Pediatric critical care medicine [Volume 3. Gastroenterological, Endocrine, Renal, Hematologic, Oncologic and Immune Systems, 2 ed.] 9781447163558, 1447163559, 9781447163589, 1447163583, 9781447163596, 1447163591, 9781447163619, 1447163613, 9781447164159, 1447164156

Table of contents :
Foreword to the First Edition
Preface to the Second Edition
References
Preface to the First Edition
Promises to Keep
Acknowledgements
Contents
Contributors
Part I: The Gastrointestinal System in Critical Illness and Injury
1: Gastrointestinal Bleeding
Introduction
Definitions
Etiology
Specific Causes of UGIB
Hemorrhagic Disease of the Newborn
Coagulation Disorders
Peptic or Esophageal Ulcerations
Mallory-Weiss Tears
Variceal Bleeding
Specific Causes of LGIB
Juvenile Polyps
Henoch Schonlein Purpura (HSP)
Meckels Diverticulum
Intussusception
Stress ulcers and their prevention
Management of GI Bleeding
Initial Management and Evaluation
Placement of a Nasogastric (NG) Tube
Laboratory Evaluation
Testing for Occult Blood
Radiologic Investigation
X-ray
Ultrasound
Air Contrast Enema
CT Scan
Tagged Red Blood Cell Scan
Meckel Scan
Angiography
Diagnostic Interventions (and Management)
Upper Endoscopy
Colonoscopy
Double Balloon Endoscopy
Capsule Endoscopy
Medical Therapy
Proton Pump Inhibitors (PPI)
H-2 Blockers
Vasoactive Drugs
Sucralfate
Recombinant Activated Factor 7
Antibiotic Therapy
Surgical Therapy
Management of Variceal Bleeding
Transjugular Intrahepatic Porto Systemic Shunt
Summary and Recommendations
References
2: Liver Failure in Infants and Children
Introduction
Etiology
Liver Failure and its Effects on Organ Function
Hepatic Encephalopathy
Clinical Manifestations
Pathophysiology
Management
Acute Kidney Injury
Pathogenesis of Hepatorenal Syndrome
Management of Hepatorenal Syndrome
Coagulopathy and Bleeding Disorders
Respiratory Dysfunction
Acute Respiratory Distress Syndrome
Hepatopulmonary Syndrome
Respiratory Support
Circulatory Derangements
Plasmapheresis in Fulminant Hepatic Failure
Liver Transplantation
Artificial Support Devices
References
3: Acute Pancreatitis
Introduction
Epidemiology
Pathophysiology
Etiology
Genetics
Diagnosis
Outcome
Assessment of Severity
Treatment
Objectives and Methods of Conservative Treatment
Objectives and Indication of Surgical Treatment
Refeeding in the Mild Form of Acute Pancreatitis
Conclusion
References
4: Abdominal Compartment Syndrome in Children
Introduction
Definitions
Intra-abdominal Pressure and Abdominal Perfusion Pressure
Intra-abdominal Hypertension (IAH)
Abdominal Compartment Syndrome
Incidence
Etiology and Risk factors of ACS
Pathophysiology of ACS
Organ System Dysfunction and the Clinical Presentation of ACS
Cardiovascular Effects
Respiratory Effects
Renal Effects
Gastrointestinal Effects
CNS Effects
Diagnosis
IAP Measurement in Children
Imaging Findings
Management of IAH and ACS
Prevention of IAH and ACS
Medical Management of IAH (Fig.  4.5)
Optimizing Fluid Balance
Improving Abdominal Compliance
Decreasing Intraluminal and Abdominal Contents
Surgical Management
Decompressive Laparotomy (DL)
Critical Care Management of the Child with ACS
Outcome of ACS
Summary
Appendix
References
5: Obesity in Critical Illness
Introduction
General Considerations for Dealing with the Critically Ill Obese Patient
Difficulties with Routine Bedside Care and Procedures
Effects of Obesity on Pharmacology
Airway Management and Obesity
Pulmonary Physiology and Obesity
Cardiovascular Physiology and Obesity
Additional Disease-Specific Considerations for the Critically Ill Obese Patient
Mechanical Ventilation
Acute Lung Injury/ARDS
Asthma
Obstructive Sleep Apnea
Cardiopulmonary Arrest
Venous Thromboembolic Disease
Obesity and Infection
Surgical Site Infections
Obesity and H1N1
Trauma
Burn Injury
Cancer
Bariatric Surgery
References
6: Nutrition in the PICU
Introduction
Nutritional Deficiencies During Critical Illness
Nutritional Assessment
Macronutrient Goals During Critical Illness
Energy Goals
Energy Balance in the PICU
Protein Goals
Nutrient Delivery in the PICU
Enteral Nutrition: Practical Considerations
Role of Transpyloric Enteral Feeding in the PICU
Barriers to EN in the PICU
Strategies to Optimize Macronutrient Intake in the PICU
Immunonutrition in the PICU
Conclusions
References
Part II: The Endocrine System in Critical Illness and Injury
7: Diabetic Ketoacidosis
Introduction
Pathophysiology
Ketoacidosis
Hyperglycemia
Dehydration
Hyperosmolarity
Electrolytic Disorders
Sodium
Potassium
Phosphorus
Calcium
Clinical and Laboratory Diagnosis of Diabetic Ketoacidosis
Treatment
Correction of Dehydration and Electrolytic Disorders
Initial phase – Fluid Expansion (1–4 h)
Maintenance phase – Rehydration stage (20–22 h)
Insulin Therapy
Complications
Electrolyte Disorders
Cardiac Arrhythmias
Aspiration of Gastric Content
Pulmonary Edema
Cerebral Edema
Prevention
References
8: Hyperglycemia, Dysglycemia and Glycemic Control in Pediatric Critical Care
Introduction
Incidence and Associations of Hyperglycemia in Pediatric Critical Care
Hypoglycemia in the PICU
Glycemic Variability
Glycemic Control Protocols in the PICU
Randomized Controlled Trial in Glycemic Control in Pediatric Critical Care
Conclusion
References
9: Hypoglycemia
Introduction
Definition
Pathophysiology
Differential Diagnosis
Clinical Manifestations
Management
References
10: The Adrenal Glands in Critical Illness and Injury
Introduction
Historical Perspective
Normal Adrenal Anatomy and Function
Adrenal Gland
Hypothalamic-Pituitary Adrenal Axis
Actions of Cortisol
Normal Response to Stress
Adrenal Insufficiency
Primary Adrenal Insufficiency
Secondary Adrenal Insufficiency
Tertiary Adrenal Insufficiency
Relative and Absolute Adrenal Insufficiency
Adrenal Insufficiency in Critical Illness
Definition of Adrenal Insufficiency
Prevalence of Adrenal Insufficiency in Pediatric Critical Illness
Possible Mechanisms for Adrenal Insufficiency in Critical Illness
Diagnosis of Adrenal Insufficiency in Critical Illness
Measurement of Cortisol Levels
Risk Factors for Adrenal Insufficiency
Pharmacokinetics of Corticosteroids in Critical Illness
Adverse Effects of Corticosteroids in Critical Illness
Management of Adrenal Insufficiency in Pediatric Critical Illness
Outcomes of Adrenal Insufficiency in Pediatric Critical Illness
Conclusion
References
11: Thyroid and Growth Hormone Axes Alteration in the Critically Ill Child
Introduction
The Thyroid Axis in Critical Illness
Thyroid Physiology
Thyroid Hormones During Critical Illness
Thyroid Function in Critically Ill Children
Evaluation of Thyroid Function in the PICU
Thyroid Hormone Treatment in PICU
Sepsis
Cardiac Surgery
The Growth Hormone Axis in Critical Illness
Growth Hormone Physiology
Growth Hormone During Critical Illness
References
Part III: The Renal System in Critical Illness and Injury
12: Applied Renal Physiology in the PICU
Introduction
Embryology and Development
Renal Hemodynamics
Renal Blood Flow
Regulation of Afferent and Efferent Arterioles
Maintenance and Modulation of Renal Hemodynamics in Disease States
Filtration
Glomerulus
The Glomerular Tuft and Cellular Elements
Glomerular Filtration and Tubuloglomerular Feedback
Glomerular Disease
Tubules
The Proximal Tubule
Sodium
Bicarbonate
Chloride
Water
Potassium
Glucose
Phosphate
Proteins
Organic Ions
Uric Acid
Dysfunction in Acute Illness
The Loops of Henle
Dysfunction in Critical Illness
The Distal Tubule and Collecting Ducts
Dysfunction in Critical Illness
The Endocrine Kidney
Known Renal Mediators of Extra-Renal Homeostasis
Organ Syndromes in Critical Illness
Conclusion
References
13: Electrolyte Disorders in the PICU
Introduction
Disorders of Sodium Homeostasis
Hyponatremia
Pathophysiology
Hyponatremia that Is Not Mediated by ADH
Hyponatremia that Is Mediated by ADH
Management
Prevention of Acute Hyponatremia
Acute Versus Chronic Hyponatremia
Treatment of SIADH
Hypernatremia
Pathophysiology
Decreased Water Intake
Renal Water Loss (A Disorder of Urinary Concentration)
Diagnosis and Management
Acute vs Chronic Hypernatremia
Disorders of Potassium Homeostasis
Hypokalemia
Pathophysiology
Clinical Manifestations (Table  13.4)
Management
Hyperkalemia
Pathophysiology
Clinical Manifestations
Management
Disorders of Magnesium Homeostasis
Hypomagnesemia
Pathophysiology
Clinical Manifestations
Management
Hypermagnesemia
Pathophysiology
Clinical Manifestations
Management
Disorders of Calcium Homeostasis
Hypocalcemia
Pathophysiology
Clinical Manifestations
Management
Hypercalcemia
Pathophysiology
Clinical Manifestations
Management
Disorders of Phosphorus Homeostasis
Hypophosphatemia
Pathophysiology
Clinical Manifestations
Management
Hyperphosphatemia
Pathophysiology
Clinical Manifestations
Management
References
14: Acid-Base Disorders in the PICU
Introduction
Acid-Base Physiology
Respiratory Compensation: Volatile Acids (CO 2)
