Anemia Toxin ingestion Hypothermia Overfeeding syndrome Idiopathic apnea of infancy: 23% Pathologic apnea is defined as an event associated with physiologic compromise, as indicated by changes in oxygenation, color, muscle tone, or bradycardia. Apneic events may be obstructive, central, or mixed. Obstructive apnea, even of brief duration (6 seconds or 2 breaths), is

considered abnormal.12 Central respiratory pauses are generally considered abnormal when they last 20 to 30 seconds or longer.8,12 Shorter central apneic episodes (6 seconds or 2 breaths) are considered abnormal when they are accompanied by physiologic compromise.12 Mixed apnea combines the features of central and obstructive episodes in the same respiratory event (usually defined by an epoch of time).12 Central apnea results from the lack of brainstem-mediated respiratory effort, as can be seen in premature infants. Obstructive apnea results from attempts to breathe against a blocked airway, as can be seen in laryngomalacia or adenotonsillar hypertrophy. Color changes result from decreased oxygenation or differential blood flow to a portion of the body. Transient plethora may result from hyperemia and localized vasodilation (often venous), whereas pallor may result from vasoconstriction. Both tend to be mediated by autonomic activity. Cyanosis is a consequence of hemoglobin desaturation and can result from impaired oxygen exchange or distribution. Differentiating the ruddy appearance of plethora from cyanosis is often difficult and can result in confusion for the caregiver and healthcare provider. Central cyanosis is most reliably identified by blue or purple discoloration or darkening of the lips or tongue. Acrocyanosis and circumoral cyanosis are not necessarily signs of a central cyanotic state or abnormal gas exchange. Acrocyanosis in newborns is common and may be due to vasomotor instability or vasoconstriction due to heat-retention efforts. Circumoral cyanosis often presents as a circular blue or purple discoloration in the perioral area, not involving the lips or tongue. It is more easily recognized in fair-skinned infants, especially with crying, breath holding, or other Valsalva-type efforts. It is likely related to congestion of the superficial venous plexus in this region. Altered muscle tone may result from neuronal activity that is centrally or peripherally mediated, as can be seen in seizures or clonus. Choking results in impaired respiration from compression or obstruction of the larynx or trachea. Choking may be due to laryngospasm, bronchospasm, regurgitation of gastric contents, or aspiration of a foreign body. Gagging or retching is manifest by the emetic center located in the medulla; triggers by various neural pathways along the digestive tract, heart, testicles, and chemoreceptor trigger zone. The response is a spasmodic contraction of the diaphragm and intercostal muscles combined with the closure of the glottis.13

DIFFERENTIAL DIAGNOSIS Because ALTE is a description rather than a diagnosis, the hospitalist must consider the underlying cause (see Table 140-1). Many of the diagnoses associated with ALTE are easy to differentiate on the basis of history and physical examination. For example, an infant presenting with an ALTE manifest by obstructive apnea and cyanosis in the context of congestion, cough, and gagging and lower respiratory wheeze would likely be diagnosed with a viral bronchiolitis infection.14,15 Interestingly, both central (especially in newborns) and obstructive events can be observed with respiratory syncytial virus (RSV) infection.16,17 An ALTE in an infant with choking and gagging in association with feeding or regurgitation likely represents underlying dysphagia or gastroesophageal reflux (GER).10,18 An ALTE in an infant associated with respiratory irregularity and abnormal repetitive musculoskeletal movements likely represents a seizure.10,19,20 Other cases are less well defined than these examples and present challenges to the practitioner who must evaluate and manage the patient. The sudden, irreproducible nature of the event may make coordinating the investigation difficult. Often, the history is incomplete or inaccurate because the caregiver is distracted by fear or medically naive. In addition, the infant may appear normal on examination. Clinical judgment must guide the evaluation and eventual disposition.

EVALUATION AND DIAGNOSIS A thorough history from the primary witness or witnesses and a careful physical examination will guide the practitioner’s assessment (Table 140-2). Indeed, both the history and the exam should be individually tailored and specific enough to provide some physiologically rational explanation for the course of events. Despite the level of concern or severity of the event, the cause can often be determined as a physiologic response such as an isolated choking episode or acrocyanosis. In the event that a reasonable explanation cannot be provided, the investigation can often be directed based on some risk stratification. Characteristics of the patient or presentation that confers greater risk of an underlying progressive diagnosis or recurrence include residual signs on exam, a prior history of ALTE, clustered events, prematurity (lessening after 48 weeks postconception), or features of non-

accidental trauma.11,21-29 TABLE 140-2

Focused History for Infants with Apparent Life-Threatening Events

Chief complaint Presence of apnea or respiratory effort (including duration) Type of color change and its distribution Any change in tone and its distribution Choking, gagging Duration of the episode Vomiting Relationship to feedings Rhinorrhea and/or cough Eye deviation Loss of consciousness Fever History of trauma or presence of bruises State of alertness before the event Place where the event occurred Caretakers during the episode and consistency of their history Type of resuscitation needed, and who performed it Review of the prehospital (emergency medical services) record, if available Current condition of the child, in the caretaker’s opinion Presence of a monitor Medicines taken by the child or by the breastfeeding mother History of ALTE in the past, and type of evaluation Past medical history, including prematurity Family history including ALTE and SIDS Social history including the sleep environment, smoke exposure, and caretakers

ALTE, apparent life-threatening event; SIDS, sudden infant death syndrome.

There is no minimum or maximum number of required tests.29,30 First, the sheer number of possible tests makes the detection of some abnormality likely. The result may be nonspecific or spurious. It may also mislead the practitioner into making a diagnosis that is coexistent but not causative31 (see Table 140-3). Next, because ALTE describes a presentation rather than a diagnosis, the workup should be directed at the suspected condition rather than following a nonspecific algorithm. Finally, testing helps in 2 canisters of SABA per month Difficulty perceiving asthma symptoms or severity of exacerbations Social history Low socioeconomic status or inner-city residence Major psychosocial problems Comorbidities

Cardiovascular, other chronic lung, or chronic psychiatric disease The physical examination provides clues to the severity of the current illness as well as the presence of comorbidities. Important physical parameters include respiratory rate, work of breathing, air entry, wheezing, and oxygen saturation. Work of breathing refers to the use of accessory muscles of respiration and also includes parameters such as nasal flaring, abdominal retractions, and depth of respiration. During an asthma exacerbation, physical findings may vary and evolve with treatment or progression of the acute condition. A quiet or silent chest is a worrisome sign as poor movement of air can be associated with respiratory insufficiency or failure. Asymmetry of auscultatory findings may indicate other conditions. Unequal breath sounds can be found with pneumonia, effusion (especially in dependent regions of the lung), or atelectasis. Unilateral breath sounds may indicate an aspirated foreign body or a pneumothorax on the side with diminished breath sounds,4 and may be accompanied by hyperresonance on that side, especially if there is significant air trapping. Chest radiographs are typically not needed for patients with known asthma and a straightforward asthma exacerbation.21 Typical radiographic findings include hyperinflation, peribronchial thickening, and atelectasis (Figure 141-1). Chest radiographs may be helpful when there is concern for pneumonia, effusion, pneumothorax, pneumomediastinum, or foreign body aspiration.

FIGURE 141-1. Typical radiographic findings in a patient with an

acute asthma exacerbation. A classification system for the severity of an asthma exacerbation is provided in Table 141-3. Patients in mild distress typically have slightly increased respiratory rates, may not use accessory muscles of respiration, and have end-expiratory wheezes with good air entry. Patients in severe distress are working hard to breathe, with inspiratory and expiratory wheezes, and are often hypoxic. Signs of impending respiratory failure are provided in (Table 141-4). For infants and children under 5 years of age, clues to breathlessness include difficulty or reluctance to feed and changes in crying pattern (e.g. softer or shorter). Changes in vital signs in these younger patients must be interpreted in the context of normal values for the age of the patient. Interestingly, paradoxical thoracoabdominal movement, a sign associated with severe respiratory distress in older children, may be seen in young children and infants even in states of mild or moderate respiratory distress. TABLE 141-3

Clinical Classification of Severity for Asthma Exacerbation in Patients ≥5 Years of Age

Source: National, Heart, Lung, and Blood Institute; National Institutes of Health; US Department of Health and Human Services. An exacerbation usually includes several parameters, but not necessarily all. These

parameters serve only as general guidelines because many have not been systemically studied.

TABLE 141-4

Indicators of Impending Respiratory Failure

Poor air movement or silent chest in combination with increased respiratory effort, bradypnea, or disorganized breathing pattern Inability to speak Increasing pulsus paradoxus or decreasing pulsus paradoxus in an exhausted patient PCO2 > 42 mm Hg Inability to lie supine Deteriorating mental status, lethargy, or agitation Diaphoresis Respiratory or cardiac arrest Objective measures of acute asthma include pulmonary function testing, pulse oximetry, and arterial blood gases. Patients with asthma exacerbations are at risk for hypoxemia. As a result, patients require frequent monitoring to ensure adequate oxygenation. During a severe exacerbation, continuous pulse oximetry is recommended whereas intermittent oximetry may be acceptable as the clinical course improves. Arterial blood gases are typically performed in critically ill patients and those with clinical deterioration or signs of respiratory insufficiency or failure. Arterial blood gases may reveal hypoxemia due to ventilationperfusion mismatch and respiratory alkalosis with hypocapnia due to hyperventilation. A normal or elevated partial pressure of carbon dioxide (PaCO2) may be the harbinger of respiratory failure22 and may be associated with a decreased blood pH due to respiratory acidosis. In addition, lactic acidosis is a particularly concerning finding in status asthmaticus and patients with lactic acidosis are also at high risk of respiratory failure. Pulmonary function tests can be used to assess lung function even during an asthma exacerbation. Spirometric indices such as the measurement of the

forced expiratory volume at 1 second (FEV1), or peak expiratory flow rate (PEFR) are most useful to assess the severity of asthma. However, since spirometry is often not readily available in the emergency setting, PEFR can be used instead. The hand-held peak flow meter measures PEFR, and normal values have been established according to age, gender, and height23 (Table 141-5). PEFR provides a measure of large airway flow by measuring the rate of airflow in liters per minute. As a flare or asthma exacerbation worsens, PEFR typically becomes lower than baseline and may reflect the severity of the exacerbation. In patients presenting to an emergency room with an asthma exacerbation, the FEV1 is typically 30% to 35% of normal,24 and the PEFR is less than 50% of normal. TABLE 141-5

Predicted Average Peak Expiratory Flow (Liters per Minute) in Normal Children and Adolescents23

Height

Height

Height

Males & Males & Males & (in) (cm) Females (in) (cm) Females (in) (cm) Females 43

109

147

51

130

254

59

150

360

44

112

160

52

132

267

60

152

373

45

114

173

53

135

280

61

155

387

46

117

187

54

137

293

62

157

400

47

119

200

55

140

307

63

160

413

48

122

214

56

142

320

64

162

427

49

124

227

57

145

334

65

165

440

50

127

240

58

147

347

66

168

454

Source: Data from Peak Flow Insert, http://www.peakflow.com/top_nav/normal_values/ index.html. This table acts a guideline. NHLBI guidelines suggesting using a personal best as baseline value.

Monitoring PEFR can also assist in tapering medication during the recovery phase of an acute hospitalization. The PEFR is effort- and technique-dependent and therefore, reliability remains a concern. It should be used in conjunction the other parameters of severity for assessments.

MANAGEMENT Asthma exacerbations are treated with a combination of supportive therapy and pharmacological interventions. Treatment is tailored to the severity of the symptoms and adjusted based on response to therapy. Adequate hydration should be established and maintained either orally or with intravenous fluids. Physiologic monitoring should include vital signs and pulse oximetry. Oxygen supplementation is provided to maintain oxygen saturations in a safe range. This range is widely debated, but most agree that levels >90% are needed, and many target levels >93% to 95%.

MEDICATIONS Adrenergic Agonists This class of medications works by stimulating the β2-adrenergic receptor causing activation of adenylate cyclase, which increases the production of cyclic 3’5-adenosine monophosphate (cAMP). This increase in cAMP depending on the site of stimulation results in bronchial smooth relaxation, skeletal muscle and cardiac muscle stimulation, and inhibition of the release of inflammatory mediators via stabilization of the mast cell membrane. Albuterol is one of the short-acting β2-adrenergic agents used as first-line therapy for an acute asthma exacerbation, and this class of agents is used first line due to their ability to rapidly and reliably open the airways. Albuterol can be administered by nebulizer, either continuously or intermittently, or by metered-dose inhaler (MDI) with a spacer device. Studies have compared the amount of medication delivered to the lungs when given by MDI with spacer versus nebulizer.25-27 The two modes are considered equivalent if the patient can use proper technique with the MDI-spacer method of delivery. Dosing information is provided in Table 141-6. TABLE 141-6

Dosages of Bronchodilators Commonly

Used for Asthma Exacerbations

Source: National, Heart, Lung, and Blood Institute; National Institutes of Health; US Department of Health and Human Services. MDI, metered dose inhaler; VHC, valved holding chamber; SABA, short-acting bronchodilator.

Paradoxical and transient worsening of hypoxia due to increased ventilation-perfusion mismatching can be seen with the administration of albuterol and the other β2-adrenergic agents. This class of medication causes increased cardiac output which leads to increased perfusion of unventilated lung.28 Other side effects include sinus tachycardia, tremor, palpitations, headache, agitation, and ventricular irritability (e.g. ventricular premature contractions, ventricular tachycardia). In addition, frequent or continuous dosing with adrenergic agents can lead to hypokalemia, therefore patients receiving such treatment should have serum potassium levels checked periodically. Non-selective adrenergic agents (e.g. epinephrine) can also cause transient hyperglycemia and elevations in neutrophil counts due to demargination.

Albuterol is actually a racemic mixture of R-albuterol and S-albuterol, with a 50:50 ratio of these two stereoisomers. Levalbuterol (Xopenex™) is made up of the R-isomer, which is felt to be the active component of the racemic product. However, the vast majority of clinical studies and in vitro pharmacology data have shown no significant differences for cardiopulmonary side effects and tremor when comparing racemic to Risomer albuterol or bronchodilator effects.29-31 Three studies found differences in rates of admission from emergency department and bronchodilation,29,30,32 while two studies found improvement with levalbuterol with decreased rates of admission from an emergency department using levalbuterol versus racemic albuterol33 or improved bronchodilation.34 Overall, in these authors’ consideration, levalbuterol does not offer any significant advantage over racemic albuterol in the treatment of asthma. Terbutaline, a selective β2-adrenergic agonist, and epinephrine, a nonselective adrenergic agonist, are used in asthmatics not responding to albuterol and corticosteroids, or who are deteriorating. These medications are given by subcutaneous injection or intravenous infusion. Bronchodilation is seen within 5 minutes of administration and can persist for 3 to 4 hours.35,36 Terbutaline can also be given by continuous IV infusion starting with a bolus and titrating the dose to the desired effect. Dosing of β2-adrenergic and bronchodilator agonists are shown in Tables 141-6 and 141-7. TABLE 141-7

Systemic Bronchodilators for Acute Asthma Exacerbations

Corticosteroids Corticosteroids are indicated in the initial treatment of status asthmaticus. They are potent anti-inflammatory medications that have been shown to hasten recovery, prevent recurrence,37-41 and prevent hospitalizations.42 Due to their mechanism of action, the effect of corticosteroids is not immediate. Steroids bind to the intracytoplasmic glucocorticoid receptor and translocate to the nucleus thereby affecting RNA transcription in both a positive and negative fashion through the transcription factors NF-κB and AP-1. In general, corticosteroids lead to downregulation of inflammatory cytokines. Corticosteroids also activate histone deacetylase that inhibits DNA transcription.43 This change in transcription leads to increased numbers of β2-adrenegeric receptors at the cell surface and decreases in airway inflammation and mucous secretion. It can take several hours to reverse airway inflammation and benefits are typically seen within 4 hours after corticosteroids are given.38,39,44 Studies comparing oral and IV corticosteroids have found no significant differences in efficacy.45,46 Oral steroids are typically preferred since IV access is not required.45,47 Dosing of corticosteroids are shown in Table 141-8. TABLE 141-8

Systemic Corticosteroids in the Setting of Asthma Exacerbations

Source: National, Heart, Lung, and Blood Institute; National Institutes of Health; US Department of Health and Human Services.

Inhaled Anticholinergic Agents Anticholinergic agents work by competitively inhibiting the neurotransmitter acetylcholine at the muscarinic junction to relieve cholinergic mediated bronchoconstriction. Nebulized atropine is associated with significant systemic absorption but anticholinergic medications such as ipratropium bromide, have fewer side effects and less systemic absorption.48 The use of inhaled ipratropium in the initial phase of treatment has been shown to be effective in reducing the need for hospitalization. A few studies have found no benefit compared to β-agonists alone, while others have a

slight advantage in 1 to 3 doses in the initial phase of acute asthma exacerbation.49 The role of ipratropium for hospitalized patients is less clear.50 Combined administration of anticholinergic and β2-agonist medications increases bronchodilation although some controversy about this persists.51,52 Despite this, many institutions use a combination of β2-agonists and anticholinergic medications during the initial phase of acute asthma exacerbations. Studies examining the use of anticholinergic medications as monotherapy have also been controversial. Dosing is listed in Table 141-6.

NONSTANDARD THERAPIES If initiation of the above standard therapies does not improve the level of respiratory distress or if symptoms progress, additional interventions may be necessary. The clinical experience and expertise available at the particular institution should be considered in the decisions. Safe transfer to a facility able to provide critical care management should be anticipated and arrangements should be expedited. Magnesium Sulfate Magnesium sulfate has been studied as a bronchodilator in severe asthma with conflicting results.53-56 Magnesium is thought to inhibit mast cell degranulation and increase bronchial dilatation due to a decrease in calcium uptake by bronchial smooth muscle.57 Its use is considered when the patient fails to improve or worsens despite treatment with continuous inhaled β2-agonist, systemic corticosteroids, and inhaled anticholinergic agents. Methylxanthines Intravenous methylxanthines, such as aminophylline, were commonly used in the past to manage asthma exacerbations due to their ability to act directly on β-adrenergic receptors and relax bronchial smooth muscle. Methylxanthines can prevent acute airway hyperresponsiveness but do not appear to have effects chronically.58-60 Studies examining the use of intravenous methylxanthines in children and adults with severe asthma have shown mixed benefits.61-66 A recent Cochrane Review found that theophylline in addition to β2-agonists and glucocorticoids (with or without anticholinergics) improves lung function within 6 hours of treatment.

However, there is no apparent reduction in symptoms, number of nebulized treatments and length of hospital stay.67 Concerns regarding toxicity and efficacy of this class of medication and the availability of newer agents limit its use. Life-threatening events such as cardiac arrhythmia and seizures are associated with toxic levels of theophylline (>30 μg/mL). Heliox Heliox is a mixture of helium and oxygen used for inhalation. This agent is thought to improve airflow by creating a gas with a similar viscosity to air but with a lower density, which in turn can increase ventilation and decrease work of breathing.68-70 Heliox is indicated in patients with a refractory asthma exacerbation and whom respiratory failure is impending. Patients with high oxygen requirements may not be able to tolerate heliox because they need a higher Fi02 than a helium-oxygen mixture can provide. Heliox can also lower body temperature due to the high thermal conductivity of the mixture, patients need to have their temperature monitored closely. Medication adverse effects are listed in Table 141-9. TABLE 141-9

Side Effect

Common Side Effects of Pharmacologic Therapies Possible Causative Agent

Comment

Hypokalemia

Adrenergic agonists

Patients on prolonged hourly or continuous inhaled therapy, or intravenous therapy should have serum potassium levels monitored

Tremor/Agitation

Adrenergic agonists

Dose-dependent

Hypertension

Corticosteroids, May require reduction

Tachycardia, Palpitations, VPCs

adrenergic agonists

of dose, discontinuation of therapy, or addition of antihypertensive medication

Adrenergic agonists, aminophylline, theophylline

Usually dosedependent Serum levels of methylxanthines should be monitored The risk is increased with hypoxemia or acidemia

Hyperglycemia/Glucosuria Corticosteroids, Resolves with adrenergic completion or agonists discontinuation of therapy Emotional Lability

Corticosteroids

Resolves with completion or discontinuation of therapy

Hyperphagia

Corticosteroids

Resolves with completion or discontinuation of therapy

Seizure

Theophylline, aminophylline

Serum levels of methylxanthines should be monitored Risk is increased in the presence of acidosis

Elevated Peripheral Neutrophil Count

Corticosteroids, adrenergic agonists (in particular epinephrine)

May interfere with utility of the white blood count in assessing for infection

INITIAL TREATMENT The initial therapy of status asthmaticus has been outlined by the NHLBI guidelines (Figure 141-2). In brief, patients are first treated with short-acting inhaled β2-adrenergic agonists (SABA) (e.g. inhaled albuterol), corticosteroids either orally or intravenously and, if needed, oxygen. Inhaled anticholinergics, such as ipratropium bromide, may be added for patients who do not demonstrate prompt improvement. Patients who demonstrate significant improvement after these initial interventions may not require hospitalizations.

FIGURE 141-2. Management of asthma exacerbations: emergency department and hospital-based care. (Source: National, Heart, Lung, and Blood Institute; National Institutes of Health; US Department of

Health and Human Services.) Patients with moderately severe symptoms who are stable or are showing signs of improvement and patients with severe symptoms who are demonstrating clear signs of improvement should be hospitalized and treated with inhaled albuterol, either every 1 to 2 hours by nebulizer or MDI-spacer, or delivered continuously via nebulizer. Corticosteroid therapy is continued orally, or if not tolerated, intravenously. Continuation of inhaled anticholinergic agents may be considered, though their benefit remains unproven. If patients continue to deteriorate, they must be monitored for respiratory insufficiency and failure. Signs of impending respiratory failure are provided in Table 141-4. An arterial blood gas can be used to confirm the condition and should reveal decreased pH, elevated partial pressure of carbon dioxide (PaCO2), and an increased alveolar-arterial oxygen gradient. Pulse oximetry remains a poor monitoring device for early detection of respiratory failure. Oxygen saturation is initially maintained despite a significant degree of hypoventilation, and the addition of supplemental oxygen would further obscure evidence of respiratory failure from this device. Patients with impending respiratory failure often need mechanical ventilatory support either invasively with endotracheal intubation or noninvasively with bilevel positive airway pressure administered via a mask.

TAPERING HOSPITAL THERAPY After patients are stabilized and demonstrate improvement, the therapies can be gradually reduced and withdrawn. Ongoing assessments of clinical parameters are performed which include respiratory rate, work of breathing, auscultatory findings, and requirement for supplemental oxygen. If the patient remains comfortable with minimal signs of respiratory distress, the dosing of inhaled β-agonists is decreased. For patients on continuous inhaled β-agonist therapy, the dose may be reduced and then subsequently transitioned to intermittent treatments, usually every 2 hours. As the patient continues to improve, the interval between treatments can be extended further. Similarly, the amount of supplemental oxygen is titrated to maintain oxygen saturations above the desired level, and eventually discontinued. Systemic corticosteroids are continued throughout the exacerbation and

maintained for several days after discharge from the hospital. If inhaled anticholinergic agents have been instituted, they are usually discontinued when albuterol begins to be tapered. Many hospitals use clinical pathways, which are tools that detail a sequence of assessments and treatments for patients with various conditions.71 Studies have shown that asthma clinical pathways shorten hospitalization and decrease the need for readmission for up to 2 weeks after discharge.72,73 An asthma clinical pathway allows multiple caregivers, including nurses, respiratory therapists, and doctors to modify treatment based on structured assessments. The NHLBI guidelines (Figure 141-2) outline specific criteria that can be used to determine a patient’s severity and frequency of therapy. It also provides criteria to assist in weaning treatments. PEFR measurements may be useful to determine readiness for reduction in medication. If the PEFR is at least 70% of baseline prior to a bronchodilator treatment (Table 141-5), it is appropriate to space the frequency of the β2-adrenergic agonist treatments. Technique and effort will affect the PEFR measurement, therefore it should be used in conjunction with other clinical indicators of improvement.

THERAPY AFTER DISCHARGE TO HOME Patients should be sent home on oral corticosteroids, the duration of which depends upon the length and severity of illness and the patient’s frequency of exacerbations. In general, an isolated exacerbation is treated with oral corticosteroids for 5 days. However, if a patient was admitted to the hospital for an extended period, they will require a prolonged course of corticosteroids and then tapering doses. A taper is prescribed to prevent a relapse of symptoms as well as to prevent an Addisonian crisis from adrenal suppression. The risk of Addisonian crisis is hypothetical and has not been shown in any study.74-76 In addition, patients receiving their second course of steroids in a month should receive a prolonged taper as well. A typical taper involves keeping the patient at a full daily dose of corticosteroids until they achieve stable clinical status and then decreasing the dose by 30% to 50% daily. Patients who required admission to the hospital may not have been on an adequate treatment plan thus the hospitalization offers the opportunity to assess the overall treatment regimen. Patients should be evaluated according

to the NHLBI guidelines and, if indicated, have their outpatient preventive treatment adjusted to the appropriate level of asthma control and disease severity. Specific drug choices are outlined in Table 141-6.

ADMISSION AND DISCHARGE CRITERIA ADMISSION CRITERIA Admission to the hospital is individualized and is based on many factors. Hospitalization should be considered in patients with Poor response to initial treatment Oxygen saturation 92% with supplemental oxygen Evidence of impending respiratory failure Inability to provide adequate monitoring outside of an intensive care setting77

DISCHARGE CRITERIA A patient is ready to go home when they have been successfully weaned to albuterol treatments every 4 to 6 hours. Prior to receiving a treatment, they should be able to breathe comfortably during ambulation or speaking. Wheezing may persist on examination but this should not be audible without a stethoscope. A plan of care should include ongoing management of the current acute exacerbation and transition to maintenance therapy. Additionally, the patient should leave with a plan of action, or asthma action plan, for management of subsequent asthma exacerbations. Efforts should be coordinated with the primary care clinician, and, if involved, the asthma

specialist. Prior to discharge, it is important to consider the environment to which the patient will return. The preventive management plans should be reviewed with the family which would include identifying any potential comorbidities and triggers present in the environment. Table 141-10 highlights a discharge checklist that was created by the NHLBI panel. TABLE 141-10

Intervention

Checklist for Hospital Discharge of Patients Who Have Asthma MD/RN Dose/Timing Education/Advice Initials • Teach purpose • Teach and check technique • For MDIs, emphasize the importance of VHC or spacer

Inhaled medications (e.g. MDI with valved holding chamber (VHC or spacer); nebulizer) SABA Corticosteroids

Select agent, dose, and frequency (e.g. albuterol)

Oral medications

Select agent, dose, and frequency (e.g. prednisone 50 mg qd for 5 days)

• Teach purpose • Teach side effects

Peak flow meter

For selected patients: measure AM and PM PEF, and record best of 3 tries each time

• Teach purpose • Teach technique • Distribute peak flow diary

2-6 puffs every 3-4 hours as needed Medium dose

Follow-up visit

Make appointment for follow-up care with primary clinician or asthma specialist

Advise patient (or caregiver) of date, time, and location of appointment, ideally within 7 days of hospital discharge

Action plan

Before or at discharge

Instruct patient (or caregiver) on simple plan for actions to be taken when symptoms, signs, or PEF values suggest airflow obstruction

MDI, metered-dose inhaler; PEF, peak expiratory flow; SABA, short-acting β2-agonist.

CONSULTATION Outpatient referral to an asthma specialist (e.g. pulmonologist, allergist) is associated with reduced rates of emergency department visits78 and is recommended for patients with the following scenarios.4 Patient has had a life-threatening asthma exacerbation. Patient is not meeting goals of asthma therapy after 3 to 6 months of treatment. Earlier referral or consultation is appropriate if physician concludes patient is unresponsive to therapy. Signs and symptoms are atypical, or there are problems in differential diagnosis. Patient requires step 4 care or higher (step 3 for children 0–4 years of age). Consider referral if patient requires step 3 care (step 2 for children 0 to 4 years of age). Patient has required more than 2 bursts of oral corticosteroids in 1 year or has an exacerbation requiring hospitalization.

Asthma specialists may be available to assist in the management of an acute asthma exacerbation as needed. Involving the specialist during a hospitalization may assist with transition after discharge. Critical care physicians should be contacted for all patients who may need management in an intensive care setting.

SPECIAL CONSIDERATIONS PREVENTION Educating the family about the pathogenesis of asthma, triggers, and medications is crucial to preventing exacerbations and admissions to the hospital. A patient that requires frequent admissions needs to have their treatment plan reassessed and be evaluated for comorbid conditions. In addition, others factors including gastroesophageal reflux, sinusitis, and others that might exacerbate asthma should be explored and eliminated if possible (Table 141-11). For children experiencing symptoms on a daily basis, there are certain controllable environmental factors such as exposure to allergens and cigarette smoke that can cause symptoms and contribute to asthma exacerbations.79 If an allergic component is considered, further evaluation can be arranged and environmental control measures recommended. Both passive and active cigarette smoking significantly increase the risk of asthma and worsen asthma symptoms.80-87 As a result, no smoking should be permitted around an asthmatic or in their home or family car. Physicians should provide assistance for caregivers to quit smoking. TABLE 141-11

Factors That Worsen Asthma Severity Animal dander

Factors That Worsen Asthma Severity and Control Measures

Control Measures Remove animal from the environment At minimum, remove animal from the bedroom

House dust mites

Encase mattress and pillows in an allergen impermeable cover Wash bedding in hot water weekly >130°F Remove carpets from the bedroom

Cockroaches

Exterminate Do not leave garbage and food exposed

Pollens

During pollen season, stay indoors with windows closed, especially in the late afternoon

Molds

Fix leaks, eliminate water sources Clean moldy surfaces

Cigarette/Tobacco Encourage family members and caregivers to smoke smoke outside Sinusitis

Promote sinus drainage Antibiotic therapy when appropriate

Gastroesophageal No eating 3 hours before bedtime reflux Elevate head of bed 6-8 inches Appropriate medications: Histamine-2 antagonist Medications

No beta-blockers Avoid aspirin and NSAIDS in patients with severe persistent asthma, nasal polyps, and aspirin sensitivity

Viral infections

Annual influenza vaccination

Irritants

Decrease exposure to wood-burning stoves, fireplaces, unvented stores or heaters, perfumes, cleaning agents, sprays

An assessment of adherence to therapy and review of relevant drug

delivery systems is important as well. Appropriate preventative medications based on daily symptoms and frequency of exacerbations should be maintained on a daily basis. These medications are essential for the prevention of asthma flares. Multiple studies have shown a strong negative correlation with the use of asthma admission and daily inhaled corticosteroids, that is, daily corticosteroids reduce asthma admissions. Suggested doses and regiments have been established in national and worldwide collaborations between pediatricians, allergists, pulmonologists, internists, and others. In 2007, the Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma was published by the NHLBI. The revised guidelines focus greatly on assessment of asthma severity based on two stratospheres, including risk and impairment. The risk domain includes frequency and severity of exacerbations and the occurrence of treatment-related adverse effects. The impairment domain is multifactorial and assesses symptoms, SABA use, pulmonary function, and uses validated questionnaires. For each patient, the more severe of these two categories dictates the level of preventive medications a patient requires and a consideration for reduction of controller therapy can be considered after at least 3 months of good control of asthma.4 Additional sources of support for families can include the Asthma and Allergy Network Mothers of Asthmatics, www.breatherville.org, and the Asthma and Allergy Foundation of America, www.aafa.org.

NEW THERAPIES Asthma is a chronic inflammatory disease affecting many Americans and researchers are actively investigating new drugs and therapies to improve the quality of life of asthmatics. Drugs that modify the immune response are currently under active investigation. Omalizumab, a recombinant humanized anti-immunoglobulin E (IgE) antibody, is an immunomodulator which is now utilized as adjunctive therapy in steps 5 or 6 care for patients with allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA. Omalizumab is approved for 6 and up and a new monoclonal antibody therapy is also available. Mepolizumab (Nucala) is available for severe eosinophilic asthma. This drug binds circulating free IgE, reducing the

level of free IgE in the bloodstream and preventing it from binding to mast cell membrane receptors. This leads to a decrease in the release of mediators in response to allergen exposure. Omalizumab also decreases FceRI expression on basophils and airway submucosal cells.88,89 Omalizumab has been found to reduce symptoms, exacerbations,90 and the use of corticosteroids. In patients who have severe persistent asthma, omalizumab results in clinically relevant improvements in quality-of-life scores.91 KEY POINTS Asthma is a chronic disorder that results in airway inflammation and smooth muscle dysfunction and manifests as recurrent episodes of wheezing, breathlessness, and chest tightness. Exacerbations can be triggered by a variety of stimuli including respiratory infections, exposure allergens or irritants, exercise, or cold. Treatment of flares must be directed at decreasing airway inflammation and relieving bronchospasms while providing supportive care. The mainstay of pharmacologic therapy includes inhaled short acting β2-adrenergic agonist therapy and systemic corticosteroids. Supportive care includes supplemental oxygen if needed and maintenance of hydration. Many of the pharmacologic agents have significant side effects and therefore appropriate monitoring is required. Patients with severe symptoms or those with moderately severe symptoms that fail to demonstrate improvement on initial therapy are candidates for admission to an intensive care setting. At the time of discharge, patients should have a clear plan for ongoing treatment of the acute exacerbation and transition to maintenance therapy. In addition, an action plan for subsequent exacerbations should be in place.

SUGGESTED READINGS Cydulka RK, Emerman CL. A pilot study of steroid therapy after emergency department treatment of acute asthma: is a taper needed? J Emerg Med. 1998;16(1):15-19. Effectiveness of routine self monitoring of peak flow in patients with asthma. Grampian Asthma Study of Integrated Care (GRASSIC). BMJ. 1994;308(6928):564-567. Gibson P, et al. The effects of self-management asthma and regular practitioner review in adults with asthma. Cochrane Database Syst Rev. Oxford, 1988. Jones KP, et al. Peak flow based asthma self-management: a randomised controlled study in general practice. British Thoracic Society Research Committee. Thorax. 1995;50(8):851-857. Karan RS, et al. A comparison of non-tapering vs. tapering prednisolone in acute exacerbation of asthma involving use of the low-dose ACTH test. Int J Clin Pharmacol Ther. 2002;40(6):256-262. Mayo PH, Richman J, Harris HW. Results of a program to reduce admissions for adult asthma. Ann Intern Med. 1990;112(11):864-871. O’Driscoll BR, et al. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993;341(8841):324-327. Practice parameters for the diagnosis and treatment of asthma. J Allergy Clin Immunol. 1995. Shuttari MF. Asthma: diagnosis and management. Am Fam Physician. 1995;52(8):2225-2235.

REFERENCES 1. American Lung Association. Trends in Asthma Morbidity and Mortality. 2001. 2. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Bethesda, MD: National Institutes of Health; 2003. 3. US Department of Health and Human Services (USDHHS), Centers for Disease Control and Prevention, National Center for Health Statistics.

Compressed Mortality File. 2005. 4. National Heart, Lung, and Blood Institute Expert Panel 3. Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 074051. 2007. Bethesda, MD: National Institutes of Health. 5. National Heart, Lung, and Blood Institute. Data Fact Sheet: Asthma Statistics. 1999. 6. Hartert TV, et al. Inadequate outpatient medical therapy for patients with asthma admitted to two urban hospitals. Am J Med. 1996;100(4):386394. 7. Pappas G, et al. Potentially avoidable hospitalizations: inequalities in rates between US socioeconomic groups. Am J Public Health. 1997;87:811-816. 8. Djukanovic R, et al. Mucosal inflammation in asthma. Am Rev Respir Dis. 1990;142(2):434-457. 9. Murray CS, Simpson A, Custovic, A. Allergens, viruses, and asthma exacerbations. Proc Am Thorac Soc. 2004;1(2):99-104. 10. Johnston S, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310:12251228. 11. Johnston SL, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med. 1996;154(3 Pt 1):654-660. 12. Shim CS, Williams MH Jr. Evaluation of the severity of asthma: patients versus physicians. Am J Med. 1980;68(1):11-3. 13. Stein MR. Possible mechanisms of influence of esophageal acid on airway hyperresponsiveness. Am J Med. 2003;115(suppl 3A):55S-59S. 14. Nelson HS. Gastroesophageal reflux and pulmonary disease. J Allergy Clin Immunol. 1984;73(5 Pt 1):547-556. 15. Busse WW. The role of respiratory infections in airway hyperresponsiveness and asthma. Am J Respir Crit Care Med. 1994;150(5 Pt 2):S77-S79. 16. Newman K, Mason UG, Schmaling K. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152:1382-1386.

17. Christopher K, et al. Vocal cord dysfunction presenting as asthma. N Engl J Med. 1983;308:1566-1570. 18. Tilles S. Vocal cord dysfunction in children and adolescents. Curr Allergy Asthma Rep. 2003;3:467-472. 19. Wood R, Milgrom H. Vocal cord dysfunction. J Allergy Clin Immunol. 1996;98:481-485. 20. Irwin RS, Glomb WB, Chang AB. Habit cough, tic cough, and psychogenic cough in adult and pediatric populations: ACCP evidencebased clinical practice guidelines. Chest. 2006;129(1 suppl):174S-179S. 21. Brooks LJ, Cloutier MM, Afshani E. Significance of roentgenographic abnormalities in children hospitalized for asthma. Chest. 1982;82(3):315-318. 22. Weiss EB, Faling LJ. Clinical significance of PaCO2 during status asthma: the cross-over point. Ann Allergy. 1968;26(10):545-551. 23. Polgar G, Promahcat V. Pulmonary Function Testing in Children. Techniques and Standards. Philadelphia: WB Saunders; 1971. 24. McFadden ER Jr. Clinical physiologic correlates in asthma. J Allergy Clin Immunol. 1986;77(1 Pt 1):1-5. 25. Idris AH, et al. Emergency department treatment of severe asthma. Metered-dose inhaler plus holding chamber is equivalent in effectiveness to nebulizer. Chest. 1993;103(3):665-672. 26. Kerem E, et al. Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr. 1993;123(2):313317. 27. Colacone A, et al. A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest. 1993;104(3):835-841. 28. Rodriques RR. Gas exchange abnormalities in asthma. Lung. 1990;168:s599-s605. 29. Qureshi F, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med. 2005;46(1):29-36. 30. Hardasmalani MD, et al. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg

Care. 2005;21(7):415-419. 31. Asmus MJ, Hendeles L. Levalbuterol nebulizer solution: is it worth five times the cost of albuterol? Pharmacotherapy. 2000;20(2):123-129. 32. Ralston ME, et al. Comparison of levalbuterol and racemic albuterol combined with ipratropium bromide in acute pediatric asthma: a randomized controlled trial. J Emerg Med. 2005;29(1):29-35. 33. Schreck DM, Babin S. Comparison of racemic albuterol and levalbuterol in the treatment of acute asthma in the ED. Am J Emerg Med. 2005;23(7):842-847. 34. Nelson HS, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol. 1998;102(6 Pt 1):943-952. 35. Dulfano MJ, Glass P. The bronchodilator effects of terbutaline: route of administration and patterns of response. Ann Allergy. 1976;37(5):357366. 36. Nou E. A clinical comparison of subcutaneous doses of terbutaline and adrenaline in bronchial asthma. Scand J Respir Dis. 1971;52(4):192-198. 37. Scarfone RJ, et al. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics. 1993;92(4):513-518. 38. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10(4):301-310. 39. Chapman KR, et al. Effect of a short course of prednisone in the prevention of early relapse after the emergency room treatment of acute asthma. N Engl J Med. 1991;324(12):788-794. 40. Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma. A critical controlled trial. Am J Med. 1983;74(5):845-851. 41. Harris JB, et al. Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators. J Pediatr. 1987;110(4):627-633. 42. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314(3):150152.

43. Didonato JA, Saatcioglu F, Karin M. Molecular mechanisms of immunosuppression and anti-inflammatory activities by glucocorticoids. Am J Respir Crit Care Med. 1996;154(2):S11-S15. 44. Connett GJ, et al. Prednisolone and salbutamol in the hospital treatment of acute asthma. Arch Dis Child. 1994;70(3):170-173. 45. Ratto D, et al. Are intravenous corticosteroids required in status asthmaticus? JAMA. 1988;260(4):527-529. 46. Szefler SJ. Glucocorticoid therapy for asthma: clinical pharmacology. J Allergy Clin Immunol. 1991;88(2):147-165. 47. Harrison BD, et al. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet. 1986;1(8474):181-184. 48. Weber RW. Role of anticholinergics in asthma. Ann Allergy. 1990;65(5):348-350. 49. Schuh S, et al. Efficacy of frequent nebulized ipratropium bromide added to frequent high dose albuterol therapy in severe childhood asthma. J Pediat. 1995;126(4):639-645. 50. Karpet JP, et al. A comparison of ipratropium and albuterol vs albuterol alone for the treatment of acute asthma. Chest. 1996;110:611-616. 51. Karpel JP, et al. A comparison of ipratropium and albuterol vs albuterol alone for the treatment of acute asthma. Chest. 1996;110(3):611-616. 52. Schuh S, et al. Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma. J Pediatr. 1995;126(4):639-645. 53. Tiffany BR, et al. Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest. 1993;104(3):831834. 54. Green SM, Rothrock SG. Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization. Ann Emerg Med. 1992;21(3):260-265. 55. Skorodin MS, et al. Magnesium sulfate in exacerbations of chronic obstructive pulmonary disease. Arch Intern Med. 1995;155(5):496-500. 56. Kuitert LM, Kletchko SL. Intravenous magnesium sulfate in acute, lifethreatening asthma. Ann Emerg Med. 1991;20(11):1243-1245.

57. Skobeloff EM. An ion for the lungs. Acad Emerg Med. 1996;3:10821084. 58. Hendeles L, et al. Safety and efficacy of theophylline in children with asthma. J Pediatr. 1992;120(2 Pt 1):177-183. 59. Crescioli S, et al. Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. Ann Allergy. 1991;66(3):245251. 60. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. Am Rev Respir Dis. 1987;136(5):1174-1178. 61. Mitra A. The current role of intravenous aminophylline in acute paediatric asthma. Minerva Pediatr. 2003;55(4):369-375. 62. Yamauchi K, et al. Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma. Respirology. 2005;10(4):491-496. 63. Yung M, South M. Randomised controlled trial of aminophylline for severe acute asthma. Arch Dis Child. 1998;79(5):405-410. 64. Huang D, et al. Does aminophylline benefit adults admitted to the hospital for an acute exacerbation of asthma? Ann Intern Med. 1993;119(12):1155-1160. 65. Self TH, et al. Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Does aminophylline add any benefit? Chest. 1990;98(6):1317-1321. 66. Strauss RE, et al. Aminophylline therapy does not improve outcome and increases adverse effects in children hospitalized with acute asthmatic exacerbations. Pediatrics. 1994;93(2):205-210. 67. Mitra A, et al. Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev. 2005(2):CD001276. 68. Gluck EH, Onorato DJ, Castriotta R. Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest. 1990;98(3):693-698. 69. Manthous, CA, et al. Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Am J

Respir Crit Care Med. 1995;151(2 Pt 1):310-314. 70. Rivera ML, et al. Albuterol nebulized in heliox in the initial ED treatment of pediatric asthma: a blinded, randomized controlled trial. Am J Emerg Med. 2006;24(1):38-42. 71. Glauber JH, Farber HJ, Homer CJ. Asthma clinical pathways: toward what end? Pediatrics. 2001;107(3):590-592. 72. Johnson KB, et al. Effectiveness of a clinical pathway for inpatient asthma management. Pediatrics. 2000;106(5):1006-1012. 73. Wazeka A, et al. Impact of a pediatric asthma clinical pathway on hospital cost and length of stay. Pediatr Pulmonol. 2001;32(3):211-216. 74. Cydulka RK, Emerman CL. A pilot study of steroid therapy after emergency department treatment of acute asthma: is a taper needed? J Emerg Med. 1998;16(1):15-19. 75. Karan RS, et al. A comparison of non-tapering vs. tapering prednisolone in acute exacerbation of asthma involving use of the low-dose ACTH test. Int J Clin Pharmacol Ther. 2002;40(6):256-262. 76. O’Driscoll BR, et al. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993;341(8841):324-327. 77. Jarjour NN. Asthma in adults: evaluation and management. In: Adkinson NF Jr, Yunginger JW, Busse WW, Bochner BS, Holgate ST, Simons FER, eds. Middleton’s Allergy: Principles and Practice. 6th ed. Philadelphia: Mosby; 2003:1269. 78. Zeiger RS, et al. Facilitated referral to asthma specialist reduces relapses in asthma emergency room visits. J Allergy Clin Immunol. 1991;87(6):1160-1168. 79. Eggleston P. Improving indoor environments: reducing allergen exposures. J Allergy Clin Immunol. 2005;116:122-126. 80. Gortmacher S, et al. Parental smoking and the risk of childhood asthma. Am J Pub Health. 1982;72:574-579. 81. Agudo A, et al. Exercise-induced airways narrowing and exposure to environmental tobacco smoke in schoolchildren. Am J Epidemiol. 1994;140:409-417. 82. Frischer T, et al. Maternal smoking in early childhood: a risk factor for bronchial responsiveness to exercise in primary-school children. J

Pediatr. 1992;121(1):17-22. 83. Arshad SH, Hide DW. Effect of environmental factors on the development of allergic disorders in infancy. J Allergy Clin Immunol. 1992;90(2):235-241. 84. Leuenberger P, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA study). Swiss study on air pollution and lung diseases in adults, SAPALDIA Team. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1222-1228. 85. Greer JR, Abbey DE, Burchette RJ. Asthma related to occupational and ambient air pollutants in nonsmokers. J Occup Med. 1993;35(9):909915. 86. Abbey DE, et al. Long-term ambient concentrations of total suspended particulates, ozone, and sulfur dioxide and respiratory symptoms in a nonsmoking population. Arch Environ Health. 1993;48(1):33-46. 87. Marquette CH, et al. Long-term prognosis of near-fatal asthma. A 6-year follow-up study of 145 asthmatic patients who underwent mechanical ventilation for a near-fatal attack of asthma. Am Rev Respir Dis. 1992;146(1):76-81. 88. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170(6):583-593. Epub 2004. 89. Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA, Townley R, Casale TB. Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J Allergy Clin Immunol. 2004;113(2):297-302. 90. Soler M, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18(2):254-261. 91. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, Beeh KM, Ramos S, Canonica GW, Hedgecock S, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-316.

CHAPTER

Aspiration

142

Mark I. Neuman

BACKGROUND The term aspiration encompasses a variety of respiratory syndromes, and many medical conditions can predispose to aspiration. Foreign body inhalation and the aspiration of infectious or noninfectious oropharyngeal secretions and gastric contents are scenarios that may lead to the development of pulmonary symptoms. An accurate and timely diagnosis of an acute or chronic aspiration syndrome requires a careful history and physical examination, because highly sensitive and specific diagnostic tests are lacking. When aspiration leads to acute injury to the airways and lung parenchyma, two specific types of aspiration syndrome can be identified: aspiration pneumonitis and aspiration pneumonia. These aspiration syndromes are distinct entities, but considerable overlap exists. Attempts to distinguish between them may be important, because the appropriate evaluation, management, treatment, and prevention strategies differ. Aspiration pneumonitis occurs after gastric contents, which are typically acidic, are inhaled into the lower respiratory tract. A prompt and intense inflammatory reaction, or pneumonitis, ensues, but bacterial infection is not a significant part of this immediate reaction. Aspiration pneumonia occurs after inhalation of nasal or oropharyngeal secretions, which contain colonizing bacteria, into the lower airways. The infectious process that develops accounts for the clinical features of aspiration pneumonia. The key to either diagnosis is identifying those patients at risk for aspiration.

PATHOPHYSIOLOGY

Even healthy adults and children may aspirate small amounts of oropharyngeal contents during sleep; however, pulmonary host defense mechanisms usually prevent the development of infection and mitigate the inflammatory response.1 There is a relatively low burden of virulent organisms colonizing the mouth and the naso- and oropharynx in healthy children; thus, aspiration of small amounts of normal flora rarely culminates in a clinically significant pulmonary infection.2 Additionally, there are protective mechanisms at all levels of the respiratory system; these include the anatomic design of the airway, functional gag and cough reflexes, the mucociliary clearance system, and the innate antibacterial and antiinflammatory properties of surfactant and airway surface liquid (Table 1421).3,4 Impairment of any of these protective barriers places a child at risk for the development of an aspiration syndrome. TABLE 142-1

Major Airway Defenses

Type of Defense

Mechanism

Upper airways

Mechanical trapping of bacteria in nasal passages and larynx, and frequent branching of upper bronchial tree

Mucociliary transport

Prevents most particulate matter in inspired air from reaching lung parenchyma

Cough reflex

Aspiration of large amounts of oropharyngeal material, including flora of the upper respiratory tract, may be prevented by cough and laryngeal reflexes

Local Immunoglobulin (primarily IgA), complement, and immunoglobulin glycoproteins such as fibronectin in airway secretions prevent colonization of the oropharynx by virulent organisms such as Streptococcus pneumoniae, Pseudomonas aeruginosa, and Klebsiella pneumoniae, which can readily cause

lower respiratory tract infection after scant aspiration of oropharyngeal contents Humoral and cellular defenses of lower respiratory tract

Nonspecific antibacterial activity of surfactant and airway surface fluid Immunoglobulin-mediated opsonization Opsonization or direct lysis by complement activation Phagocytosis and intracellular killing by alveolar macrophages Cell-mediated immunity (effector functions of T lymphocytes) Recruitment of polymorphonuclear leukocytes for phagocytosis and intracellular killing

The association between gastroesophageal reflux (GER) and the development of chronic respiratory symptoms or even aspiration pneumonia is not entirely understood. These disorders coexist, and the influence of this common gastrointestinal condition on respiratory function as well as the influence of respiratory conditions on GER, continues to be explored. Some literature suggests that reflux of gastric contents into the esophagus, as measured by pH probe, is associated with respiratory symptoms in children.5 Chronic microaspiration may explain some chronic respiratory symptoms.6,7 Further, certain respiratory conditions, including asthma, may worsen the severity of GER.7,8 Conversely, between 50% and 80% of children with chronic respiratory disease have some degree of GER. In addition to asthma, GER commonly accompanies cystic fibrosis and bronchopulmonary dysplasia.7,9,10 Other chronic medical conditions that are associated with an increased risk of aspiration syndromes are also associated with GER (Table 142-2).7 TABLE 142-2

Risk Factors for Aspiration Syndrome

Anatomic Tracheoesophageal fistula Gastrostomy or nasogastric enteral tube Tracheostomy Endotracheal tube Cleft palate or other craniofacial syndrome Pulmonary Bronchopulmonary dysplasia Bronchiolitis Respiratory distress Impaired airway reflexes (cough, gag) Sedation General anesthesia Toxic ingestion Medication Neurologic Cerebral palsy Neuromuscular disease Cerebrovascular accident Seizure Intracranial bleed Head injury Mass lesions Miscellaneous Impaired gastric motility Swallowing disorder, dysphagia Poor oral hygiene, gingivitis Although there is clearly a relationship among GER, recurrent aspiration, and respiratory disease, the specific interactions have not been fully elucidated.7,10 Nevertheless, acute and chronic respiratory disease related to

aspiration accounts for much of the morbidity and mortality in children with impaired gastric motility and swallowing disorders as well as in children with anatomic abnormalities of the aerodigestive tract, including tracheoesophageal fistula.3,7

ASPIRATION PNEUMONITIS Mendelson first described the clinical manifestations of the aspiration of gastric contents into the lower respiratory tract in 1946 in a patient who developed pneumonitis after receiving general anesthesia for an obstetric procedure.11 Any condition that depresses a child’s level of consciousness and impairs airway reflexes predisposes to aspiration. This risk factor includes exposure to alcohol, sedatives, paralytic agents, and other anesthetic agents.12,13 Loss of airway protective reflexes may also occur in children with central nervous system disorders (see Table 142-2).14,15 Infants and children with dysphagia and even respiratory distress are at increased risk of aspiration as well. Aspiration pneumonitis may occur after a witnessed episode of vomiting in a patient at risk. In such instances, a sudden change in respiratory status is often noted. However, aspiration pneumonitis may also present in a subacute fashion. It may exacerbate a preexisting condition such as cerebral palsy, or it may complicate a concurrent condition such as tachypnea in an infant with bronchiolitis. Aspiration pneumonitis should also be considered when there is a change in the respiratory status of a patient who is predisposed to aspiration (Figure 142-1).10

FIGURE 142-1. Acute multifocal pneumonia (A) in a medically complex patient presenting with acute-on-chronic respiratory failure. As part of a comprehensive evaluation, the patient underwent an

upper gastrointestinal study via the gastrostomy tube (B), which revealed a recurrent tracheoesophageal fistula in addition to an incompetent fundoplication. (Images used with permission of A. Chidekel, MD) Chemical injury to the lung may occur as a result of the inhalation of gastric acids, which are usually sterile due to their low pH.6,9 However, children receiving acid-suppressing or acid-blocking therapy (e.g. antacids, proton pump inhibitors) as well as children fed through gastrostomy or nasogastric tubes, often have an elevated gastric pH with consequent bacterial colonization of the stomach.9,16 Lung damage is related to the acidity of the aspirate, with a more pronounced inflammatory response occurring at lower levels of pH.6 Additionally, aspirates containing large amounts of particulate food matter increase the inflammatory response. With aspiration of acidic gastric contents, the fluid may be sterile, so bacterial infection is not a significant part of the early process. Aspiration pneumonitis may also occur in children who have ingested mineral oil (Figure 142-2) or hydrocarbons, which can cause severe respiratory compromise. The inhalation may occur during the ingestion or during the regurgitation that often follows. The risk of aspiration and the severity of the lung injury are related to the viscosity (volatility) of the ingested hydrocarbon; higher-viscosity liquids (e.g. oils), which are less volatile, are less dangerous than lower-viscosity liquids (e.g. furniture polishes), which have greater volatility.

FIGURE 142-2. Diffuse pulmonary infiltrates (A) in a neonate with aspiration pneumonitis from mineral oil administered as a home remedy for constipation. Bronchoalveolar lavage (BAL) cytology (B) revealed oil-red O-stained macrophages confirming the presence of lipoid pneumonia. (Images used with permission of A. Chidekel, MD.)

ASPIRATION PNEUMONIA

Aspiration pneumonia is an infectious process resulting from the inhalation of oropharyngeal secretions that are colonized by pathogenic bacteria. In contrast to aspiration pneumonitis, bacterial colonization and infection of the lower respiratory tract commonly occur. Children with dysphagia and impaired gastric motility as well as those with poor dental hygiene, are at risk for aspiration pneumonia, as are those with underlying neurologic and neuromuscular disorders.5,7,17,18 GER may predispose to the development of aspiration pneumonia; however, in a neurologically normal child, intact airway defenses such as the gag and cough reflexes usually prevent this complication.7,19 Enteral feeding through gastrostomy and nasogastric tubes also increases the likelihood of aspiration pneumonia.16,20 Patients with aspiration pneumonia may have either an acute or a gradual onset of symptoms, and the aspiration event is often unwitnessed. Critically ill children hospitalized in an intensive care setting often have multiple factors that predispose to the development of aspiration pneumonia.21 Children lying in the supine position for long periods are likely to have some degree of GER. Endotracheal intubation may also increase the risk of bacterial colonization and transmigration of bacteria from the upper to lower airway. The period immediately following removal of an endotracheal tube is also critical, because patients have depressed or impaired protective airway reflexes in the post-extubation period.12 Finally, gastroparesis and delayed gastric emptying are commonly observed among critically ill patients, including those with burns, significant trauma, and sepsis; all these conditions may increase a child’s risk of developing aspiration pneumonia.14 Much of the literature regarding the microbiologic cause of aspiration pneumonia is based on adult data from the 1970s and involved transtracheal sampling.22-24 These studies observed a predominance of anaerobic pathogens among adults with aspiration pneumonia, which differs from the typical pathogens responsible for community-acquired pneumonia. A similar study conducted in children hospitalized with aspiration pneumonia observed both aerobic and anerobic species.24 Organisms identified are listed in Box 142-1.4,25 More recent data, however, suggest that Streptococcus pneumoniae, Haemophilis influenzae, and Staphylococcus aureus account for most cases of aspiration pneumonia.4,26 Patients residing in long-term care facilities or those with frequent or prolonged hospitalization are at greater

risk for colonization with gram-negative organisms; Pseudomonas aeruginosa has emerged as a frequent etiologic agent in this population. Box 142-1 Organisms Causing Aspiration Pneumonia Gram-positive Streptococcus pneumoniae* Staphylococcus aureus* α-Hemolytic streptococci Gram-negative Haemophilis influenzae* Pseudomonas aeruginosa Acinetobacter Escherichia coli Klebsiella pneumoniae Anaerobic Bacteroides Peptostreptococcus Fusobacterium *Most common community-acquired pathogens.

DIFFERENTIAL DIAGNOSIS Community-acquired aspiration pneumonia may be clinically indistinguishable from community-acquired pneumonia without aspiration; however, an underlying disorder or other risk factor is usually present. Other respiratory processes that overlap clinically with pneumonia, such as bronchiolitis, asthma exacerbation (especially with an inciting febrile viral respiratory illness), and bronchospasm unrelated to an underlying asthma condition (e.g. inhaled chemical exposure), should be considered. Aspiration pneumonia is uncommon in otherwise healthy children without predisposing circumstances (e.g. general anesthesia).

CLINICAL PRESENTATION AND EVALUATION The diagnosis of acute aspiration syndromes is established by careful history and physical examination. Although a chest radiograph is often obtained, there are no specific diagnostic tests to confirm the diagnoses of aspiration pneumonia or pneumonitis.27 The diagnosis should be based on new respiratory signs or symptoms in a patient suspected to be at risk for aspiration or who has experienced an aspiration episode.

ASPIRATION PNEUMONITIS Following an aspiration event, there is immediate and direct injury of the airway and alveoli from the acidic fluid, followed by a second phase of intense inflammation. These events typically produce respiratory symptoms within a few hours and include cough, tachypnea, bronchospasm, and respiratory distress. Hypoxemia is common. These respiratory findings in a child with a depressed level of consciousness or another risk factor strongly suggest the diagnosis of aspiration pneumonitis, particularly if a preceding episode of emesis was witnessed or if there is a history of dysphagia or oral motor incoordination. Chest radiography may not be diagnostic, especially early in the illness, and the presence of fever is variable. Multiple factors contribute to hypoxemia, including direct alveolar damage; reflex bronchospasm in response to tracheal irritation; decreased surfactant activity, which leads to atelectasis and ventilation-perfusion mismatch; and intrapulmonary shunting.3,4,17 The symptoms of aspiration pneumonitis may range from severe to mild. Additionally, “silent” aspiration can present with hypoxemia and radiographic abnormalities without detectable symptoms. Chronic aspiration may present in a subacute fashion, with deterioration of the patient’s respiratory status occurring over a period of time.

ASPIRATION PNEUMONIA The diagnosis of aspiration pneumonia should be considered when a child at risk for aspiration develops an infiltrate in dependent lung segments. In a supine patient, the dependent portions of the lung are the posterior segments of the upper lobes; in an upright patient, the dependent portions are the basal

segments of the lower lobes. Other radiographic findings of aspiration pneumonia include abscess formation or cavitations.3 Radiographic findings are not always present in patients with aspiration pneumonia, and thus, the lack of radiographic findings should not exclude the diagnosis. Aspiration pneumonia may be clinically indistinguishable from community-acquired (nonaspiration) pneumonia; both typically present with fever, cough, and tachypnea, and consolidation may be detected on auscultation or chest radiography. Aspiration pneumonia is one predisposing cause of empyema caused by gram-negative bacteria. Most children with aspiration pneumonia have an underlying disorder predisposing to aspiration.

ADMISSION CRITERIA Hypoxia Moderate to severe respiratory distress or airway instability Failure of outpatient management strategies (e.g. home supplemental oxygen or oral antibiotics) Inadequate or unsafe nutritional strategy

TREATMENT The general treatment of a child with aspiration involves airway support and the maintenance of gas exchange. Airway clearance with inhaled medications such as albuterol, chest physiotherapy, or other devices may be indicated as well. Devices such as cough-assist machines may be particularly helpful in children with underlying neurologic or neuromuscular disorders, in whom airway clearance may be impaired (Table 142-3).17 These supportive therapies should be individualized to the patient’s clinical condition and needs. TABLE 142-3

Examples of Commonly Used Airway Clearance Techniques

Manual chest physiotherapy

Chest is clapped and vibrated to loosen secretions. Performed with or without postural

drainage. Mechanical percussion

Pneumatic or electrical devices are used to vibrate the chest to loosen secretions.

High-frequency chest wall oscillation

An inflatable vest is donned by the patient. The vest is inflated and vibrated to loosen secretions.

Vibratory positive expiratory pressure (PEP) therapy

The patient is instructed to exhale against a variable resistor that generates pulsations in the airway to loosen secretions.

Mechanical in-exsufflation

A device is used to provide pulses of positive pressure to expand the lungs and loosen secretions followed rapidly by pulses of negative pressure to clear secretions from the airway. Most often used in patients with neuromuscular disorders with a mask or mouth piece.

Intrapulmonary percussive ventilation

A device that provides vibratory pulses of air into the lungs to loosen secretions.

ASPIRATION PNEUMONITIS The treatment of patients with aspiration pneumonitis (including hydrocarbon aspiration) is primarily supportive. Suctioning of the mouth and oropharynx should be performed to remove particulate matter and gastric acid following a witnessed aspiration.3,4,17 Endotracheal intubation and the use of mechanical ventilation should be considered in any child with severe respiratory distress in the setting of aspiration pneumonitis. Prophylactic antibiotics are generally not indicated in the initial

management of a patient with aspiration pneumonitis. Patients in whom the gastric contents are not likely to be sterile (e.g. those receiving antacids or proton pump inhibitors) as well as patients with recent gastrointestinal surgery, may be more likely to develop infection, so antibiotics are often initiated. Any patient with significant illness or who fails to improve within 48 hours should be placed on empiric broad-spectrum antibiotics. For most patients, anaerobic coverage is not required. Obtaining bronchoalveolar lavage samples allows for targeted antibiotic therapy, particularly among patients with significant respiratory distress, other comorbidities, or those who fail to respond to initial therapy. There are insufficient data to recommend the use of corticosteroids in children with aspiration pneumonitis.28

ASPIRATION PNEUMONIA In contrast to the treatment of aspiration pneumonitis, antibiotics are an important component of therapy for children with aspiration pneumonia. Because pathogens are rarely recovered outside the research setting, antibiotic therapy is usually empirical. There is a paucity of prospective literature comparing antibiotic regimens among children with aspiration pneumonia. One randomized controlled trial conducted in 1997, found penicillin and clindamycin to be equally effective for the treatment of hospitalized children with aspiration pneumonia.25 Because more recent studies identify S. pneumoniae, S. aureus, and H. influenzae as the most common pathogens, ampicillin-sulbactam or a third-generation cephalosporin should be initiated as a first-line treatment for community-acquired aspiration pneumonia; alternatively, clindamycin can be used. For patients with uncomplicated aspiration pneumonia, the typical treatment duration is 7 to 10 days, though evidence regarding optimal duration of treatment is lacking.29,30 For patients at increased risk for infection from gram-negative organisms, coverage should be broadened to treat Pseudomonas aeruginosa. In this population, piperacillin-tazobactam or ticarcillin-clavulanate is an appropriate choice. Anaerobic coverage is particularly important in children with severe periodontal disease and in those with evidence of lung abscess or necrotizing pneumonia on chest radiograph.2 In these cases, if a third-generation cephalosporin is used, the addition of clindamycin or metronidazole is

recommended. Vancomycin should be administered if there is concern of methicillin-resistant Staphylococcus aureus infection.31 Systemic 28 corticosteroids are not indicated for aspiration pneumonia. Treatment of foreign body aspiration requires removal of the foreign body; usually no further treatment is needed.

CONSULTATION When the clinical picture is uncertain or a significant underlying disorder is contributing to an acute or chronic aspiration syndrome, subspecialty consultation should be considered. Acutely, pulmonology consultation may provide guidance for airway care in a patient with impaired airway clearance as well as bronchoscopy if the diagnosis is unclear. Foreign body aspiration may require otorhinolaryngology consultation for rigid bronchoscopy. Infectious disease input may be required to tailor antimicrobial therapy. In children with underlying risk factors for aspiration or impaired airway defenses, the subspecialist may recommend a specific plan of airway care and devices to help clear secretions and prevent atelectasis or mucus retention. Finally, in a child with chronic medical risk factors for aspiration or chronic respiratory and gastrointestinal symptoms, a multidisciplinary approach is required to address both the acute and the chronic aspects of the condition.

DISCHARGE CRITERIA Respiratory stability Ability to complete the required therapeutic regimens Adequate plan for airway management to minimize the risk of future aspiration episodes Safe and adequate nutritional plan

PREVENTION Because aspiration syndromes most often occur in patients with temporary or chronic impairment of airway protection, gastrointestinal dysmotility, altered gastric acidification, or swallowing difficulties, a targeted approach should be possible. Optimizing the safe delivery of nutrition and airway clearance

should be major clinical goals. Special precautions against aspiration should be in place for children with new neurologic deficits.32 Additionally, aspiration precautions should be in place for children undergoing sedation, general anesthesia, and removal of an endotracheal tube. KEY POINTS Aspiration syndromes represent a diverse group of pediatric lung and airway disorders; the two most common forms are aspiration pneumonitis and aspiration pneumonia. Aspiration pneumonitis is a sterile inflammatory process that typically follows inhalation of gastric contents. Aspiration pneumonia is a bacterial process that typically follows inhalation of infectious oropharyngeal secretions. The diagnosis of aspiration syndrome is generally clinical, with supporting radiographs. Treatment is supportive, but antibiotics play a key role in the management of aspiration pneumonia. Optimizing airway defenses, careful attention to airway maintenance and clearance, and a safe nutritional strategy may help prevent this condition in susceptible patients. There is a significant need for more sensitive and specific methods of diagnosing pulmonary aspiration. Similarly, evidence-based evaluation of supportive measures, such as inhaled medications and airway clearance devices for patients with chronic aspiration, is lacking. Improved diagnostic and therapeutic measures will enable physicians to formulate more efficient and efficacious therapeutic plans for this challenging group of patients.

SUGGESTED READING Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics. 1980;65:1115-1120.

REFERENCES 1. Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest. 1997;111:1266-1272. 2. Yoneyama T, Yoshida M, Matsui T, Sasaki H. Oral care and pneumonia. Lancet. 1999;354:515. 3. Cassiere HA, Niederman MS. Aspiration pneumonia, lipoid pneumonia, and lung abscess. In Baum GL, Crapo JD, Celli BR, Karlinsky JB, eds. Textbook of Pulmonary Diseases. 6th ed., vol 1. Philadelphia: Lippincott-Raven, 1998:645-655. 4. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344:665-671. 5. Weir KA, McMahon S, Taylor S, Chang AB. Oropharyngeal aspiration and silent aspiration in children. Chest. 2011;140:589-597. 6. Exarhos ND, Logan WD Jr, Abbott OA, Hatcher CR Jr. The importance of pH and volume in tracheobronchial aspiration. Dis Chest. 1965;47:167-169. 7. Orenstein SR, Orenstein DM. Gastroesophogeal reflux and respiratory disease in children. J Pediatr. 1988;112:847-858. 8. Simons JP, Rubinstein EN, Mandell DL. Clinical predictors of aspiration on radionuclide salivagrams in children. Arch Otolaryngol Head Neck Surg. 2008;134:941-944. 9. Bonten MJ, Gaillard CA, van der Geest S, et al. The role of intragastric acidity and stress ulcer prophylaxis on colonization and infection in mechanically ventilated ICU patients: a stratified, randomized, doubleblind study of sucralfate versus antacids. Am J Respir Crit Care Med. 1995;152:1825-1834. 10. Kikuchi R, Watabe N, Konno T, et al. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med. 1994;150:251-253. 11. Mendelson CL. The aspiration of stomach contents into the lungs during obstetric anesthesia. Am J Obstet Gynecol. 1946;52:191-205. 12. de Larminat V, Montravers P, Dureuil B, Desmonts JM. Alteration in swallowing reflex after extubation in intensive care unit patients. Crit

Care Med. 1995;23:486-490. 13. Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA. 1993;270:1965-1970. 14. Adnet F, Baud F. Relation between Glasgow Coma Scale and aspiration pneumonia. Lancet. 1996;348:123-124. 15. Leder SB, Cohn SM, Moller BA. Fiberoptic endoscopic documentation of the high incidence of aspiration following extubation in critically ill trauma patients. Dysphagia. 1998;13:208-212. 16. Grant MD, Rudberg MA, Brody JA. Gastrostomy placement and mortality among hospitalized Medicare beneficiaries. JAMA. 1998;279:1973-1976. 17. Johnson JL, Hirsch CS. Aspiration pneumonia: recognizing and managing a potential growing disorder. Postgrad Med. 2003;113:99112. 18. Healy F, Panitch HB. Pulmonary complications of pediatric neurological diseases. Pediatr Ann. 2010;39:216-224. 19. Borrelli O, Battaglia M, Galos F, et al. Non-acid gastro-oesophageal reflux in children with suspected pulmonary aspiration. Dig Liver Dis. 2010;42:115-121. 20. Srivastava R, Downey EC, O’Gorman M, et al. Impact of fundoplication versus gastrojejunal feeding tubes on mortality and in preventing aspiration pneumonia in young children with neurologic impairment who have gastroesophageal reflux disease. Pediatrics. 2009;123:338345. 21. Srivastava R, Berry JG, Hall M, et al. Reflux related hospital admissions after fundoplication in children with neurological impairment: retrospective cohort study. BMJ. 2009;339:b4411. 22. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med. 1974;56:202-207. 23. Lorber B, Swenson RM. Bacteriology of aspiration pneumonia: a prospective study of community- and hospital-acquired cases. Ann Intern Med. 1974;81:329-331. 24. Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics. 1980;65:1115-1120.

25. Jacobson SJ, Griffiths K, Diamond S, et al. A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children. Arch Pediatr Adolesc Med. 1997;151:701-704. 26. Marik PE, Careau P. The role of anaerobes in patients with ventilatorassociated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115:178-183. 27. Krishnan U, Mitchell JD, Vivian T, et al. Fat laden macrophages in tracheal aspirates as a marker of reflux aspiration: a negative report. J Pediatr Gastroenterol Nutr. 2002;35:309-313. 28. Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317:1565-1570. 29. Levison ME, Mangura CT, Lorber B, et al. Clindamycin compared with penicillin for the treatment of anaerobic lung abscess. Ann Intern Med. 1983;98(4):466-471. 30. Gudiol F, Manresa F, Pallares R, et al. Clindamycin versus penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus. Arch Intern Med. 1990;150(12):2525-2529. 31. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-e76. 32. Marks JH. Pulmonary care of children and adolescents with developmental disabilities. Pediatr Clin North Am. 2008;55:1299-1314.

CHAPTER

143

Bronchopulmonary Dysplasia and Chronic Lung Disease of Infancy Ian MacLusky

BACKGROUND Bronchopulmonary dysplasia (BPD) is an iatrogenic, chronic lung disorder of infancy that results in persistent respiratory symptoms, medical fragility, and in most cases, the long-term need for supplemental oxygen. With continuing advances in the care of critically ill neonates, the nomenclature of BPD is evolving, as is its incidence and pathogenesis. Today, BPD is often referred to as chronic lung disease of infancy (CLDI).1 Both BPD and CLDI are chronic pulmonary disorders that result from an acute and often critical respiratory illness in a newborn infant, and there is considerable overlap in their pathogenesis, risk factors, and manifestations. Thus, the two terms are generally considered to be interchangeable. BPD and CLDI develop in premature infants or critically ill neonates as a consequence of therapeutic maneuvers (oxygen and positive-pressure ventilation) required for survival. The risk of an infant developing BPD is related to gestational age, the severity of the initial illness, the duration and intensity of oxygen and ventilator therapy, and other factors that are less well characterized. These prognostic factors include variables specific to the infant, such as gender, race, genetic predilection, nutritional status, presence of patent ductus arteriosus, and other complications of newborn intensive care as well as maternal variables such as cigarette smoking during pregnancy and the presence of amnionitis.1 These factors often result in significantly different clinical courses and outcomes in infants despite apparently similar care. Most children with BPD have multisystem disease rather than isolated

pulmonary involvement. The medical fragility associated with BPD and CLDI results in an increased risk of re-hospitalization after discharge from the nursery. The pediatric hospitalist will therefore encounter infants with BPD and CLDI and will be called on to address the problems unique to this complex group of patients. Many infants with BPD or CLDI are readmitted to the hospital within the first 2 years of life, with the highest incidence of rehospitalization being in those born most prematurely.2 Respiratory illness, most notably due to respiratory syncytial virus (RSV) or other viruses, is the most common reason, causing up to two thirds of readmissions, followed by gastroenteritis, feeding difficulties, and seizures.2 Further, BPD and CLDI often have systemic manifestations that may complicate the respiratory management of these infants. If the extra-pulmonary manifestations are not recognized and addressed, they can interfere with lung growth and healing, which are necessary for the resolution of BPD and CLDI. Often the goal of therapy is to re-establish the infant’s baseline state or to diagnose and treat a new problem rather than to provide a definitive cure. This requires both skilled medical management and attention to the details of discharge planning.

CLINICAL PRESENTATION When originally described by Northway and colleagues,3 BPD occurred primarily in relatively mature infants with an average birth weight of nearly 2 kg and a gestational age of 32 weeks, who developed hyaline membrane disease due to surfactant deficiency, termed neonatal respiratory distress syndrome. These infants received what would now be considered aggressive therapy consisting of high levels of inspired oxygen and ventilator pressures that are toxic to the lung and result in a specific pattern of lung and airway injury (“classic” BPD).3 The adverse effects of oxygen and barotrauma affected primarily the distal airways, resulting in diffuse airway damage and airway obstruction that was either complete (resulting in atelectasis) or partial (resulting in a ball-valve effect and gas trapping).4 An intense inflammatory reaction ensued, which could hinder lung healing and promote further lung injury (see Figure 143-1 for pathological features of severe BPD). This nonspecific airway injury also resulted in distinctive and evolving radiographic manifestations (Figure 143-2). With a heterogeneous pattern of

focal gas trapping, atelectasis, and interstitial infiltrates followed by fibrosis (Figure 143-3).3

FIGURE 143-1. Lung pathology from an infant who succumbed to severe BPD with intractable respiratory failure demonstrating overdistended and simplified alveoli along with interstitial and interlobular scarring and inflammation.

FIGURE 143-2. Chest radiograph from an infant with evolving “new BPD” demonstrating reduced lung volumes along with diffuse and homogeneous ground glass infiltrates.

FIGURE 143-3. Chest radiographs from infants with established severe BPD demonstrating coarse interstitial markings with areas of overinflation and atelectasis (A) and severe diffuse overinflation and cystic changes (B). Owing to improvements in neonatal care and medical technology and recognition of the adverse effects of aggressive mechanical ventilation and oxygen therapy, few mature infants with hyaline membrane disease now

develop BPD. Concurrently, increasing numbers of infants born at less than 28 weeks gestation are surviving. In these infants, respiratory failure occurs due to lung immaturity as well as surfactant deficiency, because in extremely premature infants, the alveoli and peripheral airways are unformed. Oxygen therapy and mechanical ventilation necessary for survival cause alveolar growth arrest, resulting in pulmonary hypoplasia in addition to an element of peripheral airway damage and chronic inflammation (“new” BPD).5 Radiographically, the pattern is more homogeneous. Evolving medical practice and a better understanding of disease pathogenesis have resulted in altered disease definitions, incidence estimates, and risk factors. Northway originally defined BPD as occurring in any premature infant who still required oxygen past 28 days of age.3 Although various criteria have been proposed, most authorities agree that an infant should also be at least 36 weeks postconception.6 As shown in Table 143-1, a consensus conference proposed a severity-based definition of BPD for infants born at less than 32 weeks.7 This definition was recently validated to accurately identify infants at risk for adverse pulmonary and neurodevelopmental outcomes.8 TABLE 143-1

Bronchopulmonary Dysplasia: Diagnostic Criteria

Gestational Age 32 wk

36 wk PMA or discharge >28 d but 21% for at least 28 d plus

Mild BPD

Breathing room air at 36 Breathing room air by 56 wk PMA or discharge, d postnatal age or whichever comes first discharge, whichever comes first

Moderate

Need* for boys Polyarticular, RF negative

2–4 years

11–28

Polyarticular, RF positive

Late 2–7 childhood or adolescence

Arthritis of ≥5 joints for at least 6 weeks Symmetrical distribution Small joints of hands and feet are commonly involved Early joint erosions Subcutaneous nodules Girls >> boys

Systemic onset

Throughout childhood

Quotidian spiking fever

5–15

Arthritis of ≥5 joints for at least 6 weeks Insidious onset of joint symptoms Symmetrical distribution Small joints of hands and feet are commonly involved Girls > boys

Transient, salmoncolored rash Systemic features may precede arthritis Pericarditis and macrophage activation syndrome are potential complications Girls = boys Enthesitisrelated arthritis

Late 3–11 childhood or adolescence

Arthritis, more often in lower extremity joints Enthesitis involving heels, ankles, and knees Inflammatory spinal pain At risk for acute iritis Often positive for HLA B27 Boys >> girls

Psoriatic arthritis

Biphasic 2–4 years, 9–11 years

2–11

Arthritis and psoriasis Dactylitis, nail pitting, or family history of psoriasis Girls > boys

11–21

Variable

Undifferentiated

HLA, human leukocyte antigen; RF, rheumatoid factor.

The diagnosis of JIA is clinical, defined as joint swelling or limitation of

joint range of motion with joint pain or tenderness. These signs must be present consistently for at least 6 weeks in a patient younger than age 16 years. The annual incidence of JIA is estimated at 10 per 100,000 children, and the prevalence of JIA in the United States is about 1 in 1000 children younger than 16 years.2 Estimates of the actual number of American children with JIA vary between 70,000 and 100,000, including both active and inactive cases.

CLINICAL PRESENTATION Children with arthritis typically demonstrate stiffness after prolonged periods of inactivity, such as upon arising in the morning or after naps, long car rides, or sitting in class at school. Conversely, children with arthritis typically feel better after a warm bath or several minutes of activity. Cold, damp weather or swimming in cool water tends to be more difficult for children with arthritis, whereas warm weather generally relieves symptoms. Thus a child with arthritis may suffer joint stiffness in the morning but may be quite comfortable exercising strenuously later in the day. Pain is an unusual complaint in a child with JIA, and nighttime awakening is uncommon as well.3 Systemic-onset JIA, or Still’s disease, accounts for about 10% to 15% of all children with JIA. This is the subtype of JIA that most closely resembles an infectious disease. Although systemic-onset JIA can occur at any age, the peak age of onset is between 1 and 6 years. Boys and girls are equally affected. As its name implies, this is a systemic illness characterized by fever, rash, and arthritis. These children are often admitted to the hospital for evaluation of fever of unknown origin. The fever of systemic-onset JIA is described as quotidian or double quotidian; children typically have one or two spikes of fever greater than 39°C at about the same time every day. In between episodes of fever, the temperature returns to the baseline level or lower. The fever must be present for at least 2 weeks to be considered a diagnostic criterion. The rash of systemic-onset JIA is salmon pink, transient (lasting minutes to a few hours), nonpruritic, and migratory. It consists of discrete macules 2 to 5 mm in size, mostly on the trunk and proximal extremities. The rash often accompanies fever spikes, and it is typically seen after a shower. Rubbing or lightly scratching the skin elicits erythema

(Koebner phenomenon) and might be followed by the appearance of transient macular lesions. Fever and rash are found in systemic-onset JIA but are not part of the clinical picture of other subtypes of JIA. These symptoms may precede the onset of arthritis by days to months. Most children with systemiconset JIA develop chronic polyarthritis over time. Joint involvement is variable at disease onset, with anywhere from no joints to numerous joints being involved. Children with systemic-onset JIA also have laboratory evidence of systemic inflammation. The white blood cell count is usually elevated, with a predominance of neutrophils, accompanied by anemia and thrombocytosis; the erythrocyte sedimentation rate (ESR) is moderately to significantly elevated. Hepatosplenomegaly, lymphadenopathy, and serositis can also be seen in systemic-onset JIA. Polyarticular JIA is characterized by the presence of arthritis of at least 6 weeks’ duration in five or more joints. Polyarticular JIA accounts for 30% to 40% of cases of JIA and typically affects more girls than boys. Two distinct subtypes are recognized, based on the presence or absence of rheumatoid factor (RF). If the onset occurs during the first peak, at age 1 to 3 years, patients are generally RF negative. Girls affected during the second peak, just before puberty, have a disease that is more like adult rheumatoid arthritis, are RF positive, and have early erosions and often subcutaneous nodules. In both types of polyarticular JIA, the onset is generally insidious, with children gradually accruing additional swollen joints over time. Typically, the arthritis is symmetrical above and below the waist and between the left and right sides, and it often involves the small joints of the hands and feet. Fever is generally absent, but children may complain of fatigue, malaise, and anorexia. Polyarticular JIA may be accompanied by mild anemia and a modest elevation of the ESR. Synovitis in multiple joints may lead to chronic joint changes and bony erosions. Up to 50% of those with polyarticular JIA show radiographic abnormalities within 2 years of onset if not treated aggressively. Oligoarticular JIA, the most common type, accounts for about 40% of all children with JIA. It is characterized by the presence of arthritis in four or fewer joints during the first 6 months of disease. Oligoarticular JIA is more common in girls, and the onset age peaks between 2 to 4 years. Large joints are often involved, with the knee being most commonly affected. The arthritis can be asymmetric, and often only one joint is affected at presentation. Inflammatory markers are often normal or mildly increased.

Antinuclear antibodies (ANAs) are detected in about 60% of patients with oligoarticular JIA. The International League of Associations for Rheumatology (ILAR) classification distinguishes two subcategories of oligoarticular JIA depending on the number of joints involved after the first 6 months of disease. In persistent oligoarthritis, the arthritis is limited to four or fewer joints, and in extended oligoarthritis, the arthritis extends to more than four joints. About one-third of children with oligoarticular JIA go on to have extended oligoarthritis. In younger children, oligoarticular JIA often presents insidiously with refusal to walk or a limp in the morning that typically improves as the day goes on. Children seldom complain of pain, although parents may notice swelling of a knee or other large joint. This type has relatively few systemic signs such as fever. Enthesitis-related arthritis (ERA), affects ~10% of children with JIA. This subtype is characterized by arthritis and enthesitis (inflammation of tendon and ligament attachments). Most often the heels and knees are involved with enthesitis. The arthritis is more likely to involve the lower extremities. Inflammatory spinal pain and sacroiliac joint involvement can also be seen with this subtype. ERA typically affects boys after the age of 6. Most children are also positive for HLA-B27. In some cases, children present with just arthritis but have a positive family history of spondyloarthropathies in a first-degree relative. Children with ERA are at risk for painful acute anterior uveitis. Psoriatic arthritis is characterized by the presence of arthritis and psoriasis. In children without a characteristic rash of psoriasis, the diagnosis requires any two of the following: family history of psoriasis in a first-degree relative, dactylitis (swelling of a digit extending beyond joint margins), and nail pitting or onycholysis. Psoriatic arthritis comprises 2% to 11% of all JIA. There is a biphasic distribution, with an early peak at 2 to 4 years and a later one at 9 to 11 years. This subtype is more common in girls. Chronic asymptomatic uveitis can be seen with this subtype. Undifferentiated arthritis includes patients with JIA who do not satisfy criteria for inclusion in any of the other categories, or fulfill criteria for more than one category. As such, they do not have a characteristic pattern of arthritis. The ILAR criteria define several stringent exclusion criteria, which make it difficult to accurately classify some children with chronic arthritis. For instance, a child with an oligoarticular presentation who has two positive tests for RF, or systemic JIA in a boy after the age of 6, can result in a child

being placed in the “undifferentiated” category. Clinical management depends on the features of the disease in an individual patient.

COMPLICATIONS Macrophage activation syndrome (MAS) is rare, but it is the one complication of systemic JIA that is most likely to cause significant morbidity or mortality. It is discussed more fully in Chapter 151. MAS resembles hemophagocytic lymphohistiocytosis, which occurs as a familial form as a result of genetic abnormalities in natural killer T lymphocytes. It also occurs sporadically as a complication of malignancy or infection.4 In systemic-onset JIA, MAS most commonly occurs during the first 6 months of disease, during periods of active systemic inflammation that are often associated with a change in medication. MAS manifests as unremitting fever, unlike the spiking fevers of the underlying illness. Children may demonstrate bruising and mucosal bleeding from the consumptive coagulopathy seen in MAS, as well as mental status changes, hepatosplenomegaly, and diffuse lymphadenopathy. Activation of macrophages results in phagocytosis of erythrocytes, platelets, and leukocytes, so MAS should be suspected when patients with JIA present with a sudden drop in platelets, hematocrit, and white blood cells accompanied by an elevation of hepatic transaminases. Laboratory studies also demonstrate elevated triglycerides, ferritin, D-dimers, prothrombin time and partial thromboplastin time, and a fall in fibrinogen, ESR, and serum albumin. Other subtypes of JIA are not usually associated with MAS. Pericarditis is seen in about 3% to 9% of children with JIA, almost always in association with systemic-onset JIA. Older children are more likely to develop pericarditis, which may present as precordial chest pain, dyspnea, or discomfort referred to the back, shoulder, or neck, or it may be noted incidentally on chest imaging. Physical examination findings include tachycardia, cardiomegaly, or a pericardial friction rub at the lower left sternal border. Cardiac tamponade is a rare but serious complication of constrictive pericarditis. It is characterized by venous distention, hepatomegaly, and peripheral edema. Urgent evaluation and management are necessary to avoid progressive cardiovascular instability. JIA seldom causes parenchymal lung disease, but pleuritic chest pain due to a pleural effusion may accompany pericarditis or occur in isolation.

Anterior uveitis, or iridocyclitis, is a well-recognized and potentially serious complication of JIA. Uveitis in JIA is usually asymptomatic and chronic; it is most common in children with oligoarticular JIA (approximately 10%) and to a lesser extent RF-negative polyarticular JIA. A younger age, female gender, and positive ANA test increase the risk of iritis in most studies, although boys are at risk as well. Uveitis is rare in systemiconset JIA, occurring in less than 1% of cases. Acute uveitis, accompanied by pain and redness, may be associated with ERA. The detection of acute uveitis in a child suspected of having systemic-onset JIA should prompt a consideration of other causes of fever and rash, such as Kawasaki disease and acute viral infections. Children with longstanding polyarticular or systemic-onset JIA may develop involvement of the joints of the cervical spine. This can result in instability or fusion of the posterior elements, so care should be exercised when these children undergo procedures that require sedation or anesthesia. Preoperative flexion and extension views of the cervical spine may aid in the detection of cervical involvement and the avoidance of subluxation and injury to the spinal cord or brainstem with hyperextension.

DIFFERENTIAL DIAGNOSIS JIA is a clinical diagnosis made by history and physical examination. Care must be exercised in labeling a child with JIA before symptoms have been present for more than 6 weeks, because infectious arthropathies may be prolonged but ultimately transient. Conversely, although chronic inflammatory synovitis is seldom an emergency, acutely dangerous conditions must be excluded urgently in all cases. Thus a child with an acute febrile monoarthritis must be considered to have septic arthritis or osteomyelitis until proved otherwise, especially in the presence of elevated inflammatory markers. A new monoarthritis in an otherwise healthyappearing child may represent an acute post-infectious arthritis (see Chapter 152). Common causes of post-infectious arthritis include parvovirus B19, group A streptococcus, and Borrelia burgdorferi (Lyme disease). Systemic-onset JIA may be difficult to distinguish from severe infections, particularly when children present with fever before the onset of arthritis. The fevers of infectious diseases are usually hectic and spike less predictably than the fevers of systemic-onset JIA, and the fever often does not return to

baseline between spikes. Additional studies are essential in most cases to exclude other causes of prolonged unexplained fever such as infections, malignancies, and inflammatory bowel disease. When migratory arthritis and arthralgias accompany fever, acute rheumatic fever and serum sickness should be considered. Cutaneous and cardiac manifestations usually allow these conditions to be distinguished, although echocardiography may be necessary to exclude rheumatic fever. Children with either dermatomyositis or systemic lupus erythematosus can present with polyarthritis and fevers, but additional clinical or laboratory features of the underlying disease are typically present. Vasculitides such as Kawasaki disease and Henoch-Schönlein purpura often include arthritis among their symptoms. Other entities to consider are transient synovitis of the hip, slipped capital femoral epiphysis, and traction apophysitides (e.g. Osgood-Schlatter syndrome).

EVALUATION Laboratory tests may help rule out alternative diagnoses and classify the form of arthritis, but they are insufficient to confirm a diagnosis. Expected results from the complete blood count, ESR, and ANA are provided in Table 150-2. A positive ANA increases the risk for chronic uveitis. Rheumatoid factor is seen in about 5% to 10% of children with JIA, primarily in adolescent girls with RF-positive polyarticular JIA. Children with RF-positive polyarticular JIA are also often positive for anticyclic citrullinated peptide antibodies. TABLE 150-2

Type

Key Laboratory Features of Juvenile Idiopathic Arthritis

CBC

Oligoarthritis Normal

ESR Normal or mildly elevated

Likelihood of Positive ANA (%) RF/CCP 70

Negative

RF-negative polyarthritis

Mild anemia, Normal or mild mildly thrombocytosis elevated

RF-positive polyarthritis

Mild anemia, Mildly to 40 mild moderately thrombocytosis elevated

Positive for RF About 80% positive for CCP

ERA

Normal to mild anemia

5–10

Negative

Systemic

Leukocytosis, Elevated anemia, thrombocytosis

5–10

Negative

Psoriatic

Normal

30–60

Negative

Normal to mild elevation

Normal or mildly elevated

40

Negative

RF, rheumatoid factor; ANA, antinuclear antibody; CBC, complete blood cell count; ESR, erythrocyte sedimentation rate.

In healthy-appearing patients with a new monoarthritis, parvovirus B19 and Lyme titers and antistreptococcal antibodies are generally included in the initial evaluation. Evaluation for a septic joint is pursued if clinically indicated. At disease onset, imaging studies are usually normal, or they can show soft tissue swelling or effusions. Periarticular demineralization, narrowing of joint spaces, subchondral cysts, or bony erosions on plain radiographs are indicative of longstanding inflammatory arthritis. Plain radiographs are also helpful for identifying children with cervical spine abnormalities. Imaging is particularly useful when other diagnoses must be excluded. For example, lucent metaphyseal bands in the long bones of a child older than 2 years suggests a diagnosis of leukemia, especially when unexpectedly severe anemia or thrombocytopenia is also present. A radionuclide bone scan may

be helpful when osteomyelitis or malignancy is suspected, although the incidence of false positive results owing to minor trauma, altered weight bearing, and normal growth centers can significantly limit its utility. Similarly, magnetic resonance imaging is usually not necessary in a child with arthritis, although a contrast-enhanced scan may confirm the presence of subtle synovitis that is not clearly demonstrable on physical examination. When periarticular disorders are under consideration, magnetic resonance imaging may be useful because it provides clear images of adjacent soft tissues and bone. Arthrocentesis can be helpful in diagnosing JIA and excluding other causes of arthritis. Typically, synovial fluid in JIA is yellowish and cloudy, with white blood cell counts between 15,000 and 20,000 and a predominance of neutrophilic forms (75%). In septic arthritis, the fluid is usually serosanguineous and turbid, and the cell count is higher, often between 50,000 and 300,000, with more than 75% neutrophilic forms. Unlike in JIA, in septic arthritis the fluid has a low glucose level, and bacteria may be observed on Gram stain.