Metabolic Compensation and Nonvolatile Acids/Strong Ion Difference (SID)
Nonvolatile Weak Acid Buffers
Quantification of Acid-Base Status
Differential Diagnosis and Basic Management of Acid-Base Disorders
Respiratory Acidosis
Respiratory Alkalosis
Metabolic Acidosis
Elevated Anion Gap Acidosis
Non-anion Gap Acidosis
Metabolic Alkalosis
Mixed Acid-Base Disorders
Special Acid-Base Situations
Cardiopulmonary Bypass and Hypothermia: pH Stat and Alpha Stat Concepts
Hypercapnic Acidosis and Permissive Hypercapnia in Ventilatory Management
Choice of Intravenous Fluid Composition and Acid-Base Balance
References
15: Acute Kidney Injury
Introduction
Pathophysiology of AKI
Glomerular Perfusion
Filtrative Impairment
Disrupted Endothelial Function
Apoptosis and Necrosis
Iatrogenic Toxicity
Predisposition and the “at-risk” Patient: Renal Angina
Cardinal Pathophysiology: Cardiopulmonary Bypass and Sepsis
Cardiopulmonary Bypass and AKI
Sepsis and AKI
Epidemiologic Characteristics of AKI: Incidence, Definition, Classification
Incidence and Classification
Impact of AKI on Outcomes
Immediate Effects
Extra-Renal Effects
Diagnosis
Serum Testing for AKI
Creatinine
Urea
Cystatin C
Serum GFR Estimation
Urinary Testing for AKI
Output
Derived Indices
Electrolytes
Microscopy
Biomarkers for AKI
Identification of Established AKI
Prediction of AKI
Prediction of AKI Associated Morbidity
Technologic Adjuncts for AKI Diagnosis
Renal Angina and AKI
Management of AKI
Prevention Strategies
Therapeutic Strategies
Target: Aberrant Renal Vascular Tone
Target: Renal Preload
Target: Direct Cellular Injury
Target: Oxidative and Inflammatory
Target: Nutrition
Recovering from AKI
Conclusion
References
16: Kidney Disorders in the PICU: Thrombotic Microangiopathies and Glomerulonephritis
Thrombotic Microangiopathies
Thrombotic Thrombocytopenic Purpura (TTP)
Pathophysiology
Clinical Manifestations and Diagnosis
Treatment
Prognosis
Thrombocytopenia Associated Multi-organ Failure (TAMOF)
Typical Hemolytic Uremic Syndrome
Pathophysiology
Clinical Manifestations and Diagnosis
Treatment (Table  16.1)
Prognosis
Atypical HUS
Pathophysiology
Clinical Manifestations and Diagnosis
Treatment
Prognosis
Associated TMA: “xHUS”
Glomerulonephritis
Alport’s Syndrome
Anti-glomerular Basement Membrane Disease
IgA Nephropathy
Henoch-Schönlein Purpura
Systemic Lupus Erythematosis (SLE)
Membranoproliferative Glomerulonephritis
References
17: Kidney Pharmacology
Introduction
Dosage Adjustment for Renal Dysfunction
Renal Replacement Therapy and Medication Dosing
Continuous Renal Replacement Therapy (CRRT) Adjustment
Diuretics
Pharmacokinetics of Commonly Used Diuretics
Categories of Diuretics
Diuretic Resistance
References
18: Renal Replacement Therapy
Introduction
Nutritional Support in AKI
Peritoneal Dialysis
Dialysate Solutions
PD Prescription
Complications of PD
CRRT
Modes
Vascular Access
Dialysate Solution
Anticoagulation
Special Circumstances
Cancer and Bone Marrow Transplantation
Intoxications and Poisonings
Inborn Errors of Metabolism
Multiple Organ Dysfunction Syndrome (MODS)
Plasmapheresis
Neonatal CRRT and Outcome
ECMO and CRRT
CRRT Complications
Technical and Equipment Malfunction
Bleeding
Infection
Hypotension
Electrolyte Disturbances
Hypothermia
Nutritional Losses
Medication Errors
CRRT Survival
Intermittent Hemodialysis
Hemodialysis Equipment
Anticoagulation
Hemodialysis Use in Clinical Situations
Outcome in Hemodialysis
Complications of Hemodialysis
Conclusions
References
Part IV: The Hematologic System in Critical Illness and Injury
19: Transfusion Medicine
Transfusion of Red Blood Cells
Anemia in the PICU
Adaptive Mechanisms to Acute Anemia in Critically Ill Patients
Impairment of Adaptive Mechanisms to Anemia
Long-Term Adaptive Mechanisms to Anemia
Management of Anemia in the PICU
Effects of Transfused RBC on Oxygen Delivery
Immunologic Effects of Allogeneic RBC Transfusions
Length of Storage of RBC Units
Practice Patterns: Determinants of RBC Transfusion
Goal-Directed RBC Transfusion Therapy
Red Blood Cell Transfusions in Non-cardiac Patients
Stable Critically Ill Children
Unstable Critically Ill Children
Red Blood Cell Transfusions in Cardiac Patients
Limiting Blood Product Transfusion
The “Nuts and Bolts” of Packed RBC Transfusion
Whole Blood
Specific Types of Packed RBC Units
Transfusion of Frozen Plasma
Indications for Frozen Plasma Transfusion
The “Nuts and Bolts” of Frozen Plasma Transfusion
Transfusion of Platelets
Indication for Platelet Transfusion
The “Nuts and Bolts” of Platelet Transfusion
Serious Hazards of Transfusion
Acute Reactions
Transfusion-Related Acute Lung Injury (TRALI)
Transfusion-Associated Circulatory Overload (TACO)
Hypotensive Reaction
Fever
Acute Hemolytic Transfusion Reactions
Non-immunologic Hemolysis
Allergic Reactions
Infections
Acute Leukocytosis
Acute Complications of Massive Transfusion
Hypothermia
Coagulopathy
Citrate Intoxication
Hyperkalemia
Late Onset Reactions and Complications
Delayed Hemolytic Reactions
Post-Transfusion Purpura (PTP)
Infections
Transfusion Associated Graft Versus Host Disease (TA-GvHD)
Non-specific Treatment of Transfusion Reactions
References
20: Hematologic Emergencies in the PICU
Introduction
Part 1: Red Blood Cell Disorders
Anemias of Underproduction and/or Impaired Maturation
Anemias of Increased Turnover or Destruction
Sickle Cell Disease
Acute Splenic Sequestration
Acute Chest Syndrome
Cerebrovascular Accidents
Vaso-Occlusive Crisis
Functional Asplenia
Transfusion Therapy in Patients with SCD
Schistocytosis
Red Cell Membrane Defects
Red Cell Metabolism Defects
Immune-Mediated Hemolysis
Thalassemias
Secondary Hemoglobinopathies
Hemophagocytosis
Erythrocytosis
Part 2: Non-malignant White Blood Cell Disorders
Part 3: Platelet Disorders
Thrombocytopenia
Increased Consumption of Platelets
Increased Destruction of Platelets
Decreased Production of Platelets
Thrombocytosis
References
21: Coagulation Disorders in the PICU
Introduction
History
Thrombus Formation Overview and Review of Normal Coagulation Components
Platelets
Platelet Activation
Platelet Receptors
Endothelial Cells
Coagulation Cascade
Contact System
Intrinsic Coagulation Pathway
Extrinsic System
Common Pathway
Physiologic Inhibitors of Coagulation
Fibrinolysis
Complement and Leukocytes
Laboratory Evaluation of Hemostasis in the Intensive Care Unit
Modulation of the Coagulation System in the Intensive Care Unit
Bleeding in the Intensive Care Unit
Disorders of Platelets
Factor Deficiencies
Massive Transfusion Syndrome
Disseminated Intravascular Coagulation
Pathophysiology of DIC
Clinical Scoring Systems in DIC
Treatment for DIC
Extracorporeal Life Support (ECLS)
Conclusion
References
22: Therapeutic Apheresis in the Pediatric Intensive Care Unit
Introduction
Automated Apheresis Technology
Principle of Separation
Quantification of Removal
Anticoagulation
Procedures
Plasmapheresis
Erythrocytapheresis
Leukapheresis
Technical Issues in Pediatrics
Access
Volume
Blood Priming
Anticoagulation (Dose)
Hypothermia
Cooperation
Disease-Specific Indications
Apheresis and ACE Inhibitors
References
23: Thromboembolic Disorders in the PICU
Introduction
Epidemiology and Incidence
Overview of Coagulation
Pathophysiology of Pulmonary Embolism
Risk Factors for VTE
Inherited Risks
Acquired Risks
Diagnosis of Venous Thrombosis
Clinical Diagnosis
Radiologic Diagnosis
Laboratory Evaluation
Treatment of Venous Thromboembolism
Anticoagulation
Unfractionated Heparin
Low Molecular Weight Heparins
Direct Thrombin Inhibitors
Vitamin K Antagonists
Duration of Anticoagulation for VTE
Thrombolysis
Thromboprophylaxis
Outcomes
References
Part V: Oncologic Disorders in the PICU
24: Care of the Oncology Patient in the PICU
Introduction
Mediastinal Mass
Introduction
Pathophysiology
Identification of High Risk Patients
Management and Approach to the Diagnostic Work-Up
Use of Anesthesia or Deep Sedation
Conclusion
Hyperleukocytosis
Hypercalcemia
Incidence
Pathophysiology
Treatment
Acute Promyelocytic Leukemia (APL) – Leukemia-Associated Coagulopathy
Differentiation Syndrome
Lactic Acidosis of Malignancy
Balancing Therapy at the End of Life
References
25: Critical Illness as a Result of Anti-­Neoplastic Therapy
Introduction
Tumor Lysis Syndrome (TLS)
Pathophysiology
Treatment
Hyperkalemia
Hyperuricemia
Hyperphosphatemia
Hypocalcemia
Monitoring
Classification
Chemotherapy Adverse Effects
Radiation-Associated Toxicty
Radiation Pnuemonitis
Epidemiology
Pathophysiology
Clinical Signs and Symptoms
Diagnosis
Treatment
Sporadic Radiation Pneumonitis
Typhlitis
Sepsis in OncologyPatient Population
References
26: Hemophagocytic Lymphohistiocytosis Syndromes
Introduction
Pathogenesis
Clinical Features
Diagnosis
Treatment
Prognosis
Conclusion
References
27: Hematopoietic Stem Cell Transplantation in the PICU
Introduction
Indications
Hematopoietic Stem Cell Sources
Donor Selection
Transplant Conditioning Regimens
Graft Versus Host Disease (GVHD) Prophylaxis
Infection Prophylaxis
Complications Following Hematopoietic Stem Cell Transplantation
Infections
Respiratory Failure Following Hematopoietic Stem Cell Transplantation
Non-Infectious Causes of Lung Injury
Infectious Causes of Lung Injury
Management
Outcomes
Graft Versus Host Disease
Mechanism of Disease
Clinical Features
Diagnosis
Treatment
Outcome
Sinusoidal Obstruction Syndrome (Veno-
Mechanism of Disease
Clinical Features
Diagnosis
Management
Outcomes
Transplant-Associated Thrombotic Microangiopathy
Mechanism of Disease
Clinical Features and Diagnosis
Management
Outcomes
Kidney Injury Following Hematopoietic Stem Cell Transplantation
Diagnosis
Management
Outcomes
Neurologic Complications Following Hematopoietic Stem Cell Transplantation
Conclusion
References
Part VI: The Immune System in Critical Illness and Injury
28: The Immune System in Critical Illness and Injury
Introduction
Innate Immune System
Innate Immune Sensing
Pattern Recognitions Receptors (PRRs)
Humoral Elements of Innate Immune Sensing
Effectors of the Innate Immune System: Cellular Mechanisms
Professional Phagocytes
NK Cells
Humoral Innate Immune Effectors: The Complement System
Adaptive Immune System
Cellular Immunity: T Cells
Cellular and Humoral Immunity: B Cells
Interplay Between the Innate and Adaptive Immune Systems
The Immunologic Balance in Critical Illness
Immunoparalysis
Conclusions
References
29: Primary and Secondary Immunodeficiencies
Introduction
Part I Primary Immunodeficiency Syndromes
Primary Defects of Antibody Production
X-Linked (XLA or Bruton’s) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Hyper-IgM Syndrome
Selective IGA Deficiency
IgG Subclass Deficiencies
Transient Hypogammaglobulinemia of Infancy (THI)
Treatment of Antibody Deficiency Diseases
Combined Immunodeficiencies
Severe Combined Immunodeficiency (SCID)
X-linked Severe Combined Immunodeficiency (X-SCID)
Jak3 Deficiency
Omenn Syndrome
Adenosine Deaminase (ADA) Deficiency
Purine Nucleoside Phosphorylase (PNP) Deficiency
Cartilage Hair Hypoplasia (CHH)
Primary Defects of Cellular Immunity
DiGeorge Syndrome
Defective Expression of the T-Cell Receptor-CD3 Complex
Other Immunodeficiency Syndromes Associated with T Lymphocytes
Wiskott-Aldrich Syndrome (WAS)
Ataxia-Telangiectasia (A-T)
Combined Immunodeficiency (CID or Nezelof Syndrome)
Treatment of Cellular Immunodeficiency
Complement Deficiencies
Rheumatic Diseases in Complement Deficiencies
Infections in Complement Deficiencies
Hereditary Angioedema (HAE)
Treatment of Complement Deficiencies
Phagocytic Disorders
Leukocyte Adhesion Deficiency Type I (LAD)
LAD Type 2
Chronic Granulomatous Disease
Chediak-Higashi Syndrome (CHS)
Treatment of Phagocytic Disorders
Part II Secondary Immunodeficiency Syndromes
Treatment with Immunosuppressive Agents
Immunoparalysis and the Immune Response to Trauma, Surgery, Burns, and Anesthesia
Altered Immunity due to Intercurrent Illness or Insult
Treatment of Phagocytic Disorders
Part II Secondary Immunodeficiency Syndromes
Treatment with Immunosuppressive Agents
Immunoparalysis and the Immune Response to Trauma, Surgery, Burns, and Anesthesia
Altered Immunity due to Intercurrent Illness or Insult
References
30: Sepsis
Introduction
Epidemiology of Sepsis
Definition of Sepsis
Clinical Manifestations
The Immunopathobiology of Sepsis
Barrier Defenses
Molecular Events During Early Infection
Pathogen Recognition
Inflammatory Mediator Production
Complement
Coagulation Cascade
Innate Immune Cellular Contributions
PMN
Antigen-Presenting Cells (APCs)
Vascular Endothelium
Pathophysiology of Sepsis
Cardiovascular
Immune System
Pulmonary
Renal
Hepatic
Multi-organ Dysfunction Syndrome (MODS)
Management of Sepsis
Early Recognition
Early Source Control and Antibiotic Administration
Early Reversal of Shock
Fluid Resuscitation
Hemodynamic Support
Supportive Care
Corticosteroids
Conclusion
References
31: Thrombocytopenia-Associated Multiple Organ Failure Syndrome
Introduction
Thrombotic Microangiopathy (TMA)
Disseminated Intravascular Coagulation (DIC)
Mechanism of DIC
Diagnosing and Managing DIC
Thrombotic Thrombocytopenic Purpura (TTP)
Von Willebrand Factor Hyper-Adhesiveness in TTP
ADAMTS-13 (a.k.a VWF-Cleaving Protease) Deficiency in TTP
Diagnosing and Managing TTP
Hemolytic Uremic Syndrome (HUS)
Mechanisms of HUS
Diagnosing and Managing HUS
Thrombocytopenia-Associated Multiple Organ Failure (TAMOF)
Large Animal Models of VWF-Mediated Thrombotic Microangiopathy and Acquired ADAMTS-13 Deficiency
Current and Future Therapies for Thrombotic Microangiopathies
References
32: Toxic Shock Syndrome in Children
Introduction
Epidemiology
Staphylococcal Toxic Shock Syndrome
Streptococcal Toxic Shock Syndrome
Pathophysiology
Host Immunity
Clinical Manifestations
Staphylococcal Toxic Shock Syndrome
Streptococcal Toxic Shock Syndrome
Management
Staphylococcal TSS
Streptococcal Toxic Shock Syndrome
Adjunctive Therapy
Recent Developments
Conclusion
References
33: Hospital-Acquired Infections and the Pediatric Intensive Care Unit
Introduction
History and Epidemiology of Nosocomial Infections
Catheter Associated Bloodstream Infections
Scope of the Problem
Risk Factors
Diagnosis
Pathogenesis
Management and Prevention
Ventilator-Associated Pneumonia
Scope of the Problem
Diagnosis
Pathogenesis
Risk Factors
Management and Prevention
Hospital-Acquired Infections of the Urinary Tract
Scope of the Problem
Risk Factors
Diagnosis
Pathogenesis
Management and Prevention
Surgical Site Infections
Scope of the Problem
Risk Factors
Management and Prevention
Specific SSIs Commonly Encountered in the PICU
Cardiothoracic Surgery
Craniofacial Surgery
Neurosurgery
Orthopaedic Surgery
Transplant Surgery
Infection Control in the PICU
Conclusion
References
34: Anaphylaxis
Introduction
Epidemiology
Pathophysiology
Triggers
Mechanism of Symptoms
Clinical Presentation
Differential Diagnosis
Diagnosis
Treatment
Epinephrine
Mechanism of Action
Modes of Administration
Patient Positioning
Oxygen Administration and Fluid Resuscitation
Inhaled β-agonists
Histamine Blockers
Corticosteroids
Other Vasopressors
Other Agents
Treatment of Cardiorespiratory Arrest in the Management of Anaphylaxis
Prevention
References
35: Rheumatologic Disorders in the PICU
Introduction
Systemic Lupus Erythematosus (SLE)
CNS Complications of SLE
Seizures
Cerebral Vein Thrombosis
Stroke
Psychosis, Delirium, and Depression
Pulmonary Complications of SLE
SLE Pneumonitis
Pulmonary Hemorrhage
Cardiac Complications of SLE
SLE Pericarditis
SLE Endocarditis
SLE Myocarditis and Cardiomyopathy
Infectious Complications of SLE
Renal Complications of SLE
Juvenile Idiopathic Arthritis (JIA)
Infectious Complications of JIA
Cardiac Complications of JIA
Macrophage Activation Syndrome
Henoch-Schoenlein Purpura (HSP)
CNS Complications of HSP
Pulmonary Complications of HSP
Gastrointestinal Complications of HSP
Nephritis in HSP
Kawasaki Disease
Kawasaki Disease Shock Syndrome
Kawasaki Disease Management
Antiphospholipid Antibody Syndrome
Goodpasture Disease
Wegener’s Granulomatosis
Churg-Strauss Syndrome
Cardiac Complications of CSS
Pulmonary Complications of CSS
Gastrointestinal Complications of CSS
Juvenile Dermatomyositis (JDM)
CNS Complications of JDM
Pulmonary Complications of JDM
Cardiac Complications of JDM
Systemic Sclerosis
Cardiopulmonary Complications of Systemic Sclerosis
Scleroderma Renal Crisis
Behcet’s Disease
Conclusion
References
36: Infectious Disease-Associated Syndromes in the PICU
Introduction
Necrotizing Fasciitis
History and Epidemiology
Pathogenesis
Diagnosis
Clinical Manifestations
Management
Hemorrhagic Shock and Encephalopathy
History and Epidemiology
Pathogenesis
Clinical Manifestations
Laboratory Findings
Management
Rocky Mountain Spotted Fever
History and Epidemiology
Pathogenesis
Clinical Manifestations
Laboratory Findings
Management
Ehrlichiosis as a Mimicker of RMSF
Lemierre’s Syndrome
References
37: Life Threatening Tropical Infections
Introduction
Imported Diseases
Locally Prevalent Diseases
Malaria
Epidemiology
Etiology
Pathophysiology of Severe Malaria
Inflammation
Interaction Between Malaria Parasites and RBCs
Sequestration
Clinical Manifestations
Cerebral Malaria
Severe Malarial Anemia
Laboratory Findings and Diagnosis
Treatment
Adjuvant Management
Cerebral Malaria
Severe Malarial Anemia
Dengue
Epidemiology
Etiology
Pathophysiology
Disease Classification and Clinical Course
Febrile Phase
Critical Phase
Recovery Phase
Diagnosis
Treatment
Management of Dengue Hemorrhagic Fever Grade 1 and 2 (Without Shock)
Management of DHF Grades 3 and 4 (Dengue Shock Syndrome)
Typhoid and Paratyphoid Fever
Epidemiology
Etiology
Pathophysiology
Clinical Manifestations
Diagnosis
Treatment
Leptospirosis
Epidemiology
Etiology
Pathophysiology
Clinical Manifestations
Diagnosis
Treatment
References
Index