COURSE OF ILLNESS All subtypes of JIA tend to be characterized by remissions and relapses. In addition, it is not unusual for children with JIA to experience a flare of symptoms as a result of intercurrent infection. Systemic-onset JIA may follow a systemic course in which the fever, rash, and laboratory abnormalities persist. More commonly, it follows a polyarticular course, with arthritis persisting after resolution of the other systemic symptoms.5 Polyarticular JIA usually follows a chronic course over several years. About 30% of children with oligoarticular JIA have an extended oligoarticular course. Children with ERA may develop features of spondyloarthritis or inflammatory bowel disease. All subtypes of JIA have the potential to develop erosions or joint space narrowing after 2 to 5 years of persistent synovitis. Active synovitis can be detected in 30% to 55% of children with JIA 10 years after disease onset. Estimates of mortality in JIA range from 0.29 to 1.1 per 100 patients, severalfold higher than the standardized mortality rate for a similarly aged US population.

TREATMENT Children with JIA are best served by a comprehensive interdisciplinary team of healthcare providers that includes the primary care provider, pediatric rheumatologist, rheumatology nurse, social worker, and physical and occupational therapists. The aims of management in all types of JIA are to control pain, prevent and restore loss of motion in affected joints, improve overall functioning, and minimize the effects of inflammation on normal growth and development.6 Nonpharmacologic modalities such as moist heat can be especially helpful for relieving morning stiffness. The first line of pharmacologic management for all forms of JIA traditionally has been a nonsteroidal anti-inflammatory drug (NSAID). Naproxen is preferred by most rheumatologists for its ease of administration and pediatric labeling. It is usually administered at a dose of 10 to 20 mg/kg per day in two to three divided doses; as with all NSAIDs, 2 to 4 weeks of therapy is necessary before a child’s response to naproxen can be assessed. Alternative NSAIDs include meloxicam, nabumetone, ibuprofen, sulindac, tolmetin, and indomethacin. All should be administered with food to minimize gastrointestinal side effects such as abdominal pain, nausea, heartburn, or anorexia. Surveillance for gastrointestinal side effects of NSAIDs is extremely important, and H2 blocker or proton pump inhibitor therapy is often used in conjunction with NSAID therapy. Naproxen is associated with pseudoporphyria (small blisters that scar) or skin fragility in up to 10% of children; fair skin and blue or gray eye color are reported to be risk factors. Other NSAIDs are associated less often with increased skin fragility. Bruising or bleeding can also be seen with NSAIDs. In patients with systemic JIA, indomethacin can be particularly helpful to treat fever and pericarditis. Patients should be cautioned not to use other over-the-counter NSAIDs while on naproxen or a similar agent. However, acetaminophen can be used occasionally for fever or extra pain relief. Children on NSAIDs need a complete blood count, urinalysis, and levels of serum liver transaminases, blood urea nitrogen, and serum creatinine checked at baseline and every 3 to 6 months. It is important to note that all forms of JIA often require additional therapy beyond the use of NSAIDs.7 For children with oligoarticular JIA, arthrocentesis and injection of corticosteroids is often the second line of therapy. For children with other forms of JIA, medical management

frequently requires aggressive escalation of therapy using multiple agents. Corticosteroid therapy is often used as an adjunct to anti-inflammatory therapy in patients with JIA. The high frequency of side effects and lack of objective evidence that corticosteroids alter the long-term articular outcome weigh against the prolonged use of systemic corticosteroids in JIA. However, oral corticosteroids used at the lowest possible doses to minimize side effects may be useful in children with systemic-onset disease and significant and persistent systemic features such as fever. Because corticosteroids can mask other diagnoses and worsen infections, they should be used only after the diagnosis has been clearly established. Intra-articular steroid therapy in the form of triamcinolone hexacetonide is often effective in treating oligoarticular JIA, and can be used in other subtypes as well when there is persistent pain or inflammation in a few joints amenable to therapy. Topical corticosteroid ophthalmic preparations are used in the treatment of uveitis. Second-line or disease-modifying antirheumatic drugs (DMARD) are generally instituted by pediatric rheumatologists or others experienced in their use. However, the hospitalist is likely to encounter patients with an established diagnosis of JIA who are on these medications and are hospitalized for a flare of arthritis or other unrelated conditions. The following is a brief synopsis of some of the more commonly used medications.

NONBIOLOGIC DMARDS Methotrexate, a folate antagonist, is the most commonly used DMARD to treat polyarticular or systemic-onset JIA, or refractory oligoarticular JIA. Methotrexate is also used to treat children with uveitis with or without arthritis. Methotrexate is administered weekly by oral or subcutaneous routes; the latter is associated with better absorption and fewer gastrointestinal adverse effects. Although well tolerated in the majority of children, methotrexate may be associated with headache, nausea, or fatigue, usually within 1 or 2 days of administration. Oral mucosal ulcers are common unless children receive concurrent folic acid. More serious but less frequent side effects of methotrexate include leukopenia, hypersensitivity pneumonitis, and elevation of transaminases. These side effects may require modification of the dose or discontinuation of the drug. In some children intolerant to methotrexate, leflunomide may be administered. It is given orally daily or

every other day. Leukopenia and abnormal liver function tests can be observed which necessitate lowering the dose or discontinuing therapy. Older second-line medications such as hydroxychloroquine and sulfasalazine are used infrequently because more effective agents are available.

BIOLOGIC RESPONSE MODIFIERS The availability of biologic agents in particular has increased the therapeutic options for children with JIA. The most frequently used are directed against the cytokines tumor necrosis factor (TNF), interleukin 1, or interleukin 6. In addition, agents targeting T-cell costimulation and B-cells are also options for some children with JIA. All biological agents increase the risk of infection, including viral illnesses, severe bacterial infections, and reactivation of latent tuberculosis. A tuberculosis skin test should be performed before initiating treatment with a biologic agent and repeated annually. Biological agents can also exacerbate other serious bacterial or opportunistic fungal infections. Hence if a serious infection is suspected in a child on a biological agent, the medication should be withheld until the child is evaluated and appropriate antimicrobial treatment has been instituted. There is also concern that biological agents might increase the risk of malignancy in children with JIA.

ANTI-TNF AGENTS TNF is a proinflammatory cytokine known to be elevated in children with JIA. There are many agents targeting TNF, but three of them are currently used widely in children with JIA. Etanercept (Enbrel) is a soluble TNF receptor that binds TNF, thereby blocking its binding to cell surface receptors. It is given by subcutaneous injection once or twice weekly. The most frequent side effects are injection site reactions. Usually these are mild, manifesting as erythema, and do not warrant discontinuation of etanercept. Infliximab (Remicade) is a chimeric anti-TNF monoclonal antibody that binds to TNF, thereby neutralizing its biologic activity. The antibody is administered by intravenous infusion every 4 to 8 weeks. These infusions may be accompanied by fever, chills, myalgia, or headache. Premedicating with acetaminophen and diphenhydramine is often helpful. Adalimumab (Humira) is a fully humanized anti-TNF antibody given subcutaneously every other week. The most common adverse effect is a mild injection site reaction

manifested by a self-limited red rash or swelling. Cold compresses can be helpful in providing symptomatic relief. Adalimumab and infliximab are also used to treat refractory uveitis. Golimumab and certolizumab pegol are two other anti-TNF agents used in adults with RA.

OTHER BIOLOGIC AGENTS Anakinra (Kineret) is an interleukin-1 receptor antagonist. It is used primarily in the treatment of systemic onset JIA. Anakinra is given as a subcutaneous injection daily. Common side effects include injection site reactions. Other less commonly used anti-interleukin 1 agents include rilonacept and canakinumab. Tocilizumab (Actemra) is a monoclonal antibody against interleukin-6, which is elevated in systemic JIA. Actemra is indicated for use in children with JIA. It is also used in adults with RA. Actemra is given as an intravenous infusion every 2 weeks in systemic JIA. Infusion reactions might occur, and are minimized by premedicating with acetaminophen and diphenhydramine. Periodic monitoring is required to detect abnormal liver function tests, leukopenia, and thrombocytopenia or abnormal cholesterol. Abatacept (Orencia) targets T-cell activation via blockade of the costimulatory signal needed for T-cell proliferation. It can be administered either intravenously monthly, or by subcutaneous formulations. Rituximab (Rituxan) is a chimeric anti-CD20 antibody that binds and destroys CD20positive B cells. It is used in the treatment of adults with RA, and might be an option for some children with RF-positive polyarticular JIA. It is given as a set of intravenous infusions.

MANAGEMENT Ongoing pediatric rheumatology evaluation is important in the care of children with JIA. In addition, periodic evaluation by an ophthalmologist is needed to detect and treat chronic anterior uveitis. Uveitis in patients with JIA is often silent; they do not complain of eye pain and rarely present with a red eye. If undetected and untreated, uveitis can result in significant and irreversible loss of vision. For this reason, there is a recommended schedule of screening for uveitis based on type of JIA, age of onset, and ANA status. These guidelines should be strictly adhered to and can be found in the published policy statement of the American Academy of Pediatrics.8

Generally, children with JIA do well at school, and arthritis per se seldom accounts for absences. Rather, truancy is a warning sign of psychosocial difficulties. Nonetheless, children with significant arthritis might need special accommodations at school. Usually there is no need to restrict physical activity apart from avoiding direct trauma to joints, but children should be allowed to limit their activities as needed. Follow-up with a physical or occupational therapist should also be arranged to initiate a home exercise program to prevent or treat contractures, or for splints. JIA is a chronic illness, and families often have many concerns about the long-term consequences of the disease. The term arthritis may evoke images of crippled digits or wheelchairs, which are fortunately rare with today’s therapeutic options. The treatment of JIA should include education that addresses important issues such as peer relations, family dynamics, social adjustment, and vocational planning. Young adults with JIA treated by comprehensive multidisciplinary teams can surpass community standards in terms of level of schooling and professional attainment. The American Juvenile Arthritis Organization, a branch of the Arthritis Foundation, is an excellent source of information for newly diagnosed patients with JIA and their families; its link can be found at the Arthritis Foundation website (www.arthritis.org). Other sources of information include the National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health, (www.niams.nih.gov) and the American College of Rheumatology (www.rheumatology.org).

CONSULTATION Although a diagnosis of JIA can be straightforward, this is ultimately a clinical diagnosis that requires the exclusion of other causes of acute and chronic arthritis. The long-term management of children with JIA can be challenging, often involving the use of medications that require monitoring for adverse effects. Consultation with a pediatric rheumatologist, when available, can facilitate an early diagnosis and the prompt institution of appropriate medical management. Subspecialty consultation may also be helpful in the diagnostic evaluation and treatment of patients with JIA (Table 150-3). TABLE 150-3

Subspecialty Consultation to Consider in the Evaluation of Patients with Juvenile Idiopathic Arthritis Subspecialty

Potential Role

Infectious Diseases

To assist in evaluation of patients when fevers secondary to infectious disorders are suspected or in diagnostic evaluation when septic arthritis or osteomyelitis are included in the differential diagnosis

Cardiology

To assist in evaluation and management of chest pain, pericarditis, and pericardial effusions

Hematology/Oncology To assist in the evaluation of MAS or when malignancy is suspected Orthopedic Surgery

To assist with diagnostic evaluation to exclude septic arthritis or osteomyelitis

Physical/Occupational To preserve and improve range of motion Therapy and strength Ophthalmology

To screen for chronic (and clinically silent) anterior uveitis

Social Services

To assist in locating financial, educational, and social assistance

Mental Health Services

To assist in the management of affective disorders associated with chronic disease and to improve coping skills needed to manage a chronic disease and long-term medication therapy

MAS, macrophage activation syndrome

ADMISSION CRITERIA Evaluation of patients with suspected systemic-onset JIA for persistent fever, potential malignancy, or serious infection. Management of serious flares of disease associated with pain, disability, or non-articular organ system complications. Evaluation and teaching for patients with chronic disease and poor compliance with therapeutic regimens.

DISCHARGE CRITERIA Completion of evaluation for possible malignancy or serious infection. Resolution of fever and evidence of improving inflammatory markers. Establishment of a therapeutic regimen, including medication, physical or occupational therapy, ophthalmology, and social services. Discharge planning, including patient and family education and general pediatric and pediatric rheumatology follow-up. If on steroids, a plan for tapering the medication and monitoring for side effects, including measuring blood pressure and following urinalyses for glycosuria, should be considered. KEY POINTS JIA is among the most prevalent chronic diseases of childhood, affecting 1 in 1000 children younger than 16 years. Children with arthritis typically complain of joint swelling or morning stiffness; pain is unusual and suggests a mechanical rather than an inflammatory process. Aggressive treatment of synovitis with disease-modifying agents such as methotrexate and biologic agents such as anti-TNF monoclonal antibodies effectively controls arthritis and prevents long-term complications in most children. Periodic ophthalmic evaluation is an essential component of the care of children with JIA. Further refinement of biologic response modifiers, including targeted B- and T-cell monoclonal antibodies, will continue to

improve the safety and efficacy of therapy for JIA. Identification of genetically determined disease subsets will allow therapy to be individualized. Improved understanding of the pathophysiology of systemiconset JIA may necessitate its reclassification as an autoinflammatory rather than an autoimmune disorder.

SUGGESTED READINGS Clarke SL, Sen ES, Ramanan AV. Juvenile idiopathic arthritis-associated uveitis. Pediatric Rheumatol online J. 2016;14(1):27. Foster CS. Diagnosis and treatment of juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol. 2003;14:395-398. Horneff G. Update on biologicals for treatment of juvenile idiopathic arthritis. Exp Opin Biol Ther. 2013;13:361-376. Petty RE, Laxer RM, Lindsley CB, Wedderburn L. Textbook of Pediatric Rheumatology. 7th ed. Philadelphia: Elsevier; 2016. Prahalad S, Glass DN. Is juvenile rheumatoid arthritis/juvenile idiopathic arthritis different from rheumatoid arthritis? Arthritis Res. 2002;4(Suppl 3):303-310. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767-778. Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Pediatr Clin North Am. 2005;52:413-442.

REFERENCES 1. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390392. 2. Cassidy JR, Petty RE. Chronic arthritis in childhood. In: Textbook of Pediatric Rheumatology. 5th ed. Philadelphia: WB Saunders; 2005:206260. 3. McGhee JL, Burks FN, Sheckels JL, Jarvis JN. Identifying children with

chronic arthritis based on chief complaints: absence of predictive value for musculoskeletal pain as an indicator of rheumatic disease in children. Pediatrics. 2002;110:354-359. 4. Grom AA. Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum. 2004;50:689-698. 5. Oen K, Malleson PN, Cabral DA, et al. Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol. 2003;30:585-593. 6. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA. 2005;294:1671-1684. 7. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology Recommendations for the treatment of Juvenile Idiopathic Arthritis; initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63:465-482. 8. Section on Rheumatology and Section on Ophthalmology. Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 1993;.92:.295-296.

CHAPTER

151

Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome Melissa M. Hazen

BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are clinically related life-threatening immune dysregulatory processes characterized by fever, systemic inflammation, organomegaly, coagulopathy, and hematologic cytopenias. Both conditions may also include neurologic symptoms, often accompanied by cerebrospinal fluid and brain imaging abnormalities. HLH and MAS are defined histologically by the phagocytosis of hematopoietic cells by normal-appearing macrophages. This hemophagocytosis is most typically seen on samples from bone marrow aspirates, but it can also be seen in the spleen and in other lymphatic tissue. HLH may be inherited, as in the case of familial hemophagocytic lymphocytosis (FHL), or acquired. FHL is caused by genetic defects in proteins that mediate cytotoxicity in natural killer (NK) cells and cytotoxic T cells. These abnormalities lead to the impaired functioning of these cells, triggering cytokine storm and often cardiovascular collapse. Acquired HLH is typically triggered by viral infections, but it may also be associated with malignancies, acquired immunodeficiencies, and rheumatologic disorders. Historically, the diagnosis of FHL was made in infancy based on clinical criteria. With the discovery of several genetic mutations that lead to familial HLH, however, cases have been identified in older children and even adults,13 suggesting that HLH presenting at any age may be due to both inherited and acquired factors. This finding may have important implications for treatment. MAS typically exists in the context of severe rheumatologic diseases,

most commonly systemic-onset juvenile idiopathic arthritis (soJIA). Systemic lupus erythematosis (SLE) and Kawasaki disease may also permit the development of MAS, though at times MAS may be the presenting manifestation of the underlying rheumatologic disorder, greatly complicating diagnosis. MAS is considered a form of acquired HLH occurring in a specific population, and the term rheumatologic disease–associated HLH has been proposed, though the strict diagnostic criteria for HLH may not be met.4 The diagnosis of either HLH or MAS should be considered in an ill child with prolonged fever, organomegaly, elevated inflammatory markers, cytopenias, coagulopathy, neurologic symptoms, and/or evidence of liver dysfunction. A significantly elevated ferritin greater than 10,000 μg L−1 has been demonstrated to be a sensitive and specific marker of these hemophagocytic processes.5

PATHOPHYSIOLOGY FAMILIAL HLH To date, four FHL-associated genetic mutations have been identified. These mutations (Table 151-1) all affect the ability of cytotoxic cells, such as NK cells and cytotoxic T lymphocytes, to carry out the effective killing of target cells. Mutations in perforin vitiate the cytotoxic granules of cytotoxic cells, while the other genes associated with FHL affect cytotoxic granule exocytosis. Of note, HLH has also been associated with heritable primary immunodeficiencies, including Griscelli syndrome, Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome (XLP), and mutations in the ITK gene. HLH associated with XLP and ITK mutations is often triggered by Epstein-Barr virus (EBV) infection.4 TABLE 151-1

HLH Type FHL-1

FHL Types

Gene Unknown, localizes to long arm chromosome 9

Protein Expressed Unknown

FHL-2

PFR1

Perforin

FHL-3

UNC13D

Munc 13-4

FHL-4

STX11

Syntaxin 11

FHL-5

STXBP2 (UNC18B)

Munc 18-2

Source: Adapted from Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233-246.

ACQUIRED HLH/MAS Acquired HLH occurs in children without the described genetic mutations associated with familial HLH and is often triggered by infection, especially EBV. Children with some degree of acquired or iatrogenic immunocompromise, including those taking immunosuppressive drugs, infected with human immunodeficiency virus (HIV), or status-post stem-cell transplant, are at risk for developing HLH.4 Acquired HLH in the setting of autoimmune disease, most commonly soJIA and adult-onset Still disease, is known as MAS. Approximately 10% of patients with soJIA develop MAS, though as many as 30% to 50% of these patients have subclinical HLH.6,7 Several models seek to explain the manner in which known triggers interact with immunologic or inflammatory conditions to precipitate acquired HLH. The first parallels the model proposed for FHL in which the dysfunction of cytotoxic cells leads to the persistence of stimulated CD8+ T cells, driving interferon-gamma production and attendant cytokine-mediated toxicity. However, not all patients with MAS have defects in these cytotoxicity pathways, leading to hypotheses that alternative pathways may also lead to HLH, including repeated stimulation of Toll-like receptors and decreased production of IL-10.8 In both the acquired and familial forms of HLH, self-sustaining feedback of numerous proinflammatory substances, including cytokines and chemokines, leads to a dysregulated immune response and the characteristic clinical presentation.4,9

CLINICAL PRESENTATION

The diagnosis of HLH/MAS begins with considering hemophagocytosis as the cause of persistent fever in a very ill child with organomegaly, systemic inflammation, cytopenias, liver function abnormalities, or neurologic symptoms such as seizures, meningismus, or cranial nerve palsies. In addition, while many of these findings are nonspecific and can be associated with other disease processes, HLH and MAS are characterized by the severe and persistent nature of these findings. While most pediatric cases of FHL are diagnosed within the first year of life, new understanding of the spectrum of disease has led to diagnoses later in life.4,10 In addition, in the case of acquired HLH/MAS the presentation may be delayed and may occur in the context of a known autoimmune disease or may be the presenting event.

DIFFERENTIAL DIAGNOSIS Because the clinical characteristics of HLH and MAS are nonspecific, the differential diagnosis of these syndromes includes other systemic inflammatory processes, including infections, malignancies, metabolic disorders, and autoimmune diseases. It may be especially challenging to make the diagnosis of HLH or MAS in the setting of infection, as infection often triggers HLH/MAS in susceptible hosts. Therefore the isolation of an infectious agent does not rule out the possibility of HLH/MAS, as these entities may coexist. Similarly, the inability to improve the condition of a sick child with a systemic autoimmune disorder such as soJIA or SLE should raise the possibility of MAS rather than exclude it. In light of lymphadenopathy associated with HLH and MAS, lymphoma remains on the differential diagnosis. Other considerations, especially in the neonatal period, include metabolic abnormalities that may present with CNS involvement as well as hepatic dysfunction and enlargement.4

DIAGNOSTIC EVALUATION If HLH is suspected, in addition to a complete blood count, evaluation for hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia should be performed. More specific immune assays, including evaluation of NK cell numbers and function, as measured in a cytoxicity assay, can assist in identifying this disorder. Perforin, soluble CD25 (a.k.a. soluble IL-2 receptor

alpha) and soluble CD107a expression can be measured by flow cytometry and may be helpful in making the diagnosis. The criteria for the diagnosis of HLH have been formalized (Table 151-2). These criteria were designed to identify children with FHL who need a bone marrow transplant to survive, so they are quite restrictive. In an appropriate clinical setting, MAS may be diagnosed even when HLH 2004 criteria are not met. TABLE 151-2

HLH 2004 Diagnostic Criteria

The diagnosis of HLH can be established if one of either 1 or 2 is fulfilled: 1. A molecular diagnosis consistent with HLH 2. Diagnostic criteria for HLH fulfilled (5 out of 8 criteria below) (A) Initial diagnostic criteria (to be evaluated in all patients with HLH) Fever Splenomegaly Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood): Hemoglobin 20 mg/kg Elemental Iron)

Symptom

Laboratory Finding Treatment

Asymptomatic Negative KUB Observe for 6 hr—discharge home if no symptoms develop Asymptomatic Radiopaque pills on KUB

WBI and repeat KUB Determine electrolytes and SI 4-6 hr after ingestion Start deferoxamine if peak SI >500 μg/dL or metabolic acidosis

Symptomatic

Radiopaque pills on KUB

As above

or

Start deferoxamine by continuous infusion at a rate of up to 15 mg/kg/hr

Peak SI >500 μg/dL or Patient is symptomatic and SI cannot readily be obtained Symptomatic Hypotension, shock

Anion gap acidosis

Aggressive fluid resuscitation Consider CVVH if refractory acidosis Watch for cardiogenic pulmonary edema Dopamine and/or norepinephrine may be needed for refractory

hypotension Consider exchange transfusion Symptomatic

Hypoglycemia Watch for hypoglycemia and correct as needed

Acute liver failure

Coagulopathy FFP, cryoprecipitate as needed

FFP, fresh frozen plasma; KUB, abdominal radiograph; SI, serum iron concentration; WBI, whole-bowel irrigation.

Intravenous deferoxamine remains the mainstay of treatment after gut decontamination. Oral deferoxamine is not recommended. Deferoxamine may be administered intramuscularly, but the injections are painful and may cause local tissue inflammation. Once therapy with deferoxamine is instituted, clinical monitoring should include serial measurements of blood pressure, serum iron concentration (if available), hepatic transaminases, electrolytes, and the prothrombin time. Of note, serum iron levels may be falsely lowered by the presence of deferoxamine. Therapeutic end points for deferoxamine therapy include resolution of clinical symptoms and metabolic acidosis as well as narrowing of the anion gap. In the presence of deferoxamine, iron levels may not be accurate, but persistently elevated levels should raise concern. Recurrent symptomatology may warrant reinstitution of deferoxamine, which should be undertaken carefully and at a lower dose. The most dreaded complications of therapy with deferoxamine are Yersinia enteroeolitica septicemia and mucormycosis. The mechanism of this complication is unclear, but deferoxamine may provide the iron siderophore complex growth factor needed by the bacteria to induce overgrowth.10,11 Pulmonary toxicity, which is manifested as tachypnea, hypoxemia, fever, eosinophilia, preceding urticaria, and pulmonary infiltrates, may be seen in patients receiving both prolonged (>24 hours) and high (>15 mg/kg/hr) doses of intravenous deferoxamine.12-14 Hypotension, too, appears to be a doserelated effect. Ocular and otic toxicity has also been reported. Additional treatment modalities such as continuous veno-venous hemofiltration15 and exchange transfusion16 are under investigation for the severely iron-poisoned patient.

ADMISSION AND DISCHARGE CRITERIA Patients in whom signs of mild poisoning (continued vomiting, diarrhea) develop should be admitted for inpatient management. Patients who demonstrate serious systemic signs of toxicity (shock, central nervous system depression) should be considered candidates for an intensive care setting. Discharge from inpatient medical care may occur when symptoms and laboratory abnormalities have resolved and no clinical deterioration is noted after cessation of deferoxamine therapy.

ANTIHISTAMINES Over-the-counter antihistamines are ubiquitous and used for cold and allergy symptoms and as sleep aids. Most of the toxicity associated with an overdose of antihistamines is due to their anticholinergic effects. Two of the nonsedating antihistamines, terfenadine (Seldane) and astemizole (Hismanal), have been discontinued because of significant cardiac toxicity when combined with drugs that impair their metabolism through cytochrome 3A4, such as ketoconazole or erythromycin.17 Cardiotoxicity has not been reported with the use of fexofenadine (Allegra), cetirizine (Zyrtec), loratadine (Claritin), or azelastine (Astelin), all of which have limited anticholinergic side effects.18 A list of some common antihistamines is provided in Table 166-4. TABLE 166-4

Common Histamine Receptor Antagonists

Azelastine (Astelin) Bilastine (Bilaxten) Brompheniramine (Dimetane)* Cetirizine (Zyrtec) Chlorpheniramine (Chlor-Trimeton)* Cyclizine (Marezine)* Dimenhydrinate (Dramamine)* Diphenhydramine (Benadryl)*

Doxylamine* Fexofenadine (Allegra) Hydroxyzine (Atarax, Vistaril)* Loratadine (Claritin) Meelizine (Antivert)* Promethazine (Phenergan)* *Prominent anticholinergic symptoms.

CLINICAL PRESENTATION Absorption of antihistamines from the gastrointestinal tract is rapid, with the peak drug effect usually seen in 1 hour. However, after large ingestions, symptoms may not occur for several hours and may last for days. Patients who have taken an overdose of antihistamines may present with the classic anticholinergic toxidrome (Chapter 165). In addition, seizures are common after large overdoses of antihistamines. Some antihistamines, especially diphenhydramine, can cause wide-QRS tachyarrhythmias from sodium channel blockade19 as well as QT interval prolongation, placing patients at risk for malignant arrhythmias such as torsades de pointes.20 Antihistamines are often combined with other drugs in commercial products, so concomitant toxicity from sympathomimetic agents, acetaminophen, or dextromethorphan (see Chapter 169) may be encountered.

DIFFERENTIAL DIAGNOSIS Other toxicologic causes of an anticholinergic toxidrome as seen in antihistamine ingestion include poisoning from agents such as tricyclic antidepressants (i.e. amitriptyline, nortriptyline), atypical antipsychotic medications (i.e. quetiapine, olanzapine), skeletal muscle relaxants (i.e. cyclobenzaprine), antispasmodics (i.e. Donnatal, Lomotil) or ingestion of anticholinergic alkaloid plants (i.e. jimsonweed, deadly nightshade, Amanita muscaria mushrooms).

DIAGNOSTIC EVALUATION

The toxic effects of antihistamines are due mostly to anticholinergic phenomena through inhibition of both central and peripheral muscarinic cholinergic receptors. The diagnostic course for patients with a suspected overdose of antihistamines depends somewhat on the symptomatology and dose ingested. The mean dose in symptomatic children was 17.3 mg/kg in a study of 184 cases; deaths have been reported with doses as low as 33 mg/kg.21 The delirium associated with anticholinergic poisoning may lead to evaluation for central nervous system infection. Acetaminophen levels are of particular importance because many cold products contain both antihistamines and acetaminophen. Diphenhydramine may result in a falsepositive urine immunoassay for phencyclidine (PCP). Electrocardiographic evaluation, specifically checking for widening of the QRS, is warranted to look for signs of impending arrhythmia as well as the possibility of coingestants.

MANAGEMENT Activated charcoal may reduce the absorption of antihistamine drugs if administered soon after ingestion. Inpatient care should be directed at symptoms (Table 166-5). Benzodiazepines may help decrease agitation and tachycardia. Physostigmine should be considered for both diagnosis and symptom management.22 The benefits of physostigmine, which include restoration of gastrointestinal motility and improvement in mental status, must outweigh the potential risks (worsening of cardiac conduction delays). Physostigmine may be used safely when the patient has a narrow QRS complex on electrocardiography and no evidence of ingestion of other agents (e.g. class IA or IC antiarrhythmics, tricyclic antidepressants) that may cause intraventricular conduction delays. Intravenous access and cardiovascular monitoring must be established before the use of physostigmine. The initial dose of physostigmine, 0.02 mg/kg in children or 1 to 2 mg in adults, may be administered by slow intravenous infusion every 5 minutes until the anticholinergic symptoms are reversed. Additional physostigmine should not be administered if significant cholinergic symptoms develop, particularly bradycardia or excessive salivation. A dose of atropine, approximately half the dose of physostigmine, should be readily available. Redosing of physostigmine may be needed every 30 to 60 minutes. Patients considered at high risk for the development of seizures may be coadministered a

prophylactic dose of benzodiazepine. TABLE 166-5

Symptom

Treatment of Antihistamine Overdose Treatment

Agitation/delirium Physostigmine IV over 5-min period (adults, 1-2 mg; pediatric, 0.02 mg/kg)

Comments Electrocardiographic conduction delay (prolonged PR, wide QRS) is relative contraindication for physostigmine

Benzodiazepines IV Seizures

Benzodiazepines IV Physostigmine IV over 5-min period (adults, 1-2 mg; pediatric, 0.02 mg/kg)

In the setting of tricyclic antidepressant overdose, use of physostigmine has been associated with seizures and intractable cardiac arrest

Hyperthermia

Cool bath, fans, sedation

Ventricular arrhythmia

Sodium bicarbonate bolus (1-2 mEq/kg), then drip (in D5W)

Monitor electrocardiogram continuously; monitor serum electrolytes and arterial blood gases

Lidocaine bolus (1 mg/kg), then drip as needed (20-50 μg/kg/min)

Goal serum pH, 7.45-7.55 Continue 24 hr past end points of cessation of dysrhythmias, normalization of QRS complexes

Other tachyarrhythmia

Supportive treatment if hemodynamically stable

See above

May consider beta-blocker (propranolol) May consider physostigmine if refractory Torsades de pointes

Cardioversion Magnesium sulfate IV (adults, 2-6 g; pediatric, 25-50 mg/kg) Overdrive pacing

Rhabdomyolysis

Fluid resuscitation, urinary alkalinization, and maintenance of urine output at 1-2 mL/kg/hr

D5W, 5% dextrose in water.

ADMISSION AND DISCHARGE CRITERIA Patients displaying persistent changes in mental status, abnormalities in vital signs, electrocardiographic changes, or seizures should be admitted to the hospital. The severity of symptomatology may warrant admission to an intensive care setting. Discharge from inpatient medical care may occur when the patient has

become asymptomatic and no further drug absorption is anticipated.

ACETAMINOPHEN Acetaminophen, also known as paracetamol, is responsible for a large number of toxic ingestions in children each year.1 Hepatic injury is the most frequent cause of morbidity and mortality after an overdose of acetaminophen. Extensive clinical research and experience have allowed clinicians to better predict and prevent the development of hepatotoxicity.23,24 Most forms of acetaminophen are rapidly absorbed after ingestion. Extended-release acetaminophen preparations have similar pharmacokinetics as the regular-release formulations, with peak levels occurring less than 4 hours after ingestion.25 Recent FDA approval of intravenous acetaminophen presents a novel formulation of acetaminophen with potential for toxicity.26 Acetaminophen is metabolized almost exclusively in the liver; approximately 90% is glucuronidated or sulfated, 5% is excreted unchanged in urine, and the remaining 5% is oxidized by liver cytochrome enzymes, specifically CYP2E1, CYP1A2, and CYP3A4. Oxidation produces the reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI). In conditions of therapeutic dosing, NAPQI is detoxified by glutathione, whereas in conditions of decreased glutathione stores, large doses of acetaminophen, or induction of cytochrome enzymes, NAPQI overwhelms the capacity of glutathione. Free NAPQI binds to hepatocytes and causes hepatocellular damage. The risk for hepatocellular injury can be assessed by the dose ingested, the acetaminophen level, or both. In acute ingestion, patients who take more than 200 mg/kg (children) or 7.5 g (adults) are at risk for acetaminophen toxicity. Some patients who chronically exceed the recommended doses of acetaminophen appear to be particularly at risk for hepatotoxicity; such patients include those with preexisting liver disease, children with acute febrile illnesses, and patients who chronically ingest inducers of CYP2E1.2729

CLINICAL PRESENTATION

Patients who have been exposed to toxic doses of acetaminophen may have a paucity of findings on physical examination. Acetaminophen toxicity is divided into four clinical stages, and the findings of each phase are presented in Table 166-6.30 TABLE 166-6

Stages of Acetaminophen Toxicity

Time after Stage Ingestion

Clinical Findings

I

0.5 to 24 hr

Anorexia, nausea, vomiting, malaise, pallor, diaphoresis

II

24 to 48 hr

Resolution of early symptoms; right upper quadrant abdominal pain and tenderness; oliguria, elevated hepatic transaminases, prothrombin time, bilirubin,

III

72 to 96 hr

Peak of liver function abnormalities Reappearance of anorexia, nausea, vomiting Onset of fulminant hepatic failure with metabolic acidosis, coagulopathy, and renal dysfunction Changes in mental status, encephalopathy

IV

4 days to 2 wk

Resolution of hepatic dysfunction or progression to oliguric renal failure and death

DIFFERENTIAL DIAGNOSIS The early signs and symptoms of acetaminophen toxicity are nonspecific and represent a large nontoxicologic differential diagnosis. The pattern of acute

liver injury seen in acetaminophen toxicity can also be seen in iron toxicity and Amanita phalloides mushroom poisoning.

DIAGNOSTIC EVALUATION Initial laboratory analysis for a patient with a known acetaminophen overdose should begin with a serum acetaminophen level. Acetaminophen levels should be obtained in all cases of intentional overdose because acetaminophen is a frequent coingestant. Levels obtained before 4 hours after ingestion are difficult to interpret. The standard acetaminophen nomogram may be used to predict the risk for acetaminophen toxicity in patients in whom levels were obtained 4 hours or longer after a single, acute ingestion (Figure 166-1).

FIGURE 166-1. The Rumack-Matthew nomogram relating expected severity of liver toxicity to serum acetaminophen concentrations. (From Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20:1058.) In the United States, the lower line of the nomogram is used as the clinical indicator to begin treatment. Additional laboratory evaluation should consist of measurement of hepatic transaminases and determination of liver synthetic function (coagulation studies) and renal function. Repeated supratherapeutic overdoses of acetaminophen cannot be plotted on the nomogram.

MANAGEMENT N-acetylcysteine (NAC) is effective when administered by both the oral and intravenous routes. A 72-hour oral regimen has historically been used in the United States; the intravenous preparation is now more widely used due to its ease of use and shorter treatment course (21 hours). The intravenous regimen is as efficacious as oral treatment, and adherence to the full treatment protocol is better with the intravenous version. Some research has suggested that the oral treatment regimen may be more effective for patients with late presentation or chronic supratherapeutic ingestions.31 No deaths from hepatic injury have been reported in patients treated with NAC within 8 hours of overdose. No serious complications have been reported after the use of oral NAC.32 In contrast, intravenous NAC has been shown to cause urticaria, anaphylactoid reactions, and rarely, death.33,34 The risk seems to be highest in asthmatic patients. Intravenous NAC is preferred in patients with intractable vomiting despite the use of antiemetics, fulminant hepatic failure (FHF), or pregnancy. The treatment regimen for oral NAC is a loading dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for a total of 17 doses (not including the loading dose). Shorter courses have been proposed.35 Patients with persistent laboratory abnormalities may benefit from NAC past the standard 72-hour regimen. NAC may be given intravenously as a 3% solution (in 5% dextrose) as follows: 150-mg/kg loading dose over a 1-hour period, then 50 mg/kg over a 4-hour period, and then 100 mg/kg over a 16-hour period. The last infusion may be continued beyond 16 hours if evidence of liver injury develops. Transaminases, liver synthetic function (coagulation studies), and renal function should be checked initially and daily during therapy in any patient with a serum acetaminophen concentration above the treatment nomogram line. Worsening hepatic function may necessitate more frequent laboratory studies. Patients who demonstrate hepatotoxicity despite treatment with NAC will need further clinical and laboratory monitoring, including the prothrombin time, international normalized ratio (INR) clotting measure, arterial pH, lactic acid, and serum creatinine. Patients with an INR greater than 2 at 24 hours, 4 at 48 hours, or 6 at 72 hours are at high risk for the development of FHF. Any patient in whom FHF develops should be referred for possible liver transplantation. Criteria for referral and transplantation are found in Table 166-7.

TABLE 166-7

Criteria for Transplantation

Prothrombin time >100 seconds or INR >6 and Serum creatinine >3.3 mg/dL and Grade III or grade IV hepatic encephalopathy or Arterial pH 3 mmol/L that fails to correct with IV fluids Source: Adapted from Makin AJ, Williams R. Acetaminophen-induced hepatotoxicity: predisposing factors and treatments. Adv Intern Med. 1997;42:453-483. FHF, fulminant hepatic failure; INR, international normalized ratio.

ADMISSION AND DISCHARGE CRITERIA Treatment with NAC is the mainstay of acetaminophen poisoning and necessitates admission to the hospital. For a single, acute overdose taken at a known time, NAC should be administered to all patients with an acetaminophen level in the “possible and probable hepatotoxicity” range. When the time of ingestion is unknown or in cases of repeated supratherapeutic overdoses, NAC may be administered while the acetaminophen is eliminated and hepatic transaminases are monitored. Demonstration of a normal serum aspartate transaminase (AST) level 36 hours after acetaminophen ingestion essentially eliminates the possibility of liver toxicity.36 In the face of hepatic toxicity, a decline in the serum AST level may indicate clinical recovery or complete hepatocellular death and must be interpreted in the context of liver function. Patients suffering hepatic toxicity may be discharged once hepatic recovery is clearly in progress.

SALICYLATES From its introduction 100 years ago, aspirin (acetylsalicylic acid) has remained a mainstay of clinical medicine. Despite the development of newer

and more specific nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin continues to be widely used because of its multiple applications and benefits. Although reported cases of aspirin toxicity have declined in the last two decades, aspirin still accounts for tens of thousands of cases reported to poison control centers and approximately 30 deaths each year. Moreover, aspirin has a significantly higher fatality ratio than acetaminophen or ibuprofen.1 In addition to aspirin, other salicylate-containing products are commonly used, including liniments for arthritis, acne creams, sunscreens, antidiarrheals, and Chinese proprietary medications. There are also numerous combination preparations of aspirin.

CLINICAL PRESENTATION Salicylates produce analgesic, antipyretic, and anti-inflammatory effects, mostly through inhibition of cyclooxygenase and a subsequent decrease in the production of prostaglandins. Therapeutic doses of acetylsalicylic acid, 10 to 20 mg/kg for children and 650 to 1000 mg every 4 to 6 hours for adults, produce a serum salicylate level of 3 to 6 mg/dL. Of note, there are several circumstances, including Kawasaki disease and rheumatoid arthritis, in which high-dose therapy is used, with dosing in the range of 80 to 100 mg/kg. Evidence of toxicity usually appears around serum levels of 30 mg/dL. The potentially toxic acute dose is greater than 150 mg/kg, whereas chronic toxicity may occur with doses that exceed 100 mg/kg/day.37 Toxic doses for other salicylate formulations may be calculated by using known aspirin equivalencies. Salicylates are absorbed in the stomach and proximal part of the intestine. Peak serum levels in therapeutic doses occur at 1 to 2 hours (4 to 6 hours for enteric-coated tablets) but may be delayed to 10 to 60 hours in cases of overdose.38,39 The most notorious reason for delayed absorption is an aspirin bezoar, but other causes include enteric-coated products, contraction of the pylorus, and delayed gastric emptying from coingestants. The elimination half-life of salicylate in therapeutic doses is 4 hours, but it increases to 15 to 29 hours with toxic plasma levels.38 The pathophysiology of salicylate toxicity is complex. Salicylates directly stimulate the respiratory center of the medulla and result in hyperventilation

and hyperpnea. In an attempt to compensate for the respiratory alkalosis, the kidney excretes bicarbonate, thereby producing metabolic acidosis. This metabolic acidosis is exacerbated by the salicylate-driven uncoupling of mitochondrial oxidative phosphorylation, which causes an increase in oxygen consumption and carbon dioxide production as well as accumulation of lactic and pyruvic acids.40 Disruption of Krebs cycle metabolism leads to gluconeogenesis, lipolysis, and increased ketone formation. The salicylate ion itself contributes very little to the metabolic acidosis. The differential diagnosis of anion gap acidosis should be considered. The pathophysiology of the most common presenting symptoms in salicylate toxicity is found in Table 166-8. TABLE 166-8

Pathophysiology of Symptoms in Salicylate Toxicity

Symptom

Pathophysiology/Etiology

Nausea, vomiting, and epigastric discomfort

Gastrointestinal irritation

Tinnitus and deafness

Vasoconstriction of the auditory microvasculature

Sweating, hyperpyrexia, and dehydration

Uncoupling of mitochondrial oxidative phosphorylation and increased metabolism of skeletal muscle

Dehydration

Decreased oral intake, vomiting, tachypnea, diaphoresis, and obligatory early diuresis

Hyperpnea and tachypnea

Direct stimulation of the medullary respiratory center

Stimulation of the medullary chemoreceptor trigger zone

Disorientation, hallucinations, Acidosis, cerebral edema lethargy, agitation, coma,

and seizures Noncardiogenic pulmonary edema

Leukotriene-induced increased permeability of the microvasculature

Renal failure Acid-base disorders (e.g. respiratory alkalosis, mixed respiratory alkalosis, and anion gap metabolic acidosis)

Combination of direct stimulation of the medullary respiratory center (respiratory alkalosis) with renal compensation (metabolic acidosis) and uncoupling mitochondrial respiration (metabolic acid acidosis)

Hypokalemia and hyponatremia or hypernatremia

Increased renal excretion of potassium/sodium because of the anion drag of bicarbonate Hypernatremia may ensue if free H2O is lost in excess of salt in the kidneys and sweat

Hypoglycemia/hyperglycemia Salicylates enhance insulin secretion from pancreatic islet cells (hypoglycemia); also decrease peripheral glucose utilization (hyperglycemia) Hypoprothrombinemia

DIFFERENTIAL DIAGNOSIS The signs and symptoms of salicylate toxicity are common in other disorders, and represent a large nontoxicologic differential diagnosis. Other possible toxicologic etiologies include agents that cause anion gap metabolic acidosis including toxic alcohols, iron, isoniazid, massive ibuprofen ingestions, and metformin toxicity. The metabolic profile of primary respiratory alkalosis with a primary metabolic acidosis is very suggestive of salicylate toxicity,

especially in the setting of tinnitus, tachypnea, or vomiting.

DIAGNOSTIC EVALUATION Evaluation of salicylate toxicity should begin with assessment of the chronicity of the toxicity. Patients with chronic toxicity can be identified by historical clues such as extremes of age, chronic medical problems, and mental status changes out of proportion to the serum salicylate level, late presentation, and severe dehydration. Laboratory studies should include a serum salicylate level, serum chemistry panels, coagulation profile, and blood gas analysis. Evaluation for other coingestants is warranted. A chest radiograph may be indicated to evaluate for noncardiogenic pulmonary edema or aspiration pneumonitis.

MANAGEMENT As stated earlier, peak salicylate levels may be significantly delayed. Serial salicylate levels should be obtained at least every 2 to 4 hours until they are clearly decreasing, then every 4 to 6 hours until less than 30 mg/dL. Units (mg/dL versus mg/L) should be confirmed before declaration of toxic levels because there is some variability among hospitals in units of measure. The Done nomogram is no longer recommended for prediction of the severity of salicylate toxicity. Serum levels that have wide vacillations or seem to be rising despite treatment may indicate the presence of a bezoar. Treatment of salicylate toxicity centers around gastrointestinal decontamination and correction of fluid, electrolyte, and acid-base disturbances.41 Strict measurement of urine output is necessary. The various modalities for treatment of salicylate toxicity can be found in Table 166-9. Special note should be made to clinicians regarding the dangers of assistance with ventilation. Patients with salicylate-induced hyperpnea may be easily misdiagnosed as being in imminent respiratory failure. However, endotracheal intubation in these patients is a particular risk and may contribute to mortality.42 Mechanical ventilation rarely achieves the degree of respiratory alkalosis attained by unassisted ventilation, and the worsening acidosis associated with sedation and paralysis increases entry of salicylate into the brain. Moreover, mechanical ventilation should never be considered

an adequate substitute for intravenous bicarbonate therapy and, if necessary, hemodialysis. TABLE 166-9

Treatment of Salicylate Toxicity

Treatment Method

Comments

Activated charcoal

MDAC useful in cases of prolonged absorption Uncertain whether MDAC adds benefit once urinary alkalinization is achieved

1 g/kg PO initially Repeat doses of 25 g or 0.5 g/kg at 2-4 hr

Urinary 1-2 mEq/kg of NaHCO3 by IV alkalinization bolus, then D5W with 100-150 mEq/L NaHCO3 at 1-2 times maintenance requirements

Traps ionized salicylate in proximal tubule Start when salicylate levels >30 mg/dL Goal is urine pH of 7.5-8.0 (should be monitored hourly) Also monitor serum pH (should be 7.457.55) Watch carefully and correct for hypokalemia or other electrolyte imbalances Watch for fluid overload

Indications for hemodialysis

Serum levels >100 mg/dL with acute ingestion Serum levels >60 mg/dL with chronic intoxication Pulmonary edema Renal failure Congestive heart failure No response to standard therapies Altered mental status and acidemia

D5W, 5% dextrose in water; MDAC, multiple-dose activated charcoal.

ADMISSION AND DISCHARGE CRITERIA Patients who have a history of significant exposure (>150 mg/kg) should be admitted to the hospital. Other criteria for admission include rising salicylate levels, acidosis, coagulopathy, mental status changes, or persistent abnormalities in vital signs. Admission to an intensive care setting may be warranted for patients with abnormal mental status, severe acidosis, renal failure, or coagulation abnormalities. Discharge from inpatient medical care may occur when the patient has been asymptomatic and has serial falling salicylate levels below 30 mg/dL after cessation of bicarbonate therapy.

ORAL HYPOGLYCEMICS Non-insulin-dependent diabetes mellitus (NIDDM) affects 4% to 6% of adults in industrialized countries, with approximately 18.8 million affected individuals in the United States alone.43 NIDDM is a growing entity in the pediatric population as well. Oral hypoglycemics are the mainstay of treatment of NIDDM. As more patients are diagnosed with NIDDM and are prescribed these mediations, the risk of unintentional pediatric ingestions

increases.44 A brief review of glycemic control is necessary to better understand the mechanism of toxicity after an overdose of oral hypoglycemics. Glycemic control is achieved through the careful balance of hormonal, neural, and substrate mechanisms. Plasma glucose is maintained within a narrow range of 72 to 144 mg/dL. In conditions of hyperglycemia, pancreatic beta cells secrete insulin. Insulin binds to the insulin receptor, which unleashes a signaling cascade. The biologic activity of insulin results in a decrease in plasma glucose that occurs by inhibition of hepatic glucose production, increased glucose uptake, and increased glycogen stores in insulin-sensitive tissues. Hypoglycemia is corrected by the counterregulatory hormones glucagon, epinephrine, norepinephrine, cortisol, growth hormone, and adrenocorticotropic hormones. The initial response to hypoglycemia is release of glucagon, secreted from pancreatic alpha cells. Glucagon acts on the liver to increase glycogenolysis and gluconeogenesis.45 Epinephrine, synthesized in the adrenal medulla, constitutes the bulk of circulating catecholamines released in response to hypoglycemia.45 Epinephrine works primarily through β2-adrenergic receptors to increase plasma glucose by indirect stimulation of lipolysis. Cortisol is necessary for the liver to respond appropriately to glucagon and epinephrine. Long-standing hypoglycemia raises plasma cortisol levels, thereby reducing the autonomic adrenomedullary response to subsequent hypoglycemia. The combination of hypoglycemia-induced autonomic failure and glucagon depletion that occurs in patients with NIDDM increases the risk and decreases the awareness of severe hypoglycemia.46 The oral hypoglycemics work by either increasing insulin production, increasing insulin receptor sensitivity, or decreasing serum glucose levels. Table 166-10 lists the most common oral hypoglycemics and their mechanism of action. TABLE 166-10

Class

Oral Hypoglycemics Examples

Mechanism of Action Comments

Sulfonylureas (first Acetohexamide generation) Chlorpropamide Tolazamide Tolbutamide

Sulfonylureas (second generation)

Glipizide Glyburide Glimepiride

Increased insulin release Bind to the sulfonylurea receptor and inhibit the pore-forming unit of the adenosine triphosphatesensitive potassium channel, which ultimately causes insulin secretion from the beta cell

High risk for hypoglycemia Many drug interactions Exhibit ionic protein binding and are displaced by various drugs, including phenylbutazone, salicylates, sulfonamides, and warfarin

100 times more potent than first generation, although better safety profile Increased risk for hypoglycemia in patients with renal insufficiency Should be avoided in patients with severe liver disease

Biguanides

Metformin Phenformin (not available in the United States)

No increase in insulin release Inhibit lipolysis, which causes increased glucose uptake, decreased hepatic glucose production, decreased intestinal absorption of glucose, and increased insulin receptor binding

Lactic acidosis: metformin > phenformin Does not cause hypoglycemia when taken alone Should not be used in patients with congestive heart failure, metabolic acidosis, drug hypersensitivity, and renal impairment Use of iodinated radiographic contrast dyes can also precipitate metforminassociated lactic acidosis Avoid using with other drugs that affect creatinine clearance or compete with renal tubular secretion, including vancomycin, trimethoprim, triamterene,

quinidine, quinine, morphine, digoxin, amiloride, ranitidine, cimetidine, nifedipine, furosemide, nonsteroidal antiinflammatory drugs, and loop diuretics α-Glucosidase inhibitors

Acarbose Miglitol

No increase in insulin release Reversible competitive inhibition of αglucosidase on the brush border of the small bowel, delayed carbohydrate absorption, and lower postprandial glucose and insulin concentrations

Does not cause hypoglycemia when taken alone Effects by concomitant administration of intestinalabsorbing agents (charcoal) or carbohydratesplitting enzymes (amylase, pancreatin) Flatulence, borborygmi, abdominal pain, and diarrhea the most common

side effects Transaminitis and decreased serum iron also reported Gliptins

Linagliptin Sitagliptin Saxagliptin

Increase insulin release in a glucose dependent manner Block dipeptidyl peptidase 4 (DPP-4), causing increase of glucagon-like peptide 1 (GLP-1), which is active in stimulating insulin release in presence of glucose load Delay gastric emptying

Unlikely to cause hypoglycemia in mild to moderate overdose Hypoglycemia can occur in very large overdoses and when ingested with other antidiabetic agents

Incretin mimics

Exenatide

Increase insulin release in a glucosedependent manner Glucagon-like peptide 1 (GLP-1)

No hypoglycemia seen in limited number of case reports of overdose Nausea and vomiting

receptor common with agonist, which therapeutic use stimulates insulin release in presence of glucose load Delay gastric emptying Thiazolidinediones Troglitazone*

Increase sensitivity to insulin

Hepatotoxicity with troglitazone

Rosiglitazone

Bind to nuclear peroxisome proliferatoractivated receptors involved in the transcription of insulinresponsive genes and in the regulation of adipocyte differentiation and lipid metabolism

Hypoglycemia can occur with repaglinide, although less frequently than with sulfonylureas No significant drug interactions have been reported; however, concomitant use of other agents that affect the CYP3A4 system should be done with caution

Pioglitazone Meglitinide Repaglinide

Bind to nuclear peroxisome

Hypoglycemia can occur with repaglinide,

proliferatoractivated receptors involved in the transcription of insulinresponsive genes and in the regulation of adipocyte differentiation and lipid metabolism

although less frequently than with sulfonylureas No significant drug interactions have been reported; however, concomitant use of other agents that affect the CYP3A4 system should be done with caution

*Withdrawn from the U.S. market because of severe hepatotoxicity

CLINICAL PRESENTATION Although the sulfonylureas and thiazolidinediones can cause hypoglycemia in overdose, the other oral hypoglycemics can only potentiate these effects. The clinical symptoms of hypoglycemia are protean and can include unstable vital signs, fixed and dilated pupils, dysrhythmias, diaphoresis, and altered mental status. Neurologic symptoms are often most prominent. Mild neurologic symptoms of hypoglycemia include weakness, fatigue, and behavioral and cognitive dysfunction, whereas severe hypoglycemia can result in hemiplegia, decerebrate posturing, ataxia, choreoathetosis, and seizures.46 The cerebral cortex and hippocampus are the most sensitive to neuroglycopenia, and the brainstem and spinal cord are the most resistant.

DIFFERENTIAL DIAGNOSIS The nontoxicologic differential diagnosis of hypoglycemia is quite broad. Other toxicologic causes of hypoglycemia include toxicity from a diverse group of agents including beta-blockers, ethanol, salicylates, insulin,

intravenous quinine, and unripened Jamaican ackee fruit.

DIAGNOSTIC EVALUATION The onset and duration of symptoms can be predicted if the type of oral hypoglycemic agent and the time of ingestion are known. Although hypoglycemia can occur early after the ingestion of oral hypoglycemic agents, hypoglycemia may be delayed up to 48 hours after ingestion.47 Recurrent hypoglycemia has been reported as long as 94 hours after ingestion. A combination of a history of ingestion or rapid bedside testing (or both) may be needed to confirm the diagnosis of exposure to oral hypoglycemic agents. Lactic acidosis from biguanide use should be suspected in patients presenting with lethargy, vomiting, diarrhea, and an elevated anion gap metabolic acidosis.48 In patients presenting with nausea, vomiting, fatigue, dark urine, or jaundice, hepatic failure secondary to troglitazone should be considered.

MANAGEMENT The possibility of hypoglycemia must be considered in any patient with an onset of central nervous system dysfunction. Intravenous dextrose can be administered empirically if bedside testing is unavailable. Delay in treatment may result in profound sequelae, including death. The most common sequelae are neurologic, and the risk increases with prolonged hypoglycemia. Recurrent, severe hypoglycemia is associated with electroencephalographic changes and cognitive impairment, particularly in children, with reported IQ deficiencies of 6 points.49 Treatment of hypoglycemia is presented in Table 166-11. Octreotide is considered the first-line agent. The dose of octreotide is 1 to 1.5 μg/kg intravenous or subcutaneous every 6 hours until hypoglycemia resolves.50 Other metabolic abnormalities such as lactic acidosis may also need to be corrected. Sodium bicarbonate should be administered if serum pH falls below 7.1. Hemodialysis, which removes ketones, lactate, and metformin, may be necessary if the acidosis is refractory. Thiamine, 100 mg, should be administered to adults receiving glucose to prevent Wernicke encephalopathy.

TABLE 166-11

Treatment

Treatment of Hypoglycemia Mechanism of Action

Dose

Dextrose

Raises serum glucose

Neonate: 200 mg/kg (2 mL/kg of D10 by IV bolus) Child: 0.5 g/kg (2 mL/kg of D25 by IV bolus) Adult: 25 g (50 mL of D50 by IV bolus) Continuous infusion of D5, D10, or D20 can be used, but may contribute to fluctuating serum glucose levels due to stimulation of insulin release Bolus dosing of dextrose is preferred if needed for significant hypoglycemia

Octreotide

Inhibits insulin release from pancreatic beta cells

Adult: 50-100 μg q12h SC Child: 4-5 μg/kg/day divided q6h

D10, 10% dextrose.

ADMISSION AND DISCHARGE CRITERIA Ingestion of just one tablet of chlorpropamide, glipizide, or glyburide can produce hypoglycemia. Because of the long half-life and duration of action of these drugs, clinicians should have a low threshold for admitting a patient with a suspected exposure. A patient who ingests an oral hypoglycemic agent should be admitted if (1) hypoglycemia develops, (2) it is a deliberate overdose, or (3) the patient is a child, even in the absence of hypoglycemia.

While the absence of hypoglycemia within the first 8 hours of ingestion may be predictive of a benign outcome after exploratory pediatric sulfonylurea ingestion, multiple studies of sulfonylurea ingestion in children have shown that hypoglycemia can occur as late as 16 hours after ingestion.47,51,52 Even though the non-sulfonylurea oral agents do not generally cause hypoglycemia, after an overdose, patients in whom hypoglycemia develops from these agents should be admitted. Patients who present with lactic acidosis secondary to biguanide ingestion should also be admitted. If euglycemia is achieved in the emergency department and the patient is asymptomatic, the patient can be admitted to a general medical unit with the capability of frequent glucose monitoring. Patients with metabolic acidosis, continued neurologic symptoms/signs, or continued episodes of hypoglycemia despite treatment should be admitted to an intensive care setting. Patients with suspected or evident sulfonylurea poisoning may be considered safe for discharge if they can tolerate a normal overnight fast without hypoglycemia. Children with biguanide-induced acidosis may be discharged once the acidosis has resolved.

CONSULTATION Consultation with a medical toxicologist or regional Poison Control Center is indicated in all patients with toxicity from these agents. The national toll-free and confidential number for Poison Control Centers is 1-800-222-1222. Psychiatry consultation is indicated for any intentional overdose intended for self-harm. Social Work consultation may be helpful in assessing the safety of the home as well as helping families prevent recurrence of unintentional ingestions.

SPECIAL CONSIDERATIONS Most ingestions in children younger than teenage years are unintentional. Occasionally, childhood poisonings are the result of intended harmful behaviors by caregivers. Ingestions in teens are frequently intentional and may involve larger doses and higher risk of significant toxicity.

PREVENTION Prevention is very effective in reducing exposures and unintentional ingestions in small children. Counseling to parents and grandparents about keeping medications “up and away” and in locked containers should be part of the discharge planning in all of these cases. In addition, families should be made aware of methods for safe disposal of prescription drugs that are no longer in use. One option includes the Drug Enforcement Administration’s (DEA) National Prescription Drug Take Back Day which occurs twice a year across the United States, and provides local drop-off locations for unwanted prescription drugs. KEY POINTS Over-the-counter medications account for at least 20% of all toxic exposures in children younger than 6 years. Childproof packaging has significantly reduced the incidence of childhood iron poisoning, although recent repeal of iron packaging laws may result in a rise in such exposures, which can lead to gastritis, acidosis, and death. Physostigmine should be considered both for diagnosis and for symptom management of an antihistamine overdose, but the benefits must outweigh the potential risks, which include worsening of cardiac conduction delays, bradyarrhythmias, and asystole. Use of NAC for the treatment of acetaminophen toxicity is based on the clinical scenario and serum acetaminophen levels as guided by the Rumack nomogram. Treatment of salicylate toxicity focuses on gastrointestinal decontamination and correction of fluid, electrolyte, and acidbase disturbances. Activated charcoal, urinary alkalinization, and hemodialysis are adjunctive therapies that can be used. Children may have a prolonged risk for hypoglycemia after exposure to oral hypoglycemics, even after the ingestion of a single tablet or capsule, thus hospitalization and close monitoring of blood glucose are usually warranted.

REFERENCES 1. Bronstein AC, Spyker DA, Cantilena LR, Rumack BH, Dart RC. 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Philadelphia). 2012;50:911-1164. 2. Nightingale SL. From the Food and Drug Administration. JAMA. 1997;277:1343. 3. Tenenbein M. Unit-dose packaging of iron supplements and reduction of iron poisoning in young children. Arch Pediatr Adolesc Med. 2005;159:557-560. 4. Chan TP, Rangan C. Iron poisoning: a literature based review of epidemiology, diagnosis, and management. Pediatr Emerg Care. 2011;27:978-985. 5. Mcguigan MA. Acute iron poisoning. Pediatr Ann. 1996;25:33-38. 6. Chyka PA, Butler AY, Holley JE. Serum iron concentrations and symptoms of acute iron poisoning in children. Pharmacotherapy. 1996;16:1053-1058. 7. Jaeger RW, Decastro FJ, Barry RC, et al. Radiopacity of drugs and plants in vivo-limited usefulness. Vet Hum Toxicol. 1981;23(suppl 1):24. 8. Lacouture PG, Wason S, Temple AR, et al. Emergency assessment of severity in iron overdose by clinical and laboratory methods. J Pediatr. 1981;99:89-91. 9. Position paper: whole bowel irrigation. J Toxicol Clin Toxicol. 2004;42:843-854. 10. Mofenson HC, Caraccio TR, Sharieff N. Iron sepsis: Yersinia enterocolitica septicemia possibly caused by an overdose of iron. N Engl J Med. 1987;316:1092-1093. 11. Howland MA. Risks of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol. 1996;34:491-497. 12. Macarol V, Yawalkar SJ. Desferoxamine in acute iron poisoning. Lancet. 1992;339:1601. 13. Tenenbein M, Adamson IY. Desferrioxamine and pulmonary injury.

Lancet. 1992;340:428-429. 14. Ioannides AS, Panisello JM. Acute respiratory distress syndrome in children with acute iron poisoning: the role of desferrioxamine. Eur J Pediatr. 2000;159:158-160. 15. Milne C, Petros A. The use of haemofiltration for severe iron overdose. Arch Dis Child. 2010;95:482-483. 16. Carlsson M, Cortes D, Jepsen S, Kanstrup T. Severe iron intoxication treated with exchange transfusion. Arch Dis Child. 2008;93:321-322. 17. Rao KA, Adlakha A, Verma-Ansil B, et al. Torsades de pointes ventricular tachycardia associated with overdose of astemizole. Mayo Clin Proc. 1994;69:589-593. 18. Brannan MD, Reidenberg P, Radwanski E, et al. Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations. Clin Pharmacol Ther. 1995;58:269278. 19. Jang DH, Manini AF, Trueger NS, Duque D, Nestor NB, Nelson LS, Hoffman RS. Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clin Toxicol (Philadelphia). 2010;48:945-948. 20. Husain Z, Hussain K, Nair R, Steinman R. Diphenhydramine induced QT prolongation and Torsades de pointes: an uncommon effect of a common drug. Cardiol J. 2010;17:509-511. 21. Goetz CM, Lopez G, Dean BS, Krenzelok EP. Accidental childhood death from diphenhydramine overdosage. Am J Emerg Med. 1990;8:321322. 22. Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2001;37:374-381. 23. Prescott LF. Paracetamol poisoning. Prevention of liver damage. Med Chir Dig. 1979;8:391-393. 24. Rumack BH. Acetaminophen overdose in children and adolescents. Pediatr Clin North Am. 1986;33:691-701. 25. Temple AR, Mrazik TJ. More on extended-release acetaminophen. N Engl J Med. 1995;333:1508-1509.

26. Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics. 2012;129:349-353. 27. Sztajnkrycer MJ, Bond GR. Chronic acetaminophen overdosing in children: risk assessment and management. Curr Opin Pediatr. 2001;13:177-182. 28. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. 2007. http:// medicine.iupui.edu/flockhart/table.htm. Accessed June 20, 2014. 29. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;337:1112-1117. 30. Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am. 1984;2:103-119. 31. Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2009;54:606-614. 32. Miller LF, Rumack BH. Clinical safety of high oral doses of acetylcysteine. Semin Oncol. 1983;10:76-85. 33. Mant TG, Tempowski JH, Volans GN, Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed). 1984;289:217-219. 34. Sandilands EA, Bateman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol (Philadelphia). 2009;47:81-88. 35. Williamson K, Wahl MS, Mycyk MB. Direct comparison of 20-hour IV, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning. Am J Ther. 2013;20:37-40. 36. Anker AL, Smilkstein MJ. Acetaminophen. Concepts and controversies. Emerg Med Clin North Am. 1994;12:335-349. 37. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med. 1981;141:364-369. 38. Krause DS, Wolf BA, Shaw LM. Acute aspirin overdose: mechanisms of toxicity. Ther Drug Monit. 1992;14:441-451. 39. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med. 1987;16:434-436.

40. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am. 1994;12:351-364. 41. O’Malley GF. Emergency department management of the salicylatepoisoned patient. Emerg Med Clin North Am. 2007;27:333-346. 42. Greenberg MI, Hendrickson RG, Hofman M. Deleterious effects of endotracheal intubation in salicylate poisoning. Ann Emerg Med. 2003;41:583-584. 43. Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/estimates11.htm. Accessed June 20, 2014. 44. Burghardt LC, Ayers JW, Brownstein JS, et al. Adult prescription drug use and pediatric medication exposures and poisonings. Pediatrics. 2013;132:18-27. 45. Maggs DG, Jacob R, Rife R, et al. Counterregulation in peripheral tissues: effect of systemic hypoglycemia on levels of substrates and catecholamines in human skeletal muscle and adipose tissue. Diabetes. 1997;46:70-76. 46. Cryer PE. Hierarchy of physiological responses to hypoglycemia: relevance to clinical hypoglycemia in type I (insulin dependent) diabetes mellitus. Horm Metab Res. 1997;29:92-96. 47. Levine M, Ruha AM, LoVecchio F, et al. Hypoglycemia after accidental pediatric sulfonylurea ingestions. Pediatr Emer Care. 2011;27:846-849. 48. Kopec KT, Kowalski MJ. Metformin-associated lactic acidosis (MALA): case files of the Einstein Medical Center medical toxicology fellowship. J Med Toxicol. 2013;9:61-66. 49. Perros P, Frier BM. The long-term sequelae of severe hypoglycemia on the brain in insulin-dependent diabetes mellitus. Horm Metab Res. 1997;29:197-202. 50. Glatstein M, Scolnik D, Bentur Y. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Philadelphia). 2012;50:795-804. 51. Spiller HA, Villalobos D, Krenselok EP, et al. Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr. 1997;131:141-146. 52. Lung DD, Olson KR. Hypoglycemia in pediatric sulfonylurea poisoning: an 8-year poison center retrospective study. Pediatrics. 2011;127:1558-

1564.

Hazardous Household Chemicals: Hydrocarbons, Alcohols, and Caustics

CHAPTER

167

Kirstin Weerdenburg and Yaron Finkelstein

BACKGROUND Young children are frequently poisoned by agents that are attractive and readily available to them. The combination of curiosity, desire to mimic parental behavior (such as drinking from a bottle or can), newly acquired developmental milestones, and access to household products, makes children younger than 6 years particularly vulnerable to hazardous household chemicals. Thus, these substances represent the third most common poisoning exposure in young children.1 Most concerning household chemicals fall into three main categories: hydrocarbons, alcohols, and caustics. Table 167-1 lists some common products and their potentially toxic components. Among children for whom medical attention is sought for poisoning from such agents, ingestion is by far the most common route of exposure. TABLE 167-1

Contents of Common Household Products

Product

Contents

Category

Toilet bowl, porcelain cleaners

Sulfuric, hydrochloric acid

Caustic/corrosive, acid

Drain/pipe openers

Sodium, potassium

Caustic/corrosive, alkali

hydroxide Lighter fluid (naphtha), gasoline, kerosene, butane

Petroleum distillates

Hydrocarbons

Pine oil, lamp oil, potpourri Terpenes (plant Hydrocarbons oil extracts) Mouthwash

Ethanol

Alcohols

Sterno fuel, windshield wiper fluid

Methanol

Alcohols

Antifreeze

Ethylene glycol

Alcohols

Rubbing alcohol

Isopropyl alcohol

Alcohols

Airplane glue, inhalants

Toluene, xylene Aromatic/halogenated hydrocarbons

Hair relaxer crème

Sodium hydroxide

Caustic/corrosive, alkali

“No-lye” hair relaxer crème Calcium hydroxide

Caustic/corrosive, alkali

Mothballs

Aromatic hydrocarbons

Camphor

HYDROCARBONS Hydrocarbon compounds include petroleum distillates (lighter fluid, kerosene, mineral oil, naphtha, gasoline, butane); plant extract oils, also referred to as terpenes (turpentine, lamp oil, menthol, eucalyptus oil); camphor; inhalants (toluene, chlorofluorocarbons); and organic solvents (toluene, xylene, benzene).

PATHOPHYSIOLOGY After ingestion, hydrocarbon compounds enter the esophagus but also spread into the tracheobronchial tree, and the lungs are the primary target of injury. The potential for a given substance to cause direct lung injury is influenced by its (1) viscosity, (2) surface tension, and (3) volatility. Low-viscosity liquids with high volatility and low surface tension have the highest potential for pulmonary injury. Highly viscous hydrocarbons (motor oil, paraffin) very seldom cause lung injury, whereas low-viscosity substances (gasoline, kerosene) easily enter the lungs. The chemical can cause alveolar collapse and damage surfactant, which can lead to pneumonitis and in some cases can progress to respiratory failure. In addition, lipid-soluble hydrocarbons, such as terpenes and aromatics can easily cross the blood-brain barrier and cause central nervous system (CNS) depression. Other organ damage may result from a particular compound’s inherent toxicity. Table 167-2 offers a mnemonic, which lists the hydrocarbons and their specific systemic toxicity. Inhalant abuse of organic solvents is associated with a sudden death syndrome via sensitization of the myocardium to catecholamines and can also cause a chronic encephalopathy. Because petroleum distillates and terpenes account for the majority of pediatric hydrocarbon exposures, the remainder of this discussion will focus on pulmonary toxicity. TABLE 167-2

“CHAMP” Mnemonic for Hydrocarbons with Systemic Toxicity

C: Camphor

Seizures, CNS depression

H: Halogenated compounds (carbon tetrachloride, chloral hydrate)

Hepatic necrosis, arrhythmias

A: Aromatic compounds (benzene, toluene)

CNS depression, arrhythmias, white matter degeneration

M: Hydrocarbons that contain heavy Heavy metal poisoning metals (multisystem) P: Hydrocarbons as vehicles for

pesticides, other toxic compounds

Organophosphate, other compound poisoning

CLINICAL PRESENTATION Children may be brought to medical attention for a witnessed or suspected ingestion, even if asymptomatic. Patients with severe ingestion may have signs of lung injury promptly after ingestion, including tachypnea, hypoxia, cough, wheezing, or evidence of increased work of breathing. A child who develops respiratory distress within the first hours is very concerning and may progress quickly to respiratory failure. Fever develops in about 50% of patients with chemical pneumonitis and reflects the inflammatory response to the noninfectious lung injury. An aroma of the hydrocarbon may remain on the skin, clothing, or breath and suggests ingestion or exposure. Some hydrocarbon compounds may produce mild mucosal irritation as well.

DIAGNOSTIC EVALUATION Evaluation of a child after hydrocarbon ingestion or exposure should focus on the patient’s respiratory status. Careful physical examination with measurement of the respiratory rate and work of breathing as well as pulse oximetry should be performed immediately and repeated frequently. A chest radiograph should be performed on initial assessment and repeated with clinical deterioration or as part of clinical reassessment (e.g. consideration for admission or discharge). One large review of 950 children found that all patients who were both asymptomatic and had normal chest radiographs at 6 hours after exposure were suitable for discharge and did not deteriorate. In contrast, patients who have initial symptoms and infiltrates on chest radiographs usually worsen and require hospitalization.2 An elevation of the white blood count (WBC) and neutrophil count may be seen in patients with significant chemical pneumonitis. Such leukocytosis early after ingestion reflects the noninfectious inflammation associated with the lung injury. Further evaluation may be indicated, depending on the toxicities of the particular substance involved (see Table 167-2). For example, serum

transaminase studies should be considered for patients exposed to halogenated compounds.

MANAGEMENT The mainstay of treatment for these patients involves supportive care with careful monitoring of respiratory status as well as respiratory support and treatment of other concomitant organ dysfunction as necessary. Endotracheal intubation and ventilation or extracorporeal support may be needed with profound lung injury. Corticosteroids do not improve the course of hydrocarbon pneumonitis and have been associated with increased bacterial superinfection in animal studies.3 Antibiotics have also failed to show any benefits, may increase infection with resistant organisms, and are indicated only for patients in whom fever and leukocytosis persist and bacterial infection seems likely. Of note, several animal studies and a recent case report in humans suggest that the use of exogenous surfactant therapy early in the course of acute respiratory failure secondary to hydrocarbon ingestion may dramatically improve the patient’s course and should be considered as a reasonable therapeutic intervention based on pathophysiologic rationale.4

CONSULTATION Involvement of critical care specialists may be warranted in patients whose clinical condition is deteriorating and when there is an anticipated need for increasing respiratory support or level of monitoring. Social work or social services consultation may be indicated if the circumstances surrounding the ingestion raise suspicion of abuse or neglect. Consultation with a regional poison control center is appropriate, especially for children with severe or atypical symptoms or when the compound involved is highly toxic.

ADMISSION CRITERIA

Any patient with respiratory symptoms should be admitted for monitoring and support. Patients who remain asymptomatic for 6 hours after exposure may be candidates for outpatient follow-up with parental supervision.

DISCHARGE CRITERIA Patients whose respiratory symptoms have resolved sufficiently to be discharged have no further risk from hydrocarbon pneumonitis and can be sent home.

ALCOHOLS The major compounds involved in pediatric alcohol exposure include ethylene glycol, methanol, isopropanol, and most commonly, ethanol. Ethanol is readily available for adult consumption in most households and may also be found in toiletries such as mouthwash and antibacterial soap. Isopropanol is the active ingredient in rubbing alcohol. Ethylene glycol has a sweet taste and is found in antifreeze, while methanol can be found in windshield washer fluid and Sterno fuel.

PATHOPHYSIOLOGY All mentioned alcohols act to some degree on the CNS to cause intoxication, CNS depression, and hypothermia, and all are metabolized by the enzyme alcohol dehydrogenase (Figure 167-1). The mechanism of hypothermia is complex and not entirely elucidated; however, it stems from the depth of CNS depression and resultant loss of behavioral responses to cold. In young children, ethanol metabolism suppresses gluconeogenesis and ingestion may cause hypoglycemia hours after exposure. Isopropanol is metabolized to acetone, which causes ketonemia and ketonuria without acidosis; in addition, isopropanol is a gastrointestinal irritant that often causes bleeding, although it is not usually life threatening.

FIGURE 167-1. Toxic alcohol metabolism. Both methanol and ethylene glycol undergo transformation to toxic metabolites via the enzyme alcohol dehydrogenase (ADH). ADH is inhibited by ethanol and fomepizole therapy. Ethylene glycol and methanol are referred to as “toxic alcohols” because of their conversion through alcohol dehydrogenase to highly toxic metabolites (see Figure 167-1). Ethylene glycol is metabolized to glycolic and oxalic acid, which cause profound acidosis and renal failure, partially as a result of oxalate crystalluria. In addition, oxalate forms complexes with calcium, which can lead to systemic hypocalcemia and its attendant complications (e.g. seizures, tetany, dysrhythmia). Methanol is metabolized to formic acid, which also causes severe metabolic acidosis as well as unique retinal toxicity.

CLINICAL PRESENTATION After any of these ingestions patients will be intoxicated, and may have profound CNS depression and hypothermia in extreme cases. Young children and malnourished adults may become hypoglycemic between 2 to 8 hours after alcohol ingestion and present with jitters, combativeness, obtundation, or other symptoms of low blood glucose. Ingestion of isopropanol can cause intoxication along with hematemesis, ketonuria, and a strong acetone odor. Patients with ethylene glycol or methanol poisoning may initially appear intoxicated, with severe metabolic acidosis and develop organ failure within the next 24 hours. These toxic alcohols are osmotically active and can lead to

dehydration because of the osmotic diuresis that ensues after ingestion. Retinal toxicity secondary to the toxic metabolite of methanol can cause a number of visual abnormalities, including blurred vision, spots, and scotomas, a condition collectively described as “snowstorm” vision, which can progress to complete irreversible blindness. Patients poisoned with ethylene glycol are at risk for anuria and renal failure. Fatalities result from profound acidosis and metabolic perturbation.

DIAGNOSTIC EVALUATION Alcohols are not part of routine urine toxicology screening due to their high volatility. Serum levels of ethanol, isopropanol, methanol, and ethylene glycol should be obtained and correspond well with toxicity. However, these tests are not rapidly available in all hospitals. Indirect evidence of their presence may be revealed through measurements of serum electrolytes and osmolality, and blood gas analysis. Within an hour after ingestion, the presence of alcohols in serum may be detected by an elevated osmolar gap (the difference between calculated serum osmolarity and measured serum osmolality). As metabolism of ethylene glycol and methanol progresses, metabolic acidosis with an elevated anion gap develops, which is uncommon with ethanol or isopropanol metabolism. Additional testing should include urinalysis, serum creatinine, and ophthalmologic examination, depending on the toxicities associated with the suspected alcohol ingested. After ethylene glycol ingestion, oxalate crystals may be visible in urine and ketonuria occurs with isopropanol metabolism. Because fluorescein is often used as an additive to antifreeze, demonstration of fluorescence by Wood lamp examination of urine may be a sign of ingestion of this material. However, not all preparations of antifreeze contain fluorescein, and lack of its presence cannot rule out ethylene glycol ingestion.

MANAGEMENT For ethanol and isopropanol ingestion, close observation and supportive care are required, along with careful attention to blood glucose monitoring in young children. Although ethanol and isopropanol ingestion are associated with few complications, the clinician should be particularly observant of the patient’s potentially depressed mental and respiratory status.

In ethylene glycol or methanol poisoning, the mainstay of therapy is reducing the formation of toxic metabolites by inhibiting the action of alcohol dehydrogenase on the toxic alcohols. Substances such as ethanol or fomepizole (4-methylpyrazole [4-MP]) should be administered to compete with the toxic alcohols in binding to alcohol dehydrogenase. Fomepizole is superior to ethanol if available. Ethanol infusions are intoxicating and warrant frequent monitoring of blood glucose and ethanol levels (desired level, 100 mg/dL), typically in the setting of a critical care unit. Fomepizole does not cause obtundation or drowsiness, is easy to administer, and the patient can be admitted to the pediatric ward. Fomepizole also has fewer adverse effects associated with its use.5 It is safe and effective in children as well as adults.6-8 See Table 167-3 for more details of ethanol and fomepizole therapy. TABLE 167-3

Antidotes for Toxic Alcohol Ingestion

Agent

Dosage/Administration Comment

Ethanol

10% solution for IV use Loading dose: 0.8 g/kg Maintenance: 80-130 mg/kg/hr Target level: 100 mg/dL

Side effects: obtundation, hyperosmolarity, hypothermia, hypoglycemia Frequent monitoring of levels May necessitate central venous access

Fomepizole (4- Loading dose: 15 mg/kg IV methylpyrazole) over 15-min period Maintenance: 10 mg/kg q12h

Fewer side effects than ethanol Less availability Administer of q 4 h during dialysis

Increase to 15 mg/kg after 4 doses It is important to remember that the use of ethanol or fomepizole prevents the ongoing production of toxic metabolites but does not treat the toxic effects of metabolites already present. A number of treatments may help prevent end-organ damage and reverse acidosis. Sodium bicarbonate therapy can treat acidosis and reduce further entry of toxic metabolites into target tissues. Pyridoxine (1 mg/kg intravenously, maximum of 100 mg, every 6 hours) and thiamine (50 mg intravenously every 8 hours) may help detoxify the acid metabolites of ethylene glycol, and folic acid (1 mg/kg intravenously, maximum of 50 mg, every 4 hours) may help detoxify the metabolites of methanol. Hemodialysis is very effective in removing both ethylene glycol and methanol and their toxic metabolites. Hemodialysis should be considered when the serum ethylene glycol or methanol level is higher than 50 mg/dL, when there is end-organ manifestations of toxicity, in the context of a late presentation, there is a high osmolar gap without another cause, or in the context of refractory acidosis. Some patients may require repeat hemodialysis for a significant ingestion. Many experts recommend that ethanol or fomepizole infusion accompany hemodialysis because the dialysis process is not instantaneous and residual toxic alcohol may still be metabolized. However, others eschew hemodialysis in favor of prolonged alcohol dehydrogenase blockade with ethanol or fomepizole, and this option might be considered by those with considerable expertise in the treatment of toxic alcohol ingestion.

CONSULTATION Social work or social services should be considered if circumstances surrounding the ingestion raise suspicion of abuse or neglect. Ophthalmology should be consulted in cases of methanol poisoning. Nephrology should be consulted if there is a credible history of ingestion of a toxic alcohol, especially when hemodialysis is being considered.

ADMISSION CRITERIA Any patient with suspected ingestion of a toxic alcohol should be admitted unless negative serum levels are obtained or the anion and osmolar gaps remain normal on serial measurements. Abnormalities in the osmolar and anion gap should appear within 12 hours after ingestion, so a patient in whom abnormalities do not develop within this time is reassuring. It is important to note that a normal osmolar gap should be interpreted in the context of the anion gap and vice versa, as the toxic alcohol compound is metabolized, the osmolar gap will decrease and the anion gap will rise. However, patients who exhibit the CNS depression of alcohol ingestion should be admitted regardless of acid-base status. All intoxicated children should be admitted or observed until the intoxication resolves.

DISCHARGE CRITERIA Patients may be discharged once the intoxication resolves, levels of toxic alcohols are undetectable, and end-organ toxicity is either resolved or stable.

CAUSTICS Caustic substances are found in a number of readily available household products (see Table 167-1), including drain and oven cleaners, porcelain cleaners, and some detergents. Of note, ammonia and bleach packaged for household use are significantly less concentrated than many commercial preparations and are therefore associated with a much lower risk of injury. The Federal Poisoning Prevention Act of 1970 mandates that alkaline caustics greater than 2% in concentration and other caustics greater than 10% in concentration be sold in childproof containers. As a result, the number of serious pediatric caustic injuries has vastly decreased. However, severe injuries still occur, often with industrial-strength chemicals or products inappropriately stored in non-childproof containers.

PATHOPHYSIOLOGY

The degree of caustic injury depends on the properties of the substance (e.g. pH, concentration, ability to penetrate tissues); the nature of the exposure (e.g. splash, ingestion) including the volume and duration of contact; and the timeliness of initiating appropriate therapy. Severe caustic injuries are more likely to occur with a strong acid or base and in the context of large-volume or suicidal ingestion. Aside from injury as a result of direct contact with the caustic agent, some compounds cause additional toxicity through systemic absorption of components. For example, acids may be absorbed and cause metabolic acidosis, and zinc and mercuric chloride (ZnCl2, HgCl2) can be associated with heavy metal toxicity. The most common targets of caustic injury are the airway, esophagus, and gastrointestinal tract. Although acid and alkali substances produce different histopathologic patterns of injury, the clinical picture appears similar. On ingestion, the liquid traveling down the gastrointestinal tract comes in contact with esophageal epithelium and causes damage ranging from edema and erythema to necrosis and perforation. Fluid reaching the stomach may also cause burns of varying degrees to the gastric mucosa, including perforation.

CLINICAL PRESENTATION Because the tissue damage from caustic ingestion manifests immediately, patients generally become symptomatic quickly. Signs and symptoms of esophageal injury predominate, including vomiting, dysphagia, refusal to drink, hematemesis, drooling, and associated oral and oropharyngeal burns. However, it is important to remember that visible injury of the cheeks, lips, and oropharynx are not prerequisites for gastrointestinal injury, and in fact, approximately one third of children without visible injury have burns in visceral sites.9 Also, airway injury or impending collapse may cause stridor, respiratory distress, cough, and wheezing. A patient with overwhelming tissue destruction may be hemodynamically unstable with metabolic acidosis. Life-threatening complications can ensue, many of which may not occur until 72 hours after the ingestion. Severe chest pain and shortness of breath may be a sign of esophageal perforation and mediastinitis. Perforation of the stomach with resultant caustic peritonitis usually causes severe abdominal pain, a rigid abdomen, acidosis, and hemodynamic instability. Gastrointestinal hemorrhage from direct vessel injury can present with hematemesis, melena,

or shock. After the acute phase of injury, the healing process may cause gastrointestinal strictures to form, most commonly in the esophagus. Strictures should be suspected in a patient in whom dysphagia or failure to thrive develops.

DIAGNOSTIC EVALUATION Endoscopy of the upper gastrointestinal tract can delineate the location and degree of injury to the hypopharynx, esophagus, and stomach. To reduce the risk of perforation, the procedure is performed within 12 hours and preferably not later than 24 hours post-ingestion, with the greatest risk of perforation at 48 hours up to 14 days post-ingestion. Table 167-4 provides a list of indications for this diagnostic procedure. Specifically, several studies have reported the presence of two or more of the findings of vomiting, drooling, and stridor being highly predictive of a significant esophageal injury, with stridor being nearly 100% specific. In addition, the absence of these findings has a high negative predictive value. Table 167-5 describes the endoscopic classification system most commonly used to grade esophageal injuries. TABLE 167-4

Indications for Endoscopy after Caustic Ingestion

History of large-volume, intentional or suicidal ingestion, especially highly caustic products (e.g. drain cleaner) Any symptoms, including vomiting, dysphagia, hematemesis, chest or abdominal pain, drooling, refusal to drink Any signs, including stridor, respiratory distress, oropharyngeal burns, abdominal tenderness, peritoneal signs Further evaluation reveals acidosis, anemia, coagulopathy, or radiographs suggestive of perforation or mediastinitis TABLE 167-5

Endoscopic Classification of Esophageal Injury

Class Characteristics

Prognosis

I

Edema, hyperemia

Excellent; no strictures

IIa

Ulcerated, discrete

Up to 75% chance of stricture

IIb

Ulcerated, circumferential

75% chance of stricture

III

Necrosis

100% stricture formation

Radiographs of the chest may be useful if there is concern for aspiration with chemical pneumonitis, esophageal perforation, or mediastinitis. An abdominal obstruction series may reveal intraperitoneal free air in patients with distal esophageal or gastric perforation. Lateral neck films may be useful to evaluate the upper airway in cases in which stridor or respiratory distress is present and may demonstrate airway narrowing or epiglottic swelling. Laboratory studies may be warranted in some situations. For patients at risk for systemic absorption of caustic agents or with concern for severe injury, a complete blood count (CBC), coagulation studies, electrolytes, and blood gas analysis should be performed. A blood type and crossmatch should be obtained for patients with hemorrhage or peritonitis or for those in need of surgical intervention. Surgical exploration is reserved for patients with abdominal pain, tachycardia, and worsening acidosis, or radiographic evidence of catastrophic visceral perforation or mediastinitis. Management of an asymptomatic toddler who has ingested an unknown quantity of a caustic substance presents a particular challenge. A number of prospective studies in the last 20 years has demonstrated that children without symptoms or signs after 6 hours of observation will have no significant endoscopic injury and therefore do not warrant endoscopy.10,11 In addition, young children who ingest thick cream hair relaxer products may have isolated oral burns, but episodes of more extensive injury are exceedingly rare.

MANAGEMENT In the emergency department, patients may require resuscitation, including

endotracheal intubation if airway collapse is imminent. Gastrointestinal decontamination is not generally indicated. Tissue injury will have already occurred on arrival, so the introduction of either activated charcoal or a lavage tube into a potentially damaged esophagus incurs futile risk. Dilution, a process by which patients drink milk or water to decrease the concentration of the caustic substance, also has little benefit beyond the first 1 to 2 minutes of ingestion. On admission, corticosteroid therapy to prevent stricture formation is controversial but is sometimes used. Theoretically, corticosteroids prevent the collagen cross-linking that takes place during healing and stricture formation. Whereas patients with type I burns uniformly do well and patients with type III injury nearly always form strictures, patients with type II burns may be good candidates for this therapy. A number of studies have attempted to evaluate the efficacy of this treatment, but the data is contradictory, therefore making it difficult to make definitive recommendations.12-14 When used, most clinicians use either methylprednisolone (2 mg/kg/day) or dexamethasone (1 mg/kg/day), for patients with circumferential seconddegree esophageal burns. Antibiotics and H2-blockers are often given concurrently. Consultation with a specialist, usually a gastroenterologist or a general surgeon, is recommended to aid in decisions, such as when to institute oral feeding and whether nasogastric tube placement is needed. In general, patients with mild (type I, lIa) burns can be started slowly on a liquid diet as soon as tolerated, but in patients with more advanced disease (IIb, III), longer periods of restricted oral intake may be advised because of the risk for perforation. Swallowing difficulty, gastric outlet obstruction, or dysmotility may develop in patients with strictures, most often in the weeks to months after the ingestion. Alternative enteral feeding regimens may be needed and might include nasogastric, gastrostomy, or transpyloric feeding. Revision of strictures may be required for severely narrowed or obstructing segments, and therapy can include dilation or surgical resection. Patients with significant esophageal injury require lifelong surveillance for esophageal carcinoma because they are at greatly increased risk after caustic ingestion.15

CONSULTATION

Gastroenterologists are often involved in the assessment of symptomatic children. Ongoing involvement is appropriate for children with evidence of mucosal injury, feeding difficulties, or gastrointestinal bleeding. Surgical involvement should be sought early in children at risk for perforation, mediastinitis, or peritonitis. Further along the course of management, surgical services may be needed for placement of gastrostomy feeding tubes or for evaluation of strictures that may need resection. Critical care service should be consulted for patients with hemodynamic instability and those in need of airway management. Patients with injury to the upper or lower airways may warrant input from otolaryngology or pulmonology. Social services should be contacted if circumstances surrounding the ingestion raise suspicion of abuse or neglect.

ADMISSION CRITERIA Any patient with symptoms or abnormal physical examination findings after caustic ingestion. Any patient with a large-volume or intentional ingestion. Observation and discharge may be considered for a completely asymptomatic toddler in whom significant ingestion is in doubt or for a patient with cream hair relaxer exposure with oral burns only. However, such management is advisable only with close follow-up and a reliable situation in the home.

DISCHARGE CRITERIA Patients may be discharged when asymptomatic and able to tolerate oral feeding. For patients unable to feed orally, alternative enteral nutritional therapy must be established. Appropriate outpatient follow-up is needed for ongoing evaluation of known complications, most commonly stricture formation.