Citation preview

Derek S. Wheeler Hector R. Wong Thomas P. Shanley Editors

Pediatric Critical Care Medicine Volume 3: Gastroenterological, Endocrine, Renal, Hematologic, Oncologic and Immune Systems Second Edition

123

Pediatric Critical Care Medicine

Derek S. Wheeler • Hector R. Wong Thomas P. Shanley Editors

Pediatric Critical Care Medicine Volume 3: Gastroenterological, Endocrine, Renal, Hematologic, Oncologic and Immune Systems Second Edition

Editors Derek S. Wheeler, MD, MMM Division of Critical Care Medicine Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH USA

Thomas P. Shanley, MD Michigan Institute for Clinical and Health Research University of Michigan Medical School Ann Arbor, MI USA

Hector R. Wong, MD Division of Critical Care Medicine Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH USA

ISBN 978-1-4471-6415-9 ISBN 978-1-4471-6416-6 DOI 10.1007/978-1-4471-6416-6 Springer London Heidelberg New York Dordrecht

(eBook)

Library of Congress Control Number: 2014942837 © Springer-Verlag London 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

For Cathy, Ryan, Katie, Maggie, and Molly “You don’t choose your family. They are God’s gift to you…” Desmond Tutu

Foreword to the First Edition

The practitioner of Pediatric Critical Care Medicine should be facile with a broad scope of knowledge from human developmental biology, to pathophysiologic dysfunction of virtually every organ system, and to complex organizational management. The practitioner should select, synthesize and apply the information in a discriminative manner. And finally and most importantly, the practitioner should constantly “listen” to the patient and the responses to interventions in order to understand the basis for the disturbances that create life-threatening or severely debilitating conditions. Whether learning the specialty as a trainee or growing as a practitioner, the pediatric intensivist must adopt the mantle of a perpetual student. Every professional colleague, specialist and generalist alike, provides new knowledge or fresh insight on familiar subjects. Every patient presents a new combination of challenges and a new volley of important questions to the receptive and inquiring mind. A textbook of pediatric critical care fills special niches for the discipline and the student of the discipline. As an historical document, this compilation records the progress of the specialty. Future versions will undoubtedly show advances in the basic biology that are most important to bedside care. However, the prevalence and manifestation of disease invariably will shift, driven by epidemiologic forces, and genetic factors, improvements in care and, hopefully, by successful prevention of disease. Whether the specialty will remain as broadly comprehensive as is currently practiced is not clear, or whether sub-specialties such as cardiacand neurointensive care will warrant separate study and practice remains to be determined. As a repository of and reference for current knowledge, textbooks face increasing and imposing limitations compared with the dynamic and virtually limitless information gateway available through the internet. Nonetheless, a central standard serves as a defining anchor from which students and their teachers can begin with a common understanding and vocabulary and thereby support their mutual professional advancement. Moreover, it permits perspective, punctuation and guidance to be superimposed by a thoughtful expert who is familiar with the expanding mass of medical information. Pediatric intensivists owe Drs. Wheeler, Wong, and Shanley a great debt for their work in authoring and editing this volume. Their effort was enormously ambitious, but matched to the discipline itself in depth, breadth, and vigor. The scientific basis of critical care is integrally woven with the details of bedside management throughout the work, providing both a satisfying rationale for current practice, as well as a clearer picture of where we can improve. The coverage of specialized areas such as intensive care of trauma victims and patients following congenital heart surgery make this a uniquely comprehensive text. The editors have assembled an outstanding collection of expert authors for this work. The large number of international contributors is striking, but speaks to the rapid growth of this specialty throughout the world. We hope that this volume will achieve a wide readership, thereby enhancing the exchange of current scientific and managerial knowledge for the care of critically ill children, and stimulating the student to seek answers to fill our obvious gaps in understanding. Chicago, IL, USA New Haven, CT, USA

Thomas P. Green George Lister vii

Preface to the Second Edition

The specialty of pediatric critical care medicine continues to grow and evolve! The modern PICU of today is vastly different, even compared to as recently as 5 years ago. Technological innovations in the way we approach the diagnosis and treatment of critically ill children have seemingly changed overnight in some cases. Efforts at prevention and improvements in care of patients prior to coming to the PICU have led to better outcomes from critical illness. The outcomes of conditions that were, even less than a decade ago, almost uniformly fatal have greatly improved. Advances in molecular biology have led to the era of personalized medicine – we can now individualize our treatment approach to the unique and specific needs of a patient. We now routinely rely on a vast array of condition-specific biomarkers to initiate and titrate therapy. Some of these advances in molecular biology have uncovered new diseases and conditions altogether! At the same time, pediatric critical care medicine has become more global. We are sharing our knowledge with the world community. Through our collective efforts, we are advancing the care of our patients. Pediatric critical care medicine will continue to grow and evolve – more technological advancements and scientific achievements will surely come in the future. We will become even more global in scope. However, the human element of what pediatric critical care providers do will never change [1]. I remain humbled by the gifts that I have received in my life. And I still remember the promise I made to myself so many years ago – the promise that I would dedicate the rest of my professional career to advancing the field of pediatric critical care medicine as payment for these gifts. It is my sincere hope that the second edition of this textbook will educate a whole new generation of critical care professionals, and in so-doing help me continue my promise.

References 1. Wheeler DS. Care of the critically ill pediatric patient. Pediatr Clin North Am 2013;60:xv–xvi. (wWith permission by Elsevier, Inc)

Cincinnati, OH, USA

Derek S. Wheeler, MD, MMM

ix

Preface to the First Edition

Promises to Keep The field of critical care medicine is growing at a tremendous pace, and tremendous advances in the understanding of critical illness have been realized in the last decade. My family has directly benefited from some of the technological and scientific advances made in the care of critically ill children. My son Ryan was born during my third year of medical school. By some peculiar happenstance, I was nearing completion of a 4-week rotation in the Newborn Intensive Care Unit. The head of the Pediatrics clerkship was kind enough to let me have a few days off around the time of the delivery – my wife Cathy was 2 weeks past her due date and had been scheduled for elective induction. Ryan was delivered through thick meconium-stained amniotic fluid and developed breathing difficulty shortly after delivery. His breathing worsened over the next few hours, so he was placed on the ventilator. I will never forget the feelings of utter helplessness my wife and I felt as the NICU Transport Team wheeled Ryan away in the transport isolette. The transport physician, one of my supervising third year pediatrics residents during my rotation the past month, told me that Ryan was more than likely going to require ECMO. I knew enough about ECMO at that time to know that I should be scared! The next 4 days were some of the most difficult moments I have ever experienced as a parent, watching the blood being pumped out of my tiny son’s body through the membrane oxygenator and roller pump, slowly back into his body (Figs. 1 and 2). I remember the fear of each

Fig. 1 xi

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Preface to the First Edition