PREVENTION

The advances in preventive legislation have already made a significant impact on household poisonings in the United States; however, exposures still occur and are largely preventable. Careful education on the part of healthcare providers regarding the safe storage of household chemicals, both out of reach and out of attractive non-childproof containers, is still needed. Awareness of the national poison control center system can be lifesaving, so each household should have contact information readily available. KEY POINTS The risk for injury secondary to hydrocarbon ingestion is related to the nature of the substance (e.g. volatility) as well as the toxicants dissolved in the product (e.g. organophosphates). Hydrocarbons with high volatility, low viscosity, and low surface tension (e.g. gasoline, kerosene) can cause aspiration and pneumonitis. After hydrocarbon ingestion, symptomatic patients should be monitored closely. Ethanol and isopropanol can cause hypoglycemia in young children. Ethylene glycol and methanol ingestion can be life threatening, and treatment includes inhibition of alcohol dehydrogenase and potentially hemodialysis. Caustic ingestion can cause acute life-threatening injuries, including airway damage, gastrointestinal hemorrhage, and esophageal or gastric perforation with mediastinitis or peritonitis. Endoscopy within 12 hours and preferably not later than 24 hours of caustic ingestion can delineate the severity and location of the caustic injury. Children who remain asymptomatic for at least 6 hours after caustic ingestion are at low risk for injury and may be discharged if close observation can be maintained.

REFERENCES

1. Bronstein AC, Spyker DA, Cantelina LR, et al. 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Philadelphia). 2011;50:911-1164. 2. Anas N, Namasonthi V, Ginsburg CM. Criteria for hospitalizing children who have ingested products containing hydrocarbon. JAMA. 1981;246:840-843. 3. Marks Ml, Chicoine L, Légère G, Hillman E. Adrenocorticosteroid treatment of hydrocarbon pneumonia in children—a cooperative study. J Pediatr. 1972;81:366-369. 4. Mastropietro CW, Valentine K. Early administration of intratracheal surfactant (calfactant) after hydrocarbon aspiration. Pediatrics. 2011;127(6):e1600-e1604. 5. Lepik, KJ, Levy AR, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med. 2009;53(4):439-450.e410. 6. Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med. 1999;340:832-838. 7. Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001;344:424-429. 8. Borrón SW, Megarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet. 1999;354:831. 9. Previtera C, Giusti F, Guglielmi M. Predictive value of visible lesions (cheeks, lips, oropharynx) in suspected caustic ingestion: may endoscopy reasonably be omitted in completely negative patients? Pediatr Emerg Care. 1990;6(3):176-178. 10. Crain E, Gershel J, Mezey A. Caustic ingestions: symptoms as predictors of esophageal injury. Am J Dis Child. 1984;138:863-865. 11. Gaudreault P, Parent M, McGuigan M, et al. Predictability of esophageal injury from signs and symptoms: a study of caustic ingestion in 378 children. Pediatrics. 1983;71:7676-7770. 12. Anderson KD, Rouse TM, Randolph JG. A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med. 1990;323:637-640.

13. Usta, M, Erkan T, et al. High doses of methylprednisolone in the management of accidental caustic esophageal burns in children. J Pediatr Gastroenterol Nutr. 2009;48:E49. 14. Pelclová, D, Navrátil T. Do corticosteroids prevent oesophageal stricture after corrosive ingestion? Toxicol Rev. 2005;24(2):125-129. 15. Appelqvist P, Salmo S. Lye corrosion carcinoma of the esophagus: a review of 63 cases. Cancer. 1980;45:2655-2658.

CHAPTER

168

Lead, Other Metals, and Chelation Therapy Rahul Kaila and Jeffrey P. Louie

LEAD Lead is a highly toxic metal, and exposure to it can produce a wide range of adverse health effects.1,2 It is a soft, pliable metal that resists corrosion and when ingested, has a sweet taste.3,4 Lead is a ubiquitous environmental containment found in water and soil.1 The most common cause of childhood lead poisoning is ingestion of lead-containing paint chips or leadcontaminated dust as a result of normal hand-to-mouth activity.5,6 Until 1978, lead was commonly used in paints to provide pigment and color stability. Other potential sources include ingestion of drinking water, soil, and food.7 According to the US Department of Housing and Urban Development (HUD), about 25% of the nation’s current housing stock—some 24 million homes—still contains significant lead-based paint hazards.8 Although lead paint that is intact does not pose an immediate concern, lead paint that is deteriorating or is disturbed during repair or renovation activities creates a hazard. There is new evidence that lead poisoning is harmful at blood levels that were once thought safe.9-11 The effects of sustained exposure, such as learning disabilities have been observed in children with lead levels as low as 5 μg/dL, with no evidence of a threshold.11 In 2012, the Centers for Disease Control and Prevention (CDC) revised the definition of lead toxicity and lowered the “normal” blood lead level value to below 5 μg/dL.12 Lead poisoning was once a disease of poor or minority children living in older housing in the inner cities.13 Unfortunately, the number of at-risk groups has expanded as families from all strata inadvertently expose their children through home renovation activities.14 Gender differences also exist, and males appear to be more affected than females for any given exposure

source or amount.15

TOXICOKINETICS Lead ingestion is the primary route of exposure for children, whose gut absorbs 45% to 50% of a lead dose, compared with 10% to 15% in adults.16 After absorption occurs, the amount of lead entering the bloodstream is dependent on several factors: the amount or concentration of lead in the specific medium; the physicochemical characteristics of the lead compound; and specific host factors such as age, nutritional status, and fasting conditions. Once absorbed, 99% of lead binds to erythrocytes, and the remaining 1% is free to diffuse into soft tissues and bone, where it equilibrates with blood lead.17 In the body, the total lead burden can be divided into four compartments: blood (half-life 35 days), soft tissue (halflife 40 days), and the trabecular (half-life 3 to 4 years) and cortical components (half-life 16 to 20 years) of bone. Lead that is deposited in hair, teeth, nails, and bones is tightly bound and not felt to be harmful. In terms of lead’s toxicity, the most notable effect is seen in the heme synthetic pathway. Lead inhibits δ-aminolevulinic acid dehydrase and ferrochelatase (heme synthetase). As a result, δ-aminolevulinic acid cannot be converted into porphobilinogen, nor can iron be incorporated into the protoporphyrin ring. The heme precursor erythrocyte protoporphyrin (EP), commonly assayed as zinc protoporphyrin (ZPP; zinc substitutes for iron in the porphyrin moiety), increases, and heme synthesis is subsequently reduced.18 The biologic dysfunction produced by lead appears to be associated with the metal’s ability not only to bind sulfhydryl ligands but also to mimic or inhibit the action of calcium. At low concentrations, lead increases the basal release of neurotransmitters from a presynaptic nerve ending in both the peripheral and central nervous systems. Lead also has the ability to block the release of neurotransmitters during the normal action potential. This twofold effect has significant consequences on the developing nervous system and may be one of the underlying causes of the cognitive and behavioral problems seen in lead-poisoned children.18

CLINICAL PRESENTATION

The clinical presentation of lead poisoning varies widely, depending on blood lead level (BLL), age at exposure, and amount and duration of exposure. Children presenting with possible lead poisoning should be assessed for correlates of exposure and recognizable sequelae. These sequelae can include gastrointestinal (GI) complaints such as colicky pain, constipation, anorexia, and intermittent vomiting. Signs and symptoms suggestive of central nervous system (CNS) involvement include irritability, lethargy, alterations in sleep pattern, decreased attention span, and developmental delay. Acute encephalopathy may be seen in children with BLLs greater than 70 μg/dL. These children can develop persistent vomiting and become drowsy and possibly ataxic. As the encephalopathy worsens, the level of consciousness deteriorates further, and seizures or even coma can occur.19 The decision to admit a child for the treatment of lead poisoning is multifaceted and is never based solely on the BLL. Besides the BLL, the medical evaluation, environmental history, social history, and laboratory facilities available at the admitting hospital are all important factors. It is important that the hospital laboratory have the capacity to run a BLL with a relatively prompt turnaround of results. Asymptomatic patients with BLLs greater than 45 to 50 μg/dL are generally managed as inpatients. Involvement by a medical toxicologist or pediatric environmental health subspecialist is not essential but may be valuable. Symptomatic children, regardless of BLL, should receive immediate subspecialty consultation. All children with signs or symptoms suggesting lead encephalopathy should be evaluated for admission to the pediatric intensive care unit or transfer to a tertiary center where critical care can be provided if necessary.20

DIAGNOSTIC EVALUATION The evaluation of lead poisoning includes a venous BLL, detailed environmental and social histories, and systematic physical examination. Laboratory Studies The following laboratory data should be obtained to aid in making the diagnosis: Repeat BLL—confirmatory test must be a venous BLL, because specimens obtained by finger stick are less reliable ZPP or EP level

Complete blood count with differential Serum iron studies: iron, ferritin, total iron binding capacity, or if available, reticulocyte hemoglobin content

RADIOGRAPHIC STUDIES An abdominal radiograph is recommended for any child admitted with newly diagnosed lead poisoning or a child with known lead poisoning who has an abrupt increase in BLL. Radiopaque specks in the GI tract, particularly the stomach and small intestine, may represent lead-containing particles, leading to consideration of gut decontamination (Figure 168-1). Characteristic lead lines are radiodensities in metaphyseal plates of the long bones; these represent periods of bone growth arrest. Radiographs of the long bones (distal radius or proximal tibia-fibula) for growth arrest lines may be of importance in growing children with BLL excess of 50 μg/dL, but not useful in management of the lead poisoning. Lead measurement of hair, fingernail, and dentin is not recommended.

FIGURE 168-1. Child with paint chip in bowel. Developmental Evaluation Children with BLLs greater than 20 μg/dL should have thorough neurologic evaluations, including developmental screening tests to identify possible developmental delay. Speech and language screening is recommended on admission, because speech delay is very common in lead-poisoned children. Children with abnormal screening tests should be referred for formal neuropsychological testing. Social and Environmental Assessment All families warrant a complete social work assessment. The local health department’s childhood lead poisoning prevention program should be notified of the child’s admission and can advise pediatric care providers and families how to obtain environmental assessments. Local public health nurses may be able to identify lead hazards when they make home visits. They can also provide risk-reduction education and make recommendations to the family about how to diminish the hazard.

MANAGEMENT The treatment of childhood lead poisoning involves the elimination of additional exposure and adequate nutrition. When these measures fail, chelation therapy should be considered. Gut Decontamination When there is radiographic evidence of lead densities in the stomach or small intestine of children with BLLs greater than 45 μg/dL, the GI tract must be evacuated to eliminate further absorption, gut decontamination should occur before chelation. For small radiodensities, a cathartic such as magnesium citrate can be administered once orally at a dose of 4 mL/kg. An effect is usually seen in 30 minutes to 3 hours. Magnesium citrate may cause hypovolemia and electrolyte imbalance and should not be used repeatedly or in patients with renal impairment. Adequate hydration should be established before initiating this therapy. For larger or multiple radiodensities, whole-bowel irrigation is preferable. This can be accomplished with a polyethylene glycol solution (GoLYTELY, CoLyte). Polyethylene glycol solution is given orally or instilled by nasogastric tube at a dose of 20 to 40 mL/kg per hour, up to a maximum of 1000 mL/hr for a minimum of 4 hours, or until the rectal effluent is clear. Effect of action is usually 30 to 60 minutes. Contraindications to polyethylene glycol solution include bowel perforation, adynamic ileus, significant GI hemorrhage, intestinal obstruction, and inability to protect the airway. A follow-up radiograph may be indicated to document removal or transit of the density after GI decontamination.20 Nutrition Nutrition can play a pivotal role in the prevention and treatment of lead poisoning, especially in young children. To decrease their susceptibility to lead intoxication, children should be provided with balanced nutrition, including adequate amounts of foods rich in calcium (e.g. milk, cheese, yogurt), iron (e.g. beef, ham, beans, green leafy vegetables), and ascorbic acid (e.g. citrus fruit, tomatoes, broccoli). Lead-poisoned children should be assessed for iron deficiency, because lead is more readily absorbed when iron stores are depleted. Lead-poisoned children who are iron deficient should receive oral iron supplementation at a dose of 4 to 6 mg/kg per day.21 Chelation Therapy Table 168-1 provides a quick guide to chelation therapy.

TABLE 168-1

Chelation Therapy Based on Clinical Presentation and Blood Lead Level

Chelating Clinical Agent and Presentation Dose

Route

Duration

Asymptomatic patients with BLL 70 μg/dL) should be evaluated for admission to an intensive care setting; the poison control center, toxicology consulting service, or pediatric environmental health service should be consulted immediately. Lead encephalopathy is a life-threatening emergency that should be treated using contemporary standards for the intensive care treatment of increased intracranial pressure, including appropriate pressure monitoring, osmotic therapy, and drug therapy in addition to chelation therapy. If the admitting hospital does not have intensive care services, toxicology or the local poison control center should be asked for advice on stabilizing the patient for transfer. A lumbar puncture should not be performed on any child suspected of having lead encephalopathy. Children with signs and symptoms of encephalopathy or a venous BLL greater than 100 μg/dL should receive nothing by mouth (usually for the first 24 hours), and parenteral fluid therapy should begin immediately; total volume is restricted to basal requirements plus ongoing losses to avoid excessive intravenous fluid administration. Although it is desirable to evacuate residual lead from the gut, this should not delay the start of chelation therapy in severely lead-poisoned children. For acute encephalopathy or a BLL greater than 100 μg/dL, BAL and CaNa2EDTA are coadministered for a total of 5 consecutive days, as detailed earlier. The use of CaNa2EDTA alone is avoided in children with lead levels greater than 70 μg/dL because it may precipitate encephalopathy by causing a redistribution of lead to the brain, resulting in a lethal increase in intracranial pressure.25 Patients with Clinical Signs and Symptoms of Acute Encephalopathy

CONSULTATION Consider consultation with toxicology or a poison control center for guidance in treatment and acute and long-term management. If encephalopathy is present, the inclusion of critical care specialists and neurology services is warranted. Contact local authorities for lead abatement programs and referral for early intervention.

ADMISSION CRITERIA

All children with elevated BLLs and symptoms of toxicity, particularly encephalopathy (e.g. headache, ataxia, sleepiness) or evidence of raised intracranial pressure Children with venous BLLs of 45 to 69 μg/dL who are not candidates for oral therapy with succimer (e.g. no lead-free housing available, unable to tolerate enteral therapy, concern about noncompliance, inadequate followup) Children with venous BLLs greater than 70 μg/dL

DISCHARGE CRITERIA Children with BLLs less than 45 μg/dL can be discharged home, with the understanding that outpatient chelation will most likely be required. As a general rule, children whose admission BLL is less than 70 μg/dL will have an end-of-chelation BLL of less than 45 μg/dL, making them candidates for discharge after a single course of chelation. Before the child is discharged, the home should be inspected to ensure it is a lead-safe environment. A repeat BLL obtained at the end of chelation determines the need for reinstitution of chelation therapy: If the BLL is 45 to 69 μg/dL at the end of the first course, a second course of chelation therapy is necessary, which is best done as an inpatient. If, at the end of the first course of chelation, the BLL is 70 μg/dL or greater, dual therapy with BAL and CaNa2EDTA should be reinitiated. A minimum of 2 days must elapse before restarting intravenous CaNa2EDTA (a chelation “honeymoon”) to minimize the risk of nephrotoxicity and permit at least partial recovery from the urinary losses of zinc produced by CaNa2EDTA. Referral to an early intervention program is advised for lead-poisoned children suspected of having a developmental handicap (e.g. speech delay). Availability of lead-safe housing at the time of discharge (e.g. with friends or relatives or in designated transitional housing) if the child’s residence remains contaminated. Institution of plans for lead abatement in the home where the exposure occurred.

FOLLOW-UP CARE The first follow-up visit should be scheduled for 7 to 14 days after chelation to allow for a period of re-equilibration. At this visit, a BLL and ZPP or EP level are repeated to determine whether subsequent outpatient chelation is needed. Many children require more than one round of outpatient chelation therapy. The time interval of follow-up care is detailed in the Centers for Disease Control and Prevention lead screening guidelines (http:// www.cdc.gov/nceh/lead). During follow-up visits, pediatric care providers can assess the patient and family’s compliance with recommended riskreduction practices and the abatement or reduction of lead hazards as well as address dietary factors to ensure an adequate intake of calcium, ascorbic acid, and iron. All children with significant lead exposure, and especially those who have undergone chelation, need routine screening for lead-induced developmental injuries such as speech or language impairments, learning disabilities, and behavioral disturbances. If at any time during follow-up a possible developmental delay is identified, the child should immediately be referred for a complete developmental evaluation and for neuropsychological testing if older than 4 years.27,28

ARSENIC Arsenic is the 20th most abundant element in the earth’s crust. It is found worldwide as a pollutant and is a known carcinogen. It is released into the environment by volcanoes, through the weathering and smelting of arseniccontaining minerals and ores, and by commercial and industrial processes. It is also found in some folk and naturopathic remedies. Children are commonly exposed to arsenic by the ingestion of contaminated well water or by contact with arsenate wood preservatives, such as copper chromium arsenate found in pressure-treated wood. Arsenic exists in organic and inorganic forms. Trivalent arsenic (As+3) is considered the most toxic form, followed by pentavalent arsenic (As+5). Organic arsenic is the nontoxic form that is commonly found in seafood, particularly shellfish. Arsenic is well absorbed by all routes. Once absorbed, arsenicals disrupt cellular metabolism by interacting with sulfhydryl groups and by inhibiting enzymatic pathways required for the production of adenosine triphosphate. Arsenic is rapidly cleared from the blood (1-hour half-life), and excretion is almost exclusively

renal.29

CLINICAL PRESENTATION The clinical presentation of arsenic poisoning depends on the route, dose, timing, and duration of exposure. The characteristic presentation of acute arsenic poisoning is described as dysphagia associated with a metallic taste. Within hours of exposure, diffuse capillary and endothelial cell damage results in vasodilation and leakage of plasma, which precipitates a hemorrhagic gastroenteritis. In severe cases, extensive third spacing of fluids combined with fluid loss may lead to cardiovascular collapse consisting of hypotension, shock, and even death. Electrocardiogram findings may include nonspecific T-wave changes and a prolonged Q-Tc interval that may occur promptly or after a delay of several days. Acute tubular necrosis may also occur after a large ingestion. Acute poisoning can cause delirium, encephalopathy, seizures, and coma. A delayed sensorimotor peripheral neuropathy may appear within 3 weeks after acute ingestion. Chronic arsenic poisoning develops insidiously and includes peripheral neuropathy and dermal changes. “Raindrop” lesions of the skin can take years to manifest and are characteristically described as hypo- and hyperpigmentation with hyperkeratosis. Skin, bladder, and lung malignancies have been observed in adults. General manifestations of chronic arsenic toxicity can include malaise, weakness, anorexia, alopecia, headache, diarrhea, nausea, vomiting, leukopenia, and anemia.29,30

DIAGNOSTIC EVALUATION AND MANAGEMENT The diagnosis of arsenic poisoning is based on a history of exposure combined with a characteristic presentation. Arsenic levels can be obtained from urine, blood, hair, and nail samples. Urine is the preferred biomarker for arsenic exposure and must be obtained as a timed (8- to 24-hour) urine collection. A “spot” urine sample is not accurate but may be helpful in acute poisoning. There are two methods of measuring arsenic in urine samples: fractionated (speciated) measurement for inorganic plus organic arsenic, or total arsenic level (this must be done 1 week after seafood abstinence to avoid false-positive results). Urine arsenic has a reference value of less than 25

μg/dL. Blood arsenic levels are rarely useful because of the short half-life. Normal blood levels vary based on background exposures but are typically less than 3 μg/dL. Hair and nail levels are of limited value owing to external contamination. Because arsenic is readily excreted in urine, elimination of exposure is the most effective treatment. In symptomatic patients, BAL at a dose of 3 to 5 mg/kg intramuscularly every 4 to 6 hours can be administered and should continue until the urinary arsenic level is less than 50 μg/L per 24 hours. Nausea and vomiting are common side effects, but hypertension and lacrimation have also been described with multiple injections. Ampules of BAL in peanut oil may still exist, thus patients with peanut allergies should be monitored closely. Chelation is rarely needed outside the setting of symptomatic acute poisoning; however, if chelation is prescribed, succimer is the preferred agent at a dose of 10 mg/kg orally 3 times a day for 5 days, then twice a day for 14 days.31,32

CONSULTATION Chelation should be undertaken only after consultation with a medical toxicologist

ADMISSION CRITERIA Symptomatic arsenic poisoning requiring parenteral chelation therapy

DISCHARGE CRITERIA Completion of parenteral therapy and resolution of symptoms Identification and elimination of source of arsenic exposure

MERCURY Mercury is a naturally occurring metal that is present throughout the environment. It has been used in medications, disinfectants, thermometers, dental amalgams, and ethnic remedies. In the United States, coal-fired power

plants are the biggest source of mercury emissions in the air.33 Mercury exists in three primary forms, each with a different toxicity: elemental or metallic mercury (Hg°), inorganic mercury salts (Hg+1 [mercurous], Hg+2 [mercuric]), and organic or alkyl mercury (e.g. methylmercury). Inorganic mercury is readily converted to methylmercury by aquatic microorganisms and can bioaccumulate in the tissues of large carnivorous fish. The toxicokinetics of mercury vary, depending on the route of absorption and chemical form. Elemental, inorganic, and organic mercury can all be absorbed after inhalation. Elemental mercury is poorly absorbed orally; conversely, organic mercury is well absorbed (Table 168-3). Dermal absorption is limited for all forms of mercury. Elemental and inorganic mercury have a half-life of 40 to 60 days and are excreted via urine. Organic mercury has a half-life of 70 to 90 days and is eliminated via bile and feces. TABLE 168-3

Mercury Absorption and Target Organs EXPOSURE

Mercury Form

Inhalation Oral

Target Organ

Elemental (metallic) mercury Hg0 liquid, Hg0 vapor

Major

Acute: lungs

Minor

Chronic: CNS/PNS, erethism Other: kidney, acrodynia

Inorganic mercury salts Hg+1 (mercurous), Hg+2 (mercuric)

Minor

Major

Acute: Gl (caustic injury) Chronic: CNS/PNS, erethism, triad (tremor, neuropsychiatric disturbances, gingivostomatitis)

Other: kidney, acrodynia Organic (alkyl) mercury methylmercury, ethylmercury, dimethylmercury

Minor

Major

Acute and chronic: CNS/PNS, teratogen Other: kidney, liver

CNS/PNS, central nervous system/peripheral nervous system; erethism, irritability, excitability, decreased concentration; Gl, gastrointestinal.

CLINICAL PRESENTATION Acute inhalation of elemental mercury vapor is the main cause of toxicity. Symptoms may develop within a few hours and include nausea, vomiting, chills, metallic taste, tachypnea, dyspnea, abdominal pain, and diarrhea. These symptoms may subside in a few days or progress to interstitial pulmonary fibrosis, noncardiogenic pulmonary edema, interstitial chemical pneumonitis, and hemoptysis. Elemental liquid mercury can irritate the skin and cause allergic reactions. Chronic inhalation of elemental mercury vapor produces the classic triad of tremor, neuropsychiatric disturbances, and gingivostomatitis. Acrodynia (painful extremities) is a rare disease that affects primarily young children with chronic exposure. Symptoms include irritability, photophobia, pink discoloration of the hands and feet, and polyneuritis. Acute ingestion of inorganic mercury salts is caustic to the Gl tract and can produce a sudden onset of corrosive stomatitis, hemorrhagic gastroenteritis, and abdominal pain. Acute oliguric renal failure from acute tubular necrosis may also occur within days of exposure. Chronic manifestations of inorganic mercury toxicity are similar to those of elemental mercury. Organic mercury affects primarily the central nervous system, causing paresthesias, ataxia, dysarthria, spasticity, hearing impairment, and progressive visual field constriction. Perinatal exposure to methylmercury, a known potent teratogen, can produce severe congenital abnormalities such as neuroencephalomyelopathy and micrognathia.34

DIAGNOSTIC EVALUATION AND MANAGEMENT The diagnosis of mercury poisoning depends on the integration of characteristic findings with a history of known or potential exposure and the presence of a positive biomarker. Whole blood or, preferably, urine can be used to determine metallic and inorganic mercury levels. Whole blood samples are preferred for organic mercury levels, because that form is excreted in feces. Hair samples have limited value. Removing the mercury source and preventing additional exposure are the best treatments. Elemental and inorganic mercury poisoning can be treated with oral succimer at a dose of 10 mg/kg orally 3 times a day for 5 days, then twice a day for 14 days. Alternatively, intramuscular BAL can be given initially at a dose of 3 to 5 mg/kg every 4 hours for 2 days, then 2.5 to 3 mg/kg every 6 hours for 2 days, then 2.5 to 3 mg/kg every 12 hours for 1 to 3 days. Organic mercury has been treated with oral succimer; however, data on its effectiveness are limited. Chelation therapy is rarely indicated and should be initiated only after consultation with a medical toxicologist.22,35-37 KEY POINTS Lead Lead poisoning remains a common problem, affecting an estimated 300,000 children in the United States. Severe lead poisoning, defined as a BLL greater than 45 μg/dL, requires immediate intervention. Hospitalization is recommended for these children, with the goals of providing immediate environmental protection and the rapid institution of chelation therapy. In rare circumstances, children with BLLs of 45 to 55 μg/dL can be considered for outpatient therapy if a safe environment and 100% compliance with the outpatient chelation regimen can be assured. The chelation agents of choice for asymptomatic hospitalized children with BLLs of 45 to 70 μg/dL are succimer and CaNa2EDTA. Children with BLLs greater than 70 μg/dL should receive dual chelation therapy with CaNa2EDTA and BAL. BAL, which should be initiated before CaNa2EDTA, is given until the

BLL has fallen below 70 μg/dL, at which time CaNa2EDTA alone can be given. Arsenic Arsenic is a heavy metal with a short half-life. Exposure commonly occurs from ingestion of contaminated well water or by contact with arsenate wood preservatives (e.g. pressure-treated wood). Acute toxicity presents initially with dysphagia associated with a metallic taste. Endothelial damage ensues, with vasodilation and leakage of plasma, which can lead to hemorrhagic gastroenteritis and progress to cardiovascular collapse. Neurotoxic effects can progress to coma. Evidence of chronic poisoning develops over years with peripheral neuropathy, dermal changes, and hair loss. Chelation therapy is indicated for symptomatic patients with acute poisoning. Mercury Mercury exists in three primary forms, each with a different toxicity: elemental or metallic mercury (Hg°), inorganic mercury salts (Hg+1 [mercurous], Hg+2 [mercuric]), and organic or alkyl mercury (e.g. methylmercury). Elemental, inorganic, and organic mercury can all be absorbed after inhalation which is the main cause of toxicity. Symptoms may develop within a few hours and include nausea, vomiting, chills, metallic taste, tachypnea, dyspnea, abdominal pain, and diarrhea. These symptoms may subside in a few days or progress to interstitial pulmonary fibrosis, noncardiogenic pulmonary edema, interstitial chemical pneumonitis, and hemoptysis. Urine should be used to determine metallic and inorganic mercury levels. Removing the mercury source and preventing additional exposure are the best treatments. Elemental and inorganic mercury poisoning can be treated with oral succimer at a dose of 10 mg/kg orally 3 times a day for 5

days, then twice a day for 14 days.

SUGGESTED READINGS Agency for Toxic Substances and Disease Registry. Toxicological Profile for Mercury. Atlanta, GA: US Public Health Service; 1999. Dart RC, Bond GR. Gastrointestinal decontamination. In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:32-39.

REFERENCES 1. Angle CR. Childhood lead poisoning and its treatment. Ann Rev Pharmacol Toxicol. 1993;33:409-434. 2. Kosnett MJ. Lead. In: Ford MD, Delaney KA, Ling U, Erickson T, eds. Clinical Toxicology. Philadelphia: WB Saunders; 2001:723-735. 3. Laraque D, Trasande L. Lead poisoning: successes and 21st century challenges. Pediatr Rev. 2005;26:432-435. 4. Yip L. Heavy metal poisoning. In: Irwin RS, Rippe JM, eds. Irwin & Rippe’s Intensive Care Medicine. 4th ed. Philadelphia: LippincottRaven; 1999:1637-1653. 5. Jacobs DE, Clickner RP, Zhou JY, et al. The prevalence of lead-based paint hazards in US housing. Environ Health Perspect. 2002;110:A599A606. 6. Llop S, Lopez-Espinosa M, Rebagliato M, et al. Gender differences in the neurotoxicity of metals in children. Toxicology. 2013;311:3-12. 7. McLaine P, Navas-Acien A, Lee Robert, et al. Elevated blood lead levels and reading readiness at the start of kindergarten. Pediatrics. 2013;131:1081-1089. 8. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Lead. Atlanta, GA: US Department of Health and Human Services; 2003.

9. Dart RC. Succimer. In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:266-268. 10. Centers for Disease Control and Prevention Advisory Committee on Childhood Lead Poisoning Prevention. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA: US Department of Health and Human Services; January 4, 2012. www.cdc.gov/nceh/lead/ACCLPP/Final_Document_030712pdf. Accessed March 3, 2015. 11. Jones AL, Flanagan RJ. Dimercaprol. In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:185-186. 12. Canfield RL, Henderson CR Jr, Cory-Slechta DA, et al. Intellectual impairment in children with blood lead concentrations below 10 μg per deciliter. N Engl J Med. 2003;348:1517-1526. 13. Pirkle JL, Brody DJ, Gunter EW, et al. The decline in blood lead levels in the United States: the National Health and Nutrition Examination Surveys (NHANES). JAMA. 1994;272:284-329. 14. Shannon MW. Etiology of lead poisoning. In: Pueschel SM, Linakis JG, Anderson AC, eds. Lead Poisoning in Childhood. Baltimore: Paul H. Brookes; 1996:37-57. 15. Yip L. Calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA). In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:169-172. 16. American Academy of Pediatrics, Committee on Drugs. Treatment guidelines for lead exposure in children. Pediatrics. 1995;96:155-160. 17. Piomelli S, Rosen JF, Chisolm JJ Jr, Graef JW. Management of childhood lead poisoning. J Pediatr. 1984;105:523-532. 18. Shannon MW, Graef JW. Lead intoxication in infancy. Pediatrics. 1992;89:87-90. 19. Ziegler EE, Edwards BB, Jensen RL, et al. Absorption and retention of lead by infants. Pediatr Res. 1978;12:29-34. 20. Rabinowitz MB, Wetherill GW, Kopple JD. Kinetic analysis of lead metabolism in healthy humans. J Clin Invest. 1976;58:260-270. 21. Bellinger D, Sloman J, Levitón A, et al. Low-level lead exposure and

children’s cognitive function in the preschool years. Pediatrics. 1991;87:219-227. 22. Osterhoudt KC. Toxicologic emergencies. In: Fleisher G, Ludwig S. Textbook of Pediatric Emergency Medicine. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2012:1203. 23. Bellinger DC, Stiles KM, Needleman HL. Low-level lead exposure, intelligence and academic achievement: a long-term follow-up study. Pediatrics. 1992;90:855-861. 24. Liebelt EL, Shannon MW. Oral chelators for childhood lead poisoning. Pediatr Ann. 1994;23:616-619. 25. Hryhorczuk D, Eng J. Arsenic. In: Ford MD, Delaney KA, Ling LJ, Erickson T, eds. Clinical Toxicology. Philadelphia: WB Saunders; 2001:716-721. 26. Watanabe T, Hirano S. Metabolism of arsenic and its toxicological relevance. Arch Toxicol. 2013;87:969-979. 27. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Arsenic. Atlanta, GA: US Department of Health and Human Services; 2000. 28. Cullen NM, Wolf LR, St Clair D. Pediatric arsenic ingestion. Am J Emerg Med. 1995;13:432-435. 29. Hall AH. Chronic arsenic poisoning. Toxicol Lett. 2002;128:69-72. 30. Myers G, Davidson P, et al. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology. 1997;18:819-830. 31. Chiang WK. Mercury. In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: WB Saunders; 2001:737-1153. 32. American Academy of Pediatrics: Committee on Environmental Health. Technical report: mercury in the environment: implications for pediatricians. Pediatrics. 2001;108:1505-1510. 33. Baum CR. Treatment of mercury intoxication. Curr Opin Pediatr. 1999;11:265-268. 34. Ozuah PO. Mercury poisoning. Curr Probl Pediatr. 2000;30:91-99. 35. Kosnett M. The role of chelation therapy in the treatment of arsenic and

mercury poisoning. J Med Toxicol. 2013;9:347-354. 36. Rubin R, Strayer DS, eds. Environmental and nutritional pathology. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:266. 37. Dapul H, Laraque D. Lead poisoning in children. Adv Pediatr. 2014;61:313-333.

Drugs of Abuse

CHAPTER

169

Heather J. Becker and Carl R. Baum

BACKGROUND Drugs of abuse continue to have a significant impact on healthcare utilization in the pediatric population. The pediatric hospitalist should consider drugs of abuse in the differential diagnosis of any patient who presents with altered mental status (hallucinations, stupor, coma), abnormal motor activity (tremor, seizure), or behavioral disturbance (agitation, outburst, withdrawal, depression, suicidal or homicidal ideation). Each fall, the American Association of Poison Control Centers publishes its annual summary of poisoning exposures reported to its member centers. In 2011, there were a total of 2.3 million exposures reported, 1158 of which led to a fatality.1 Of these fatalities, 41 (3.5%) involved a child (10 μm) will primarily affect mucous membranes and upper airways. Lower water soluble irritants (chlorine, phosgene) and smaller particles (25%), seizure, or abnormal cerebellar function.

AIRWAY AND LUNG INJURY

The airway should be protected early, and any signs of airway compromise indicate the need for direct laryngoscopy and prompt elective endotracheal intubation. Indications for early endotracheal intubation and mechanical ventilation are provided in Table 171-2. In the setting of acute mucosal inflammation, intubation with smaller endotracheal tubes than expected for age may be necessary. TABLE 171-2

Indications for Early Endotracheal Intubation

Signs of upper airway obstruction Altered level of consciousness associated with loss of cough or gag reflex Persistent hypoxia (PaO2, 60 mmHg on >60% inspired oxygen) Need for aggressive pulmonary toilet Treatment of smoke inhalation and parenchymal lung damage focuses on supportive care to maximize respiratory function. Weaning of the oxygen concentration should begin only after there is confirmation of a normal COHb level (by CO-oximetry) and correction of ventilation-perfusion mismatch. ABG analysis is a valuable tool for monitoring acid-base status (pH), oxygenation (as measured by the arterial partial pressure of dissolved oxygen [PaO2] and the calculated arterial saturation level [SaO2]), ventilation (measured by the arterial partial pressure of dissolved carbon dioxide [PaCO2]), and gas exchange at the alveolar level (assessed by the alveolararterial gradient). In the setting of pulmonary edema from increased capillary leak, delivery of peak end-expiratory pressure support by endotracheal tube will maintain small-airway patency and improve alveolar gas exchange. Because airway obstruction is usually mechanical, adequate humidification and pulmonary toilet are the mainstays of supportive care. Particulate matter may cause hypersensitivity and bronchoconstriction, especially in children with a previous reactive airway history. Bronchodilators such as nebulized albuterol may help alleviate lower airway obstruction. The use of steroids and prophylactic antibiotics is not indicated in the setting of acute lung injury from smoke inhalation. Corticosteroids have been associated with a

significant increase in the risk for death and infectious complications and should not be used in the treatment of burn patients.3,16 Antibiotic use should be reserved for clinical signs of infectious pneumonia, which rarely occur during the first 24 hours.3 Prophylactic antibiotics may select for more resistant organisms and are not recommended.3 The use of certain exogenous surfactants has been shown to effectively restore endogenous surfactant function after inhalational injury by wood smoke.17,18

CARBON MONOXIDE POISONING Patients suspected of suffering CO poisoning should have 100% oxygen therapy initiated with the intention of decreasing the blood half-life of COHb. Delivery of 100% inspired oxygen should be continued until COHb has fallen below 5%. The half-life of COHb is decreased from approximately 4 to 6 hours in patients breathing room air at sea level (normobaric, 1 atm) to 60 to 90 minutes with 100% inspired oxygen. Treatment with 100% oxygen at hyperbaric treatment pressures (usually 3 atm) increases the oxygen concentration in blood and further shortens the half-life of COHb to 20 to 30 minutes. By increasing the competition for hemoglobin binding sites, elimination of CO occurs more quickly.19 Patients with significant CO poisoning are at risk for delayed neurologic sequelae, including cognitive and memory difficulties, personality changes, peripheral neuropathies, and neurologic deficits. The role of hyperbaric oxygen (HBO) therapy in the prevention of delayed neurologic sequelae is controversial. HBO therapy can inhibit the leukocyte adherence that initiates the cerebral vasculitis from severe CO poisoning. Several clinical studies have showed conflicting evidence on the potential benefit or lack of benefit with HBO therapy.20-23 A recent Cochrane Review concluded there is no evidence to support the use of hyperbaric oxygen for treatment of patients with CO poisoning.24 The decision about HBO should be made individually based on the history, clinical presentation, and degree of neurologic impairment in conjunction with your local poison center or hyperbaricist. Certain criteria that have been traditionally used as indications to consider HBO therapy include any history of loss of consciousness or syncope, focal or persistent neurologic symptoms, ischemic changes on electrocardiography, pregnant patients with COHb levels higher than 15% or any signs of fetal distress, significantly elevated

COHb levels (>25%), seizure, and abnormal cerebellar function.23,25,26 Measured COHb levels do not correlate with the severity of CO poisoning and should not be used alone when deciding on appropriate therapy. HBO therapy should not delay resuscitative measures or addressing more acute sequelae or symptoms such as myocardial infarction, or seizures. HBO therapy can be safely administered to patients who are hemodynamically stable and those without pulmonary air trapping. In view of the lack of empirical support for the efficacy of HBO in CO poisoning long or potentially dangerous (e.g. helicopter) transport to an HBO facility should be discouraged.

CYANIDE POISONING Concurrent poisoning with hydrogen cyanide has been reported and should be considered in patients who are victims of a closed-space fire.27 Cyanide toxicity should be suspected in those who have altered levels of consciousness and persistent or worsening lactic acidosis (blood lactate level >10 mmol/L) not responsive to maximal oxygenation and fluid resuscitation, hypotension, cardiovascular collapse, or cardiac arrest. There are multiple treatments for cyanide toxicity, but two treatments are more readily available.28 Hydroxocobalamin has surpassed the traditional cyanide kit as the more available antidote available in emergency departments. Hydroxocobalamin combines with cyanide to form cyanocobalamin, which is nontoxic. Starting dose in pediatrics is 70 mg/kg (Max 5 g) IV, which can be repeated if necessary. Adverse effects include red dislocation of secretions, urine, and mucous membranes, and hypertension.29 Colorimetric assays and laboratory tests will also be affected after administration. The traditional cyanide antidote kit consists of sodium nitrite and sodium thiosulfate. Sodium nitrite induces methemoglobinemia. Methemoglobin (MeHb) has a high affinity for cyanide, producing cyanomethemoglobin. MeHb therefore acts as a cyanide scavenger, preventing its binding to cytochrome oxidase. Nitritemediated vasodilation may also play a role. The dose of sodium nitrite 10 mg/kg (or 0.33 cc of the 3% solution in the cyanide antidote kit) up to a maximum of 300 mg (10 cc). The objective is to raise the MeHb fraction to now more than the low teens. Although the induction of MeHb in a victim of smoke inhalation theoretically raises concern for its additive effects with

COHb on functional hemoglobin, such concerns appear to be unfounded in non-anemic patients with treated with high-flow oxygen. Studies on such patients have shown that despite the induction of MeHb, the falling COHb fraction results in a net increase in functional hemoglobin.30 Adverse effects of sodium nitrite include hypotension, nausea, and vomiting. On the other hand, sodium thiosulfate can be safely given for cyanide poisoning in the setting of smoke inhalation. Sodium thiosulfate binds to cyanide to produce thiocyanate, which is then renally eliminated. The pediatric dose is 250 mg/kg (max 12.5g) IV. Adverse effects also include hypotension, nausea, and vomiting.31 Sodium thiosulfate and hydroxocobalamin can be given together, but should not be given in the same IV, as they will bind and be ineffective.

ADMISSION CRITERIA Hospitalization is indicated for patients with Hemodynamic instability (intensive care setting) The need or potential need for endotracheal intubation and mechanical ventilation (consider the intensive care setting) Evidence of airway compromise that has yet to demonstrate steady improvement High risk for airway injury despite being asymptomatic during the initial period of observation (e.g. signs of airway erythema or edema, prolonged or severe exposure to smoke, other victims with similar exposure who have demonstrated clinical deterioration) Evidence of significant CO or cyanide poisoning, especially if symptoms persist after normalization of COHb levels

DISCHARGE CRITERIA Stabilization of all airway and pulmonary issues Normalization of COHb levels Resolution of all toxin-associated symptoms

CONSULTATION

Critical care: For patients with a severe cardiopulmonary insult or instability Otolaryngology/pulmonology: For patients with evidence of airway injury Medical toxicology: For patients with significant CO or cyanide poisoning, or exposure to other inhaled toxins

SPECIAL CONSIDERATIONS The high minute ventilation characteristic of children puts them at increased risk for smoke inhalation injury as compared with adults.

PREVENTION (CDC RECOMMENDATIONS)32 Smoke alarms Carbon monoxide detectors Cook with care Attempt to quit smoking Safe space heater use Escape plan KEY POINTS The airway should be protected early, and any signs of airway compromise indicate the need for direct laryngoscopy and prompt elective endotracheal intubation. Even without skin burns or upper airway injury, significant lower airway involvement can occur in a child who inhales toxic particles in smoke. Lung injury and chest x-ray findings can be delayed. Exposure to combustion or smoke in a closed or partially closed space puts the patient at high risk for CO and/or cyanide poisoning. Obtain a COHb level and lactate concentration for evaluation.

REFERENCES 1. Karter MJ. Fire Loss in the United States during 2011, Quincy (MA). National Fire Protection Association Fire Analysis and Research Division; September 2012. 2. Centers for Disease Control and Prevention (CDC). Vitals signs: unintentional injury deaths among persons aged 0-19 years—United States, 2000-2009. MMWR Morb Mortal Wkly Rep. 2012;61:270-276. 3. Miller K, Chang A. Acute inhalation injury. Emerg Med Clin North Am. 2003;21:533-557. 4. Pruitt BA, Flemma RJ, DiVincenti FC, et al. Pulmonary complications in burn patients. A comparative study of 697 patients. J Thorac Cardiovasc Surg. 1970;59:7-20. 5. Stefanidou M, Athanaselis S, Spiliopoulou C. Health impacts of fire smoke inhalation. Inhal Toxicol. 2008;20:761-766. 6. Lee AS, Mellins RB. Lung injury from smoke inhalation. Paediatr Respir Rev. 2006;7:123-128. 7. Ciorciari AJ. Environmental emergencies. In: Crain EF, Gershel JC, eds. Clinical Manual of Emergency Pediatrics. 3rd ed. New York: McGrawHill; 1997:163-189. 8. From the Centers for Disease Control and Prevention. Deaths from motor-vehicle-related unintentional carbon monoxide poisoning— Colorado, 1996, New Mexico, 1980-1995, and United States, 19791992. JAMA. 1996;276:1942-1943. 9. Geehr EC, Saluzzo R, Bosco S, et al. Emergency health impact of a severe storm. Am J Emerg Med. 1989;7:598-604. 10. Varon J, Marik PE, Fromm RE, Gueler A. Carbon monoxide poisoning: a review for clinicians. J Emerg Med. 1999;17:87-93. 11. Carvajal H F, Griffith JA. Burn and inhalation injuries. In: Fuhrman BP, Zimmerman JJ, eds. Pediatric Critical Care. 3rd ed. Philadelphia: CV Mosby; 2006:1565-1576. 12. Duffy BJ, McLaughlin PM, Eichelberger MR. Assessment, triage, and early management of burns in children. Clin Pediatr Emerg Med. 2006;7:82-93.

13. Joffe MD. Burns. In: Fleisher GR, Ludwig S, Henretig FM, eds. Textbook of Pediatric Emergency Medicine. Philadelphia: Lippincott Williams & Wilkins; 2005:1517-1524. 14. Rabinowitz PM, Siegel MD. Acute inhalation injury. Clin Chest Med. 2002;23:707-715. 15. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med. 1991;325(25):1761-1766. 16. Jeng M, Kou YR, Sheu C, Hwang B. Effects of exogenous surfactant supplementation and partial liquid ventilation on acute lung injury induced by wood smoke inhalation in newborn piglets. Crit Care Med. 2003;31:1166-1174. 17. Nieman GF, Paskanik AM, Fluck RR, Clark WR. Comparison of exogenous surfactants in the treatment of wood smoke inhalation. Am J Respir Crit Care Med. 1995;152:597-602. 18. Martin JD, Osterhoudt KC, Thorn SR. Recognition and management of carbon monoxide poisoning in children. Clin Pediatr Emerg Med. 2000;1:244-250. 19. Judge BS, Brown MD. To dive or not to dive? Use of hyperbaric oxygen therapy to prevent neurologic sequelae in patients acutely poisoned with carbon monoxide. Ann Emerg Med. 2005;46:462-466. 20. Annane D, Chadda K, Gajdos P, et al. Hyperbaric oxygen therapy for acute domestic carbon monoxide poisoning: two randomized controlled trials. Intensive Care Med. 2011;27(3):486-492. 21. Sheinkestel CD, Bailey M, Myles PS, et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Med J Aust. 1999;170:203-210. 22. Thom SR, Taber RL, Mendiguren II, et al. Delayed neurologic sequelae after carbon monoxide poisoning; prevention by treatment with hyperbaric oxygen. Ann Emerg Med. 1995;25:474-480. 23. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med. 2002;347(14):1057-1067. 24. Buckley NA, Juulink DN, Isbister, et al. Hyperbaric oxygen for carbon monoxide poisoning (review). Cochrane Database Sys Rev.

2011;13(4):CD002041. 25. Kao LW, Nanagas KA. Carbon monoxide poisoning. Med Clin North Am. 2005;89:1161-1194. 26. Wratney AT, Cheifetz IM. Gases and drugs used in support of the respiratory system. In: Slonim AD, Pollack MM, eds. Pediatric Critical Care Medicine. Philadelphia: Lippincott Williams & Wilkins; 2006:717729. 27. Grabowska T, Skowronek R, Nowicka J, et al. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clin Toxicol (Philadelphia). 2012;50:759-763. 28. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;29(7):541-552. doi: 10.1080/10308440802304944. 29. Cyanokit [package insert]. Columbia, MD: Meridian Medical Technologies, Inc; March 2010. 30. Kirk MA, Gerace R, Kulig KW. Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit. Ann Emerg Med. 1993;22(9):1413-1418. 31. Nithiodote [package insert]. Scottsdale, AZ: Hope Pharmaceuticals; January 2011. 32. Centers for Disease Control and Prevention (CDC). Fire Prevention. October 2011. http://www.cdc.gov/features/fireprevention/. Accessed February 10, 2014.

CHAPTER

172

Heat Disorders Lise E. Nigrovic and Michele M. Burns

BACKGROUND Heat disorders such as heat exhaustion and heatstroke result from a failure of the body’s regulatory mechanisms to maintain a constant body temperature. Individuals at the extremes of age and those with chronic diseases are the most vulnerable. Approximately 400 people die annually in the United States from heat-related illness.1 Fever, on the other hand, is an elevation in body temperature secondary to mediators of inflammation and involves an adjustment in the physiologic set point (see Chapter 24). Malignant hyperthermia, another thermoregulatory disorder, results from a triggering exposure in a genetically susceptible individual. Heat disorders occur most commonly in the summer months or in tropical regions. Although elderly patients are most severely affected, healthy children are also susceptible. Young children have suboptimally developed thermoregulatory controls and are dependent on others to provide them with fluids and to keep them from unsafe environments. Only 4% of the heatrelated deaths in the United States occur in children younger than 14 years.1 Comorbid conditions such as obesity, physical disabilities that limit rapid egress from a warm environment, or cystic fibrosis increase a child’s susceptibility to heat stress.

PATHOPHYSIOLOGY The human body maintains a relatively constant body temperature despite wide swings in environmental temperature. Heat is acquired both endogenously (from basal metabolism, muscle activity, hormonal effects, and sympathetic stimulation) and exogenously (when environmental temperature

exceeds body temperature). Heat is lost to the environment by radiation (up to 60% of losses), evaporation of sweat (22% to 25%), conduction (3%), and convection (12% to 15%). The hypothalamus, the body’s primary thermoregulator, maintains the core body temperature within a narrow range. Increases in body temperature result in sympathetically mediated peripheral blood vessel dilation (increased radiation losses), increased sweat gland activity (higher evaporative losses), and reduced endogenous heat production. Hyperthermia occurs when the body cannot adequately dissipate excess exogenous or endogenous heat. Malignant hyperthermia is a group of genetic myopathies associated with a defect in the calcium channels of skeletal muscles.2 Most patients are asymptomatic until exposed to the triggering agent. A muscle biopsy is needed to confirm the predisposing defect. Implicated triggers include medications such as inhaled anesthetics and neuromuscular blockers as well as physical stressors (Table 172-1). TABLE 172-1

Drugs That Can Cause Malignant Hyperthermia

Type of Agent

Causative Drugs

Inhalation anesthetic

Halothane Isoflurane Enflurane Desflurane Sevoflurane

Depolarizing muscle relaxant

Succinylcholine

Other

Phenothiazines

CLINICAL PRESENTATION Table 172-2 describes the symptoms, clinical and laboratory findings,

treatment, and prognosis of the three major types of heat-related illnesses: heat cramps, heat exhaustion, and heatstroke. TABLE 172-2

Descriptions of Heat Illnesses

Heat Cramps

Heat Exhaustion

Heatstroke

Core body Normal temperature

Elevated (≤39°C)

Very elevated (≥40°C)

Symptoms

Weakness

Confusion

Thirst

Delirium

Headache

Seizures

Nausea, vomiting

Coma

Painful muscle spasms

Diarrhea Physical Hard knot in examination muscle belly

Tachycardia

Tachycardia

Orthostatic hypotension

Circulatory collapse

Diffuse sweating

Anhidrosis Central nervous system dysfunction

Laboratory studies

Hyponatremia Hypo- or hypernatremia Low urine sodium

Hypo- or hypernatremia

Hemoconcentration Hemoconcentration Urinary concentration

Acute renal failure Rhabdomyolysis

Therapy

Prognosis

Oral rehydration

Passive cooling

Active cooling

Electrolyte solutions

IV rehydration

Cardiorespiratory support (dobutamine)

Excellent

Excellent

High mortality

HEAT CRAMPS Heat cramps are painful muscle spasms that typically occur several hours after vigorous exertion. They are thought to be due to repletion of water without adequate salt intake. The voluntary muscles of the calves, thighs, and shoulders are most commonly affected. Symptoms typically last only a few minutes but may recur. The affected muscles feel hard to palpation. Laboratory abnormalities may include hyponatremia with very low or undetectable urine sodium.

HEAT EXHAUSTION Heat exhaustion occurs secondary to water or salt depletion, or both. Affected patients experience systemic complaints, including fatigue, weakness, nausea, vomiting, diarrhea, and headache. Irritability may be a prominent sign in infants and nonverbal children. The core temperature is mildly elevated (40°C) associated with central nervous system dysfunction. Anhidrosis is frequently but not universally observed. Neurologic symptoms include progressive lethargy, confusion, headache, delirium, seizures, and coma. On physical examination, patients are tachycardic, hypotensive, and tachypneic (hyperventilation causes a respiratory alkalosis). Laboratory abnormalities may include hyponatremia or hypernatremia, hypokalemia, hemo- and urinary concentration, acute renal failure, and elevated liver function tests. The extent and severity of the central effects depend on the extent of the hyperpyrexia. Rhabdomyolysis may occur as a result of thermal injury to myocytes. Circulating myoglobin as well as thermal and ischemic insults can result in acute renal compromise.

MALIGNANT HYPERTHERMIA When a susceptible individual is exposed to a triggering agent, the uncontrolled influx of calcium into the muscle cell results in muscle contraction, accelerated metabolism, and resultant hyperthermia. Initially, end-tidal carbon dioxide increases and arterial oxygen decreases, with muscle rigidity and a rapid rise in body temperature.2,4 Laboratory evaluation reveals acidosis as well as hyperkalemia, hyperphosphatemia, hypocalcemia, and myoglobinuria from muscle breakdown. Although serum creatinine starts to rise almost immediately due to the rhabdomyolysis, peak levels are not seen until several days after the exposure.

DIFFERENTIAL DIAGNOSIS Other causes of myositis or tonic muscle contractions can present with features similar to heat cramps, including viral or drug-induced myositis and electrolyte imbalances leading to tetany. Increased body temperature can

occur secondary to a wide range of causes (Table 172-3). Encephalitis or other causes of encephalopathy, especially when accompanied by fever, can mimic heatstroke. TABLE 172-3

Causes of Hyperthermia

Sepsis Central nervous system infection Environmental exposure Tetanus Typhoid fever Thyroid storm Pheochromocytoma Catatonia Hypothalamic stroke Status epilepticus Cerebral hemorrhage Dystonic reaction Toxicologic ingestion Source: Data from Lanken PN, Manaker S, Hanson CW III, eds. The Intensive Care Unit Manual. Philadelphia: Saunders; 2001.

Many drug-induced hyperthermia syndromes exist. These include serotonin syndrome, neuroleptic malignant syndrome, acute drug withdrawal, and poisoning with sympathomimetic drugs, salicylates, thyroid hormones, or anticholinergics.

DIAGNOSTIC EVALUATION Patient history should be targeted to heat exposure, hydration status, and predisposing factors including problems with heat dissipation. The physical examination should focus on identifying the signs of heat illness as well as determining the severity of the condition. A core temperature must be obtained with a rectal thermometer. Laboratory assessments that may aid in the evaluation are listed in Table 172-4, along with typical derangements.

Depending on the other diagnostic concerns, additional studies such as imaging of the head; urine toxicology screen; cultures of blood, urine, or cerebrospinal fluid; and chest radiograph may be indicated. TABLE 172-4

Laboratory Studies for the Evaluation of Heat Disorders

Study

Common Abnormalities

Complete blood count

Leukocytosis, hemoconcentration, and, if DIC is present, thrombocytopenia

Serum electrolytes: sodium, potassium, chloride, bicarbonate

Variable derangements indicative of dehydration

Blood urea nitrogen, serum creatinine

Elevations consistent with dehydration or renal injury

Hepatic enzymes

Elevated if there is hepatic injury

Creatine kinase

Elevated with rhabdomyolysis

PT, INR, PTT, Ddimer

Elevated with DIC

Urinalysis

Elevated specific gravity, proteinuria, ketonuria, dipstick-positive for blood without red blood cells on microscopic examination

DIC, disseminated intravascular coagulation; INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time.

MANAGEMENT Heatstroke victims should have careful cardiovascular monitoring. Airway protection may be required to prevent aspiration. Patients with elevated core body temperatures should be aggressively cooled. Core body temperature should always be checked with a rectal or esophageal thermometer and

monitored frequently. Active cooling should be initiated to bring core body temperature down to between 38.5°C and 39.0°C.5 Victims should be removed from the hot environment and their clothing removed. Rapid cooling can begin either by emersion in cold water with ice or by evaporative cooling. Gastric or peritoneal lavage can be considered as a supplemental cooling method in severe cases. Cooled intravenous fluids are not used because of the risk of an arrhythmia with an already stressed myocardium. Delays in the onset of treatment have been associated with worse outcomes and longer durations of hospital stay.6 Fluid and electrolyte replacement is extremely important in the effective therapy of heat illnesses.7 Heat cramps can be effectively treated with rest as well as oral salt and water replacement. Passive stretching of the affected area can help resolve muscle cramps. Heat exhaustion requires intravenous rehydration with unrestricted dietary sodium. Electrolyte imbalances should be corrected slowly over 12 to 24 hours. Heatstroke victims require aggressive fluid resuscitation to maintain cerebral perfusion. If urine output cannot be maintained at greater than 1 mL/kg per hour with aggressive fluid repletion, the addition of diuretics (e.g. furosemide, mannitol) should be considered.5 Hypotension refractory to intravenous fluids warrants vasopressor therapy. Dobutamine (5 to 20 μg/kg per minute), a β1-adrenergic agent, should be selected because it both increases cardiac contractility raising blood pressure and causes peripheral vasodilation allowing ongoing heat loss. Agents with α-adrenergic activity, such as dopamine, epinephrine, and norepinephrine, should be avoided because the resulting peripheral vasoconstriction minimizes heat dissipation. Isoproterenol, a β-adrenergic agent, may increase myocardial oxygen consumption beyond oxygen delivery capacity. The initial management of malignant hyperthermia requires discontinuing the offending agent. Hyperventilation with 100% oxygen and volume replacement should begin immediately. As soon as the diagnosis of malignant hyperthermia has been made, dantrolene should be given (2.5 mg/kg body weight up to every 5 minutes until muscle relaxation is achieved; only rarely is a total dose of 10 mg/kg needed to control rigidity and tachycardia).8 Dantrolene causes muscle relaxation directly by blocking the release of calcium from the sarcoplasmic reticulum.9 Each 20-mg vial of dantrolene

contains 3 g of mannitol, which should be taken into account if further diuretic therapy is being considered. External cooling measures should be initiated to treat hyperthermia. Benzodiazepines or paralysis should be considered for patients with persistent shivering. Cardiac arrhythmias resulting from malignant hyperthermia should be treated with procainamide and calcium chloride. Rhabdomyolysis may develop as a complication of heatstroke or malignant hyperthermia. Creatine kinase levels typically peak several days after the heat or drug exposure. Monitoring for electrolyte imbalances and renal injury (evidenced by urine myoglobin) is required.10 Ample hydration should be maintained, and some experts recommend alkalization (target urine pH >6.5). Disseminated intravascular coagulation, seizure, renal failure, hepatic dysfunction, and acute respiratory distress syndrome can complicate heatstroke and should be managed appropriately, typically in an intensive care setting.

ADMISSION AND DISCHARGE CRITERIA The majority of otherwise healthy patients with heat cramps and heat exhaustion can be treated with cooling and rehydration in the primary care office or emergency department without hospital admission. Patients with heatstroke or other evidence of end-organ injury (e.g. rhabdomyolysis), druginduced hyperthermia syndromes, coexisting chronic medical conditions, or malignant hyperthermia generally warrant inpatient stabilization. Children can be discharged once all of the following have occurred: return to hemodynamic stability, return to baseline mental status, ability to maintain adequate hydration and resolution of rhabdomyolysis with decreasing levels of creatine kinase, and clearance of myoglobinuria.

CONSULTATION Involvement of critical care specialists is indicated for patients who require or are anticipated to need intensive care support. Nephrologists may be helpful for patients at risk for or with evidence of renal injury, especially those with severe rhabdomyolysis.

Emergency consultation for a patient thought to have malignant hyperthermia can be obtained by calling the hotline (800-MH-HYPER or 800-644-9737) or reviewing the website (www.mhaus.org/hotline.html).

SPECIAL CONSIDERATIONS PREVENTION The best preventative approaches for heat illnesses are activity restriction11 and avoidance of environmental situations that put a child at risk for heat illness (Table 172-5). The National Weather Service and the Centers for Disease Control and Prevention issue heat advisories through local broadcasting systems that can alert individuals and communities to dangerous conditions. Prevention tips are provided in Table 172-5. TABLE 172-5

Recommendations for the Prevention of Heat Illness

Drink plenty of nonalcoholic fluids Replace salts and minerals (e.g. salt-containing foods, sports drinks) Dress in lightweight, light-colored, loosely fitted clothing Avoid or limit sun exposure Avoid outdoor activity, especially during midday and afternoon Seek out air-conditioned environments (e.g. shopping mall, public library, heat-relief shelter) Check on individuals at increased risk for heat injury Source: Adapted from the Centers for Disease Control and Prevention website. Extreme Heat: A Prevention Guide to Promote Your Personal Health and Safety.

Early recognition of malignant hyperthermia and prevention of exposure to triggering agents are the most effective therapies for this life-threatening condition. Preoperative assessments should include careful questioning about reactions to anesthesia in the patient or family members. To prevent recurrences, patients should carry malignant hyperthermia medical identification bands at all times.

KEY POINTS Heat-related conditions are usually a result of heat exposure and inadequate hydration. Heat cramps typically involve the calves, thighs, and shoulders and are usually managed with rest and hydration. Features of heat exhaustion include weakness, irritability, vomiting, diarrhea, diaphoresis, elevated body temperature, and orthostasis. Heatstroke is a life-threatening condition that presents with a significant elevation in core body temperature, changes in mental status, and often, cardiovascular instability. Sweating may be absent. Malignant hyperthermia represents a group of genetic myopathies that result in muscle rigidity and severe elevations in core body temperature upon exposure to triggers (e.g. anesthetic agents and succinylcholine). Rapid cooling and appropriate management of fluid and electrolyte derangements are the mainstays of therapy for heat disorders. Dantrolene is used in the treatment of malignant hyperthermia.

SUGGESTED READING Singleton KD, Wischmeyer PE. Oral glutamine enhances heat shock protein expression and improves survival following hyperthermia. Shock. 2006;25(3):295-299.

REFERENCES 1. Jardine DS. Heat illness and heat stroke. Pediatr Rev. 2007;28(7):249258. 2. Denborough M. Malignant hyperthermia. Lancet. 1998;352(9134):11311136.

3. Bouchama A, Knochel JP. Heat stroke. N Engl J Med. 2002;346(25):1978-1988. 4. Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293(23):2918-2924. 5. Lugo-Amador NM, Rothenhaus T, Moyer P. Heat-related illness. Emerg Med Clin North Am. 2004;22(2):315-327, viii. 6. Zeller L, Novack V, Barski L, Jotkowitz A, Almog Y. Exertional heatstroke: clinical characteristics, diagnostic and therapeutic considerations. Eur J Intern Med. 2011;22(3):296-299. 7. Von Duvillard SP, Braun WA, Markofski M, Beneke R, Leithauser R. Fluids and hydration in prolonged endurance performance. Nutrition. 2004;20(7-8):651-656. 8. Halloran LL, Bernard DW. Management of drug-induced hyperthermia. Curr Opin Pediatr. 2004;16(2):211-215. 9. Hadad E, Cohen-Sivan Y, Heled Y, Epstein Y. Clinical review: treatment of heat stroke: should dantrolene be considered? Crit Care. 2005;9(1):86-91. 10. Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006;118(5):2119-2125. 11. Bergeron MF, Devore C, Rice SG. Policy statement—climatic heat stress and exercising children and adolescents. Pediatrics. 2011;128(3):e741-e747.

Hypothermia and ColdRelated Injuries

CHAPTER

173

Jeffrey P. Louie

BACKGROUND In the United States, hypothermia should be a preventable disease, yet between 1999 and 2011, an average of 1301 people per year die of excessive natural cold.1,2 The majority of reported mortality cases involve victims older than 19 years and two thirds of all victims are male. Predisposing factors that increase the risk for hypothermia are listed in Table 173-1. TABLE 173-1

Risk Factors Predisposing to Hypothermia

General conditions Malnutrition Hypothyroidism Hypoglycemia Immobility Extreme ages: neonates and geriatrics Intoxications/ingestions Trauma Neuromuscular disorders Infection Sepsis Maintaining the body’s core temperature is essential for human life. It is dependent on basal metabolism and physical activity. The human body can

lose heat by four mechanisms: (1) radiation, or transfer of heat through infrared energy; (2) evaporation, which includes respiration; (3) convection, or transfer of heat by the movement of air currents; and (4) conduction, or heat loss through direct contact with another object. When conduction and convection are combined, heat loss may be as high as 10% to 15%, which is why removing cold and wet clothes is essential in the initial management. Hypothermic patients are traditionally classified into three categories according to core temperature: mild (32°C to 35°C), moderate (30°C to 31.9°C), and severe (less than 30°C). The lower the core temperature, the more organ systems are affected and the greater the potential for morbidity and mortality. In the pre-hospital setting, obtaining an accurate core temperature is impractical. Thus, clinical criteria were developed by wilderness search and rescue teams and emergency medical services providers. The criteria are as follows: HT I—Conscious and shivering (core temperature 35°C to 32°C); HT II—Impaired consciousness, not shivering (100 mmHg Reduce suctioning frequency if tolerated Increase humidity ENT evaluation if persistent

Shortness of breath during or post suctioning

Prolonged suctioning

Limit suctioning to 10–15 seconds

Thick/yellow/green/malodorous Infection secretions

Send lower airway secretions for bacterial culture, viral studies Review previous culture results for pathogen/antibiotic sensitivities to guide antibiotic treatment if required

Neck skin breakdown

Usually due to secretions/short neck/humidity

Use of barrier (e.g. Duoderm) Treat potential infection

Unable to pass suction catheter

Suction catheter too large

Try smaller suctioning catheter

Secretions partially blocking air passage Buildup of mucous in tracheotomy tube

If inner cannula present, remove and clean Instill 3–5 mL normal saline into tracheotomy tube and cough or suction

Labored breathing

Possible tube occlusion

Reposition tracheotomy tube and/or reposition head and neck Suction Change tracheotomy tube

Hemorrhage around tracheotomy

Large vessel hemorrhage

Hold pressure around site with hand Emergent ENT involvement

REFERENCES 1. Wollman BS, Horacio BD, Walus-Wigle J, et al. Radiologic, endoscopic and surgical gastrostomy: an institutional evaluation and meta-analysis of the literature. Radiology. 1995;197:699-704. 2. Friedman JN, Ahmed S, Connolly B, et al. Complications associated with image guided gastrostomy and gastrojejunostomy tubes in children. Pediatrics. 2004;114:458-446 3. Spentzas T, Auth M, Hess P, et al. Natural course following pediatric tracheostomy. J Intensive Care Med. 2010;25(1):39-45 4. Deutsch, E. Tracheostomy: pediatric considerations. Respir Care.

2010;55 (8):1082-1090. 5. Joseph, R. Tracheostomy in infants: parent education for home care. Neonat Network. 2011;30(4):231-242. 6. Bissel, C. Aaron’s Tracheostomy Page. www.tracheostomy.com.

CHAPTER

183

Do-Not-AttemptResuscitation Orders Armand H. Matheny Antommaria

BACKGROUND With medicine’s increasing capabilities, situations arise in which possible interventions will not serve the patient’s or the family’s goals of care. Under such circumstances, the decision to forgo treatment, even potentially lifesaving treatment, may be appropriate. This chapter discusses one means of limiting treatment: do-not-attempt-resuscitation (DNAR) orders. It describes the historical development of DNAR orders, outlines the process of writing such orders, and explains why they should generally not be written unilaterally. The related issues of family presence during resuscitation and DNAR orders in the operating room and outside the hospital are also reviewed.

CARDIOPULMONARY RESUSCITATION AND DO-NOTATTEMPT-RESUSCITATION ORDERS Do-not-resuscitate (DNR) orders developed out of the recognition that cardiopulmonary resuscitation (CPR) lacks efficacy in certain patient populations and that a formal process of advance planning was needed. Although modern CPR was initially developed for patients suffering anesthesia-induced cardiac arrest, it became the standard of care for cardiac arrest in hospitalized patients regardless of their underlying diagnoses. Experience, however, demonstrated that the effects of CPR were often transient. In some institutions, covert decision-making processes evolved to withhold or limit resuscitation efforts. Hospitals developed DNR policies in the 1970s to address the need for both a decision-making process and a means to communicate these decisions.1

There are limited data in the pediatric literature regarding the efficacy of CPR in hospitalized patients. In reviewing the literature it is important to focus on patient-centered outcomes. A retrospective review of data from the National Registry of Cardiopulmonary Resuscitation (NRCPR) found that 52% of children who experienced an in-hospital cardiac arrest resuscitation (pulseless cardiac arrest requiring chest compressions, defibrillation, or both, that elicited an emergency resuscitation response and resulted in a resuscitation record) had return of spontaneous circulation for greater than 20 minutes and 27% survived to hospital discharge. Of the children who survived to discharge, 65% had a good neurological outcome defined as a Pediatric Cerebral Performance Category of normal functioning, mild disability, or moderate disability.2 A retrospective review of in-hospital cardiac arrests in 15 children’s hospitals within the Pediatric Emergency Care Applied Research Network (PECARN) found that 48.7% of patients between 1 day and 18 years of age who received greater than 1 minute of chest compressions and had return of circulation for at least 20 consecutive minutes survived to hospital discharge.3 This compares to 51% in the NRCPR study.2 Using different criteria, the PECARN investigators found a higher rate of good neurological outcomes; among survivors who had prearrest and discharge Pediatric Cerebral Performance Category scores available, 94.3% had discharge scores of normal or mild disability or no change in score.3 Information regarding the efficacy of CPR within specific diagnostic categories is even more limited. The PECARN study found pre-existing hematologic, oncologic, or immunologic disorders and pre-existing genetic or metabolic disorders were associated with increased hospital mortality.3 Based on the limited efficacy of CPR, some authors prefer the term donot-attempt-resuscitation (DNAR).4 Reinforcing that many resuscitation attempts are not successful is important because families may have false high expectations of the efficacy of CPR based on television’s depiction of CPR.5,6 More recently, the term allow natural death (AND) has been proposed. Proponents argue that DNR sounds cold and cruel, and that AND is warmer and more comforting.7 A single study reports that nursing students and other college students, but not nurses, are statistically more likely to endorse an AND order than a DNR order in response to a near-death scenario.8 Critics of this proposed change argue that unlike DNAR, AND

does not convey which specific procedures will be withheld. For example, it is not clear whether an AND order precludes therapeutic treatments such as vasopressors and antibiotics.9,10 Even if CPR might be effective, there may be situations in which it is ethical to withhold it. For example, in terminally ill patients, it may only prolong the dying process. More controversially, the patient’s quality of life may be so diminished that it need not be maintained. The Patient Self-Determination Act, which became effective in 1991, requires most health care institutions to ask adult patients on admission whether they have advance directives; however, there are few mechanisms for parents or guardians to express their wishes for their children or for adolescents to express their wishes should they lose medical decision-making capacity.11,12 Hospitalists should review the goals of treatment—curative, uncertain, or primarily comfort—with the families of children with special healthcare needs (Table 183-1). The patient’s primary care provider may be a valuable resource, especially if he or she has a longstanding or close relationship with the patient and family and has discussed treatment goals with them. Discussing the goals of treatment is particularly important when significant changes occur in the child’s clinical condition. If there is a possibility of cardiorespiratory arrest, especially if there is a low likelihood of survival or survival would not be in the child’s best interest, the hospitalist should discuss the risks and benefits of CPR, and a DNR order should be considered. This difficult topic can be broached by asking, “What is your hope for your child?” TABLE 183-1

Six-Step Protocol to Negotiate Goals of Care

1. Create the right setting. 2. Determine what the patient and the family know. 3. Ask how much they want to know and discuss with you. 4. Discuss goals of therapy. 5. Recommend medical care that contributes to patient goals. 6. Explicitly address care (such as cardiopulmonary resuscitation) that does not contribute to goals and recommend against it.

Source: Used with permission from VitalTalk.

DNR orders generally prohibit CPR regardless of the cause of the arrest. If the DNR order is based on a low likelihood of survival and if different causes of arrest have different survival rates, this should be discussed.13 For example, a family might desire intubation and mechanical ventilation for respiratory depression that is a side effect of anticonvulsants. Hospitalists should be cautious about permitting families to pick and choose components of CPR. For example, administering medications while withholding chest compressions lacks a pathophysiologic rationale; the medications cannot be effective if they are not circulated. It may, however, be reasonable to specify a limited duration of resuscitation efforts. The hospitalist should carefully document conversations with the patient and the patient’s family in the medical record. This is particularly important because of the limited continuity within some hospitalist systems. The hospitalist should also write a formal order, ensuring that it is internally consistent. DNAR orders should be reviewed periodically and any time there is a significant change in the patient’s medical condition. Hospitalists should communicate the substance of their discussions to primary care providers and complete out-of-hospital DNAR orders (see later) if appropriate at the time of discharge. DNAR orders should not be interpreted to represent a broad decrease in the intensity of care, especially when such limitations have not been discussed and agreed upon.14 DNAR orders should be implemented in the context of palliative care, including managing pain and symptoms and addressing emotional and spiritual needs (see Chapter 10).15 Hospitalists should be familiar with the policies of the hospitals and the laws of the states where they practice. Hospitals may require the attending physician to write the initial DNAR order, prohibit verbal or telephone orders, and specify how frequently the order must be renewed. States may restrict the circumstances in which a DNAR order can be entered, such as only if the patient is terminally ill. These statutes are controversial; some consider them unconstitutional or unethical.16 Evidence of low survival rates after CPR in specific patient populations has led some authors to argue that it is futile and that physicians can unilaterally withhold it.17 Definitions of futility are problematic, however,

because they incorporate values that patients and families may not share. The disputed procedure generally has a physiologic effect, but parties disagree on what likelihood of success justifies the procedure or the value of the outcome to the patient. Permitting physicians to unilaterally withhold treatment violates patients’ autonomy. Such decisions are particularly problematic because physicians tend to undervalue the quality of life of individuals with disabilities.18,19 Disagreements between patients or other decision makers and the medical staff have led to the implementation of specific procedural steps to mediate such disagreements or to facilitate the transfer of care to a physician willing to carry out the family’s wishes.20

FAMILY PRESENCE There is a growing move to permit families to be present during resuscitation attempts. For example, the American Heart Association’s PALS Provider Manual states, “… healthcare providers should offer the opportunity [for family members to be present during the attempted resuscitation of a loved one] whenever possible.”21 It should be noted that family presence protocols are structured and include an assessment of the patient and the family, preparation of the family for the event, and support of the family by a trained facilitator during and after the experience.22 Initial studies report that family presence does not delay essential care and family members believe their presence was valuable.23

OTHER CONTEXT ANESTHESIA AND SURGERY DNR orders during anesthesia and surgery may be problematic because anesthesia promotes some degree of cardiovascular instability, and it can be difficult and artificial to separate anesthesia from resuscitation. Additionally, procedure-specific DNAR orders may restrict anesthesiologists’ and surgeons’ discretion in cases of unexpected but easily reversible events. Professional organizations contend that DNAR orders should not be automatically rescinded in the operating room but should be reevaluated. Hospitalists should review the DNAR order and treatment goals with the

patient and his or her parents, as well as the anesthesiologists and surgeons, before sedation or surgery. If the DNAR order is suspended, a temporal endpoint should be established.24,25

OUTSIDE THE HOSPITAL Children with special health care needs live in many contexts: they may live at home or in an extended-care facility, they may attend school, and they may be hospitalized intermittently. The efficacy of CPR in the outpatient setting is lower than the inpatient setting; a prospective population-based cohort study in the United States and Canada reports that 6.4% of individuals less than 20 years of age who experienced out-of-hospital nontraumatic cardiac arrest survived to hospital discharge.26 This study unfortunately does not report the patient’s neurological outcomes. Sometimes the families of children with DNAR orders may legitimately need to activate the emergency medical services (EMS) system. For example, the child could be in status epilepticus or suddenly develop distressing symptoms. Performing CPR is, however, the default for first responders and EMS personnel. Many states authorize “portable” or out-of-hospital DNAR orders that EMS personnel are required to comply with and that protect them from liability for doing so. Some programs are applicable to minors. Hospitalists should be aware of state regulations and complete such documents if available.27 Physician Orders for Life-Sustaining Treatment (POLST) are one example. This form not only includes a section for CPR but also sections for medical interventions, antibiotics, artificially administered nutrition, summary or medical conditions, and contact information. Choices within the medical interventions section include comfort measures only, limited additional interventions, and full treatment.28 If out-of-hospital DNAR orders are not available, hospitalists should discuss the risks and benefits of calling 911 with the family. Code status should also be documented on the child’s emergency information form, which includes a concise summary of his or her medical condition(s), medications, and special health care needs.29,30 Out-of-hospital DNAR orders and emergency information forms may also facilitate patients’ readmission to the hospital. Children with chronic or terminal conditions who are at risk of dying may also attend school. The American Academy of Pediatrics recommends that

pediatricians work with school nurses to incorporate a specific action plan into the student’s individualized heath care plan.31 Hospitalists must continue to define their role in such conversations, particularly when patients do not have a functional medical home. KEY POINTS Given their responsibilities for patient care, education, administration, and research, hospitalists have many opportunities to improve the treatment of children with special health care needs, especially at the end of life.32 In terms of direct patient care, they can participate in discussions about the patient’s prognosis and help clarify the goals of treatment. They coordinate care with other disciplines, such as anesthesia and surgery, and facilitate transitions home or to extended-care facilities. Additionally, given their teaching roles, hospitalists can educate students and residents about these important issues.33,34 Many hospitalists also have administrative responsibilities and may be involved in formulating, revising, or updating hospital policies on DNAR orders and related matters.

REFERENCES 1. Burns J. DNR (do not resuscitate). In: Post SG ed. Encyclopedia of Bioethics. Vol 2, 3rd ed. New York: Macmillan Reference; 2003:683685. 2. Nadkarni VM, Larkin GL, Peberdy, MA, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295:50-57. 3. Meert KL, Donaldson A, Nadkarni V, et al. Multicenter cohort study of in-hospital pediatric cardiac arrest. Pediatr Crit Care Med. 2009;10:544553. 4. Hadorn DG: DNAR: Do not attempt resuscitation. N Engl J Med. 1989;320:673.

5. Jones GK, Brewer KL, Garrison HG. Public expectations of survival following cardiopulmonary resuscitation. Acad Emerg Med. 2000;7:4853. 6. Diem SJ, Lantos JD, Tulsky JA. Cardiopulmonary resuscitation on television. Miracles and misinformation. N Engl J Med. 1996;334:15781582. 7. Cohen RW. A tale of two conversations. Hastings Cent Rep. 2004;34:49. 8. Venneman SS, Narnor-Harris P, Perish M, Hamilton M. “Allow natural death” versus “do not resuscitate”: three words that can change a life. J Med Ethics. 2008;34:2-6. 9. Chessa F. “Allow natural death”–not so fast. Hastings Cent Rep. 2004;34:4. 10. Chen YY, Youngner SJ. “Allow natural death” is not equivalent to “do not resuscitate”: a response. J Med Ethics. 2008;34:887-888. 11. Sahler OJ, Greenlaw J. Pediatrics and the Patient Self-Determination Act. Pediatrics. 1992;90:999-1001. 12. Weir RF, Peters C. Affirming the decisions adolescents make about life and death. Hastings Cent Rep. 1997;27:29-40. 13. Choudhry NK, Choudhry S, Singer PA. CPR for patients labeled DNR: the role of the limited aggressive therapy order. Ann Intern Med. 2003;138:65-68. 14. Henneman EA, Baird B, Bellamy PE, et al. Effect of do-not-resuscitate orders on the nursing care of critically ill patients. Am J Crit Care. 1994;3:467-472. 15. Himelstein BP, Hilden JM, Boldt AM, Weissman D. Pediatric palliative care. N Engl J Med. 2004;350:1752-1762. 16. Burns JP, Edwards J, Johnson J, et al. Do-not-resuscitate order after 25 years. Crit Care Med. 2003;31:1543-1550. 17. Blackhall U. Must we always use CPR? N Engl J Med. 1987;317:12811285. 18. Blaymore Bier JA, Liebling JA, Morales Y, Carlucci M. Parents’ and pediatricians’ views of individuals with meningomyelocele. Clin Pediatr (Phila). 1996;35:113-117.

19. Wolraich ML, Siperstein GN, O’Keefe P. Pediatricians’ perceptions of mentally retarded individuals. Pediatrics. 1987;80:643-649. 20. Medical futility in end-of-life care: report of the Council on Ethical and Judicial Affairs. JAMA. 1999;281:937-941. 21. American Heart Association. Pediatric Advanced Life Support Provider Manual. AHA; 2011. 22. Eckle NJ ed. Presenting the Option for Family Presence. 2nd ed. Des Plaines, IL: Emergency Nurses Association; 2001. 23. Dudley NC, Hansen KW, Furnival RA, Donaldson AE, Van Wagenen KL, Scaife ER. The effect of family presence on the efficiency of pediatric trauma resuscitations. Ann Emerg Med. 2009;53:777-784. 24. Waisel DB, Burns JP, Johnson JA, et al. Guidelines for perioperative donot-resuscitate policies. J Clin Anesth. 2002;14:467-473. 25. Fallat ME, Deshpande JK. Do-not-resuscitate orders for pediatric patients who require anesthesia and surgery. Pediatrics. 2004;114:16861692. 26. Atkins DL, Everson-Stewart S, Sears GK, et al. Epidemiology and outcomes from out-of-hospital cardiac arrest in children: the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest. Circulation. 2009;119:1484-1491. 27. Sabatino CP. Survey of state EMS-DNR laws and protocols. J Law Med Ethics. 1999;27:297-315. 28. Schmidt TA, Hickman SE, Toile SW. Honoring treatment preferences near the end of life: the Oregon physician orders for life-sustaining treatment (POLST) program. Adv Exp Med Biol. 2004;550:255-262. 29. Policy statement–emergency information forms and emergency preparedness for children with special health care needs. Pediatrics. 2010;125:829-837. 30. Emergency Information Form for Children with Special Needs. http:// www.acep.org/content.aspx?id=26276. 31. Murray RD, Antommaria AH: Honoring do-not-attempt-resuscitation requests in schools. Pediatrics. 2010;125:1073-1077. 32. Srivastava R, Landrigan C, Gidwani P, et al. Pediatric hospitalists in Canada and the United States: A survey of pediatric academic

department chairs. Ambul Pediatr. 2001;1:338-339. 33. Khaneja S, Milrod B. Educational needs among pediatricians regarding caring for terminally ill children. Arch Pediatr Adolesc Med. 1998;152:909-914. 34. Sahler OJ, Frager G, Levetown M, et al. Medical education about endof-life care in the pediatric setting: principles, challenges, and opportunities. Pediatrics. 2000;105:575-584.

PART

Procedures Part Editor James M. Callahan, MD

184 Procedural Sedation 185 Radiology for the Pediatric Hospitalist 186 Ultrasonography for the Pediatric Hospitalist 187 Lumbar Puncture 188 Cerebrospinal Fluid Shunt Assessment 189 Bladder Catheterization 190 Arterial Blood Gas 191 Vascular Access 192 Intraosseous Catheters 193 Umbilical Artery and Vein Catheterization 194 Phlebotomy 195 Noninvasive Positive-Pressure Ventilation 196 Emergent Airway Management 197 Replacing a Tracheostomy Tube 198 Thoracentesis 199 Arthrocentesis

IV

CHAPTER

184

Procedural Sedation Mythili Srinivasan and Michael Turmelle

SEDATION AND ANALGESIA The goals of sedation and analgesia are to relieve pain and suffering and to allow diagnostic and therapeutic procedures to proceed with comfort, safety, efficacy, and efficiency. The needs of the patient and the specific goals of sedation must be considered on an individual basis, with attention to patient safety and minimization of anxiety, pain, and memory. Adherence to the guidelines for the monitoring of sedated patients developed by the American Academy of Pediatrics (AAP), the American Society of Anesthesiologists (ASA), and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) is essential.1-4 Please note that the information provided in this chapter is not sufficient guidance for the safe administration of procedural sedation. Each institution should have its own training and certification requirement as well as a procedure for maintaining competence in providing procedural sedation. It is our responsibility as hospitalists to ensure that our patients are cared for in systems that provide for safe, efficient and effective sedation. The following definitions for the level of sedation have been adopted by the AAP, ASA, and JCAHO.1-4 Minimal sedation (anxiolysis): A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are usually maintained. Moderate sedation or analgesia: A drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light to moderate tactile stimulation. No interventions are required to maintain a patent airway, and

spontaneous ventilation is adequate. Cardiovascular function is usually maintained. Deep sedation or analgesia: A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to maintain independent ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained. General anesthesia: A drug-induced loss of consciousness during which patients cannot be aroused, even by painful stimulation. The ability to maintain independent ventilatory function is often impaired. Patients often require assistance in maintaining a patent airway, and positive-pressure ventilation may be required because of depressed spontaneous ventilation or depression of neuromuscular function. It is important to note that patients’ responses to medications and doses can vary tremendously. Thus healthcare providers intending to achieve moderate sedation should be prepared to manage unintended deep sedation, and during attempts to achieve deep sedation, the provider should be capable of managing a brief period of general anesthesia, including maintaining a patent airway, effective ventilation, and cardiovascular function.

PRESEDATION EVALUATION HISTORY AND PHYSICAL EXAMINATION All children scheduled to undergo sedation should be screened for potential adverse events during sedation and recovery. A presedation evaluation includes a focused history and physical examination, with attention to the airway and cardiorespiratory status. A focused history can be guided by the mnemonic AMPLE (Table 184-1). TABLE 184-1

AMPLE History

A

Allergies to medications, latex, food

M

Medications–current

P

Past medical history, including sedation history

L

Last meal, fluid intake

E

Events leading to procedure

The evaluation of a potentially difficult airway includes a history of previous problems with sedation or anesthesia, stridor, snoring, sleep apnea, and any recent respiratory illness. Patients with significant obesity, short neck, small mandible, dysmorphic facial features, small mouth opening, large tongue or tonsils, or nonvisible uvula are at increased risk of airway obstruction even with moderate sedation. The patient’s physical status as classified by the ASA can be useful in assessing sedation risk (Table 184-2).3 ASA class I and II children are at low risk for adverse events during sedation when they are carefully monitored. Anesthesiology consultation should be considered when planning the sedation of an ASA class III patient. TABLE 184-2

American Society of Anesthesiologists Physical Classification

Class Disease State I

No organic, physiologic, biochemical, or psychiatric disturbance

II

Mild to moderate systemic disturbance

III

Severe systemic disturbance

IV

Severe systemic disturbance that is life-threatening

V

Moribund patient with little chance of survival

PRESEDATION FASTING There is no proven relationship between the duration of fasting before sedation and the risk of aspiration in humans. However, the general

consensus is that fasting likely reduces the risk of aspiration. For elective procedures, the ASA consensus recommendations should be followed (Table 184-3).5 For nonelective procedures, the patient should be fasted as soon as the potential need for sedation is identified. Although the risk of clinically significant aspiration is low, it should be weighed carefully against the need to perform a diagnostic or therapeutic procedure quickly. The lightest effective sedation should be used. TABLE 184-3

Fasting Guidelines for Elective Sedation

Type of Food of Liquid

Age

Time (hr)

Clear liquids

All ages

2

Breast milk

Newborn–6 mo

4

Infant formula

All ages

6

Solids

>6 mo

6

SEDATION PLANNING SELECTION OF AN AGENT The selection of medications is guided by the desired effect: analgesia, anxiolysis, amnesia, or some combination. Desired depth of sedation must be considered carefully. The lightest effective sedation is preferred, but because of the wide variety of individual responses, clinicians should be trained and prepared to administer increasingly deeper sedation, guided by the patient’s response. The clinician should consider using effective nonpharmacologic techniques such as distraction, imagery, and parental involvement whenever possible.

PERSONNEL For minimal and moderate sedation, one person with the appropriate training and experience is responsible for the procedural sedation and analgesia. This person may be the same individual who will be performing the procedure. A

second person who is knowledgeable in basic pediatric life support is also required. That person is responsible for monitoring the patient’s cardiopulmonary status and for recording these data on a sedation record; he or she may also assist in brief, interruptible tasks once the level of sedation is stabilized. For deep sedation, a provider with training in advanced pediatric life support must be in the room. The person administering deep sedation should perform direct monitoring of the patient and should not be the person primarily responsible for the procedure. The sedation provider can offer brief assistance with the procedure, as long as attention is still being paid to the patient’s physiologic status. Problems with ventilation and oxygenation are easily managed when they are recognized quickly. Because deeper than intended sedation may occur in any patient, it is generally recommended that the sedation provider be prepared to manage deep sedation even when only moderate sedation is intended.

MONITORING For minimal and moderate sedation, a minimum of pulse oximetry is strongly recommended.1-4 In addition, continuous monitoring of the heart rate and respiratory rate and intermittent noninvasive blood pressure measurements are generally recommended. If intravenous access is not otherwise established, it is not required but should be carefully considered. For deep sedation, continuous electrocardiographic heart rate and respiratory rate as well as pulse oximetry and noninvasive blood pressure monitoring are strongly recommended.1-4 If available, end-tidal carbon dioxide monitoring is also recommended throughout the sedation and recovery. Intravenous access is also recommended. In addition to electrophysiologic monitoring, the child’s color, airway patency, and rate and depth of respiration should be monitored by direct observation. This is especially important when giving additional medicine and immediately after the procedure. Completion of the painful parts of the procedure may cause children to experience deepening of the sedated state.

MEDICATIONS

Many reasonable choices for safe sedation and analgesia exist. It is probably best for clinicians to become familiar with a limited number of agents or combinations of agents to meet sedation goals. This allows healthcare providers to become more experienced with each drug’s indications, pharmacokinetic and pharmacodynamic profiles, dosing, responses, drug interactions, and adverse effects, and develop a more thorough understanding of its use. It is also important to use agents that best meet the needs of the individual patient and the procedure, based on whether the goal is simple anxiolysis, prolonged decreased motion, pain control, or some combination.

PENTOBARBITAL Pentobarbital is a short-acting barbiturate with sedative-hypnotic effects without analgesia. Route: Intravenous (IV) is preferred, but intramuscular (IM) administration is also possible. Dose: IV: 2.5 to 7.5 mg/kg (can be given as initial dose of 2.5 mg/kg followed by increments of 1.25 mg/kg to achieve desired effect); maximum dose 150 mg. IM: 4 to 6 mg/kg. Pharmacokinetics: The onset of action is less than 60 seconds when given IV and 10 to 30 minutes when given IM. Recovery time is 50 to 75 minutes. Side effects: Respiratory depression associated with pentobarbital is dose dependent.6 Significant agitation is often seen in patients during recovery. Contraindicated in patients with liver disease, moderate to severe renal impairment, and porphyria. Reversal agent: None. Uses: Pentobarbital is used primarily for nonpainful radiologic procedures.

MIDAZOLAM Midazolam is a water-soluble benzodiazepine that has more potent amnestic effects and a quicker onset than diazepam. Route: IV, intranasal (IN), PO. Dose: IV: 0.05 mg/kg for anxiolysis, 0.1 mg/kg for sedation; subsequent

doses of 0.05 mg/kg may be given every 2 to 5 minutes to reach desired effect; maximum single dose 2.5 to 5 mg with a maximum total dose of 6 to 10 mg. IN: 0.2 to 0.4 mg/kg; maximum dose 10 mg (use the injectable form of the drug; may be irritating and large volumes may not be absorbed and will drip down into the posterior pharynx and be swallowed)7 PO: 0.5 to 1 mg/kg; maximum dose 20 mg. Pharmacokinetics: Onset of action is less than 1 minute, with a peak at 2 to 6 minutes when given IV, 5 to 15 minutes when given IN, and 15 to 20 minutes when given PO. Recovery time is 30 to 90 minutes. Side effects: Respiratory depression, which is much more common when administered with opioids. Reversal agent: IV flumazenil 0.02 mg/kg repeated at 60-second intervals as needed. Uses: As an amnestic, midazolam is used alone to provide anxiolysis. It may also be combined with an analgesic (e.g. fentanyl, ketamine) for painful procedures.