Fig. 2

day when we would be told of the results of his daily head ultrasound, looking for evidence of intracranial hemorrhage, and then the relief when we were told that there was no bleeding. I remember the hope and excitement on the day Ryan came off ECMO, as well as the concern when he had to be sent home on supplemental oxygen. Today, Ryan is happy, healthy, and strong. We are thankful to all the doctors, nurses, respiratory therapists, and ECMO specialists who cared for Ryan and made him well. We still keep in touch with many of them. Without the technological advances and medical breakthroughs made in the fields of neonatal intensive care and pediatric critical care medicine, things very well could have been much different. I made a promise to myself long ago that I would dedicate the rest of my professional career to advancing the field of pediatric critical care medicine as payment for the gifts that we, my wife and I, have been truly blessed. It is my sincere hope that this textbook, which has truly been a labor of joy, will educate a whole new generation of critical care professionals, and in so-doing help make that first step towards keeping my promise. Cincinnati, OH, USA

Derek S. Wheeler, MD, MMM

Acknowledgements

With any such undertaking, there are people along the way who, save for their dedication, inspiration, and assistance, a project such as this would never be completed. I am personally indebted to Michael D. Sova, our Developmental Editor, who has been a true blessing. He has kept this project going the entire way and has been an incredible help to me personally throughout the completion of this textbook. There were days when I thought that we would never finish – and he was always there to lift my spirits and keep me focused on the task at hand. I will be forever grateful to him. I am also grateful for the continued assistance of Grant Weston at Springer. Grant has been with me since the very beginning of the first edition of this textbook. He has been a tremendous advocate for our specialty, as well as a great mentor and friend. I would be remiss if I did not thank Brenda Robb for her clerical and administrative assistance during the completion of this project. Juggling my schedule and keeping me on time during this whole process was not easy! I have been extremely fortunate throughout my career to have had incredible mentors, including Jim Lemons, Brad Poss, Hector Wong, and Tom Shanley. All four are gifted and dedicated clinicians and remain passionate advocates for critically ill children, the specialties of neonatology and pediatric critical care medicine, and me! I want to personally thank both Hector and Tom for serving again as Associate Editors for the second edition of this textbook. Their guidance and advice has been immeasurable. I have been truly fortunate to work with an outstanding group of contributors. All of them are my colleagues and many have been my friends for several years. It goes without saying that writing textbook chapters is a difficult and arduous task that often comes without a lot of benefits. Their expertise and dedication to our specialty and to the care of critically ill children have made this project possible. The textbook you now hold in your hands is truly their gift to the future of our specialty. I would also like to acknowledge the spouses and families of our contributors – participating in a project such as this takes a lot of time and energy (most of which occurs outside of the hospital!). Last, but certainly not least, I would like to especially thank my family – my wife Cathy, who has been my best friend and companion, number one advocate, and sounding board for the last 22 years, as well as my four children – Ryan, Katie, Maggie, and Molly, to whom I dedicate this textbook and all that I do.

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Contents

Part I

The Gastrointestinal System in Critical Illness and Injury Derek S. Wheeler

1

Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brent Whittaker, Priya Prabhakaran, and Ujjal Poddar

3

2

Liver Failure in Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ann E. Thompson

13

3

Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raffaele Pezzilli

29

4

Abdominal Compartment Syndrome in Children . . . . . . . . . . . . . . . . . . . . . . . Ori Attias and Gad Bar-Joseph

39

5

Obesity in Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael Hobson and Jennifer Kaplan

57

6

Nutrition in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nilesh Mehta

69

Part II

The Endocrine System in Critical Illness and Injury Jefferson P. Piva

7

Diabetic Ketoacidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jefferson P. Piva, Pedro Celiny Ramos Garcia, and Ricardo Garcia Branco

8

Hyperglycemia, Dysglycemia and Glycemic Control in Pediatric Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael S.D. Agus, Edward Vincent S. Faustino, and Mark R. Rigby

83

93

9

Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bettina von Dessauer and Derek S. Wheeler

103

10

The Adrenal Glands in Critical Illness and Injury. . . . . . . . . . . . . . . . . . . . . . . Kusum Menon

109

11

Thyroid and Growth Hormone Axes Alteration in the Critically Ill Child . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ricardo Garcia Branco, Pedro Celiny Ramos Garcia, and Jefferson P. Piva

Part III

12

119

The Renal System in Critical Illness and Injury James D. Fortenberry

Applied Renal Physiology in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ravi S. Samraj and Rajit K. Basu

129

xv

xvi

Contents

13

Electrolyte Disorders in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gabriel J. Hauser and Aaron F. Kulick

147

14

Acid-Base Disorders in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James D. Fortenberry, Kiran Hebbar, and Derek S. Wheeler

173

15

Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rajit K. Basu

191

16

Kidney Disorders in the PICU: Thrombotic Microangiopathies and Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lyndsay A. Harshman, Patrick D. Brophy, and Carla M. Nester

213

17

Kidney Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maria José Santiago Lozano, Jesús López-Herce Cid, and Andrés Alcaraz Romero

233

18

Renal Replacement Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sue S. Sreedhar, Timothy E. Bunchman, and Norma J. Maxvold

241

Part IV

The Hematologic System in Critical Illness and Injury Jacques Lacroix

19

Transfusion Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marisa Tucci, Jacques Lacroix, France Gauvin, Baruch Toledano, and Nancy Robitaille

259

20

Hematologic Emergencies in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Martin C.J. Kneyber

287

21

Coagulation Disorders in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geoffrey M. Fleming and Gail M. Annich

297

22

Therapeutic Apheresis in the Pediatric Intensive Care Unit . . . . . . . . . . . . . . . Stuart L. Goldstein

319

23

Thromboembolic Disorders in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ranjit S. Chima, Dawn Pinchasik, and Cristina Tarango

327

Part V

Oncologic Disorders in the PICU Robert F. Tamburro Jr.

24

Care of the Oncology Patient in the PICU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert J. Greiner, Stacey Peterson-Carmichael, Jennifer A. Rothman, Kenneth W. Gow, Robert F. Tamburro Jr., and Raymond Barfield

343

25

Critical Illness as a Result of Anti-Neoplastic Therapy . . . . . . . . . . . . . . . . . . . Robert J. Greiner, Kevin M. Mulieri, Robert F. Tamburro Jr., and Raymond Barfield

363

26

Hemophagocytic Lymphohistiocytosis Syndromes. . . . . . . . . . . . . . . . . . . . . . . Stephen W. Standage and Alexandra H. Filipovich

385

27

Hematopoietic Stem Cell Transplantation in the PICU . . . . . . . . . . . . . . . . . . . Shilpa K. Shah, Sonata Jodele, Stella M. Davies, and Ranjit S. Chima

395

Contents

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Part VI

The Immune System in Critical Illness and Injury Derek S. Wheeler

28

The Immune System in Critical Illness and Injury . . . . . . . . . . . . . . . . . . . . . . Jessica G. Moreland

421

29

Primary and Secondary Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . Rajesh K. Aneja and Alexandre T. Rotta

431

30

Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James L. Wynn, Jan A. Hazelzet, Thomas P. Shanley, Hector R. Wong, and Derek S. Wheeler

453

31

Thrombocytopenia-Associated Multiple Organ Failure Syndrome . . . . . . . . . Trung C. Nguyen, Yong Y. Han, James D. Fortenberry, Zhou Zhou, Miguel A. Cruz, and Joseph A. Carcillo Jr.

481

32

Toxic Shock Syndrome in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yu-Yu Chuang and Yhu-Chering Huang

493

33

Hospital-Acquired Infections and the Pediatric Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Erin Parrish Reade, Gregory A. Talbott, and Mark E. Rowin

509

34

Anaphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shilpa K. Shah and Erika L. Stalets

531

35

Rheumatologic Disorders in the PICU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steven W. Martin and Michael R. Anderson

543

36

Infectious Disease-Associated Syndromes in the PICU . . . . . . . . . . . . . . . . . . . Isaac Lazar and Clifford W. Bogue

567

37

Life Threatening Tropical Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gabriela I. Botez and Lesley Doughty

577

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

607

Contributors

Michael S.D. Agus, MD Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Michael R. Anderson, MD, FAAP University Hospitals Case Medical Center, Cleveland, OH, USA Rajesh K. Aneja, MD Critical Care Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Gail M. Annich, MD Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, Ann Arbor, MI, USA Ori Attias, MD Pediatric Intensive Care Unit, Meyer Children’s Hospital, Rambam Medical Center, Haifa, Israel Raymond Barfield, MD, PhD Department of Pediatric Hematology/Oncology, Duke University, Durham, NC, USA Gad Bar-Joseph, MD Department of Pediatric Intensive Care, Meyer Children’s Hospital, Rambam Medical Center, Haifa, Israel Rajit K. Basu, MD Pediatric Critical Care, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA Clifford W. Bogue, MD Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA Gabriela I. Botez, MD Department of Pediatric Cardiology, University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada Ricardo Garcia Branco, MD, PhD Department of Pediatric Intensive Care Unit, Addenbrookes Hospital, Cambridge, Cambridgeshire, UK Patrick D. Brophy, MD Department of Pediatrics, University of Iowa Children’s Hospital, Iowa City, IA, USA Timothy E. Bunchman, MD Department of Pediatric Nephrology, Children’s Hospital of Richmond, Viriginia Commonwealth University School of Medicine, Richmond, VA, USA Joseph A. Carcillo Jr., MD Pediatric Intensive Care Unit, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Ranjit S. Chima, MD Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinatti, OH, USA Yu-Yu Chuang, MD Department of Pediatrics, St. Mary’s Hospital, Luodong, Luodong, Yilan, Taiwan