DEXMEDETOMIDINE Dexmedetomidine is a selective α-2 adrenergic receptor agonist that has sedative, anxiolytic, hypnotic, and some analgesic properties. Route: IV, PO, or IN. Dose: IV, generally administered as a loading dose of 1 to 3 μg/kg over 10 minutes followed by maintenance infusion of 1 to 2 μg/kg/hr.8 Pharmacokinetics: Onset of sedation is usually by the end of the bolus dose. Mean recovery time can range from 30 to 60 minutes. Side effects: There is generally no significant respiratory depression. It is contraindicated in patients with liver disease and moderate to severe renal impairment. It is also contraindicated in patients on digoxin or beta blockers, and patients with cardiovascular compromise, moyamoya disease, arteriovenous malformations, and new-onset stroke.9 There can be transient hypertension, bradycardia, and sinus arrest during the bolus infusion of dexmedetomidine. Hypotension and bradycardia can be seen during the maintenance infusion. Reversal agent: None

Uses: Dexmedetomidine alone is used for nonpainful radiological procedures. It may also be used in combination with an analgesic (e.g. fentanyl, ketamine) for painful procedures. Recovery agitation which is common with pentobarbital is not seen with dexmedetomidine.

KETAMINE Ketamine is a dissociative agent that rapidly provides sedation, amnesia, and analgesia. Route: IV, IM. IV route is preferable due to faster recovery and less emesis.10-12 Dose: IV: 1 to 2 mg/kg followed by repeat doses of 0.5 to 1 mg/kg as needed. IM: 2 to 4 mg/kg. Pharmacokinetics: The onset of action is 30 to 60 seconds when given IV and 3 to 10 minutes when given IM. A return to coherence occurs in approximately 15 minutes with IV and in 15 to 30 minutes with IM. Side effects: Respiratory depression can occur; however, effective spontaneous respirations are generally preserved, and airway reflexes remain intact.13 Laryngospasm is a rare but potentially serious adverse reaction. Absolute contraindications for ketamine are age less than 3 months and known or suspected schizophrenia.10 Relative contraindications are airway instability, cardiovascular disease, active pulmonary disease, major oropharyngeal procedures, increased intracranial or intraocular pressure, porphyria, and thyroid disease.10 Because ketamine can cause increased salivation, traditional sedation training had recommended the use of coadministered anticholinergic to minimize oral secretions and thus decrease the risk of respiratory adverse events. However, recent meta-analysis by Green et al has shown that co-administered anti-cholinergic is a significant predictor of adverse airway and respiratory events.14 Similarly, midazolam has been co-administered with ketamine in the past to minimize adverse emergence reaction. However, co-administered midazolam did not have any effect on recovery agitation and furthermore is a risk factor for adverse airway and respiratory events.14,15 Neither of these agents are routinely recommended for use with ketamine sedation. Reversal agent: None.

Uses: The relative lack of respiratory depression and sparing of airway reflexes make ketamine a popular choice for short, painful procedures.

PROPOFOL Propofol is a nonbarbiturate sedative-hypnotic agent that has no analgesic effect. Route: IV. Dose: 0.5 to 2 mg/kg can provide sedation for short procedures. For prolonged painless sedation, propofol is maintained at a constant infusion rate of 100 to 200 μg/kg per minute after induction with 1 to 2 mg/kg. Pharmacokinetics: The onset of action is less than 1 minute. Plasma levels fall quickly because of metabolic clearance and rapid redistribution, so a continuous infusion is needed to maintain sedation longer than a few minutes. Median recovery time when used for longer procedures such as MRI is about 30 minutes. Side effects: Propofol can cause respiratory depression, apnea, and hypotension.16,17 Owing to its extremely short half-life, it can be difficult to titrate its effect. Thus propofol should be administered only by experienced providers with advanced airway skills.18 (When using propofol, the sedation provider must be dedicated to monitoring the patient and should not be involved in the procedure being performed.) Propofol causes pain at the injection site. Administering lidocaine through the IV prior to propofol can reduce this side effect. Propofol is contraindicated in patients with allergies to egg or soy. Reversal agent: None. Uses: The quick onset of action and short duration make propofol an attractive drug for brief, nonpainful procedures. It may also be used in combination with an analgesic (e.g. ketamine, fentanyl, morphine) for painful procedures.

FENTANYL Fentanyl is a high-potency opioid that has minimal adverse hemodynamic effects.

Route: IV, IN. Dose: 1 to 2 μg/kg IV, usually given as 0.5 μg/kg infused over 30 to 60 seconds and repeated to effect; 1 to 2 μg/kg IN.7 Pharmacokinetics: The onset of action is 30 to 60 seconds IV, and the duration of action is 5 to 10 minutes.18 The onset of action is 5 to 10 minutes when given IN. Side effects: The major side effect of fentanyl is respiratory depression, which is dose related but can occasionally occur with low doses. The risk of respiratory depression is significantly increased when fentanyl is given with benzodiazepines or barbiturates. Hypotension and chest wall rigidity are rare adverse events that can occur with rapid infusion of large doses. Reversal agent: Naloxone 0.001 to 0.01 mg/kg, given every 60 seconds until the patient awakens. Uses: As an analgesic, fentanyl is used for painful procedures. It is frequently combined with a sedative-hypnotic for procedural sedation.

NITROUS OXIDE Nitrous oxide (N2O) is a colorless, odorless gas which provides analgesia, sedation, amnesia, and anxiolysis. Route: Inhalational agent. Dose: Administered with oxygen at a concentration of 50% to 70% nitrous. Pharmacokinetics: Onset of action is within 1 minute with peak effect within 2 to 3 minutes. N2O is not metabolized but instead exhaled by the patient resulting in rapid recovery of the patient within 5 to 10 minutes after discontinuation of the agent. It is recommended that 100% oxygen be administered for 2 to 3 minutes after discontinuation of N2O to prevent diffusion hypoxia and improve scavenging of exhaled N2O and thus reduce the environmental exposure of sedation providers, nursing staff, and family members to N2O. Side effects: Common side effects are nausea/vomiting and in some cases hallucination, which can be disturbing to children causing agitation. N2O is contraindicated in patients with any trapped air in a body cavity such as

pneumothorax, recent tympanoplasty, bowel obstruction, or recent intraocular surgery, wherein gas bubbles may have been introduced during surgery.19 N2O irreversibly inactivates vitamin B12 and is thus contraindicated in patients with a deficiency in vitamin B12 or the enzyme 5, 10 methylenetetrahydrofolate reductase.20,21 Finally, N2O is contraindicated in patients either being treated or having been treated within the past year with bleomycin sulfate, because the high concentrations of oxygen used during N2O sedation can cause pulmonary toxicity in these patients.22 Nitrous oxide is not recommended for use in pregnant patients in the first two trimesters of pregnancy. Reversal agent: None. Uses: The rapid onset and recovery and the lack of need for an IV makes N2O a useful agent for short, painful procedures. It can be combined with an opioid agent to achieve a deeper level of sedation.

SUGGESTED READING McCain DA, Hug CC. Intravenous fentanyl kinetics. Clin Pharmacol Ther. 1980;28:106-114.

REFERENCES 1. Cote CJ, Wilson S. Guidelines for monitoring and management of pediatric patients before, during and after sedation for diagnostic and therapeutic procedures: update 2016. Pediatrics. 2016;138(1):e20161212. 2. Cote CJ, Wilson S. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Paediatr Anaesth. 2008;18:9-10. 3. American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002;96:10041017. 4. Joint Commission on Accreditation of Healthcare Organizations.

Standards and intents for sedation and anesthesia care. In: Revisions to Anesthesia Care Standards, Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2001 (updated 2004). http://www.jcaho.org/ standard/aneshap.html. 5. American Society of Anesthesiologists. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspirations: application to healthy patients undergoing elective procedures. Anesthesiology. 1999;90:896-905. 6. Strain JD, Harvey LA, Foley LC, Campbell JB. Intravenously administered pentobarbital sodium for sedation in pediatric CT. Radiology. 1986;161:105-108. 7. Del Pizzo J, Callahan JM. Intranasal medications in pediatric emergency medicine. Pediatr Emerg Care. 2014;30(7):496-501. 8. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth. 2008;18:403-411. 9. McMorrow SP, Abramo TJ. Dexmedetomidine sedation: uses in pediatric procedural sedation outside the operating room. Pediatr Emerg Care. 2012;28:292-296. 10. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57:449-461. 11. Roback MG, Wathen JE, MacKenzie T, Bajaj L. A randomized, controlled trial of i.v. versus i.m. ketamine for sedation of pediatric patients receiving emergency department orthopedic procedures. Ann Emerg Med. 2006;48:605-612. 12. Green SM, Krauss B. Should I give ketamine i.v. or i.m.? Ann Emerg Med. 2006;48:613-614. 13. White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119-136. 14. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children.

Ann Emerg Med. 2009;54:158-168; e151-154. 15. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54:171-180; e171-174. 16. Bryson HM, Fulton BR, Faulds D. Propofol. An update of its use in anaesthesia and conscious sedation. Drugs. 1995;50(3):513-559. 17. Green SM. Propofol for emergency department procedural sedation— not yet ready for prime time. Acad Emerg Med. 1999;6:975-978. 18. Srinivasan M, Turmelle M, Depalma LM, Mao J, Carlson DW. Procedural sedation for diagnostic imaging in children by pediatric hospitalists using propofol: analysis of the nature, frequency, and predictors of adverse events and interventions. J Pediatr. 2012;160:801806. 19. Becker DE, Rosenberg M. Nitrous oxide and the inhalation anesthetics. Anesth Prog. 2008;55:124-130. 20. Hathout L, El-Saden S. Nitrous oxide-induced B deficiency myelopathy: perspectives on the clinical biochemistry of vitamin B. J Neurol Sci. 2011;301:1-8. 21. Selzer RR, Rosenblatt DS, Laxova R, Hogan K. Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med. 2003;349:45-50. 22. Gilson AJ, Sahn SA. Reactivation of bleomycin lung toxicity following oxygen administration. A second response to corticosteroids. Chest. 1985;88:304-306.

CHAPTER

185

Radiology for the Pediatric Hospitalist Lindsay S. Baron, Horacio Padua, Frederick Grant, and Jeanne S. Chow

BACKGROUND The purpose of this chapter is to familiarize hospitalists with common pediatric imaging examinations so that they can order the most appropriate test for the patient and be able to properly inform and prepare the patient and family before the study. The techniques, indications, and patient preparation for common pediatric imaging examinations are described here. Given the wide array of choices, it is sometimes difficult for clinicians to determine the best exam for a particular clinical situation. Discussion with a radiologist regarding available options is strongly encouraged. Many common clinical scenarios are addressed in the American College of Radiology Appropriateness Criteria, a regularly updated, evidence-based internet resource designed to assist clinicians in choosing the best test to answer their clinical question. Following a discussion of radiation safety and contrast agents (for nonnuclear medicine studies), the chapter is divided into imaging studies that require ionizing radiation (conventional radiographs, fluoroscopy, computed tomography [CT], and nuclear medicine examinations) and those that do not (ultrasound [US] and magnetic resonance imaging [MRI]). Vascular and nonvascular interventional procedures are described at the end of the chapter. With the exception of some interventional procedures, parents may remain with their child when any of these examinations are performed. Pregnant mothers and siblings under the age of 18 will be asked to wait in a separate area for studies utilizing radiation. Ionizing radiation exposure in the fetus is known to cause miscarriages and malformations and carries a small but real risk for the development of childhood cancers.1 Parents and other

personnel who remain in the same room during x-ray or CT examinations must wear lead shielding for protection. For patients who are pregnant, studies with ionizing radiation are contraindicated unless the medical need (such as a ventilation-perfusion [V/Q] scan in a patient at high risk for pulmonary embolis) outweighs the medical risk. MRI is avoided in early pregnancy but has increasing utility for fetal assessment later in pregnancy.

RADIATION SAFETY Whenever considering a radiographic examination for any patient, one must be cognizant of the amount of radiation that the patient will receive, especially if the patient has a chronic condition. The guiding principle behind radiation protection is that radiation exposures should be kept “as low as reasonably achievable (ALARA).” This principle must be especially adhered to in children because for the same dose, children are more susceptible to radiation effects than adults.2 As knowledge of the risks of medical radiation has grown in recent years, radiologists have responded by lowering the doses of common medical tests. Referring physicians have also responded by ordering fewer tests with ionizing radiation. The clinician may find himself or herself confronted by a concerned parent regarding the necessity of a test that uses ionizing radiation. Table 185-1 provides a real-world reference for clinicians and parents when discussing these risks. While appropriate indications for evaluation of a pediatric patient with an exam utilizing ionizing radiation cannot be stressed enough, the benefit of a clinically indicated exam far outweighs its potential risks. Other imaging modalities such as US or MRI should be considered as alternatives when appropriate, with the caveat that they are not necessarily superior for a given clinical condition, and there may be a need for sedation or general anesthesia with MRI. Studies performed in pediatric hospitals are much more likely to use the lowest possible radiation dose compared to adult counterparts.3 TABLE 185-1

Ionizing Radiation Dose Estimates Average Estimated

Comparable to Weekly Natural Background

Procedure Effective Dose

Radiation

KUB child

0.1–0.2 mGy

1–2 weeks

VCUG child

0.12 mGy

9 day background radiation

CT scan abdomen

10 mGy

1–2 years of background radiation

RNC

0.015 mGy

1 day of background radiation

Source: Data from Department of Radiology, Boston Children’s Hospital, personal communication, Keith Strauss, M.Sc. RNC, radionuclide cystography.

CONTRAST MATERIALS Natural variation in tissue density and water content is what makes radiographic diagnosis possible. Contrast agents are often used to enhance these differences. Contrast agents are given through the body’s natural or surgically created orifices intravenously, or both, depending on the goals of the exam. These agents aid in visualizing certain organ systems, such as the gastrointestinal (GI) tract or the genitourinary system, but they can also more accurately assess certain disease processes; for example, the presence of tumor or infection.4

ENTERIC CONTRAST Enteric contrast may be used during GI fluoroscopic exams, CT of the abdomen and pelvis, or MRI, for certain bowel indications. Several varieties of enteric contrast exist. Barium sulfate suspension is an inert white liquid that attenuates the passage of x-rays and is commonly used during fluoroscopy. It comes in different consistencies, depending on its intended use. Barium has a chalklike taste, but its palatability can be improved with mild flavoring. Doublecontrast barium studies involve the use of barium and gas. These studies introduce gas into the intestines to distend the bowel and create a thin coat of barium on the bowel mucosal surfaces to assess mucosal detail. Because

double-contrast studies require strict patient cooperation and are most useful for mucosal detail, they are not routinely performed in the pediatric population; more typically, single-contrast studies are performed. The main effect of barium is constipation, therefore additional hydration is recommended after barium studies. For this reason, barium is relatively contraindicated in those with cystic fibrosis or constipation. It is also contraindicated in those with bowel perforation, as excess barium within the peritoneal cavity causes barium peritonitis (Figure 185-1). Barium is commonly used to evaluate children for aspiration and tracheoesophageal fistula, as it is not inherently toxic to lung tissue.

FIGURE 185-1. This AP radiograph of the abdomen shows the chronic residual of barium lining the peritoneal cavity after extravasation from perforated bowel. Water-soluble low-osmolar non-ionic agents are used for enteric contrast in neonates and cases in which barium use is contraindicated. They are also commonly used for CT examinations. Enteric use of water-soluble highosmolar contrast agents is generally limited to therapeutic enemas; for example, in a cystic fibrosis patient with meconium ileus equivalent, or in a

neonate with meconium ileus. Many different iodinated contrast agents are available that can also be used to evaluate the GI tract. Enteric contrast agents for MRI can be either positive (appear bright) or negative (appear dark) and are chosen based on the exam indication. Popular agents include water, Miralax, and blueberry juice (which contains manganese and causes T2 shortening). Gadolinium-containing enteric contrast is also available.

INTRAVENOUS CONTRAST Iodinated contrast agents are used intravenously for CT and the now rarely performed intravenous pyelogram. The osmolality of the available agents varies widely. Most hospitals now primarily use low-osmolar contrast, particularly in children, as these are far less likely to cause adverse effects such as fluid shifts or allergic reaction.5 If there has been a previous contrast reaction, premedication with steroids is mandatory, or an alternative examination should be sought (Table 185-2). As with any medication, administration of contrast agents is generally safe but may cause adverse reactions ranging from benign urticaria to death from fulminant anaphylaxis. Once intravenous contrast is administered, subsequent contrast administration is limited to a total of 7 cc/kg dose per 24 hours to limit nephrotoxicity. This should be kept in mind when scheduling examinations, particularly when done in a separate department (e.g. cardiac catheterization) or an outside institution. TABLE 185-2

Premedication Regimens for Patients with History of Contrast Reactions

Younger Older Patients Patients 13 hours prior to

Prednisone, 1 mg/kg PO (maximum of 20 mg per dose and

Prednisone, 15mg/5 mL; 1 mg/kg PO (maximum of 20

Patients Unable to Take Oral Medication

exam

60 mg/day)

mg per dose and 60 mg/day

12 hours prior to exam 7 hours prior to exam

Methylprednisolone, 1 mg/kg IV

Prednisone, 1 mg/kg PO

2 hours prior to exam 1 hours prior to exam

Prednisone, 15 mg/5 mL; 1 mg/kg PO

Methylprednisone, 1mg/kg IV

Prednisone, 1 mg/kg PO and diphenhydramine, 1 mg/kg PO or IV

Prednisone, 15 Diphenhydramine, 1 mg/5 mL; 1 mg/kg mg/kg IV PO and diphenhydramine, 1 mg/kg PO or IV

There are no established guidelines for avoiding contrast-induced nephropathy in children.6 Children with renal dysfunction should be imaged with alternate modalities when possible. When an exam with intravenous contrast is required, children should be treated with similar caution as an adult in the same situation. MRI contrast agents containing gadolinium are frequently used in the pediatric population, although as some agents have not yet been approved for use in children and none are approved for children under 2, use is often offlabel. This contrast agent is administered intravenously. Some MRI contrast agents may also be administered parenterally. These agents have an

extremely low incidence of adverse reactions and allergy is rare. Gadolinium chelates are not known to be nephrotoxic at approved doses; however, they must be used with caution in patients with severe renal dysfunction due to the risk of nephrogenic systemic fibrosis (NSF).6 Although US contrast agents are more widely used in adult patients, their use is still experimental in the pediatric population in the United States.

PATIENT COOPERATION For most imaging examinations performed in children, sedation or general anesthesia is not necessary. With the advent of multidetector CT scanners increasing the speed with which information is obtained, far fewer patients need to be sedated to obtain diagnostic images than in prior decades. However, a small number of patients undergoing CT and a larger number undergoing MRI need to be sedated or even placed under general anesthesia. The benefit of information obtained from these studies must outweigh the risk of possible adverse events from sedation or general anesthesia. During studies where occasional motion is less disruptive to the diagnostic quality of the exam, such as fluoroscopy, distraction can be an adequate alternative to sedation. Diversion techniques may be used by a child life expert or the parent. Exciting toys and portable electronics have proven their value in guiding children through exams that would otherwise have required sedation (Figure 185-2).

FIGURE 185-2. An infant lying on the fluoroscopy table prior to a voiding cystourethrogram. The patient is playing with a colorful toy that will be used to distract him throughout the procedure.

CONVENTIONAL RADIOGRAPHS Plain radiographs, commonly known as x-rays, are produced when a beam of photons penetrates through a part of the body and strikes a film. Although more sophisticated imaging modalities exist, the conventional radiograph remains an invaluable means by which to evaluate certain organ systems. They provide a rapid, widely available, low-radiation means to diagnose and monitor a multitude of conditions.

CHEST A chest radiograph is perhaps most commonly ordered for the evaluation of shortness of breath, chest pain, or pneumonia in the pediatric population. Although the lungs do occupy the majority of the chest, the mediastinum, heart, pulmonary vasculature, diaphragm, pleura, and bones can also be

initially evaluated on the chest radiograph. Additional common indications in the hospitalized patient include evaluation for pulmonary blood flow pattern, cardiac anomalies, support device position, pneumothorax, and foreign body aspiration. Two views of the chest should be obtained whenever possible. In older children and adults, standing posteroanterior (PA) and lateral views are the standard preferred projections. Those unable to stand or sit because of age or disability will have radiographs obtained while supine, in anteroposterior (AP) and cross-table lateral or lateral decubitus projections. Ideally, images should be obtained during inspiration, which is often a challenge in infants and young children who are unable to cooperate. In these patients, crying during the exam is actually beneficial, as it causes expansion of the lungs.

ABDOMEN Abdominal radiographs are most commonly ordered for evaluation of the bowel gas pattern when there is clinical suspicion for ileus or bowel obstruction. The presence of increased stool burden, organomegaly, abnormal calcifications, or pneumoperitoneum (Figure 185-3) may also be assessed. In neonates, the course and position of umbilical arterial and venous lines is best assessed on an abdominal radiograph.

FIGURE 185-3. Supine (A) and left lateral decubitus (B) radiographs demonstrate massive pneumoperitoneum. Upright and decubitus radiographs are more sensitive than supine radiographs for detecting subtle free air.

Supine and standing upright views are obtained in any radiographic evaluation of the abdomen for concern of bowel obstruction. If the patient is too young or sick to stand, a left lateral decubitus film is obtained in place of the upright view. If intussusception is suspected, a decubitus or prone view may be obtained to aid in filling the cecum with air, which would prove the absence of an ileocolic intussusception. The exception to the usual requirement for two views of the abdomen is for the evaluation of renal calculi or stool burden. In this case, a single kidneys, ureters, bladder (KUB) view usually suffices.

SKULL Skull radiographs remain the preferred means by which to evaluate any infant or child suspected of having a calvarial fracture. Although CT and MRI are far better for evaluation of the brain and even bone in some cases, a fracture can very easily be overlooked with these imaging modalities, especially if the orientation of the fracture is in the same plane as image acquisition. Additionally, skull radiographs are useful for evaluation of the sutures in suspected cases of craniosynostosis. AP, bilateral lateral (with each side of the head close to the film cassette), and Towne’s view (the x-ray tube is angled inferiorly to better visualize the occipital bone) projections are routinely obtained in the skull series (Figure 185-4).7

FIGURE 185-4. Lateral view of the skull shows an elongated calvarium, likely representing sagittal suture synostosis (A). Nonvisualization of the sagittal suture on AP and Town’s views of the skull (arrowheads) confirms the diagnosis (B, C).

EXTREMITIES When the area of abnormality can be localized to a particular joint or location, such as the forearm, a dedicated radiographic series coned down to that anatomic location is performed. AP and lateral views are the basic radiographs obtained when evaluating the musculoskeletal system. These projections are frequently supplemented with an oblique or specialized views,

as required by the clinical situation. Although CT and MRI may evaluate the musculoskeletal system in greater detail, radiography alone can be diagnostic without the aid of additional imaging, and in most cases it provides additional important information essential to diagnosis. Therefore radiography remains central to the diagnosis of bone lesions and should be the first imaging step in the evaluation of any bone pathology.

SPINE In radiographic evaluation of the spine, the number of views obtained depends on which part of the spine is studied (i.e. cervical, thoracic, or lumbar) and the indication. As with most other locations, radiographs of the spine begin with PA and lateral views. Additional views are often obtained to better evaluate specific anatomy. For example, in the setting of trauma, additional views are obtained to visualize the dens and the C7-T1 junction. If the dens or the C7-T1 junction is not clearly visualized, the radiologist cannot “clear” the cervical spine. For further evaluation of these focal areas, CT is sometimes needed. Full cervical spine CT evaluation is not typically recommended in children, in keeping with the ALARA principle. The incidence of spinal fractures is relatively low in the pediatric population, so CT is reserved for further investigation of any focal area of tenderness that the patient may have or for more thorough evaluation of any region of abnormality seen on plain films. For the evaluation of lower back pain in an adolescent, bilateral oblique views are obtained in addition to the standard AP and lateral views to better evaluate the pars interarticularis. If a fracture or spondylolysis is noted on plain films and grading of the pars defect is necessary, obtaining a focused CT scan limited to the region of abnormality is recommended to decrease the amount of radiation that the pelvis receives. This practice is especially important in females because the ovaries may be in the radiation field.

SOFT TISSUES OF THE NECK Radiographic evaluation of the soft tissues of the neck is indicated in suspected cases of epiglottitis, croup, and retropharyngeal abscesses. AP and lateral radiographs are the typical projections obtained. In a case of suspected epiglottitis, a healthcare provider should accompany the patient to the

radiology department in case the airway becomes obstructed. To prevent airway obstruction, placing the patient in a supine position to obtain radiographs is contraindicated.

PORTABLE RADIOGRAPHS The radiographic examinations just described are best performed within the radiology department; however, sometimes the patient is too sick to leave the intensive care unit or emergency room, and thus portable radiographs may be obtained. There is sometimes temptation to order portable examinations for patient or staff convenience. This should be strongly discouraged as they often provide inferior diagnostic information when compared with standard radiographs. Portable series should be reserved for critically ill patients who cannot be transported, because suboptimal patient positioning and external conditions may limit the evaluation.

FLUOROSCOPY Fluoroscopy uses continuous x-rays to allow evaluation of dynamic processes in the patient. Unlike many other types of imaging studies, a radiologist performs these exams and acquires the images, rather than a technologist. Most fluoroscopy studies also use a contrast material to better demarcate the anatomic area of interest. Digital pulsed fluoroscopy units are recommended for use in children and are now the standard of care in children. These units emit a beam of photons only a fraction of the time compared with traditional continuous units, thereby dramatically reducing the radiation dose.8 Gonadal shielding and careful image coning also significantly decrease patient radiation exposure.

NECK/AIRWAY Fluoroscopy is very useful in the dynamic evaluation of the airway, glottis, and diaphragm. While CT and MRI are gradually replacing fluoroscopy in evaluation of the tracheobronchial tree and soft tissues of the neck, it should be remembered that fluoroscopy of these anatomic locations requires no patient preparation or sedation and may provide valuable information. The

natural difference between the density of gas in the airways and lungs and the adjacent soft tissues provides the contrast for these studies; no additional contrast is necessary. Fluoroscopy is a simple noninvasive test to evaluate children who are suspected of having aspirated a foreign body when plain radiographs are equivocal or further confirmation is necessary to look for air-trapping. In addition, fluoroscopy is frequently used for further evaluation after plain radiographs suggest a prevertebral soft tissue mass as well as to evaluate movement of the vocal cords and diaphragm.

MODIFIED BARIUM SWALLOW (SWALLOWING STUDY) A swallowing study is performed to evaluate the oral and pharyngeal phases of swallowing and to detect the presence of aspiration with different consistencies of liquid and food. Often a radiologist and speech pathologist perform the exam jointly. All tested items are first mixed with barium, allowing their visualization with x-ray. Infants and young children sit in a specially designed chair affixed to the fluoroscopy table (Figure 185-5). Older children may stand during the exam. The parent or speech pathologist administers the various preparations to the child while the radiologist controls the fluoroscopy unit. Swallowing is observed with different consistencies of barium preparations, including solids, purees, and thick and thin liquids. The parent may provide favorite food items for testing, which has the dual benefit of replicating the child’s home diet and increasing likelihood of patient cooperation.

FIGURE 185-5. During a modified barium swallow, children sit in special chairs affixed to the fluoroscopy table and consume various consistencies of solids and liquids mixed with barium. The infant (A) and child seat (B) are shown here.

ESOPHAGRAM (BARIUM SWALLOW) Esophagrams evaluate the appearance and motility of the esophagus. Indications depend on the patient’s age. Newborns are most commonly evaluated for symptoms of choking or wheezing—to look for a vascular ring or sling, esophageal stricture, or tracheoesophageal fistula. Older children with symptoms of dysphagia or a feeling that something is “stuck” in the throat may be assessed for abnormal esophageal motility, narrowing, or a foreign body obstructing the esophagus. The examination is performed with the patient lying on the fluoroscopy table. In children, esophagrams are most often performed as single-contrast studies. In general, a child must be able to cooperate by drinking contrast and lying on the table. Infants can be fed barium via bottle or by injection into the mouth via syringe. In certain situations, such as evaluation for postoperative esophageal leak or tear, a nasoenteric tube can be inserted into the proximal esophagus to allow water-soluble contrast to be injected directly. This does not provide the same amount of information as a properly performed esophagram and is limited to use in specific clinical situations.

UPPER GI SERIES

An upper GI (UGI) examination studies the digestive system from the mouth to the duodenojejunal junction. This study is performed on an emergency basis in a child suspected of having malrotation with symptoms of obstruction (Figure 185-6), but it is more commonly ordered for evaluation of unexplained vomiting and detection of gastroesophageal reflux. It is useful for evaluating the esophagus, stomach, and duodenum and the location of the ligament of Treitz. Because the column of contrast is followed dynamically, peristalsis as well as the appearance of the intestine, is evaluated.

FIGURE 185-6. A single image from an upper GI in a patient with bilious vomiting demonstrates malrotation; the fourth portion of the duodenum does not reach the expected location of the ligament of Treitz to the left of the spine at the level of the pylorus. For patients suspected of having an obstruction at the level of the second portion of the duodenum (i.e. secondary to duodenal atresia, an annular pancreas, or a duodenal web), UGI examination is not necessary; a plain film of the abdomen is usually diagnostic because gas within the distended stomach and proximal duodenum serves as a good contrast agent to delineate the level of obstruction. The child must be able to drink oral contrast, or alternatively have contrast instilled via nasogastric tube or gastrostomy tube (this would preclude evaluation of the esophagus). The child must refrain from food or drink prior to the examination, as outlined in Table 185-3.

TABLE 185-3

Timing for NPO Status Prior to Procedure

Newborn–6 months old

2 hours before the procedure

6 months–2 years old

3 hours before the procedure

2–4 years old

4 hours before the procedure

4 years or older

6 hours before the procedure

In general, a UGI series is performed with barium. Water-soluble contrast agents are preferred in recently postoperative patients or others where there is concern for intestinal perforation.

SMALL BOWEL SERIES A small bowel series is used to evaluate the small intestine from the ligament of Treitz to the ileocecal valve. It is often performed in conjunction with a UGI series but can be performed separately. It is useful in evaluating the site of small bowel obstruction, small bowel masses, and inflammatory bowel disease. The examination is performed almost exclusively with barium because water-soluble contrast tends to become diluted and lose its opacity before reaching the ileum. This examination requires a child to cooperate in consuming a large volume of barium in order to opacify the entire small bowel. Water-soluble contrast agents are used when the patient is recently postoperative or when there is concern for bowel perforation, to avoid barium peritonitis. The duration of this examination depends on the time needed for the contrast to pass through the small intestine, which can take many hours in some cases. Patients and families should be informed of the possibility that they may spend an extended period of time in the radiology department.

CONTRAST ENEMA A contrast enema is most frequently indicated for the evaluation of distal intestinal obstruction in a newborn infant as occurs with Hirschsprung disease, ileal atresia, or meconium ileus. Older patients with a suspected mass, inflammatory bowel disease, or a stricture can likewise be evaluated

with a contrast enema. Bowel preparation is not required for most pediatric lower GI contrast studies. The exception is the rarely performed double-contrast (air and barium) lower intestinal study. Prior to beginning the study, the radiologist will perform a brief rectal exam to exclude any obstructing mass or lesion, and then place a soft rectal catheter. Barium or water-soluble contrast is then instilled into the rectum by gravity technique through the catheter while fluoroscopic images are taken. At the conclusion of the study, contrast is drained from the patient.

INTUSSUSCEPTION REDUCTION An important diagnostic and therapeutic use for GI fluoroscopy is diagnosis and reduction of ileocolic intussusception. Institutions vary greatly in the workup and management of suspected intussusception.9 We recommend an abdominal radiograph as the screening examination. When the cecum is clearly identified or other causes of abdominal pain are revealed, further imaging may not be necessary.10 Alternatively, an abdominal radiograph may show definite evidence of intussusception. If plain films are unrevealing and additional imaging is needed, abdominal US is recommended. US can reliably demonstrate intussusception with high specificity and sensitivity. It can also evaluate for other causes of the patient’s symptoms. Rather than obtaining a US examination, some pediatric radiologists prefer to proceed directly to an enema, which may both diagnose and reduce the intussusception (Figure 185-7).

FIGURE 185-7. A single image from an air enema reduction of an intussuception demonstrates the intussusceptum as a soft tissue density within the colon (arrow). Air is being insufflated into the rectum via a soft catheter (arrowhead). This 2-year-old presented with intermittent abdominal pain and bloody stools. A scout film of the abdomen is first obtained to evaluate for pneumoperitoneum. During the enema, a surgeon should be in attendance in the event of bowel perforation, tension pneumoperitoneum, and the need for emergency surgery. The risks and benefits of the procedure are explained to the parents in detail before the examination, and informed consent is obtained. The patient should not be sedated because the instinctive Valsalva maneuver performed by a crying or agitated child provides both a natural protective mechanism to prevent bowel perforation as well as a higher pressure gradient to aid in reduction of the intussusception. Air or barium is instilled per rectum under fluoroscopic guidance. The pressure of the contrast or air reduces the intussusception. After the procedure, radiographs are obtained to assess for successful reduction and any complications. Contraindications to enema reduction are bowel perforation or signs of peritonitis.

INTRAVENOUS PYELOGRAM

The intravenous pyelogram (IVP) is now a rarely performed study, which has been replaced by a combination of US, nuclear medicine studies, CT, and MRI, depending on the indication. Occasionally this study is useful for evaluating girls with ectopic ureters or patients after pyeloplasty, as just a few images can show both the function and anatomy of the kidneys.

VOIDING CYSTOURETHROGRAM The voiding cystourethrogram (VCUG) evaluates for vesicoureteral reflux (Figure 185-8) and the function and appearance of the bladder and urethra. This study is commonly performed in patients with a history of pyelonephritis or hydronephrosis. VCUG also can detail complex congenital anomalies such as ambiguous genitalia and anorectal malformations.

FIGURE 185-8. Voiding cystourethrogram image demonstrates bilateral vesicoureteral reflux, grade 3 on the right and grade 2 on the left. This child presented with a febrile urinary tract infection diagnosed by catheter specimen. During the examination, the bladder is catheterized and dilute watersoluble contrast is instilled into the bladder through the catheter by gravity. Fluoroscopy is performed during bladder filling and voiding. A cyclic study, when the bladder is refilled after voiding, is performed in infants. For older

children, the bladder is typically filled one time only to its predicted capacity based on age. When the study is performed in an environment comfortable for the patient, family, and physician and the parents and children are well informed and reassured, sedation can often be avoided.11 If sedation is used, midazolam and nitrous oxide can be administered without any negative outcome on the results of the examination.12 Prophylactic antibiotics before VCUG, previously recommended by the American Heart Association for high-risk patients, are no longer recommended.13 Radionuclide cystography (RNC) is an alternative to VCUG for evaluating reflux and is discussed in the Nuclear Medicine section.

RETROGRADE URETHROGRAM A retrograde urethrogram is performed in males to examine the anterior urethra only. The most common indication for this examination is evaluation for urethral trauma (Figure 185-9) or stricture. A catheter is gently placed in the very tip of the urethra, and contrast is then slowly introduced under fluoroscopic visualization.

FIGURE 185-9. An oblique view of the urethra during a retrograde urethrogram demonstrates contrast extravasation along the course of the urethra due to a tear of the bulbar urethra. This boy suffered a skateboard injury.

NUCLEAR MEDICINE Nuclear medicine studies are based on the tracer method. Images are acquired after administration of trace (picomolar or nanomolar) amounts of

radiopharmaceuticals, which are organ- and function-specific compounds labeled with a radioactive isotope. Each radiopharmaceutical has a typical distribution pattern in the body, and alteration in either the pattern or timecourse of this distribution can be a marker for disease or functional abnormality. Over 20 different radiopharmaceuticals are in routine use for imaging a wide range of conditions. Nuclear medicine studies are acquired with a gamma camera, which can detect a wide variety of radiopharmaceuticals that emit low-energy gamma radiation. Most radiopharmaceuticals are labeled with the radioisotope technetium-99m, which has a half-life of 6 hours and a low-energy emission matched to the sensitivity of the gamma camera. Another common radioactive label is radioactive iodide (either iodine-123 or iodine-131), which is used to label some radiopharmaceuticals and also to image and treat thyroid diseases. Not all radiopharmaceuticals are administered via intravenous injection; xenon-133 gas is used for lung scans. Depending on the physiological or disease question, a nuclear medicine study can be performed as either a dynamic or intermittent static study. Images can be acquired of the whole body, of a specific region of the body, or as a magnified view of a small organ or body part. Single-photon emission computed tomography (SPECT) is an imaging method used to create threedimensional images with a gamma camera. Occasionally additional drugs, such as furosemide or sincalide, are used as part of a nuclear medicine study. Another method of imaging nuclear medicine studies is positron emission tomography (PET). PET primarily is used to image radiopharmaceuticals labeled with fluorine-18, a positron emitter with a half-life of 110 minutes. Nearly all PET studies are performed with the radioactive glucose analog 18Ffluorodeoxyglucose (18F-FDG), which can be used to assess metabolic activity of tumors, the brain, and the heart. Unlike many other imaging studies, nuclear medicine examinations provide both anatomic and functional information, but the anatomic resolution usually is not as high as with other radiological studies, such as CT or MRI. Co-registering nuclear medicine and either CT or MR images to create fusion images can provide additional information about both function and anatomy. Many nuclear medicine departments have hybrid cameras that can perform both a nuclear medicine study (SPECT or PET) and a CT during the same imaging study.

Most nuclear medicine studies require patient preparation specific to the study. This patient preparation is necessary to facilitate appropriate imaging of the physiological activity of interest. For example, many GI studies require a period of fasting. Most FDG-PET scans also require pre-test fasting to ensure appropriate physiological handling of the radiolabeled glucose. Other studies, such as renal studies, may require adequate hydration before the study is started. Overlying objects such as jewelry may interfere with imaging, but residual barium contrast from a prior radiographic study also can disrupt nuclear medicine imaging. Although nuclear medicine studies typically provide only low doses of radiation, the radiation exposure can be minimized by using radiopharmaceutical doses based on patient size and appropriate for children.

GENITOURINARY IMAGING A variety of nuclear medicine studies demonstrate the form and function of the kidneys. These examinations may require venous access or bladder catheterization (or both) and hydration before the examination. Dynamic Renal Scintigraphy Dynamic renal scintigraphy and diuresis renography are used to evaluate renal cortical function and the urinary collecting system. Dynamic renal scintigraphy is commonly used to assess hydronephrosis or hydroureteronephrosis, reflux nephropathy, and renal transplants. Occasionally, this study is used to evaluate acute renal failure or hypertension. Dynamic renal scintigraphy is performed with the radiopharmaceutical 99mTc- mercaptoacetyl-triglycine (99mTc-MAG3), which is excreted by active renal tubular transport. 99mTc-diethylene-triaminepentacetic acid (99mTc-DTPA) is a less commonly used alternative to 99mTcMAG3. Dynamic renal scintigraphy depends on the rapid excretion of radiopharmaceutical through the kidney. This requires three steps: (1) renal perfusion and cortical uptake of 99mTc-MAG3, (2) cortical transit of 99mTcMAG3 into the renal collecting system, and (3) excretion of 99mTc-MAG3 through the urinary collecting system. Imaging and quantitative measure of each of these steps provides information about renal function. The pattern of cortical uptake, which is measured during the first 2 minutes of the study, can identify regions of cortical hypoperfusion or scar as well provide a measure

of differential (left vs. right) renal function. Although this provides an approximate differential function, a renal cortical scan will provide a more accurate indication of differential renal function. The rate of cortical transit, typically 3 to 6 minutes, is an indicator of renal function. The rate and pattern of 99mTc-MAG3 excretion is used to assess collecting system drainage. Delayed drainage may indicate collecting system obstruction but also may occur with low urine flow or in a markedly dilated collecting system. With diuresis renography, urine flow is increased, typically with intravenous saline infusion and intravenous administration of furosemide, to help distinguish collecting system obstruction from other causes of delayed collecting system drainage (Figure 185-10).

FIGURE 185-10. (A) Output results and (B) images from a MAG3 study demonstrate left-sided obstruction with a time activity curve showing that the half time of radiotracer excretion is greater than 20 minutes, or in the obstruction range. The curve for the right kidney is normal. It was known prenatally that the patient had left-sided pelvic dilatation. Several patient factors can confound interpretation of the studies. Infants, especially those younger than 1 month, have functionally immature kidneys, which may delay cortical uptake and excretion of radiopharmaceutical.14,15 In older children, impaired renal function can slow urinary excretion of radiopharmaceutical and limit evaluation of the urinary collecting system. Recent administration of radiographic contrast may transiently diminish radiopharmaceutical excretion. Renal Cortical Scintigraphy Renal cortical scintigraphy is a static imaging study that provides both a visual and quantitated evaluation of renal cortical function. The main indications for cortical scintigraphy are

evaluation of acute pyelonephritis or renal scarring and assessing differential (left vs. right) renal function. Renal cortical scintigraphy also is used to evaluate patients with renal ectopia or renal dysplasia. Renal cortical scintigraphy is performed with the radiopharmaceutical 99mTc-dimercaptosuccinic acid (99mTc-DMSA), which is taken up and trapped in the cells of the proximal tubules. Images are acquired 3 to 4 hours after intravenous administration of 99mTc-DMSA. Images can be acquired in a variety of ways, including planar images, with a pinhole collimator, or by SPECT. These images can provide detailed function-structure information about the renal cortex. Cortical defects can be seen with cortical infarcts or scars as well as with other cortical lesions, such as tumors and cysts. Because 99mTc-DMSA is trapped in the renal cortex and excreted very slowly, renal cortical scintigraphy can provide a more precise measure of differential function than dynamic renal scintigraphy. Radionuclide Cystogram RNC is performed to diagnose vesicoureteral reflux. Preparation and bladder catheterization of the patient are identical to that for VCUG, described earlier in this chapter. RNC usually is performed with the radiopharmaceutical 99mTc-pertechnetate, which is instilled through a urinary catheter into the bladder. In patients who have had bladder augmentation, the preferred radiopharmaceutical is 99mTc-pertechnetate– labeled sulfur colloid. Dynamic images are acquired by gamma camera to allow identification of vesicoureteral reflux of tracer. The indications for deciding whether to perform RNC or VCUG to evaluate vesicoureteral reflux vary from institution to institution and from physician to physician. RNC is a very sensitive examination for determining the presence of reflux (Figure 185-11), and exposes the patient to a low dose of radiation. However, VCUG provides more detailed anatomic information about the bladder, sites of ureteral insertion, the male urethra, and the possibility of duplex collecting systems. The risks and benefits of each examination should be considered and the choice tailored to each patient.

FIGURE 185-11. Selected images from a radionuclide cystography demonstrate bilateral grade 2 vesicoureteral reflux in a child whose sibling has reflux. The refluxed material drains promptly. Glomerular Filtration Rate Determination of glomerular filtration rate (GFR) uses the radiopharmaceutical 99mTc-DTPA, which is excreted solely by glomerular filtration. The patient should be well hydrated before the examination. After intravenous administration of 99mTc-DTPA, blood samples are obtained (usually at 2, 3, and 4 hours). The rate of radiopharmaceutical clearance is used to determine the GFR (mL/min). Alternative methods, such as 24-hour creatinine clearance, provide less precise measures of GFR.16 In children, GFR values may be expressed in terms of body surface area (mL/min/m2) or in terms of the idealized adult body surface area (mL/min/1.7 m2)

SKELETAL IMAGING

Bone Scintigraphy (Bone Scan) Bone scans are one of the most frequently performed nuclear medicine studies. One common indication for bone scan is osteomyelitis or evaluation for suspected bone infection in a child with fever. Sports medicine injuries, including possible stress fractures and lower back pain related to suspected pars interarticularis injury, are also common indications for a bone scan. Bone scans may be used to evaluate the skeleton in cases of suspected nonaccidental trauma (child abuse) (Figure 185-12). Other clinical indications for skeletal scintigraphy include avascular necrosis, osteoid osteoma, complex regional pain syndrome (reflex sympathetic dystrophy [RSD]), and primary and secondary bone tumors.

FIGURE 185-12. Bone scan images of (A) torso and upper extremities and (B) pelvis, distal right upper extremity and lower extremities in a child who presented to the emergency room with lethargy. Increased radiotracer uptake is demonstrated in the (A) metaphysis of the right distal humerus (arrowhead) and (B) right radius (arrow), bilateral tibia and right talus (curved arrow). Bone scintigraphy typically uses the radiopharmaceutical 99mTcmethylene diphosphonate. After intravenous administration of 99mTc-MDP, regional or whole-body scanning can be performed 2 to 3 hours later. 99mTcMDP uptake is proportional to bone turnover or osteogenesis. Therefore

increased 99mTc-MDP uptake is seen at sites of increased bone turnover associated with bone stress, fracture, tumor, or infection. In children, increased uptake is seen at the physes (growth plates). Decreased bone uptake can be seen at sites of bone infarct/necrosis or lytic bone lesions. A three-phase bone scan includes images acquired at three phases of bone uptake: (1) immediate perfusion, (2) early soft tissue tracer accumulation, and (3) skeletal-phase images acquired 2 to 3 hours after tracer administration. Typically, a three-phase bone scan is used to evaluate a specific bone site for possible osteomyelitis. Due to the increased local perfusion (hyperemia) associated with a bone infection, increased tracer is seen in images acquired at all three phases. Other causes of a positive three-phase bone scan can include tumors and acute fracture. Another indication for a three-phase bone scan is evaluation of complex regional pain syndrome (CRPS), also known as RSD. CPRS is associated with regional changes in blood flow, the effects of which can be seen on all three phases of a three-phase bone scan. In adults, CRPS almost always is associated with regional hyperemia, with a threephase bone scan showing increased perfusion, increased soft tissue accumulation of tracer, and diffusely increased skeletal uptake. Children with CPRS may have either increased or decreased regional perfusion in the affected limb. Despite the examination’s high sensitivity, bone scans are not highly specific because increased bone turnover is seen with many pathological processes, including bone stress, fracture, infection, and tumors. The pattern of abnormal uptake is important to determining the disease process. In some institutions, bone scans are performed using 18F-sodium fluoride, which is imaged with a PET scanner. It is helpful to correlate findings on bone scan with the patient’s age, clinical history, symptoms, and radiographs or other imaging studies. Additionally, the sensitivity and specificity of conventional radiographs can be increased with the addition of information from a bone scan. Abnormal findings on bone can guide a targeted evaluation with conventional radiographs.

HEPATOBILIARY IMAGING Hepatobiliary Scan The hepatobiliary scan uses the radiopharmaceuticals 99mTc-disofenin or 99mTc-mebrofenin, which share the same hepatocyte

uptake, transport, and excretion pathways as bilirubin. Therefore hepatobiliary scans can be used to evaluate hepatocellular function and to assess excretion through the biliary tree and gallbladder. After intravenous administration of radiopharmaceutical, dynamic imaging of the liver and biliary system is performed for 1 hour. In older children, a hepatobiliary scan is used to evaluate gallbladder function. In patients with typical acute calculous cholecystitis, cystic duct obstruction will prevent accumulation of radiopharmaceutical in the gallbladder. Gallbladder contraction will prevent filling, so patients must be fasting for at least 4 hours prior to hepatobiliary scan. However, prolonged fasting (greater than 24 hours) also may decrease gallbladder filling due to stasis of a filled gallbladder. Another cause of delayed gallbladder filling is chronic cholecystitis, so some departments will acquire additional images to evaluate for delayed gallbladder filling. In pediatric patients, cholecystitis may not be associated with complete obstruction of the cystic duct. In patients with acalculous cholecystitis or with chronic cholecystitis, the gallbladder may fill with radiopharmaceutical, but will have impaired gallbladder contraction. Gallbladder function can be assessed by stimulating gallbladder contraction with a fatty meal or by slow intravenous administration of sincalide (an analog of cholecystokinin) and continuing gallbladder imaging for another 30 to 60 minutes. In infants, hepatobiliary scans most commonly are used to evaluate suspected congenital biliary atresia or other congenital abnormalities of the hepatobiliary tree. Hepatobiliary excretion of radiopharmaceutical into the bowel demonstrates an intact biliary tree and essentially excludes the diagnosis of biliary atresia (Figure 185-13).17 Occasionally, hepatobiliary scans may be used to evaluate other abnormalities of the biliary tract, such as choledochal cysts.18 Patients undergoing evaluation for biliary atresia do not need to be fasting, but should be pretreated with phenobarbital for 3 to 5 days before the study to stimulate hepatocellular function, enhance biliary excretion, and increase the specificity of the study.

FIGURE 185-13. (A) DISIDA scan of a 5-week-old with elevated direct bilirubin and non-visualization of the gallbladder on ultrasound demonstrates no radiotracer uptake in the gallbladder or bowel after 4.5 hours. The patient was pretreated with phenobarbital prior to the examination. Exploratory laporotomy demonstrated biliary atresia and the patient underwent a Kasai portoenterostomy. (B) In the example of a normal DISIDA scan, radiotracer is seen in the gallbladder (arrowhead) and within the bowel (arrow).

GASTROINTESTINAL IMAGING A variety of nuclear medicine studies can be used to evaluate the GI system.19 For many studies the patient must fast for 4 hours before the examination. GI nuclear medicine studies should not be performed when there is residual barium contrast from prior radiographic studies. Gastric Emptying Quantitative assessment of gastric function can be performed by observing the gastric emptying of a radiolabeled meal. The most typical meal is scrambled eggs labeled with 99mTc-labeled sulfur colloid, which will bind to egg proteins. Other suitable solid meals include foods with radiolabeled cheese. For adults, a standard mixed meal including radiolabeled eggs, bread, jelly, and water is now recommended. Infants and children with nasogastric or percutaneous gastric feeding tubes will require a radiolabeled liquid meal, such as milk or formula. The volume of feeding must be individualized and is determined in collaboration with the referring

physician and family. A good rule of thumb is to provide a meal size similar to that typically associated with symptoms. For pediatric gastric empting studies, patients are encouraged to finish the radiolabeled meal within 10 minutes, and then dynamic imaging is performed for 1 hour. Region-of-interest analysis is used create a time-activity curve to quantify gastric emptying and evaluate the pattern of emptying. The pattern of gastric emptying is important, as rapid emptying or a lag-time with no gastric emptying may be abnormal. Solid meals typically show a linear pattern of gastric emptying, while with a liquid meal, the pattern of emptying should resemble an exponential decay curve. There are no generally applicable standard values for pediatric gastric emptying.20 This is due in part to the varieties of meal composition, patient positioning, and instrumentation among departments, but also reflects the difficulty in recruiting normal children for reference studies. Gastroesophageal Reflux Gastroesophageal reflux can be assessed on a standard gastric emptying study. Gastroesophageal reflux may be identified by visual inspection or by region-of-interest analysis of the esophagus (Figure 185-14). If there is a high suspicion for tracheobronchial aspiration, it may be appropriate to perform a radionuclide salivagram before challenging the patient with a gastric empting/gastroesophageal reflux study.

FIGURE 185-14. Selected images from a gastric emptying study demonstrate intermittent gastroesophageal reflux (arrowhead) in a patient with persistent vomiting after feeds. Radionuclide Salivagram A salivagram is the study of choice to assess for tracheobronchial aspiration of pharyngeal contents. Patients with difficulty handling their oral secretions or those suspected of aspiration are candidates for testing. The study is performed by placing a small drop of saline containing 99mTc-labeled sulfur colloid under or on the back of the

tongue. Dynamic imaging is performed for up to 1 hour. Aspiration is demonstrated by tracer accumulation in the trachea or bronchial tree. Once aspiration is identified, continued imaging may demonstrate bronchial clearance of tracer. Meckel Scan In children, the Meckel scan can be the first study of choice to evaluate GI bleeding. The Meckel scan is used to localize ectopic gastric mucosa that can be associated with intestinal ulceration and bleeding. Ectopic gastric mucosa typically is located in a Meckel diverticulum, but also can be found in intestinal duplication cysts. The scan is performed with 99mTcpertechnetate, which accumulates in gastric mucosa. Uptake in ectopic gastric mucosa may be obscured by tracer accumulation in the urinary collecting system or by tracer excreted from the stomach into the duodenum. Tracer uptake also may be seen in inflamed intestinal mucosa. Rarely, active GI bleeding may be detected by accumulation of labeled blood within the intestinal lumen. Gastrointestinal Bleeding Scan Active GI bleeding can be evaluated with a nuclear medicine bleeding study. The patient’s own red blood cells can be labeled in vitro (outside the body) or in vivo (in the body). In vitro labeling is more specific and is associated with less background tracer activity, but requires handling and readministration of the patient’s blood. With either technique, red blood cells are labeled with technetium-99m, and dynamic imaging is performed of the abdomen and pelvis. Typically imaging time is 1 hour, but additional delayed imaging may be performed. Only areas of active bleeding during the time of imaging are revealed. In cases of intermittent bleeding, delayed imaging may help to identify a bleed up to 24 hours after injection. Delayed images will detect the presence of GI bleeding but will not be as useful in defining a location, due to normal movement of bowel contents.

PULMONARY IMAGING Pulmonary nuclear medicine studies assess regional pulmonary blood flow and ventilation and are useful for a variety of clinical indications.21 Lung Perfusion Scan A lung perfusion scan is performed after intravenous administration of 99mTc-labeled microaggregated albumin

(99mTc-MAA), which is trapped in the capillary bed of the lungs. Particle accumulation is in proportion o pulmonary blood flow, which allows determination of differential lung perfusion (left vs. right) and regional perfusion within each lung. Transient capillary occlusion occurs in less than one in a thousand capillaries and is cleared within hours. The most common pediatric indication for a lung perfusion scan is the evaluation of children with congenital heart disease. If there is a right-to-left (pulmonary-tosystemic) cardiac shunt, a portion of the 99mTc-MAA particles will enter the systemic circulation. MAA particles will be trapped in proportion to perfusion. Because of this possibility of a cardiac shunt and due to the smaller number of pulmonary capillaries in the pediatric lung, fewer 99mTcMAA particles are used in children, compared to adults. Lung Ventilation Scan Ventilation scans usually are performed in conjunction with perfusion scans, but occasionally may be used to assess primary airway diseases, including cystic fibrosis, lobar emphysema, asthma, and pulmonary hypoplasia. A ventilation scan can be performed with inhalation of either xenon-133 gas or aerosolized 99mTc-DTPA. An advantage of Xe-133 is that, as a gas, dynamic imaging can be performed to assess regional ventilation, washout, and air trapping. Aerosolized 99mTcDTPA clears too slowly for dynamic imaging, but does facilitate acquisition of multiple planar images to better localize ventilation defects. Lung Ventilation/Perfusion Scan A combined V/Q scan of the lungs allows comparison between the patterns of perfusion and ventilation. In adults, this exam is most often performed to evaluate for pulmonary embolus. A pulmonary embolus will demonstrate a perfusion and ventilation mismatch, characterized by ventilation without perfusion. While this is a less common indication in children, the ventilation-perfusion scan is used to evaluate children with repaired congenital diaphragmatic hernia or complex congenital cardiopulmonary disease.

CARDIAC IMAGING Pediatric cardiovascular nuclear medicine studies detect and quantify abnormal cardiac shunts, evaluate myocardial perfusion, determine cardiac output and ejection fraction, and demonstrate cardiac function and wall

motion.22 Echocardiography and MRI are also used cooperatively in these indications. Myocardial Perfusion Imaging In children with known heart disease, myocardial perfusion studies can provide useful clinical information.23 Myocardial perfusion is assessed with the radiopharmaceutical 99mTcmethoxyisobutyl isonitrile (99mTc-sestamibi; 99mTc-MIBI). Uptake of 99mTcMIBI is relative to perfusion, so that regions of relative hypoperfusion will appear with decreased radiopharmaceutical uptake. Images are acquired with dynamic SPECT and with cardiac gating, which allows for assessment of possible abnormalities in cardiac wall motion. The usual approach is to perform gated cardiac SPECT during rest and then to repeat the study after a period of cardiac stress. The most common form of cardiac stress is exercise, using clearly defined protocols of treadmill exercise. Some patients, particularly younger children, may perform better with a bicycle exercise protocol. Pharmacological stress protocols are used in adults but are used very rarely in children. Regions of ischemia show decreased myocardial perfusion after stress compared to rest, while myocardial scars will have decreased perfusion with both studies. Using a gated study permits assessment of ventricular ejection fraction and cavity size at rest and after stress. Common indications for myocardial perfusion imaging include chest pain, trauma, cardiac transplantation, Kawasaki disease, and anomalous coronary arteries.

ENDOCRINE IMAGING Thyroid Scintigraphy Thyroid scintigraphy can provide anatomic and physiologic information about the thyroid gland. The most common indication is evaluation of hyperthyroidism. Graves disease is characterized by increased autonomous iodine uptake, while subacute thyroiditis results in minimal iodine uptake. Other indications include evaluation of congenital hypothyroidism, localization of ectopic thyroid tissue, and rarely, evaluation of a thyroid nodule. For the most part, a thyroid scan should be used to evaluate a thyroid nodule only when it may be autonomous, as indicated by a suppressed serum TSH level.24 Thyroid scans can be performed with 99mTcpertechnetate or radioactive isotopes of iodine, such as iodine-123 or iodine131. Each radiopharmaceutical has potential advantages and disadvantages.

Iodine isotopes have more specific thyroid uptake, with less uptake in tissues such as salivary gland. Iodine isotopes also permit quantitative assessment of iodine uptake, but 99mTc-pertechnetate usually provides a lower radiation dose. For most indications, iodine-123 provides the best balance of image quality and radiation dose. Whole-body imaging with iodine-123 is used to evaluate patients with differentiated thyroid cancers, including papillary and follicular carcinomas. Whole-body scans are used to identify and localize remnant thyroid tissue in the neck and iodine-avid metastatic disease. Appropriate patient preparation is necessary before performing thyroid scintigraphy. Patients with hyperthyroidism must discontinue antithyroid drugs, usually for 3 days before the study. Patients must avoid iodine uptake, both from foods and iodinated radiologic contrast. Iodine in a patient’s body can lead to misleading results or interfere with thyroid scintigraphy. This is particularly important with thyroid cancer imaging. Most patients are placed on a strict low-iodine diet for 7 to 14 days and cautioned to avoid contrastenhanced radiologic studies for 6 to 8 weeks prior to whole body imaging.25 Parathyroid Gland Imaging Parathyroid scans are used to identify and localize abnormal parathyroid glands. Ultrasound also is used evaluate the parathyroid glands, and the most accurate localization of abnormal parathyroid tissue may be with the combined use of a parathyroid scan and US.26 Parathyroid imaging relies on the nonspecific uptake of 99mTcmethoxyisobutyl isonitrile (99mTc-sestamibi; 99mTc-MIBI) in mitochondrialrich tissues such as adenomas. Because the adjacent thyroid gland also may take up 99mTc-MIBI, two strategies have been developed to increase the specificity for abnormal parathyroid glands. A dual-phase study images at two time points—typically 20 minutes and 2 hours after radiopharmaceutical administration. By 2 hours, 99mTc-MIBI will wash out of normal thyroid and parathyroid tissue but will be retained in most adenomatous tissue. This is the preferred method in most pediatric institutions. A second approach is the dual-isotope study, which combines a parathyroid scan with a thyroid scan. Image subtraction is used to identify abnormal parathyroid tissue. Both approaches have high sensitivity for parathyroid adenomas but will detect only about half of hyperplastic parathyroid glands. The most common indications for parathyroid imaging are evaluation for parathyroid adenoma in patients with primary hyperparathyroidism, and evaluation of patients with

renal failure.

CENTRAL NERVOUS SYSTEM IMAGING Nuclear medicine studies of the central nervous system are used in the evaluation of seizure disorders but also may be indicated for trauma and brain tumors. Seizure Imaging Epileptogenic foci may be located using either brain SPECT or PET. Brain SPECT uses either 99mTc-ethyl cysteinate dimer (99mTc-ECD) or 99mTc- hexamethylpropyleneamine oxime (99mTc-HMPAO). For each, uptake is proportional to regional brain perfusion, which is increased during seizure (ictal) activity and relatively decreased during the interictal period. Uptake is rapid, and essentially occurs during the first pass after intravenous administration. When radiopharmaceutical is administered during an ictal event, increased perfusion leads to increased uptake and trapping of radiopharmaceutical in the region of the epileptogenic focus. Reliable imaging can be performed many hours after the seizure and radiopharmaceutical administration. Digital subtraction of ictal and interictal images may help to identify regions of increased ictal uptake (Figure 18515).

FIGURE 185-15. SPECT images from a brain scan obtained in the interictal state in a child with seizures demonstrates marked asymmetric uptake in the left temporal lobe. PET is also used to evaluate children with refractory epilepsy who are being considered for surgical cure. Functional alterations related to ictal or interictal states can be detected with FDG-PET.27 Brain Perfusion Brain SPECT using either 99mTc-ECD or 99mTc-HMPAO also can be used to assess cerebral perfusion in other conditions, such as moyamoya disease or in the determination of brain death. In some departments, brain perfusion is assessed with dynamic imaging after intravenous administration of 99mTc-pertechnetate. This approach provides a rapid and dynamic demonstration of brain perfusion but does not permit delayed brain SPECT. Radionuclide Cisternography Normal and abnormal flow of cerebrospinal fluid (CSF) can be assessed by radionuclide cisternography.

Indications for radionuclide cisternography include evaluation of communicating hydrocephalus, CSF leaks, and CSF shunt patency. This procedure also may be used to confirm normal CSF flow before intrathecal administration of chemotherapy. Imaging is performed after intrathecal administration of 111In-DTPA either by lumbar puncture or through an indwelling intracranial catheter.

INFECTION IMAGING Bone Scan Common indications for bone scans are osteomyelitis or evaluation for suspected bone infection in a child with fever (see Bone Scintigraphy). White Blood Cell Scan The white blood cell scan images the accumulation of the patient’s own white blood cells at a site of inflammation or infection. The white cells must be removed by phlebotomy, labeled with either technetium-99m or indium-111, and then reinfused into the patient’s circulation. Depending on the radioisotope label, whole-body or regional scans may be acquired at 4 hours, 1 day, or 2 days after the labeled white blood cells are infused. 18F-FDG

PET or PET/CT PET or PET/CT with the radiopharmaceutical 18F-FDG is becoming an alternative method of functional infection imaging. 18F-FDG uptake by white blood cells at sites of inflammation and infection can provide a useful method for identifying sites of occult or multifocal infection. Patients must fast for at least 4 hours before radiopharmaceutal administration. In many children, intense uptake in brown adipose tissue (BAT) can interfere with interpretation of the study. Uptake in BAT is enhanced by cold exposure, and may be more prominent in children, females, and lean patients. BAT uptake can be decreased by having patients dress warmly while traveling to the department before the study, but this may not minimize the problem. Most pediatric nuclear medicine departments have protocols that heat the patient in a warm room or use pharmacological intervention to minimize interference from BAT.

TUMOR IMAGING

A variety of radiopharmaceuticals can be used for the evaluation of tumors based on the tumor type and location. Although many tumor-specific agents have been used in the past, the majority of pediatric tumor imaging now uses PET with 18F-FDG. 18F-FDG

PET or PET/CT Most functional pediatric tumor imaging uses PET or PET/CT with the radiopharmaceutical 18F-FDG. Tumor viability is assessed by using 18F-FDG uptake as an indicator of tumor metabolic activity and may have a utility for imaging lymphomas, most solid tumors, and brain tumors. Depending on tumor type, FDG-PET may be most useful for staging, assessing response to therapy, and/or follow-up surveillance for tumor recurrence. Patients must fast for at least 4 hours before radiopharmaceutal administration. In many children, intense uptake in BAT can interfere with interpretation of the study. Uptake in BAT is enhanced by cold exposure, and may be more prominent in children, females, and lean patients. BAT uptake can be decreased by having patients dress warmly while traveling to the department before the study, but this may not minimize the problem. Most pediatric nuclear medicine departments have protocols that heat the patient in a warm room or use pharmacological intervention to minimize interference from BAT. MIBG Scan Metaiodobenzylguanidine (MIBG) is an analog of norepinephrine that can be radiolabeled with either iodine-123 or iodine-131 and used to image sympathochromaffin tissues. Due to better image quality, 123I-MIBG usually is the radiopharmaceutical of choice. The primary pediatric indication for 123I-MIBG imaging is neuroblastoma (Figure 18516), but occasionally it may be used to identify or localize a pheochromocytoma or paraganglioma. I-MIBG is more specific than CT or MRI for preoperative and postoperative evaluation of neuroblastoma.28 Images are acquired 1 day after intravenous administration of 123I-MIBG. Imaging typically includes a whole-body scan acquired either as a wholebody sweep or multiple static images. In most cases, SPECT is performed of the torso. Numerous medications can interfere with tumor uptake of MIBG, and the patient’s medications must be evaluated carefully before MIBG imaging.

FIGURE 185-16. This 6-month-old underwent a renal ultrasound for follow-up of prenatal renal pelvic dilatation. (A) US demonstrates an echogenic mass cephalad to the right kidney (marked). (B) An MIBG study demonstrates abnormal radiotracer uptake in the area seen on US (arrowhead), and in the left humerus (arrow). This patient had metastatic neuroblastoma. 111In-Pentreotide

(Octreoscan) Scan Pentreotide is a ligand for somatostatin receptors that usually are located on neuroendocrine tumors, including carcinoid tumors and gastroenteropancreatic tumors. Imaging typically is performed 1 day after administration of 111In-pentreotide and includes whole-body and SPECT imaging. Radiopharmaceutical excretion in the gut may interfere with imaging abdominal disease. Therefore some departments also will acquire images of the torso at 4 hours or 2 days after 111In-pentreotide administration. Another approach is to use a bowel preparation, such as an osmotic laxative or polyethylene glycol solution, to clear residual radiopharmaceutical from the bowel. Bone Scan 99mTc-MDP (see Skeletal Imaging) is used for the evaluation of primary bone tumors, especially osteosarcomas and metastatic bone tumors. Tumors with increased osteogenic activity cause areas of increased radiotracer uptake on bone scans. Tumors that cause pure osteolysis demonstrate decreased uptake, but this is rarely encountered by bone scan. Occasionally, skeletal imaging will use 18F-sodium fluoride, which is imaged with a PET scanner.

Gallium Scan In the past, gallium-67 scintigraphy frequently was used for tumor imaging. It was useful for evaluation of Hodgkin and non-Hodgkin lymphoma, infections, and nonmalignant conditions such as sarcoidosis.29 For the most part, gallium scans have been replaced by FDG-PET scans, which can provide higher image quality and lower radiation dose. Gallium scans are still used for tumor evaluation when PET or PET/CT is not available.

COMPUTED TOMOGRAPHY/COMPUTED AXIAL TOMOGRAPHY CT or computed axial tomography (CAT) scans, like conventional radiographs and fluoroscopy, create images based on the variable absorption of x-rays by different body tissues. Differences in tissue density and composition affect the ability of x-rays to pass through the body, and ultimately create images. CT is widely available, and image acquisition is rapid. In a critically ill patient, all life support systems are compatible with the CT scanner, unlike MRI, which has restrictions regarding metallic objects in the scanner area. During a CT scan, the patient lies flat in the bore of the scanner while the x-ray tube rotates around him. A ring of detectors replaces the film used in conventional radiography.30 In recent years, the number of rings or rows of detectors continues to increase, which has decreased scan time considerably while also potentially increasing the radiation dose if adjustments are not made. During a CT examination, the patient must hold still, which with newgeneration scanners can frequently be accomplished with minimal or no sedation. CT scan times are now often only seconds long, but any motion during the scan can degrade the imaging. Therefore careful assessment of a child’s ability to hold still before examination is recommended. CT scans have excellent spatial resolution, and large areas of the body may be rapidly imaged. With the data acquired, images can be reconstructed in many planes and formatted to enhance the conspicuity of soft tissues, bones, or vascular structures. The ease and speed of obtaining this type of information need to be weighed against the patient’s potential radiation risk and the cost of the examination.

The diagnostic accuracy of most CT scans is improved with contrast agents. The appearance of bowel without contrast may mimic or disguise pathology. Bowel contrast agents can be given by mouth or via stomas, nasogastric or gastric tubes, or rectum, according to the indication. The quantity depends on the patient’s age. Patients may also receive intravenous contrast to enhance the conspicuity of vascular and soft tissue structures. Required contrast flow rate varies with the type of exam requested, and an IV of appropriate gauge must be placed prior to the study. Patients with previous contrast allergies need to be premedicated (see prior section on Contrast Agents), or other tests should be considered. Increasingly, MRI is supplanting CT as the initial test for many neurologic indications such as sensorineural hearing loss, spondylolysis, hydrocephalus evaluation, and head and neck tumors.

BRAIN IMAGING Head CT is often requested in the pediatric population for the evaluation of acute change in neurologic status. For the evaluation of trauma, head CT is the imaging modality of choice. CT is excellent for the evaluation of intracranial hemorrhage (Figure 185-17). CT is also the preferred imaging modality for the evaluation of intracranial calcifications. With CT, beamhardening artifact can limit assessment of the posterior fossa and temporal lobe regions.

FIGURE 185-17. A large epidural hematoma is causing mass effect with minimal splaying of the falx to the contralateral side (arrowhead), and mild effacement of the left frontal horn (arrow). This hematoma was associated with a skull fracture. The patient was brought emergently to the operating room following the CT scan. In children with shunted hydrocephalus, head CT is often the most rapidly available imaging modality with which to assess ventricular size if shunt malfunction is suspected, although this is being supplanted in some locations by rapid-sequence MRI.31 In the evaluation of these patients, it is imperative to compare the current examination with the prior neuroimaging, and effort should be made to acquire these studies from outside institutions if necessary. Head CT may be performed without or with the administration of an intravenous contrast agent. Depending on the urgency of the examination, our practice is to administer contrast in cases in which treatment may be altered immediately based on the findings; for example, in the evaluation of an extraaxial abscess. In cases in which a lesion is suspected on CT and contrast would aid in further evaluation but the information is not going to change the immediate course of management (e.g. tumor requiring further characterization), administering contrast is deferred and instead brain MRI is

obtained.

HEAD AND NECK IMAGING CT is particularly useful in the evaluation of trauma or infection involving the head and neck. The exam should be limited to the anatomic area of interest. Imaging data can and should be reconstructed in multiple anatomic planes. Three-dimensional models are now easily created and may help in surgical planning. Contrast is administered in most cases of suspected infection. Although exposing the orbits to ionizing radiation should be avoided as much as possible, contrast-enhanced CT of the orbits is necessary in cases of suspected deeper extension of orbital cellulitis, where there is a potential risk for loss of vision (Figure 185-18).

FIGURE 185-18. Contrast-enhanced axial images through the orbits demonstrate right-sided preseptal soft tissue inflammatory changes, proptosis, with mass effect on the globe from the adjacent subperiosteal abscess (arrowheads). These findings are secondary to spread of infection from adjacent sinusitis; note the opacification of the right-sided paranasal sinuses. Temporal bone CT is frequently part of the workup in cases of sensorineural or conductive hearing loss.

CT of the paranasal sinuses is indicated in cases of chronic or complicated sinusitis. The raw data obtained from the axial images is used intraoperatively to guide the surgeon during functional endoscopic sinus surgery. Superficial neck masses can be easily evaluated by US, which is generally the initial study of choice. Following US, some surgeons may request neck CT because it allows easier assessment of the surrounding anatomic structures. Contrast-enhanced neck CT is useful for the evaluation of any neck mass and can distinguish the many reactive lymph nodes located in this region in a pediatric patient versus a mass lesion of another cause (Figure 185-19).

FIGURE 185-19. A contrast-enhanced axial image through the neck demonstrates a low-density lesion in the right lateral retropharynx with scalloping wall enhancement, consistent with an abscess.

SPINE IMAGING Spine CT is a vital adjunct in the workup of spinal trauma. To keep the radiation dose as low as reasonably achievable, only the area of clinical concern should be scanned. In the setting of trauma, images of the cervical

spine obtained at our institution are limited to the area of concern. This same concept holds true for imaging the lumbar spine in cases of suspected trauma or spondylolysis. At times patients have previous plain radiographs or bone scans that can aid the radiologist in scanning a limited area of interest; if these are not available, relying on the referring clinician’s assessment of the level of concern is necessary. Larger portions of the spine are sometimes imaged for preoperative planning in patients with severe scoliosis, where the formation of a three-dimensional model is very helpful to the surgeon. For evaluation of the intervertebral disks or paraspinal soft tissues, MRI should be performed (discussed later in this chapter).

CHEST AND CARDIOVASCULAR IMAGING Indications for chest CT are evaluation of the lung parenchyma, mediastinum, pleural spaces, soft tissues, bones, and cardiovascular structures (Figure 185-20). Because of the natural density difference between normal lung parenchyma and abnormal soft tissues within the lung, studies to evaluate the lungs often do not require intravenous contrast. High-resolution images are useful to assess for interstitial lung disease. Evaluation of the mediastinum, great vessels, pulmonary masses, and pleural disease typically requires intravenous contrast administration. The use of CT to assess heart disease is controversial in children because of the high radiation dose, and is most commonly used when there are contraindications to MRI.

FIGURE 185-20. CT scan of the chest. These axial images of the lower chest demonstrate the difference in lung and soft tissue windows. This patient has a history of congenital heart disease and presented with sepsis from bilateral pneumonia. (A) The lung windows emphasize the lung parenchyma. (B) The soft tissue windows help to distinguish the different soft tissues, including the consolidated lung (l) and pleural effusions (*) bilaterally.

ABDOMEN/PELVIS IMAGING Indications for abdominal and pelvic CT are numerous. However, because US is non-irradiating and does not require sedation, it is the study of choice for the initial investigation of most abdominal and pelvic abnormalities in children (Figure 185-21). US and MRI are superior to CT in evaluation of the uterus and ovaries. Administration of bowel and intravenous contrast is typically required for imaging the abdomen and pelvis, with the exception of

evaluating renal stone disease.

FIGURE 185-21. (A) An axial image of a large mass, likely renal in nature is seen here. With a reformatted image in the coronal plane (B), the tumor can be seen in its craniocaudal extent with a rim of renal parenchyma visualized at the inferior aspect of the mass, confirming its renal origin, consistent with a Wilms tumor in this young child.

EXTREMITY IMAGING The ability to create multiplanar reconstructions makes CT ideal for the evaluation of complex fractures, especially before surgery as well as congenital anomalies (Figure 185-22). After surgery, metallic hardware artifact may obscure bony and soft tissue detail. CT and MRI may help better characterize bone lesions that do not have a typical plain film appearance. Masses within the soft tissues of the extremities are usually better characterized by US or MRI than by CT.

FIGURE 185-22. CT reconstruction. An oblique sagittal reconstruction of the tarsal bones demonstrates a membranous talonavicular coalition (arrow) in a patient who presented with a painful flatfoot.

ULTRASOUND Ultrasound is the most common cross-sectional imaging modality in children due to its wide availability, relative affordability, dynamic imaging, and lack of ionizing radiation. Rarely does a child need to be sedated for an US. US produces images based on the different reflectivity of sound waves that each tissue inherently possesses. This is the examination of choice for the pediatric abdomen and pelvis, gonads, infant hips, neonatal brain, and neonatal spine. US can be used to assess blood flow and is an excellent noninvasive test to evaluate the patency of arteries and veins throughout the body. US also provides images in real time, which is extremely useful in evaluation of the bowel and heart. Cardiac US, or echocardiography, is not discussed in this section. Most US examinations do not require patient preparation, with the

exception of abdominal and pelvic US, which are discussed later in this section.

HEAD ULTRASOUND Ultrasound plays a major role in evaluation of the neonatal brain, particularly in a premature or near-term infant who is critically ill and cannot be transported to radiology or cannot undergo a lengthy examination such as MRI. US may be performed at the bedside, is quick, and provides crucial information needed to manage some of these patients. Sonography of the brain is possible until the anterior fontanelle is too small to image through; the age at which this occurs is variable. Although the fontanelle may not completely close until 18 to 24 months, image quality is often significantly degraded much sooner secondary to the size of the transducer required to obtain images. The smallest transducer used in our department for head US has an interface measuring up to 2.5 cm. Imaging via the anterior fontanelle is used first and foremost because it is the largest nonossified membranous junction of the parietal bone. To better assess the posterior fossa, the sonographer may also attempt imaging through the posterior fontanelle or posterolateral (mastoid) fontanelle if these are patent.32 Head US is mostly used to evaluate for the presence of intracranial hemorrhage at the germinal matrix (Figure 185-23) and periventricular leukomalacia in preterm infants. More definitive characterization of periventricular leukomalacia suspected on US may be made with MRI when the patient is stable. Serial US examination in a patient known to have an intracranial hemorrhage is a means with which to monitor ventricular size and spare the patient the considerable amount of ionizing radiation that would be incurred if head CT were used.

FIGURES 185-23. (A) Coronal and (B) sagittal views, respectively, from a head ultrasound show a relatively large bleed (white arrow) at the caudothalamic groove (2 white arrows). Head US may also be used for the evaluation of parenchymal calcifications or septations in a cyst, both of which may be too small to be seen with CT or MRI. US is useful in the evaluation of midline congenital anomalies, vascular malformations, and extra-axial collections. Not only is a gray-scale index used to evaluate the brain parenchyma, but color Doppler imaging capabilities also make evaluation of intracranial arteries and veins possible. Color Doppler imaging plus real-time examination capability makes it possible to evaluate change in intracranial arterial parameters in response to increased intracranial pressure.33,34

NECK ULTRASOUND Ultrasound is an excellent initial tool for evaluation of neck masses. It is commonly used to distinguish lymphadenitis from other neck masses such as a congenital cyst, lymphatic malformation, or neoplasm. With color Doppler, increased or decreased vascularity of a neck mass may be demonstrated and can aid in determining the cause of the mass. If the initial US provides a diagnosis, further evaluation with CT or MRI could be avoided along with potential complications from sedation, contrast, or radiation exposure (in the case of CT).

SPINE ULTRASOUND Ultrasound of the spine is performed until the posterior elements ossify, between 2 and 3 months of age. Beyond this age, full visualization of the contents of the canal may not be possible. Appropriate indications in a neonate include a suspected tethered cord, fatty filum, or distal thecal sac mass. Although US examination of the lumbar spine is frequently requested because a sacral dimple or pit or a hairy patch is found on neonatal physical examination,35 a study demonstrated that all spinal US findings for the indication of simple sacral dimples, pits, or sinuses were normal.36 This study recommends that patients with an abnormal antenatal scan, a cutaneous lesion other than a simple dimple or pit, and any congenital abnormality or any neurologic signs or symptoms associated with occult spinal dysraphism be evaluated with lumbar spine US.

ABDOMEN AND PELVIS IMAGING Abdominal Ultrasound A so-called “complete abdominal US” primarily evaluates the upper abdomen and includes images of the liver, gallbladder, pancreas, spleen, kidneys, bladder, portions of the aorta and IVC, and a general sweep of the abdomen and pelvis for ascites. The size and configuration as well as blood flow, of these organs is examined in real time, and masses can be excluded with this imaging modality. More limited exams are also frequently obtained for particular clinical indications, with a focus only on the right upper quadrant or kidneys, for example. US can be useful in evaluation of the bowel, especially in the evaluation of pyloric stenosis (Figure 185-24), intussusception, appendicitis, and bowel wall thickening.

FIGURE 185-24. Ultrasound image of the right upper quadrant in a 4week-old boy with projectile vomiting demonstrates pyloric stenosis. The thickened muscularis of the pylorus (marked) measures greater than 3 mm. Patients need to fast for 2 to 6 hours prior to an upper abdominal US, depending on the age and indication. The main deterrents to obtaining diagnostic-quality images are bowel gas, large body habitus, and difficulty positioning the patient. Pelvic Ultrasound Ultrasound is useful in the initial evaluation of pelvic pain, pelvic mass, amenorrhea or dysmenorrhea, and müllerian duct anomalies. It is the best imaging modality for the evaluation of suspected ovarian torsion.37 MRI is also useful in evaluation of the female pelvic organs, and is discussed later. For pelvic US in females, a full urinary bladder is the best way to view the pelvic organs. A full urinary bladder is also useful to evaluate the bladder itself. As with US of the upper abdomen, bowel gas, large body habitus, and difficulty with patient positioning may limit diagnostic yield. Additionally, in

the pelvis, an underfilled urinary bladder may prevent adequate visualization of the pelvic organs. The uterus and ovaries can be evaluated by transabdominal scanning, with a full urinary bladder used as the acoustic window, as discussed above. Additional transvaginal images are often obtained in sexually active females, as they provide more detailed images of the endometrium and adnexa. This is especially important in cases of early pregnancy when ectopic pregnancy is being considered.

EXTREMITY AND SUPERFICIAL ORGAN IMAGING Ultrasound is useful in the evaluation of palpable soft tissue masses anywhere in the body, including the extremities, to determine whether they are solid, cystic, or vascular (or any combination) in nature. The use of US in evaluation of the musculoskeletal system has increased significantly in recent years. Ultrasound is also very useful to evaluate superficial organs such as the thyroid gland or testes. The combination of high-resolution imaging and no ionizing radiation makes US especially ideal in examining the testes. US is the best imaging modality for the evaluation of a painful scrotum and easily distinguishes testicular torsion (Figure 185-25) from other causes of pain.

FIGURE 185-25. Ultrasound of the left scrotum in a boy who presented with acute left scrotal pain demonstrates skin thickening

and hypervascularity surrounding the testicle, which shows no internal flow by color Doppler. At surgery, the patient was found to have testicular torsion.

MAGNETIC RESONANCE IMAGING MRI creates images through the manipulation of magnetic fields. No ionizing radiation is required. Natural differences in water content cause various tissues to respond differently to an applied magnetic field and allow creation of detailed images. MRI studies vary in length, but most take at least 30 minutes to complete, often longer depending on the sequences required. Individual sequence time varies widely, but is generally in the range of 2 to 8 minutes. During this time, the patient must lay still within the bore of the magnet. Even a small amount of motion may cause enough degradation of image quality that an entire sequence needs to be repeated. Depending on the age of the patient, sedation or even general anesthesia may need to be administered to obtain images of diagnostic quality. For a newborn, we use the “feed and wrap” method as an alternative to sedation. The bore of an MRI is smaller than that of CT and some with even mild claustrophobia have difficulty completing the exam. Sedation should be considered for these patients as well. Open-bore MRI machines are sometimes available; however, the image quality varies widely and discussion with the radiologist regarding the indication for the exam and the appropriate choice of magnet is recommended. Metal within a patient’s body, in the form of an implanted medical device, such as a pacemaker, or residua from prior injury, such as bullet fragments, can cause not only artifact on images and destruction of the device, but physical damage to the patient through superheating. Prior to scheduling a patient for MRI, one should carefully screen for the possibility of indwelling metal. In the case of medical devices, the device maker should have easily accessible information regarding MRI compatibility of the device. Prior successful completion of an MRI study is not evidence that the device is compatible and should not be taken as such. As the magnet is always on, a magnetic field exists around the MRI scanner even when no exam is being performed. Every person who enters the examination room must be cleared before entering. This includes hospital staff as well as parents who might like to accompany their child during the exam.

BRAIN IMAGING Brain MRI provides superb depiction of brain parenchyma, making it possible to diagnose subtle lesions and evaluate small structures that might be missed with CT. MRI also provides superior evaluation in regions where one is limited with CT because of beam-hardening artifact; specifically, the temporal lobe or posterior fossa. MRI diagnosis of ischemia and infarction is often straightforward. Because of the clear demonstration of myelination patterns, MRI exceeds any imaging modality for the evaluation of developmental delay. Almost any white matter abnormality is best evaluated with MRI. MRI is the gold standard for evaluation of the brain parenchyma when imaging is indicated in the workup of a patient with seizures (Figure 185-26). Although CT is useful in the acute management of any patient with new signs or symptoms that suggest the possibility of an intracranial lesion or mass, brain MRI is often necessary to better distinguish not only the lesion but also the lesion’s effects on adjacent parenchymal structures.

FIGURE 185-26. (A) Head CT of this child with seizures does not show the white matter to extend well into the periphery, as it should, but rather shows the low density of the white matter located more centrally (white arrowheads). This patient has band heterotopia, also known as double cortex, better depicted on brain MRI. (B) Shows

white matter (black arrowheads) followed by a “band” of cortex (black arrow), followed by a thin layer of white matter (white arrowheads), followed by cortical gray matter as one proceeds peripherally.

FACE/NECK IMAGING Face or neck lesions, or both, in the pediatric population are frequently examined with MRI because of its excellent soft tissue differentiation, especially when intracranial extension is suspected; for example, with skull base, nasal, or orbital lesions. In addition, if cross-sectional imaging of an isolated neck mass is needed and the patient has a contraindication to the administration of iodinated contrast for CT, MRI or US should be performed instead.

SPINE IMAGING The indications for spine MRI are vast, and include evaluation of developmental abnormalities, neoplasm or, increasingly, scoliosis. Spine MRI is also used for the evaluation of any inflammatory process, whether it involves the vertebrae or is located deeper in the central canal (i.e. osteomyelitis or transverse myelitis, respectively) (Figure 185-27). In the evaluation of spinal ligamentous injury after trauma, MRI is also superior to CT despite the latter’s superior ability to detect fractures. Certain sequelae of spine trauma such as nerve root avulsion can be depicted with MRI as well. Finally, for any pediatric patient with back pain, MRI may be indicated in the search for an intraspinal or paraspinal mass.

FIGURE 185-27. This sagittal T1-weighted post-contrast image of the lumbosacral spine shows abnormal enhancement involving the L2 and L3 vertebrae with abnormal enhancement involving the prevertebral soft tissues and a marked decrease in the disc height at this level. These findings are consistent with vertebral osteomyelitis/discitis. There is no evidence of epidural extent of the infection, but the disc minimally bulges posteriorly.

CARDIAC/CHEST/VASCULAR IMAGING MRI is useful for the evaluation of cardiac, vascular, and soft tissue structures of the chest. CT currently remains superior to MRI in evaluating parenchymal lung disease.

Cardiovascular anatomy, cardiac function, perfusion and blood flow, and pulmonary vascular anatomy can be assessed with cardiac MRI, an examination that complements echocardiography. Cardiovascular imaging is performed with cardiac gating, which means that images are timed to the cardiac cycle. Because patient cooperation is crucial and breath holding is often required, young or uncooperative patients typically undergo general anesthesia for cardiovascular imaging. Although CT scans are often the initial cross-sectional imaging modality for evaluating noncardiac anatomy of the chest, MRI is particularly useful for evaluating the mediastinum and soft tissues of the chest wall. Chest MRI is excellent in the evaluation of congenital abnormalities of this region, such as bronchopulmonary foregut malformations. Vascular imaging throughout the body can be achieved with or without the use of gadolinium intravenous contrast. MR angiograms and MR venograms are excellent noninvasive studies for assessing vascular anatomy and patency.

EXTREMITY IMAGING One of the most common indications for MRI is evaluation of the extremities. MRI is used to evaluate the joints for bony, ligamentous, tendinous, and cartilaginous injury. It is very useful in evaluating the composition and extent of soft tissue and bony masses and infections.

ABDOMEN AND PELVIS IMAGING Like CT, MRI offers multiplanar evaluation of the abdominal and pelvic solid organs, the bowel, the peritoneal cavity, surrounding soft tissues, and bones. Abdominal imaging with MRI is well established and is particularly valuable in evaluation of the liver, biliary tree, and pancreas. While fluoroscopy with enteroclysis has traditionally been the preferred method for evaluation of the bowel, use of MRI for bowel imaging, such as in the setting of Crohn’s disease, has advanced in recent years.38 MRI is superior to CT for evaluation of the female pelvic organs and is a useful adjunct to US of the pelvis. CT and US are often preferred over MRI because MRI is more time consuming and thus more often requires sedation, is more costly, and is less

available.

INTERVENTIONAL RADIOLOGY Interventional radiology is a field that continues to evolve. Interventional radiologists can now perform many procedures previously relegated to surgeons. Image-guided therapy and interventions, which are minimally invasive, have a low risk for complications and morbidity. On an outpatient basis, interventional radiologists now perform many procedures previously done surgically and requiring a lengthier hospital admission. With new advances in this field, the radiologist can not only provide diagnostic information but also deliver primary therapy in many instances and frequently during the same visit. The possibility of diagnosis and treatment in one setting is important to consider, especially if the patient will need sedation under general anesthesia. Consultation with the interventional radiologist is important for comprehensive patient care. In the workup of complex cases, multiple subspecialty consultation along with the interventional radiologist may be needed. There are important differences that arise when interventional radiology procedures are performed on pediatric versus adult patients. The first involves sedation and anesthesia. Many procedures, although minimally invasive, are painful. Certain procedures also stand a greater chance for success with a quiet, still patient. With this in mind, procedural sedation and anesthesia are far more frequently administered to pediatric patients. Not only does one need to administer the appropriate sedative in these cases so that the patient remains motionless as for other diagnostic imaging studies, but administration of an analgesic is also usually necessary.39 In general, the level of sedation is usually deeper for interventional radiology procedures, and general anesthesia is frequently administered, thereby increasing the overall risk associated with the procedure. In addition, patients in a hospital setting requiring an interventional radiology procedure have a far more complex medical history and usually have acute pathology, which in turn further increases the overall risk associated with the procedure when combined with the need for sedation. The overall risk should always be weighed against the benefits gained by performing the particular interventional procedure. Consulting the anesthesiologist and interventional radiologist during complex clinical scenarios cannot be stressed enough. In

an ideal situation, there is an anesthesiologist dedicated to the interventional division. This person is familiar with the various procedures performed and tailors the sedation to the particular case being performed. In addition to differences in sedation between pediatric and adult patients, there are differences related to iodinated contrast administration, technique, and equipment needed to perform a given procedure, not to mention the overall differences in pathophysiology and differential diagnoses between pediatric and adult disease. Nonetheless, many of the interventional techniques are directly transferable from adult patients to children, particularly nonvascular interventions. It is, however, not unusual for interventional radiologists and surgeons trained and experienced with adults to refer pediatric patients to a pediatric specialist for image-guided procedures because of the aforementioned issues. Conversely, pediatric interventional radiologists may not be facile in all interventional radiology techniques, and collaboration with their adult counterparts is common. It should be noted that there are very few dedicated training programs in pediatric interventional radiology, and these specialists primarily practice at tertiary pediatric referral centers. Another issue regarding pediatric interventional procedures relates to radiation exposure. Many adult interventional radiologists use fluoroscopy and CT as image guidance modalities for the sake of speed and ease of use; they tend to use US guidance less frequently. Typical radiation doses for an adult interventional procedure can sometimes be unacceptable for a pediatric patient. To avoid ionizing radiation, most pediatric interventional radiologists use US whenever possible. Altering the fluoroscopy and CT parameters during interventional procedures also helps in decreasing the overall radiation dose to the patient. Given the possibilities of extended exposure time during complex procedures, patients are counseled and occasionally consented for radiation exposure risk.