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Jesús López-Herce Cid, MD PhD Pediatric Critical Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain Miguel A. Cruz, PhD Medicine/Cardiovascular Research Section, Houston, TX, USA Stella M. Davies, MBBS, PhD Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Lesley Doughty, MD Department of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Edward Vincent S. Faustino, MD Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA Alexandra H. Filipovich, MD Cancer and Blood Diseases Institute/ Bone Marrow Transplantation, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Geoffrey M. Fleming, MD Division of Critical Care Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA James D. Fortenberry, MD, MCCM, FAAP Department of Pediatric Critical Care, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, USA Pedro Celiny Ramos Garcia, MD, PhD Pediatric Department, Hospital São Lucas da PUCRS, Porto Alegre, RS, Brazil Pediatric Intensive Care Unit, H. São Lucas da PUCRS, Porto Alegre, RS, Brazil Department of Pediatrics, School of Medicine, Pontificia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil France Gauvin, MD, FRCPC, MSc Division of Pediatric Critical Care Medicine, Department of Pediatrics, Faculté de Médecine, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada Stuart L. Goldstein, MD Department of Pediatrics, Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Kenneth W. Gow, MSc, MD, FRCSC, FACS Department of General and Thoracic Surgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA Robert J. Greiner, MD Division of Hematology/Oncology, Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA, USA Yong Y. Han, MD Department of Critical Care Medicine, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Lyndsay A. Harshman, MD Department of Pediatrics, University of Iowa Children’s Hospital, Iowa City, IA, USA Gabriel J. Hauser, MD, MBA Pediatrics, Pharmacology and Physiology, Department of Pediatrics, Critical Care and Pulmonary Medicine, Medstar Georgetown University Hospital, Washington, DC, USA Jan A. Hazelzet, MD, PhD Department of Pediatrics, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands Kiran Hebbar, MD, FCCM, FAAP Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Contributors

Contributors

xxi

Michael Hobson, MD Division of Critical Care Medicine, Pediatric Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Yhu-Chering Huang, MD, PhD Department of Pediatrics, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan Sonata Jodele, MD Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Jennifer Kaplan, MD, MS Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Martin C.J. Kneyber, MD, PhD Division of Paediatric Intensive Care, Department of Paediatrics, Beatrix Children’s Hospital, University Medical Centre Groningen, The University of Groningen, Groningen, The Netherlands Aaron F. Kulick, MD Nephrology and Endocrinology, Pittsburgh, PA, USA Jacques Lacroix, MD Department of Pediatrics, Sainte-Justine Hospital, Montreal, QC, Canada Isaac Lazar, MD Pediatric Intensive Care Unit, Soroka Medical Center, Beer Sheva, Israel Maria José Santiago Lozano, MD, PhD Pediatric Critical Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain Steven W. Martin, MD Department of Pediatrics, Sparrow Hospital Children’s Center, Lansing, MI, USA Norma J. Maxvold, MD Department of Pediatrics Critical Care Medicine, Children’s Hospital of Richmond, Richmond, VA, USA Nilesh Mehta, MD Department of Critical Care Medicine, Children’s Hospital Boston, Boston, MA, USA Department of Anesthesia, Harvard Medical School, Boston, MA, USA Kusum Menon, MD, MSc Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada Jessica G. Moreland, MD Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA Kevin M. Mulieri, BS, Pharm. D. Pharmacy Department, Penn State Hershey Medical Center, Hershey, PA, USA Carla M. Nester, MD Department of Internal Medicine and Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Trung C. Nguyen, MD Department of Pediatrics, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX, USA Stacey Peterson-Carmichael, MD Divisions of Pediatric Critical Care and Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA Raffaele Pezzilli, MD Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi, Bologna, Italy Dawn Pinchasik, MD Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

xxii

Jefferson P. Piva, MD, PhD Pediatric Emergency and Critical Care Department, Hospital de Clinicas de Porto Alegre-Brazil, Porto Alegre (RS), Brazil Department of Pediatrics, School of Medicine, Universidade Federal do Rio Grande do Sul (UFGRS), Rua Ramiro Barcelos, Porto Alegre (RS), Brazil Ujjal Poddar, MD Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Priya Prabhakaran, MD Department of Pediatrics, Section of Critical Care, Children’s of Alabama, Birmingham, AL, USA Erin Parrish Reade, MD, MPH Division of Critical Care, Department of Pediatrics, University of Tennessee College of Medicine-Chattanooga, Children’s Hospital at Erlanger, Chattanooga, TN, USA Mark R. Rigby, MD, PhD, FAAP, FCCM Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, IN, USA Nancy Robitaille, MD, FRCPC Division of Hematology-Oncology, Department of Pediatrics, Faculté de Médecine, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada Andrés Alcaraz Romero, MD, PhD Pediatric Critical Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain Jennifer A. Rothman, MD Department of Pediatrics, Duke University Medical Center, Durham, NC, USA Alexandre T. Rotta, MD, FCCM, FAAP Department of Pediatrics, Riley Hospital for Children at Indiana University Health, Cleveland, OH, USA Mark E. Rowin, MD Department of Pediatrics, Children’s Hospital at Erlanger, Chattanooga, TN, USA Ravi S. Samraj, MD Department of Pediatric Critical Care, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA Shilpa K. Shah, DO Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Thomas P. Shanley, MD Michigan Institute for Clinical and Health Research, University of Michigan Medical School, Ann Arbor, MI, USA Sue S. Sreedhar, MD Department of Pediatric Intensive Care Unit, Virginia Commonwealth University, Children’s Hospital of Richmond, Richmond, VA, USA Erika L. Stalets, MD Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Stephen W. Standage, MD Pediatric Critical Care Medicine, Center for Lung Biology Seattle Children’s Hospital and University of Washington School of Medicine, Seattle, WA, USA Gregory A. Talbott, MD Department of Pediatrics, Children’s Hospital at Erlanger, Chattanooga, TN, USA Robert F. Tamburro Jr., MD, MSc Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA, USA Cristina Tarango, MD Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Contributors

Contributors

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Ann E. Thompson, MD, MHCPM Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Baruch Toledano, MD, FRCPC, MSc Division of Pediatric Critical Care Medicine, Department of Pediatrics, Faculté de Médecine, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada Marisa Tucci, MD Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, QC, Canada Bettina von Dessauer, MD, MSc Pediatric Intensive Care Unit, Roberto del Río, Santiago, Chile Derek S. Wheeler, MD, MMM Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Brent Whittaker, MD Department of Pediatrics, Section of Critical Care, Spectrum Health, Grand Rapids, MI, USA Hector R. Wong, MD Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA James L. Wynn, MD Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA Zhou Zhou, MD, PhD State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

Part I The Gastrointestinal System in Critical Illness and Injury Derek S. Wheeler

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Gastrointestinal Bleeding Brent Whittaker, Priya Prabhakaran, and Ujjal Poddar

Abstract

Gastrointestinal hemorrhage requiring admission to the intensive care unit is uncommon. An understanding of the etiologies of upper and lower gastrointestinal bleeding, many of which have a specific predilection to occur at certain ages, is crucial in using diagnostic techniques efficiently. The management of gastrointestinal hemorrhage should begin with a rapid but thorough assessment of the child’s hemodynamic stability and amount of blood loss. Restoration of hemodynamic stability with volume expansion and appropriate use of blood products is the initial goal of therapy followed by measures to specifically localize and manage the bleeding. A multidisciplinary team approach including gastroenterologists and surgeons is essential in the treatment of these children. Endoscopy of both the upper and lower gastrointestinal tract are useful diagnostic and potentially therapeutic tools that should be performed in select cases after hemodynamic stability has been achieved. Critically ill children often have risk factors that make them prone to developing stress ulcers which can cause significant bleeding, and high-risk groups will benefit from acid-suppressive therapy with histamine receptor antagonists and/or proton pump inhibitors. Keywords

Gastrointestinal bleeding • Endoscopy • Stress ulcer

Introduction Gastrointestinal (GI) bleeding can run the spectrum from a positive test for occult blood to life threatening hemorrhage. As such, GI bleeding can be challenging to manage. The B. Whittaker, MD (*) Department of Pediatrics, Section of Critical Care, Spectrum Health, 100 Michigan St Ne, Grand Rapids, MI 49503, USA e-mail: [email protected] P. Prabhakaran, MD (*) Department of Pediatrics, Section of Critical Care, Children’s of Alabama, 102, CPPI Building, 1600, 7th Avenue South, Birmingham, AL 35233, USA e-mail: [email protected] U. Poddar, MD Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh 226014, India e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_1, © Springer-Verlag London 2014

incidence of GI bleeding in a recent population-based survey of the frequency of upper gastrointestinal bleeding (UGIB) in children from 2 months to 16 years of age was 1–2 per 10,000 children annually. In another study of over 40,000 visits to the pediatric emergency department (ED), 0.3 % of all children presented with rectal bleeding [1]. Although the incidence of clinically significant GI bleeding is low, it requires urgent evaluation and management. GI bleeding is more often present than appreciated in critically ill patients admitted to the pediatric intensive care unit (PICU). A study of patients transferred to the PICU demonstrated the prevalence of GI bleeding to be 17 % (194/1,114). Half of these cases of GI bleeding were acquired in the PICU. Most importantly, of the patients who acquired bleeding while in the PICU, 16 % had clinically significant bleeding [2]. Given the large volume of the GI tract, significant internal bleeding can occur prior to clinical presentation. This makes it imperative to keep a high index of suspicion for ongoing 3

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bleeding and a close watch on vital signs with serial examinations. Fortunately, the majority of these hemorrhages are not severe and do not require admission to the intensive care unit [3]. The incidence of GI bleeding has not been found to have any relationship to age, sex, or race [4]. Shock, prolonged surgery, and trauma have been identified as risk factors for clinically significant GI bleeding [5]. Coagulopathy, acute respiratory failure, and Pediatric Risk of Mortality Score (PRISM) greater than ten have also been found to be risk factors for severe UGIB. Children with clinically significant UGIB have an increased risk of mortality and prolonged PICU stay with attendant higher cost [5].