VASCULAR PROCEDURES Diagnostic Angiography Diagnostic angiography is not performed as routinely in the pediatric population because of the availability of less invasive modalities such as CT or MR angiography. Still, this procedure remains the gold standard for the diagnosis of vascular diseases. Some of the indications for conventional angiography in children include localization of

hemorrhage, renal vascular hypertension, complications of organ transplantation, and the workup of vascular malformations.40-51 Important precautionary measures need to be taken during this procedure for a pediatric patient because the risk for complications, particularly those related to the puncture site (i.e. vasospasm with the potential for arterial thrombosis), is higher than in an adult patient. This procedure is contraindicated in a patient who is medically unstable. Relative contraindications include substantial electrolyte imbalance, cardiac arrhythmia, a documented serious reaction to contrast administration, impaired renal status, coagulopathy, inability to lie flat on the table, residual barium in the abdomen, and pregnancy.52 A comprehensive clinical history and physical examination, with special attention to the common femoral and more distal arterial pulses, should be obtained. Screening laboratory studies may include a complete blood count (CBC), Chem-7, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). All patients require some form of sedation, particularly to reduce motion artifact during imaging. Previous imaging studies, when necessary, should be available. Informed consent for the procedure is necessary. The interventional radiologist performing the procedure should obtain this consent so that the procedure itself, its benefits and risks, and any questions can be fully discussed. Preprocedural medications such as antibiotics are not routinely used. Angiography is performed in a dedicated angiography suite with sterile technique. Arterial access is typically gained via puncture of the common femoral artery. A vascular sheath is placed to lessen trauma to the vessel during catheter exchanges. Catheters and guidewires are placed under fluoroscopic guidance to access the desired vessels. Intravascular contrast is administered via a mechanical injector at a high flow rate through the catheter as serial radiographic images are obtained. Digital techniques are used to subtract background information, such as bony structures, so that only images of the blood vessels remain (Figure 185-28). It is essential that no motion be present during this process to avoid blurring of images. Typically, images are obtained during a breath hold. During abdominal imaging, glucagon is routinely given to slow bowel motility, which can also interfere with optimal imaging.

FIGURE 185-28. Abdominal aortogram performed with digital subtraction. This 13-year-old female was under general anesthesia, and breath hold and glucagon were utilized to reduce motion artifact. The patient was involved in a fall with a splenic laceration by CT. Multiple areas of contrast extravasation consistent with bleeding are noted (arrows). As mentioned earlier, vessels in children are particularly prone to vasospasm and thrombosis. The presence of a catheter and guidewire in the vessel may be enough to induce spasm. It is typical to heparinize a patient during this procedure, particularly infants. Induced hypercapnia during anesthesia is another strategy used to reduce the propensity for vasospasm. After completion of the procedure, pressure on the arterial puncture site is typically held for 5 to 10 minutes, depending on the patient’s coagulation status. It is suggested that patients attempt to limit activity for approximately 24 hours after arterial puncture, after which they may resume normal activity. Lower extremity pulses, particularly on the puncture side, are monitored for possible spasm or impending thrombosis. Hydration at one to two times maintenance is recommended to promote renal clearance of contrast. There are maximum limits on the amount of contrast that can be administered to a patient because of nephrotoxicity. At our institution, this limit is 7 mL/kg in 24 hours, including any other contrast administration on the same day that may have been used for diagnostic imaging (CT, IVP, etc.). Monitoring of renal function by serum creatinine levels is not an absolute requirement after the procedure except in high-risk patients.

Primary Vascular Interventions In the vascular arena, primary interventions can be divided into restoring patency to blood vessels (angioplasty, stenting) or occluding them (embolization, sclerotherapy). One of the more common uses of angioplasty is for treatment of patients with renovascular hypertension secondary to either fibromuscular dysplasia or renal artery stenosis. Vessels may be occluded via particle embolization in a patient with massive hemoptysis. Embolization and sclerotherapy are used for the treatment of congenital vascular malformations (arteriovenous, venous, or lymphatic malformations).53-58 In general, preprocedural preparation is similar to that for diagnostic angiography. For certain procedures, corticosteroids may be administered to reduce the inflammatory response. Prophylactic antibiotics may also be administered during certain vascular interventions. Because treatment of vascular malformations may be complicated and require staged interventions, consultation with the interventional radiologist is essential before discussing these procedures and treatment options with the parents. Vascular Access Procedures Image-guided venous access, which includes peripherally inserted central catheter (PICC) and central venous line placement, is generally reserved for patients in whom multiple attempts at gaining venous access without image guidance have proved futile. Success rates for placement of PICCs and central venous catheters under US and fluoroscopic guidance are excellent.59 Preprocedural preparation usually involves fasting for sedation or anesthesia and is generally reserved for younger patients. Review of the patient’s previous imaging examinations and history of previous line placement is essential before the procedure to assess whether there is any known venous obstruction, thrombosis, or stricture. Under US guidance, PICC placement is usually performed in the upper part of the arm with a basilic vein puncture. US guidance is also used for placement of central venous lines and is typically performed via an internal jugular vein approach. In theory, any vein that can be visualized with US can be punctured. This is particularly important in the patient where the more traditional routes of access are not suitable. Preservation of venous access, particularly in a pediatric patient with chronic disease, is important, so the smallest, least invasive catheters are used to reduce repetitive trauma to the veins. Most catheters placed under image guidance can be used immediately after the procedure.

NONVASCULAR INTERVENTIONS Percutaneous Drainage of Fluid Collections and Abscesses Minimally invasive image-guided drainage of fluid collections and abscesses, such as those that might arise as a result of complications of appendicitis, is common (Figure 185-29).60-62 Indications for the procedure include: (1) reduction in size of collections causing symptoms (such as bowel or urinary obstruction), (2) characterization of fluid (both chemical and microbiologic), and (3) prevention of sepsis in patients with infected collections not responding to antibiotic treatment alone. Contraindications include a percutaneously inaccessible area, intervening bowel being the most common cause of an inaccessible area, and coagulopathy. Review of previous imaging studies and laboratory values, and consultation with the pediatric surgeon are needed before performing this procedure. Sedation or general anesthesia is needed in all age groups. The procedure can usually be performed under US guidance. CT guidance is occasionally used for more difficult collections. In most cases, after aspiration, a drainage catheter is left within the cavity for several days. Fluid output from these catheters is monitored daily. The catheters may become obstructed, which could require tube flushing, repositioning, or even tube replacement in certain cases. Drainage catheters are removed at the bedside without sedation in most instances.

FIGURE 185-29. Ultrasound-guided drainage of superficial abscess. This two-year-old male developed a superficial abscess after open appendectomy. (A) Preprocedure CT. (B) Ultrasound appearance with the access needle in position. (C) Fluoroscopic image after placement of a pigtail drainage catheter. Image-guided thoracentesis and paracentesis can be performed with similar techniques and preprocedural preparation as for the procedures described earlier. With regard to thoracentesis, consultation with a pediatric surgeon is recommended, particularly for complex effusions or empyemas because the patient may be a more suitable candidate for video-assisted thoracoscopic surgery (VATS) or large-bore chest tube drainage (or both). Use of tissue plasminogen activator through small-bore pigtail catheters has been very successful in draining complex collections that may be loculated.63,64 Given this, image-guided chest tube placement tends to be the first line of therapy at our institution in these situations (Figure 185-30).

FIGURE 185-30. Ultrasound-guided thoracentesis and chest tube placement. This 18-year-old male with developmental delay developed a right lower lobe pneumonia with a complex pleural effusion. (A, B) Pre-procedure appearance under chest x-ray and CT, respectively. (C) Ultrasound appearance of the collection with a catheter needle in position. (D) Placement of a pigtail catheter in the collection under fluoroscopy. Percutaneous Image-Guided Biopsy Minimally invasive biopsy of tumors and other lesions is gaining more acceptance as histologic techniques become more sophisticated. Imaging guidance not only increases the safety of the procedure but also affords the ability to be very precise in targeting specific abnormalities, particularly if they are small (Figure 185-31). The vast majority of these biopsies can be performed on an outpatient basis under conscious sedation or with a short-lasting general anesthetic. Fine-needle aspirates as well as small-core biopsies can be obtained by the interventional radiologist. Preprocedural preparation is similar to that for other percutaneous techniques described earlier: fasting status for the patient before sedation/anesthesia, evaluation of the patient’s history, imaging

examinations, laboratory analysis (CBC, PT/PTT, INR), and cessation of anticoagulant medications for at least 10 days before biopsy. Open surgical biopsy is necessary in certain cases, such as a large tumor that is partially necrotic, because fine-needle aspiration or even a small core biopsy may not yield adequate specimens. Similarly, in certain cases the patient may need to proceed to immediate surgical excision because of a deleterious mass effect on adjacent structures. Seeding of the biopsy tract is possible for certain tumors. It is best to consult with the oncologist and oncology surgeon when contemplating ordering a minimally invasive biopsy of a presumed tumor.

FIGURE 185-31. CT-guided biopsy of compressed T3 vertebral body. This 13-year-old female presented with scapular pain and a collapsed T3 vertebral body on MRI. This image demonstrates placement of a coaxial needle and trephine biopsy needle by CT guidance. Percutaneous Gastrostomy/Gastrojejunostomy Placement The preferred route of gastrostomy placement, endoscopic or percutaneous, is institution and patient dependent. Percutaneous image-guided gastrostomy placement is increasingly common as it is less costly and quicker to perform and may be associated with fewer complications.65 In the pediatric population, gastrostomy placement is often considered if nutritional requirements for growth and development are not being met. In patients with severe reflux, who are at increased risk for aspiration, transgastric jejunal feeding tubes can be placed. Percutaneous feeding tube placement may use fluoroscopy or US guidance. In a pediatric setting, the procedure is routinely performed with general anesthesia. The stomach is insufflated with air via an NG tube. Ultrasound is used to delineate the solid organs. Barium enema can

be performed to delineate the transverse colon. Once the stomach is distended with air, percutaneous needle puncture is made with both fluoroscopic and US guidance. Guidewire access is then obtained. The tract is then dilated and tube placed over the wire. Optionally, gastropexy with percutaneously deployed retention sutures can also be deployed. The procedure can be performed on an outpatient basis. The stoma is allowed to mature for about 8 to 12 weeks before attempting to place a transgastric jejunal tube. These tubes are placed under fluoroscopic guidance to ensure placement in the proximal jejunum. Getting the feeding tube to the proximal jejunum can be challenging in many instances, and it is not uncommon that radiation exposure is prolonged in both the patient and operator. These feeding tubes frequently need to be replaced because they can become obstructed or the patient inadvertently pulls the tube out, which in turn increases the cumulative radiation exposure. Consideration for this increased radiation dose must be balanced against the potential benefits/risks of surgical fundoplication for treating the reflux. Percutaneous Cecostomy Many patients with chronic neurologic, developmental, or metabolic diseases are plagued with chronic constipation. In this group of patients, placement of a catheter within the cecum with the administration of regular antegrade enemas can be life changing.66 Placement of a cecostomy tube is similar to placement of a gastrostomy tube, again performed under US and fluoroscopic guidance. Cecal air distension is performed via colonic insufflation via rectal tube, and direct percutaneous puncture is made with image guidance. Preprocedural preparation is similar to gastrostomy placement. Hepatic and Biliary Interventions In the pediatric population, interventions involving the liver are common. Image-guided liver biopsy is now the preferred standard of care at our institution and has replaced blind biopsies. Several papers have shown a decrease in bleeding complications with image-guided biopsy.67 Liver biopsy is necessary for diagnosis of many metabolic and infectious diseases involving the liver, most commonly viral hepatitis as well as monitoring of therapy. Many patients taking hepatotoxic medications also require monitoring. At institutions that perform liver transplantation, biopsy is routinely performed to monitor for organ rejection. Percutaneous liver biopsy is performed with the same techniques as described earlier for image-guided biopsy, with careful attention to avoiding adjacent

vessels or transgressing the liver capsule and inadvertently puncturing nearby structures. Performance of the procedure can be challenging in that many of these patients may be coagulopathic. A coagulation profile should be obtained prior to biopsy. If a coagulopathy exists, blood products should be available for correction or resuscitation as necessary. The biopsy is performed with sedation or anesthesia. A hematocrit level is obtained 4 hours after the procedure. A significant decrease in hematocrit or the presence of pain after the procedure warrants further workup and possible blood transfusion. In patients with severe uncorrectable coagulopathy, liver biopsy can alternatively be performed with a transvenous approach via the right internal jugular vein, and the liver parenchymal specimen obtained by puncturing through the right or middle hepatic vein. Biliary interventions are not common in the pediatric population. Most biliary procedures in this population are performed through endoscopic or surgical methods. Noninvasive methods for evaluation of the biliary system, such as magnetic resonance cholangiopancreatography (MRCP), are becoming more available, thus precluding the need for endoscopy and cholangiopancreatography. Interventional biliary procedures are sometimes performed in liver transplantation patients with complications involving the biliary–enteric anastomosis. Balloon cholangioplasty of strictures at these anastomoses is performed with good results (Figure 185-32).68 Other biliary interventions that are common in the adult population, such as biliary stone removal or common bile duct stenting, are performed rarely in children. Preprocedure preparation for biliary interventions includes the administration of prophylactic antibiotics to cover Gram-negative organisms.

FIGURE 185-32. Balloon cholangioplasty of biliary duct structure after split liver transplant. (A) Cholangiogram demonstrating nonopacification of the bowel and common bile duct anastamosis. (B) Inflated angioplasty balloon with a “waist” at the point of structure (arrow). (C) External/internal biliary stent catheter post dilatation. Urologic Interventions Percutaneous nephrostomy is performed primarily for relief of urinary tract obstruction. In the pediatric population, this is often performed in the setting of congenital obstruction of the ureteropelvic junction. Nephrostomy may also be indicated in the setting of postoperative edema of the ureterovesical junction after ureteral reimplantation surgery for vesicoureteral reflux. Relief of obstruction secondary to nephrolithiasis, the most frequent indication in the adult population, is not as common in children. Techniques are similar to that for

drainage of fluid collections, with the same preprocedure preparation of the patient. Prophylactic antibiotics are usually administered. Whereas in adult institutions the procedure is performed under fluoroscopic guidance, US guidance is more commonly used in children. Using US reduces the radiation dose to the patient, and having Doppler affords one the ability to locate an avascular plane to access the collecting system. A small pigtail catheter is placed within the renal pelvis after aspiration of urine. This catheter can form a mature tract, thus making the renal pelvis easier to access so that future interventions can be performed, such as balloon dilation or stent placement for a stricture. The catheter can remain within the renal pelvis for several weeks with proper care on an outpatient basis. Musculoskeletal Interventions Musculoskeletal interventions account for a large portion of the nonvascular pediatric interventional radiology practice. Percutaneous bone biopsy under either fluoroscopic or CT guidance can be helpful in the diagnosis of both neoplastic and infectious disease. Therapeutic interventions are also becoming more commonplace as technology advances. Needle biopsy followed by treatment of osteoid osteomas with radiofrequency ablation under imaging guidance is well documented and highly effective (Figure 185-33).69 Percutaneous biopsy of presumed histiocytosis lesions can be followed by direct injection of a steroid into the lesion with good results. Preoperative embolization of aneurysmal bone cysts and tumors has significantly reduced the morbidity associated with these operations. Primary sclerotherapy for aneurysmal bone cysts is also being performed.70 General anesthesia for pain control is usually required with the same preprocedural preparation as for image-guided biopsy. Most of these procedures can be performed on a day surgery basis. Again, consultation with the orthopedic surgeon, oncologist, and interventional radiologist is essential.

FIGURE 185-33. Radiofrequency ablation of radial osteoid osteoma. (A) Preoperative appearance on CT. (B) Radiofrequency probe traversing the nidus under CT.

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surgical endoscopic, and percutaneous endoscopic gastrostomy/gastrojejunostomy: comparative study and cost analysis. Cardiovasc Intervent Radiol. 1998;21(4):324-328. 66. Chait PG, Shandling B, Richards HM, et al. Fecal incontinence in children: treatment with percutaneous cecostomy tube placement–a prospective study. Radiology. 1997;203(3):621-624. 67. Nobili V, Comparcola D, Sartorelli MR, et al. Blind and ultrasoundguided percutaneous liver biopsy in children. Pediatr Radiol. 2003;33(11):772-775. 68. Kling K, Lau H, Colombani P. Biliary complications of living related pediatric liver transplant patients. Pediatr Transplant. 2004;8(2):178184. 69. Torriani M, Rosenthal DI. Percutaneous radiofrequency treatment of osteoid osteoma. Pediatr Radiol. 2002;32(8):615-618. 70. Falappa P, Fassari FM, Fanelli A, et al. Aneurysmal bone cysts: treatment with direct percutaneous Ethibloc injection: long-term results. Cardiovasc Intervent Radiol. 2002;25(4):282-290.

CHAPTER

186

Ultrasonography for the Pediatric Hospitalist Matthew Garber and J. Kate Deanehan

INTRODUCTION Point-of-care ultrasound (POCUS) refers to non-radiologist clinicians who perform an ultrasound during a clinical encounter with their patient. Rather than performing a comprehensive exam of an organ or body part, the POCUS sonographer uses the ultrasound to answer a specific, focused clinical question, or as an aid in performing a procedure. Ultrasound delivers no ionizing radiation and usually does not require sedation; additionally, POCUS delivers immediate results at the point of care. POCUS has been used in adult emergency medicine for over 20 years, and is making its way into pediatric emergency rooms and critical care settings. While many pediatric hospitalists are familiar with procedural ultrasound, diagnostic POCUS is relatively new to the field. The purpose of this chapter is to familiarize hospitalists with POCUS in general, including basic physics and use of the machine as well as review indications that have been used or show promise for future use in pediatric medicine.

STARTING A PROGRAM Developing a productive and sustainable pediatric hospital medicine POCUS program requires significant expertise, resources, and time. No standards for credentialing and quality assurance exist for pediatric hospitalists, yet both are fundamental. Training standards have been published by the American College of Radiology and the American Institute of Ultrasound in Medicine, but pediatric emergency medicine physicians have found consensus guidelines from the American College of Emergency Physicians more geared to the focused POCUS exam, and therefore more applicable to them.1

Programs should establish minimum numbers of exams and didactic hours, and work with the hospital’s credentialing committee. Partnerships with radiology can form the basis for quality assurance and aid in credentialing. Local pediatric or adult emergency medicine programs may have expertise in purchasing and maintaining appropriate portable equipment, and often set the standard in training, monitoring, and clinical use of POCUS. The point person for the program needs to be well trained in ultrasonography, understand the goals of POCUS, and be able to instruct and evaluate other clinicians as well as set competency standards. Evidence of improved patient outcomes should dictate which specific examinations are taught and performed. Each program must decide which examinations suit their particular needs, but there is no substitute for routine, frequent use with expert feedback in building competency.

EQUIPMENT Although advances in ultrasound technology have produced more affordable portable machines with excellent image quality, the purchase and maintenance of equipment is expensive. Leaders of the ultrasound program must consider multiple factors before meeting with vendors. Machine choice depends on specific examinations considered in the initial training (and examinations that may be added later), the sophistication of the user, power supply, size and maneuverability of the unit and its stand (which depends on location of use and storage), interfaces with hospital radiology systems and the internet, durability, costs, and service package. Service packages must be scrutinized, including the speed of replacing parts, and how software updates are handled. Programs may want to start with a limited number of machines to gain experience before full purchase. While sophisticated bells and whistles may be appealing for the technically savvy, complicated machines may intimidate the novice, and may not add value depending on the goals of the program. Probes (transducers) are defined by their footprint and frequency (Figure 186-1). The footprint is the part of the probe that touches the patient’s skin and sends out the ultrasonic waves. A wide footprint gives a wider field of view but may not fit into small spaces, e.g. intercostals. High-frequency probes have better spatial resolution, yielding better image quality but less penetration. Low-frequency probes have better penetration and therefore can

image deeper structures, but have less resolution. A program that uses the ultrasound solely for procedures only needs a high-frequency probe. Most programs will need at least two probes for each machine, depending on the structures imaged.

FIGURE 186-1. Probes. (Left) Low-frequency small footprint probe used in cardiac imaging. (Right) High-frequency linear probe used for procedures and superficial structures. (Used with permission of Jason Levy.)

ULTRASOUND BASICS ULTRASOUND PHYSICS Ultrasound is a sound wave that is beyond the audible frequency range of the human ear, >20,000 Hz, but ultrasound for medical use usually ranges from 2 to 15 MHz. Electricity causes crystals in the probe head to vibrate (the piezoelectric effect). This energy is transmitted through the medium as a longitudinal wave, with particles in the medium vibrating back and forth in the direction of the wave. Properties of the medium—stiffness and density— determine the velocity of the wave. Reflected waves return to the transducer and make the crystals vibrate, inducing an electric current which is translated into images on the screen. The strength and timing of the returning waves is

translated into color (gray scale) and position on the screen, respectively. Dense tissues (bone, diaphragm) are highly reflective, or echogenic, and appear white on the screen, while less dense tissues (fluid) are anechoic and appear black. Different shades of gray denote the in-between structures (liver, spleen). Air is the enemy of ultrasound, as it scatters the sound waves, hiding the structures beneath it.

BASIC CONTROLS (BUTTONOLOGY) While the user will have to learn how to turn the machine on and off, input patient information, attach the probes, maximize image quality, switch among scanning modes, save the image, and send the image somewhere for review or documentation, only maximizing image quality is discussed in this section. Most units have presets, which optimize image quality for a particular exam, e.g. cardiac, renal, pediatric, but adjustments are needed to achieve the best image. The most important controls are frequency, gain (and time gain compensation), focus, and depth. Choose the highest frequency probe that allows visualization of the structure (deeper structures require lower frequencies) and if the probe has a frequency range, adjust to maximize resolution while maintaining adequate depth. The gain is controlled by the amplifier in the unit. Increasing the gain makes the signals appear brighter, and decreasing the gain makes them darker. The image should be bright enough to see weak signals, but not so bright as to obscure subtle areas of altered echo texture. The time gain compensation (also called depth gain compensation because the longer a wave takes to return, the farther or deeper it is) allows one to adjust the gain at specified depths without making other parts of the screen too bright or too dark. The depth of the focus can be adjusted manually. The focus is where the ultrasound beams converge and is the region where the best image quality is obtained. The depth is the maximum depth of the structures displayed on the screen. Decreasing the depth not only makes the shallower structures bigger on the screen, it also increases the temporal resolution (the ability to see events occurring closely in time, such as fetal heart movements).

SCANNING TECHNIQUES Orientation For most imaging the sonographer stands to the right of the patient with the probe in his right hand, and adjusts the machine with his left hand. The probe has a probe marker (dot, ridge, light) on its lateral edge, which corresponds to a dot or logo on the left side of the screen. By convention, the probe marker points to the right side of the patient when scanning transversely (Figure 186-2) and cephalad when scanning longitudinally (also referred to as sagittally) (Figure 186-3). Everything is reversed in cardiac imaging. The sonographer stands to the left of the patient, the probe marker points to the left of the patient, and the mark on the screen is on the right. Since both markers are reversed, the picture looks the same. Basically what is next to the marker on the probe is next to the marker on the screen. The top of the screen corresponds to where the probe is placed on the patient (skin), and the bottom is the opposite from that (think of the waves penetrating through the body). In a typical transverse orientation, the left side of the screen represents the right side of the patient and is similar to a CT scan. In a typical longitudinal orientation, left to right on the screen corresponds to cephalad to caudad on the patient.

FIGURE 186-2. Transverse orientation. Transverse probe position and transverse view of inferior vena cava.

FIGURE 186-3. Longitudinal orientation. Longitudinal (sagittal) probe position and longitudinal view of the inferior vena cava. Imaging Modalities The most common imaging modality is B-mode (brightness), which presents a real-time two-dimensional image as described in the orientation section above. M-mode (motion) is obtained through one slice of tissue such as a heart valve; the position of the border of a structure (its distance from the probe) is plotted vertically on the screen, with the horizontal axis representing time. This allows velocity to be deduced. Although there are a few forms of Doppler ultrasound (pulsed wave, continuous wave, color), basically Doppler ultrasound takes advantage of the frequency shift of moving objects and can detect velocity. In color Doppler, objects (e.g. blood) of increasing velocity are displayed in increasing intensities of red as they move toward the probe and increasing intensities of blue as they move away from the probe. Note that the colors have nothing to do with oxygenation. Also note that the chosen colors are opposite of the spectral absorption lines observed in astronomy (i.e. red-shifted stars are moving away from us).

DIAGNOSTIC EXAMINATIONS TRAUMA The focused assessment by sonography in trauma (FAST) exam was one of the first applications of POCUS in the emergency room. The original focus of the FAST exam was detection of blood in the abdomen, but this evolved to include the heart. The four primary views are the right upper quadrant, left

upper quadrant, subxiphoid, and suprapubic. Ideally, the exam takes less than 1 to 2 minutes. Both abdominal and cardiac probes can be used—the small footprint of the cardiac probe is helpful when visualization between ribs is necessary; the lower frequency abdominal probe is useful when visualizing obese patients where depth is needed. Anatomy Fresh blood appears anechoic (black) on ultrasound, and clotted blood appears gray. Morrison’s pouch, the hepatorenal recess, is the most common place for intra-abdominal blood to collect. Technique • Right Upper Quadrant A sagittal view is obtained by placing the probe either in the midaxillary line on the lower rib cage or below the right costal margin. The probe may need to be moved laterally or posteriorly to avoid gas in the hepatic flexure. Observe Morrison’s pouch. Scan for black fluid in potential spaces. Observe the right costophrenic angle (Figure 186-4 and Figure 186-5).

FIGURE 186-4. Morrison’s pouch. Normal hepatorenal recess. (Used with permission of Jason Levy.)

FIGURE 186-5. Morrison’s pouch free fluid. Fluid (hypoechoic) collection in Morrison’s pouch. Place the probe under the xiphoid almost parallel with the skin surface, directed toward the patient’s left shoulder. Ideally, the probe’s lateral surface makes an angle of 15 degrees with the skin (Figure 186-6). The left lobe of the liver and all four chambers of the heart are viewed. Observe for black fluid around the heart. The parasternal long axis view may be used when the subxiphoid view is not definitive (see the Cardiac section). Consider a pneumothorax if cardiac images cannot be obtained. Subxiphoid

FIGURE 186-6. Subxiphoid view probe position. This view may be difficult to obtain. Place the probe parallel with the ribs in the mid or posterior axillary line. Scan potential spaces between diaphragm and spleen and spleen and kidney for free fluid (Figure 186-7). Left Upper Quadrant

FIGURE 186-7. Left upper quadrant view with blood. The entire pelvis should be scanned from top to bottom with the probe in the transverse plane and then side to side in sagittal plane. In a normal transverse suprapubic view, the pouch of Douglas is the most dependent site (standing or supine) in the entire peritoneal cavity. The first sonographic sign of blood in the pelvis is often two small black triangles on either side of the rectum, the so-called bow tie sign. Scan the rectovesical pouch in males for free fluid (Figure 186-8). Suprapubic

FIGURE 186-8. Suprapubic view. Blood (hypoechoic) in the pouch of Douglas. (Used with permission of Jason Levy.) Pediatric Limitations/Future Indications Children are more likely to be managed non-operatively and have a higher incidence of solid organ injury without free fluid, limiting the usefulness of the FAST exam. Smaller volumes of free fluid in children impair the sensitivity of the FAST exam, though specificity is good. A positive FAST exam may expedite and prioritize surgical intervention, and also may be repeated during the evaluation without exposing the child to the ionizing radiation inherent in repeat CT scanning. One study combined a FAST with a physical exam and achieved 100% sensitivity.2 If this study is replicated, the FAST exam may replace routine CT scanning in the normotensive pediatric trauma patient.

CARDIAC

The cardiac POCUS can answer basic questions such as, is the heart beating? Is there a pericardial effusion? Adult emergency room physicians have become facile with the evaluation of the pulseless patient both from traumatic and non-traumatic causes. Pediatric emergency medicine physicians may be able to accurately assess for significant left ventricular systolic dysfunction, vascular filling, and the presence of pericardial effusion.3 Anatomy The long axis of the heart is defined as the plane from the atria to the apex (basically a diagonal line from the right shoulder to the left hip). The short axis of the heart is perpendicular to the long axis. As discussed in the Orientation section, the probe markers on the probe and screen are reversed and the examiner stands to the left of the patient. A small-footprint cardiac probe is used, generally with a frequency range around 1.5 to 4 MHz. Technique • Parasternal Long Axis This is the one view in ultrasonography where the probe marker on the probe does not match the one on the screen, and therefore the picture on the screen is actually reversed right to left. Rather than trying to correct the image mentally, sonographers generally develop pattern recognition for this view and immediately suspect when the probe has been reversed; however, they must still check the probe marker to make sure the patient does not have dextrocardia. Place the probe on the patient with the probe marker pointing to the patient’s right shoulder, close to the sternum in one of the rib spaces from 2 to 5, whichever location provides the best view. Adult patients may need to assume a left lateral position to move the lung away from the heart, but supine usually works for pediatric patients. This view shows the left atrium and ventricle, the aorta and left ventricular outflow tract, the right ventricle and right ventricular outflow tract, the aortic and mitral valves, the interventricular septum, the inferior/posterior wall of the left ventricle, the papillary muscles and chordae tendinae, and the descending aorta. Pericardial fluid will gravitate to the dependent portion of the pericardial cavity posterior to the inferior/posterior wall of the left ventricle but anterior to the descending aorta. In contrast, a pleural effusion in that region will be located posterior to the pericardial sac below the descending aorta. This view allows observation of wall motion, i.e. contractility of the left ventricle, motion of valve leaflets, any abnormal echogenic focus in the chambers, major defects in the interventricular septum, wall thickness, chamber and aortic root sizes, and valve abnormalities, but POCUS is generally limited to detecting effusions and

gross abnormalities of wall motion (Figure 186-9).

FIGURE 186-9. Parasternal long axis view. LA, left atrium; LV, left ventricle; Ao, Aorta; RV, right ventricle. Obtain an optimal parasternal long axis view, and then rotate the probe 90 degrees clockwise so the indicator on the probe points toward the patient’s left shoulder. Note that the orientation is now back to normal, the probe indicator matches the marker on the screen, and the image on the screen is no longer reversed right to left. Angulate the probe cephalad to caudad to obtain images at different levels of the heart. At the aortic level (the probe might be partially off the chest to obtain this view, the normal valve has the Mercedes insignia appearance) the left and right atria, right ventricle, pulmonary artery and valve, and tricuspid valve can be seen (Figure 186-10). At the mitral valve level (the mitral valve is described as a fish mouth) the right ventricle, interventricular septum, mitral valve leaflets, and left ventricular posterior walls are seen. Angling more caudally, the papillary muscles come into view sitting on the posterior wall of the left ventricle. The right ventricle and interventricular septum can also be seen (Figure 186-11). Parasternal Short Axis

FIGURE 186-10. Parasternal short axis view at the aortic level. LA, left atrium; RA, right atrium; RV, right ventricle; PA, pulmonary artery; AoV, aortic valve.

FIGURE 186-11. Parasternal short axis at the level of the papillary muscles. The subcostal is the same as the subxiphoid obtained in the FAST exam. The apical four- and five-chamber (the five-chamber view includes the aorta and aortic valve) views have the patient in the left lateral position; start at the apex located around the fifth intercostal space in the midclavicular line, and follow the long axis of the heart. Other Views

Pediatric Limitations/Future Indications Although the pediatric heart is often easy to image, congenital and many acquired cardiac diseases are too

complex for the POCUS sonographer to accurately diagnose. Indications are currently limited to diagnosing pericardial effusions and detecting motion in cardiac arrest (rare in pediatrics). Future indications may include screening for cardiomyopathy in acutely ill patients (e.g. to distinguish viral myocarditis from severe bronchiolitis, or in the evaluation of tachypnea in a neonate) but few studies3,4 currently support the safety or efficacy of this practice.

PULMONARY Because ultrasonic waves do not penetrate air, early pulmonary ultrasound focused on diseases of the pleura such as pneumothorax. Sonographers then discovered that certain ultrasound artifacts could be used in the interpretation of lung ultrasonography. Additionally, diseased lung with interstitial edema or consolidation decreases lung air and allows reflection of the ultrasound beam. Pulmonary ultrasound is now one of the most promising areas in POCUS. POCUS of the lung and pleura in adults is supported by international evidence-based recommendations.5 Tsung et al used POCUS during the 2009 H1N1 flu epidemic to create an algorithm that categorized patients as having bronchiolitis, viral pneumonia with bacterial pneumonia, bacterial pneumonia, asthma, or pneumothorax.6 A study by Shah et al.7 concluded, “Clinicians are able to diagnose pneumonia in children and young adults using POCUS, with high specificity.” Those authors also achieved a high sensitivity (86%), and the mean exam time was short (7 minutes). Another study compared formal ultrasound to chest x-ray in bronchiolitis, and found that all patients with a normal ultrasound also had a normal chest x-ray.8 Anatomy The pleura are seen as a bright line on imaging. Lung sliding is the scintillating motion of the healthy parietal and visceral pleura sliding against each other in rhythm with respiration. In the healthy lung, air prevents visualization of the lung parenchyma; however, reverberation artifacts called A-lines can be seen. These are repetitive horizontal lines parallel to the pleura. Other artifacts called comet tails are produced by the visceral pleura, perpendicular to the pleura. Artifacts called B-lines are seen in conditions with increased lung water such as pulmonary edema. B-lines are well-defined hyperechoic vertical comet-tail artifacts arising strictly from the pleural line

that move with lung sliding, spread to the edge of the screen without fading, and erase A lines.9 In a pneumothorax, there is absence of lung sliding and comet tails, but A-lines persist. A pleural effusion is visualized as a dependent anechoic collection between two bright lines (the parietal and visceral pleura). Technique Using a high-frequency linear array transducer with presets set for soft tissue and a maximum depth of 8 cm, scan the lung in 6 zones: right and left in the midclavicular line (anterior), midaxillary line (lateral), and in the parasagittal lines medial to the scapula (posterior). Scan both in the transverse and longitudinal orientation in each location (Figure 186-12). Abnormalities in one orientation should be confirmed in the other. In the longitudinal orientation, the pleural line lies between two rib shadows. Observe lung sliding and A-lines that characterize normal lung tissue. Absence of lung sliding indicates pleural disease. The pleura may be separated (e.g. pneumothorax) or adhered (e.g. atelectasis). Presence of Alines in the absence of lung sliding is highly suggestive of a pneumothorax.

FIGURE 186-12. Longitudinal probe positioning for lung ultrasound. (Used with permission of Jason Levy.) Lung consolidation is seen as subpleural echo-poor or tissue-like region with blurred margins or wedge-shaped borders. Sonographic air bronchograms are hyperechoic linear elements in the consolidated lung.7 Sonographic lung consolidation of less than 1 cm does not show up on chest x-ray and may not be reflective of clinically significant pneumonia. Observe for B-lines. Studies in adults show that more than two B-lines in

one view indicate pathology such as pulmonary edema (lung sliding preserved) or pneumonia (absent lung sliding)9 (Figure 186-13).

FIGURE 186-13. Lung; B lines: vertical lines that arise from the pleura and go all the way to the bottom of the screen. (Used with permission from Rachel G. Rempell.) Pediatric Limitations/Future Indications A dearth of studies is the main limitation in pediatric pulmonary POCUS. Since most pediatric admissions are respiratory, POCUS has the potential to play a large role in pediatric hospital medicine, especially if entities such as asthma, bronchiolitis, and pneumonia can be accurately and quickly distinguished by the POCUS sonographer.

PROCEDURAL APPLICATIONS CENTRAL VENOUS ACCESS

POCUS-guided central venous access has been shown to improve success rates and decrease complications in adults, compared to landmark techniques.10 In fact, the 2001 Agency for Healthcare Quality and Research report on reducing medical errors placed ultrasound guidance for central venous catheter placement in its “Top 11” list.11 While similar studies have been performed in children and small infants, none involved clinicianperformed POCUS.12,13 A national survey of pediatric intensivists revealed that 82% of 128 survey responders used POCUS for vascular access, and they preferred the internal jugular vein when using the ultrasound.14 Static ultrasound guidance refers to using the ultrasound to define the anatomy and mark the course of vessels (at least two points) on the skin. After marking the sites, the machine is put away and the procedure is basically performed in the traditional manner using the sonographically identified landmarks. This technique has advantages over a pure landmark technique because of anatomic variability, thrombosed veins, and other abnormalities such as scarring from previous procedures. When the static technique is used, the patient must be positioned before sonography and remain in that position for the procedure. The static technique improves success rates but doesn’t decrease complications as much as dynamic ultrasonography. Dynamic ultrasonography visualizes the vessel, puncture, and cannulation in real time. Either a two-person technique (with the more experienced sonographer holding the ultrasound probe and the other clinician performing the procedure) or a one-person technique can be employed. The vessel can be imaged transversely or longitudinally. The internal jugular is the most common vein used in adults requiring central venous access, but the same basic technique can also be used for the femoral vein. Ultrasound imaging of the subclavian vein is difficult because of the clavicle, and cannulation of this vein is associated with more complications; only experienced sonographers should attempt ultrasoundguided subclavian vein cannulation. Ultrasound guidance has not been shown to be superior to landmark technique when cannulating the external jugular vein.15 Because the transverse technique is preferred for the novice, only that technique is explained below, utilizing the internal jugular vein as example.

Technique Using a high-frequency linear probe and vascular presets, identify the relevant anatomy. Both arteries and veins appear round in the transverse plane and tubular in the longitudinal plane, but there are many distinguishing characteristics (Figure 186-14). Veins appear larger, have a thinner, less muscular wall, and can be compressed by applying pressure with the probe (unless a clot is present). The internal jugular becomes larger with Valsalva. Arteries appear more pulsatile, but vein movement with respiration can be confused with arterial pulsation. Pulse Doppler more clearly shows the difference between arterial pulsations and the phasic appearance of veins.

FIGURE 186-14. Vasculature of neck. Left side: small, round, thickwalled carotid artery; right side: large, thin-walled internal jugular vein. (Used with permission of Jason Levy.) Once a target vessel for cannulation has been identified, the patient should be prepped and draped in the usual sterile fashion and the ultrasound placed where the practitioner can easily see the screen. The ultrasound probe should be placed in a sterile cover and sterile gel used for the procedure. The marker on the probe transducer should be facing the same direction as the

marker on the screen (i.e. to the proceduralist’s left). This is important with needle redirection such that if the needle is moved toward the left side of the probe, it will move toward the left on the screen. When the internal jugular vein has been identified in cross-section and confirmed with compressibility and color flow, the sonographer should center the vein on the screen. Using the dynamic method, the finder needle should then be lined up with the center of the probe and inserted into the skin at a 45-degree angle. The needle should appear as a bright spot on ultrasound (Figure 186-15) and can be followed by slowly moving the probe forward as the needle is advanced. When directly over the vein, the needle will appear to tent the vessel wall prior to puncturing through it. Once the needle is in the vein, blood should be aspirated back and the remainder of the procedure can occur in the normal fashion, using the Seldinger technique.

FIGURE 186-15. Needle above the internal jugular vein with posterior shadowing. (Used with permission of Jason Levy.) Pitfalls When using ultrasound statically, the vessel for cannulation should be identified after the patient has been properly positioned for the procedure. Patient movement or repositioning may change the anatomical relationships of the vessels and lead to difficulty with cannulation. With the dynamic method, it is important to identify the needle with ultrasound before it is advanced into deeper structures. If the needle is inserted into the skin too far from the probe, the needle may enter the vessel before it is seen on ultrasound. Alternatively, if the needle is inserted too close to the probe, it will pass under the probe before encountering the vessel.

The transducer beam should be angled toward the needle, and if not visualized, the beam should be fanned until the needle is identified.

PERIPHERAL VENOUS ACCESS Peripheral intravenous catheter placement in children can be challenging, especially in those patients who are dehydrated, obese, or have chronic medical problems with known difficult access. The use of ultrasound in patients with difficult access has been shown to improve success rates and decrease overall time to intravenous catheter placement as well as the number of attempts and needle redirections necessary.16 The most common locations for ultrasound-guided peripheral venous access attempts are the brachial, cephalic, and basilica veins of the upper arm, as these locations often offer the best visualization. However, other sites such as the saphenous vein can also be used. Technique Peripheral venous cannulation is performed using the same technique as for central venous catheter placement. A high-frequency linear probe is used to identify the desired vein. Similar to traditional intravenous catheter placement, it is helpful to have a tourniquet in place when looking for candidate vessels. The desired vein for cannulation should be identified in cross-section (probe held in the transverse position) and relevant anatomy for the particular site should be reviewed, including proximity to other structures such as arteries and nerves. Compressibility and lack of pulsatile flow should be confirmed. It is important to note that, because of the decreased velocity of blood flow in the smaller veins, there may not be any identifiable color change or Doppler signal when looking with color flow or Doppler. Once the vein is confirmed, catheter placement can proceed as described for central venous cannulation using either the static or dynamic method. Pitfalls Peripheral veins are easily compressible and it is not uncommon for the novice sonographer to apply too much pressure with the ultrasound probe, thereby compressing and obscuring the veins. It is also important to note the depth of a peripheral vein identified on ultrasound prior to attempted cannulation, as standard intravenous catheters will not be long enough to reach the deeper veins of the upper arm. Long catheters are available and should be used in these circumstances.

ABSCESS DRAINAGE Soft tissue infections are seen commonly in the pediatric population. While some abscesses are easily diagnosed based on physical exam findings, others are more ambiguous and may appear to be cellulitis or induration when in fact there is a drainable fluid collection present. Several studies in adult patients have shown that ultrasound is accurate in correctly diagnosing abscesses and can be used to guide the appropriate management of patients in whom physical exam findings cannot differentiate between an indurated cellulitis and a drainable abscess.17,18 In addition, ultrasound can be used to identify structures of importance that may be near the abscess, including vessels and nerves which are considerations for patient safety when planning incision and drainage. Technique Soft tissue ultrasound is performed using a high-frequency linear probe placed over the area of interest. The soft tissue area being evaluated should be scanned in two perpendicular planes to get a sense of the overall size of any drainable collection. Cellulitis will appear as thickening and increased echogenicity of the subcutaneous fat, often with a “cobblestone” appearance (Figure 186-16). Abscess, however, will appear as an ill-defined, hypo- or anechoic mass (Figure 186-17). Color flow should be placed over the area of interest to evaluate for any surrounding vessels (Figure 186-18) and to confirm that there is no internal vascularity as might be seen with an arteriovenous malformation or lymph node.

FIGURE 186-16. Cellulitis. The appearance of inflamed skin on ultrasound with “cobblestone” appearance. (Used with permission of Jason Levy.)

FIGURE 186-17. Pus-filled abscess. (Used with permission of Jason Levy.)

FIGURE 186-18. Color flow. Right carotid artery and internal jugular with color. (Used with permission of Jason Levy.) Pitfalls Lymph nodes, vascular malformations, and hematomas may all have a similar appearance to an abscess on ultrasound. Lymph nodes will appear more homogenous and round with distinct borders (Figure 186-19). In addition, they will often have internal vascularity on color flow unless they are necrotic. Vascular malformations can be distinguished by the presence of internal color flow, which an abscess should lack. A hematoma may also have a similar appearance to an abscess on ultrasound but would be differentiated by a recent history of trauma.

FIGURE 186-19. Lymph node. Lymph nodes have a more rounded appearance on ultrasound. (Used with permission of Jason Levy.)

BLADDER CATHETERIZATION AND SUPRAPUBIC ASPIRATION Urinary bladder catheterization and suprapubic aspiration are bedside procedures performed in children for diagnostic and occasionally therapeutic interventions. Bladder ultrasound is easily performed and can give the practitioner useful information, including the exact location of the bladder and whether or not urine is present prior to attempting urine collection. In addition, ultrasound can be used dynamically to guide needle placement during suprapubic aspiration. Multiple studies have demonstrated that ultrasound use prior to bladder catheterization reduces the number of unsuccessful attempts at the procedure and can be used to predict patients in whom catheterization is likely to be unsuccessful based on bladder size.19,20 Similarly, ultrasound has also been shown to increase the success rate of suprapubic aspirations, limiting the number of failed attempts.21 Technique Bladder ultrasound is performed using either a high-frequency linear probe or a low-frequency abdominal probe. The view is the same as that for the suprapubic (or pelvic) view used in the FAST examination. Starting with the probe held in the transverse orientation (marker toward the patient’s right side), place the probe just superior to the symphysis pubis, angled down toward the patient’s feet. A bladder containing urine will appear

as a well-circumscribed, fluid-filled (anechoic) structure in the midline of the pelvis. Once identified, the bladder should be measured in at least two planes (Figure 186-20). While studies have differed in regard to what measurements define a full bladder, generally urine collection will be successful if the bladder measures more than 2 cm (from wall to wall) in both planes.

FIGURE 186-20. Bladder measured in two different planes. (Used with permission of Jason Levy.) Pitfalls A common mistake is placing the probe too superior on the abdomen/pelvis. Sliding or angling the probe toward the patient’s feet will then often bring the bladder into view. Less commonly, the bladder may be off midline to the right or left. An empty bladder will also be difficult to visualize. In this case, the patient can be given fluids and the ultrasound repeated in 20 to 30 minutes to see if the bladder has filled.

REFERENCES 1. Moore CL, Gregg S, Lambert M. Performance, training, quality assurance, and reimbursement of emergency physician-performed ultrasonography at academic medical centers. JUM. 2004;23(4):459466. 2. Suthers SE, Albrecht R, Foley D, et al. Surgeon-directed ultrasound for trauma is a predictor of intra-abdominal injury in children. Am Surg.

2004;70(2):164-167. 3. Longjohn M, Wan J, Joshi V, Pershad J. Point-of-care echocardiography by pediatric emergency physicians. Pediatr Emerg Care. 2011;27(8):693-696. 4. Sivitz A, Nagdev A. Heart failure secondary to dilated cardiomyopathy: a role for emergency physician bedsideultrasonography. Pediatr Emerg Care. 2012;28(2):163-166. 5. Volpicelli G, Elbarbary M, Blavais M, et al. International Liaison Committee on Lung Ultrasound (ILC-LUS) for International Consensus Conference on Lung Ultrasound (ICC-LUS). International evidence based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012;38(4):577-591. 6. Tsung JW, Kessler DO, Shah VP. Prospective application of clinicianperformed lung ultrasonography during the 2009 H1N1 influenza A pandemic: distinguishing viral from bacterial pneumonia. Crit Ultrasound J. 2012;4(16):1-9. 7. Shah VP, Tunik MG, Tsung JW. Prospective evaluation of point-of-care ultrasonography for the diagnosis of pneumonia in children and young adults. Arch Pediatr Adolesc Med. 2012;107:E1-E7. 8. Caiulo VA, Gargani L, Caiulo S. Lung ultrasound in bronchiolitis: comparison with chest X-ray. Eur J Pediatr. 2011;170:1427-1433. 9. Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis acute respiratory failure: the BLUE protocol. Chest. 2008;134:117-125. 10. Levy JA, Noble VE. Bedside ultrasound in pediatric emergency medicine. Pediatrics. 2008;121(5):e1404-e1412. 11. Rothschild J. Ultrasound guidance of central vein catherterization. Evid Rep Technol Assess (Summ). 2001;43:245-253. 12. Khouloud AS, Julia G, Abdulaziz B, Yves CJ, Sylvain R. Ultrasound guidance for central vascular access in the neonatal and pediatric intensive care unit. Saudi J Anaesth. 2012;6(2):120-124. 13. Di Nardo M, Tomasello C, Pittiruti M, et al. Ultrasound-guided central venous cannulation in infants weighing less than 5 kilograms. J Vasc Access. 2011;12(4):321-324.

14. Lambert RL, Boker JR, Maffei FA. National survey of bedside ultrasound use in pediatric critical care. Pediatr Crit Care Med. 2011;12(6):655-659. 15. Mitre CI, Golea A, Acalovschi I, et al. Ultrasound-guided external jugular vein cannulation for central venous access by inexperienced trainees. Eur J Anaesthesiol. 2010;27(3):300-303. 16. Constantino TG, Parikh AK, Satz WA, et al. Ultrasonography-guided peripheral intravenous access versus traditional approaches in patients with difficult intravenous access. Ann Emerg Med. 2005;46(5):456-461. 17. Squire BT, Fox C, Anderson C. ABSCESS: applied bedside sonography for convenient evaluation of soft tissue infections. Acad Emerg Med. 2005;12(7):601-606. 18. Tayal VS, Hasan N, Norton J, et al. The effect of soft-tissue ultrasound on the management of cellulitis in the emergency department. Acad Emerg Med. 2006;13(4):384-388. 19. Chen L, Hsiao AL, Moore CL, et al. Utility of bedside bladder ultrasound before urethral catheterization in young children. Pediatrics. 2005;115(1):108-111. 20. Munir V, Barnett P, South M. Does the use of volumetric bladder ultrasound improve the success rate of suprapubic aspiration of urine? Pediatr Emerg Care. 2002;18(5):346-349. 21. Milling TJ, Jr, Van Amerongen R, Melville L, et al. Use of ultrasonography to identify infants for whom urinary catheterization will be unsuccessful because of insufficient urine volume: validation of the urinary bladder index. Ann Emerg Med. 2005;45(5):510-513.

CHAPTER

187

Lumbar Puncture Timothy Gibson

Lumbar puncture (LP) is a frequently performed procedure by hospital-based physicians. Although its description may sound frightening to parents or other laypersons, in actuality, it is a fairly simple and straightforward procedure in most patients.

INDICATIONS LP is performed whenever cerebrospinal fluid (CSF) is needed for evaluation.1 The most typical scenario for a pediatric hospitalist is a febrile patient in whom meningitis is a concern, and a majority of such patients are neonates or infants with nonspecific signs and symptoms of meningitis. Other indications include evaluation of suspected central nervous system (CNS) bleeding, measurement of intracranial pressure (ICP), as in pseudotumor cerebri, and investigation of suspected inflammatory conditions of the CNS. In patients with confirmed pseudotumor cerebri, removal of CSF via LP is sometimes done to acutely lower ICP, providing symptom relief and preventing complications that may result from untreated increased ICP.

CONTRAINDICATIONS The practitioner should always consider whether it is safe to perform LP. If a patient has increased ICP, such as from a cerebral mass, release of pressure during LP may potentially precipitate shifting of intracranial contents from an area of high pressure to one of low pressure (i.e. cerebral herniation). If this is at all a possibility, the patient should have CNS imaging performed before a spinal tap is done. The risk is significantly less in infants who have an open fontanelle. The same is true for significant intracranial bleeding. In general, if the patient does not have focal neurologic findings on physical examination

or demonstrate signs or symptoms of increased ICP by history or on physical examination, it is safe to perform LP before imaging. LP is relatively contraindicated in patients with underlying bleeding diatheses to avoid the formation of a hematoma around the spinal column or within the surrounding soft tissues. If this problem is suspected, laboratory studies such as a complete blood count and coagulation studies should be performed before LP is attempted.

ANATOMY CSF is produced in the choroid plexuses of the lateral ventricles. It circulates between the lateral ventricles and around the spinal cord and cerebrum in the subarachnoid space. The goal of LP is to obtain a sample of CSF in the safest possible manner, which is achieved by puncturing the dura mater in the lumbar region, below the termination of the spinal cord itself, where only the cauda equina is found. In young children, the inferior termination of the spinal cord is at the level of L3, and in older children it is even higher. Thus LP can nearly always be performed safely, barring any anatomic anomaly, which is usually obvious, by inserting the spinal needle between the spinous processes of L4 and L5. To locate this interspace, palpate the posterior superior iliac crests; the L4–L5 interspace is located at that level. On the patient’s back you will feel the spinous processes of the vertebrae. When the needle is inserted, it will penetrate the skin and then the supraspinous ligament, the interspinous ligament, and the ligamentum flavum before puncturing the dura mater to enter the subarachnoid space, where CSF is found (Figure 187-1).

FIGURE 187-1. The spinal needle is inserted between the L4 and L5 vertebrae.

EQUIPMENT Virtually all hospitals will have a commercially made LP tray that contains most of the equipment needed to perform LP (Table 187-1). Although these kits all contain local anesthetic, most do not contain topical anesthetic (e.g. EMLA, ELA-Max). One will also need to obtain an appropriately sized spinal needle based on the age or size of the patient (Table 187-2). It should also be noted that some pediatric LP kits have no manometer, so to measure opening pressure, a manometer must be obtained from an adult LP kit. TABLE 187-1

Equipment Needed for Lumbar Puncture

Lumbar puncture tray Spinal needle (see Table 187-2) Sterile collecting tubes Sterile drapes Povidone-iodine (Betadine) swabs or sterile sponges and tray to pour Betadine Gauze

Manometer (may need to be added) Syringe and local anesthetic (1% lidocaine) Sterile gloves Betadine solution Bandage TABLE 187-2

Spinal Needle Size Based on Age

Neonate–2 years

22-gauge, 1½-inch needle

2–12 years

22-gauge, 2½ inch needle

Older than 12 years

20- or 22-gauge, 3½ inch needle

PROCEDURE PREPARATION Before beginning, the practitioner should consider issues of analgesia. If LP is anticipated, the patient should have a topical anesthetic applied widely to the lower lumbar area in the midline. Topical anesthetics take approximately 35 to 50 minutes to take effect, so some foresight is needed. For positioning, the two options are to have the patient either sitting up or lying on the side. In either position, the goal is to get the patient to flex the back while drawing up the legs to maximize the size of the intervertebral space between L4 and L5. Recent studies using ultrasound to evaluate the size of the intervertebral spaces during various positions have shown that flexing the neck does not increase this size, and is associated with more upper airway obstruction in infants being restrained.2 Older patients often prefer to be sitting, but infants are more often positioned on their side. The latter will be discussed because an infant requiring LP will be encountered much more frequently.

TECHNIQUE The patient is usually placed in the lateral decubitus position. Some practitioners prefer to have the patient lying with the patient’s head on the

side of the practitioner’s dominant hand and the feet to their non-dominant side. Others prefer the patient’s head to the side of the practitioner’s nondominant hand. An important factor in determining the eventual success of LP is the skill of the person who restrains the patient. The holder should flex the spine by simultaneously holding the infant’s shoulders and flexing the hips, pulling the knees to the chest while keeping the patient as still as possible. It is also important that the holder keep the back vertical, with an imaginary line between the posterior superior iliac crests lying perpendicular to the table. Open the LP tray in sterile fashion and place it close by so that you can reach the tray with one hand during the procedure. The kit also has only one spinal needle. Not only should one make sure that it is an appropriate size, but it is also a good idea to have one or two extra needles on the tray in case they are needed. Once the patient is positioned, put on sterile gloves and use gauze or a swab stick soaked with povidone-iodine (Betadine) to sterilize the area, starting at the desired entry site and moving out in a circular fashion, sterilizing most of the lumbosacral area. Place a fenestrated drape over the patient such that only this sterilized area is visible. The drape is large enough in an infant to cover the posterior superior iliac spines and will be sterile; thus one is able to palpate the spines and locate the L4–L5 interspace simultaneously. The L3–L4 interspace is also acceptable. When the space is located, draw up 1 to 2 mL of lidocaine, which is included in the kit. With the use of topical anesthetics, the skin in the area should be blanched and anesthetized. After topical anesthesia, create a wheal with injectable lidocaine just below the skin, and proceed as deep into the intervertebral space as the thin ⅝-inch needle will allow. Aspirate back to be sure that there is not blood or CSF return. Then, pull the needle out slowly while injecting the lidocaine as you go. Once the lidocaine is administered, you are ready to insert the spinal needle, again making sure that it is the appropriate size. It should be noted that the larger the gauge of the needle, the more likely the patient will have a “spinal headache” because of CSF leakage after the procedure (see Complications). If the child’s head is to the same side as your dominant hand, place your non-dominant thumb over the lower of the spinous processes that you have chosen (i.e. L5 for the L4–L5 interspace). With your thumb on the spinous process, the rest of your left hand can still be on the posterior superior iliac crest, both to ensure landmarks and also to assist in stabilization of the patient. While holding the spinal needle with your dominant thumb and first finger close to its end, insert it, bevel up, through

the skin pointing toward the umbilicus (slightly cephalad). Use your nondominant thumb as a fulcrum to steady the needle as you insert it. Some practitioners find it easier to have the patient’s head to the side of their nondominant hand. With this technique, the natural extension of your dominant arm tends to direct the needle in a slightly cephalad direction as you insert it. If using this technique, the fingers of your non-dominant hand can rest on the iliac crest to ensure landmarks and help to steady the patient. The practitioner’s non-dominant thumb should then palpate the more cephalad spinous process of the interspace that you are using (e.g. L4 for the L4–L5 interspace). The needle is slowly inserted in a slightly cephalad direction using the thumb over the spinous process as a fulcrum. If there is immediate bony resistance, you are probably in contact with the spinous process, so pull the needle back and redirect it, most commonly more cephalad. Once you are past the superficial bony structures, insert the needle slowly. If you think that you may be in the subarachnoid space, remove the stylet and watch for CSF flow. Experienced practitioners may feel a “pop” as they penetrate the dura mater to enter the subarachnoid space. If there is no flow of CSF, it may help to rotate the needle 90 degrees. If there is still no flow of CSF, reinsert the stylet and advance the needle a few millimeters further. Literature has shown that removing the stylet after completely penetrating the skin and advancing the spinal needle without the stylet leads to higher success rates, but there is concern that it may be associated with a higher incidence of intraspinal epidermoid tumors, presumably from introduction of dermis and epidermis into the spinal canal.3 The slow advancement of the needle is performed repeatedly until flow of CSF is obtained. If blood flows from the needle, the venous plexus just outside the epidural space (see Figure 187-1) may have been punctured, a so-called traumatic tap. Blood from a traumatic tap will clot, as opposed to bloody CSF, which will not. In addition, blood from a traumatic tap will gradually lessen as flow occurs, whereas bloody CSF will be homogeneous. If you are convinced the fluid is blood and not CSF, remove the needle completely and make another attempt in a different interspace. Once CSF flow has begun, opening pressure can be measured by attaching a manometer. This apparatus is a bit clumsy, and attaching it often requires the help of an assistant. The patient must be still and not struggling, to obtain an accurate reading, which is often impossible in infants. The patient’s legs must also be fully extended. Either way, once flow begins,

collect specimens in the sterile tubes included in the kit, 1 mL per tube. Tube 1 is sent for culture, Gram stain, and bacterial antigen detection; tube 2 is sent for protein and glucose; and tube 3 is sent for cell counts. It is good practice to draw off a fourth tube and have the laboratory store it in case other studies are desired later. If the LP was performed for increased intracranial pressure, more CSF can be drained off as therapy. The amount should be guided by frequent measurements of ICP using the LP kit manometer. As above, since this requires a cooperative patient, sedation is often required. Once the desired amount of CSF is removed, reinsert the stylet and remove the needle in one quick movement. Apply a bandage and make sure that any excess Betadine is wiped off the patient.

COMPLICATIONS There is always the risk of bleeding or infection when performing an LP, and this possibility should be discussed with the family in advance. The risk of herniation was discussed earlier. In small infants, respiratory compromise can occur, but more as a result of positioning and restraint than the LP itself. In general, young patients should be on a monitor while being tightly held. In the adult or older adolescent population, up to 30% will experience headache after LP.4 This is thought to be due to a small leak of CSF through the puncture in the dura. These headaches usually respond to analgesics and fluids. Caffeine may also be effective. For a prolonged headache, an epidural blood patch can be applied to stop the leak, but this is not generally necessary. Hematomas in the subdural or epidural space are reported but are rare. If the patient has neurologic deficits after LP, traumatic bleeding must be ruled out. Finally, as noted above, there is a risk of pushing superficial dermal material into the subarachnoid space during LP. This can generally be avoided by having the stylet in the needle whenever it is advanced and when it is removed.

SPECIAL CONSIDERATIONS In patients who have had unsuccessful attempts at LP because of body habitus, anatomic abnormality, an inability to obtain CSF, or a “traumatic tap,” several radiologic modalities are available to assist the hospitalist. Fluoroscopy allows the radiologist, via serial spine x-rays while the needle is

gradually inserted, to visualize penetration through the appropriate interspinal space, and can suggest that the needle is in the subarachnoid space. CT gives greater detail but is associated with higher levels of radiation exposure. Ultrasound can visualize the anatomy of the spine in real time and is not associated with radiation exposure.5 If there was a previous traumatic tap, ultrasound can also delineate the presence and extent of any epidural hematoma, and guide subsequent attempts away from the affected interspaces. Lastly, many pediatric tertiary care centers have pediatric neurosurgeons who can be an invaluable consulting resource for difficult lumbar punctures.

REFERENCES 1. Cronan K, Wiley J. Lumbar puncture. In: Henretig F, King C, eds. Textbook of Pediatric Emergency Procedures. Baltimore: Williams & Wilkins; 2008:505-514. 2. Abo A, Chen L, Johnston P, Santucci K. Positioning for lumbar puncture in children evaluated by bedside ultrasound. Pediatrics. 2010;125(5):e1149-1153. 3. Per H, Kumanda S, Gumus H, et al. Iatrogenic epidermoid tumor: late complication of lumbar puncture. J Child Neurol. 2007;22(3):332-336. 4. Janssens E, Aerssens P, Alliet P, et al. Post-dural puncture headache in children. A literature review. Eur J Pediatr. 2003;162:117-121. 5. Nomura JT, Leech SJ, Shenbagamurthi S, Sierzenski PR, O’Connor RE, Bollinger M, Humphrey M, Gukhool JA. A randomized controlled trial of ultrasound-assisted lumbar puncture. J Ultrasound Medicine. 2007;26(10):1341-1348.

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188

Cerebrospinal Fluid Shunt Assessment Christine S. Cho and Jill C. Posner

BACKGROUND Cerebrospinal fluid (CSF) shunt systems are used to treat hydrocephalus by draining excess CSF to an alternative location in the body. A shunt has three segments: a proximal catheter, a valve and reservoir or reservoirs, and a distal catheter. The proximal catheter is commonly placed in a ventricle of the brain, but it may also be placed in a cyst. The valve of the shunt system controls the drainage of CSF. Some examples of valve mechanisms include regulation by differential pressure, siphon resistance (which prevents overdrainage in the upright position), flow regulation (in which different flow rates change the regulation mechanism), and external adjustment. Shunt systems often have one or two reservoirs (sometimes referred to as bubbles) that can be either part of or separate from the valve. CSF can be accessed from the reservoir to help diagnose shunt infection or malfunction. The distal catheter is commonly inserted into the peritoneal cavity, but it can also be placed in the right atrium, pleural cavity, and rarely, the gallbladder or ureters.

INDICATIONS Evaluation of a CSF shunt is indicated when the clinical history and physical examination suggest the diagnosis of shunt malfunction or shunt infection, or both. Because the symptoms of shunt malfunction may be subtle or nonspecific, the clinician should always keep malfunction in the differential when evaluating a child with a CSF shunt. In infants and preverbal children, the symptoms (Table 188-1) may be difficult to differentiate from those of other diseases. The parental history is valuable for giving the practitioner an understanding of the patient’s baseline as well as perspective on how shunt

malfunction normally manifests in the child. TABLE 188-1

Symptoms of Shunt Malfunction

Headache Change in vision Nausea Vomiting Behavioral or personality change Sleepiness Irritability Change in mental status Abnormal gait Seizures Shunt infection is most common in the first few months after placement or revision of a shunt. CSF shunts that end in the peritoneal cavity can also become infected from a primary abdominal infection. Symptoms of shunt infection include those of shunt malfunction as well as fever and erythema or edema of the skin along the shunt site. Please see Chapter 107 for further discussion of device-related infections.

CONTRAINDICATIONS There are no contraindications to evaluation of a CSF shunt.

PROCEDURE The majority of CSF shunt assessment is done through the history, physical examination, and radiologic studies. The history should include an assessment of the type and location of the shunt and its reservoir or reservoirs. Common signs on physical examination that suggest shunt malfunction are listed in Table 188-2. The shunt can also be evaluated by pumping the reservoir (Table 188-3). This procedure should be interpreted cautiously because it is not a sensitive method of detecting shunt

malfunction. Pumping the shunt may also be associated with entrapment of tissue in the proximal catheter so should only be done after consulting a pediatric neurosurgeon. TABLE 188-2

Physical Examination Findings in Patients with Shunt Malfunction

Sleepiness or lethargy Hypotonia Macrocephaly Split sutures Bulging fontanelle Sunsetting Sixth cranial nerve palsy Papilledema (late finding) Decreased visual acuity Palpable kinks, fluid collections, or disconnections along the shunt Abdominal mass or tenderness (suggesting distal CSF fluid collection that impedes resorption) TABLE 188-3

Manual Assessment of Ventriculoperitoneal Shunt Function

Distal Obstruction

Proximal Obstruction

Single Resistance felt when reservoir pressure is applied to the reservoir bubble

Delayed filling of reservoir when pressure is released after compression of this reservoir*

Double Resistance felt when reservoir pressure is applied to the distal reservoir bubble

Delayed filling of proximal reservoir when pressure is released while still holding down the distal reservoir*

*Delayed filling would also occur when the ventricle is well drained and therefore cerebrospinal fluid would not be flowing into the shunt.

To pump a single-reservoir shunt, compress the reservoir bubble and note the refilling time. Difficulty in compression of the bubble suggests distal obstruction, whereas delay of more than 1 second in refilling suggests proximal obstruction. In a double-reservoir shunt, first compress and hold the proximal bubble and then compress the distal bubble. Difficulty compressing the distal reservoir suggests distal shunt obstruction. Then release the proximal bubble while holding pressure on the distal one. Sluggish refilling of the proximal reservoir suggests proximal obstruction. If the patient is clinically stable, radiologic studies are useful adjuncts to the clinical history and physical examination in diagnosing shunt malfunction. Brain imaging is the mainstay of this evaluation. A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the head will evaluate ventricular size. To assess whether the ventricles are enlarged, compare them with a previous baseline CT or MRI. When CT is used, attempts to minimize radiation exposure based on specific imaging protocols should be undertaken. Specific imaging protocols have been developed to specifically look for ventricular size in these patients who often undergo repetitive imaging. A shunt series is a series of radiographs that follow the course of the shunt from the skull to its distal end. The tubing is visualized by these radiographs and inspected for disconnection or kinks. This has traditionally been used in the evaluation of possible shunt malfunctions. Some neurosurgeons now feel that this series of radiographs adds little to the evaluation of possible shunt malfunction, especially when a scout view obtained as part of CT or MRI imaging of the head may show the majority of the shunt course and may be used to look for catheter interruptions. Rarely, shunt systems can be evaluated with radionuclide studies. Radioactive material is injected and followed as it flows through the shunt system. After these initial steps in the assessment of CSF shunt systems, if necessary, the shunt can be punctured to measure pressure and obtain a sample of CSF for laboratory testing (see below).

COMPLICATIONS

Pumping the reservoir may cause obstruction of the shunt by trapping choroid plexus or debris in the shunt tubing. Failure to recognize the signs and symptoms of shunt malfunction may lead to progressive deterioration of a patient’s clinical status. Patients with signs of impending herniation need immediate intervention.

SPECIAL CONSIDERATIONS Slit-ventricle syndrome may decrease the utility of CT in evaluating shunt malfunction. Because of chronic overdrainage, these patients will have normal or small ventricles despite shunt malfunction.

CEREBROSPINAL FLUID SHUNT PUNCTURE The first steps in evaluating the function of a CSF shunt are a careful history, physical examination, and radiologic evaluation of the shunt system. Shunt infection and malfunction can also be assessed by puncture of the shunt reservoir with a needle to measure pressure and obtain CSF for laboratory testing. Discussion with a pediatric neurosurgeon should always be held before puncture of the shunt reservoir.

INDICATIONS Indications for CSF shunt puncture include (1) direct measurement of CSF pressure, (2) drainage of excess CSF, (3) obtaining a sample of CSF for laboratory evaluation, and (4) infusion of antibiotic or chemotherapeutic drugs. Obtaining CSF is especially useful when a culture is needed to evaluate for shunt infection.

CONTRAINDICATIONS Infection of the skin overlying the reservoir is a contraindication to CSF shunt puncture.

PROCEDURE

1. Assemble the equipment (Table 188-4). 2. Identify the type of shunt, location of the reservoir or reservoirs, and preferred tapping site. Shunt reservoirs may be located on the ventricular catheter, on the valve, or both. 3. If necessary, cut the hair over the area of the reservoir to be tapped. 4. Prepare the skin over the reservoir with povidone–iodine solution. 5. Wash your hands and put on a mask, sterile gown, and sterile gloves. 6. Lay sterile drapes to create a sterile field in which to perform the puncture. 7. Puncture the reservoir with the butterfly needle. Dome-shaped bubble reservoirs should be punctured at approximately a 45-degree angle to the skin. Reservoirs on the ventricular catheter should be punctured at a 90degree angle to the skin. 8. Hold the butterfly tubing perpendicular to the floor at the level of the ear. The pressure in cm H2O is the height of the CSF fluid column in the tubing. Alternatively, a manometer can also be attached. 9. Observe the flow of CSF and whether it is absent, slow, or fast. 10. Brisk flow and/or high opening pressure indicates distal obstruction. Slow or absent flow and/or decreased opening pressure indicates proximal obstruction in the setting of dilated ventricles on computed tomography. 11. Remove fluid into sterile tubes for culture and laboratory assessment. 12. If needed, continue to drain CSF by using the measured pressure as a guide. 13. Remove the butterfly needle and apply dressing.

COMPLICATIONS Puncture of a CSF shunt can cause local infection of the skin or introduce infection into CSF. Complications also include bleeding, hematoma, CSF leakage at the site of puncture, and possible damage to the reservoir or valve, or both. TABLE 188-4

Equipment for CSF Shunt Puncture

Scissors Povidone–iodine solution Sterile gloves

Sterile gown Mask Sterile drapes or towels Butterfly needle (23 or 25 gauge) Pressure manometer (optional) Syringe Sterile tubes for CSF Sterile dressing

SPECIAL CONSIDERATIONS No special considerations need be taken with CSF shunt puncture.

SUGGESTED READINGS Albright AL, Pollack IF, Adelson PD. Principles and Practice of Pediatric Neurosurgery. New York: Thieme; 1999. Raimondi AJ. Pediatric Neurosurgery. Theoretical Principles–Art of Surgical Technique. 2nd ed. New York: Springer; 1998.

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189

Bladder Catheterization Sandra Schwab

BACKGROUND Urinary bladder catheterization in children can serve as both a diagnostic and a therapeutic intervention. Catheterization is a simple, sterile procedure that can be performed at the bedside in most circumstances. Ease of performing procedure, ability of nursing to catheterize, and decreased pain are some reasons catheterization has largely replaced suprapubic aspiration as the primary method of urine collection in young children.1 Children usually tolerate the procedure well when it is done carefully, requiring only a topical anesthetic, if any.2,3

INDICATIONS The most common indication for urinary bladder catheterization is collection of urine for analysis and culture. A catheter specimen is recommended to rule out urinary tract infection in those children who are not yet toilet trained or who are unable to cooperate with a midstream clean-catch specimen. Catheterization is also indicated to relieve urinary retention or obstruction. This may be due to anatomic abnormalities such as posterior urethral valves or prolapsing ureterocele, inflammation of the urethra, or mechanical obstruction related to blood clots or debris in the bladder. Neurogenic bladder may also cause retention requiring catheterization. In critically ill patients, urinary catheterization is used to monitor urine output and assess fluid status.

CONTRAINDICATIONS Few contraindications exist for urinary catheterization. A general practitioner

should not catheterize patients with known urethral trauma or acute pelvic fracture. Careful consideration should be given to catheterization in patients with recent genitourinary surgery or known genital abnormality such as hypospadias. Consultation with a urologist is recommended before placing a catheter in any of these patients.

ANATOMY A catheter is placed into the bladder via the urethral meatus. In males, the meatus is located in the center of the glans of the penis. If the patient is uncircumcised, the foreskin may need to be gently retracted to expose the urethra. In females, the urethra is located between the clitoris and the vaginal introitus. The labia majora and minora obscure the urethra in most patients and will need to be spread in order to visualize the meatus (Figure 189-1).

FIGURE 189-1. Transurethral bladder catheterization; anatomy and position in the female. (Reproduced with permission from Dieckmann RA, Fiser DH, Selbst SM, eds. Illustrated Textbook of Pediatric Emergency and Critical Care Procedures. St Louis: Mosby; 1997:415. Copyright © Elsevier.)

EQUIPMENT Catheters come in many shapes and sizes; common sizes are listed in Table 189-1. The two most common catheters used in children are a straight catheter and a self-retaining Foley catheter. A straight catheter is used for one-time or intermittent catheterization. If long-term catheterization is anticipated, a Foley catheter is appropriate. Choose the smallest lumen

possible to pass the catheter easily and accomplish the goals of catheterization. In a newborn or infant, a 5-French feeding tube can be used if an 8-French catheter is too large. Table 189-2 lists the other supplies needed to perform a bladder catheterization. TABLE 189-1

Catheter Sizes

Age

Size (French)

Newborn

8

Young child

10

Adolescent

12

Adult

16

TABLE 189-2

Catheterization Supplies

Sterile cleansing solution (iodine, povidone–iodine [Betadine]) Sterile drapes Sterile gloves Lubricant Catheter Syringe Sterile water Collection device 2% Lidocaine hydrochloride jelly (optional)

PROCEDURE PREPARATION Position the patient supine, and restrain as necessary for age. Sterile technique should be maintained throughout the procedure. If using a Foley catheter, test the balloon for competency by filling it with sterile water, then

empty it. Place sterile drapes around the penis or perineum. Using the nondominant hand, retract the foreskin and grasp the penis or spread the labia to expose the urethral meatus. Cleanse the urethral opening and surrounding tissue with sterile or antiseptic solution.4 If desired, slowly inject viscous lidocaine into the urethral opening.

TECHNIQUE Extend the penile shaft so that it is perpendicular to the abdomen in order to straighten the urethra in males (Figure 189-2). After lubricating the tip, slowly advance the catheter into the bladder. Resistance in males is frequently the result of volitional constriction of the external sphincter and can usually be overcome with firm, steady pressure. Advance a Foley catheter its entire length into the bladder. Stop advancing a straight catheter once urine is obtained. Urine should flow easily into the collection container. If no urine is obtained, consider irrigating the catheter with sterile water to confirm urine return. In females, absence of urine return may indicate misplacement into the vagina. If the catheter is removed and additional attempts are necessary to obtain urine, consider using a new, sterile catheter to reduce contamination.5 Once the Foley catheter is advanced its entire length, inflate the balloon with sterile water, and pull the catheter back until resistance is met, indicating that the balloon is at the bladder neck. If using a straight catheter, remove the catheter after the bladder is emptied. If the patient is an uncircumcised male, be sure to replace the foreskin to its original position. If a Foley catheter is to be left in place, secure the catheter by taping it to the child’s leg.

FIGURE 189-2. Transurethral bladder catheterization; position in the male. (Reproduced with permission from Dieckmann RA, Fiser DH, Selbst SM, eds. Illustrated Textbook of Pediatric Emergency and Critical Care Procedures. St Louis: Mosby; 1997:415. Copyright © Elsevier.)

COMPLICATIONS If continued resistance is met while attempting catheterization, stop. Potential complications of catheterization include localized trauma, creation of a false passage, and future stricture formation. Other rare complications include urinary retention, bladder perforation, knotting of the catheter while in the bladder, and introduction of bacteria with resultant infection.

REFERENCES 1. Krozer E, Rosenbloom E, Goldman D, Lavy G, Rosenfeld N, Goldman M. Pain in infants who are younger than 2 months during suprapubic aspiration and transurethral bladder catheterization: a randomized, controlled study. Pediatrics. 2006;118:e51-e56. 2. Vaughan M, Paton EA, Bush A, Pershad J. Does lidocaine gel alleviate the pain of bladder catheterization in young children? a randomized controlled trial. Pediatrics. 2005;116(4):917.

3. Gerard LL, Cooper CS, Duethman KS, et al. Effectiveness of lidocaine lubricant for discomfort during pediatric urethral catheterization. J Urol. 2003;170:564-567. 4. Al-Farsi S, Oliva M, Davidson R, Richardson SE, Ratnapalan S. Periurethral cleaning prior to urinary catheterization in children: sterile water versus 10% povidone-iodine. Clin Pediatr. 2009;48(6):656. 5. Wingerter S, Bachur R. Risk factors for contamination of catheterized urine specimens in febrile children. Pediatr Emerg Care. 2011;27(1):1.

CHAPTER

190

Arterial Blood Gas Esther Maria Sampayo and Mirna M’farrej

BACKGROUND Arterial puncture or arterial blood gas sampling is a necessary procedure in the evaluation of any critically ill patient, especially those with significant respiratory distress or compromise. The ability to measure (and interpret) pH, PCO2, and PO2 in these patients is an essential skill for the pediatric hospitalist. Although the procedure itself is similar to venipuncture or phlebotomy, there are significant potential complications that all people who perform the procedure must be aware of.

INDICATIONS Arterial puncture is performed for limited sampling and is a routine procedure in the management of critically ill and injured children.1 Arterial blood gas sampling provides information about lung ventilation through the interpretation of PCO2 and information about tissue oxygenation through the interpretation of PO2 for patients with respiratory distress and/or cardiovascular compromise, and is often needed to clarify abnormal capnography or pulse oximetry readings. Quantification of the levels of dyshemoglobins such as carboxyhemoglobin and methemoglobin may be obtained as well. Acid–base problems are associated with a number of diseases, such as diabetic ketoacidosis, shock, severe dehydration, metabolic diseases, and certain toxic ingestions. These conditions are often diagnosed by, or treatment decisions are based on, the interpretation of arterial pH, PCO2, and bicarbonate (HCO3) levels.

CONTRAINDICATIONS Collateral circulation of the hand must be assessed when attempting radial artery puncture or catheterization. The Allen test is a simple procedure that has demonstrated consistent and valid results in the assessment of collateral blood flow to the hand.2,3 It is performed by placing pressure to occlude the radial and ulnar arteries simultaneously for 20 seconds at the wrist. During that time, the patient’s hand is elevated above the level of the heart while making a tight fist. The clenched fist is released, and one observes the hand become pale from decreased circulation. After the hand blanches white, one releases pressure over the ulnar artery while retaining pressure over the radial artery. If the patient has adequate collateral circulation, the hand should flush or become pink again as a sign of restored circulation within 5 to 7 seconds. Arterial puncture should not be attempted at that site if return of perfusion takes longer, indicating inadequate collateral circulation. In a young, difficult, or unconscious patient, a modified Allen test can be performed (Figure 1901).

FIGURE 190-1. Modified Allen test. (A) Close the child’s hand with firm pressure while simultaneously occluding the ipsilateral radial and ulnar arteries with the index finger and thumb of the opposite hand. (B) After a few seconds to allow an adequate reduction of blood volume in the hand, release the hand while maintaining point pressure on the radial and ulnar arteries. When this maneuver is performed properly, this hand should appear paler than the other one. (C) Release the pressure applied to the ulnar artery while maintaining point pressure on the radial artery. Reperfusion of the entire hand should occur within a few seconds if sufficient collateral circulation is present. (Reproduced with permission from Dieckmann RA, Fiser DH,

Selbst SM, eds. Illustrated Textbook of Pediatric Emergency and Critical Care Procedures. St Louis: Mosby; 1997:166. Copyright © Elsevier.) Extra precautions should be taken when performing arterial blood sampling on patients receiving anticoagulants or those with bleeding disorders. Arterial access should be avoided when the patient has an infection or burn of the overlying skin puncture site.

EQUIPMENT Although prepackaged arterial puncture kits are commercially available, only minimal equipment is needed: Butterfly or regular needle (25 gauge for newborns, 23 gauge for older infants or young children) Heparinized syringe that can be sealed air-tight Iodophor or other antiseptic solution to prepare the puncture site Sterile drapes and gauze Sterile gloves Arm board and tape Local or topical anesthetic (in an awake or conscious patient) Transillumination or bedside ultrasound can be used to locate the artery One should place an arterial catheter if it is determined that frequent arterial blood gas sampling will be required during the patient’s care.4

ANATOMY Arterial blood gas samples can be obtained from a number of sites, including the following: Radial artery at the wrist—the most popular site for arterial blood sampling because of its easy accessibility, superficial location, and availability of collateral circulation. Brachial artery at the antecubital fossa, right above the crease and just medial to the biceps tendon.

Dorsalis pedis artery on the dorsal aspect of the midfoot between the extensor hallucis and extensor digitorum longus while the foot is in plantar flexion. Posterior tibial artery at the foot between the medial malleolus and the calcaneal tendon while the foot is in dorsiflexion. Femoral artery below the midpoint of the inguinal ligament. This site should be used only as a last resort in emergent situations because of the increased risk of side effects. Umbilical artery in the neonate can be accessed for hours to days after delivery.

PROCEDURE Radial artery puncture: Hold the wrist in extension 30 to 45 degrees, or affix the extended joint to an arm board with tape. Do not overextend the wrist, because this may occlude the pulse. The point of maximal impulse of the radial artery can be palpated on the palmar aspect of the wrist at the second transverse wrist crease proximal to the hand. Perform the Allen test for ulnar collateral flow to assess if the radial artery can be punctured.4 Prepare the area in a sterile fashion. Slightly anchor the artery with the index and middle fingers of the nondominant hand to prevent rolling. Local anesthesia is optional and can be achieved with topical cream anesthetic or local infiltration of 1% lidocaine, avoiding infusion into the vessel. Hold the 23- to 25-gauge butterfly needle or prepackaged heparinized syringe with the dominant hand like a pencil or a dart, with the bevel of the needle upward. Holding the needle at about a 30- to 45-degree angle, puncture the skin just distal to where the index finger is palpating the radial pulsation, aiming away from the hand. Slowly advance the needle until there is a pulsating flash of blood in the hub of the needle, indicating arterial rather than venous access. Hold the needle and syringe in that position, allowing the syringe to fill with blood either passively or with aspiration to the amount desired. If no blood return occurs before meeting bony resistance, the needle should be slowly withdrawn in order to reenter the arterial lumen. When finished, remove the needle and immediately apply firm pressure at the puncture site for at least 5 minutes. Remove the needle, and expel any air bubbles in the upright syringe by tapping the bubbles to the top. Seal the syringe with the cap provided. Deposit the syringe in a bag of ice, and send it to the laboratory immediately.

COMPLICATIONS The most significant potential complication of arterial puncture is permanent damage to the artery that interferes with the arterial supply to the distal aspect of the extremity. This is especially serious in patients who have absent or reduced collateral circulation. Damage can result from sheering of the intima, thrombus of the lumen, pseudoaneurysm formation, or arteriovenous fistula.5,6 These complications are more commonly seen as a result of catheter placement or repetitive punctures. A more common complication is hematoma formation, which can be quite significant after arterial puncture and can be reduced with the proper application of direct pressure. To reduce infection, one should always employ sterile technique and avoid using sites with overlying cellulitis. A number of potential errors can also occur owing to the transport or timing of the blood gas sample or to the patient’s underlying condition (Table 190-1).7 TABLE 190-1

Blood Gas Sampling Errors

Air or air bubbles in the syringe: equilibration between blood and air causes PO2 to be altered and PCO2 to decrease Delay in icing or analyzing blood gas sample: allows for metabolism, causing a decrease in PO2 and pH and an increase in PCO2 Venous or venous admixture sample: correlates with clinical presentation and oxygen saturation as measured by pulse oximetry (SpO2) Alterations in temperature (< or >37°C): Fever: PO2 and PCO2 are increased and pH decreased Hypothermia: PO2 and PCO2 are decreased and pH increased Excess heparin in syringe: dilutional acidic effect causes alterations in PO2, PCO2, and pH Leukocytosis and thrombocytosis may elevate PCO2 and lower pH

REFERENCES 1. Saladino R, Bachman D, Fleisher G. Arterial access in the pediatric emergency department. Ann Emerg Med. 1990;19:382-385. 2. Hosokawa K, Hata Y, Yano K, et al. Results of Allen test on 2940 arms. Ann Plast Surg. 1990;24:149-151. 3. Cable DG, Mullany CJ, Schaff HV. The Allen test. Ann Thoracic Surg. 1999;67:876-877. 4. Henretig FM, King C. Arterial puncture and catheterization. In: Henretig FM, King C eds. Textbook of Pediatric Emergency Procedures. Baltimore: Williams & Wilkins; 2008:715-725. 5. Kim D, Orron DE, Skillman JJ, et al. Role of superficial femoral artery puncture in the development of pseudoaneurysm and arteriovenous fistula complicating percutaneous transfemoral cardiac catheterization. Cathet Cardiovasc Diagn. 1992;25:91-97. 6. Brown MM. Another complication of arterial cannulation. Anesthesia. 1991;46:326. 7. Bageant RA. Variations in arterial blood gas measurements due to sampling techniques. Respir Care. 1975;20:565.

CHAPTER

191

Vascular Access Frances M. Nadel, Suzanne Beno, and Anne Marie Frey

BACKGROUND Many pediatric patients will need some form of vascular access during their initial evaluation or hospitalization. The child’s severity of illness or injury, type of infusion needed, duration of therapy, and skill of the provider will often determine the type of line selected. Ultrasound-guided vascular access is an important advance in safety and efficacy and is discussed in a separate chapter. This chapter reviews the insertion and monitoring needed for peripheral intravenous access, central venous access, and peripherallyinserted central catheters (PICC lines).

PERIPHERAL INTRAVENOUS ACCESS Even at hospitals with a team dedicated to placing intravenous lines, the hospitalist may be called upon to obtain peripheral intravenous (PIV) access, especially when others have been unsuccessful.

INDICATIONS PIV access is obtained to administer medications, fluids, or blood products. It may also be used for frequent phlebotomy draws. A line may be placed at the same time as obtaining a blood sample “just in case” the lab results should require IV access.

CONTRAINDICATIONS Avoid areas distal to a fracture, as there may be vascular disruption, and it

may be difficult to assess for swelling associated with extravasated IV fluids or medications. When possible, avoid areas with edema, burns or cellulitis, or abnormal skin integrity. A vein that has been scarred from frequent use may be difficult to access.

ANATOMY Common IV sites include veins in the dorsum of the hand, the forearm, and the antecubital fossa. The cephalic vein that courses over the distal radius is a reliable site that is often overlooked and is affixed firmly to the underlying fascia. If the upper extremity is being used, the nondominant hand is preferable. Figure 191-1 shows common sites for placement of an IV catheter in the upper extremity. In infants, the lower extremities (i.e. feet) or the scalp can be considered as sites for IV placement. The saphenous vein is predictably located anterior to the medial malleolus and so can be accessed blindly. In general, attempt access distally first, in case additional attempts are required in the proximal extremities. The external jugular access site may be difficult to obtain as well as secure, and should be done by experienced personnel only.

FIGURE 191-1. Venous anatomy of the upper extremity.

EQUIPMENT Table 191-1 lists the equipment needed to place an IV line. It is important to have everything assembled and easily available before starting the procedure. In children, IV access often requires a second health care provider to help restrain the child properly. Most hospitals use over-the-needle catheters that include a safety, self-sheathing device. Use the largest bore and shortest catheter possible when rapid administration of medication, fluids, or blood is needed. A 24- or 22-gauge catheter is usually suitable for infants and young children and 18-, 20-, or 22-gauge catheters are used for older children. TABLE 191-1

Equipment Needed for Placement of an Intravenous Line

Appropriate-sized angiocatheter Skin cleanser (e.g. 70% ethyl alcohol, povidone–iodine, chlorhexidine) Tourniquet (or rubber bands if placing a scalp IV line) T-connectors and needleless port Normal saline flush and 3- or 5-mL syringe Tape, transparent dressing, arm board, and other devices to secure catheter in place Additional 3- or 5-mL syringes if blood is being drawn simultaneously or vacutainer blood transfer device to use with specimen tubes Gauze Gloves, nonsterile Topical anesthetic—cream or spray (optional) Topical antibiotic cream (optional) Laboratory specimen tubes when applicable

PROCEDURE Setup and Preparation Most children consider needle sticks the most distressing and painful part of their hospital care. When time is available, it is

important to prepare the family and child for the procedure honestly and in age-appropriate terms. The families of children who frequently undergo IV access may have helpful hints toward success. Parents, guardians, and child life specialists can provide comfort and distraction during the procedure. Methods to Anesthetize the Skin When time permits, there are many topical anesthetic preparations that can be used in conjunction with nonpharmacological methods to reduce the pain and distress of IV insertion. These anesthetics are applied directly to the potential IV site(s). Onset of numbness varies between products, and may take up to 30 to 60 minutes to work. A small bleb of lidocaine buffered with sodium bicarbonate in a 9-to-1 ratio can be superficially injected over the vein for more immediate anesthesia, but it may obscure visualization and palpation of the vein. Technique procedure.

Universal precautions should be used during the entire

1. Identify possible sites. Hand-held illuminators may assist in direct visualization of a vein. 2. If time permits, apply a topical anesthetic to numb the site. 3. Hot packs, tapping the vein, placing the extremity in a dependent position, or having the child open and close their hand may help with vasodilation and identification. 4. Prepare your equipment: a. Cut tape and occlusive dressing. b. Have any blood sampling tubes ready. c. Hook the extension tubing to the needleless access port. If no blood is being drawn, flush the tubing/port with saline. 5. Apply a tourniquet proximal to the site. Make sure not to make it so tight that it impedes arterial flow. 6. Don gloves and apply the antiseptic in a circular fashion, allowing it to dry the required time before attempting access. 7. Have an assistant restrain the limb proximally. 8. With the bevel of the catheter facing up, puncture the skin at a 30- to 45degree angle and slowly advance the needle until you see flashback of blood in the needle hub (Figure 191-2). 9. Advance the needle/catheter only slightly more to make sure the catheter is in the vein (Figure 191-3).

10. Tilt the needle parallel to the skin, advance the plastic portion, and activate the self-sheathing needle system (Figure 191-4). 11. Place your finger proximal to the catheter tip to staunch blood flow. 12. Connect your port/tubing to the catheter. 13. Clean and dry the area. A tincture of a topical antiseptic cream may be applied as well. 14. Secure the catheter in place using tape and/or transparent occlusive dressing (Figure 191-5). 15. To collect blood samples, attach an empty syringe or vacutainer to the extension tubing. 16. Remove the tourniquet and flush with saline. 17. Further secure the line by attaching an arm board to the extremity. Use of a soft circumferential arm restraint to further prevent IV dislodgement may be helpful in young children. Common Problems

FIGURE 191-2. The needle punctures the vein before the catheter.