B. Whittaker et al. Table 1.1 Hematemesis: well appearing or ill appearing patient Age Neonate/ infant

Childrenadolescents

Well appearing Swallowed maternal blood, hemorrhagic disease of the newborn, immune mediated thrombocytopenia, milk protein allergy, clotting factor deficiency Epistaxis, Mallory-Weiss, gastritis, peptic ulcer, variceal bleeding due to Extra Hepatic Portal Venous Obstruction(EHPVO), caustic ingestion

Critically ill appearing Stress ulcer, sepsis, DIC

Sepsis, DIC, variceal bleeding from liver disease, stress ulcers

Definitions

Table 1.2 Melena or hematochezia: well appearing or ill appearing patient

Several definitions of GI bleeding are used in the medical literature. Upper GI bleeding (UGIB) is typically defined as bleeding arising proximal to the ligament of Treitz, near the end of the duodenum, while lower GI bleeding (LGIB) is typically defined as bleeding from a site distal to the ligament of Treitz, which includes the remainder of the small intestine, colon, and rectum [6]. Hematemesis is defined as the presence of bright red or coffee ground material in emesis. Melena is defined as the presence of dark, tarry black stools formed from the breakdown of blood in the GI tract. Hematochezia is defined as bright red or maroon colored blood per rectum. Hematemesis and melena are usually associated with UGIB, while hematochezia is typically a manifestation of LGIB. Hematochezia could represent brisk UGIB in up to 12 % of cases [7]. However, as a general dictum, the higher in the gastrointestinal tract the origin of the bleed is, the darker the stool.

Age Neonate/ infant

Well appearing Anal fissure, swallowed maternal blood, vascular malformation

Toddler

Meckel’s diverticulum, polyps, vascular malformation, fissures intestinal duplications Polyps, vascular malformations, meckel’s diverticulum, hemorrhoids

Etiology The diagnostic approach to the evaluation of GI bleeding in children should be targeted to the most likely causes in each age group. It is also useful to classify these children based upon presentation into typically well appearing or ill appearing (Tables 1.1 and 1.2).

Specific Causes of UGIB Hemorrhagic Disease of the Newborn Neonates have low stores of vitamin K. Breast milk is low in vitamin K, and the contribution of gut flora to vitamin K production is not present at birth. Therefore the levels of the vitamin K dependent clotting factors can be low, and patients can present with bleeding, including severe GI bleeding. In the United States, vitamin K supplementation is routine in

Childrenadolescents

Ill appearing Necrotizing Enterocolitis(NEC), Sepsis, Disseminated Intravascular Coagulation(DIC), ischemic bowel, malrotation with volvulus, Hirschsprungs enterocolitis Intussusception, volvulus, small bowel obstruction, infectious diarrhea

Henoch Schonlein Purpura (HSP), Hemolytic Uremic Syndrome (HUS), Sepsis, DIC

newborns, but parental refusal or delivery at home could result in no supplementation. Classic hemorrhagic disease of the newborn occurs between day 1 and 14, while the late variety presents between 2 and 12 weeks of life. Other causes of Vitamin K deficiency include maternal medication use (phenobarbital, phenytoin, or warfarin) [8], prolonged diarrhea, malabsorption, and antibiotic therapy. A prolongation of the Prothrombin Time (PT) which corrects with the administration of vitamin K is diagnostic. Lack of response to Vitamin K should prompt work-up for inherited disorders of coagulation.

Coagulation Disorders Coagulation defects, inherited or acquired, are significant risk factors for GI bleeding. Patients with severe hemophilia type A or B have a lifetime risk of GI bleeding between 10 and 25 %, usually associated with gastric disease [9]. Patients with less severe hemophilia (mild, moderate or carrier) do not seem to share this risk. Disseminated intravascular coagulation (DIC) and liver failure are common acquired causes of coagulopathy in critically ill children.

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Peptic or Esophageal Ulcerations Ulcerations are not an uncommon cause of UGIB. One study identified gastric lesions in 83 % of full term infants undergoing Esophago Gastro Duodenoscopy (EGD) for evaluation of upper GI bleeding [10]. One of the major risk factors for GI bleeding due to peptic or esophageal ulcerations among children is exposure to non-steroidal anti-inflammatory drugs (NSAIDs) [11]. NSAIDs inhibit cyclooxygenase, which is vital in the synthesis of gastroprotective prostaglandins. Viral infections, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and adenovirus can cause severe esophagitis with ulceration in immune-suppressed children. Candida esophagitis is also an important cause of UGI bleeding in immunocompromised hosts, and may also be an adverse effect of acid suppressive therapy [12, 13]. Identification of candida esophagitis beyond infancy should prompt an immune work up. Helicobacter pylori is frequently associated with peptic ulcers [11] and may have some influence in critical illness. It is now standard of care to treat H. pylori infections with triple therapy including Amoxicillin, Clarithromycin and a proton-pump inhibitor (PPI) for 1–2 weeks.

5 Table 1.3 Infectious causes of GI bleeding Viruses (rotavirus) Shigella E. Coli Salmonella Yersinia Giardia C Difficile

thrive should raise the suspicion for Inflammatory Bowel Disease (IBD), such as Crohn’s or Ulcerative Colitis, or may indicate an allergic colitis. Workup of suspected infectious diarrhea should include stool cultures, and evaluation for ova and parasites.

Juvenile Polyps Juvenile polyps are a common cause of LGIB in children. The prevalence of these hamartomatous lesions is at least 1 in 15 patients undergoing colonoscopy for a variety of indications [18]. In addition to juvenile polyps, children can also have polyps secondary to inherited polyposis syndromes such as Gardner syndrome and Peutz-Jeghers syndrome.

Mallory-Weiss Tears Mallory-Weiss tears are shallow, horizontal tears in the esophagus, usually near the gastroesophageal junction and are caused by forceful and/or or recurrent emesis. Presenting symptoms include vomiting, hematemesis, and abdominal pain or painful swallowing. While not commonly seen in children, Mallory-Weiss tears can be seen in up to 13 % of pediatric patients being evaluated for upper GI bleeding [14].

Variceal Bleeding Increased resistance to blood flow through the hepatic portal system increases blood flow through alternative vessels. These vessels include those in the esophagus, stomach and ano-rectal areas, leading to varices, which are exposed to higher flow and higher pressures than is normal. Resistance to flow can be caused by intrinsic liver disease leading to cirrhosis, or obstruction such as portal vein thrombosis [15]. Due to the higher pressure and thin walls, these vessels can bleed profusely. In addition, varices are at a high risk of rebleeding, even after sclerotherapy. Patients can have up to 9 % rebleeding rate at 3 years and 31 % rebleeding rate at 9 years [16, 17].

Henoch Schonlein Purpura (HSP) HSP is a vasculitic disorder that usually presents with palpable purpura, usually of the lower extremities. Gastrointestinal vasculitis can present with severe abdominal pain, intussusception, and LGIB. In a study of 208 in patients with HSP only five children had LGIB that required a transfusion, while stool tested positive for occult blood in a significantly greater number of children [19].

Meckels Diverticulum Meckel’s diverticulum is a remnant of the omphalomesenteric duct during the development of the gastrointestinal system, which may contain heterotopic gastric mucosa. Meckel’s diverticulum can be found in 2 % of the general population and is often asymptomatic. Most patients with symptomatic meckel’s diverticulum tend to be males under the age of 2 years. Although it is more common in the pediatric population than in the adult population, it is still an infrequent cause of LGIB in the pediatric population (4 %) [20]. The LGIB that occurs in children with Meckels diverticulum can be profuse and is typically painless. Identification of a Meckels diverticulum is radiologically confirmed [20].

Specific Causes of LGIB

Intussusception

Blood in the stool in the context of diarrhea is concerning for an infectious or inflammatory etiology. An acute onset of diarrhea is suspicious for an infectious etiology (Table 1.3). Chronic diarrhea associated with weight loss or failure to

Intussusception is the most common cause of bowel obstruction in children, with a rate of 56 per 100,000 per year in the US. It has a peak incidence between ages 5 and 10 months, but is rarely seen in adults. The classic symptoms include severe, episodic abdominal pain, vomiting and bloody (currant jelly)

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stools [21, 22]. Many of the symptoms are non-specific which can lead to an incorrect initial diagnosis [22].