FIGURE 191-3. Advance the needle and catheter into the vein.

FIGURE 191-4. Withdraw the needle, leaving the catheter in place intravenously.

FIGURE 191-5. Occlusive adherent dressing with transparent tape in chevron configuration. 1. If there is no blood flow after an initial flashback, loosen the tourniquet, remove the metal stylet, and flush a small amount of saline. If it flushes easily without swelling subcutaneously you can continue to advance the catheter slowly into the vessel. 2. Once the metal stylet has been removed, it should not be reinserted into the catheter, as it may cause catheter shearing. 3. If the IV stops working after it is taped, apply gentle traction on the IV to locate a functional position and retape. Follow-Up The IV line should be checked by medical personnel to ensure the adequacy of the site (no signs of infection, no erythema) and that it is infusing without any problem (e.g. pain, high pressure on the pump).

COMPLICATIONS IV dislodgement and intravenous infiltrates are common complications. The amount and substance extravasated determines whether there will be local injury. Most infiltrates require only elevation and compression. However, hospital policy as well as consultation with your pharmacist and/or hospital vascular access team may help identify more specific therapies to prevent further tissue injury from certain vesicants. Serious complications are rare. Arterial puncture, phlebitis, cellulitis, thrombus formation, catheter fragment embolism or air embolism, and tendon/nerve injury are less common problems.

CENTRAL VENOUS ACCESS Central venous cannulation (CVC) involves percutaneously placing a vascular catheter into a high-flow vein located in either the thorax or the abdomen. It is an essential skill for the resuscitation and stabilization of critically ill or injured children. The main sites of access include the femoral, internal and external jugular, and subclavian veins.

INDICATIONS CVC should be considered for patients needing the following: Vascular access for circulatory failure if peripheral access is unobtainable Infusion of vasoactive medications, blood products, or large volumes of fluid when rapid distribution and onset of therapy are vital Insertion of devices such as transvenous pacemakers or Swan-Ganz catheters Ongoing measurements of venous pressures or mixed venous blood gases Delivery of hypertonic fluids such as total parenteral nutrition and chemotherapy Long-term vascular access for repeated medication administration or frequent blood sampling.

CONTRAINDICATIONS

CVC should not be attempted at sites with abnormal vasculature. Relative contraindications include a bleeding diathesis or hypercoagulable state as well as overlying cellulitis, acute inflammation, or skin injury at the planned site of entry. Other contraindications specific to the individual sites are discussed with each approach.

EQUIPMENT Table 191-2 lists the equipment needed for central venous catheter placement. Virtually all hospitals use commercially available, prepackaged kits that contain most of the necessary equipment; however, they may not contain local anesthetic or a scalpel blade. Squirt some sterile saline onto the tray for flushing after access is obtained. TABLE 191-2

Equipment Needed for Central Venous Catheter Placement

Catheter Flexible guidewire Finder needle Sterile gloves, gowns, masks, and drapes Sterile gauze Antiseptic solution Syringes Heparinized saline Silk suture on straight needle, needle holder Transparent dressing Tissue dilator Number 11 scalpel Topical anesthetic It is important to note that the equipment in each kit is size-specific. If one has opened more than one kit of different sizes, it is extremely important to ensure that the equipment is not mixed up. For example, a guidewire from

one kit may not be long enough to accommodate a catheter from another.

PROCEDURE Several different catheters and techniques have been used for percutaneous CVC, with each involving a slightly different technique. By far the most common is the Seldinger technique, which is based on passing a catheter over a guidewire. This technique is discussed here. It is important to recognize that different patients need varying amounts of sedation and analgesia for this procedure, based on their age and clinical condition. The success of the procedure can be greatly enhanced by immobilization and proper positioning as well as ensuring that all necessary equipment is available and ready before beginning. The chosen site is sterilely prepared, draped, and anesthetized with local anesthetic. Then puncture the skin and blood vessel with a small-gauge needle attached to a syringe while applying gentle negative suction until there is free flow of blood. Remove the syringe, placing your thumb over the hub, and thread the guidewire through the needle into the vein. Remove the needle used for entry, leaving the wire in place. Make a small incision, using a number 11 scalpel, at the entry site to facilitate insertion of a larger catheter. Advance the catheter of choice (Table 191-3) over the guidewire into the desired vessel and remove the wire. It is vitally important to hold the end of the wire at all times to prevent inadvertently losing it in the vessel. Different kits have different sizes of catheters. Some will require dilation of the vessel before insertion. When dilation is necessary, insert the dilator over the wire after the skin incision has been made. Once the dilator is removed, the catheter can be easily advanced over the wire into the vessel. The catheter is then sutured in place and the site is dressed with a transparent occlusive dressing. There is evidence that chlorhexidine-impregnated dressings may decrease CVC colonization and bloodstream infections. TABLE 191-3

Catheter Choice for Pediatric Patients

AVERAGE CATHETER DIAMETER (FRENCH) AND LENGTH (CM)

Internal Jugular

Age

Femoral

Subclavian

1 mo

3

15.7

3

6.0

3

5.5

3 mo

3

17.3

3

6.6

3

6.0

6 mo

3/4

19.1

3

7.3

3

6.6

9 mo

3/4

20.1

3

7.6

3

6.9

12 mo

3/4

21.1

3

8.0

3

7.3

18 mo

3/4

22.9

3

8.7

3

7.9

2 yr

3/4

24.2

3

9.2

3

8.3

4 yr

4

28.1

4

10.6

4

9.6

6 yr

4

31.4

4

11.8

4

10.7

8 yr

4/5

34.2

4/5

12.9

4/5

11.7

10 yr

4/5

36.8

4/5

13.8

4/5

12.5

12 yr

4/5

39.9

4/5

15.0

4/5

13.5

14 yr

5

44.0

5

16.5

5

14.9

16 yr

5

46.3

5

17.3

5

15.7

Source: Reproduced with permission from Lavelle J, Costarino A Jr. Central venous access and central venous pressure monitoring. In: Henretig FM, King C, eds. Textbook of Pediatric Emergency Procedures. 2nd ed. Baltimore: Lippincott Williams & Wilkins; 2008:256.

SITE-SPECIFIC CONSIDERATIONS Femoral Vein This is the most popular approach for pediatric central venous access (Figure 191-6). Advantages include (a) distance from the head and chest, and thus minimal interference with the evaluation and treatment of critically ill children, (b) the requirement of less technical expertise, and (c) the easily exposed anatomy. Disadvantages include contamination risk,

difficulty securing the line, and difficulty in obese patients. Relative contraindications include abnormal vascular anatomy, abdominal trauma, tumor, or ascites, femoral hernia, and future need for cardiac catheterization.

FIGURE 191-6. Femoral venous anatomy. The entry point is identified 1 to 2 cm medial to the femoral artery and 1 to 2 cm below the inguinal ligament. If pulses are weak or absent, the site can be estimated to be halfway between the pubic symphysis and the anterior iliac spine, still 1 to 2 cm below the inguinal ligament. Optimal patient positioning requires abduction and external rotation of the hip, often facilitated by placing a towel beneath the ipsilateral buttock. Perform needle entry at a 45-degree angle, taking care not to puncture the inguinal ligament or above to avoid causing a bowel perforation or retroperitoneal hematoma. Internal Jugular Vein Internal jugular venous access is less common than the femoral approach but is considered the entry site of choice by many experienced physicians because of the inherent advantages of increased stability, patient comfort, and more accurate central venous pressure measurements. The complication rate is somewhat higher than with a femoral line and includes inadvertent laceration of the carotid artery, thoracic duct, or stellate ganglion as well as pneumothorax. Of the three approaches (median, anterior, and lateral) used in cannulating the internal jugular vein, the median

approach is the most popular. All methods require the patient’s head to be turned 30 degrees away from the puncture site while in the Trendelenburg position. Landmarks for the median approach involve locating the midpoint between the sternal notch and the mastoid process at the apex of the triangle formed by both heads of the sternocleidomastoid muscle. The internal jugular vein is lateral to the carotid artery. Insert the needle at a 30-degree angle and aim toward the ipsilateral nipple. External Jugular Vein Although the external jugular vein can be readily identified most of the time, the chance of successful CVC is low. However, complications such as pneumothorax, carotid artery puncture and hematoma, and injury to the sympathetic chain are lower than in the internal jugular vein site. The patient should be in 15 to 30 degrees of Trendelenburg, with the head turned 45 degrees to the contralateral side. Puncture the skin where the external jugular vein crosses over the sternocleidomastoid muscle. Subclavian Vein This is the least common site for percutaneous CVC in children. Identification of landmarks is difficult in children because of their small size and increased chest wall compliance, but the use of ultrasoundguided catheterization is a promising technique. Complications of pneumothorax and subclavian artery puncture are considered traditionally highest with this approach. Access the subclavian vein from either a supraclavicular or infraclavicular site. The patient should be supine in 10 to 25 degrees of Trendelenburg. The entry site for the supraclavicular approach is one finger-width lateral to the clavicular head of the sternocleidomastoid muscle superior to the clavicle. Direct the needle so it bisects the angle formed by the clavicle and the sternocleidomastoid, aiming toward the contralateral nipple, and advancing the needle two to three times the width of the clavicle. The entry site for the infraclavicular approach is just lateral to the midclavicular line below the clavicle. Advance the needle 2 to 4 cm toward the sternal notch parallel to the chest wall.

COMPLICATIONS Site-specific complications have been addressed above. Other general complications include thrombosis, infection (cellulitis, bacteremia), air embolus, vascular or cardiac perforation, and cardiac arrhythmia. Guidewires have been lost in the central circulation, requiring surgical removal. This can

be prevented by always securely holding the proximal end of the wire. Use sterile technique to minimize the risk of infection.

PERIPHERAL INSERTED CENTRAL CATHETERS A peripherally inserted central catheter (PICC) is a longer catheter that is inserted percutaneously into a peripheral vein of the arm, leg or scalp, depending on the age and size of the patient and vein availability. PICCs are not considered an emergent vascular access option and are usually reserved for intermediate-term vascular access in non-emergent situations. In most settings, clinicians may have the opportunity to utilize an indwelling PICC for IV access or be called upon to troubleshoot problems when patients have an existing PICC. Physicians who have had additional training may insert PICCs as well. PICCs are made of silicone or polyurethane and vary in diameter and length, ranging from 28 gauge and 1.9 French for neonates to 3 and 5 French single- and double-lumen sizes for older pediatric patients. Triple-lumen PICCs are also available, but the larger diameter often precludes use in children. An upper extremity PICC tip resides in the lower one-third of the superior vena cava, at the junction of the superior vena cava and right atrium. For lower-extremity insertions the PICC tip should reside in the thoracic inferior vena cava. Power-injectable PICCs are also available for children who require injection of contrast media for computed tomography and other studies. PICCs coated with antimicrobial and antithrombogenic material have also been recently introduced to prolong catheter lifespan and dwell time.

INDICATIONS PICCs are intended for intermediate term use (weeks to months) for vascular access in a hospital, extended care facility, or home care setting. PICCs are most commonly used for intravenous antibiotic or antimicrobial therapy, parenteral nutrition, and fluids. PICCs may be used for chemotherapeutic agents, blood products, and infusates classified as vesicants or with properties of irritating pH levels and osmolarities. Blood samples can be obtained from PICCs 3 French and larger.

CONTRAINDICATIONS PICCs are not inserted in areas distal to a fracture or other injury or if a venous occlusion exists. PICCs should not be inserted through skin that appears infected or with signs of dermatologic disease that might increase the risk for the area to become infected. When possible, in patients who might require a PICC (e.g. a patient being admitted for osteomyelitis) avoid using antecubital veins for peripheral IV access.

ANATOMY The most used PICC insertion sites in neonates and children are the veins of the antecubital area, including the median cubital basilic, basilic, median cubital cephalic, and cephalic veins, in that order of preference. The cephalic vein has a more tortuous path that makes PICC insertion more difficult. The large saphenous vein may be used to place a PICC in neonates and children who are not yet mobile. With the increasing popularity of ultrasound usage for PICC insertion, the basilic and brachial above the antecubital fold and the femoral vein distal to the groin area may be used as well.

EQUIPMENT Virtually all hospitals use commercially available prepackaged kits that contain most of the necessary equipment; however, they may not contain local anesthetic or a scalpel blade. It is important for a practitioner who will be inserting a PICC to be familiar with the kits that are used at their institution. A general list of equipment needed is found in Table 191-4. In addition, all the necessary items to provide maximum sterile barrier precautions should be obtained before beginning the procedure, including sterile drapes for the field as well as a sterile gown, hat, and mask for the practitioner placing the PICC and any other clinicians who will be assisting with the procedure. TABLE 191-4

Equipment List for PICC insertion

Tourniquet Sterile gloves, gowns, masks, and drapes; gauze

Tape measure Catheter Sterile PICC kit: may contain 1-mL syringe for anesthetic, two 5-mL syringes for flush, scissors, threaded tape strips, drapes, finder needle, scalpel, dilator, guide wire, catheter Sterile flush solution Topical anesthetic cream Buffered lidocaine Peripheral IV safety catheter 29-gauge needle and syringe for intradermal lidocaine use Securement device Luer-locking microbore extension set (depending on PICC design) Needle-less injection cap Sterile labels for drugs/solutions on sterile field

PROCEDURE Setup and Preparation Typically, children require procedural sedation and cardiorespiratory monitoring during insertion. The procedure usually occurs in the interventional radiology suite, procedure room, or at the bedside in critical care areas. As with any painful procedure, assessment of a child’s activity, anxiety, and potential need for sedation prior to the procedure will help to improve success. Technique Use maximum sterile barrier precautions for all PICC insertions (establish sterile field, sterile gown, hat, mask, sterile drapes for body of patient and insertion site). One of three methods is usually used for PICC insertion: 1. Winged steel butterfly needle—used most frequently in premature neonates, but even in this setting this technique has been gradually replaced by other methods. 2. Peel-away IV catheter—very popular due to the ease of use, which is similar to insertion of a peripheral IV catheter. 3. Seldinger, modified Seldinger, micro-introducer technique—this method

is becoming the most popular due to the ability to place a larger gauge catheter via a small gauge introducer needle or catheter, and is used in conjunction with ultrasound. See Table 191-5 for a stepwise list of PICC insertion using this technique. Care and Maintenance Once inserted, care and maintenance of the PICC should be according to institutional policies. Sites should be inspected frequently for signs of complications. Suggest care and maintenance techniques are found in Table 191-6. TABLE 191-5

Stepwise Insertion of a PICC using Ultrasound Guidance and a Modified Seldinger Technique

Vascular Assessment (Non-Sterile) 1. Instruct the patient on the purpose of the ultrasound and how it will feel. 2. Wash hands. 3. Place the patient with the arm to be accessed extended at 45 degrees to the trunk of the body. Apply liberal amount of ultrasound gel to the probe or patient arm where you want to visualize a vein. 4. Position the probe with the ridge down toward the user and probe 90 degrees to the skin surface. 5. Identify fluid filled structures and vessels as dark circles. Locate arteries and veins by moving the probe over the vessels and analyzing the compression quality of the vessel walls. Arteries do not compress easily. 6. Move the ultrasound probe and follow basilic vein distally up the arm, compressing the vein and noting its characteristics of increasing size and tributaries. Note the arteries in relation to the veins through compression and pulse. Note approximate size and depth. 7. Note the position of the probe and vein for later reference. You may mark the area with a skin marker so that you can more

readily return there for placement. 8. Remove ultrasound gel from subject and clean probe head with compatible disinfectant PICC Line Placement using Ultrasound 1. Complete preliminary steps for PICC insertion (orders, consent, identify patient, time out, etc.). 2. Assemble equipment and prep patient, and set up maximum sterile barrier as per protocol for PICC placement using modified Seldinger technique. 3. Apply sterile ultrasound gel to the probe. 4. Cover probe and probe cord with sterile plastic sheath, removing all air, and secure with rubber bands/strap to keep gel on face of probe. 5. Have assistant place tourniquet on extremity. 6. Apply sterile ultrasound gel to probe or selected insertion site. Place ultrasound probe on selected area and revisualize vein. Move probe to center vein in the ultrasound screen. 7. Instill local anesthesia intradermally at insertion site. 8. Insert peripheral catheter or needle just through the skin. 9. Watch the ultrasound screen and proceed to advance needle toward vein. 10. Once through the vein, you should be able to visualize the bevel of the needle in approximately the center of the vein. Observe for flashback in catheter needle or flashback chamber. 11. Remove ultrasound probe from site without disturbing position of needle in the vein. Remove peripheral catheter stylet, if appropriate. 12. Carefully insert wire partway into the access device. Slowly advance wire to below axilla. Do not force the wire. Wire should advance freely in the vein. If using fluoroscopy, wire may be inserted to desired location in the superior vena cava. 13. Enlarge the insertion site opening using a needle or scalpel to make a small (2 mm) opening for dilator to pass easily.

14. Thread dilator peel-away assembly over wire into vessel. 15. Remove wire and dilator, leaving peel-away in place. 16. Thread PICC into peel-away to premeasured length and verify tip location in vena cava or at cavoatrial junction. 17. Remove peel-away sheath (see Figure 191-7). 18. Secure, apply dressing, and flush PICC (see Figure 191-8) per institutional protocol. 19. Document insertion in medical record, indicating size, length of PICC, tip location, and related details. TABLE 191-6

Suggested Maintenance of PICC in Infants and Children

FIGURE 191-7. Peel-away sheath with PICC in place.

FIGURE 191-8. PICC with gauze and transparent dressing.

To Maintain Patency

Dressing

• 1–2 mL of • Initially heparinized transparent saline 10 dressing over units/mL gauze; changed every 12– in 48 hours to 24 hours transparent only • Flush • Dressing volume changed weekly should for all but 1.9 equal a French neonatal minimum of PICCs, or more twice the frequently if

Connector Tubing/Cap Change Comments • Extension tubing considered part of catheter if placed aseptically during insertion procedure • Not changed unless

• Used for intermediateterm therapies but no dwell limit set • Can clot, dislodge, or break and is not repairable in most cases • 3 French or larger may be

internal catheter volume • Continuous infusion preferred for 1.9 French and smaller PICCs

loose, soiled, wet, compromised

compromised • Cap changed no more frequently than every 72 hours

used for blood sampling discard volume = 3 × volume in device and attached tubing • Use securement device to prevent dislodgement

COMPLICATIONS CVCs in pediatric patients are not without risks of complications. Review the patient’s vascular access device history and past complications in planning for the appropriate central venous access device. Central venous catheter complications are usually divided into insertion complications and postinsertion complications. Post-insertion complications are often treatable in the emergency department setting. The most frequently reported neonatal and pediatric PICC complications are: Malposition of the tip of the catheter, which can often be adjusted postinsertion or via rewire of the device. Occlusion due to small size of PICCs. This may be treated with alteplase in many cases. Pain/phlebitis, which can usually be treated successfully with application of heat locally. Dislodgment. Documented infection. Catheter fracture; in the case of PICCs, the device should be removed. Several studies have shown that utilization of specialized vascular access teams for PICC insertion and oversight of PICC and CVC maintenance are

associated with standardization of practices and closer monitoring of catheter sites leading to decreased complications.

BIBLIOGRAPHY Andropoulos DB, Bent ST, Skjonsky B, Stayer SA. The optimal length of insertion of central venous catheters for pediatric patients. Anesth Analg. 2001;93:883-6. Costello JM, Clapper TC, Wypij D. Minimizing complications associated with percutaneous central venous catheter placement in children; recent advances. Pediatr Crit Care Med. 2013;4(3):273-283. Doellman D. Pediatric PICC insertions: easing the fears in infants and children. J Assoc Vasc Access. 2004;9(2):68-71. Doellman D, Pettit J, Catudal JP, Buckner J, et al. Best practice guidelines in the care and maintenance of pediatric central venous catheters. Pediatrics Vascular Access Network of the Association for Vascular Access. February, 2010. www.pedivan.org. Frey AM. Peripherally inserted central catheters in neonates and children:, odified Seldinger (microintroducer) technique. J Vasc Access Devices. 2002;7(2):9-16. Frey AM. PICC Complications in neonates and children. J Vasc Access Devices. 1999;4(2):17-26. Halm MA. Effects of local anesthetics on pain with intravenous catheter insertion. J Crit Care. 2008;17(3):265-268. Intravenous Nurses Society. Peripherally inserted central catheters. Position Paper #8. 1988. Jumani K, Advani S, Reid NG, et al. Risk factors for peripherally inserted central venous catheter complications in children. JAMA Pediatr. 2013;167(5):429-435. Knue M, Doellman D, Rabin K, Jacobs BR. The efficacy and safety of blood sampling through peripherally inserted central catheter devices in children. J Infus Nurs. 2005;28(1):30-35. Lavelle J, Costarino Jr. Central venous access and central venous pressure monitoring. In: Henretig FM, King C eds. Pediatric Emergency Procedures. 2nd ed. Philadelphia, PA: Williams & Wilkins; 2008:247-272. Nichols I, Doellman D. Pediatric peripherally inserted central catheter placement: application of ultrasound technology. J Infus Nurs.

2007;30(6):351-356. Peterson K. The development of central venous access device flushing guidelines utilizing an evidence-based practice process. J Pediatr Nurs 2013;28:85-88. Pettit J, Wyckoff M. Peripherally Inserted Central Catheters Guideline for Practice. 2nd ed. Glenview, IL: National Association of Neonatal Nurses. www.NANN.org. Rauch D, Dowd D, Eldridge D, et al. Peripheral difficult venous access in children. Clin Pediatr. 2009;48(9):895-901. Reigart JR, Chamberlain KH, Eldridge D, et al. Peripheral intravenous access in pediatric inpatients. Clin Pediatr. 2012;51(5):468-472.

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Intraosseous Catheters Eron Y. Friedlaender and Lauren E. Marlowe

BACKGROUND Intraosseous (IO) cannulation is an effective and reliable means of rapidly accessing the central circulation for the administration of fluids, medications, and blood products. The non-collapsible intramedullary venous sinuses offer great stability during states of profound vasoconstriction and circulatory failure, such as shock and cardiac arrest, when peripheral access is emergently needed but untenable.1,2 Highly vascular marrow spaces are capable of absorbing large volumes of fluids, medications, and blood products with rapid distribution to the rest of the body.3 The procedure can be safely performed with minimal training by pre-hospital providers as well as by staff skilled in pediatric hospital, emergency, or critical care medicine.4,5 Power-assisted devices for IO placement have made this procedure even more accessible to providers of all skill levels.6-8

INDICATIONS IO access is indicated for pediatric patients requiring resuscitative efforts in whom placement of a peripheral intravenous catheter is unsuccessful or cannot rapidly be established.1,2 For patients in cardiac arrest, IO placement should be performed before all other means of securing access and should be considered early as an alternative to central venous access in the resuscitative efforts of patients with sepsis in whom peripheral access cannot be readily obtained.1,9 The procedure can be attempted in patients of any age in whom peripheral access is unsuccessful.10 Manual IO cannulation is generally successful in 30 to 60 seconds.1

Access with powered devices can be achieved in as little as 5 to 10 seconds with success rates of >90%.11,12 IO catheters are intended to be used during immediate resuscitative efforts only.1 Once a patient has been stabilized, peripheral IV or central venous access should be secured for long-term use. IO lines can deliver any medication, fluid, or blood product prepared for intravenous administration.3,13 A strong evidence base supports IO use for neuromuscular blockade as well as for resuscitative medications such as catecholamines (bolus preparations and continuous infusions), lidocaine, calcium, and sodium bicarbonate.14-18 In general, the onset of action and drug levels in the central circulation following IO delivery are comparable to those achieved with intravenous administration.1,16 Boluses of crystalloids, colloids, blood products, and viscous medications must be delivered under pressure, either manually with a large-caliber syringe or with the assistance of a pressure bag, to overcome the resistance of the emissary veins running through the bony cortex, which are responsible for transporting materials from the intramedullary space to the central circulation.10 Blood samples obtained from the marrow space can be sent for culture and type and cross-match, and can be used to analyze pH, hemoglobin, bicarbonate, and electrolytes with accuracy comparable to venous blood samples.19,20 Importantly, blood obtained from the medullary cavity does not reflect an accurate peripheral complete blood count and differential.

CONTRAINDICATIONS Few contraindications to the use of IO catheters exist. Absolute contraindications include a recent fracture in the bone to be used for the procedure, recent unsuccessful IO attempt in the same bone, or underlying bone disease such as osteopenia or osteogenesis imperfecta given the high risk of fracture in these patient populations.1,3 Relative contraindications include overlying cellulitis or burn at the site of puncture.

EQUIPMENT Needles used for IO cannulation should be sturdy enough to penetrate bone and long enough to reach the marrow cavity.3 Several catheters can be used

to establish IO access: the Jamshidi bone aspiration-infusion needle, the Cook IO infusion needle, or a wide-gauge spinal needle with an internal stylet. There are also several semiautomatic devices available for IO insertion including the battery powered EZ-IO drill (Vidacare, San Antonio, TX) and the spring-loaded Bone Infusion Gun (BIG) (Weismen, Yokemen, Israel) All function effectively, but the evidence base suggests that the EZ-IO may be placed most rapidly.7,11 The Jamshidi infusion needle may be placed with greater ease than the Cook infusion needle and the BIG.21,22 Table 192-1 lists the other equipment needed for IO placement. TABLE 192-1

Equipment Needed for Intraosseous Catheter Placement

Appropriate personal protective equipment Antiseptic solution (per institutional protocol) 1% lidocaine for topical anesthesia 3- or 5-mL syringe for collecting blood Sterile saline flushes Gauze and tape to secure device Pump or pressure-bag

ANATOMY IO needles can be placed into any intramedullary space, but the distal lower extremities are preferred given their large marrow cavities, low potential for injury to surrounding tissues, and distance from the airway and chest where resuscitative measures may be ongoing. The proximal tibia, just inferior to the tibial plateau, has been identified as the most appropriate initial site for placement. The distal femur (1 cm proximal to the femoral plateau) is an alternate insertion site in infants, while the distal tibia (proximal to the medial malleolus) may be used in older children.17 The proximal humerus is an option for IO cannulation in adults, but is not recommended in children.23 IO infusion may also be successful in bones without medullary cavities, including the calcaneus and radial styloid.24

PROCEDURE PREPARATION The following discussion describes placement in the proximal tibia, the preferred site for IO cannulation in children. Place the patient in the supine position and prop the knee over a rolled towel or blanket at 30 degrees of flexion, allowing the patient’s heel to rest on the stretcher. Palpate along the anteromedial surface of the bone, 1 to 3 cm (or approximately 1 finger breadth) below the tibial tubercle to identify a smooth, flat surface for needle placement. Using sterile technique, clean and drape the area. In conscious or awake patients, anesthetize the skin and underlying periosteum with 1% lidocaine (without epinephrine). Using a small needle, place a wheal of lidocaine in the skin, and then slowly direct the anesthetic along the path of the IO needle. Alternately pull back on the syringe while advancing the needle to confirm that the vascular space has not been entered.

TECHNIQUE Manual Firmly grasp the patient’s lower extremity over the distal anterior thigh with one hand. With the other hand, hold the hub of the IO catheter in the palm, and grasp the IO needle close to the tip with the thumb and index finger. The operator should avoid placing any part of his or her hand behind the site of insertion to prevent inadvertent puncture should the needle pass through the bone and posterior soft tissues. Ensure that the stylet is in place and that the bevels are aligned. Direct the bevel distally and introduce the IO needle at a 90-degree angle through the skin. Use continuous rotary motion with steady, firm downward pressure at a 45- to 60-degree angle away from the growth plate to enter the cortex (Figure 192-1). A significant drop in resistance indicates successful penetration of the marrow space.25,26

FIGURE 192-1. Intraosseous needle placement in the proximal tibia. Power-Assisted The EZ-IO is a battery-powered drill that can drive a needle through bone. To begin, select an appropriate needle size based upon the patient’s weight. Ensure that the needle is securely inserted into the needle driver. As with manual IO placement, use one hand to firmly stabilize the patient’s lower extremity by holding the distal anterior thigh. Position the drill at a 90-degree angle to the site of insertion. Engage the trigger and use slow and steady pressure to penetrate the tissue, allowing the driver to do the work. Once a drop in resistance is detected, release the trigger. Holding the needle in place, pull the driver completely off the needle and remove the stylet. Attach the EZ-connect extension tubing.26,27 Securing an IO catheter A correctly placed IO needle should remain upright without support. To confirm placement, remove the stylet and attempt to draw back bone marrow contents with a 3- or 5-mL syringe. Despite successful insertion, blood may not always be aspirated. However, a correctly placed catheter should flush easily with saline. Due to the intrinsic high resistance of the medullary cavity, high pressures may be required. Monitor closely for evidence of extravasation into the surrounding tissues manifesting

as increased circumference of the extremity proximate to the infusion site, increased resistance to product infusion through the needle, or tense soft tissues in the area surrounding the needle. Once appropriate placement of the IO needle has been confirmed, secure it in place. Ensure direct visualization of the insertion site to monitor for dislodgment, subcutaneous infiltration, and local skin reactions. Connect the IO needle to a syringe or intravenous tubing. The IO may be used immediately for infusion of fluids, medications, or blood products. Follow all medication infusions with a saline flush.

COMPLICATIONS Serious complications associated with IO catheters are rare.28 The most common complications observed are local edema or extravasation of fluid.29 Perhaps most significant are through-and-through penetration of the bone and failure to perform the procedure satisfactorily.30,31 Infrequently, osteomyelitis and subcutaneous abscess have been associated with this procedure.32 Additional serious complications include tibial fracture, compartment syndrome, and cerebral arterial air embolism.33-36 Despite evidence of bone marrow and fat emboli in patients after IO infusion, this appears to be of no clinical significance.37 IO catheter use has minimal effects on the long-term growth and health of the bone and bone marrow.38,39

REFERENCES 1. Pediatric Advanced Life Support. American Heart Association, 2010. 2. Advanced Trauma Life Support for Doctors: Student Course Manual. Chicago, IL: American College of Surgeons; 2008. 3. Roberts JR, Hedges JR. Clinical Procedures in Emergency Medicine. Philadelphia, PA: Saunders/Elsevier; 2010. 4. Fowler R, Gallagher JV, Isaacs SM, et al. The role of intraosseous vascular access in the out-of-hospital environment (resource document to NAEMSP position statement). Prehosp Emerg Care. 2007;11(1):6366. 5. Smith RJ, Keseg DP, Manley LK, et al. Intraosseous infusions by

prehospital personnel in critically ill pediatric patients. Ann Emerg Med. 1988;17(5):491-495. 6. Levitan RM, Bortle CD, Snyder TA, et al. Use of a battery-operated needle driver for intraosseous access by novice users: skill acquisition with cadavers. Ann Emerg Med. 2009;54(5):692-694. 7. Myers LA, Russi CS, Arteaga GM. Semiautomatic intraosseous devices in pediatric prehospital care. Prehosp Emerg Care. 2011;15(4):473-476. 8. Gazin N, Auger H, Jabre P, et al. Efficacy and safety of the EZ-IO™ intraosseous device: out-of-hospital implementation of a management algorithm for difficult vascular access. Resuscitation. 2011;82(1):126129. 9. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37(2):666-688. 10. Kleinman ME, Chameides L, Schexnayder SM, et al. Pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2010;126(5):e1361-1399. 11. Horton MA, Beamer C. Powered intraosseous insertion provides safe and effective vascular access for pediatric emergency patients. Pediatr Emerg Care. 2008;24(6):347-350. 12. Gillum L, Kovar J. Powered intraosseous access in the prehospital setting: MCHD EMS puts the EZ-IO to the test. JEMS. 2005;30 (10)suppl:24-25. 13. Buck ML, Wiggins BS, Sesler JM. Intraosseous drug administration in children and adults during cardiopulmonary resuscitation. Ann Pharmacother. 2007;41(10):1679-1686. 14. Berg RA. Emergency infusion of catecholamines into bone marrow. Am J Dis Child. 1984;138(9):810-811. 15. Tobias JD, Nichols DG. Intraosseous succinylcholine for orotracheal intubation. Pediatr Emerg Care. 1990;6(2):108-109. 16. Sacchetti AD, Linkenheimer R, Lieberman M, et al. Intraosseous drug administration: successful resuscitation from asystole. Pediatr Emerg

Care. 1989;5(2):97-98. 17. McNamara RM, Spivey WH, Sussman C. Pediatric resuscitation without an intravenous line. Am J Emerg Med. 1986;4(1):31-33. 18. Orlowski JP, Porembka DT, Gallagher JM, et al. Comparison study of intraosseous, central intravenous, and peripheral intravenous infusions of emergency drugs. Am J Dis Child. 1990;144(1):112-117. 19. Orlowski JP, Porembka DT, Gallagher JM, et al. The bone marrow as a source of laboratory studies. Ann Emerg Med. 1989;18(12):1348-1351. 20. Ummenhofer W, Frei FJ, Urwyler A, et al. Are laboratory values in bone marrow aspirate predictable for venous blood in paediatric patients? Resuscitation. 1994;27(2):123-128. 21. Hartholt KA, van Lieshout EMM, Thies WC, et al. Intraosseous devices: a randomized controlled trial comparing three intraosseous devices. Prehosp Emerg Care. 2010;14(1):6-13. 22. Halm B, Yamamoto LG. Comparing ease of intraosseous needle placement: Jamshidi versus cook. Am J Emerg Med. 1998;16(4):420421. 23. Paxton JH, Knuth TE, Klausner HA. Proximal humerus intraosseous infusion: a preferred emergency venous access. J Trauma. 2009;67(3):606-611. 24. McCarthy G, O’Donnell C, O’Brien M. Successful intraosseous infusion in the critically ill patient does not require a medullary cavity. Resuscitation. 2003;56(2):183-186. 25. Burg MD. Textbook of Pediatric Emergency Procedures. 2nd ed. Blackwell Publishing; 2009. 26. Nagler J, Krauss B. Videos in clinical medicine. Intraosseous catheter placement in children. N Engl J Med. 2011;364(8):e14. 27. Vidacare website. http://www.vidacare.com/EZ-IO/Index.aspx. Accessed May 25, 2013. 28. Hansen M, Meckler G, Spiro D, et al. Intraosseous line use, complications, and outcomes among a population-based cohort of children presenting to California hospitals. Pediatr Emerg Care. 2011;27(10):928-932. 29. Fiorito BA, Mirza F, Doran TM, et al. Intraosseous access in the setting

of pediatric critical care transport. Pediatr Crit Care Med. 2005;6(1):5053. 30. Christensen DW, Vernon DD, Banner W Jr, et al. Skin necrosis complicating intraosseous infusion. Pediatr Emerg Care. 1991;7(5):289290. 31. LaSpada J, Kissoon N, Melker R, et al. Extravasation rates and complications of intraosseous needles during gravity and pressure infusion. Crit Care Med. 1995;23(12):2023-2028. 32. Stoll E, Golej J, Burda G, et al. Osteomyelitis at the injection site of adrenalin through an intraosseous needle in a 3-month-old infant. Resuscitation. 2002;53(3):315-318. 33. Bowley DMG, Loveland J, Pitcher GJ. Tibial fracture as a complication of intraosseous infusion during pediatric resuscitation. J Trauma. 2003;55(4):786-787. 34. Vidal R, Kissoon N, Gayle M. Compartment syndrome following intraosseous infusion. Pediatrics. 1993;91(6):1201-1202. 35. Galpin RD, Kronick JB, Willis RB, et al. Bilateral lower extremity compartment syndromes secondary to intraosseous fluid resuscitation. J Pediatr Orthop. 1991;11(6):773-776. 36. Van Rijn RR, Knoester H, Maes A, et al. Cerebral arterial air embolism in a child after intraosseous infusion. Emerg Radiol. 2008;15(4):259262. 37. Orlowski JP, Julius CJ, Petras RE, et al. The safety of intraosseous infusions: risks of fat and bone marrow emboli to the lungs. Ann Emerg Med. 1989;18(10):1062-1067. 38. Fiser RT, Walker WM, Seibert JJ, et al. Tibial length following intraosseous infusion: a prospective, radiographic analysis. Pediatr Emerg Care. 1997;13(3):186-188. 39. Claudet I, Baunin C, Laporte-Turpin E, et al. Long-term effects on tibial growth after intraosseous infusion: a prospective, radiographic analysis. Pediatr Emerg Care. 2003;19(6):397-401.

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Umbilical Artery and Vein Catheterization Bryan Upham, revised by Julianne Prasto

BACKGROUND Unique to the neonate, lifesaving central access can be achieved through catheterization of the umbilical vessels. Umbilical artery catheterization can routinely be performed in newborns up to 24 hours old and occasionally in those up to 1 week old. Umbilical vein catheterization is feasible up to 2 weeks of age.1

INDICATIONS Indications for central access include volume expansion, blood transfusion, infusion of resuscitative medications, administration of hypertonic solutions including parenteral nutrition, and frequent laboratory draws. Peripheral access should be attempted first but should not delay central access in a critically ill infant. Arterial catheters are indicated in newborns requiring frequent arterial blood gases and/or invasive blood pressure monitoring. An umbilical artery catheter has the advantage of rapid insertion and may also be used to deliver fluids, medications, and blood products.

CONTRAINDICATIONS Overlying soft tissue infection (e.g. omphalitis), peritonitis, possible necrotizing enterocolitis, and abdominal anomalies (e.g. omphalocele) are contraindications to placing an umbilical vessel catheter.2 Umbilical lines should not be placed in infants greater than 2 weeks of age and should be avoided in patients with known thrombotic disease. Finally, one must

remember that these are central lines and are not placed for routine blood sampling or administration of fluids or medications.

EQUIPMENT NONSTERILE Radiant warmer with light source Cardiorespiratory monitor Pulse oximeter Measuring tape Surgical mask with face shield, surgical cap D5W, D10W, or 0.45% NaCl infusion setup with heparin 1 unit/mL (unless medications are incompatible with heparin) Soft infant restraints Adhesive tape

STERILE Povidone–iodine solution Sterile drapes, gauze, gloves, gown Scalpel (number 11 or 15) Curved hemostats (2) Straight forceps 3-0 silk suture Needle driver Scissors Umbilical tape Umbilical catheters (3.5, 5, or 8 French with end hole) Umbilical vein catheter size = 5 Fr (3.5 Fr if 1500 g; 3.5 Fr if 50,000/μL and INR 0.5 implies exudate) LDH level (pleural to plasma LDH ratio >0.6 implies exudate) Other tests appropriate to the clinical situation (e.g. Gram stain and cultures if concern for infection, or cytology if concern for malignancy). Treatment of a transudative pleural effusion is directed at the underlying cause. If the fluid is exudative, additional tests must be considered based on the history and physical examination findings. The pH, glucose level, and Gram stain of the pleural fluid can help determine whether a parapneumonic effusion should be drained by tube thoracostomy. The differential diagnosis of a pleural effusion includes other diseases that may be apparent with additional testing such as cell count with differential (fluid should be collected in EDTA tube for this), culture and sensitivity, cytology for malignant cells, and amylase, antinuclear antibody, and complement levels.

COMPLICATIONS The most common major complication of thoracentesis is pneumothorax.

Other potential complications include laceration of an intercostal neurovascular bundle and subsequent hemothorax, inadvertent puncture of subdiaphragmatic organs (e.g. liver, spleen), and local infection or pain. Patients may also experience transient hypoxia associated with thoracentesis. Finally, hypotension or pulmonary edema can occur if too much fluid is removed too quickly. In an adult-sized patient, no more than 1000 to 1500 mL of fluid should be removed at a time. In children, one should avoid taking off more than a few hundred milliliters at one time.

REFERENCES 1. Soldati G, Smargiassi A, Inchingolo R, Sher S, Valente S, Corbo GM. Ultrasound-guided pleural puncture in supine or recumbent lateral position - feasibility study. Multidiscip Respir Med. 2013;8(1):18. 2. Daniels CE, Ryu JH. Review: improving the safety of thoracentesis. Curr Opin Pulm Med. 2011;17(4):232-236. 3. Sachdeva A, Shepherd RW, Lee HJ. Thoracentesis and thoracic ultrasound: state of the art in 2013. Clin Chest Med. 2013;34(1):1-9. 4. VHA Directive 2010-023. Ensuring correct surgery and invasive procedures. http://www1.va.gov/vhapublications/ViewPublication.asp? pub_ID=2243. Accessed April 27, 2013. 5. Hibbert RM, Atwell TD, Lekah A, et al. Safety of ultrasound-guided thoracentesis in patients with abnormal preprocedural coagulation parameters. Chest. 2013;144(2):456-463.

CHAPTER

199

Arthrocentesis Eron Y. Friedlaender and Adelaide E. Barnes

INTRODUCTION Patients presenting with joint pain or swelling should receive a thorough examination to rule out the presence of joint disease. Periarticular diseases such as tendinitis, bursitis, or cellulitis may mimic articular disease and therefore the clinician must first determine whether the patient’s constellation of signs and symptoms originate from the joint itself or from another contiguous structure. At times, such a distinction is difficult to make.1 Arthrocentesis, the puncture and aspiration of a joint, can facilitate this evaluation as both a diagnostic and therapeutic tool in the assessment of musculoskeletal disease and trauma. This procedure can often be done at the bedside using local anesthesia, without radiographic guidance or significant risk to the patient.

INDICATIONS The diagnostic indications for arthrocentesis include confirmation of nontraumatic joint disease and ligamentous or bony injury. The former includes the identification of infectious or immunologic markers in the synovial fluid. In contrast, the presence of blood in the joint space affirms traumatic injury; more specifically, the finding of blood and fat globules may be used to identify an intra-articular fracture. The therapeutic indications for arthrocentesis include pain relief secondary to a tense effusion or hemarthrosis and the direct instillation of anti-inflammatory medications for the management of severe rheumatic arthritides. The physician should consider consultation with the primary specialist for patients with chronic hematologic or rheumatologic disease

prior to performing this procedure.2

CONTRAINDICATIONS Although some authors argue that infection in the tissues overlying the puncture site (a skin abscess or cellulitis) is an absolute contraindication to arthrocentesis given the theoretical risk for spread of infection into the joint space, others state that this is a relative contraindication and the risk–benefit ratio must be discussed thoroughly prior to performing the procedure.1-3 Additional relative contraindications to the procedure include bacteremia (because it may also facilitate the spread of infection to the joint space), active anticoagulation, fracture around the joint space (because aspiration may increase the chance of infection),4 and joint prostheses. Given the rarity of joint prostheses in the pediatric population and the high risk of infection, orthopedic consultation should be obtained if considering arthrocentesis.2,4 In addition, bleeding diatheses should be corrected with appropriate clotting factors or blood product replacement before arthrocentesis to prevent a significant hemarthrosis.1,2,4

EQUIPMENT Table 199-1 lists the equipment needed to perform arthrocentesis. TABLE 199-1

Equipment Needed for Arthrocentesis

Antiseptic solution (iodine, povidone–iodine [Betadine]) Sterile drapes Sterile gloves Alcohol wipes Saline solution or other cleansing agents Marking pen Sterile gauze dressings (2 × 2 inch and/or 4 × 4 inch) Sterile tubes for fluid collection Test tubes (red top and lavender top)

Sterile syringes 18- or 20- (shoulder, elbow, knee, and ankle joints) or 22- to 23(wrist and small joints) gauge, 1.5-inch needles Topical anesthetic (vapocoolant, lidocaine–prilocaine paste [EMLA]) Local anesthetic (1% lidocaine solution) Bandage and dressing If sedating: procedural sedation equipment

ANATOMY The optimal site for needle insertion should be selected based on provider experience, the most straightforward access to the joint space, and avoidance of vital structures. Successful arthrocentesis begins with a careful examination of the affected joint and familiarity with the local anatomy. Palpable bony landmarks are most often used to identify the insertion site, and knowledge of the locations of tendons, nerves, and blood vessels is essential to avoid potential complications. As a rule, arthrocentesis of any joint is more safely done on extensor surfaces to avoid the majority of neurovascular and tendinous structures. In addition, the synovial membrane tends to lie more superficially on extensor surfaces compared with flexor surfaces.

PROCEDURE PREPARATION Arthrocentesis requires a cooperative and comfortable patient to minimize complications and allow for successful joint aspiration. It is essential that the patient be relaxed, as tense muscles will narrow the space and may make the procedure longer and more difficult. Consider procedural sedation in patients who will not tolerate the procedure with appropriate local anesthesia alone. Sterile technique is mandatory to reduce the risk of iatrogenic joint infection. Consider marking the chosen insertion site prior to cleaning the field. Prepare the site using an antiseptic surgical scrub. In order to optimize the bactericidal effect of the povidone–iodine solution, adequate drying is

necessary. Once it has dried, remove the povidone–iodine solution with an alcohol wipe, as the introduction of the solution into the joint space may precipitate an inflammatory reaction. Next, position the patient such that the opening to the joint space is maximized. Anesthetize the skin at the needle insertion site with either a vapor coolant or application of a topical lidocaine preparation. Infiltrate the skin and subcutaneous tissues with 1% or 2% lidocaine using a small-gauge needle, taking care not to introduce anesthetic into the joint space, which might affect subsequent synovial fluid analysis.

TECHNIQUE Insert an 18- or 20-gauge needle attached to an empty sterile syringe into the joint space at 10 to 20 degrees above the horizontal. Enter the joint in one fluid motion along a straight line; side-to-side manipulation of the needle risks permanent damage to the articular cartilages or ligaments. Draw back on the syringe plunger as the needle is advanced toward the space until fluid flows easily into the syringe. Synovial fluid collected for culture must be placed in a sterile vial. Fluid collected for a cell count requires a specimen tube containing EDTA. Fluid sent for crystal analysis requires a tube prepared with sodium heparin. It is essential that synovial fluid be analyzed soon after it is obtained, because cell counts and crystals may lose accuracy within hours.5 Table 199-2 highlights synovial fluid analysis for the most common causes of joint effusions in the pediatric population.3,5-10 Synovial fluid glucose and protein are often inaccurate markers and are generally less informative than other studies. Ordering these studies should be discouraged, as they may provide misleading or redundant information.1,5 TABLE 199-2

Synovial Fluid Evaluation

PMN, polymorphonuclear lymphocyte; WBC, white blood cell

Once fluid has been obtained or the desired amount of fluid removed, the needle should be removed slowly and in a straight line. Sterile gauze should be used to occlude the site once the needle has been removed. When the procedure is completed, dress the needle insertion site and wrap the joint to prevent reaccumulation of intra-articular fluid.

COMPLICATIONS There are few complications associated with arthrocentesis. There is a small risk of joint infection, but this is negligible if using proper aseptic technique and minimal even in the setting of bacteremia or overlying infection.1,3 A small amount of traumatic capsular bleeding may occur, but this is rarely significant unless in the setting of a coagulopathy. Hemarthroses in patients with a major bleeding risk may be avoided by administering correction prior to the procedure. Other complications include hypersensitivity reaction to the local anesthetic, which can be prevented with thorough history taking and permanent cartilage damage if the articular surface is nicked or scraped by the needle. KEY POINTS Ultrasound has been shown to facilitate proper needle placement for joint aspiration and may be more reliable than traditional palpation guided technique.1 For particularly complex or small joints, ultrasound may improve accuracy.11 As bedside ultrasound becomes more readily available, clinicians may become increasingly more facile at using it as an adjunct when performing this procedure. Arthrocentesis allows for a prompt and accurate diagnosis of an acutely painful, inflamed, swollen, or injured joint. Although many clinicians may be wary of joint fluid aspiration, when performed properly it provides a wealth of clinical information and is associated with few complications. Clinicians should always be familiar with the anatomy of the affected joint. Sterile technique and local anesthesia are standard of care when

performing this procedure.

REFERENCES 1. Parillo S, Morrison DS, Panacek EA. Arthrocentesis. In: Roberts J, Hedges J eds. Clinical Procedures in Emergency Medicine. Philadelphia: WB Saunders; 2009:971-985. 2. Green DA, Macias CG. Athrocentesis. In: King C, Henretig F eds. Textbook of Pediatric Emergency Procedures. Baltimore: Lipincott Williams & Wilkins; 2007:954-961. 3. Moore GF. Arthrocentesis technique and intraarticular therapy. In: Koopman WJ ed. Arthritis and Allied Conditions. Vol. 1. Philadelphia: Lippincott Williams & Wilkins; 2005:775-786. 4. Cimpello LB, Deutsch RJ, Dixon C, et al. Arthrocentesis: general considerations. In: Fleisher G, Ludwig S eds. Textbook of Pediatric Emergency Medicine. Philadelphia: Lippincott Williams & Wilkins; 2010:1817-1819. 5. Brannan SR, Jerrard DA. Synovial fluid analysis. J Emerg Med. 2006:30(3):331-339. 6. Cassidy JT, Petty RE, Laxer RM, Lindsley C. Textbook of Pediatric Rheumatology. Philadelphia: Saunders; 2010:211-235. 7. Thompson A, Mannix R, Bachur R. Acute pediatric monoarticular arthritis: distinguishing Lyme arthritis from other etiologies. Pediatrics. 2009;123:959-965. 8. John J, Chandran L. Arthritis in children and adults. Pediatr Rev. 2011;32:470-480. 9. Milewski MD, Cruz AI, Miller CP, et al. Lyme arthritis in children with joint effusions. J Bone Joint Surg. 2011;93:252-260. 10. Feder HM. Lyme disease in children. Infect Dis Clin North Am. 2008;22:315-326. 11. Balint PV, Kane D, Hunger J, et al. Ultrasound guided versus conventional joint and soft tissue fluid aspirations in rheumatology practice: a pilot study. J Rheumatol. 2002;29:2209-2213.

Index Note: Page numbers followed by f, t, or b refer to the page location of figures, tables, or boxes respectively. References starting with “eTable” refer to the tables available online. A A-a (alveolar-arterial) gradient, 83, 108 AAP (American Academy of Pediatrics), 51 Abacavir, 593 Abatacept, 122, 844 Abdominal imaging. See also Gastrointestinal (GI) imaging angiography, 1027, 1027f computed tomography, 1022, 1023f magnetic resonance imaging, 1026 point-of-care ultrasound, 1035f, 1036–1037, 1036f radiographs. See Abdominal radiographs Abdominal mass, 61–63 diagnostic evaluation of, 62 differential diagnosis of, 61–62, 62t key points, 63 pathophysiology of, 61, 62t patient history in, 61 physical examination in, 61 special considerations in, 62–63 Abdominal pain, 63–66 in appendicitis. See Appendicitis

in biliary disease, 355 in cerebrospinal shunt infection, 585 in cystic fibrosis, 811, 811t diagnostic evaluation of, 65–66 differential diagnosis of, 63–64, 63t, 64t, 864t in dyspepsia, 366 in Henoch-Schönlein purpura, 832–833 management of, 66 in pancreatitis, 388, 391–392 patient history in, 64–65 in pelvic osteomyelitis, 569 in pericarditis, 252 physical examination in, 65 recurrent, 764–765 upper, 366–368, 367t, 368t with vomiting, 864t Abdominal radiographs, 1008, 1008f in appendicitis, 864 in duodenal atresia, 153 in fecal impaction, 363, 364f in gastrointestinal bleeding, 97 in Henoch-Schönlein purpura, 834 in lead poisoning, 932, 932f in pancreatitis, 389 Abdominal trauma in abuse, 168 diagnostic evaluation of, 874, 874f liver, 874t, 875, 920 small and large bowel, 875 splenic, 874, 1027f Abdominal wall defects, 706–707, 706f, 707f Abducens nerve palsy, 502, 671 ABG. See Arterial blood gas (ABG) Abnormal uterine bleeding (AUB), 194–199 admission and discharge criteria for, 198 clinical presentation of, 195 consultation for, 198

diagnostic evaluation of, 195–196 differential diagnosis of, 195, 195t key points, 199 management of, 196–198, 197t pathophysiology of, 194–195 special considerations in, 199 ABR (auditory brainstem response) test, 699 Abscess brain. See Brain abscess Brodie, 569 deep neck. See Deep neck space infections dental. See Dental abscess intracranial, 506–507, 506f lung, 528–529 subperiosteal. See Subperiosteal abscess ultrasound-guided drainage of, 1028, 1028f, 1040, 1040f Absidia infection, 285t Absolute neutrophil count (ANC), 439 Abstinence syndrome, neonatal. See Neonatal abstinence syndrome (NAS) Abuse and neglect cutaneous injuries in, 161–163 admission and discharge criteria for, 163 clinical presentation of, 161–162, 896 consultation for, 163 diagnostic evaluation of, 162–163 differential diagnosis of, 162, 162t, 896 key points, 163 management of, 163 special considerations in, 163 differential diagnosis of, 168 head trauma in. See Abusive head trauma (AHT) imaging of, 167–168 in head trauma, 168. See also Abusive head trauma (AHT) key points, 168 in skeletal trauma, 167–168, 167f, 167t, 168t in visceral trauma, 168 legal issues in, 174–177

child protective services, 174–175 civil child protective court, 175 criminal court, 175 discovery process, 176 expert and non-expert testimony, 176 key points, 177 mandated reporting, 173, 174 medical documentation, 176 record keeping, 173 testimony process, 176–177 medical. See Medical child abuse orofacial trauma in, 129 orthopedic trauma in, 893 Abusive head trauma (AHT), 164–166. See also Abuse and neglect admission and discharge criteria for, 166 brain injury in, 164 clinical presentation of, 164–165 consultation for, 166 diagnostic evaluation of, 165, 167, 168 differential diagnosis of, 165 epidemiology of, 164 eye injury in, 890–891, 891f key points, 166 management of, 165–166 prevention of, 166 Acalculous cholecystitis, 359 Acanthocytes, 426t ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors Acetaminophen for fever, 94 metabolism of, 920 poisoning/overdose, 916, 920–922, 921f, 921t Acetylcholine esterase (AChE) inhibitors, 659 Acidemia, 67, 418 Acidosis, 66–72. See also Metabolic acidosis; Respiratory acidosis in chronic renal failure, 616 definition of, 67, 418

differential diagnosis of, 67–69, 68f, 69t key points, 72 management of, 70 pathophysiology of, 66–67 patient history in, 67 physical examination in, 67 Acinetobacter spp. infections, 466t Acne in immunosuppressed host, 302–303, 303f neonatal, 267t Acneiform eruptions, 303 ACP (American College of Physicians) Journal Club, 10 Acquired immunodeficiency syndrome (AIDS), 590, 590t. See also HIV infection Acrodermatitis, papular, 553 Acrodermatitis enteropathica, 127t, 279, 279f Acrodynia, 936 ACTH (adrenocorticotropic hormone), 327, 336 Activated charcoal, 915, 916t, 923t Activated thromboplastin time (aPTT), 452 Acute chest syndrome (ACS), 435 Acute disseminated encephalomyelitis (ADEM), 688f in acquired demyelinating disorders, 682–683 clinical presentation of, 654, 682t, 683–684 diagnostic evaluation of, 654, 682t, 684, 684f, 688f differential diagnosis of, 68f, 684 epidemiology of, 682t prognosis of, 684 treatment of, 654, 684 Acute flaccid paralysis, 655 Acute gastroenteritis (AGE), 541–552 admission and discharge criteria for, 552 bacterial, 541–543, 542t clinical presentation of, 544–548, 546t, 547t complications of, 548–549, 549t consultation for, 552 diagnostic evaluation of, 549–550, 549t

differential diagnosis of, 549, 864t epidemiology of, 541, 543–544, 544–545t, 546t etiology of, 541–542, 542t key points, 558 pathophysiology of, 542–543 prevention of, 552 treatment of, 550–552, 551t, 552t viral, 541, 542, 542t Acute generalized exanthematous pustulosis (AGEP), 268t, 292 Acute glomerulonephritis, 618 Acute hematogenous osteomyelitis (AHO), 566. See also Osteomyelitis Acute hemolytic transfusion reaction (AHTR), 459t, 461–462 Acute hemorrhagic edema of infancy (Finkelstein disease), 833 Acute inflammatory demyelinating polyradiculopathy (AIDP). See GuillainBarré syndrome (GBS) Acute kidney injury (AKI), 611–614 admission and discharge criteria for, 614 classification of, 611, 611t clinical presentation of, 611–612 consultation for, 614 diagnostic evaluation of, 612, 612t, 613t differential diagnosis of, 626t pathophysiology of, 611, 612t prevention of, 614 treatment of, 612–614, 613t in tubulointerstitial nephritis. See Tubulointerstitial nephritis (TIN) Acute lymphoblastic leukemia (ALL), 733–734, 734f, 734t Acute myeloid leukemia, 127t, 733, 734f Acute otitis media (AOM) cerebral sinus venous thrombosis and, 677 complications of, 500t, 501–502, 501f diagnostic evaluation of, 115 ecthyma gangrenosum and, 283 fever in, 473 headaches in, 645 irritability in, 115 neutropenia and, 442

pathophysiology of, 500–501 treatment of, 465t, 501, 502 vomiting in, 156 Acute promyelocytic leukemia, 734f Acute renal failure (ARF). See Acute kidney injury (AKI) Acute rheumatic fever (ARF), 255–259 admission and discharge criteria for, 258, 258t clinical presentation of, 256–257, 256t consultation for, 258 diagnostic evaluation of, 257, 257t differential diagnosis of, 257 epidemiology of, 255–256 future directions in, 259 key points, 259 management of, 257–258 pathophysiology of, 256 primary prevention of, 258–259, 258t recurrent, 258, 259, 259t secondary prevention of, 259, 259t Acute splenic sequestration, 436 Acyclovir for anogenital herpes, 191t for HSV encephalitis, 496 for viral infections in transplant recipient, 606t AD. See Atopic dermatitis (AD) Adalimumab adverse effects of, 122t, 378, 378t, 844 for inflammatory bowel disease, 378 for juvenile idiopathic arthritis, 844 mechanisms of action of, 122 ADAMSTS13 deficiency, 622 Addison disease, 337–338 ADEM. See Acute disseminated encephalomyelitis (ADEM) Adenoidectomy, 879 Adenosine phosphate (ADP) receptor antagonist poisoning/overdose, 976–977 Adenovirus infections

acute gastroenteritis, 541, 542t, 544, 545t, 547t periorbital cellulitis, 504 transmission-based precautions, 17t in transplant recipient, 601, 606t ADH (antidiuretic hormone), 345 Adjustment disorder with depressed mood, 754, 755 Adolescents abnormal uterine bleeding in. See Abnormal uterine bleeding (AUB) developmental implications in response to hospitalization, 32–33 eating disorders in. See Eating disorders sexually transmitted infections in. See Sexually transmitted infections (STIs) suicide/suicide attempts in, 758–759. See also Suicidality vomiting in, 155t Adrenal cortex, 336 Adrenal gland, 336 Adrenal gland disorders. See Adrenal insufficiency; Congenital adrenal hyperplasia (CAH); Hyperadrenal states Adrenal hypoplasia congenita, 405t Adrenal insufficiency admission and discharge criteria for, 338 clinical presentation of, 337 consultation for, 338 diagnostic evaluation of, 338 differential diagnosis of, 337–338, 337t, 417t key points, 340 management of, 338 pathophysiology of, 337 Adrenal medulla, 336 Adrenarche, premature, 338 Adrenergic agonists. See β adrenergic agonists Adrenergic antagonists. See β adrenergic blockers Adrenocorticotropic hormone (ACTH), 327, 336 Adrenoleukodystrophy, 338 AEC (ankyloblepharon-ectodermal dysplasia-clefting) syndrome, 268t Aeromonas hydrophila, 577 Against medical advice (AMA), 46

Agammaglobulinemia, 210 AGE. See Acute gastroenteritis (AGE) AGEP (acute generalized exanthematous pustulosis), 268t, 292 Aggression, 768, 986. See also Agitation Agitation, 767–771 clinical presentation of, 768 consultation for, 771 diagnostic evaluation of, 768–769, 769f differential diagnosis of, 768 key points, 771 management of, 769f, 770–771, 770t, 771 pharmacologic considerations, 771 risk factors for, 768, 768f AHO (acute hematogenous osteomyelitis), 566. See also Osteomyelitis AHO (Albright’s hereditary osteodystrophy), 331 AHT. See Abusive head trauma (AHT) AHTR (acute hemolytic transfusion reaction), 459t, 461–462 AIDP (acute inflammatory demyelinating polyradiculopathy). See GuillainBarré syndrome (GBS) AIDS (acquired immunodeficiency syndrome), 590, 590t. See also HIV infection Airway emergent management of, 1070–1072, 1071t foreign body in. See Foreign body aspiration Airway obstruction in child with severe neurologic impairment, 985, 990 endotracheal intubation for, 692–693, 1071–1072 noninvasive positive-pressure ventilation for, 1066 AIS. See Arterial ischemic stroke (AIS) AKI. See Acute kidney injury (AKI) Alagille syndrome, 216t, 405t Alanine transaminase (ALT), 356, 554, 554t Albright’s hereditary osteodystrophy (AHO), 331 Albumin in hepatitis, 554t in nephrotic syndrome, 628 Albuterol

for asthma, 788, 789t for bronchiolitis, 518 Alclometasone, 280 Alcohol poisoning, 928–929, 928f Alcohol withdrawal syndrome, 941–942, 942t, 943, 943t Alkaline phosphatase, 554t ALL (acute lymphoblastic leukemia), 733–734, 734f, 734t Allen test, modified, 1048, 1048f Allergic contact dermatitis, 268t, 278 Allergy/allergic reactions. See also Asthma; Atopic dermatitis (AD) anaphylaxis. See Anaphylaxis to drugs. See Drug allergy reactions to food, 281 to transfusion, 459t, 462 Allopurinol, 741, 741t Allow natural death (AND) order, 997 α-fetoprotein, 79 α-glucosidase inhibitors, 923–925, 924t, 925t ALPS (autoimmune lymphoproliferative syndrome), 208 ALT (alanine transaminase), 356, 554, 554t ALTE. See Apparent life-threatening event (ALTE) Altered mental status (AMS), 72–76 causes of, 74t diagnostic evaluation of, 75–76, 75t key points, 76 management of, 76 as oncologic emergency, 747, 747t patient history in, 72–73 physical examination in, 73–74, 73t Alveolar-arterial (A-a) gradient, 83, 108 Alveolar oxygen (PaO2), 107–108, 110t AMA (against medical advice), 46 Ambiguous genitalia, 710–711 American Academy of Pediatrics (AAP), 51 American College of Physicians (ACP) Journal Club, 10 American Pediatric Association (APA), 51 American Society of Anesthesiologists (ASA) physical classification, 1003,

1004t Amikacin for bacterial meningitis, 495t for cystic fibrosis exacerbations, 813t in lock therapy, 584t Aminocaproic acid, 448–449 Aminophylline, 790, 790t 5-Aminosaliclyates, 378, 378t Amlodipine, 103, 103t Ammonia, in hepatitis, 554t Amoxicillin allergy to, 203 for chlamydia, 189t for endocarditis prophylaxis, 244t for GAS pharyngitis, 258t for Lyme disease, 851t Amoxicillin-clavulanate, 814t Amphetamine poisoning/overdose, 916t Ampicillin allergy to, 203 for bacterial meningitis, 495t for endocarditis prophylaxis, 244t for osteomyelitis, 567t for septic shock, 147t Ampicillin/sulbactam for cystic fibrosis exacerbations, 813t for pelvic inflammatory disease, 190t AMPLE history, 1003, 1003t AMS. See Altered mental status (AMS) Amylase, elevated, 388–389, 389t ANA (antinuclear antibody), 120, 853–854, 854t Anakinra, 122, 122t, 844 Anaphylactoid reactions, to contrast material, 203 Anaphylaxis, 201–202 as acute transfusion reaction, 459t, 462 admission and discharge criteria for, 202 clinical presentation of, 201, 202t

consultation for, 202 differential diagnosis of, 201 epidemiology of, 201 pathophysiology of, 201 treatment of, 201 Anaplasma phagocytophila, 488 ANCA (antineutrophilic cytoplasmic antibody), 619 ANC (absolute neutrophil count), 439 AND (allow natural death) order, 997 Anemia, 425–432 admission and discharge criteria for, 431 in chronic renal failure, 616 classification of, 428t clinical presentation of, 425 consultation for, 431–432 diagnostic evaluation of, 425–426, 425t, 426t differential diagnosis of, 426, 428t future directions in, 432 hemolytic. See Hemolytic anemia in hemolytic uremic syndrome, 623 key points, 432 macrocytic, 428t, 429 microcytic, 428t. See also Iron-deficiency anemia normocytic, 428–429, 428t postoperative, 894 Anemia of chronic disease, 428–429 Anemia of inflammation, 428 Anesthesia. See also Procedural sedation and analgesia classification of, 1003 physical status classification for, 1003, 1004t Aneuploidy, 399 Aneurysm cerebral, 669, 675, 678 coronary artery, 77, 212, 830, 831 mycotic, 240 Angelman syndrome, 405t, 407 Angioedema, 203–204, 290

Angiography, 1027, 1027f. See also Magnetic resonance angiography (MRA) Angiotensin-converting enzyme (ACE) inhibitors adverse effects of, 103, 203–204 for dilated cardiomyopathy, 248 for hypertension, 103, 103t Angiotensin receptor blockers (ARBs), 103t, 104 Animal bites. See Bite wounds Anion gap acidosis. See also Metabolic acidosis diagnostic evaluation of, 69–70 differential diagnosis of, 67–68 etiology of, 69t, 420, 420t Anion gap calculation, 421, 631 Ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome, 268t Annular urticaria, 295, 295f Anogenital warts, 186, 191t Anorectal malformations, 708 Anorexia, in palliative care setting, 36 Anorexia nervosa, 179, 179t. See also Eating disorders Anoxia, 108 Antalgic gait, 650t Anterior horn cell diseases, 654–655 Anterior mediastinal mass, 745–746 Anthrax, cutaneous, 285t Antibiotic(s). See also specific drugs and diseases for acute otitis media, 502 allergy to, 203 for bacterial infections, 465–466t for bite wounds, 963 cross-reactivity among, 203 desensitization protocol, 204t for shock, 147, 147t Antibiotic lock therapy, 583, 584t Antibiotic-resistant bacteria, 18 Anticholinergics for asthma, 788, 789t, 790 poisoning/overdose, 916t, 919–920 Anticipatory grief, 37–38

Anticoagulants. See also Heparin; Warfarin for cerebral sinus venous thrombosis, 677 poisoning/overdose, 972–978, 974t for venous thromboembolism, 456 Anticonvulsant hypersensitivity syndrome. See Drug rash with eosinophilia and systemic symptoms (DRESS) Antidepressants, 756–757, 756t, 761 Antidiuretic hormone (ADH), 345 Antidotes, 917t, 929t Anti-double-stranded DNA (dsDNA), 854t Antiemetics, 343–344, 551 Antiepileptic drugs, 640t, 641t Antigen testing, in pneumonia, 531 Antihistamines, 280, 919–920, 919t Anti-LA/SSB, 854t Antineutrophilic cytoplasmic antibody (ANCA), 619 Antinuclear antibody (ANA), 120, 853–854, 854t Anti-phospholipid antibodies, 854t Antipsychotics, 774–775, 774t, 776t Antipyretics, 93, 94 Antiretroviral therapy, 591, 593 Anti-Rh0D, 448, 449t Anti-ribonucleoprotein, 854t Anti-Ro/SSA, 854t Anti-Sm, 854t Antithrombin deficiency, 455t Antithrombotics, 676–677 Anti-TNF agents, 844 Antivenom, 967 Antral web, 370 AOM. See Acute otitis media (AOM) Aortic coarctation. See Coarctation of the aorta Aortic regurgitation, 257, 257t Aortic stenosis, 236, 406 Aortic trauma, 873–874 APA (American Pediatric Association), 51 APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal

dysplasia), 207, 208 Apgar scoring, 691, 691t Apheresis, 462–463 Aphthous ulcers, 508 Apical, 128 Aplastic anemia, 443 Apnea central pathologic, in infancy, 779t, 781–782, 783 obstructive sleep, 782 pathologic, 777 Apparent life-threatening event (ALTE), 777–781 admission and discharge criteria for, 782–783 clinical presentation of, 777 consultation for, 782 course of illness, 781 definition of, 84, 777 diagnostic evaluation of, 714, 778–779, 778t, 780t, 781 differential diagnosis of, 777–778 discharge planning for, 781, 781t epidemiology of, 777 future directions in, 783 key points, 783 pathophysiology of, 84, 777, 778t treatment of, 781 Apparent mineralocorticoid excess syndrome, 339 Appendicitis, 862–865 abdominal pain in, 64–65 admission and discharge criteria for, 865 clinical presentation of, 863 consultation for, 865 course of illness, 863 diagnostic evaluation of, 65, 864 differential diagnosis of, 863–864, 865t epidemiology of, 862 key points, 865 pathophysiology of, 863 prevention of, 865

treatment of, 865 Apremilast, 280 APS (autoimmune polyglandular syndrome), 338 aPTT (activated thromboplastin time), 452 APVU system, 915, 915t Aqueous crystalline penicillin G, 192t Arborvirus infections, 491, 492, 494–495, 496 ARBs (angiotensin receptor blockers), 103t, 104 Arcanobacterium haemolyticum infection, 510, 511 ARF. See Acute rheumatic fever (ARF) ARF (acute renal failure). See Acute kidney injury (AKI) Argatroban, 456 Arginase deficiency, 410. See also Urea acid cycle defects Aripiprazole, 774t Arrhythmia(s). See also Electrocardiogram (ECG) after drowning, 960 in antihistamine overdose, 920t with chest pain, 79 in dilated cardiomyopathy, 247 in electrical injury, 900 in hyperkalemia, 352, 613 in hypertrophic cardiomyopathy, 249 in substance abuse, 939 syncope and, 149, 150 Arrhythmogenic right ventricular cardiomyopathy (ARVC), 227–228 Arsenic poisoning, 935, 936 Arterial blood gas (ABG) in acidosis, 69–70 complications of, 1049 contraindications for, 1048 formulas and pearls, 110t indications for, 1047–1048 procedure for, 1048–1049, 1048f sampling errors in, 1049t Arterial ischemic stroke (AIS). See also Stroke clinical presentation of, 670–671, 671t definition of, 664–665

diagnostic evaluation of, 674–675, 674t epidemiology of, 665 pathophysiology and risk factors, 665, 665t, 667f, 668f, 669f recurrence of, 679 treatment of, 676 Arterial oxygen (PaO2), 108, 110t Arterial partial pressure of carbon dioxide. See PaCO2 (arterial partial pressure of carbon dioxide) Arterial thrombosis, 455 Arteriovenous malformations (AVMs), 270–271 Arthritis. See also specific types clinical presentation of, 118–119, 118t etiology of, 120t in Henoch-Schönlein purpura, 832 infection-associated. See Infection-associated arthritis juvenile idiopathic. See Juvenile idiopathic arthritis (JIA) Arthrocentesis, 843, 1076–1078, 1077t ARVC (arrhythmogenic right ventricular cardiomyopathy), 227–228 ASA (American Society of Anesthesiologists) physical classification, 1003, 1004t Asboe-Hansen sign, 265 ASD (atrial septal defect), 217, 217f, 236 Asenapine, 774t Aspartate transaminase (AST) in biliary tract disease, 356 in hepatitis, 554, 554t in juvenile dermatomyositis, 837, 838t Aspergillus infection differential diagnosis of, 285t in transplant recipient, 602, 604, 605t treatment of, 605t Asphyxia, at birth. See Birth asphyxia Aspiration. See also Foreign body aspiration in child with severe neurologic impairment, 989 during feeding, 394 salivagram in, 1017 Aspiration pneumonia

clinical presentation of, 799 diagnostic evaluation of, 797f pathophysiology of, 529, 798, 798b treatment of, 799–800 Aspiration pneumonitis clinical presentation of, 799 diagnostic evaluation of, 798f pathophysiology of, 529, 797–798 treatment of, 799 Aspiration syndromes, 796–800 admission and discharge criteria for, 799–800 clinical presentation of, 799 consultation for, 800 differential diagnosis of, 798–799 key points, 799 pathophysiology of, 796–797, 796t prevention of, 800 risk factors for, 796, 797t treatment of, 799–800, 799t Aspirin for acute rheumatic fever, 257–258 for Kawasaki disease, 829–830 poisoning/overdose. See Salicylate poisoning/overdose sensitivity to, 203 for stroke prevention, 676 Asplenia, 449t, 607 Assent, 42, 42t AST. See Aspartate transaminase (AST) Astasia-abasia (psychogenic gait), 650t Asthma, 785–794 admission and discharge criteria for, 792, 793t clinical presentation of, 785 consultation for, 792 control measures for, 793, 793t definition of, 785 diagnostic evaluation of, 786–788, 786t, 787f, 787t, 788t, 824 differential diagnosis of, 517, 785–786

epidemiology of, 785 exacerbations of, 785, 787t key points, 794 pathophysiology of, 785 risk factors for death in, 786t treatment of adverse effects of, 790t after discharge to home, 792 future directions in, 793–794 initial, 790–792, 791t nonstandard, 790 pharmacologic, 788–790, 789t, 790t tapering in hospital, 792 Astrovirus infections, 541, 542t, 545t, 547t Ataxia-telangiectasia, 208 Atenolol, 103t, 325 Atlantoaxial rotatory subluxation (Grisel syndrome), 136, 879 Atopaxar, 976 Atopic dermatitis (AD), 275–281 admission criteria for, 281 aggravating factors in, 281 bacterial superinfection in, 277–278, 277f, 281 clinical presentation of, 275–277, 275t, 276t consultation for, 281 diagnostic evaluation of, 279, 279t differential diagnosis of, 278–279, 278f, 279f discharge criteria for, 281 epidemiology of, 275 future directions in, 281 genetic factors in, 275 Kaposi varicelliform eruption in, 277–278, 278f key points, 281 pathophysiology of, 275 treatment of, 279–281 Atrial enlargement, ECG in, 223, 224f Atrial septal defect (ASD), 217, 217f, 236 Atrioventricular septal defect (AVSD), 235, 236f

AUB. See Abnormal uterine bleeding (AUB) Auditory brainstem response (ABR) test, 699 Auscultation for blood pressure measurement, 99 in cardiac examination. See Cardiac examination Autoantibodies, 853–854, 854t Autoimmune disorders, 207–208 Autoimmune hemolytic anemia, 430 Autoimmune hypothyroidism, 322. See also Hypothyroidism Autoimmune lymphoproliferative syndrome (ALPS), 208 Autoimmune pancreatitis, 392 Autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia (APECED), 207, 208 Autoimmune polyglandular syndrome (APS), 338 “Autonomic storming,” 985–986 Autonomic syncope, 148–149, 149f. See also Syncope Autonomy, 40 AV block, 224 Avoidant-restrictive food intake disorder, 180. See also Eating disorders AVSD (atrioventricular septal defect), 235, 236f Axis, ECG, 223, 223f Azathioprine, 281, 378, 378t Azithromycin for cervicitis, 190t for chancroid, 190t for chlamydia, 189t for cystic fibrosis, 812 for cystic fibrosis exacerbations, 814t for GAS pharyngitis, 258t for gonorrhea, 189t, 190t for nongonococcal urethritis, 190t for pelvic inflammatory disease, 190t for pertussis, 536t Aztreonam for cystic fibrosis, 812 for cystic fibrosis exacerbations, 813t, 814t for fever and neutropenia, 745t

B Bacillus cereus infection, 285t, 543, 545t, 547t Back pain, 894–895, 895f Baclofen for spasticity, 990–991 withdrawal syndrome, 943, 943t, 991 Bacterial infections. See also specific bacteria acute gastroenteritis. See Acute gastroenteritis (AGE) in bronchiolitis, 516 empirical treatment of, 465–467t in immunosuppressed host, 301 meningitis. See Meningitis in neonates and young infants, 468–474, 469t, 470t, 471t in older infants and toddlers, 473–474 pneumonia. See Pneumonia prevention of, 472, 474 in transplant recipient, 600, 604. See also Transplant recipient, infections in urinary tract. See Urinary tract infections (UTIs) Bacterial vaginosis, 188t, 191t Bacteroides fragilis infections, 466t Bag-mask ventilation (BMV), 692, 693f, 1071 BAL (British anti-lewisite, dimercaprol) for lead poisoning, 933t, 934 for mercury poisoning, 936 Barbiturate poisoning/overdose, 916t Barbiturate withdrawal syndrome, 942, 942t, 943t Barium contrast, 1007, 1007f Barium enema, 97, 861, 861f, 1011 Barium swallow, 1010–1011 Bartonella henselae infection, 513, 514, 962 Basophilic stippling, 426t Battle sign, 884 BAT (brown adipose tissue) uptake, 1018 BBD (bladder and bowel dysfunction), 559, 559t BCA (bichloracetic acid), for genital/perianal warts, 191t Becker muscular dystrophy (BMD), 660, 660t, 661

Beckwith-Wiedemann syndrome, 405t, 407–408 Behavioral activation, 755 Benazepril, 103t Beneficence, 41 Benign neutropenia of childhood, 442 Benzathine penicillin G, 192t, 258t, 259t Benzodiazepines for antihistamine poisoning/overdose, 920t withdrawal syndrome, 942, 942t for withdrawal syndromes, 943, 943t Bereavement, palliative care and, 37–38 Bernard Soulier syndrome, 455 Betamethasone dipropionate, 280 β-adrenergic agonists adverse effects of, 788, 790t for asthma, 788, 789t, 792 for bronchiolitis, 518 β-adrenergic blockers adverse effects of, 104 for dilated cardiomyopathy, 248 for hypertension, 103t, 104 for hypertrophic cardiomyopathy, 249 11-β-hydroxylase deficiency, 337 Bezoars, 370 Bicarbonate in body fluids, 346t for diabetic ketoacidosis, 318 for renal tubular acidosis, 633 Bichloracetic acid (BCA), for genital/perianal warts, 191t Bicuspid aortic valve, 218, 220f BIG-IV (botulism immune globulin intravenous), 658, 970 Biguanides, 923–925, 924t, 925t Bilevel positive airway pressure, 1064–1065, 1065f. See also Noninvasive positive-pressure ventilation (NPPV) Biliary adenocarcinoma, 358 Biliary atresia, 357 Biliary cirrhosis, in cystic fibrosis, 811

Biliary disease, 355–360. See also specific diseases admission and discharge criteria for, 360 consultation for, 360 diagnostic evaluation of, 355–357, 356t, 1016, 1016f differential diagnosis of, 355, 356t key points, 360 pancreatitis in, 358, 386 pathophysiology of, 355 Biliary dyskinesia, 359 Bilious emesis, 153 Bilirubin. See also Hyperbilirubinemia; Neonatal hyperbilirubinemia in biliary disease, 356 in hepatitis, 554, 554t transcutaneous vs. total serum measurement of, 726 Binge-eating disorder, 180. See also Eating disorders Bioethics. See Ethical issues Biologic response modifiers, 122, 122t, 843–844 Biopsy, percutaneous image-guided, 1029–1030, 1029f Biphasic fever, 93t Bipolar disorder, 772. See also Psychosis Birth asphyxia, 691–696 admission criteria for, 695–696 clinical presentation of, 691, 691t differential diagnosis of, 691–692 discontinuing resuscitation for, 695 epidemiology of, 691 key points, 695 pathophysiology of, 691 treatment of, 692–694, 693f, 693t, 694f Birth injury, 701–706 extracranial, 703, 704f fractures, 701 intracranial hemorrhage, 704–705 key points, 706 peripheral nerve damage, 701–703, 702f Bisacodyl, 364t, 365t Bisphosphonates, 334

Bite marks, in child abuse, 161–162 Bite wounds, 961–965 admission criteria for, 964 clenched-fist hand injuries, 965 clinical presentation of, 962, 962t, 963f consultation for, 964 diagnostic evaluation of, 962 discharge criteria for, 964 empirical treatment of, 465t, 963 epidemiology of, 961 key points, 965 pathophysiology of, 961–962 prevention of, 965 rabies prophylaxis for, 854t, 964–965 treatment of, 963–964, 963t BK virus infection, 602, 605t, 606t Black widow spider bite, 968–969, 968t Bladder and bowel dysfunction (BBD), 559, 559t Bladder catherization complications of, 1047 contraindications to, 1046 equipment for, 1046, 1046t, 1047t indications for, 1046 procedure for, 1046–1047, 1046f, 1047f ultrasound guidance for, 1040–1041, 1041f Blalock-Taussig shunt, 230, 230f, 231f, 234 Bleeding disorders. See Coagulation disorders Blindness, cortical, 645, 886 B-lines, 1038, 1038f Blistering distal dactylitis, 269t Blisters. See also Vesicobullous diseases in burn injury, 896, 898 in epidermolysis bullosa, 306, 307f Blood culture in bacterial infections, 470, 474 in catheter-related bloodstream infections, 582 in pneumonia, 530

Blood donation, testing for, 461 Blood gases arterial. See Arterial blood gas (ABG) capillary, 110t venous, 110t Blood pressure, 99–100, 215. See also Hypertension; Hypotension “Blue dot” sign, 908 Blue rubber bleb nevus syndrome, 271 BMD (Becker muscular dystrophy), 660, 660t, 661 BMI (body mass index), 381 BMV (bag-mask ventilation), 692, 693f, 1071 Body mass index (BMI), 381 Boerhaave syndrome, 905 Bone and joint infections osteomyelitis. See Osteomyelitis septic arthritis, 466t, 570–571, 570t Bone marrow donation, 748. See also Hematopoietic stem cell transplant (HSCT) Bone marrow failure, 429, 443 Bone pain, 118, 118t Bone scintigraphy (bone scan) in bone tumors, 1019 indications for, 1014, 1015f interpretation of, 1016 in juvenile idiopathic arthritis, 843 in osteomyelitis, 567, 567t, 568f three-phase, 1016 Bone tumors, 738, 738f Bordetella pertussis, 534. See also Pertussis Borrelia burgdorferi. See Lyme disease/arthritis Boston protocol, for febrile infants, 469–470, 470t, 472 Botulinum neurotoxin type A (BNT-A), 990 Botulism, infant. See Infant botulism Botulism immune globulin intravenous (BIG-IV), 658, 970 Bowel injuries, 875 BPD. See Bronchopulmonary dysplasia (BPD) Brachial plexus, 702f

Brachial plexus birth palsy, 701, 702f, 703, 892–893 Bradycardia, with respiratory distress, 141 Brain abscess clinical presentation of, 492 diagnostic evaluation of, 493, 494f pathophysiology of, 490 treatment of, 465t, 496 Brain imaging. See Head and neck imaging Brain tumors, 735–736, 736t Branchial cleft cyst, 125, 135 Breastfeeding allergen-eliminated diets during, 116–117 contraindications to, 696 evaluation of, 90 failure of, 350 HIV transmission through, 590, 715 hyperbilirubinemia and, 725–726 in neonatal abstinence syndrome, 731 recommendations for, 696 support for, 699 vitamin D supplementation for, 331 Breastfeeding jaundice, 726 Breast milk jaundice, 355 Breath-holding spells, 85 British anti-lewisite. See BAL (British anti-lewisite, dimercaprol) Brodie abscess, 569 Bronchiolitis, 515–520 admission criteria for, 519 asthma and, 517 clinical presentation of, 515–516 complications of, 516 consultation for, 519 course of, 516–517, 517t diagnostic evaluation of, 516 differential diagnosis of, 516, 785 discharge criteria for, 519 epidemiology of, 515, 515f

etiology of, 515 key points, 524 prevention of, 520, 520t treatment of, 517–519, 517t, 518f, 1066 Bronchodilators, 518. See also β-adrenergic agonists Bronchopulmonary dysplasia (BPD), 801–806 admission criteria for, 806 clinical presentation of, 801–803, 802f consultation for, 805–806 diagnostic criteria for, 801–802, 803t differential diagnosis of, 805, 805t discharge criteria for, 806 epidemiology of, 802–803, 803t key points, 806 pathophysiology of, 801 prevention of, 806 treatment of, 803–805 Brown adipose tissue (BAT) uptake, 1018 Brown recluse spider bite, 968–969, 968t Brudzinski sign, 491, 492 Brugada syndrome, 150, 227, 227f Bruises. See Ecchymoses Budesonide, 377 Bulimia nervosa, 179–180, 179t. See also Eating disorders Bulla, 265, 265t, 266f, 267f. See also Vesicobullous diseases Bullous arthropod reaction, 269t Bullous congenital ichthyosiform erythroderma, 268t Bullous lupus erythematosus, 268t Bullous pemphigoid, 268t Bundle branch block, 225, 225–226f Buprenorphine, 732, 944 Burkholderia cepacia, 813t, 814t Burkitt lymphoma, 735 Burns, 896–900 admission criteria for, 899, 899t chemical, 900 in child abuse, 161, 896

clinical presentation of, 896, 897f consultation for, 899 differential diagnosis of, 896 discharge criteria for, 899 epidemiology of, 896 initial management of, 896–897, 898f key points, 901 pathophysiology of, 896 prevention of, 899 treatment of, 897–899 Burr cells. See Schistocytes C Caffeine withdrawal, 943t CAH (congenital adrenal hyperplasia), 337, 337t, 710–711 Calcaneovalgus, 892 Calcineurin inhibitors, 280 Calcinosis, 836–837, 837f Calcitonin, 334 Calcitriol, 333 Calcium, 329 Calcium channel blockers for hemolytic uremic syndrome, 622 for hypertensive urgency/emergency, 103, 103t poisoning/overdose, 73, 74t, 917t Calcium chloride, 352 Calcium disodium edetate (CaNa2EDTA), 933–934, 933t Calcium glubionate, 332 Calcium gluconate, 352 Calcium regulation, 329–330 Calcium regulation disorders. See Hypercalcemia; Hypocalcemia Calcium stones, 912 Calicivirus infections, 541, 542t Calories, daily needs for, 383, 383t Campylobacter jejuni infections epidemiology of, 544, 544t pathophysiology of, 541, 542t, 543

treatment of, 466t, 551t Campylobacter perfringens infections, 543 Canakinumab, 122, 122t Cancer. See Childhood cancer Candesartan, 103t Candida/candidiasis in catheter-related bloodstream infections, 581t, 583 congenital, 267t diagnostic evaluation of, 604 differential diagnosis of, 285t, 508 in immunosuppressed host, 301 neonatal, 267t in transplant recipient, 602, 604, 605t Capillary blood gas, 110t Capillary malformation-arteriovenous malformation (CM-AVM), 271 Capillary malformations (port-wine stains), 270 Capnography, 824 Capsule endoscopy, 376 CAPTA (Child Abuse Prevention and Treatment Act), 174 Captopril, 103t Caput succedaneum, 703, 704f Carbamate poisoning, 916t Carbamazepine, 641t Carbon dioxide end-tidal, 71, 824, 825f, 1004 partial pressure of. See PaCO2 (arterial partial pressure of carbon dioxide) Carbon monoxide poisoning clinical presentation of, 946 diagnostic evaluation of, 113, 946, 946t pathophysiology of, 945 treatment of, 947–948, 947f Carboxyhemoglobin (COHb), 113, 946, 946t Cardiac cycle, 217f Cardiac examination, 215–220 auscultation in clicks, 218, 219f, 220f heart sounds, 216–217, 217f, 218f

murmurs. See Murmurs opening snap, 217, 219f pericardial friction rub, 218 general observation in, 215 inspection in, 216 key points, 220 palpation in, 216 vital signs in, 215–216 Cardiac imaging. See also Echocardiogram computed tomography, 1022 magnetic resonance imaging, 1026 nuclear medicine studies, 1017–1018 point-of-care ultrasound, 1036–1037, 1037f Cardiac injuries, 873–874 Cardiac syncope, 149–150. See also Syncope Cardiac tamponade, 842 Cardiogenic shock, 144, 144t Cardiomyopathy diagnostic evaluation of, 79 dilated. See Dilated cardiomyopathy in epidermolysis bullosa, 313 hypertrophic. See Hypertrophic cardiomyopathy restrictive. See Restrictive cardiomyopathy Cardiopulmonary resuscitation (CPR), 997–998 Cardiorespiratory monitors, home, 781, 781t Care coordination, for child with severe neurologic impairment, 987 Carey Coombs murmur, 257 Carnitine, 422 Carotid artery dissection, 135 Castleman disease, 298 Casts, 893, 894f Catatonia, 772. See also Psychosis Cat bites. See Bite wounds Catecholaminergic polymorphic ventricular tachycardia (CPVT), 228 Cat-eye syndrome, 405t Catheter(s) bladder. See Bladder catherization

central venous. See Central venous catheters (CVCs) intraosseous, 1056–1057, 1056f, 1057t peripherally inserted central. See Peripherally inserted central catheter (PICC) Catheter-related bloodstream infections, 581–582, 581t, 583t. See also Central venous catheters (CVCs) Cat-scratch disease, 513, 514, 962 Caustic ingestion, 927t, 929–931, 930t CBC. See Complete blood count (CBC) CCTR (Cochrane Controlled Trials Register), 10 CDH (congenital diaphragmatic hernia), 707–708, 708f CDS (clinical decision support), 21, 21t, 22 CDSR (Cochrane Database of Systematic Reviews), 10 Cefazolin for cystic fibrosis exacerbations, 813t for endocarditis prophylaxis, 244t for infective endocarditis, 243t in lock therapy, 584t Cefepime for bacterial meningitis, 495t for fever and neutropenia, 745t for osteomyelitis, 567t for septic shock, 147t Cefixime, 189t, 190t Cefotaxime, 147t, 495t, 851t Cefotetan, 190t Cefoxitin, 190t Cefpodoxime, 190t Ceftazidime for bacterial meningitis, 495t for cystic fibrosis exacerbations, 813t for fever and neutropenia, 745t in lock therapy, 584t Ceftriaxone for bacterial meningitis, 495t for chancroid, 190t for chemoprophylaxis for contacts in meningococcal meningitis, 497t

for endocarditis prophylaxis, 244t for epididymitis, 190t for gonococcal conjunctivitis, 889 for gonorrhea, 189t, 190t for infective endocarditis, 242t for Lyme disease, 851t for neurosyphilis, 192t for osteomyelitis, 567t for pelvic inflammatory disease, 190t for septic shock, 147t for syphilis, 192t Cefuroxime, 189t, 190t, 851t Cellulitis admission criteria for, 575 clinical presentation of, 574, 574f consultation for, 575 definition of, 131, 573 diagnostic evaluation of, 575 differential diagnosis of, 574–575 discharge criteria for, 575 pathophysiology of, 573–574 periorbital, 465t, 503–506, 504f, 574 prevention of, 575–576 treatment of, 465t, 575 Cementum, 128 Central apnea, in infancy, 781–782 Central (cerebral) hypotonia, 650 Central nervous system (CNS) imaging computed tomography, 1020–1021, 1021f nuclear medicine studies, 1018, 1019f ultrasound, 1023 Central nervous system (CNS) infections, 489–497 admission criteria for, 496 bacterial meningitis. See Meningitis, bacterial brain abscess. See Brain abscess consultation for, 497 differential diagnosis of, 490t

discharge criteria for, 497 encephalitis. See Encephalitis in HIV-infected child, 592 HSV meningitis, 490–491 prevention of, 497, 497t Central nervous system (CNS) tumors, 735–736, 736t Central venous catheters (CVCs) complications of, 1053 contraindications to, 1051–1052 equipment for, 1052, 1052t indications for, 1051 infections related to clinical presentation of, 581 consultation for, 584 diagnostic evaluation of, 581–582, 581t differential diagnosis of, 581 discharge criteria for, 584 pathophysiology of, 580–581, 580f, 581t prevention of, 17, 584 treatment of, 582–583, 582t, 583t procedure for, 1052 site-specific considerations in, 1052–1053, 1052f thrombosis in, 456–457, 743 types of, 580, 580t ultrasound-guided placement of, 1038–1039, 1039f Cephalexin for cystic fibrosis exacerbations, 814t for endocarditis prophylaxis, 244t for osteomyelitis, 569 Cephalohematoma, 703, 704f Cephalosporins, 203, 244t, 258t Cerebellar ataxia, 650t Cerebral aneurysm, 669, 675, 678 Cerebral arteriopathy, 665, 667f Cerebral edema in abused child, 168 in acute disseminated encephalomyelitis, 684

in diabetic ketoacidosis, 320 in drowning, 960 fluid resuscitation and, 348, 350 in hyperammonemia, 409 in hyperglycemia, 318 Cerebral (central) hypotonia, 650 Cerebral palsy, 651, 990. See also Severe neurologic impairment Cerebral salt wasting, 886 Cerebral sinovenous thrombosis (CSVT). See also Stroke clinical presentation of, 671 diagnostic evaluation of, 674t, 675 pathophysiology and risk factors for, 665–666, 669, 669f recurrence of, 679 treatment of, 677 Cerebrospinal fluid (CSF) analysis in febrile neonates and young infants, 470–471, 471t in Guillain-Barré syndrome, 656 in meningitis and encephalitis, 493 in multiple sclerosis, 687 in neuromyelitis optica, 689 in optic neuritis, 685 in transverse myelitis, 686 Cerebrospinal fluid (CSF) circulation, 881, 881f, 1018 Cerebrospinal fluid (CSF) shunt assessment 0f, 1044–1045, 1044t, 1045t dysfunction of, 985, 1044, 1044t headache in child with, 645 for hydrocephalus, 882 infections in, 584–587, 585t, 586f puncture of, 1045, 1045t Certolizumab, 378, 378t Cervical lymphadenitis, 133, 513–514, 513t, 878 Cervical lymphadenopathy, 827 Cervical spine injuries, 871–872, 885 instability of, 135 osteomyelitis of, 135, 569–570

stenosis of, 135 Cervicitis, 186, 187, 190t CF. See Cystic fibrosis (CF) CFTR mutations, 392, 809, 809t CHAMP mnemonic, for hydrocarbon toxicity, 927, 927t Chancroid, 190t Charcot-Marie-Tooth (CMT) disease/syndrome, 405t, 657 Charcot’s triad, 355, 359 Chelation therapy, for lead poisoning, 933–934, 933t Chemical burns, 900 Chemotherapy, adverse effects of, 303 Chest compressions, in neonates, 693 Chest imaging computed tomography, 1021–1022, 1022f magnetic resonance imaging, 1026 radiograph. See Chest radiograph ultrasound, 530 Chest pain, 77–80 diagnostic evaluation of, 80 differential diagnosis of, 77–80, 78t, 79t, 92 key points, 80 management of, 80 patient history in, 77 physical examination in, 77 Chest radiographs in aspiration pneumonitis, 798f in asthma, 786, 787f in bronchiolitis, 516 in bronchopulmonary dysplasia, 802f in caustic ingestion, 930 in cystic fibrosis, 812f, 813f in drowning, 959, 959f in foreign body aspiration, 817f, 818f, 818t indications for, 1008 in pancreatitis, 389 in pericarditis, 254, 254f in pneumomediastinum, 905–906, 905f, 906f

in pneumonia, 529–530, 530f, 531f in pneumothorax, 902, 902f views for, 1008 Chest tube placement, 1029, 1029f Chiari I malformation, 136 Chickenpox (varicella), 269t, 482t, 668f Child abuse and neglect. See Abuse and neglect Child Abuse Prevention and Treatment Act (CAPTA), 174 Child development assessment in medical settings, 30 implications for hospitalized child, 31–33 streams and milestones, 30, 31t, 32t Childhood cancer, 733–739. See also Oncologic emergencies admission and discharge criteria for, 738 bone tumors, 738, 738f brain tumors, 735–736, 736t consultation for, 738 embryonal tumors, 738 epidemiology of, 733 extracranial solid tumors, 736–738, 736t, 737f future directions in, 739 genetic syndromes and, 733, 733t key points, 738 leukemia. See Leukemia lymphoma, 734–735 neuroblastoma, 339, 737, 737f, 1020f risk factors for, 733 Child life services, 26 Child protective services, 174–175 Child with medical complexity (CMC) approach to care of, 981–982 definition of, 981 do-not-attempt-resuscitation orders for. See Do-not-attempt-resuscitation (DNAR) orders enterostomy tube feeding in, 993–996, 994f future directions in, 982 hospitalist and, 981

severe neurologic impairment. See Severe neurologic impairment Chlamydia trachomatis infections conjunctivitis, 888 diagnostic evaluation of, 188t empirical treatment of, 466t treatment of, 189t Chloride, in body fluids, 346t Chlorpromazine, 774t Choking, 816, 817t. See also Foreign body aspiration Cholangiogram, C48.245 Cholangitis, 358–359, 360 Cholecalciferol (vitamin D3), 333 Cholecystectomy, 358 Cholecystitis, 358–359, 437 Choledochal cysts, 355, 357–358, 357f Cholelithiasis, 358, 437 Cholera clinical presentation of, 547t epidemiology of, 544, 545t pathophysiology of, 542, 542t, 543 treatment of, 551t Cholestasis. See Biliary disease Chromosome(s), 399–400, 401f, 402f. See also Genetic disorders Chronic glomerulonephritis, 619 Chronic granulomatous disease, 210 Chronic inflammatory demyelinating polyneuropathy (CIDP), 211t, 212, 656–657, 657f Chronic lung disease of infancy (CLDI). See Bronchopulmonary dysplasia (BPD) Chronic lymphocytic leukemia, 211t, 212 Chronic renal failure (CRF), 614–618 admission and discharge criteria for, 617 classification of, 614–615, 615t clinical presentation of, 615 consultation for, 617 diagnostic evaluation of, 616, 616t epidemiology of, 615

etiology of, 615, 615t key points, 618 pathophysiology of, 615 prevention of, 617–618 treatment of, 616–617 in tubulointerstitial nephritis. See Tubulointerstitial nephritis (TIN) Chronic respiratory insufficiency, 1067 Chronic static encephalopathy (CSE), 651 Cidofovir, 606t Cinacalcet, 334 Ciprofloxacin for chancroid, 190t for chemoprophylaxis for contacts in meningococcal meningitis, 497t for cystic fibrosis exacerbations, 814t Circumcision, 698 Cisternography, radionuclide, 1018 Citalopram, 756, 756t, 766 Citrobacter spp. infections, 188t CK (creatine kinase), 661, 663 Clarithromycin for cystic fibrosis exacerbations, 814t for GAS pharyngitis, 258t for pertussis, 536t Clavicle fracture, during delivery, 701 CLDI (chronic lung disease of infancy). See Bronchopulmonary dysplasia (BPD) Cleft lip and palate, 709 Clenched-fist hand injuries, 965 Clindamycin for bacterial vaginosis, 191t for cystic fibrosis exacerbations, 814t for endocarditis prophylaxis, 244t for GAS pharyngitis, 258t for osteomyelitis, 569 for pelvic inflammatory disease, 190t for septic shock, 147t for toxic shock syndrome, 486

Clinical decision support (CDS), 21, 21t, 22 Clinical practice guideline (CPG), 22 Clobazam, 641t Clonidine, 944 Clostridial myonecrosis (gas gangrene), 578 Clostridium botulinum, 658, 969, 970. See also Infant botulism Clostridium difficile infection clinical presentation of, 547t, 548 complications of, 548 diagnostic evaluation of, 549t, 550 epidemiology of, 543, 544t pathophysiology of, 542, 542t, 543 transmission-based precautions, 17t, 18 in transplant recipient, 600 treatment of, 466t, 551t Clostridium perfringens infection, 543, 545t, 547t CLOVES syndrome, 271, 272 Clozapine, 774t Clubfoot (talipes equinovarus), 892, 892f CM-AVM (capillary malformation-arteriovenous malformation), 271 CMC. See Child with medical complexity (CMC) CMT (Charcot-Marie-Tooth) disease/syndrome, 405t, 657 CMV infections. See Cytomegalovirus (CMV) infections CNS. See under Central nervous system (CNS) Coaching, 56 Coagulase-negative staphylococci (CONS) in catheter-related bloodstream infections, 581t, 582, 583 in cerebrospinal fluid shunt infections, 584 in infective endocarditis, 240t Coagulation cascade, 451–452, 452f, 972, 972f Coagulation disorders in chronic renal failure, 617 clinical presentation of, 452 diagnostic evaluation of, 452–453, 453f future directions in, 457 hemophilia. See Hemophilia key points, 457

pathophysiology of, 451–452, 452f purpura in, 262 Coarctation of the aorta clinical presentation of, 236 pathophysiology of, 233 physical examination in, 215 treatment of, 233, 236 Cocaine, 916t, 939t Cochrane Controlled Trials Register (CCTR), 10 Cochrane Database of Systematic Reviews (CDSR), 10 Codeine, 879 Cognitive behavioral therapy, 755, 766 Cognitive development, 30, 31t, 32t COHb (carboxyhemoglobin), 113, 946, 946t Colchicine, 254 Cold agglutinin disease, 431 Colectomy, 377 Colic, 116 Colitis, severe, 377–378, 377t. See also Acute gastroenteritis (AGE); Inflammatory bowel disease (IBD) Collagen vascular disease, pericarditis in, 253 Colonoscopy, in inflammatory bowel disease, 376, 376f Coma, 73t. See also Altered mental status (AMS) Coma blister, 268t Comanager, pediatric hospitalist as, 27–28 Common variable immunodeficiency (CVID), 208, 210 Communication in care handoffs, 39 with consultants, 48 medicolegal issues in, 45 Comparative effectiveness research healthcare variation and, 8 pediatric hospital medicine and, 4–5 Compartment syndrome, 453, 893 Competence, 42 Complete blood count (CBC) in appendicitis, 864

in coagulation disorders, 452 definition of, 425, 425t in febrile neonates and young infants, 470, 470t Complex glycerol kinase deficiency, 405t Computed tomography (CT), 1019–1020 abdomen/pelvis, 1022, 1023f in appendicitis, 864 brain, 1020, 1021f chest and cardiovascular, 1021–1022, 1022f contrast agents for, 1007 in drowning, 960 extremity, 1022, 1023f in foreign body aspiration, 819 in gastrointestinal bleeding, 97 in headache, 646, 647t head and neck, 1020–1021, 1022f in head trauma, 871, 872f, 885, 885f, 1021f in hydrocephalus, 882 in mastoiditis, 501, 501f in orbital cellulitis, 504, 505f in osteomyelitis, 567, 567t in pneumonia, 530, 530f, 531f in pneumothorax, 902–903, 903f in Pott puffy tumor, 506, 506f radiation dose from, 1006t spine, 1021 in stroke, 667f, 668f, 670f, 674–675, 674t in subdural empyema, 506f Computerized Physician Order Entry (CPOE), 22, 23 Concurrent care, 37 Condylomata acuminata. See Anogenital warts Confidentiality, 49 Confusion, 73t. See also Altered mental status (AMS) Congenital adrenal hyperplasia (CAH), 337, 337t, 710–711 Congenital anomalies, 706–711 abdominal wall defects, 706–707, 706f, 707f ambiguous genitalia, 710–711

anorectal malformations, 708 cleft lip and palate, 709 congenital diaphragmatic hernia, 707–708, 708f in infants of diabetic mothers, 723, 723t key points, 711 neural tube defects, 708–709 VACTERL syndrome, 216t, 709–710, 710f Congenital diaphragmatic hernia (CDH), 707–708, 708f Congenital disorders of glycosylation, 653 Congenital erosive and vesicular dermatosis, 268t Congenital heart disease, 228–238. See also specific disorders admission and discharge criteria for, 237 central access and paradoxical embolization in, 238 clinical presentation of, 227, 228 consultation for, 237 diagnostic evaluation of, 229–230 differential diagnosis of, 229, 229t empiric treatment of, 229 endocarditis prophylaxis for, 237 epidemiology of, 228 feeding/growth issues and, 238 key points, 238 management of, 230–231, 230f, 231f in neonates, 84, 229, 229t, 231–234, 232f, 233f, 699 pacemakers and implantable defibrillators for, 238 pathophysiology of, 228 presenting with heart failure or murmur in infancy, 234–236, 235f, 236f, 237f presenting with murmur in childhood, 236 prevention of, 238 respiratory syncytial virus infection and, 237–238 Congenital hypothyroidism, 322–325 Congenital infections, 713–719. See also specific infections admission and discharge criteria for, 717, 718 clinical presentation of, 714–715 consultation for, 718 diagnostic evaluation of, 714f, 716, 716t, 717t, 718f

differential diagnosis of, 715–716 epidemiology of, 713–714 pathophysiology of, 714 prevention of, 718 treatment of, 716–717, 718f Congenital Langerhans cell histiocytosis, 267t Congenital muscular dystrophy, 660t Congenital myasthenic syndrome, 659 Congenital myopathies, 659–660 Congenital myotonic dystrophy, 661–662 Congestive heart failure. See Heart failure Conjunctivitis, 697, 888–889 CONS. See Coagulase-negative staphylococci (CONS) Consciousness altered levels of. See Altered mental status (AMS) loss of, in minor head injury, 871 in seizures, 637, 637t Constipation, 362–366 admission and discharge criteria for, 365 in child with severe neurologic impairment, 986, 989 clinical presentation of, 363 consultation for, 365 course of illness, 364 diagnostic evaluation of, 363–364, 363t, 364f differential diagnosis of, 362t, 363, 864t epidemiology of, 362 in epidermolysis bullosa, 312 etiology of, 362–363, 362t future directions in, 366 in infant botulism, 658, 970 key points, 366 in palliative care setting, 36 prevention of, 365–366 treatment of, 364–365, 364t, 365t Consultant(s) communication with, 48 disagreements with, 48

pediatric hospitalist as, 27–28 Contact dermatitis, allergic, 268t, 278 Continuous positive airway pressure (CPAP), 518, 1064, 1065f. See also Noninvasive positive-pressure ventilation (NPPV) Contrast agents, 203, 1006–1007, 1007f, 1007t Contrast enema, 861, 861f, 1011 Conversion disorder, 763–764, 765–766 Coral snake envenomation, 967, 967t Corneal abrasion, 313 Corneal laceration, 890, 890f Corneal xerophthalmia, 355 Coronal, 128 Coronary artery aneurysm, 77, 212, 830, 831 Corticosteroids for adrenal crisis, 338 adverse effects of, 302–304, 378t, 790t for asthma, 788, 790t, 792 for atopic dermatitis, 280 for bronchiolitis, 518–519 for bronchopulmonary dysplasia, 804 for croup, 522, 522t for demyelinating syndromes, 682 for DRESS, 291 for erythema multiforme, 296 for graft-versus-host disease, 750 for hypercalcemia, 334 for immune thrombocytopenic purpura, 448, 449t for inflammatory bowel disease, 377, 378 for juvenile dermatomyositis, 838, 838f for juvenile idiopathic arthritis, 843 for nephrotic syndrome, 629 for pneumonia, 533 for rapidly progressive glomerulonephritis, 620 for Stevens-Johnson syndrome/toxic epidermal necrolysis, 299f for systemic lupus erythematosus, 854 topical, 280 for tubulointerstitial nephritis, 626

Corticotropin-releasing hormone (CRH), 327 Costochondritis, 80 Cough in asthma, 786 in foreign body aspiration, 817 psychogenic, 786 Cow milk protein allergy, 89, 96, 116 Coxsackievirus infection (hand, foot, and mouth disease), 269t, 508, 509f COX-1 inhibitors, 93 COX-2 inhibitors, 93 CPAP (continuous positive airway pressure), 518, 1064, 1065f. See also Noninvasive positive-pressure ventilation (NPPV) CPG (clinical practice guideline), 22 CPOE. See Computerized Physician Order Entry (CPOE) CPR (cardiopulmonary resuscitation), 997 CPVT (catecholaminergic polymorphic ventricular tachycardia), 228 C-reactive protein (CRP) in appendicitis, 864 in bacterial infections, 473–474 in osteomyelitis, 567, 569 Creatine kinase (CK), 661, 663 Creatinine clearance, 612, 612t, 613t CRF. See Chronic renal failure (CRF) CRH (corticotropin-releasing hormone), 327 Cri du chat (5p deletion) syndrome, 404, 405t Crisaborole, 280 Critical aortic stenosis, 233 Crohn disease, 127t, 375. See also Inflammatory bowel disease (IBD) Crotaline envenomation, 966–967 Croup. See Laryngotracheitis (croup) Croup (laryngotracheitis), 520–524 admission criteria for, 522–523 clinical presentation of, 520–521 consultation for, 522 course of illness, 521–522 diagnostic evaluation of, 521, 521f differential diagnosis of, 521, 521t

discharge criteria for, 523 epidemiology of, 520 etiology of, 520 treatment of, 522, 522t CRP. See C-reactive protein (CRP) Crying, intractable. See Irritability and intractable crying Cryoprecipitate, 460 Cryotherapy, 191t Cryptosporidium infections clinical presentation of, 547t, 548 epidemiology of, 543, 545t pathophysiology of, 542, 542t, 543 treatment of, 552t CSE (chronic static encephalopathy), 651 CSF analysis. See Cerebrospinal fluid (CSF) analysis CSVT. See Cerebral sinovenous thrombosis (CSVT) CT. See Computed tomography (CT) Currant jelly stool, 154, 861 Cushing syndrome, 339 Cutaneous anthrax, 285t Cutaneous diphtheria, 285t Cutaneous injuries, in abuse and neglect. See Abuse and neglect, cutaneous injuries in CVCs. See Central venous catheters (CVCs) CVID (common variable immunodeficiency), 208, 210 Cyanide gas poisoning, 945, 946, 948 Cyanosis, 81–85 in apparent life-threatening event, 777 definition of, 81 diagnostic evaluation of, 83, 84f differential diagnosis of, 81–82, 83f, 777 key points, 85 management of, 83–84 pathophysiology of, 81 patient history in, 81, 82t physical examination in, 81, 82t with respiratory distress, 141

Cyanotic spells, 84 Cyclic neutropenia, 127t Cyclooxygenase (COX), 93 Cyclophosphamide, 620, 855 Cyclospora infection, 543, 545t, 547t, 552t Cyclosporine adverse effects of, 302, 303, 378, 378t for atopic dermatitis, 280 Cystic fibrosis (CF), 809–814 admission and discharge criteria for, 814 causes of, 811f clinical presentation of, 809, 809t complications of, 391, 812–814, 812f, 813f, 813t, 814t consultation for, 814 course of illness, 810–811, 810t, 811f, 811t diagnostic evaluation of, 809–810, 810t epidemiology of, 809 key points, 814 pathophysiology of, 809, 809t treatment of, 811–812 Cystography, radionuclide, 910, 1006t, 1014, 1015f Cytomegalovirus (CMV) infections congenital, 714, 714f, 716t, 717t in immunosuppressed host, 302 transfusions and, 461 in transplant recipient, 600, 605t, 606t D Dabigatran, 974–975 Dactylitis, 435, 848 Danger space, 131, 132f, 512 Dantrolene, 951 Database of Abstracts of Reviews of Effects (DARE), 10 DDAVP. See Desmopressin acetate (DDAVP) D-dimer test, 453 DebRA (Dystrophic EB Research Association of America), 315 Debrancher deficiency, 417t

Deceptive practices, 43 Decision-making capacity, 42 Deep neck space infections parapharyngeal, 134–135, 511–512, 512f peritonsillar, 133, 134f, 466t, 511, 511f retropharyngeal, 133–134, 134f, 466t, 511, 1022f Deep soft tissue abscess, 465t Deep venous thrombosis (DVT). See Venous thromboembolism Deferoxamine, for iron toxicity, 919, 919t Deflazacort, 661 Dehydration admission criteria for, 344 classification of, 341 complications of, 634 diagnostic evaluation of, 86, 341–342, 342t differential diagnosis of, 341 discharge criteria for, 344 initial management of, 341 key points, 344 pathophysiology of, 341, 341t scoring system for, 342, 342t treatment of according to severity, 546t algorithm for, 343f antiemetics, 343–344 intravenous fluid therapy, 343, 346t, 347–348, 347t, 349t oral rehydration therapy, 342 subcutaneous rehydration therapy, 343 Delayed hemolytic transfusion reaction (DHTR), 462 Delirium, 772 Delivery room medicine, 691–695 admission criteria and consultation for, 694–695 bag-mask ventilation in, 692, 694f circulatory support, 693 discontinuing resuscitation in, 695 endotracheal intubation in, 692–693 meconium-stained amniotic fluid, 695

medications in, 694 multiple gestations, 695 newborn assessment and differential diagnosis in, 691–692, 691t pathophysiology of, 691 pneumothorax, 695 preterm infants. See Premature/preterm infants resuscitation in, 692, 693f supplemental oxygen requirement in, 692, 693t vascular access in, 693–694 ventilation assistance in, 692 Delusions, 772, 772t. See also Psychosis Demeclocycline, 350 Demyelinating syndromes, 681–690 acute disseminated encephalomyelitis. See Acute disseminated encephalomyelitis (ADEM) admission criteria for, 689 characteristics of, 681 clinically isolated syndromes, 685–687, 685t, 686f, 687f clinical presentation of, 681 consultation for, 689 diagnostic evaluation of, 681, 689 differential diagnosis of, 681, 682t, 683t discharge criteria for, 689 key points, 689 multiple sclerosis (MS), 687–688, 688f neuromyelitis optica, 688–689 treatment of, 681–682 Dental abscess complications of, 130t diagnostic evaluation of, 129, 129f differential diagnosis of, 129, 129t management of, 129–130, 129f, 134 pathophysiology of, 127, 128f, 134 patient history in, 128 physical examination in, 128 prevention of, 130b Dental caries

in child with severe neurologic impairment, 990 complications of, 127, 128 in epidermolysis bullosa, 307 Dentin, 128 Depression, 753–757 admission and discharge criteria for, 757 clinical presentation of, 753 consultation for, 757 diagnostic evaluation of, 754–755, 755t differential diagnosis of, 754, 754t pathophysiology of, 753, 753t physical illness and, 753 prevention of, 757 special considerations in, 757 treatment of, 755–757, 756t Dermatitis allergic contact, 268t, 278 atopic. See Atopic dermatitis seborrheic, 278, 278f Dermatitis herpetiformis, 268t Dermatomyositis. See Juvenile dermatomyositis Dermatophyte infection, 269t, 301 Desensitization, for drug allergy, 204f, 205–206, 205f Desmopressin acetate (DDAVP) for diabetes insipidus, 328, 350–351 for von Willebrand disease, 454 Desonide, 280 Desoximetasone, 280 Detoxification. See Poisoning; Withdrawal syndromes Developmental delay, 988 Developmental dysplasia of the hip, 699–700, 700t, 891–892 Device-related infections, 580–587 catheter-related bloodstream infections, 581–582, 581t, 583t. See also Central venous catheters (CVCs) in cerebrospinal fluid shunts, 584–587, 585t, 586t epidemiology of, 580 Dexamethasone

for bronchiolitis, 519 for croup, 522, 522t for spinal cord compression, 746 for thyroid storm, 325 Dexamethasone suppression test, 339 Dexmedetomidine, 943, 944, 1004 Dextranomer/hyaluronic acid, 911 Dextromethorphan, 939t, 940t Dextrose, for hypoglycemia, 416, 722, 723t DGI (disseminated gonococcal infection), 186, 187 DHTR (delayed hemolytic transfusion reaction), 462 Diabetes insipidus (DI) diagnostic evaluation of, 327–328 differential diagnosis of, 327 special considerations in, 328 treatment of, 328, 350–351 Diabetes mellitus clinical presentation of, 317 comorbidities of, 321 in cystic fibrosis, 811 diagnostic evaluation of, 317, 319f differential diagnosis of, 317 epidemiology of, 317 hyperglycemic states in, 317–318. See also Hyperglycemia infants of mothers with, 722–724, 723f, 723t new therapies for, 321 prevention of, 321 Diabetic ketoacidosis (DKA) clinical presentation of, 317 complications of, 320 diagnostic evaluation of, 317 differential diagnosis of, 864t management of, 318–320 Diagnostic errors, 14 Dialysis. See Hemodialysis; Peritoneal dialysis Diarrhea, 85–88. See also Acute gastroenteritis (AGE) bloody

in acute renal failure, 611 in bacterial gastroenteritis, 542–543 differential diagnosis of, 549 in dysentery, 548 in graft-versus-host disease, 749 causes of, 86, 87t definition of, 85 diagnostic evaluation of, 86 differential diagnosis of, 86, 87t in HIV infection, 593 key points, 88 management of, 86–88 pathophysiology of, 86 patient history in, 86 physical examination in, 86 Diazepam, 640t, 642 DIC. See Disseminated intravascular coagulation (DIC) Diclofenac gel, 121t Dicloxacillin, 569, 814t Didanosine, 593 Diffusing capacity for carbon monoxide (DLCO), 822–823 DiGeorge syndrome, 208, 405t, 407 Digoxin, 247 Dilated cardiomyopathy admission and discharge criteria for, 248 clinical presentation of, 245 diagnostic evaluation of, 246–247, 246t, 247f differential diagnosis of, 245, 246t management of, 247–248 Dimercaprol. See BAL (British anti-lewisite, dimercaprol) Diphenhydramine, 770 Diphtheria, cutaneous, 285t Diplegia, 654 Direct Coombs test, 425t Direct inguinal hernia, 870 Direct thrombin inhibitor poisoning/overdose, 974–975 Discharge planning, 26, 40, 40t

Disease-modifying antirheumatic drugs (DMARDs), 122, 122t, 843–844 Disimpaction, 364, 364t Disseminated gonococcal infection (DGI), 186, 187 Disseminated intravascular coagulation (DIC) clinical presentation of, 262, 262f diagnostic evaluation of, 457 differential diagnosis of, 622 as oncologic emergency, 742–743, 743t pathophysiology of, 450, 457 treatment of, 450, 457 Distal intestinal obstruction syndrome, 811, 811f Distal renal tubular acidosis, 631–632, 632t. See also Renal tubular acidosis (RTA) Distributive shock, 143–144, 144t Diuretics for dilated cardiomyopathy, 248 for hypercalcemia, 334 for hypertension, 103t, 104 for hyponatremia, 350 DKA. See Diabetic ketoacidosis (DKA) DLCO (diffusing capacity for carbon monoxide), 822–823 DMARDs (disease-modifying antirheumatic drugs), 122, 122t, 843–844 Dobutamine, 247, 951 Documentation. See Medical records Docusate enema, 364t Dog bites. See Bite wounds Do-not-attempt-resuscitation (DNAR) orders, 38, 997–998, 997t Dopamine, 146, 247 Dornase alfa, 812 Dosage-sensitive sex reversal, 405t Double effect, doctrine of, 43, 43t Double quotidian fever, 93t Down syndrome (trisomy 21), 216t, 400–401, 403t Doxycycline for cervicitis, 190t for chlamydia, 189t for cystic fibrosis exacerbations, 814t

for ehrlichiosis, 488 for epididymitis, 190t for gonorrhea, 189t for Lyme disease, 851t for lymphogranuloma venereum, 190t for nongonococcal urethritis, 190t for pelvic inflammatory disease, 190t for Rocky Mountain spotted fever, 487–488 for septic shock, 147t for syphilis, 192t DO2 (tissue oxygen delivery), 108, 110t, 111t DRESS. See Drug rash with eosinophilia and systemic symptoms (DRESS) Droperidol, 774t Drowning, 957–960 admission and discharge criteria for, 960 clinical presentation of, 958, 958t complications of, 960 consultation for, 960 differential diagnosis of, 958 epidemiology of, 958 key points, 960 pathophysiology of, 958 prevention of, 960 terminology, 957–958 treatment of, 958–960, 959f Drug abuse. See Drugs of abuse exposure; Substance abuse Drug allergy reactions admission criteria for, 206 classification of, 202–203 consultation for, 206 diagnostic evaluation of, 204–205 discharge criteria for, 206 drug categories causing, 203–204 epidemiology of, 203 key points, 206 management of, 204f, 205–206, 205f risk factors for, 203t

Drug-associated rash, 287–293 acute generalized exanthematous pustulosis, 268t, 292 admission criteria for, 293 consultation for, 293 diagnostic evaluation of, 288 differential diagnosis of, 288 discharge criteria for, 293 drug-induced lupus, 292 drug-induced vasculitis, 292 drug rash with eosinophilia and systemic symptoms. See Drug rash with eosinophilia and systemic symptoms (DRESS) epidemiology of, 287–288 exanthematous eruptions, 288–289, 288f, 288t fixed drug eruption, 289, 289f, 289t key points, 293 pathophysiology of, 288t photosensitivity reactions, 289–290 serum sickness, 292–293 urticarial drug eruption, 290, 290f Drug-induced lupus, 292 Drug rash with eosinophilia and systemic symptoms (DRESS) with anticonvulsants, 203 clinical presentation of, 290–291, 291f diagnostic evaluation of, 291 genetic factors in, 291 pathophysiology of, 290 treatment of, 291 Drugs of abuse exposure. See also Substance abuse admission and discharge criteria for, 940 clinical presentation of, 937–938, 939t consultation for, 940 diagnostic evaluation of, 939 differential diagnosis of, 938–939 epidemiology of, 938, 938t key points, 941 prevention of, 940, 940t treatment of, 939–940, 940t

DsDNA (anti-double-stranded DNA), 854t D-transposition of the great arteries (d-TGA), 232–233, 234f Duchenne muscular dystrophy (DMD) cardiac disease in, 216t clinical presentation of, 660–661, 660t, 661f genetic factors in, 405t, 660t Dumping syndrome, 369–371, 369t Duodenal atresia, 153 Duodenal web, 370 Duplication 17p11.2, 405t DVT (deep venous thrombosis). See Venous thromboembolism Dyshidrotic eczema, 268t Dyspepsia, 366–368, 367t, 368t. See also Gastroesophageal reflux disease (GERD) Dysphagia, 393–394, 989 Dyspnea, in palliative care setting, 36 Dysthymic disorder, 754 Dystrophic EB Research Association of America (DebRA), 315 Dysuria, 187

E EAEC (enteroaggregative Escherichia coli), 542, 548 Ear, nose, and throat problems, 877–880 epistaxis, 878 key points, 880 neck mass, 878–879, 879t noisy breathing, 877–878, 877t, 878f postoperative care, 879 Eating disorders, 179–183 admission criteria for, 183, 183t clinical presentation of, 179–180, 179t complications of, 182–183, 182t consultation for, 183 diagnostic evaluation of, 180–181, 181t differential diagnosis of, 180, 180t discharge criteria for, 183 epidemiology of, 179 key points, 183 management of, 181–182, 181t EB. See Epidermolysis bullosa (EB) Ebstein’s anomaly, 218 EBV (Epstein-Barr virus) infection, 600–601, 605t, 606t, 852 Ecchymoses, 137, 161, 261, 261f ECG. See Electrocardiogram (ECG) Echocardiogram in acute rheumatic fever, 257, 257t in dilated cardiomyopathy, 246–247, 247f in infective endocarditis, 240–241, 241f in pericarditis, 254, 254f in stroke, 675 Ecthyma, 285t Ecthyma gangrenosum (EG), 282–287 causes of, 282–283, 283t clinical presentation of, 284–286, 284f consultation for, 286 diagnostic evaluation of, 286

differential diagnosis of, 285–286, 285t in immunosuppressed host, 301 key points, 287 management of, 286 pathophysiology of, 282 prevention of, 286–287 Ectodermal dysplasia, 268t Ectopic beats, 222 Ectopic pregnancy abdominal pain in, 61 consultation for, 193 differential diagnosis of, 864t pelvic inflammatory disease and, 185 ultrasound in, 1024 Eczema, 276. See also Atopic dermatitis (AD) Eczema herpeticum, 277–278, 278f Edema. See also Cerebral edema; Pulmonary edema in hypernatremia, 350 in hyponatremia, 348 in nephrotic syndrome, 627–628, 629f EDMD (Emery-Dreifuss muscular dystrophy), 660t Edrophonium (Tensilon) test, 663 Edwards syndrome (trisomy 18), 216t, 401–402, 403t Effective care, 7 EG. See Ecthyma gangrenosum (EG) EGFR (epidermal growth factor receptor) inhibitors, 303 Ehrlichia spp., 488 EHRs. See Electronic health records (EHRs) EIEC (enteroinvasive Escherichia coli), 542, 548. See also Escherichia coli infections Ejection clicks, 218, 219f, 220f Electrical injury, 900 Electrocardiogram (ECG) characteristics of by age, 222t axis, 223, 223f PR interval, 223–225, 224f

P wave, 223, 224f QRS complex, 225, 225–226f, 225t QT interval, 227 Q wave, 225 rate, 221 rhythm, 222–223 ST segment, 225–227, 226f T wave, 227, 227f key points, 228 in specific conditions arrhythmogenic right ventricular cardiomyopathy, 227–228 Brugada syndrome, 227, 227f catecholaminergic polymorphic ventricular tachycardia, 228 drowning, 960 hypokalemia, 351–352 hypothermia, 953, 953f pericarditis, 253–254, 253f technical aspects of, 221 Electroclinical syndromes, 637, 638t. See also Seizures Electrogastrography, 370 Electrolytes in acute kidney injury, 613 in body fluids, 346t in chronic renal failure, 616 deficit calculation, 345–346 disturbances of. See specific abnormality maintenance requirements for, 345 regulation of, 344–345 Electromyography (EMG), 656, 663 Electronic health records (EHRs) current state in children’s hospitals, 20–21 downtime alternatives, 22–23 federal incentives for adoption of, 21, 21t pediatric-specific functions, 20, 20t structure and components of, 20, 20t unintended consequences, 23 11p13 deletion (WAGR) syndrome, 404, 405t

Elliptocytosis, 427f EM. See Erythema multiforme (EM) Emancipated minors, 42, 46 Emery-Dreifuss muscular dystrophy (EDMD), 660t Empyema, 528, 533, 534t Enalapril, 103t Enalaprilat, 102, 103t Enamel, dental, 128 Encephalitis arboviral, 491, 492, 494–495, 496 diagnostic evaluation of, 493 enteroviral/parechoviral, 490–491, 492, 493, 496 etiology of, 490t herpesviridae, 490–491, 492, 493–494, 496–497 Encephalopathy in HIV infection, 592 in lead poisoning, 934 in liver failure, 374 Endocarditis. See Infective endocarditis Endocrine imaging, 1018 End-of-life care. See Hospice care; Palliative care Endoscopic retrograde cholangiopancreatography (ERCP), 356–357, 358, 359, 390 Endoscopic surgery, for nephrolithiasis, 912–913 Endoscopic third ventriculostomy, 882–883, 883f Endotracheal intubation, 692–693, 1071–1072 End-tidal carbon dioxide, 71, 824, 825f, 1004 ENO (exhaled nitric oxide), 823 Entamoeba histolytica infection clinical presentation of, 547t epidemiology of, 545t pathophysiology of, 542, 543 risk factors for, 545t treatment of, 552t Enteral nutrition delivery devices for, 383. See also Enterostomy tubes indications for, 382f, 383, 383t

in pancreatitis, 390 Enteroaggregative Escherichia coli (EAEC), 542, 548. See also Escherichia coli infections Enterobacter spp., 581t Enterococcus spp. in catheter-related bloodstream infections, 581t in cerebrospinal fluid shunt infections, 585t in infective endocarditis, 240t Enterococcus faecalis infections, 466t Enterococcus faecium infections, 466t Enterocolitis, necrotizing, 96, 154 Enterohemorrhagic Escherichia coli infections. See Shiga toxin-producing Escherichia coli (STEC, enterohemorrhagic) infections Enteroinvasive Escherichia coli (EIEC), 542, 548t. See also Escherichia coli infections Enteropathogenic Escherichia coli (EPEC), 542. See also Escherichia coli infections Enterostomy tubes characteristics of, 994f complications of, 995 gastroesophageal reflux and, 995 indications for, 994 methods for placement, 994 outcomes of, 995–996 Enterotoxigenic Escherichia coli (ETEC) infections. See also Escherichia coli infections clinical presentation of, 547t, 548 epidemiology of, 544t pathogen characteristics, 542, 542t pathophysiology of, 543 treatment of, 551t Enterovirus infections congenital, 715, 716t, 717t meningitis/encephalitis, 491, 492, 494 stomatitis in, 128t transmission-based precautions for, 17t Enthesitis-related arthritis, 841, 841t, 842t. See also Juvenile idiopathic

arthritis (JIA) Envenomation, 966–969 clinical presentation of, 966, 967t epidemiology of, 966 key points, 969 snake bites, 966–968, 986t spider bites, 285t, 968–969, 968t Enzyme replacement therapy, 662 Eosinophilia, drug rash with systemic symptoms and. See Drug rash with eosinophilia and systemic symptoms (DRESS) Eosinophilic pustular folliculitis, 267t EPEC (enteropathogenic Escherichia coli), 542. See also Escherichia coli infections Epidermal growth factor receptor (EGFR) inhibitors, 303 Epidermolysis bullosa (EB), 305–315 admission criteria for, 314 clinical presentation of, 267f, 269t, 306–308, 306f, 306t, 307f complications of, 307–308, 309t consultation for, 313–314 diagnostic evaluation of, 308, 308f differential diagnosis of, 307t, 308 discharge criteria for, 314 epidemiology of, 305 key points, 315 neonatal, 267t pathophysiology of, 305, 306t special considerations in, 314–315, eTable 67–5 subtypes of, 305, 306t treatment of, 308–313, 309t, 310f, 311f Epidermolysis bullosa acquisita, 268t Epidermolytic hyperkeratosis, 268t Epididymitis, 185, 187, 190t Epidural hematoma, 884, 885f, 895, 1021f Epidural hemorrhage, 705 Epigastric hernia, 870 Epiglottitis admission criteria for, 524

clinical presentation of, 512, 521, 523 consultation for, 524 course of illness, 524 diagnostic evaluation of, 132, 141, 523, 524f differential diagnosis of, 523 discharge criteria for, 524 key points, 524 prevention of, 524 special considerations in, 512 stridor in, 79, 521t treatment of, 465t, 523–524 Epinephrine for anaphylaxis, 201 for asthma, 789t nebulized racemic, 518, 522, 522t in neonatal resuscitation, 694 Epistaxis, 878 Eplerenone, 103t Epstein-Barr virus (EBV) infection, 600–601, 605t, 606t, 852 Erb-Duchenne paralysis, 701, 702f ERCP (endoscopic retrograde cholangiopancreatography), 356–357, 358, 390 Ergocalciferol (vitamin D2), 333 Erosion, 265, 265t, 266f. See also Vesicobullous diseases Erysipelas, 465t, 573–576, 574f Erythema infectiosum (fifth disease), 482t Erythema marginatum, 257 Erythema multiforme (EM), 294–296 admission criteria for, 296 clinical presentation of, 268t, 294–295, 295f, 481–482, 482f consultation for, 296 diagnostic evaluation of, 296 differential diagnosis of, 285t, 295–296, 295f discharge criteria for, 296 drug-related, 203 forms of, 294 key points, 296 prevention of, 296

treatment of, 296 triggers of, 295t Erythema toxicum neonatorum, 267t Erythroderma, 482, 483f Erythromycin for chancroid, 190t for chlamydia, 189t, 889 for cystic fibrosis exacerbations, 814t for nongonococcal urethritis, 190t for pertussis, 536t pyloric stenosis and, 858, 889 Escharotomy, 897 Escherichia coli infections acute gastroenteritis. See also Acute gastroenteritis (AGE) clinical presentation of, 547t, 548 epidemiology of, 544, 544t, 546t pathophysiology of, 541–542, 542t treatment of, 466t catheter-related bloodstream infections, 581t urinary tract, 559. See also Urinary tract infections (UTIs) Escitalopram, 756, 756t Esmolol, 102, 102f, 103t Esophageal atresia, 153 Esophageal injury, after caustic ingestion, 929, 930t Esophageal varices, 95, 96t, 97 Esophagitis, 95 Esophagram, 1010–1011 Essential care, 43 Estrogen, 198 ESWL (extracorporeal shock wave lithotripsy), 912 Etanercept, 122, 122t ETEC. See Enterotoxigenic Escherichia coli (ETEC) infections Ethanol for ethylene glycol or methanol poisoning, 928–929, 929t in lock therapy, 584t poisoning, 928–929, 928f withdrawal syndrome, 941–942, 942t, 943, 943t

Ethical issues advocating for patients, 43 in care of child with severe neurologic impairment, 986–987 competence, 42 deceptive methods, 43 decision-making capacity, 42 doctrine of double effect, 43, 43t essential care, 43 euthanasia, 43 futile treatment, 43 hospital resources for, 42 permission, assent, or consent, 42, 42t principles of, 41–42, 42t social media and boundaries, 43 withholding or withdrawing life-sustaining treatment, 43 Ethinyl estradiol, 196, 197t, 198 Ethosuximide, 641t Ethylene glycol poisoning, 928–929, 928f Euthanasia, 43 Evans syndrome, 448 Evidence-based medicine, 9–11, 9t, 10t, 11t Ewing sarcoma, 738 Exanthema subitum (roseola), 482t Exchange transfusion for hyperleukocytosis, 742 for neonatal hyperbilirubinemia, 727, 728f, 729f Exercise tests, 824 Exhaled nitric oxide (ENO), 823 External jugular vein, for central venous access, 1053 Extracorporeal photophoresis, 462 Extracorporeal shock wave lithotripsy (ESWL), 912 Extracranial hematomas, 884. See also Head trauma Extrapyramidal side effects, 774, 775t Eye injury, 889–891, 890f, 891f F Facioscapulohumeral muscular dystrophy (FSHD), 660t

Factitious disorder, 764 Factitious disorder by proxy, 169. See also Medical child abuse Factor V Leiden, 455t Factor VIII deficiency. See Hemophilia replacement of, 454t, 460 Factor IX deficiency. See Hemophilia replacement of, 454t, 460 Factor Xa inhibitor poisoning/overdose, 975–976 Failure to thrive (FTT), 88–91. See also Malnutrition causes of, 89, 90t definition of, 88 diagnostic evaluation of, 90, 91f key points, 91 management of, 90–91, 91f pathophysiology of, 88 patient history in, 88, 89t physical examination in, 88–89, 89t special considerations in, 91 Fainting. See Syncope Famciclovir, 191t Familial dysautonomia (FD, Riley-Day syndrome), 657 Familial hemophagocytic lymphohistiocytosis (FHL), 845, 846, 846t Familial hypocalciuric hypercalcemia (FHH), 332 Familial Mediterranean fever, 575 Family-centered care, 25–26 Fanconi syndrome, renal, 419, 419t, 420 Fasciitis, necrotizing, 285t, 577–579, 578f Fasting, presedation, 1003, 1004t Fatigue, in palliative care setting, 35–36, 35t Fatty acid oxidation defects, 414–415, 417t Febrile neutropenia, 744–745, 744t, 745t Febrile non-hemolytic transfusion reaction, 459t, 462 Febrile seizures, 604–642 admission and discharge criteria for, 642 classification of, 640

clinical presentation of, 641 consultation for, 642 definition of, 640 diagnostic evaluation of, 641–642, 642t differential diagnosis of, 641, 641t epidemiology of, 640–641 etiology of, 640 future directions in, 643t genetic factors in, 640–641 key points, 643 prognosis of, 642, 642t treatment of, 642 Feeding issues, 393–397 dysphagia, 393–394, 989 feeding aversion, 395–396 gastroesophageal reflux. See Gastroesophageal reflux disease (GERD) key points, 397 FEES (fiberoptic endoscopic evaluation of swallowing), 394 Felbamate, 641t Female genitalia care, in infants, 698 Femoral hernia, 870 Femoral vein, for central venous access, 1052–1053, 1052f FENa (fractional excretion of sodium), 612, 613t, 626t FeNO (fractional exhaled nitric oxide), 823 Fentanyl, 1005 Fetus disrupted transition to newborn, 691–692. See also Delivery room medicine hydronephrosis in, 908, 909f Fever, 92–94, 468–474. See also Hyperthermia after hematopoietic stem cell transplant, 750 and arthritis, 849, 850t definition of, 92 diagnostic evaluation of, 93 differential diagnosis of, 93 in HIV-infected child, 591–592, 592t in juvenile idiopathic arthritis, 840

in Kawasaki disease, 827 key points, 94 management of, 93–94 in neonates and young infants, 468–474, 470t, 471t and neutropenia, 744–745, 744t, 745t in older infants and toddlers, 473–474 pathophysiology of, 92 patient history in, 92, 93t patterns of, 93t physical examination in, 92–93 prolonged, 477, 478t. See also Fever of unknown origin (FUO) with rash. See Rash, fever-associated recurrent, 479t in sickle cell disease, 434, 434f Fever of unknown origin (FUO), 477–480 admission and discharge criteria for, 480 clinical presentation of, 477 consultation for, 480 definition of, 477 diagnostic evaluation of, 479–480, 480t differential diagnosis of, 477–478, 478t key points, 480 treatment of, 480 “Fever phobia,” 93 FEV1 (forced expiratory volume), 821, 821t 18F-FDG PET/CT, 1018–1019 FFP (fresh frozen plasma), 460 FHH (familial hypocalciuric hypercalcemia), 332 FHL (familial hemophagocytic lymphohistiocytosis), 845, 846, 846t Fiberoptic endoscopic evaluation of swallowing (FEES), 394 Fibrinolytic poisoning/overdose, 978 Fifth disease (erythema infectiosum), 482t Finkelstein disease (acute hemorrhagic edema of infancy), 833 5p deletion (cri du chat) syndrome, 404, 405t Fixed drug eruption, 289, 289f, 289t, 295–296 FLAIR. See Fluid-attenuated inversion recovery (FLAIR) Flow-volume curves, 821–822, 821f

Fluid(s) deficit calculation, 345, 346t, 347t maintenance requirements for, 345, 345t regulation of, 344–345 Fluid-attenuated inversion recovery (FLAIR) in acute disseminated encephalomyelitis, 684, 684f, 688f in arterial ischemic stroke, 667f in intracerebral hemorrhage, 670f in multiple sclerosis, 687, 688f in optic neuritis, 685, 686f in post-varicella vasculopathy, 668f Fluid therapy for burns, 897 enteral, 342, 343f, 346–347 for hypernatremia, 350 for hyponatremia, 348–349 hypotonic vs. isotonic, 348 intravenous, 343, 347–348, 550 for pyloric stenosis, 858 for tumor lysis syndrome, 740t Flumazenil, 1004 Fluocinolone, 280 Fluocinonide, 280 Fluoroscopy, 1010–1012, 1010f, 1011f, 1011t, 1012f. See also specific studies Fluoxetine, 756t Fluphenazine, 774t Fluticasone, 280 Fluvoxamine, 756t Focal seizure, 637, 637t. See also Seizures Folate deficiency, 429 Folic acid, for ethylene glycol poisoning, 928 Fomepizole, for alcohol poisoning, 928, 929t Fondaparinux, 975 Food allergy, 281 Foodborne illness, 544. See also Acute gastroenteritis (AGE) Forced expiratory volume (FEV1), 821, 821t

Forced vital capacity (FVC), 821, 821t Foreign body aspiration admission criteria for, 819 clinical presentation of, 817 diagnostic evaluation of, 817–818, 817f, 818f, 818t differential diagnosis of, 523 discharge criteria for, 819 epidemiology of, 816 future directions in, 819 key points, 819 pathophysiology of, 816, 817t prevention of, 819 treatment of, 818–819 Formula feeding, 696–697 Fosphenytoin, 640t 4p deletion (Wolf-Hirschhorn) syndrome, 404, 405t Fractional excretion of sodium (FENa), 612, 613t, 626t Fractional exhaled nitric oxide (FeNO), 823 Fractures during delivery, 701 rib, 167, 167f, 874 skull, 167, 884, 885, 1021f. See also Abusive head trauma (AHT); Head trauma FRC (functional residual capacity), 822, 822f Fresh frozen plasma (FFP), 460 Friction blister, 268t Frostbite clinical presentation of, 954, 954f consultation for, 957 key points, 957 pathophysiology of, 952 prevention of, 957 special considerations in, 957 treatment of, 956 Fructosemia (hereditary fructose intolerance), 414, 417t Fructose-1,6-biphosphatase deficiency, 417t FSHD (facioscapulohumeral muscular dystrophy), 660t

FTT. See Failure to thrive (FTT) Functional residual capacity (FRC), 822, 822f Fundoplication, 396–397 Fungal infections. See also specific infections in catheter-related bloodstream infections, 583 in immunosuppressed host, 301–302 in transplant recipient, 602, 604–605, 605t FUO. See Fever of unknown origin (FUO) Furosemide for hypercalcemia, 334 for hyperkalemia, 352 for hypertension, 103t for syndrome of inappropriate antidiuretic hormone secretion, 329 for tumor lysis syndrome, 740t Fusarium infection, 285t Fusobacterium spp. infections, 134, 466t Futile care, 43 FVC (forced vital capacity), 821, 821t G Gabapentin, 641t GABHS infections. See Group A β-hemolytic streptococcus (GABHS) infections Gait alterations, 649, 650t. See also Limp Galactosemia, 417t Gallium scan, 1019 γ-glutamyl transpeptidase (GGT), 554t Ganciclovir, 606t Gangliosidoses, 653 Gas gangrene (clostridial myonecrosis), 578 GAS pharyngitis. See Group A β-hemolytic streptococcus (GABHS) infections Gastric emptying disorders, 369–371, 369t, 370t Gastric emptying study, 396t, 1017, 1017f Gastric lavage, 915, 916t Gastritis, 96–97, 96t Gastroenteritis, acute. See Acute gastroenteritis (AGE)

Gastroesophageal reflux disease (GERD), 396–398 admission and discharge criteria for, 398 in child with severe neurologic impairment, 986, 989 clinical presentation of, 154, 395, 395t, 779t consultation for, 398 diagnostic evaluation of, 395, 396t, 779t, 1017, 1017f with gastrostomy tube, 995 key points, 398 treatment of, 396–398, 396t Gastrointestinal (GI) bleeding, 94–98 diagnostic evaluation of, 97, 98f, 1017 key points, 98 lower, 96–97, 96t management of, 97–98, 98f patient history in, 94, 95t physical examination in, 94, 95t special considerations in, 98 upper, 91–92, 96t Gastrointestinal (GI) imaging. See also Abdominal imaging in biliary disease, 357, 357f nuclear medicine studies, 1016–1017, 1016f in vomiting evaluation, 396t Gastrointestinal (GI) infections acute gastroenteritis. See Acute gastroenteritis (AGE) hepatitis. See Hepatitis intra-abdominal, 465t, 557 peritonitis. See Peritonitis Gastrointestinal (GI) obstruction, 857–862 clinical presentation of, 857 differential diagnosis of, 857, 857t intussusception, 65, 154, 860–861, 860f, 864t key points, 862 malrotation and volvulus, 96, 859–860, 859f, 860f pyloric stenosis, 154, 857–858, 858f Gastroparesis, 369–371, 369t, 370t Gastroschisis, 706–707, 706f Gastrostomy tube feeding, 397, 993–996, 994f

Gastrostomy tube placement, 1030–1031 Gata2 deficiency, 208 GBS. See Guillain-Barré syndrome (GBS) GBS infections. See Group B Streptococcus (GBS) infections General anesthesia, 1003 Gene therapy, for hemophilia, 454 Genetic disorders. See also specific disorders clinical presentation of, 399, 400t contiguous gene syndromes with chromosomal deletions, 404–406, 405–406t contiguous gene syndromes with segmental duplications, 406–408 diagnosis of, 399 Genitalia ambiguous, 710–711 care of, in infants, 698 Genital ulcers, 185–187 Genital warts, 186, 191t, 302 Gentamicin for bacterial meningitis, 495t for infective endocarditis, 242t, 243t in lock therapy, 584t for pelvic inflammatory disease, 190t for septic shock, 147t GERD. See Gastroesophageal reflux disease (GERD) German measles. See Rubella (German measles) Germ cell tumors, 738 GGT (γ-glutamyl transpeptidase), 554t Giannotti-Crosti syndrome, 553 Giardia intestinalis (lamblia) infection clinical presentation of, 547t pathophysiology of, 542, 545t sexually transmitted, 186 treatment of, 552t GI bleeding. See Gastrointestinal (GI) bleeding Gingival hyperplasia, 303 Glanzmann thrombasthenia, 455 Glasgow Coma Scale, 73, 73t, 873t

Glatiramer acetate, 687 Gliptins, 923–925, 924t, 925t Glomerular filtration rate, 1014 Glomerulonephritis, 618–620, 626t Glucagon, 201, 416 Glucagon stimulation testing, 416 Glucocorticoids, 336. See also Corticosteroids Glucose infusion rate (GIR), 416 Glucose-6-phosphatase dehydrogenase (G6PD) deficiency, 417t, 430 Glycerin suppository, 364t Glycogen storage diseases, 414, 662 Glycopyrrolate, 990 Golimumab, 378, 378t Gonococcal conjunctivitis, 889 Gonorrhea, 188t, 189–190t, 467t Gottron papules, 836, 836f Gowers sign, 649, 661t Graft-versus-host disease (GVHD), 355, 462, 749–750, 750t Gram-negative bacilli in catheter-related bloodstream infections, 581, 583 in cerebrospinal fluid shunt infections, 584 Granulocytes, 460 Granulomatous disease, 332 Graves disease, 322–323, 325. See also Hyperthyroidism Grisel syndrome (atlantoaxial rotatory subluxation), 136, 879 Groin mass/swelling, 867t Group A coxsackievirus infection (hand, foot, and mouth disease), 269t, 508, 509f Group A β-hemolytic streptococcus (GABHS) infections cellulitis, 573–574. See also Cellulitis necrotizing fasciitis, 577. See also Necrotizing fasciitis osteomyelitis, 566, 567t pharyngitis acute rheumatic fever and, 255, 256 clinical presentation of, 510 diagnostic evaluation of, 510 pathophysiology of, 256

treatment of, 258, 258t, 465t, 511 toxic shock syndrome, 485–487, 486t Group B Streptococcus (GBS) infections cellulitis, 573, 574. See also Cellulitis in neonates and young infants, 469, 469t, 490 osteomyelitis, 566, 567t perinatally acquired, 472, 719–720, 720f prevention of, 472 treatment of, 467t Growth failure in bronchopulmonary dysplasia, 804 in chronic renal failure, 617 in hypothyroidism, 322, 323f G6PD (glucose-6-phosphatase dehydrogenase) deficiency, 417t, 430 Guillain-Barré syndrome (GBS) Campylobacter infection and, 543, 656 clinical presentation of, 656 diagnostic evaluation of, 656 differential diagnosis of, 686 epidemiology of, 655 pathophysiology of, 656 treatment of, 212, 656 variants of, 656 GVHD (graft-versus-host disease), 462, 749–750, 750t H HACEK organisms, 240t Haemophilus influenzae infections chemoprophylaxis for contacts, 497t in cystic fibrosis, 813t, 814t empirical treatment of, 466t Hailey-Hailey disease, 269t Hallucinations, 772, 772t. See also Psychosis Hallucinogens, 939t, 940t Haloperidol, 769f, 774, 774t Hammer toes, 657, 657f Hand, foot, and mouth disease (group A coxsackievirus infection), 269t, 508,

509f Hand hygiene, 16 Haptoglobin, 425t Hashimoto thyroiditis, 322. See also Hypothyroidism Hay-Wells syndrome, 268t HCT. See Hematopoietic stem cell transplant (HSCT) Headache, 644–648 admission criteria for, 647 in brain tumor, 735 classification of, 644, 644t clinical presentation of, 644 consultation for, 647 course of illness, 647 diagnostic evaluation of, 646, 647t differential diagnosis of, 646, 646t discharge criteria for, 647 epidemiology of, 644 future directions in, 648 with increased intracranial pressure, 644–645, 644t, 645t key points, 647 migraine, 645–646, 645t secondary causes of, 645 in stroke, 670–671, 678 treatment of, 647 Head and neck imaging computed tomography, 1020–1021, 1021f, 1022f. See also Computed tomography (CT) magnetic resonance imaging, 1025–1026, 1025f. See also Magnetic resonance imaging (MRI) radiographs, 1009–1010 ultrasound, 1022–1023, 1024f Head trauma, 884–886 abusive. See Abusive head trauma (AHT) admission and discharge criteria for, 886 clinical presentation of, 884–885 consultation for, 886 diagnostic evaluation of, 872f, 885, 885f

epidemiology of, 871, 884 extracranial hematomas, 884 intracranial hemorrhage, 884 key points, 886 minor, 871 pathophysiology of, 884 prevention of, 886 skull fractures, 884 special considerations in, 886 treatment of, 885–886 Healthcare variations comparative effectiveness research and, 10 conceptual frameworks for, 6–7 historical perspectives on, 6 hospital medicine and studies of, 10 in pediatrics, 3–4, 6 Health Information Technology for Economic and Clinical Health (HITECH) Act, 21 Hearing screening, in newborns, 699 Heart disease congenital. See Congenital heart disease physical examination in. See Cardiac examination Heart failure in acute rheumatic fever, 257, 258 in chronic renal failure, 617 congenital heart disease presenting as, 234–236, 235f, 236f, 237f in dilated cardiomyopathy, 245 in infective endocarditis, 242, 244t treatment of, 248 Heart rate, 109t Heart sounds, 216–217 Heat cramps, 949–950, 950t Heat disorders, 949–952 admission and discharge criteria for, 951 clinical presentation of, 949–950, 950t consultation for, 951 diagnostic evaluation of, 951, 951t

differential diagnosis of, 950 epidemiology of, 949 key points, 952 pathophysiology of, 949 prevention of, 951, 952t treatment of, 951 Heat exhaustion, 950, 950t Heatstroke, 950, 950t, 951 Heinz bodies, 426t, 427f Helicobacter pylori infection, 208, 367 Heliotrope rash, 836, 837f Heliox for asthma, 790 for bronchiolitis, 518 for croup, 522, 522t Helmet cells. See Schistocytes Hemangioma admission criteria for, 273–274 clinical presentation of, 272, 272f congenital, 272 diagnostic evaluation of, 272 management of, 273 with PHACES association, 273f subglottic, 878 ulcerated, 273f Hemarthrosis, 453 Hematemesis, 94 Hematochezia, 94 Hematocrit, 425t Hematopoietic stem cell transplant (HSCT), 748–750 allogeneic, 748 background for, 748–749 in epidermolysis bullosa, 314 fever following, 750 graft-versus-host disease following, 749–750 immunizations following, 750 indications for, 748, 748t

infections following. See also Transplant recipient, infections in; specific infections preventive therapy and prophylaxis for, 604, 605t timing of development of, 598–599, 599f intravenous immunoglobulin in, 211t, 212 medication issues in, 750 procedure for, 749 syngeneic, 748 Hematuria asymptomatic, 618 in nephrolithiasis, 911 in renal venous thrombosis, 634 Hemiplegic gait, 650t Hemodialysis for chronic renal failure, 617 for hemolytic uremic syndrome, 622 for hypercalcemia, 335 for hyperkalemia, 352 for poisoning/overdose, 916, 923t, 928–929 for urea acid cycle defects, 411 Hemoglobin, 425t Hemoglobinopathies, 429–430. See also Sickle cell disease (SCD) Hemoglobin-oxygen dissociation curve, 518f Hemolytic anemia immune-mediated, 430–431 inherited, 429–430 microangiopathic, 431 pathophysiology of, 429 treatment of, 431 Hemolytic disease of the newborn, 431 Hemolytic uremic syndrome (HUS), 621–623 acute gastroenteritis and, 548, 621 admission and discharge criteria for, 623 atypical, 621 categories of, 621 clinical presentation of, 621–622 diagnostic evaluation of, 622

differential diagnosis of, 622, 864t early identification of, 623 epidemiology of, 621 key points, 623 microangiopathic anemia in, 431 pathophysiology of, 431, 450, 621, 621t prevention of, 623 prognosis of, 622 treatment of, 431, 622–623 Hemophagocytic lymphohistiocytosis (HLH), 208, 845–847, 846t Hemophilia clinical presentation of, 453 future directions in, 454, 457 genetic factors in, 406t incidence of, 453 treatment of, 453–454, 454t types of, 453 Hemoptysis, in cystic fibrosis, 812f, 813 Henoch-Schönlein purpura, 832–835 admission and discharge criteria for, 835 clinical presentation of, 97, 138, 262, 262f, 832–833, 832f consultation for, 835 diagnostic evaluation of, 263, 833–834, 834t differential diagnosis of, 833 epidemiology of, 832 key points, 835 outcome and follow-up for, 835 pathophysiology of, 263, 832 treatment of, 834–835 Heparin adverse effects of, 203 for cerebral sinus venous thrombosis, 677 poisoning/overdose, 977–978 for stroke prevention, 676 for venous thromboembolism, 456, 456t Hepatitis, 552–558 admission criteria for, 556

clinical presentation of, 553–554 consultation for, 556 diagnostic evaluation of, 554–555, 554t, 555t differential diagnosis of, 373, 373t, 554 discharge criteria for, 556 epidemiology of, 552–553 etiology of, 552 key points, 558 prevention of, 556 treatment of, 555–556 Hepatitis B vaccine, 698, 698f Hepatobiliary scintigram (HIDA scan) in biliary tract disease, 356, 357, 359, 1016f indications for, 1016 Hepatoblastoma, 738 Hepatomegaly, 61, 62t Hepatoportoenterostomy (Kasai procedure), 357 Hereditary fructose intolerance (fructosemia), 414, 417t Hereditary neuropathy with pressure palsies (HNPP), 405t, 544 Hernias, 866–970 definition of, 866 direct inguinal, 870 epigastric, 870 femoral, 870 incarcerated, 866 incisional, 870 inguinal. See Inguinal hernia key points, 870 sliding, 866 Spigelian, 870 strangulated, 866 umbilical, 869–870 Herpangina, 508, 509f Herpes simplex virus (HSV) infections anogenital, 188t, 191t in atopic dermatitis, 277–278, 278f clinical presentation of, 269t

congenital, 714–715, 716–717, 716t, 717t differential diagnosis of, 285t disseminated, 186 encephalitis, 490–491, 492, 493–494, 496–497 in immunosuppressed host, 302 in neonates and young infants, 267t, 268t, 469, 471, 473 prevention of, 473 stomatitis, 128t, 508, 509f in transplant recipient, 601, 605t, 606t Herpes zoster. See Varicella-zoster virus (VZV) infections HHS (hyperglycemic hyperosmolar syndrome), 318, 320 HHV-6 (human herpesvirus 6) infection. See Human herpesvirus 6 (HHV-6) infection HIDA scan. See Hepatobiliary scintigram (HIDA scan) High-flow nasal cannula (HFNC), 518, 1065. See also Noninvasive positivepressure ventilation (NPPV) High reliability organization (HRO), 14 High steppage, 650t Hirschsprung disease, 153–154, 363 Histamine H2 receptor antagonists, 396 HITECH (Health Information Technology for Economic and Clinical Health) Act, 21 HIV infection, 589–595 acute, 193, 590 admission and discharge criteria for, 594 classification of, 590t coinfection with anogenital herpes, 191t congenital, 715, 716, 716t, 717t consultation for, 593–594 diagnostic evaluation of, 188t, 590–591 differential diagnosis of, 593 epidemiology of, 59–590 infections in, 591–593, 592t key points, 595 medicolegal issues in testing for, 46 non-occupational exposure to, 193f, 594–595, 594t, 595t, 963–964 occupational exposure to, 594, 594t, 595t

oral manifestations of, 127t prevention of, 590–591 progression of, 590 treatment of, 211t, 212, 591 HLA (human leukocyte antigen) typing, 748 HLH (hemophagocytic lymphohistiocytosis), 208, 845–847, 846t HNPP (hereditary neuropathy with pressure palsies), 405t, 544 Hodgkin lymphoma, 735 Holliday-Segar formula, for fluid requirements, 345, 345t Holt-Oram syndrome, 216t Horner syndrome, 701, 885, 892 Hospice care, 37, 37t Hospitalist, 52. See also Pediatric hospitalist(s) Howell-Jolly bodies, 426t, 427f HPS (hypertrophic pyloric stenosis), 369–371 HRO (high reliability organization), 14 HSCT. See Hematopoietic stem cell transplant (HSCT) HSV infections. See Herpes simplex virus (HSV) infections Human bites. See Bite wounds Human granulocytic anaplasmosis, 488 Human herpesvirus 6 (HHV-6) infection, 602, 606t Human immunodeficiency virus (HIV) infection. See HIV infection Human leukocyte antigen (HLA) typing, 748 Human monocytic ehrlichiosis, 488 Human papillomavirus (HPV) infections, 302 Humerus fracture, during delivery, 701 HUS. See Hemolytic uremic syndrome (HUS) Hyaluronidase, 901 Hydralazine, 102, 102f, 103t, 203 Hydroa vacciniforme, 268t Hydrocarbon ingestion, 926–927, 927t, 931 Hydrocele, 867f, 867t Hydrocephalus clinical presentation of, 882t diagnostic evaluation of, 882 differential diagnosis of, 882, 882t key points, 886

pathophysiology of, 881–882, 881f, 882t prevention of, 884 special considerations in, 884 treatment of, 882–883, 883f Hydrochlorothiazide, 103t, 912 Hydrocortisone, 147, 327, 338 Hydrocortisone acetonide, 280 Hydrocortisone valerate, 280 Hydronephrosis, 908–909, 909f Hydrops of the gallbladder, 359–360 Hydroxocobalamin, 948 Hydroxychloroquine, 121t, 122, 839, 855 21-Hydroxylase deficiency, 337 Hydroxyurea, 437 Hyperadrenal states admission and discharge criteria for, 340 clinical presentation of, 338–339 consultation for, 340 diagnostic evaluation of, 339–340 differential diagnosis of, 339 key points, 340 management of, 340 pathophysiology of, 338 Hyperaldosteronism, 339 Hyperammonemia, 409–410, 410t, 411t. See also Urea acid cycle defects Hyperbaric oxygen therapy, 947–948 Hyperbilirubinemia in biliary disease, 356 classification of, 725, 726t in hepatitis, 554t neonatal. See Neonatal hyperbilirubinemia Hypercalcemia admission and discharge criteria for, 335 classification of, 331t clinical presentation of, 330 consultation for, 335 definition of, 330

diagnostic evaluation of, 332, 334f, 335t differential diagnosis of, 331–332 familial hypocalciuric, 332 key points, 335 in Williams-Beuren syndrome, 406 Hypercalcemia of malignancy, 332 Hypercalciuria, 912 Hyperglycemia. See also Diabetes mellitus admission and discharge criteria for, 320 clinical presentation of, 317 consultation for, 321 diagnostic evaluation of, 317–318, 319f differential diagnosis of, 317 with ketoacidosis. See Diabetic ketoacidosis (DKA) key points, 321 management of, 318–320 pathophysiology of, 317 without acidosis, 317–318, 320 Hyperglycemic hyperosmolar syndrome (HHS), 318, 320 Hyper-IgE syndrome, 279 Hyperinsulinism, 415, 417t Hyperkalemia in chronic renal failure, 616 clinical presentation of, 351–352 definition of, 351 diagnostic evaluation of, 352 management of, 352 pathophysiology of, 351, 351t in tumor lysis syndrome, 741, 742t Hyperkalemic renal tubular acidosis, 632 Hyperleukocytosis, 742 Hypernatremia in chronic renal failure, 616 clinical presentation of, 350 definition of, 350 in diabetes insipidus. See Diabetes insipidus (DI) diagnostic evaluation of, 350

management of, 350 pathophysiology of, 350 Hyperparathyroidism, 332 Hyperphosphatemia, 616, 741, 742t Hypersplenism, 450 Hypertension, 99–104 in chronic renal failure, 617 definition of, 99 diagnostic evaluation of, 100–101, 100f in hemolytic uremic syndrome, 622 key points, 104 pathophysiology of, 100 subspecialty referral indications for, 104 treatment of acute, 101–102, 102f, 103t long-term, 102–104, 103t Hypertensive emergency, 102, 102f, 103t Hypertensive urgency, 102, 102f, 103t Hyperthermia, 92, 950, 950t Hyperthyroidism clinical presentation of, 322–323 diagnostic evaluation of, 324 differential diagnosis of, 324 in Graves disease, 322–323 key points, 326 neonatal, 322 treatment of, 325 Hypertrichosis, 303 Hypertrophic cardiomyopathy admission and discharge criteria for, 249 clinical presentation of, 248 consultation for, 249 diagnostic evaluation of, 222f, 249 differential diagnosis of, 248 genetic factors in, 248 management of, 249 pathophysiology of, 248

risk factors for sudden death in, 249t Hypertrophic pyloric stenosis (HPS), 369–371 Hyperuricemia, 740–741, 741f, 741t, 742t Hypervitaminosis A, 332 Hypervitaminosis D, 332 Hyphema, of eye, 890, 890f Hypocalcemia admission and discharge criteria for, 335 in chronic renal failure, 616 classification of, 330, 330t clinical presentation of, 330 consultation for, 335 definition of, 330 diagnostic evaluation of, 332, 333f, 335t differential diagnosis of, 330–331 key points, 335 management of, 332–333 in tumor lysis syndrome, 741, 742t Hypochromia, 426t Hypoglycemia, 105–107, 413–418, 721–722 admission criteria for, 418 clinical presentation of, 105, 105t, 413–414, 417t, 780t consultation for, 418 definition of, 105 diagnostic evaluation of, 105–106, 106t, 107f, 415–416, 415f, 416t, 780t differential diagnosis of, 105, 106t, 414–415, 417t discharge criteria for, 418 extrinsic causes of, 414 intrinsic causes of, 414 ketotic, 415, 417t key points, 107, 418 management of, 106–107, 416, 417t in neonates, 413–414, 721–722, 722t pathophysiology of, 105, 413 toxicologic, 923–924, 925t Hypokalemia, 351, 351t, 352 Hyponatremia

in chronic renal failure, 616 clinical presentation of, 348 definition of, 348 diagnostic evaluation of, 348 management of, 348–350, 349t Hypoparathyroidism, 331, 331t Hypopituitarism, 326–327, 417t Hypoplastic left heart syndrome, 230–231, 230f, 231f, 233, 234, 234f Hypotension, 143t, 951. See also Shock Hypothalamic-pituitary-adrenal axis, 336 Hypothalamus, 326 Hypothermia, 952–957 admission and discharge criteria for, 956 classification of, 952 clinical presentation of, 953–954, 953f, 953t consultation for, 956 diagnostic evaluation of, 954, 955f differential diagnosis of, 954 epidemiology of, 952 key points, 957 prevention of, 957 risk factors for, 952, 952t special considerations in, 957 therapeutic, 886 treatment of, 955f, 956 Hypothyroidism clinical presentation of, 322, 323f, 370 diagnostic evaluation of, 324 differential diagnosis of, 323–324 infantile hemangioma and, 272 key points, 326 treatment of, 325, 325t Hypotonia and weakness, 648–664 acute, in previously normal child, 654 in acute disseminated encephalomyelitis, 654 admission criteria for, 664 in anterior horn cell diseases, 654–655

approach to, 648 in Charcot-Marie-Tooth disease/syndrome, 405t, 657 in chronic inflammatory demyelinating polyneuropathy. See Chronic inflammatory demyelinating polyneuropathy (CIDP) clinical presentation of, 648–650, 649t in congenital disorders of glycosylation, 653 in congenital myopathies, 659–660 consultation for, 663–664 diagnostic evaluation of, 662–663, 663f differential diagnosis of, 648, 648t discharge criteria for, 664 in familial dysautonomia, 657 in Guillain-Barré syndrome. See Guillain-Barré syndrome in infant botulism, 658 in leukodystrophies, 652–653 in lower motor neuron disease, 654 in lysosomal storage diseases, 653 in metabolic disease, 658 in metabolic myopathies, 662 in mitochondrial diseases, 156–157, 652 in muscular dystrophies, 660–662, 660t, 661f in myasthenia gravis, 658–659 in neuromuscular junction defects, 658 in peripheral neuropathies, 655 in progressive encephalopathy and psychomotor regression, 651–652 in spinal cord disease, 654 in spinal muscular atrophy, 654–655 unilateral with upper motor neuron signs, 654 in upper motor neuron disorders, 650–651 Hypovolemic shock causes of, 143, 143t clinical presentation of, 143 pathophysiology of, 143, 143t Hypoxemia, 107–113 in bronchopulmonary dysplasia, 803 definition of, 81, 113 diagnostic evaluation of, 110, 110t, 111t

differential diagnosis of, 110, 111f, 111t in drowning, 958, 960 key points, 113 management of, 110, 111f, 112, 112t pathophysiology of, 107–108, 108f patient history in, 109 physical examination in, 11t, 109–110 special considerations in, 112–113 treatment of, 803 Hypoxia, 81, 108 Hypoxic-ischemic injury, 958 I IBD. See Inflammatory bowel disease (IBD) Ibuprofen for fever, 94 for joint pain, 121, 121t for viral arthritis, 850 ICH. See Intracerebral hemorrhage (ICH) Ichthyosis bullosa of Siemens, 268t ICP. See Increased intracranial pressure (ICP) Idiopathic hypercalcemia of infancy, 332 Idraparinux, 975 IHI (Institute for Healthcare Improvement), 14 IHPS (infantile hypertrophic pyloric stenosis), 857–858 Iloperidone, 774t Imaging studies computed tomography. See Computed tomography (CT) contrast materials for, 1006–1007, 1007f, 1007t fluoroscopy, 1010–1012, 1010f, 1011f, 1011t, 1012f. See also specific studies interventional. See Interventional radiology magnetic resonance imaging. See Magnetic resonance imaging (MRI) nuclear medicine. See Nuclear medicine patient cooperation in, 1007–1008, 1008f portable radiographs, 1010 positron emission tomography (PET), 1013, 1018

radiation safety for, 1006, 1006t radiographs, 1008–1010, 1008f, 1009f. See also specific types single-photon emission computed tomography (SPECT), 1018, 1019f ultrasound. See Ultrasound Imipenem, 813t Imiquimod, 191t, 302 Immersion, 958. See also Drowning Immune hemolytic anemia, 212 Immune reconstitution inflammatory syndrome (IRIS), 593 Immune thrombocytopenic purpura (ITP) admission and discharge criteria for, 449 clinical presentation of, 261, 262f, 447–448 consultation for, 449 definition of, 447 diagnostic evaluation of, 261, 448 differential diagnosis of, 448, 448t management of, 211–212, 211t, 448–449, 449t special considerations in, 449 Immunizations. See also Vaccine(s) after hematopoietic stem cell transplant, 750 in asplenic patients, 607 in sickle cell disease, 434 in transplant recipient and close contacts, 607 for travelers, 552 Immunodeficiency, polyendocrinopathy, enteropathy X-linked (IPEX), 207, 208 Immunodeficiency diseases, primary. See Primary immunodeficiency diseases Immunosuppressed host. See also Transplant recipient cutaneous disorders in, 300–304, 301t graft-versus-host disease. See Graft-versus-host disease infections, 300–302, 301f medication-related, 302–304 neoplastic, 302 sepsis in, 466t Impetigo, 269t Implantable defibrillators, 238

Impulse aggression, 768. See also Agitation Inborn errors of metabolism diagnostic evaluation of, 69, 70t, 71, 72f hypoglycemia in, 414–415, 417t. See also Hypoglycemia metabolic acidosis in, 420. See also Metabolic acidosis signs and symptoms of, 71, 71t treatment of, 71–72, 422, 422t Incidental findings, 48–49 Incisional hernia, 870 Incontinentia pigmenti, genetic, 267t Increased intracranial pressure (ICP) clinical presentation of, 155, 644–645, 644t, 645t etiology of, 883t hydrocephalus and, 882, 883. See also Hydrocephalus as oncologic emergency, 746 treatment of, 677–678, 883 Incretin mimics, 923–925, 924t, 925t Indirect Coombs test, 425t Indomethacin, 121t Infant botulism, 969–971 admission and discharge criteria for, 971 clinical presentation of, 658, 780t, 970 complications of, 971, 971t consultation for, 971 diagnostic evaluation of, 658, 970 differential diagnosis of, 970 epidemiology of, 658, 969, 970 key points, 971 pathophysiology of, 969–970 prognosis of, 970–971 special considerations in, 971 treatment of, 658, 970 Infantile acropustulosis, 267t Infantile hemangioma admission criteria for, 273–274 clinical presentation of, 272, 272f diagnostic evaluation of, 272–273

management of, 273 with PHACES association, 273f ulcerated, 273f Infantile hypertrophic pyloric stenosis (IHPS), 857–858 Infants congenital heart disease in. See Congenital heart disease developmental implications in response to hospitalization, 30 developmental milestones, 30, 30t fever in, 468–474, 470t, 471t liver failure in, 373, 374t noisy breathing in, 877–878, 877t, 888 pathologic central apnea in, 781–782, 783 pulmonary function testing in, 823, 823f vomiting in, 153t, 154–155, 154t Infants of diabetic mothers, 722–724, 723f, 723t Infection(s) in bite wounds. See Bite wounds bone and joint. See Osteomyelitis; Septic arthritis cardiac. See Infective endocarditis; Myocarditis; Pericarditis central nervous system. See Central nervous system (CNS) infections congenital. See Congenital infections device-related. See Device-related infections gastrointestinal. See Acute gastroenteritis (AGE); Hepatitis perinatal, 719–720 skin and soft tissue. See Skin and soft tissue infections Infection-associated arthritis, 847–851. See also Septic arthritis admission and discharge criteria for, 851 clinical presentation of, 848–849, 848t consultation for, 851 diagnostic evaluation of, 849–850, 850t, 1077t differential diagnosis of, 843, 849, 849t, 850t key points, 851 pathophysiology of, 848 prevention of, 851 treatment of, 850–851, 851t Infection control for medical devices, 17–18

as patient safety issue, 16, 16t principles of, 16–17 for problem pathogens, 18 Infective endocarditis admission criteria for, 242 clinical presentation of, 240 complications of, 242, 243t consultation for, 242 diagnostic evaluation of, 240–241, 240t, 241f, 241t differential diagnosis of, 240 discharge criteria for, 242 key points, 244 pathophysiology of, 239, 240t prophylaxis for, 237, 243, 244t treatment of, 241–242, 242t, 243t Inferior vena cava filters, 456 Infiltration, intravenous, 900–901 Inflammatory bowel disease (IBD), 375–378 admission criteria for, 378 clinical presentation of, 127t, 376, 376t diagnostic evaluation of, 376, 376f, 377t differential diagnosis of, 376 discharge criteria for, 378 epidemiology of, 375 future directions in, 378 pathophysiology of, 375 treatment of, 377–378, 377t Inflammatory mastocytosis, 267t Infliximab, 122t, 378, 378t, 844 Influenza pneumonia and, 528, 533 transmission-based precautions, 17t in transplant recipient, 601, 606t Informed consent definition of, 45 medicolegal issues in, 45–46, 46t process for obtaining, 42, 42t

Informed permission, 42, 42t Inguinal hernia admission and discharge criteria for, 869 anticipatory guidance for, 869 clinical presentation of, 866 consultation for, 869 diagnostic evaluation of, 867 differential diagnosis of, 864t, 867, 867f, 867t direct, 870 pathophysiology of, 866, 866f treatment of, 867–869, 868f Inhalation injury, 945–948 admission and discharge criteria for, 948 clinical presentation of, 896, 945–946 consultation for, 948 diagnostic evaluation of, 946, 946t epidemiology of, 945 key points, 948 pathophysiology of, 945 prevention of, 948 special considerations in, 948 treatment of, 946–948, 947f 111In-pentreotide scan, 1019 Institute for Healthcare Improvement (IHI), 14 Institute of Medicine (IOM), 13–14 Insulin, 318–319, 320t, 352 Interferon beta, 687 Internal jugular vein, for central venous access, 1053 Interstitial nephritis. See Tubulointerstitial nephritis (TIN) Interventional radiology, 1026–1027 cecostomy, 1031 drainage of fluid and abscesses, 1027f, 1028–1029 gastrostomy/gastrojejunostomy placement, 1030–1031 hepatic and biliary, 1030f, 1031 image-guided biopsy, 1029–1030, 1029f musculoskeletal, 1031–1032, 1031f urologic, 1031

vascular, 1027–1028, 1027f Intra-abdominal infection, 465t, 557 Intracerebral hemorrhage (ICH). See also Stroke; Subarachnoid hemorrhage (SAH) clinical presentation of, 671 diagnostic evaluation of, 675 pathophysiology and risk factors for, 669, 670f recurrence of, 679 treatment of, 677–678 Intracranial abscess, 506–507, 506f Intracranial hemorrhage as birth injury, 704–705 epidural, 705 epidural hematoma, 884, 885f, 895, 1021f head trauma and, 884. See also Head trauma subdural, 704–705 subdural hematoma, 884, 885f Intractable crying. See Irritability and intractable crying Intraesophageal pH monitoring (pH probe), 395, 396t Intraosseous catheters, 1056–1057, 1056t, 1057f Intravenous catheter central. See Central venous catheters (CVCs) peripheral. See Peripheral intravenous access peripherally inserted central. See Peripherally inserted central catheter (PICC) Intravenous immunoglobulin (IVIG) adverse effects of, 213, 460, 830, 830t for chronic inflammatory demyelinating neuropathy, 657 for demyelinating syndromes, 682 for dilated cardiomyopathy, 242 for DRESS, 291 for erythema multiforme, 296 for Guillain-Barré syndrome, 212, 656 for immune thrombocytopenic purpura, 211–212, 211t, 448, 449t indications for, 211–212, 211t, 460 Kawasaki disease, 829–830 key points, 213

manufacture of, 211 mechanisms of action, 211 off-label uses for, 212–213 special considerations in, 213 for Stevens-Johnson syndrome/toxic epidermal necrolysis, 299, 299f Intravenous infiltrates, 900–901 Intravenous pyelogram (IVP), 1012 Intubation, endotracheal, 692–693, 1071–1072 Intussusception, 860–862 admission and discharge criteria for, 861 clinical presentation of, 65, 154, 861 consultation for, 861 diagnostic evaluation of, 861, 861f, 1011, 1012f differential diagnosis of, 861, 864t with enterostomy tube, 995 epidemiology of, 861 key points, 862 pathophysiology of, 860, 860f treatment of, 861, 1011 Iodoquinol, 552t IOM (Institute of Medicine), 13–14 IPEX (immunodeficiency, polyendocrinopathy, enteropathy X-linked), 207, 208 Ipratropium, 788, 789t Irbesartan, 103t IRIS (immune reconstitution inflammatory syndrome), 593 Iron formulations, 918t for iron-deficiency anemia, 428 poisoning/overdose, 918–919, 918t, 919t Iron-deficiency anemia diagnostic evaluation of, 427f, 428, 428t oral manifestations of, 127t pathophysiology of, 427–428 treatment of, 428 Iron overload, transfusion-associated, 462 Irradiation, of blood products, 460–461

Irritability and intractable crying, 114–117 characteristics of, 114 in child with severe neurologic impairment, 985, 985t definition of, 114 diagnostic evaluation of, 115 differential diagnosis of, 115, 116t, 117t key points, 117 management of, 115 new, in hospitalized patient, 117–118 pathophysiology of, 114 patient history in, 114, 115t physical examination in, 114–115 special considerations in, 115–117 Isopropanol poisoning, 928–929 Isradipine, 103t ITP. See Immune thrombocytopenic purpura (ITP) Ivacaftor, 811 IVIG. See Intravenous immunoglobulin (IVIG) IVP (intravenous pyelogram), 1012 J Janeway lesions, 240 Jaundice. See also Hyperbilirubinemia in biliary atresia, 357 in choledochal cyst, 358 in cholelithiasis, 358 clinical presentation of, 355 diagnostic evaluation of, 356–357 differential diagnosis of, 725–726, 726t JCPHM (Joint Council of Pediatric Hospital Medicine), 51 Jehovah’s Witnesses, blood transfusion refusal by, 47 Joint Council of Pediatric Hospital Medicine (JCPHM), 51 Jones criteria, for acute rheumatic fever, 256, 256t Jugular septic thrombophlebitis (Lemierre syndrome), 134 Juvenile dermatomyositis, 836–839 admission and discharge criteria for, 839 clinical presentation of, 836–837, 836f, 836t, 837f

consultation for, 839 diagnostic evaluation of, 837–838, 838f, 838t differential diagnosis of, 837 epidemiology of, 836 key points, 839 pathophysiology of, 836 special considerations in, 839 treatment of, 838–839, 838f Juvenile idiopathic arthritis (JIA), 840–845 admission and discharge criteria for, 844–845 clinical presentation of, 136, 840–841, 841t complications of, 842 consultation for, 844, 844t course of illness, 843 diagnostic evaluation of, 120–121, 842–843, 842t differential diagnosis of, 120, 842 enthesitis-related, 841 epidemiology of, 840 future directions in, 845 key points, 845 oligoarticular, 841 polyarticular, 840–841 systemic-onset, 840 treatment of, 121–122, 121t, 122t, 843–844 Juvenile myasthenia gravis, 658–659 K Kallmann syndrome, 405t Kaposiform hemangioendothelioma (KHE), 272, 273 Kaposi varicelliform eruption, 277–278, 278f Karyotype, 399, 401f Kasabach Merritt phenomenon (KMP), 272, 273 Kasabach Merritt syndrome (KMS), 450 Kasai procedure (hepatoportoenterostomy), 357 Kawasaki disease/syndrome, 827–831 admission and discharge criteria for, 831 biliary disease in, 355, 359

clinical presentation of, 125, 127t, 827–828, 828t complications of, 828 consultation for, 831 diagnostic evaluation of, 828–829, 830t differential diagnosis of, 125, 295, 298, 355, 486, 829, 830t epidemiology of, 827 incomplete/atypical, 828 key points, 831 outcome and follow-up for, 831 pathophysiology of, 827 refractory, 830 treatment of, 211t, 212, 829–930, 829f, 830t vaccinations in, 831 Keratosis pilaris, 278 Kernicterus, 725. See also Neonatal hyperbilirubinemia Kernig sign, 491, 492 Ketamine, 939t, 940t, 1004–1005 Ketoacidosis, 420 Ketotic hypoglycemia, 415, 417t KHE (Kaposiform hemangioendothelioma), 272, 273 Kidney nuclear medicine studies of, 1013–1014, 1013–1014f, 1015f venous anatomy of, 634f Kindler syndrome, 268t, 305, 308 Kingella kingae infections, 566, 567t, 568 Klebsiella spp. infections, 466t Klippel-Trenaunay syndrome, 271, 272 Klumpke paralysis, 701 KMP (Kasabach Merritt phenomenon), 272, 273 KMS (Kasabach Merritt syndrome), 450 Koebner phenomenon, 840 Korotkoff sounds, 99 Krabbe disease, 652, 658 Kugelberg-Welander disease, 655 Kwashiorkor, 380. See also Malnutrition L

Labetalol, 102, 102f, 103t Lacosamide, 641t La Crosse encephalitis, 491, 492, 494–495, 496 Lactic acidosis, 420, 420t Lactulose, 364, 365t Lamotrigine, 641t Langerhans cell histiocytosis, 267t, 327 Language development, 30, 31t Laparoscopy, for inguinal hernia repair, 867–868, 868f Large-cell lymphomas, 735 Laryngomalacia, 805, 877, 878f Laryngotracheal reconstruction, 879 Laryngotracheitis. See Croup (laryngotracheitis) Lateral sinus thrombosis, 501f, 502 Lead poisoning admission and discharge criteria for, 934–935 clinical presentation of, 932 consultation for, 934 diagnostic evaluation of, 932, 932f epidemiology of, 931 follow-up care for, 935 key points, 936 toxicokinetics of, 931 treatment of, 932–934, 933t Lean Six Sigma, 13 Leflunomide, 122, 843 Left bundle branch block, 225, 226f Left ventricular hypertrophy, 225, 225f Legal issues. See Medicolegal issues Leigh disease/syndrome (subacute necrotizing encephalomyelopathy), 156, 652 Lemierre syndrome (jugular septic thrombophlebitis), 134 Lethargy, 73t. See also Altered mental status (AMS) Leukapheresis, 462, 742 Leukemia acute lymphoblastic, 733–734, 734f, 734t acute myeloid, 127t, 733, 734f

chronic lymphocytic, 211t, 212 chronic myeloid, 733 epidemiology of, 733 genetic syndromes associated with, 733t vs. idiopathic thrombocytopenic purpura, 448t Leukocyte adhesion deficiency disorder, 127t Leukocytoclastic vasculitis, 262, 262f, 263 Leukodystrophies, 652–653 Leukoreduction, 460 Leukotriene receptor antagonists, 203 Levalbuterol, 788, 789t Levetiracetam, 640t, 641t Levofloxacin, 189t, 190t Levothyroxine, 325, 325t Lichen simplex chronicus, 278, 278f Lidocaine, 920t Limb deficiencies/deformities, 892 Limb-girdle muscular dystrophy, 660t Limp, 117–122 diagnostic evaluation of, 119f, 120–121 differential diagnosis of, 120 key points, 122 management of, 119f, 121–122, 121t, 122t pathophysiology of, 117 patient history in, 118–119 physical examination in, 119 Linear IgA disease (chronic bullous disease of childhood), 268t Lipase for cystic fibrosis, 812 elevated, 388–389, 389t Lipid apheresis, 463 Lisinopril, 103t Listeria monocytogenes infections, 466t Littre hernia, 868 Liver injury of, 874t, 875, 920 interventional radiology procedures for, 1031

transplantation, 921, 921t Liver failure, 372–375 admission criteria for, 375 clinical criteria for, 372 clinical presentation of, 373 complications of, 373, 373t consultation for, 375 diagnostic evaluation of, 374, 374t differential diagnosis of, 373, 373t discharge criteria for, 375 key points, 375 prevention of, 375 treatment of, 374–375 LMWH. See Low molecular-weight heparin (LMWH) Long-QT syndrome, 150 Lorazepam, 640t, 769f, 770 Losartan, 103t Lower motor neuron disease/signs, 649, 649t, 654 Low molecular-weight heparin (LMWH) for cerebral sinus venous thrombosis, 677 poisoning/overdose, 977–978 for stroke prevention, 676 for venous thromboembolism, 456 Loxapine, 774t Ludwig angina (submandibular space infection), 134–135, 511 Lumbar puncture. See also Cerebrospinal fluid (CSF) analysis anatomy, 1042, 1042f complications of, 1043 contraindications to, 493, 1042 equipment for, 1042, 1042t, 1043t in febrile seizure, 641–642, 642t in headache, 646, 647t indications for, 1041–1042 preparation for, 1042–1043 refusal of, 46–47 special considerations in, 1043–1044 technique for, 1043

Lund and Browder burn estimate, 898f Lung abscess, 528–529 Lung perfusion scan, 1017 Lung transplantation, 810 Lung ventilation/perfusion scan, 1017 Lung ventilation scan, 1017 Lung volumes, 822, 822f Lyme disease/arthritis clinical presentation of, 848t diagnostic evaluation of, 850, 1077t pathophysiology of, 848 treatment of, 851, 851t Lymphadenitis, 123–126 cervical, 133 definition of, 123 diagnostic evaluation of, 125f, 126 differential diagnosis of, 124–125, 124t key points, 126 vs. lymphadenopathy, 125 management of, 126 patient history in, 123, 123t physical examination in, 123–124, 123t, 124t Lymphadenopathy, vs. lymphadenitis, 125 Lymphatic malformations, 270, 271 Lymph nodes, 124t Lymphoblastic lymphoma, 734–735, 735f Lymphocytic vasculitis, 263 Lymphogranuloma venereum, 190t Lymphohistiocytosis, familial hemophagocytic, 845, 846, 846t Lysosomal storage diseases, 653

M MAC infections. See Mycobacterium avium complex (MAC) infections Macrocytosis, 426t Macrophage activation syndrome (MAS), 842, 845–847, 846t Macrosomia, 723–724 “Magic mouthwash,” 509 Magnesium citrate, 932 Magnesium hydroxide, 365t Magnesium sulfate, 790, 920t Magnetic resonance angiography (MRA), 665f, 667f, 668f, 674–675, 674t Magnetic resonance imaging (MRI), 1024–1025 abdomen/pelvis, 1026 in acute disseminated encephalomyelitis, 684, 684f, 688f in appendicitis, 864 brain, 1025, 1025f in brain abscess, 493, 494f cardiac/chest/vascular, 1026 contrast agents for, 1007 extremity, 1026 face/neck, 1026 in headache, 646, 647t in head trauma, 885 in juvenile dermatomyositis, 838, 838f in multiple sclerosis, 685, 688f in neuromyelitis optica, 689 in osteomyelitis, 567, 567t, 568f spine, 1026 in stroke, 667f, 669f, 674–675, 674t in transverse myelitis, 686, 687f Magnetic resonance pancreatography (MRCP), 357, 357f, 389 Major depressive episode, 754 Male genitalia care, in infants, 698 Malignant hyperthermia, 949, 950, 950t, 951 Malingering, 764 Malnutrition, 380–385. See also Failure to thrive (FTT) admission criteria for, 385

classification of, 381 clinical presentation of, 380, 381t consultation for, 385 diagnostic evaluation of, 380–382, 381t discharge criteria for, 385 epidemiology of, 380 key points, 385 management of, 382–384, 382f pathophysiology of, 380 prevention of, 385 risk factors for, 381t special considerations in, 384–385 Malrotation, 859–860, 859f, 862, 1011f Mandated reporting, 173, 174. See also Abuse and neglect Mannitol, 320, 740t, 746 Marasmus, 380. See also Malnutrition MAS (macrophage activation syndrome), 842, 845–847, 846t Mastocytosis, inflammatory, 267t Mastoidectomy, 502 Mastoiditis, 501–502, 501f Maximum expiratory pressure (PEmax), 823 Maximum inspiratory pressure (PImax), 823 MCAD (medium-chain acyl-CoA dehydrogenase) deficiency, 414–415 McArdle disease, 662 MCD (minimal change disease), 629. See also Nephrotic syndrome Mean corpuscular hemoglobin (MCH), 425t Mean corpuscular hemoglobin concentration, 425t Mean corpuscular volume, 425t Meaningful Use, of electronic health records, 21, 21t Measles (rubeola), 17t, 128t, 482t Meckel diverticulum, 96–97 Meckel scan, 1017 Meconium, 697 Meconium ileus, 810 Meconium-stained amniotic fluid, 695 Medical child abuse clinical presentation of, 170–171, 171t

consultation for, 173 diagnostic evaluation of, 171–172, 172f differential diagnosis of, 171 discharge criteria for, 173 epidemiology of, 170 key points, 173 management of, 172–173 pathophysiology of, 170 patient history in, 171t special considerations in, 173 terminology of, 169–170 Medical error, 13–14 Medically complex child. See Child with medical complexity (CMC) Medical records, 19–20, 47–48. See also Electronic health records (EHRs) Medication alerts, 22 Medication errors, 14 Medicolegal issues in child abuse and neglect. See Abuse and neglect, legal issues in in communication, 45 confidentiality, 49 in documentation, 47–48 in follow-up care, 49–50 in hospital discharge, 49, 49t informed consent. See Informed consent in interactions with consultants, 48 refusal of care, 46–47 in treatment of incidental findings, 48–49 Mediterranean fever, familial, 575 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, 414–415 Medline searches, 10, 10t Medroxyprogesterone acetate, 196, 197t Megaloblastic anemia, 429 Melena, 94 Meleney’s synergistic gangrene, 578 Menetrier disease, 370 Meningismus, 131 Meningitis

admission criteria for, 496 bacterial clinical presentation of, 491 epidemiology of, 489–490 pathophysiology of, 490, 490t treatment of, 465t, 495–496, 495t clinical presentation of, 135 consultation for, 497 diagnostic evaluation of, 493 discharge criteria for, 497 enteroviral/parechoviral, 490–491, 492, 493, 496 key points, 497 prevention of, 497, 497t Meningocele, 709 Meningococcal infections admission and discharge criteria for, 485 chemoprophylaxis for contacts, 485, 497t classification of, 482–483 clinical presentation of, 483–484, 483f, 484f consultation for, 485 diagnostic evaluation of, 484 differential diagnosis of, 484, 484t, 486 empirical treatment of, 467t epidemiology of, 482–483 pathophysiology of, 483 prevention of, 17t, 485 treatment of, 485 Mentorship, 56 Mepolizumab, 793 6-Mercaptopurine, 378, 378t Mercury poisoning, 935–936, 936t Meropenem, 495t, 745t, 813t Metabolic acidosis, 418–423 admission criteria for, 422 consultation for, 422 definition of, 67 diagnostic evaluation of, 69–70, 69f, 70t, 419–422, 421t, 780t

differential diagnosis of, 67–69, 68f, 69t, 419, 419t, 420t discharge criteria for, 422 future directions in, 423 in hyperkalemia, 352 key points, 422 management of, 70, 422, 422t physiology of, 418–419 in renal tubular acidosis, 632. See also Renal tubular acidosis (RTA) Metabolic acrodermatitis enteropathies, 268t Metabolic disorders. See Inborn errors of metabolism Metabolic myopathies, 662 Metabolic syncope, 150. See also Syncope Metabolic syndrome, 775, 775t Metaphyseal lesions, 167, 167f Metatarsus adductus, 781 Methacholine challenge test, 824 Methadone, 732, 943–944 Methamphetamine, 938, 939t Methanol poisoning, 928–929, 928f Methemoglobin, 948 Methemoglobinemia, 84, 112–113 Methicillin-resistant Staphylococcus aureus (MRSA) infections, 18, 467t, 813t Methimazole, 325 Methotrexate adverse effects of, 121t, 378t, 843 for atopic dermatitis, 281 for inflammatory bowel disease, 378 for juvenile dermatomyositis, 838–839, 838f for juvenile idiopathic arthritis, 843 for juvenile rheumatoid arthritis, 121t, 122 Methylprednisolone for asthma, 790t for demyelinating syndromes, 682 for DRESS, 291 for hemolytic anemia, 431 for Henoch-Schönlein purpura, 834

for optic neuritis, 685 for rapidly progressive glomerulonephritis, 620 for systemic lupus erythematosus, 854 Methylxanthines, 790, 790t Metoclopramide, 371, 396 Metoprolol, 103t Metronidazole, 190t, 191t, 378, 378t, 552t MIBG scan, 1019, 1020f Microcytosis, 426t Midazolam, 640t, 1004 Migraine, 155, 645–646, 645t, 648 MII (multiple intraluminal impedance) monitoring, 396t Milia, 265, 265t, 307f Miliaria, 267t Milk scan, 394, 396t Miller-Dieker syndrome, 405t Miller-Fisher variant, Guillain-Barré syndrome, 656 Milrinone, 247 Mineral oil, 364t, 365t Minimal change disease (MCD), 629. See also Nephrotic syndrome Minocycline, 203, 813t, 814t Minoxidil, 103t Mitochondrial diseases, 156–157, 652 Mitral regurgitation, 257, 257t Mitral stenosis, 217, 219f Mitral valve prolapse, 218, 219f Mixing studies, 452 Modified Allen test, 1048, 1048f Modified barium swallow, 1010, 1010f Molindone, 774t Molluscum contagiosum, 302 Monoclonal cryoglobulinemia, 285t Monosomy, 399, 405t Montelukast, 203 Mood disorders, 772. See also Depression; Psychosis Moraxella catarrhalis infections, 466t Morganella spp. infections, 467t

Morphine, 438 Mosaicism, 399 Moyamoya disease, 435, 668f MRA (magnetic resonance angiography), 665f, 667f, 668f, 674–675, 674t MRCP (magnetic resonance pancreatography), 357, 357f, 389 MRI. See Magnetic resonance imaging (MRI) MRSA (methicillin-resistant Staphylococcus aureus) infections, 18, 467t, 813t Mucor infection, 285t Mucositis, 303 Multiple gestations, 695 Multiple intraluminal impedance (MII) monitoring, 396t Multiple sclerosis (MS), 682t, 687–688, 688f Münchausen Syndrome by proxy, 169, 780t. See also Medical child abuse Murmurs in acute rheumatic fever, 257 in coarctation of the aorta, 236 intensity of, 218 location and radiation of, 217f, 219–220, 220f in neonates, 218 in patent ductus arteriosus, 235. See also Patent ductus arteriosus (PDA) quality of, 220 timing of, 219 in ventricular septal defect, 234–235. See also Ventricular septal defect (VSD) Murphy sign, 355 Muscle biopsy, 663, 838 Muscle strength testing, 647, 650t Muscular dystrophies, 660–662, 660t, 661f. See also specific diseases Myasthenia gravis, 658–659 Mycobacterium avium complex (MAC) infections, 124 Mycobacterium tuberculosis infections, 17t, 18, 124, 513. See also Tuberculosis Mycophenolate mofetil, 855 Mycoplasma pneumoniae infections, 17t, 466t, 528. See also Pneumonia Mycotic aneurysm, 240 Mydriasis, 885

Myelomeningocele, 709 Myocardial ischemia, 73–74, 77–78 Myocardial perfusion imaging, 1017–1018 Myocarditis, 79, 245 Myotonic muscular dystrophy, 660t N N-acetylcysteine (NAC), 921 Nafcillin for bacterial meningitis, 495t for cystic fibrosis exacerbations, 813t for infective endocarditis, 243t NaHCO3 (sodium bicarbonate), 352 Nail bed capillaroscopy, 836, 837f NAIT (neonatal alloimmune thrombocytopenia), 449–450 Naloxone for fentanyl reversal, 1005 in neonatal resuscitation, 694 withdrawal symptoms caused by, 944 Naproxen, 121, 121t, 841, 843 NAS. See Neonatal abstinence syndrome (NAS) Nasal cannula, 112t Nasal intermittent positive pressure ventilation, 1065, 1065f. See also Noninvasive positive-pressure ventilation (NPPV) Nasogastric feedings, 383, 383t Natalizumab, 687 National Marrow Donation Program (NMDP), 748 Nausea and vomiting, 35, 366, 894. See also Vomiting Neck imaging. See Head and neck imaging Neck infections. See also Deep neck space infections cervical lymphadenitis, 513–514, 513t neck mass in, 878 neck pain in, 133 Neck mass, 878–879, 879t, 1021, 1021f Neck pain diagnostic evaluation of, 131–132 differential diagnosis of, 133t, 134–136

key points, 136 pathophysiology of, 131 patient history in, 133 physical examination in, 133 Neck stiffness, 131 Necrotizing enterocolitis, 96, 154 Necrotizing fasciitis, 285t, 577–579, 578f Neglect. See Abuse and neglect Neisseria gonorrhoeae infections. See Gonorrhea Neisseria meningitidis infections. See Meningococcal infections Neonatal abstinence syndrome (NAS), 729–732. See also Withdrawal syndromes admission and discharge criteria for, 732 clinical presentation of, 729–730, 730t, 942 diagnostic evaluation of, 730 differential diagnosis of, 730 epidemiology of, 729 key points, 732 pathophysiology of, 729–730 prevention of, 732 treatment of, 730–732, 731f, 943t Neonatal alloimmune thrombocytopenia (NAIT), 449–450 Neonatal hyperbilirubinemia, 725–729 admission and discharge criteria for, 729 clinical presentation of, 355, 725 diagnostic evaluation of, 726–727, 727f differential diagnosis of, 725–726, 726t epidemiology of, 725 key points, 729 pathophysiology of, 725 prevention of, 729 screening for, 698, 726 treatment of, 727, 728f, 729t Neonatal lupus, 853, 854f Neonatal opiate solution (NOS), 732 Neonates. See also Delivery room medicine abstinence syndrome in. See Neonatal abstinence syndrome (NAS)

alloimmune neutropenia in, 443 birth asphyxia in. See Birth asphyxia birth injuries in. See Birth injury congenital anomalies in. See Congenital anomalies congenital infections in. See Congenital infections conjunctivitis in, 697, 888–889 critical congenital heart disease in, 84, 229, 229t, 231–234, 232f, 233f, 699 developmental dysplasia of the hip in, 699–700, 700t fever in, 468–474, 470t, 471t hyperbilirubinemia in. See Neonatal hyperbilirubinemia hyperthyroidism in, 322 hypocalcemia in, 330, 330t hypoglycemia in, 413–414, 721–722, 722t liver failure in, 373, 374t with meconium-stained amniotic fluid, 695 noninvasive positive-pressure ventilation in, 1066 normal ECG in, 223, 223f perinatally acquired infection in, 719–720, 720f persistent pulmonary hypertension in, 692, 711–713, 712t petechiae and purpura in, 138–139 pneumothorax in, 695, 705, 705f premature/preterm. See Premature/preterm infants renal venous thrombosis in, 634 respiratory distress in, 142t Rh incompatibility, 431 shock in, 145, 145t, 147 testicular torsion in, 907 thrombocytopenia in, 449–450 transfusions in, 458–459, 461 transient tachypnea in, 711–713, 712t umbilical artery and vein catherization in. See Umbilical artery and vein catherization vesicobullous disorders in, 268–268t vomiting in, 153, 153t well full-term. See Well newborn withdrawal syndromes, 942, 943t, 944 Nephritis

glomerulonephritis, 618–620, 626t lupus, 854, 855t tubulointerstitial. See Tubulointerstitial nephritis (TIN) Nephrolithiasis, 911–913, 912f Nephrotic syndrome, 627–630 admission criteria for, 629–630 classification of, 627, 628t clinical presentation of, 627–628 complications of, 629, 629t consultation for, 630 diagnostic evaluation of, 628–629 differential diagnosis of, 628, 628t discharge criteria for, 630 epidemiology of, 627 key points, 630 pathophysiology of, 627, 628f, 629f prevention of, 630 treatment of, 629 Nerve conduction studies, 663 Nesiritide, 247–248 Neural tube defects, 708–709 Neuroblastoma clinical presentation of, 737 diagnostic evaluation of, 737, 737f, 1020f differential diagnosis of, 737 epidemiology of, 339 pathophysiology of, 339 Neurocardiogenic (vasovagal) syncope, 148, 149f. See also Syncope Neuroleptic malignant syndrome, 771, 774, 775t Neurologic impairment. See Severe neurologic impairment Neuromuscular junction defects, 658 Neuromyelitis optica (NMO), 682t, 688–689 Neuropathic pain, 118, 118t Neurosurgical issues, 881–886. See also Head trauma; Hydrocephalus Neurosyphilis, 192t Neutropenia, 439–446 admission and discharge criteria for, 444–445

alloimmune, 443 in aplastic anemia, 443 benign, of childhood, 442 clinical presentation of, 442 consultation for, 445 definition of, 439 diagnostic evaluation of, 441t, 443, 444f differential diagnosis of, 440t drug-induced, 443 and fever, 744–745, 744t, 745t immune-mediated, 442 inherited forms of, 443 isolated, 439 key points, 446 management of, 443–444, 444f, 445t pathophysiology of, 442 prevention of, 446 primary autoimmune, 442–443 secondary autoimmune, 443 secondary to infection, 442 Neutrophils, 439 Newborns. See Neonates Nicardipine, 102, 102f, 103t NICH (non-involuting congenital hemangioma), 272 Nifedipine, 102, 102f, 103, 103t Night blindness, 355 Nikolsky sign, 265, 572 Nitazoxanide, 552t Nitroprusside, 102, 103t Nitrous oxide, 1005 NMO (neuromyelitis optica), 682t, 688–689 NMO-IgG, 689 Noisy breathing, 877–878, 877t, 888 Nonaccidental trauma. See Abuse and neglect Non–anion gap acidosis. See also Metabolic acidosis diagnostic evaluation of, 70 differential diagnosis of, 68, 419

etiology of, 69t, 419t Nondisjunction, 399 Non-Hodgkin lymphoma, 734–735 Noninvasive positive-pressure ventilation (NPPV), 1064–1069 advantages of, 1064 contraindications to, 1067, 1068t indications for, 1066–1067, 1066t initiation and monitoring of, 1068–1069 interfaces for, 1067–1068, 1068f key points, 1069 limitations and complications of, 1069 modes of, 1064–1066, 1065f in neonates, 692, 693f, 694f Non-involuting congenital hemangioma (NICH), 272 Nonmaleficence, 41 Nonsteroidal anti-inflammatory drugs (NSAIDs) for abnormal uterine bleeding, 198 adverse effects of, 121t, 834 for fever, 93–94 for Henoch-Schönlein purpura, 834 for joint pain, 121 for juvenile idiopathic arthritis, 843 mechanism of action, 93 for pericarditis, 254 sensitivity to, 203 Nonthyroidal illness (sick euthyroid syndrome), 324 Noonan syndrome, 216t Norethindrone acetate, 196, 197t Norovirus infection, 17t, 545t, 547t NOS (neonatal opiate solution), 732 NPPV. See Noninvasive positive-pressure ventilation (NPPV) NSAIDs. See Nonsteroidal anti-inflammatory drugs (NSAIDs) Nuclear medicine, 1012–1017. See also specific studies cardiac imaging, 1017–1018 central nervous system imaging, 1018 endocrine imaging, 1018 in gastrointestinal bleeding, 97

gastrointestinal imaging, 1016–1017 genitourinary imaging, 1013–1014, 1013–1014f hepatobiliary imaging, 1016, 1016f infection imaging, 1018 pulmonary imaging, 1017 skeletal imaging, 1014–1016 tumor imaging, 1018–1019 Nummular dermatitis, 278, 278f O OAE (otoacoustic emissions) test, 699 Obstructive sleep apnea syndrome, 714, 782, 782t, 990, 1067 Obtundation, 73t, 889. See also Altered mental status (AMS) Occult blood, stool, 94 Octreotide, 371, 923, 925t Oculo-pharyngeal muscular dystrophy, 660t Ofloxacin for chlamydia, 189t for epididymitis, 190t for nongonococcal urethritis, 190t for pelvic inflammatory disease, 190t Olanzapine adverse effects of, 775 for agitation, 769f, 770 for psychosis, 774, 774t Olmesartan, 103t Omalizumab, 793–794 Omphalitis, 469 Omphalocele, 706–707 Oncologic emergencies, 739–747, 739t. See also Childhood cancer cardiopulmonary, 745–746 fever and neutropenia, 744–745, 744t, 745t future directions in, 747 hematologic, 742–743, 743t key points, 747 metabolic, 739–741, 740t, 741t, 742t neurologic, 746–747, 747t

Ondansetron, 157, 343–344, 551 1p36 deletion syndrome, 406 Open globe injury, 890, 890f Opening snap, 217, 219f Ophthalmia neonatorium, 697, 888–889 Ophthalmic conditions, 887–891 eye care in obtunded patients, 889 herpes zoster ophthalmicus, 889 history taking in, 887 key points, 891 ophthalmia neonatorium, 697, 888–889 orbital cellulitis, 465t, 503–506, 505f, 887–888 physical examination in, 887, 888f preseptal cellulitis, 887–888 red eye, 887, 889f trauma, 889–891, 890f Opioids in pancreatitis, 390 poisoning/overdose, 916t for vaso-occlusive pain crisis, 438 withdrawal syndrome, 942, 942t, 943–944, 943t Opsoclonus-myoclonus syndrome, 737 Optic neuritis, 682t, 685, 685t, 686f Oral cavity infections in HIV infection, 593 pharyngitis. See Pharyngitis stomatitis, 127, 128t, 508–510, 509f Oral contraceptives, 196, 197t Oral hypoglycemics, 923–925, 924t Oral lesions, 127, 127t, 130–131, 131t Oral rehydration solution (ORS), 342, 343f, 546t, 550 Oral trauma, 129, 130 Oral ulcers, 508, 853f, 853t Orbital cellulitis, 465t, 503–506, 505f, 887–888, 1021f Order sets, 22 Organophosphate poisoning, 916t Orkambi, 811

Ornithine transcarbamoylase (OTC) deficiency, 409. See also Urea acid cycle defects Orthopedic conditions, 891–895 back pain, 894–895, 895f brachial plexus birth palsy, 701, 702f, 703, 892–893 cast care, 893, 894f compartment syndrome, 453, 893 congenital, 891–893, 892f developmental dysplasia of the hip, 699–700, 700t, 891–892 postoperative complications, 893–894 trauma, 893 Osborn wave, ECG, 953, 953f Oseltamivir, 533 Osler nodes, 240 Osmolal gap, 70 Osmolality of contrast agents, 1007 plasma/urine, 613t serum. See Serum osmolality urine. See Urine osmolality Osmotic demyelination syndrome, 348 Osteogenesis imperfecta, 128 Osteoid osteoma, 136, 1031, 1031f Osteomyelitis, 566–570 chronic, 569 clinical presentation of, 567 diagnostic evaluation of, 567, 567f, 568f, 1026f differential diagnosis of, 567 discharge criteria for, 570 epidemiology of, 566 etiology of, 566, 567t pathophysiology of, 566–567 pelvic, 569 Pseudomonas, 569 recurrent, 569 in sickle cell disease, 569 treatment of, 465t, 567–569

vertebral, 135, 569–570 Osteopenia, 991 Osteosarcoma, 738, 738f OTC (ornithine transcarbamoylase) deficiency, 409. See also Urea acid cycle defects Otitis media. See Acute otitis media (AOM) Otoacoustic emissions (OAE) test, 699 Otolaryngology. See Ear, nose, and throat problems Ovarian torsion/cyst, 864t Ovid, 10 Oxacillin for bacterial meningitis, 495t for infective endocarditis, 243t for osteomyelitis, 567t Oxalic acid, 912 Oxcarbazepine, 641t Oxygenation Index (OI), 707 Oxygen cascade, 107 Oxygen delivery systems, 112t Oxygen saturation. See Pulse oximetry (SpO2) Oxygen therapy, 517–518, 806 Oxyhemoglobin saturation-desaturation curve, 108, 108f P Pacemakers, 238 Pachyonychia congenita, 269t Packed red blood cell (pRBC) transfusion in childhood cancer patients, 743, 743t cytomegalovirus-negative, 461 dosage calculation for, 458 fresh, 461 indications for, 458 irradiated, 460–461 leukocyte-reduced, 460 in neonates, 458–459 volume-reduced, 461 washing for, 461

PaCO2 (arterial partial pressure of carbon dioxide) in acute chest syndrome, 435 in asthma, 786, 787t, 792 formulas and pearls, 110t pathophysiology of, 107–108 in respiratory failure, 1068t Pain abdominal. See Abdominal pain chest. See Chest pain neck. See Neck pain vaso-occlusive, 435–436 Pain disorders, 764–766 Pain management, 36, 36t, 746–747 Paliperidone, 774t Palivizumab, 520, 520t, 606t Palliative care bereavement programs and, 37–38 for complex chronic conditions, 35 concurrent care and, 37 discussing with family, 34–35 dispelling stigma of, 35 goals of, 34 identification of patients needing, 34, 34f quality of life considerations in, 37 spiritual issues in, 38 symptom management in, 35–37, 35t, 36t transitions to home or hospice care, 37, 37t Palpation, of abdomen, 65 Pamidronate, 334 Pancreas divisum, 386 Pancreatic insufficiency, 810–811 Pancreatic pseudocyst, 391 Pancreatitis, 386–392 admission and discharge criteria for, 391 autoimmune, 392 chronic, 391–392 clinical presentation of, 388

complications of, 391 consultation for, 391 diagnostic evaluation of, 389–390 differential diagnosis of, 388–389, 389t drug-related, 386, 388t epidemiology of, 386 etiology of, 358, 386, 387t, 388t future directions in, 392 genetic factors in, 388, 392 key points, 392 pathophysiology of, 386–388 postoperative, 894 recurrent, 391 treatment of, 390–391 Pancytopenia, 440–442. See also Neutropenia PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), 212 PAN (polyarteritis nodosa), 263 PaO2 (alveolar oxygen), 107–108, 110t Paracetamol. See Acetaminophen Parainfluenza virus infection, 17t, 602, 606t Paraneoplastic pemphigus, 298 Parapharyngeal infections, 134–135, 511–512, 512f Parapharyngeal space, 131, 132f Parapneumonic effusion, 528, 531f, 533, 534t Parathyroidectomy, 334 Parathyroid gland imaging, 1018 Parechoviral meningitis/encephalitis clinical presentation of, 492 diagnostic evaluation of, 494 epidemiology of, 491 treatment of, 496 Parenteral nutrition, 382f, 383–384, 384t, 390 Parkes Weber syndrome, 271 Paromomycin, 552t Paroxysmal cold hemoglobinuria, 430 Paroxysmal sympathetic hyperactivity, 985–986

Pars interarticularis, 895, 895f Partial rebreather oxygen delivery, 112t Parvovirus B19 infection complications of, 430, 848t, 849 congenital, 715, 716t, 717t in transplant recipient, 601 PAR-1 antagonist poisoning/overdose, 976 Pasteurella multocida infections, 467t, 961 Pastia lines, 482 Patau syndrome (trisomy 13), 216t, 403, 403t Patent ductus arteriosus (PDA) differential diagnosis of, 229, 229t heart sounds in, 220 pathophysiology of, 235, 236f treatment of, 236 Patient safety, 13–14. See also Infection control PBSCs (peripheral blood stem cells), 749. See also Hematopoietic stem cell transplant (HSCT) PDA. See Patent ductus arteriosus (PDA) PDSA (Plan-Do-Study-Act), 12 PE. See Plasma exchange (PE, plasmapheresis) Peak expiratory flow rate (PEFR) in asthma, 786, 788, 792 indications for, 822 normal values for, 787t technique for, 822 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), 212 Pediatric condition falsification, 169. See also Medical child abuse Pediatric hospitalist(s) billing issues for, 28 career opportunities for, 53–56, 54t, 55t as comanager, 28 communication skills of, 25–26, 39, 40, 40t as consultants, 27–28 employment and compensation models for, 51–52 evolution of, 27

future directions of, 28–29 professional organizations for, 51 staff development for, 55t, 56 subspecialty models for, 52 Pediatric hospital medicine current directions in, 4–5 current status of, 3 education programs in, 3 efficiency of, 3 ethical issues. See Ethical issues family-centered care in, 25–26 future directions in, 5 healthcare variation and, 10 outcome measures for, 4 primary care physicians’ attitude toward, 3 process measures for, 3–4 quality of, 3 Pediatric Hospital Medicine (PHM) conference, 51 Pediatric NIH Stroke Scale, 672–673t Pediatric Research in Inpatient Settings (PRIS), 51 Pediatric Ulcerative Colitis Disease Activity Index (PUCAI), 377–388, 377t PEFR. See Peak expiratory flow rate (PEFR) PEG (percutaneous endoscopic gastrostomy), 994 Pelizaeus-Merzbacher syndrome, 406t Pelvic imaging computed tomography, 1022 magnetic resonance imaging, 1026 point-of-care ultrasound, 1035–1036, 1035f, 1036f ultrasound, 1024 Pelvic inflammatory disease (PID) diagnostic evaluation of, 186t, 189 differential diagnosis of, 187 pathophysiology of, 186 treatment of, 190t, 465t Pelvic masses, 736–738, 736t PEmax (maximum expiratory pressure), 823 Pemphigus

neonatal, 268t paraneoplastic, 268t Pemphigus foliaceus, 268t Pemphigus vulgaris, 268t Penicillin, 203, 244t, 288–289 Penicillin G aqueous crystalline, 192t for bacterial meningitis, 495t benzathine, 192t, 258t, 259t for infective endocarditis, 242t for Lyme disease, 851t procaine, 192t Penicillin V, 258t, 259t Penicillin VK, 434t Pentobarbital, 1004 111In-Pentreotide scan, 1019 Percussion, of abdomen, 65 Percutaneous cecostomy, 1031 Percutaneous endoscopic gastrostomy (PEG), 994 Pericardial friction rub, 218 Pericardiocentesis, 255 Pericarditis, 251–255 admission and discharge criteria for, 255 bacterial, 252–253 causes of, 252t clinical presentation of, 78–79, 252, 252f consultation for, 255 diagnostic evaluation of, 253–254, 253f, 254f, 254t differential diagnosis of, 252–253 drug-related, 253t ECG in, 226–227 in juvenile idiopathic arthritis, 842 key points, 255 management of, 254–255 pathophysiology of, 251 tuberculous, 253 viral, 252

Perinatal infection, 719–720 Periodic fever, 93t Periodic fever, aphthous stomatitis, and adenopathy (PFAPA), 125 Periorbital cellulitis, 465t, 503–506, 504f, 574 Peripheral blood stem cells (PBSCs), 749. See also Hematopoietic stem cell transplant (HSCT) Peripheral intravenous access anatomy for, 1049, 1050f complications of, 1051 contraindications to, 1049 equipment for, 1049–1050, 1050t follow-up for, 1051 indications for, 1049 pitfalls in, 1039, 1051 procedure for, 1050–1051, 1051f technique for, 1039 Peripherally inserted central catheter (PICC) anatomy, 1053 complications of, 1054 contraindications to, 1053 equipment for, 1053, 1054t indications for, 1053 maintenance of, 1054, 1055t procedure for, 1053–1054, 1054t, 1055f ultrasound-guided placement of, 1028, 1054t Peripheral nerve injury, during delivery, 701–703, 702f Peripheral neuropathies, 655. See also specific disorders Peritoneal dialysis, 617 Peritonitis admission criteria for, 558 in appendicitis, 863 clinical presentation of, 64, 557 consultation for, 557 diagnostic evaluation of, 557 differential diagnosis of, 557 discharge criteria for, 558 with gastrostomy tube, 995

key points, 558 treatment of, 557 Peritonsillar abscess, 133, 134f, 466t, 511, 511f Peritonsillar space, 131 Perphenazine, 774t Persistent pulmonary hypertension of the newborn (PPHN), 692, 711–713, 712t Pertussis, 534–536 admission criteria for, 536 clinical presentation of, 534–535 complications of, 535 consultation for, 536 diagnostic evaluation of, 535 differential diagnosis of, 535 discharge criteria for, 536 epidemiology of, 534 infection control, 17t, 18, 535 pathophysiology of, 534 postexposure prophylaxis for, 536t prevention of, 536 treatment of, 466t, 535, 536t Pes cavus, 657, 657f PET (positron emission tomography), 1013 Petechiae, 137, 261, 484t. See also Purpura Peutz-Jeghers syndrome, 127t PFA (platelet function assay), 452 PFAPA (periodic fever, aphthous stomatitis, and adenopathy), 125 pH, urinary, 63t, 632 PHACES association, 272, 273f Pharyngitis admission criteria for, 511 clinical presentation of, 510 diagnostic evaluation of, 510 differential diagnosis of, 189, 510, 510t epidemiology of, 510 etiology of, 510, 510t gonococcal, 186, 189, 189t

group A β-hemolytic streptococcal. See Group A β-hemolytic streptococcus (GABHS) infections treatment of, 510–511 Phenobarbital adverse effects of, 641t for barbiturate withdrawal, 943t for neonatal abstinence syndrome, 732 for seizures, 640t Phentolamine, 901 Phenylketonuria (PKU), 699 Phenytoin, 641t Pheochromocytoma, 339, 340 Philadelphia protocol, for febrile infants, 469–470, 470t, 472 Phlebotomy, 1062–1063, 1063f, 1063t, 1064f Phlegmon, 131, 133 PHM (Pediatric Hospital Medicine) conference, 51 Phosphate, 318, 334 Phosphorylase deficiency, 417t Photosensitivity reactions, drug-related, 289–290, 304, 304f Phototherapy, 727, 728f pH probe, 395, 396t Physical development, 30, 31t Physical restraints, 770 Physical status classification, American Society of Anesthesiologists, 1003, 1004t Physician Orders for Life-Sustaining Treatment (POLST), 998 Physician-patient-parent communication, 30, 32–33 Physiologic jaundice, 355, 725–726. See also Neonatal hyperbilirubinemia Physostigmine, 920, 920t Piagetian stages of development, 30, 32t PICC. See Peripherally inserted central catheter (PICC) PID. See Pelvic inflammatory disease (PID) PImax (maximum inspiratory pressure), 823 Pimecrolimus, topical, 280 Pimozide, 774t Piperacillin, 813t Piperacillin/tazobactam, 147t, 567t

Pitressin, 328 Pituitary function disorders admission and discharge criteria for, 329 causes of, 326 in child with severe neurologic impairment, 986 clinical presentation of, 326–327 consultation for, 329 diabetes insipidus. See Diabetes insipidus (DI) genetic factors in, 326, eTable 70–1 hypopituitarism. See Hypopituitarism key points, 329 pathophysiology of, 326 Pituitary gland, 326 Pityriasis alba, 278 PKU (phenylketonuria), 699 PLAID (PLCG2-associated antibody deficiency and immune dysregulation), 208–209 Plan-Do-Study-Act (PDSA), 12 Planned aggression, 768 Plasma exchange (PE, plasmapheresis) for chronic inflammatory demyelinating neuropathy, 657 for demyelinating syndromes, 682 for Guillain-Barré syndrome, 656 Plasma transfusion, 460 Platelet aggregation studies, 452 Platelet disorders, 451, 455 Platelet function assay (PFA), 452 Platelet pheresis, 463 Platelet transfusion aliquoting for, 461 in childhood cancer patients, 743, 743t dosage calculation for, 459 indications for, 459 for neonatal thrombocytopenia, 450 preparation of, 459–460 refractoriness to, 460 volume-reduced, 461

PLCG2-associated antibody deficiency and immune dysregulation (PLAID), 208–209 Pleural effusions, 529, 530f, 1076 Pleural fluid analysis/culture, 531, 533t, 1076 PML. See Progressive multifocal leukoencephalopathy (PML) PMS2 mutations, 208 Pneumocystis jiroveci (PJP) pneumonia, 592, 604, 605t Pneumomediastinum, 904–906, 905f, 905t, 906f Pneumonia, 527–534 admission and discharge criteria for, 533–534 aspiration. See Aspiration pneumonia in child with severe neurologic impairment, 984, 990 clinical presentation of, 528 complications of, 528–529, 529f consultation for, 534 diagnostic evaluation of imaging, 529–530, 530f, 531f laboratory, 530–532 differential diagnosis of, 529, 864t in drowning, 960 epidemiology of, 527 etiology of, 527–528, 527t in HIV-infected child, 592 necrotizing, 528, 529f treatment of, 466t, 532–533, 532t, 534t, 1066 Pneumonitis, aspiration. See Aspiration pneumonitis Pneumoperitoneum, 1008f Pneumothorax, 901–904 admission and discharge criteria for, 904–905 clinical presentation of, 902 consultation for, 905 in cystic fibrosis, 813, 813f diagnostic evaluation of, 902–903, 902f, 903f differential diagnosis of, 902 epidemiology of, 901–902 key points, 906 in neonates, 695, 705, 705f

pathophysiology of, 902 prevention of, 905 treatment of, 903, 904f Podofilox, 191t Podophyllin, 191t Point-of-care ultrasound (POCUS), 1033–1041 for abscess drainage, 1040, 1040f for bladder catheterization and suprapubic aspiration, 1040–1041, 1041f cardiac, 1036–1037, 1037f for central venous access, 1038–1039, 1039f equipment for, 1034, 1034f for peripheral venous access, 1039 principles of, 1034–1035, 1035f program development for, 1033 pulmonary, 1037–1038, 1038f in trauma, 1035–1036, 1035f, 1036f Poisoning, 915–917. See also specific drugs/substances antidotes, 917t clinical presentation of, 915t diagnostic evaluation of, 915–916, 916t epidemiology of, 915 indications for transfer, 917t initial management of, 915, 915t key points, 925 prevention of, 925 treatment of, 916–917, 916t, 917t Poliomyelitis, 655 POLST (Physician Orders for Life-Sustaining Treatment), 998 Polyarteritis nodosa (PAN), 263 Polychondritis, relapsing, 135 Polychromasia, 426t, 427f Polycythemia, 780t Polyethylene glycol, 364, 365t, 932 Polyethylene glycol-electrolyte solution, 364, 364t Polysomnography, 824, 825f Pompe disease, 662 POPE (postobstructive pulmonary edema), 879

Porphyria(s), 127t, 269t Portable radiographs, 1010 Portal hypertension, 95 Port-wine stains (capillary malformations), 270 Positive pressure ventilation (PPV). See Noninvasive positive-pressure ventilation (NPPV) Positron emission tomography (PET), 1013, 1018 Post-infectious glomerulonephritis (PIGN), 618 Postobstructive pulmonary edema (POPE), 879 Post-pericardiotomy syndrome, 253 Post-streptococcal glomerulonephritis (PSGN), 618 Post-streptococcal reactive arthritis (PSRA), 848–849, 848t, 850 Post-transplant lymphoproliferative disorders (PTLDs), 601 Postural orthostatic tachycardia syndrome (POTS), 149 Post-varicella arteriopathy, 665, 668f Potassium. See also Hyperkalemia; Hypokalemia in body fluids, 346t for diabetic ketoacidosis, 318 for hypokalemia, 352 maintenance requirements for, 345 Potocki-Shaffer syndrome, 405t POTS (postural orthostatic tachycardia syndrome), 149 Pott puffy tumor, 506, 506f PPD (purified protein derivative) test, 126 PPHN (persistent pulmonary hypertension of the newborn), 692, 711–713, 712t PPIs (proton pump inhibitors), 396 Prader-Willi syndrome, 405t, 407, 650–651 PRBC (packed red blood cell) transfusion, 458–459 Precordial catch syndrome, 80 Prednisolone, 519, 790t Prednisone for acute demyelinating syndromes, 682 for asthma, 790t for chronic inflammatory demyelinating neuropathy, 657 for DRESS, 291 for hemolytic anemia, 431

for Henoch-Schönlein purpura, 834 for muscular dystrophy, 661 for nephrotic syndrome, 629 for rapidly progressive glomerulonephritis, 620 for systemic lupus erythematosus, 854 Preductal oximetry, 692, 693t Preference-sensitive care, 7 Pregnancy ectopic. See Ectopic pregnancy gonorrhea treatment in, 190t syphilis treatment in, 192t Prehn sign, 187 Premature/preterm infants bronchopulmonary dysplasia in, 803, 803t. See also Bronchopulmonary dysplasia (BPD) intravenous immunoglobulin for, 212 respiratory depression in, 695 Preseptal cellulitis, 887–888 Prevertebral space, 512 Prevotella spp. infections, 467t Priapism, 436–437 Primary immunodeficiency diseases, 207–210 agammaglobulinemia, 210 allergic disorders in, 209 asymptomatic, 209 autoimmune disorders in, 207–208 cancer susceptibility in, 208 chronic granulomatous disease, 210 common variable immunodeficiency, 208, 210 diagnostic evaluation of, 209 genetic factors in, 210 infections in, 207 inflammatory conditions in, 208–209 intravenous immunoglobulin for, 211, 211t key points, 210 patient history in, 207, 207t physical examination in, 209

severe combined immune deficiency, 209–210 severe combined immune deficiency, 209–210 transient hypogammaglobulinemia of infancy, 210 types of, 209–210 Primary sclerosing cholangitis, 360 PR interval, 223–225 PRIS (Pediatric Research in Inpatient Settings), 51 Probenecid, 190t, 192t Probiotics, 551 Procaine penicillin G, 192t Procedural sedation and analgesia, 1003–1005 agents for, 1004–1005 in interventional radiology, 1026 levels of, 1003 monitoring for, 1003–1004 personnel for, 1003 presedation evaluation, 1003, 1003t, 1004t presedation fasting, 1004, 1004t selection of agent, 1003 Proctitis, 186, 187 Proctocolitis, 186 Progressive encephalopathy, 651–652 Progressive multifocal leukoencephalopathy (PML), 687 Progressive pigmented purpuric dermatosis, 263, 263f Propofol, 943, 1005 Propranolol adverse effects of, 273 for hypertension, 103t for infantile hemangioma, 273 for tachycardia in hyperthyroidism, 325 for thyroid storm, 325 Propylthiouracil (PTU), 325 Prostaglandin E1, 147, 229 Protein, daily needs for, 383t Protein C deficiency, 455t Protein–energy malnutrition, 380. See also Malnutrition Protein S deficiency, 455t

Proteinuria, 628 Proteus mirabilis infections, 467t Prothrombin, 554t Prothrombin G20210A, 455t Prothrombin time (PT), 452 Proton pump inhibitors (PPIs), 396 Protozoal infections, 542, 542t, 545t, 548, 549t. See also Acute gastroenteritis (AGE); specific protozoa Providencia spp. infections, 467t Provocative challenge testing, 824 Proximal renal tubular acidosis, 631, 631t. See also Renal tubular acidosis (RTA) PRSS1 mutations, 392 Pseudocyst, pancreatic, 391 Pseudohyponatremia, 348 Pseudohypoparathyroidism, 331 Pseudomonas aeruginosa infections catheter-related bloodstream infections, 581t in cystic fibrosis, 812, 813t, 814t in ecthyma gangrenosum, 282–283, 283t, 284 osteomyelitis, 567t, 569 treatment of, 467t Pseudoparalysis of Parrot, 702 Pseudopseudohypoparathyroidism, 331 Pseudosyndactyly, 307 Pseudotumor cerebri, 645 Psoas sign, 863 Psoriasis, 268t, 279, 279f Psoriatic arthritis, 841, 841t, 842t Psychogenic gait (astasia-abasia), 650t Psychomotor regression, 651–652 Psychosis, 771–775 admission criteria for, 775 clinical presentation of, 772, 772t consultation for, 775 diagnostic evaluation of, 773 differential diagnosis of, 772, 773t

discharge criteria for, 775 epidemiology of, 771–772 risk factors for, 773 treatment of, 773–775, 774t, 775t PT (prothrombin time), 452 PTU (propylthiouracil), 325 PUCAI (Pediatric Ulcerative Colitis Disease Activity Index), 377–388, 377t Pulmonary contusions, 873 Pulmonary edema in bronchopulmonary dysplasia, 804 in dilated cardiomyopathy, 246 in drowning, 959–960, 959f etiology of, 77 with fluid resuscitation, 435, 613 in inhalation injury, 947 in mercury poisoning, 936 postobstructive, 879 in total anomalous pulmonary venous return, 234 Pulmonary embolism, 79, 455 Pulmonary function testing in asthma, 786 capnography, 824 consultation for, 824 diffusing capacity for carbon monoxide, 822–823 equipment and personnel for, 820–821 exhaled nitric oxide, 823 future directions in, 825 indications for, 820 in infants, 823, 823f inpatient applications of, 820 key points, 825 lung volumes, 822, 822f polysomnography, 824, 825f provocative challenge testing, 824 pulse oximetry. See Pulse oximetry (SpO2) respiratory muscle strength, 823 spirometry, 821–822, 821f, 821t

Pulmonary hypertension, 79, 85, 804–805 Pulmonary imaging nuclear medicine studies, 1017 point-of-care ultrasound, 1037–1038, 1038f radiograph. See Chest radiograph Pulmonary stenosis, 218, 220f, 236 Pulp, tooth, 128 Pulse, 215 Pulse oximetry (SpO2) by age and altitude, 109t formulas and pearls, 110f in hypoxemia, 109–110 indications for, 824 in respiratory distress, 141 technique for, 824 Pulsus paradoxus, 141, 216, 252, 252f Purified protein derivative (PPD) test, 126 Purpura, 137–139, 261–264 in child abuse, 261, 261f clinical presentation of, 263 definition of, 137, 261 diagnostic evaluation of, 137–138, 138t, 264, 264f differential diagnosis of, 137, 137t extravascular, 261 Henoch-Schönlein. See Henoch-Schönlein purpura immune thrombocytopenic. See Immune thrombocytopenic purpura (ITP) intravascular, 261–262, 261f, 262f key points, 139, 264 management of, 264 in neonate, 138–139 pathophysiology of, 137, 261–264, 261t patient history in, 137, 138t physical examination in, 137, 138t pigmented, 263, 263f treatment of, 138 vascular, 262–263, 262f, 263f Purpura fulminans, 137, 262, 262f, 484f

Pustule, 265, 265f, 266f. See also Vesicobullous diseases P wave, 223, 224f Pyloric stenosis, 154, 857–858, 858f, 862, 1024f Pyloromyotomy, 858 Pyoderma gangrenosum, 285t Pyomyositis, 576–577, 578 Pyridoxine, 928 Q QRS complex, 225, 225–226f, 225t QT interval, 227 Quadriparesis, 654 Quality improvement tools, 12–13, 13f Quality of care, 12–14, 13f Quartan fever, 93t Quetiapine, 774t Q wave, 225 R Rabies, 964–965, 965t Raccoon eyes, 884 Radiation safety, 1006, 1006t Radiographs, conventional, 1008–1010, 1008f, 1009f abdominal. See Abdominal radiographs chest. See Chest radiographs head and neck, 1009–1010 portable, 1010 spinal, 1009 Radioiodine ablation, 325 Radiology. See Imaging studies Radionuclide studies. See also Nuclear medicine cisternography, 1018 cystography, 910, 1006t salivagram, 1017 Radiopharmaceuticals, 1012–1013 Ramstedt pyloromyotomy, 371 Rapid antigen detection test (RADT), 510

Rapidly involuting congenital hemangioma (RICH), 272 Rapidly progressive glomerulonephritis, 618–620, 618t Rapid thoracic compression (RTC) technique, 823 Rasburicase, 741, 741t Rash drug-associated. See Drug-associated rash fever-associated, 481–489 in anaplasmosis, 488 categories of, 481–482 in classic childhood exanthems, 482t in ehrlichiosis, 488 in Kawasaki disease, 827 in meningococcal infections. See Meningococcal infections in Rocky Mountain spotted fever, 487–488 in toxic shock syndrome, 485–487, 486t in Henoch-Schönlein purpura, 832, 832f in juvenile idiopathic arthritis, 840 in systemic lupus erythematosus, 853t Reactive arthritis, 848, 848t, 850, 850t Readmission rates, 4 Rebound tenderness, 863 Recurrent abdominal pain, 764–765 Recurrent respiratory papillomatosis (RRP), 878 Red blood cell count, 425t Red blood cell distribution width, 425t Red blood cell indices, 425t Red blood cell membrane abnormalities, 430 Red blood cell metabolism abnormalities, 430 Red blood cell transfusion. See Packed red blood cell (pRBC) transfusion Red cell exchange, 462 Red eye, 887, 889f Red man syndrome, 203 Refeeding syndrome, 182, 384–385 Reflex sympathetic dystrophy, 575 Refusal of care, 46–47 Reiter syndrome, 186 Relapsing fever, 93t

Relapsing polychondritis, 135 Renal biopsy, 620 Renal failure acute. See Acute kidney injury (AKI) chronic. See Chronic renal failure (CRF) Renal osteodystrophy, 616–617 Renal scintigraphy in hydronephrosis, 909 procedure for, 1013–1014, 1013–1014f in urinary obstruction, 909 in urinary tract infections, 564, 564t Renal transplantation, 617 Renal tubular acidosis (RTA), 630–633 admission and discharge criteria for, 633 classification of, 630 clinical presentation of, 632 diagnostic evaluation of, 632–633, 633t differential diagnosis of, 632 key points, 633 pathophysiology of, 631–632, 631f, 631t, 632t treatment of, 633 Renal tumors, 737–738, 737f Renal venous thrombosis (RVT), 633–635, 634f Renin-angiotensin-aldosterone system (RAAS), 336, 345 Reservoir nebulizer, 112t Respiratory acidosis causes of, 71t definition of, 67 diagnostic evaluation of, 68–69, 69f differential diagnosis of, 68–69, 69t pathophysiology of, 70–71, 71t treatment of, 71 Respiratory distress, 139–142 diagnostic evaluation of, 141 differential diagnosis of, 142t initial assessment of, 139–140 key points, 142

management of, 141–142 pathophysiology of, 139 patient history in, 140, 140b physical examination in, 140–141, 140b Respiratory infections acute otitis media and, 500–501. See also Acute otitis media (AOM) bronchiolitis. See Bronchiolitis laryngotracheitis. See Laryngotracheitis (croup) pharyngitis. See Pharyngitis pneumonia. See Pneumonia sinusitis and, 503. See also Sinusitis Respiratory muscle strength, 823 Respiratory rate, 109t Respiratory syncytial virus (RSV) infection in bronchiolitis, 515. See also Bronchiolitis in bronchopulmonary dysplasia, 804 complications of in congenital heart disease, 237–238 transmission-based precautions, 17t in transplant recipient, 602, 606t Restrictive cardiomyopathy, 249–250, 250t Resuscitation cardiopulmonary, 997–998 in delivery room. See Delivery room medicine Reticulocyte count, 425t Reticulocytosis, 426t, 427f Retinoblastoma, 738 Retrograde urethrogram, 1012, 1012f Retropharyngeal infections, 133–134, 134f, 466t, 511 Retropharyngeal space, 131, 132f Reverse T3, 322, 322t Rewarming techniques, 956 Reye syndrome, 94, 831 RF (rheumatoid factor), 120–121 Rhabdomyolysis, 920t, 951 Rhabdomyosarcoma, 738 Rheumatic fever, acute. See Acute rheumatic fever (ARF)

Rheumatoid factor (RF), 120–121 Rhizopus infection, 285t, 301f Ribavirin, 519, 606t Rib fractures, 167, 167f, 874 RICH (rapidly involuting congenital hemangioma), 272 Richter hernia, 868 Rickettsia rickettsii, 487. See also Rocky Mountain spotted fever (RMSF) Rifampin for bacterial meningitis, 495t for chemoprophylaxis for contacts in meningococcal meningitis, 497t for infective endocarditis, 243t Right bundle branch block, 225, 225f Right ventricular hypertrophy, 225, 225f Riley-Day syndrome (familial dysautonomia), 657 Risperidone, 769f, 770, 774t Ritter’s disease. See Staphylococcal scalded skin syndrome (SSSS) Rituximab adverse effects of, 122t, 448 for immune thrombocytopenic purpura, 448, 449t for juvenile rheumatoid arthritis, 122, 844 Rochester protocol, for febrile infants, 469–470, 470t, 472 Rocky Mountain spotted fever (RMSF), 486, 487–488 Root canal, 128 Root canal treatment, 128 Roseola (exanthema subitum), 482t Rotavirus infection clinical presentation of, 547, 547t epidemiology of, 544, 545t immunization for, 552 pathophysiology of, 542, 542t transmission-based precautions, 17t Roth spots, 240 Roux-en-Y choledochojejunostomy, 358 RRP (recurrent respiratory papillomatosis), 878 RSV infection. See Respiratory syncytial virus (RSV) infection RTA. See Renal tubular acidosis (RTA) RTC (rapid thoracic compression) technique, 823

Rubella (German measles) clinical presentation of, 482t, 849 complications of, 482t congenital, 715, 716t diagnostic evaluation of, 717t Rubeola (measles), 17t, 128t, 482t Rufinamide, 641t Rule of 9s, 897 Rumack-Matthew nomogram, 921f Russell-Silver syndrome, 405t RVT (renal venous thrombosis), 633–635, 634f S Sacral dimple, 709, 1023 Safety, patient, 13–14. See also Infection control SAH. See Subarachnoid hemorrhage (SAH) St. Louis virus encephalitis, 491, 492, 494–495, 496 Salicylate poisoning/overdose, 923t admission and discharge criteria for, 923 clinical presentation of, 916t, 922, 922t diagnostic evaluation of, 922 differential diagnosis of, 922 treatment of, 922–923, 923t Saline, nebulized, 519 Saline enema, 364t Salivary glands infection of, 135 medications affecting flow of, 131t radionuclide study of, 1017 Salmonella spp. infections acute gastroenteritis clinical presentation of, 547t, 548 epidemiology of, 544, 544t pathophysiology of, 542t, 543 treatment of, 467t, 551t in neonates and young infants, 469 osteomyelitis, 566, 567t

Samter’s triad, 203 Scabies, 267t, 269t, 278, 279f Scalp scaling, 279 Scarlet fever, 127t, 355, 482, 482t, 483f SCD. See Sickle cell disease (SCD) Schistocytes, 426t, 427f Schizophrenia, 772. See also Psychosis School-aged children developmental implications in response to hospitalization, 32 vomiting in, 155t SCID (severe combined immune deficiency), 209–210 Scoliosis in child with severe neurologic impairment, 983, 990 complications of spinal fusion for, 893, 894 in congenital myopathies, 659 in Duchenne muscular dystrophy, 661 secondary, 136 spine imaging in, 1021, 1026 Scrotal swelling/pain, 115, 1024, 1025f “Seatbelt syndrome,” 875 Seborrheic dermatitis, 278, 278f Sedation, procedural. See Procedural sedation and analgesia Sedative-hypnotics. See also Benzodiazepines; Procedural sedation and analgesia poisoning/overdose, 916t withdrawal syndrome, 942, 942t, 943, 943t, 944 Seizures, 637–643 in child with severe neurologic impairment, 985, 988 classification of, 637, 637t clinical presentation of, 637 in conversion disorder, 765 course of illness, 639 diagnostic evaluation of, 75, 637–639, 639t computed tomography, 1025f magnetic resonance imaging, 1025, 1025f SPECT/PET, 1018, 1019f differential diagnosis of, 637, 638t, 764

epidemiology of, 637 febrile. See Febrile seizures future directions in, 643t key points, 643 in poisoning/overdose, 920t precipitating factors for, 638t, 639t stroke and, 670, 676 treatment of, 639–640, 640t in hyponatremia, 348–349 in palliative care setting, 36–37 Selective serotonin reuptake inhibitors (SSRIs), 756t for depression, 756–757 withdrawal syndrome, 942, 943t Senna, 365t Sepsis, 466t Septic arthritis diagnostic evaluation of, 570, 570t, 1077t differential diagnosis of, 570, 849t epidemiology of, 570 pathophysiology of, 570 treatment of, 466t, 571 Septic shock pathogens in, 147t pathophysiology of, 143–144 risk factors for, 144 treatment of, 147, 147t, 212 Serotonin syndrome, 756–757 Serratia spp. infections, 467t Sertraline, 756t Serum osmolality calculation of, 69–70 in diabetes insipidus, 327 in diabetic ketoacidosis, 318–319, 321 in hypernatremia, 350 in metabolic acidosis, 421 physiology of, 344–345 in SIADH, 328

Serum sickness, 292–293 Severe combined immune deficiency (SCID), 209–210 Severe neurologic impairment. See also Child with medical complexity (CMC) acute care issues in, 984–986, 984f care coordination for, 987 comorbid conditions in, 987–988, 988t airway concerns and pneumonia, 984–985, 989–990 behavioral issues and aggression, 986 dental disease, 991 endocrinopathy, 986, 991 growth, nutrition, and gastrointestinal issues, 986, 989 irritability, 985, 985t, 992, 992t musculoskeletal, 990–991 neurologic, 985, 988–989 paroxysmal sympathetic hyperactivity, 985–986 renal/urologic, 991 sensory impairment, 989 skin, 991 sleep disturbances, 991–992 ethical issues in, 986–987 familial effects of, 992, 992t key points, 987, 992, 992f pathophysiology of, 983, 983t Sexual abuse. See Abuse and neglect Sexually transmitted infections (STIs), 185–194. See also specific infections admission criteria for, 189 clinical presentation of, 185–186, 186t consultation for, 189 diagnostic evaluation of, 187–189, 188f, 188t differential diagnosis of, 187 discharge criteria for, 189 epidemiology of, 185 key points, 194 pathophysiology of, 185 prevention of, 194 special considerations in, 193, 193f

treatment of, 189, 189–192t Shaken impact syndrome. See Abusive head trauma (AHT) Shiga toxin-producing Escherichia coli (STEC, enterohemorrhagic) infections. See also Escherichia coli infections clinical presentation of, 547t complications of, 548. See also Hemolytic uremic syndrome (HUS) epidemiology of, 544t pathogen characteristics, 542, 542t treatment of, 551t Shigella spp. infections clinical presentation of, 547t, 548 epidemiology of, 545t pathophysiology of, 541, 542, 542t treatment of, 467t, 551t Shivering, 953–954 SHM (Society of Hospital Medicine), 51 Shock, 143–147. See also Septic shock; Toxic shock syndrome (TSS) causes of, 144t definition of, 143 diagnostic evaluation of, 145, 146t differential diagnosis of, 145 key points, 147 management of, 145–147, 146f, 147t in neonate, 145, 145t organ dysfunction in, 144, 145t pathophysiology of, 143–144, 143t patient history in, 144 physical examination in, 144–145, 145t progression of, 144 risk factors for, 144, 145t transport in, 147 Shunt, cerebrospinal fluid. See Cerebrospinal fluid (CSF) shunt SIADH. See Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Sialadenitis, 135 Sick euthyroid syndrome (nonthyroidal illness), 324 Sickle cell disease (SCD), 433–437

admission criteria for, 437 clinical presentation of, 433 complications of, 433, 433t acute chest syndrome, 435 acute splenic sequestration, 436 cholelithiasis and cholecystis, 358, 437 fever, 434, 434t osteomyelitis, 569 priapism, 436–437 stroke, 434–435, 676 transient aplastic crisis, 437 vaso-occlusive pain, 435–436 diagnostic evaluation of, 426t, 427f discharge criteria for, 437 future directions in, 437 health maintenance in, 433–434 key points, 437 pathophysiology of, 433 SIGECAPS, mnemonic for depression, 754, 755t Silver nitrate, 899 Silver sulfadiazine, 899 Sinecatechins ointment, 191t, 302 Single-photon emission computed tomography (SPECT), 1018, 1019f Sinus arrhythmia, 215, 221 Sinusitis, 502–507 complications of, 503–507, 504f, 505f, 506f, 1021f epidemiology of, 502–503 pathophysiology of, 503, 503f treatment of, 466t Sirolimus, 304 SIRS (systemic inflammatory response syndrome), 388, 390 Situational depression, 754, 755 Six Sigma, 13 6-minute walk test, 824 SJS. See Stevens-Johnson syndrome (SJS) Skeletal imaging bone scintigraphy, 567t, 1014–1016, 1015f, 1018, 1019

in child abuse, 167–168, 168t computed tomography, 1022, 1023f magnetic resonance imaging, 1026 radiograph, 1009 ultrasound, 1024 Skin, histology of, 264, 265f Skin and soft tissue infections, 572–579 cellulitis. See Cellulitis erysipelas, 465t, 573–576, 574f necrotizing fasciitis. See Necrotizing fasciitis pyomyositis, 576–577, 578 staphylococcal scalded skin syndrome, 269t, 298, 572–573, 572f Skin cancer, 302 Skin fragility syndrome, 268t Skin substitutes, 898 Skull fractures, 167, 884, 885, 1021f. See also Abusive head trauma (AHT); Head trauma injuries at birth, 703, 704f radiographs, 1008–1009, 1009f SLE. See Systemic lupus erythematosus (SLE) Sleep disturbances, in child with severe neurologic impairment, 991–992 Slipping rib syndrome, 80 SMA (spinal muscular atrophy), 654–655 Small bowel injuries, 875 Small bowel series, 1011 Smith-Magenis syndrome, 405t SMN1 gene, 654–655 Smoking, pneumothorax and, 902 Snake bites, 966–968, 986t “Snowstorm” vision, 928 Social and emotional development, 30, 31t Social media, 43 Society of Hospital Medicine (SHM), 51 Sodium. See also Hypernatremia; Hyponatremia in body fluids, 346t deficit calculation, 345–346, 346t, 347t

maintenance requirements for, 345 Sodium bicarbonate (NaHCO3), 352 Sodium iodide, 325 Sodium nitrite, 948 Sodium phosphate enema, 364t Sodium polystyrene sulfonate, 352 Sodium thiosulfate, 948 Solid organ transplantation (SOT) infections following. See also Transplant recipient, infections in; specific infections preventive therapy and prophylaxis for, 604, 605t timing of development of, 598–599, 599f Sorbitol, 352 Spastic diplegic gait, 650t Spasticity, 990–991 SPC (statistical process control), 12, 13f SPECT (single-photon emission computed tomography), 1018, 1019f Spherocytosis, 426t, 427f, 430 Spider bites, 285t, 968–969, 968t Spigelian hernia, 870 Spinal cord compression, 746 Spinal cord injuries, 871–872 Spinal cord lesions, 654 Spinal fusion, 893–894 Spinal imaging computed tomography, 1021 magnetic resonance imaging, 1026, 1026f radiograph, 1009 Spinal muscular atrophy (SMA), 654–655 SPINK1 mutations, 388, 392 Spirometry, 821–822, 821f, 821t. See also Pulmonary function testing Spironolactone, 103t Spleen acute sequestration of, 436 injury of, 874, 874t Splenectomy, 449t Splenomegaly, 61, 374

Spondyloarthropathy, 136 Spondylolisthesis, 895, 895f Spondylolysis, 895, 895f SpO2. See Pulse oximetry (SpO2) Sputum culture, 530 Staff development, 55t, 56 Standard precautions, 16–17 Staphylococcal scalded skin syndrome (SSSS), 269t, 298, 572–573, 572f Staphylococci, coagulase-negative. See Coagulase-negative staphylococci (CONS) Staphylococcus aureus infections in atopic dermatitis, 277, 277f, 281 catheter-related bloodstream infections, 581t, 583 in cerebrospinal fluid shunt infections, 584r in cystic fibrosis, 813t, 814t differential diagnosis of, 285t foodborne, 543, 545t, 547t infective endocarditis, 239, 240t methicillin-resistant, 18, 467t, 813t necrotizing fasciitis, 577 orbital cellulitis, 505 osteomyelitis, 566, 567t. See also Osteomyelitis peritonitis, 557 pyomyositis, 576–577 septic arthritis, 570 toxic shock syndrome, 485–487, 486t in transplant recipient, 600. See also Transplant recipient, infections in treatment of, 467t, 567t Staphylococcus epidermis infections, 467t, 584t Staphylococcus pneumoniae infections, 469 Statistical process control (SPC), 12, 13f Status epilepticus, 637, 639 Stavudine, 593 STEC infections. See Shiga toxin-producing Escherichia coli (STEC, enterohemorrhagic) infections “Steeple sign,” 521, 521f Stem cell transplant. See Hematopoietic stem cell transplant (HSCT)

Stertor, 985 Stevens-Johnson syndrome (SJS), 297–300 admission criteria for, 299 causes of, 297 clinical presentation of, 268t, 297–298, 298f, 481, 482f consultation for, 299 differential diagnosis of, 298 discharge criteria for, 300 epidemiology of, 297 genetic factors in, 297 oral manifestations of, 127t pathophysiology of, 297 prognosis of, 299 treatment of, 298–299 intravenous immunoglobulin for, 213 Still’s disease, 840, 841t, 842t. See also Juvenile idiopathic (rheumatoid) arthritis (JIA) STIs. See Sexually transmitted infections (STIs) Stomatitis, 127, 128t, 508–510, 509f Stool cultures, 549–550, 549t Stooling patterns, normal, 362t Strength testing, 649, 650t Streptococcus agalactiae infections. See Group B Streptococcus infections Streptococcus pneumoniae infections antigen testing, 531 infective endocarditis, 240t orbital cellulitis, 505 periorbital cellulitis, 504 peritonitis, 557 pneumonia, 528. See also Pneumonia treatment of, 467t, 474 Streptococcus pyogenes infections. See Group A β-hemolytic streptococcus (GABHS) infections Stridor in caustic ingestion, 929–930 in child with severe neurologic impairment, 985 in infants, 877–878, 877t

in respiratory distress, 142 Stroke, 664–679 admission and discharge criteria for, 678 consultation for, 678–679 diagnostic evaluation of, 671–672, 672–673t, 674–675, 674t differential diagnosis of, 666t, 671 epidemiology of, 665 key points, 679 recurrence of, 679 risk factors for, 665, 666t in sickle cell disease, 434–435, 676 treatment of, 675–678 types of, 664–665. See also Arterial ischemic stroke (AIS); Cerebral sinovenous thrombosis (CSVT); Intracerebral hemorrhage (ICH); Subarachnoid hemorrhage (SAH) Struvite stones, 912 ST segment, 225–227, 226f Stupor, 73t. See also Altered mental status (AMS) Sturge-Weber syndrome, 271 Subacute necrotizing encephalomyelopathy (Leigh disease/syndrome), 156, 652 Subarachnoid hemorrhage (SAH). See also Stroke as birth injury, 705 clinical presentation of, 671 in head trauma, 884. See also Head trauma pathophysiology and risk factors for, 669, 670f recurrence of, 679 treatment of, 677–678 Subcutaneous rehydration therapy, 343 Subdural hematoma, 884, 885f Subdural hemorrhage, 704–705 Subgaleal hemorrhage, 703, 704f Subglottic hemangioma, 878 Subglottic stenosis, 878 Sublingual space, 131 Submandibular space infection (Ludwig angina), 134–135, 511 Submersion, 958. See also Drowning

Subperiosteal abscess mastoiditis and, 501 orbital cellulitis and, 505, 505f, 506, 506f sinusitis and, 503, 1021f Substance abuse. See also Drugs of abuse exposure clinical presentation of, 937–938, 939t epidemiology of, 937, 938t in pregnancy, 729. See also Neonatal abstinence syndrome (NAS) Succimer for lead poisoning, 933–934, 933t for mercury poisoning, 936 Sucking lister, 267t Sudden infant death syndrome (SIDS) apparent life-threatening event and, 777, 781 infant botulism and, 970 Suicidality, 758–762 admission and discharge criteria for, 761 clinical presentation of, 759 consultation for, 761–762 diagnostic evaluation of, 759–761 epidemiology of, 758 key points, 762 management of, 761 pathophysiology of, 758–759 prevention of, 762 risk factors for, 759, 760t Sulfadiazine, 259t Sulfasalazine, 121t, 122 Sulfonylureas for diabetes mellitus, 923–925, 924t poisoning/overdose, 414, 416 Superior mediastinal syndrome, 746 Superior mesenteric artery syndrome, 154, 894 Superior vena cava syndrome, 746 Supply-sensitive care, 7 Suprapubic aspiration, 1040–1041, 1041f Surgical site infection, 894

Swallowing, 393. See also Dysphagia Swallowing study, 394, 1010, 1010f Sweat chloride test, 809–810 Sweet syndrome, 285t “Swinging flashlight test,” 887, 888f Swiss cheese model of error, 14 Sydenham chorea, 257 Syncope, 147–151 definition of, 147 diagnostic evaluation of, 150 differential diagnosis of, 148–150, 148t, 149f, 150t key points, 150 management of, 150 pathophysiology of, 147–148 patient history in, 148, 148t physical examination in, 148 special considerations in, 150 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) consultation for, 329 diagnostic evaluation of, 328 differential diagnosis of, 328 in head trauma, 886 as oncologic emergency, 741 postoperative, 894 risk factors for, 328 treatment of, 328–329 Synovial fluid studies, 570t Syphilis clinical presentation of, 187t congenital, 267t, 715, 716t, 717, 717t, 718f diagnostic evaluation of, 188t differential diagnosis of, 187 stages of, 186, 187t treatment of, 192t, 467t Systemic inflammatory response syndrome (SIRS), 388, 390 Systemic lupus erythematosus (SLE), 852–856 admission and discharge criteria for, 855–856

clinical presentation of, 127t, 852–853, 853t, 854f consultation for, 856 diagnostic evaluation of, 853–854, 854t, 855t differential diagnosis of, 292, 854t epidemiology of, 852 key points, 856 pathophysiology of, 852 renal disease in, 855t special considerations in, 856 treatment of, 854–855

T Tachyarrhythmias, 221–222 Tachycardia, 142 TACO (transfusion-associated circulatory overload), 459t, 462 Tacrolimus, topical, 280 TA (tufted angioma), 272, 273 TA-GVHD (transfusion-associated graft versus host disease), 462 Takayasu’s arteritis, 215 Talipes equinovarus (clubfoot), 892, 892f TAPVR (total anomalous pulmonary venous return), 234 TAR (thrombocytopenia-absent radii), 450 Target cells, 426t Tay-Sachs disease, 653 TBI. See Traumatic brain injury (TBI) TCA (trichloroacetic acid), 191t TcB (transcutaneous bilirubin), 726 TEC (transient erythroblastopenia of childhood), 429 Tegaserod, 366, 371 Temperature, body. See Fever; Hyperthermia; Hypothermia TEN. See Toxic epidermal necrolysis (TEN) Tensilon (edrophonium) test, 663 Tension pneumothorax, 903. See also Pneumothorax Terbutaline, 788, 789t Tertian fever, 93t Testicular torsion, 187, 864t, 907–908, 908f Tetanus prophylaxis, 963–964, 963t Tetracycline, 192t Tetralogy of Fallot, 84, 231–232, 232f THAM (tromethamine), 422 THAN (transient hyperammonemia of the newborn), 409–410 Theophylline, 790 Theory of Constraints, 12–13, 13f Therapeutic plasma exchange, 462 Thermal injuries. See Burns Thiamine, for ethylene glycol poisoning, 928 Thiazide diuretics, 332. See also Hydrochlorothiazide

Thiazolidinediones, 923–925, 924t, 925t Thiopurines, 378, 378t Thioridazine, 774t Thiothixene, 774t Thirst, 345 Thoracentesis anatomy for, 1074–1075 complications of, 1076 contraindications to, 1074 equipment for, 1075, 1075t indications for, 1074 procedure for, 1075–1076, 1075f, 1076f ultrasound-guided, 1028–1029, 1029f Thoracic trauma, 873–874, 873t Thrombectomy, 456 Thrombin time, 452 Thrombocytopenia caused by consumption in hemolytic uremic syndrome. See Hemolytic uremic syndrome (HUS) in hypersplenism, 450 in Kasabach-Merritt syndrome, 450 in thrombotic thrombocytopenic purpura (TTP), 431, 450, 622 caused by decreased consumption, 450–451 definition of, 447 differential diagnosis of, 447t, 448, 448t in disseminated intravascular coagulation. See Disseminated intravascular coagulation (DIC) immune-mediated immune thrombocytopenic purpura. See Immune thrombocytopenic purpura (ITP) neonatal, 449–450 key points, 451 as oncologic emergency, 742–743, 743t petechiae and purpura in, 137, 137t with platelet dysfunction, 451 Thrombocytopenia-absent radii (TAR), 450 Thromboembolectomy, 676

Thrombolysis, 676 Thrombosis in central venous catheter, 456–457, 743 in disseminated intravascular coagulation. See Disseminated intravascular coagulation (DIC) in inflammatory bowel disease, 378 key points, 457 as oncologic emergency, 743 renal venous, 633–635, 634f venous. See Venous thromboembolism Thrombotic thrombocytopenic purpura (TTP), 431, 450, 622 Thumb sign, 523, 524f Thymectomy, 659 Thyroid disorders, 321–322, 325–326 Thyroidectomy, 325 Thyroid function tests, 322t Thyroiditis, 135 Thyroid scintigraphy, 1018 Thyroid-stimulating hormone (TSH), 322t Thyroid storm, 325 TIA (transient ischemic attack), 665 Ticarcillin, 813t Tick(s), 487, 488 Tick paralysis, 656 TIN. See Tubulointerstitial nephritis (TIN) Tinidazole, 190t, 191t, 552t Tissue oxygen delivery (DO2), 108, 110t, 111t Tissue plasminogen activator (tPA), 676 TLC (total lung capacity), 822, 822f TMP-SMZ (trimethoprim-sulfamethoxazole), 536t, 813t, 814t Tobramycin for bacterial meningitis, 495t for cystic fibrosis, 812 for cystic fibrosis exacerbations, 813t, 814t Tocilizumab, 122t, 844 Todd’s paralysis, 654 Tolmetin sodium, 121t

Tonsillectomy, 879 Tooth avulsion, 130 Tooth eruption, 127t Topiramate, 641t TORCH organisms/infections, 650, 713–714. See also specific infections Torsades de pointes, 920t Torticollis, 131 Total anomalous pulmonary venous return (TAPVR), 234 Total lung capacity (TLC), 822, 822f Total serum bilirubin (TSB), 726 Toxic epidermal necrolysis (TEN), 297–300 admission criteria for, 299 causes of, 297 clinical presentation of, 268t, 297–298 consultation for, 299 differential diagnosis of, 298, 573 discharge criteria for, 299, 300 epidemiology of, 297 genetic factors in, 297 key points, 300 pathophysiology of, 297 prognosis of, 299 treatment of, 213, 298–299 Toxic erythema of chemotherapy, 303 Toxic shock syndrome (TSS), 485–487, 486t Toxidromes, 915, 916t Toxoplasmosis congenital, 714f, 715, 716, 716t, 717t in transplant recipient, 605t TPA (tissue plasminogen activator), 676 Tracheal aspirates, 530 Tracheitis, 984–985 Tracheobronchomalacia, 805 Tracheostomy complications of, 996, 996t emergency care of, 985 indications for, 996

tube replacement in, 1072–1074, 1073f Tracheostomy mask, 112t TRALI (transfusion-associated lung injury), 459t, 462 Tranexamic acid, 198 Transcutaneous bilirubin (TcB), 726 Transfusion adverse effects of, 459t, 461–462 benefits of, 458 in childhood cancer patients, 743, 743t clinical considerations in, 458 of cryoprecipitate, 460 cytomegalovirus-negative, 461 errors in, 458 frequency of, 457–458 of granulocytes, 460 of intravenous immunoglobulin. See Intravenous immunoglobulin (IVIG) leukocyte-reduced, 460 of packed red blood cells. See Packed red blood cell (pRBC) transfusion of plasma, 460 of platelets, 459–460 refusal by Jehovah’s Witnesses, 47 testing prior to, 461 Transfusion-associated circulatory overload (TACO), 459t, 462 Transfusion-associated graft versus host disease (TA-GVHD), 462 Transfusion-associated lung injury (TRALI), 459t, 462 Transient aplastic crisis, 437 Transient bullous dermolysis of the newborn, 267t Transient erythroblastopenia of childhood (TEC), 429 Transient hyperammonemia of the newborn (THAN), 409–410 Transient hypogammaglobulinemia of infancy, 210 Transient ischemic attack (TIA), 665 Transient neonatal myasthenia, 658 Transient neonatal pustular melanosis, 267t Transient synovitis, 570, 570t, 849, 849t, 850 Transient tachypnea of the newborn (TTN), 711–713, 712t Transmission-based precautions, 17, 17t Transplant recipient. See also Immunosuppressed host

infections in admission and discharge criteria for, 605 clinical presentation of, 598 consultation for, 607 diagnostic evaluation of, 602–603t, 602–604 differential diagnosis of, 600–602, 602–603t pathophysiology of, 598 prevention of, 604, 605t, 607 timetable for development of, 598–599, 600f treatment of, 604–605, 605t, 606t key points, 607 Transposition of the great arteries. See D-transposition of the great arteries (d-TGA) Transverse myelitis, 682t, 686–687, 687f, 895 Trauma abdominal, 168, 874–875, 874f, 874t, 1027f burns. See Burns cervical spine, 871–872 chemical burns, 900 electrical injury, 900 epidemiology of, 870–871 eye, 889–891, 890f head. See Head trauma initial assessment in, 871 key points, 875 nonaccidental cutaneous. See Abuse and neglect orthopedic, 893 point-of-care ultrasound in, 1035–1036, 1035f, 1036f rib fractures, 167, 167f, 874 thoracic, 873–874, 873t Traumatic brain injury (TBI), 164, 884. See also Abusive head trauma (AHT); Head trauma Traveler’s diarrhea, 552 Trendelenburg gait, 118, 119f, 650t Treponema pallidum infections. See Syphilis Triamcinolone, 280 Trichloroacetic acid (TCA), 191t

Trichomoniasis, 188t, 190t Trichorhinophalangeal syndrome, 405t Trichosporon infection, 302 Tricuspid atresia, 231, 232f Triiodothyroxine (T3), 321–322, 322t Trimethoprim-sulfamethoxazole (TMP-SMZ), 536t, 813t, 814t Trismus, 131 Trisomy, 399 Trisomy 1q21, 405t Trisomy 7q11.2, 405t Trisomy 13 (Patau syndrome), 216t, 403, 403t Trisomy 18 (Edwards syndrome), 216t, 401–402, 403t Trisomy 21 (Down syndrome), 216t, 400–401, 403t Tromethamine (THAM), 422 TSB (total serum bilirubin), 726 TSH (thyroid-stimulating hormone), 322t TSS (toxic shock syndrome), 485–487, 486t TTN (transient tachypnea of the newborn), 711–713, 712t TTP (thrombotic thrombocytopenic purpura), 431, 450, 622 Tuberculosis adrenal insufficiency in, 337–338 anti-TNF therapy and, 378 arthritis in, 120 communicability of, in children, 18 as contraindication to breastfeeding, 696 duodenal, 370 fever in, 478 hypercalcemia in, 332 immune reconstitution inflammatory syndrome and, 593 lymphadenitis/lymphadenopathy in, 124, 126, 513 pericarditis in, 252, 253 transmission-based precautions for, 17, 17t, 18 Tubulointerstitial nephritis (TIN), 624–627 admission and discharge criteria for, 626 clinical presentation of, 624–625 consultation for, 626 diagnostic evaluation of, 625–626, 626t

differential diagnosis of, 625, 626t epidemiology of, 624 key points, 627 pathophysiology of, 624, 625t prevention of, 626–627 treatment of, 626 Tufted angioma (TA), 272, 273 Tumor lysis syndrome, 739–741, 740t, 741t Turner syndrome, 216t, 404 T wave, 227, 227f 22q deletion, 232, 406–407 22q11 deletion, 216t T3 (triiodothyroxine), 321–322, 322t T4 (thyroxine), 321–322, 322t U UAG (urinary anion gap), 70, 632 Ulceration, 265, 265t, 266f. See also Vesicobullous diseases Ulcerative colitis, 375. See also Inflammatory bowel disease (IBD) Ullrich muscular dystrophy, 660t Ultrasound, 1022 abdominal, 1023–1024, 1024f in appendicitis, 864 in biliary disease, 356, 358, 359 extremity, 1024 in fetal hydronephrosis, 909, 909f head, 1022–1023, 1024f in Henoch-Schönlein purpura, 834 in liver failure, 374 neck, 1023 in nephrolithiasis, 912, 912f in neuromuscular disorders, 663 in pancreatitis, 389 pelvic, 1024 in pneumonia, 530 point-of-care. See Point-of-care ultrasound (POCUS) in pyloric stenosis, 858, 858f, 1024f

renal and bladder, 564, 564t, 635 scrotum, 1024, 1025f spine, 1023 in testicular torsion, 908, 908f in vomiting evaluation, 396t Ultraviolet light therapy, 280 Umbilical artery and vein catherization, 1058–1062 complications of, 1062 contraindications to, 1058 equipment for, 1058–1059 indications for, 1058 procedure for, 1059–1061, 1059f, 1060f, 1061f Umbilical cord blood, 748–749 Umbilical cord care, 697–698 Umbilical hernia, 869–870 Upper GI series advantages and disadvantages of, 396t in gastrointestinal bleeding, 97 in gastrointestinal obstruction, 859, 859f, 860f indications for, 396t in malrotation, 1011f procedure for, 1011, 1011t Upper motor neuron signs/disorders, 649, 649t, 650–651, 654 Urea acid cycle defects admission and discharge criteria for, 412 amino acid abnormalities in, 411t clinical presentation of, 156, 409, 410t consultation for, 412 diagnostic evaluation of, 410–411, 411t differential diagnosis of, 409–410, 411t future directions in, 412 genetic factors in, 410 incidence of, 410 key points, 412 management of, 411–412, 412t pathophysiology of, 409, 410f prevention of, 412

prognosis of, 412 Ureteroneocystostomy, 911 Urethral trauma, 1012, 1012f Urethritis causes of, 185 clinical presentation of, 185 differential diagnosis of, 187 gonococcal, 189t nongonococcal, 190t Uric acid metabolism, 740, 741f Uric acid stones, 912 Urinary alkalinization, 923t Urinary anion gap (UAG), 70, 632 Urinary catheters, 17–18 Urinary tract infections (UTIs), 559–565 admission criteria for, 565 clinical presentation of, 560–561, 561–563f course of illness, 564 diagnostic evaluation of, 561–562, 561–563f, 563t, 564, 564f differential diagnosis of, 561, 864t discharge criteria for, 565 epidemiology of, 559, 559t in neonates and young infants, 469, 469t, 470 pathophysiology of, 559–560 postdischarge considerations in, 565 recurrent, 565 treatment of, 466t, 565 vesicoureteral reflux and, 910 Urinary tract obstruction, 909–910 Urine osmolality in acute kidney injury, 613t in diabetes insipidus, 327 in hypernatremia, 350 in hyponatremia, 348 regulation of, 3454 in SIADH, 328 Urine tests, in acute kidney injury, 612, 613t

Urologic conditions hydronephrosis, 908–909, 909f interventional radiology procedures for, 1031 nephrolithiasis, 911–913, 912f obstruction, 909–910 testicular torsion, 187, 864t, 907–908, 908f vesicoureteral reflux. See Vesicoureteral reflux (VUR) Urticaria, annular, 295, 295f Urticarial drug eruption, 290, 290f UTIs. See Urinary tract infections (UTIs) Uveitis, 842, 844 V Vaccine(s). See also Immunizations hepatitis A, 556 hepatitis B, 556, 698, 698f pertussis, 536 rabies, 964–965 rotavirus, 552 VACTERL syndrome/anomalies, 216t, 709–710, 710f Vaginitis, 185, 187, 188t Vaginosis, bacterial, 188t, 191t Valacyclovir, 191t Validity, 11, 11t Valproic acid, 640t, 641t Valsartan, 103t Value in Pediatrics (VIP) network, 51 Vancomycin for bacterial meningitis, 495t for cystic fibrosis exacerbations, 813t for endocarditis prophylaxis, 244t for infective endocarditis, 242t, 243t in lock therapy, 584t for osteomyelitis, 567t, 568 red man syndrome and, 203 for septic shock, 147t Varicella (chickenpox), 269t, 482t, 668f

Varicella-zoster virus (VZV) infections clinical presentation of, 269t congenital, 715, 716t, 717t diagnostic evaluation of, 269t in immunosuppressed host, 302 ocular, 889 stomatitis, 128t transmission-based precautions for, 17t in transplant recipient, 601, 605t, 606t Vascular anomalies, 270–274 classification of, 270, 270t key points, 274 malformations admission criteria for, 271–272 classification of, 270–271, 270t diagnostic evaluation of, 271 management of, 271 tumors admission criteria for, 273–274 classification of, 272 diagnostic evaluation of, 272–273, 272f, 273f management of, 273 Vasculitides, 285t Vasculitis diagnostic evaluation of, 138t drug-induced, 292, 292f leukocytoclastic, 262, 262f, 263 with petechiae and purpura, 137t, 261t, 262. See also Henoch-Schönlein purpura; Kawasaki disease/syndrome; Systemic lupus erythematosus (SLE) renal, 619–620 in Rocky Mountain spotted fever, 487 Takayasu’s arteritis, 215 Vaso-occlusive pain crisis, 435–436 Vasopressin. See Desmopressin acetate (DDAVP) Vasovagal (neurocardiogenic) syncope, 148, 149f. See also Syncope VCUG. See Voiding cystourethrogram (VCUG)

Venous blood gas, 110t Venous malformations, 270, 271f Venous thromboembolism clinical presentation of, 455 diagnostic evaluation of, 455–456 differential diagnosis of, 455, 455t genetic factors in, 455, 455t incidence of, 455 in nephrotic syndrome, 629 pathophysiology of, 455 treatment of, 456, 456t Ventilation-perfusion mismatch, 110, 786, 803 Ventilator-associated pneumonia, 18 Ventricular septal defect (VSD), 234–235, 235f Ventriculoperitoneal shunt (VP). See Cerebrospinal fluid (CSF) shunt Venturi mask, 112t Verapamil, 249 Verruca vulgaris, 302 Vertebral artery dissection, 135, 669f Vesicants, 900 Vesicle, 265, 265t, 266f Vesicobullous diseases admission criteria for, 269–270 clinical presentation of, 265, 266f consultation for, 269t definitions in, 265, 265t diagnostic evaluation of, 265, 269t differential diagnosis of, 265, 267–268t, 268–269t discharge criteria for, 270 in infants and children, 268–269t key points, 270 management of, 267, 269 in neonates, 267–268t Vesicoureteral reflux (VUR) admission criteria for, 911 consequences of, 910 consultation for, 911

diagnostic evaluation of, 564, 910–911 epidemiology of, 559–560 grading of, 560f, 910f key points, 911 persistence of, 560f postdischarge considerations in, 565 treatment of, 911 urinary tract infections and, 559–560, 910 VFS (videofluoroscopic feeding study), 394 Vibrio cholerae 01,0139. See Cholera Vibrio vulnificus, 574 Videofluoroscopic feeding study (VFS), 394 Vigabatrin, 641t VIP (Value in Pediatrics) network, 51 Viral infections. See also specific viruses acute gastroenteritis, 541, 542t, 545t, 549t. See also Acute gastroenteritis (AGE) arthritis, 848, 848t, 849, 850 in immunosuppressed host, 302 infection control, 17t, 18 pneumonia. See Pneumonia in transplant recipient, 600–602, 605t, 606t. See also Transplant recipient, infections in Viridans streptococci infection in cerebrospinal fluid shunt, 585t infective endocarditis, 239, 240t in transplant recipient, 600 Vitamin A deficiency, 355 Vitamin B12 deficiency, 429 Vitamin D deficiency, 233, 331–333, 331t Vitamin D supplements, 697 Vitamin D2 (ergocalciferol), 333 Vitamin D3 (cholecalciferol), 333 Vitamin K antagonist poisoning/overdose, 972–974, 974t Vitamin K deficiency, 355 Vitamin K dependent clotting cascade, 973f

Vitamin K1, 374, 697 Vocal cord dysfunction, 786 Vocal cord paralysis, 877–878 Voiding cystourethrogram (VCUG) indications for, 564, 564t procedure, 1008f, 1012 radiation exposure from, 1006t in vesicoureteral reflux, 1012f Volvulus, 96, 859–860, 859f, 860f Vomiting. See also Acute gastroenteritis (AGE) causes of in children and adolescents, 155t gastrointestinal, 153–155 in infants and toddlers, 154t in newborns and infants, 153t non-gastrointestinal, 155–156 by organ system, 152t diagnostic evaluation of, 156f, 396t differential diagnosis of, 395, 864t in gastroparesis, 369–370 key points, 157 management of, 156–157, 157f, 343–344 pathophysiology of, 151 patient history in, 151, 153 physical examination in, 153 von Willebrand disease (vWD), 454–455 von Willebrand factor (vWFct), 454 Vorapaxar, 976 Voriconazole, 304, 304f VP (ventriculoperitoneal shunt). See Cerebrospinal fluid (CSF) shunt VSD. See Ventricular septal defect (VSD) VUR. See Vesicoureteral reflux (VUR) VZV infections. See Varicella-zoster virus (VZV) infections W WAGR (11p13 deletion) syndrome, 404, 405t “Waiter’s tip” position, 701, 702f

Warfarin poisoning/overdose, 972–974, 974t for stroke prevention, 676 for venous thromboembolism, 456 Warm-reactive autoimmune hemolytic anemia, 430 Warts, 302 Waterhouse-Friderichsen syndrome, 338 Waterlow criteria, in malnutrition, 381, 381t Weakness. See Hypotonia and weakness Well newborn admission criteria for, 698 assessment of, 696, 696t, 697t breastfeeding of, 696 congenital heart disease screening in, 698 elimination in, 697 female genitalia care, 698 formula feeding of, 696–697 hearing screening in, 698 hepatitis B immunization in, 698, 698f hyperbilirubinemia screening in, 698, 726 key points, 700 male genitalia care, 698 metabolic screening in, 698 ocular prophylaxis in, 697 parental support services, 698 umbilical cord care for, 697–698 vitamin supplementation in, 697 weight loss and gain in, 697 Wells syndrome, 575 Werdnig-Hoffman disease, 655 West Nile neuroinvasive syndromes, 491, 492, 494–495, 496 Wheezing in asthma, 785, 786t. See also Asthma in bronchopulmonary dysplasia, 804. See also Bronchopulmonary dysplasia (BPD) in foreign body aspiration, 817 Whipple procedure, 392

White blood cell (WBC) count, 864 White blood cell (WBC) scan, 1018 Whole-bowel irrigation, 915, 916t Whooping cough. See Pertussis Williams-Beuren syndrome, 405t, 406 Williams syndrome, 216t, 332 Wilms tumor, 737–738, 737f, 1023f Wilson disease, 373, 374 Wiskott-Aldrich syndrome atopic dermatitis in, 279 clinical presentation of, 208, 209, 450 treatment of, 451 Withdrawal syndromes admission and discharge criteria for, 944 clinical presentation of, 941–942, 942t differential diagnosis of, 942, 942t, 943t epidemiology of, 941 key points, 944 treatment of, 943–944, 943t Withholding/withdrawal of life-sustaining treatment, 43 Wolff-Parkinson-White (WPW) syndrome, 224–225, 224f Wolf-Hirschhorn (4p deletion) syndrome, 404, 405t X X-linked ichthyosis, 405t Y Yersinia enterocolitica infections epidemiology of, 544, 545t pathophysiology of, 541, 542t, 543 treatment of, 467t, 551t Z Zanamivir, 533 Zellweger syndrome, 652–653 Zidovudine, 590, 591, 716 Ziprasidone, 774, 774t

Zonisamide, 641t Zoster. See Varicella-zoster virus (VZV) infections