B. Whittaker et al.

Management of GI Bleeding Initial Management and Evaluation

Stress ulcers and their prevention The gastric milieu is acidic to facilitate the action of proteolytic enzymes, which begin the digestion of food. The proteolytic activity of pepsin is greatest in an acidic environment, and activity is negligible at a neutral pH [23]. Even in a healthy population, the barrier between the gastric mucosa and the environment sometimes fails, resulting in peptic ulcers, gastritis, pain, and bleeding. In the critically ill patient, the gastric mucosa is exposed to ischemic challenges as well. The resultant breach of the protective barrier causes the digestive enzymes and acid to directly injure the gastric tissue. This is the postulated pathway for the development of stress ulcers. The most common risk factors that have been found to be consistently associated with the development of stress ulcers in the ICU are mechanical ventilation, anticoagulation, multi-organ failure, and head injury. Histaminereceptor blockers (H2 Blockers) and Proton Pump Inhibitors (PPI’s) are frequently used for stress ulcers prophylaxis. The acidic nature of the stomach plays a vital role in the defense of the body against pathogens and so there is some concern about the risks of modifying gastric pH in the critically ill patient. Raising the gastric pH may increase the risk of pneumonia in the mechanically ventilated patient (ventilator-associated pneumonia, or VAP). There is some literature that suggests that this may also increase the risk of acquiring infections due to Clostridium difficile [24]. Hence, while H2 blockers and PPIs are safe, well tolerated, and decrease the incidence of stress ulcers in the critically ill population, their use is not entirely without risk. Additionally, early introduction of enteral feeds [25] has been found to be protective against stress ulcer development. While continuous enteral feeding does increase the gastric pH, it may also increase the risk of infection in critically ill patients [26]. For example, a recent meta-analysis showed higher hospital mortality for critically ill adults who were fed enterally and received an H2 blocker [27]. Proton pump inhibitors are more effective in raising gastric pH than histamine – receptor blockers alone. In addition there may be some tachyphylaxis to parenteral histaminereceptor blockers, lowering their efficacy after the first few days. In mechanically ventilated patients, the highest risk of stress ulcers is in those children who require mechanical ventilation for longer than 48 h. There is literature that suggests that 60 % of mechanically ventilated patients who develop GI bleeding do so on the first day of mechanical ventilation [28], therefore, if stress ulcer prophylaxis is warranted, it should be started with the onset of mechanical ventilation.

The following questions should be answered in the child with possible GI bleeding after rapid assessment and stabilization of the patient. First, is it blood? Ingestion of dyes, berries, beets, licorice, iron, bismuth, charcoal or other foods can discolor the stool and mimic bleeding. Second, is it from the GI tract? Hematemesis, melena or hematochezia in the first 48–72 h of life may represent swallowed maternal blood. In breastfeeding patients, lesions in the breast or around the nipple also can be a source of maternal blood. The Apt test, which is used to confirm maternal origin of blood, is based on the ability of fetal hemoglobin to resist alkali denaturation [29]. Epistaxis and bleeding from the oral cavity can also masquerade as GI bleeding. After identifying that the patient does indeed have a GI bleed, the next step is to evaluate the magnitude of the blood loss. Determination of volume of blood loss is based on history, physical exam and laboratory evidence. A focused history and physical exam can give valuable clues concerning the etiology of the bleed and the severity of the bleed. The physical exam should be rapid with special concern for the vital signs and a rectal examination should be performed in all cases of suspected lower GI bleeds (Tables 1.4 and 1.5). Some general caveats can be helpful: • Blood streaking the outside of the stool may indicate minimal blood loss. • Frank melena is associated with blood loss of at least 2 % of the total blood volume [9]

Table 1.4 History in GI bleeding History Pain

Dysphagia/ odynophagia Emesis Epistaxis Medications or ingestions Breastfeeding Diarrhea/sick contacts Stooling pattern Dietary Umbilical vein catheter Weight

Conditions Severe, intermittent pain: intussusception or bowel obstruction Painless: meckels, polyp, vascular malformation Esophagitis-pill, peptic or infectious Mallory-Weiss tears Source of bleeding, or coagulopathy NSAIDs, steroids (peptic ulcers) Aspirin or warfarin Foreign bodies, ingestions of caustic substances Ingested maternal blood Infectious diarrhea IBD Acholic stool-biliary atresia with cirrhosis Lack of stools-Hirschsprung’s disease Milk protein allergy Extra hepatic portal vein obstruction (EHPVO) Chronic weight loss in adolescent-IBD

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Table 1.5 Physical exam Area Vitals General Eyes Nose Mouth

Abdomen

GU

Neuro Skin

Findings HR, BP Growth parameters Edema Icterus Pallor Epistaxis Perioral pigmentation/ freckling Thrush Trauma/recent tonsillar surgery Liver size or tendernessliver disease Splenomegaly, caput medusae Lower Quadrant masses/tenderness Ascites Hyperactive bowel sounds Skin tags Fissures Fistulas Mental status Petechiae Purpura Jaundice Telangiectasia/spider angiomas Abnormal bruising

Concerns for Hypovolemia Chronic GI bleeding Liver disease Bleeding/anemia Coagulopathy, may be source of blood Peutz-Jeghers syndrome Esophagitis May be oral bleeding Liver disease

(SVR) increases due to vasoconstriction caused by a surge in circulating catecholamines, extravascular fluid is mobilized to the intravascular space to maintain preload and blood volume, heart rate increases which improves cardiac output and fluid is retained due to the secretion of anti-diuretic hormone. Initial resuscitation with isotonic fluids should be followed with blood products as needed. Due to the marked decrease in oxygen carrying capacity due to anemia, administration of supplemental oxygen is beneficial. In emergencies, blood volume should be rapidly restored with O negative uncrossmatched blood. Caution must be exercised to avoid the temptation to over resuscitate, because it can increase the severity of bleeding, particularly if it variceal in origin by increasing pressure in the splanchnic circulation Coagulopathy or thrombocytopenia, these should be corrected promptly.

Portal hypertension Intussusception

Liver disease Upper GI bleed May be the source for bleeding Constipation Crohn’s disease Encephalopathy ITP, TTP HSP, DIC Liver disease Liver disease Coagulopathy or anticoagulant use

• Depending on the acuity of the loss, loss of up to 10–15 % of the blood volume may not be associated with any hemodynamic changes. • Fifteen to thirty percent blood loss causes tachycardia and increased systemic vascular resistance. • Acute losses of greater 30–40 % of total blood volume will cause hypotension [30]. In patients with chronic blood loss, compensation can maintain blood pressures with small fractions of normal hemoglobin levels. Prompt assessment and support of the airway and breathing should be followed by circulatory support if needed. Evaluation of heart rate, capillary refill, peripheral pulses, and temperature of the extremities, blood pressure, and mental status may help to identify compensated or uncompensated shock. It is prudent to remember that hypotension is a late sign of shock and hypovolemia in children because of their robust ability to compensate for acute volume loss. In the setting of an acute hemorrhage, several compensatory mechanisms are activated. Systemic vascular resistance

Placement of a Nasogastric (NG) Tube Analysis of the nasogastric aspirate is the traditionally accepted way of distinguishing between upper and lower gastrointestinal sources of bleeding, with frank blood or coffee ground aspirate being suggestive of UGIB. However, the lack of blood in an NG aspirate is neither sensitive nor specific. A negative NG aspirate does not preclude the necessity of upper endoscopy [31]. The presence of blood in the NG aspirate, or lack of clearing of the aspirate is predictive of high risk lesions (active bleeding or visible vessel) which may require endoscopic therapy, and improves endoscopic visualization [32]. NG insertion is generally a safe procedure, but is not without risk. Studies on adult patients have demonstrated a 0.3–2 % complication rate with pneumothorax being most common. Other complications are related to malpositioned tubes. Physical examination to confirm correct NG placement can be misleading and should be confirmed by additional techniques [33]. Although some practitioners feel that esophageal varices are a relative contraindication to the placement of an NG tube, there is data to support that it can be safely performed [34].

Laboratory Evaluation Initial laboratory evaluation of the patient with a significant GI bleed should include hemoglobin/hematocrit, platelet count, MCV, BUN/Creatinine measurement and coagulation studies. Other pertinent studies such as liver function tests should be obtained based on the clinical context. Laboratory tests may also give a few clues of the etiology of the bleeding, the severity of the bleeding, and the chronicity of the bleeding. Several studies have looked at the ratio of BUN/Creatinine in differentiating between an upper and lower GI bleeds in the pediatric population [35]. An elevated

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BUN/creatine ratio (greater than 30) is usually reflective of partial digestion of blood in the GI tract and is somewhat predictive of UGIB, although it can rarely be seen with LGIB.

Testing for Occult Blood These tests are based on the oxidation of alpha-guaiaconic acid to blue quinine by hydrogen peroxide. Hemoglobin has pseudo-peroxidase activity. The developer for the test contains hydrogen peroxide which, in the presence of hemoglobin, oxidizes the guaiac [36]. Several foods have peroxidase activity (horseradish, cauliflower, broccoli, and poorly cooked meat) and render the test falsely positive for occult blood. Alternatively, high doses of the anti-oxidant vitamin ascorbic acid can cause a false negative test by interfering with this reaction. Occult blood testing is also pH-dependent; pH 4. The dose of ranitidine is also age dependent: 1.5 mg/kg IV every 8 h in term babies to 1.5 mg/kg IV every 6 h in older children [48].

H-2 Blockers

Capsule Endoscopy One option that has gained increasing popularity recently is capsule endoscopy. A self contained camera is swallowed. It transmits images to a receiver, and makes it possible to evaluate the complete length of the intestines. Capsule endoscopy is frequently able to identify lesions [44]. In the best case, they are a minimally invasive, low risk option to identify lesions. In some cases they can replace the need for an EGD, but do not have any therapeutic interventions. In some smaller children, usually between the ages of 3 and 6, the children are unable or unwilling to swallow the capsule which necessitates an EGD for placement either in the stomach or the duodenum. The major risk of the procedure is retained capsule, which could necessitate surgical intervention.

Medical Therapy The majority of all GI bleeding will stop spontaneously without intervention. However, medical management of GI bleeding may be required.

Proton Pump Inhibitors (PPI) The use of acid suppressive medications is justified by the preponderance of peptic causes of UGIB. Omeprazole is frequently administered for this purpose. The metabolism of omeprazole is age-dependent, with low rates in infants less than 10 days of age, and increased metabolism between 1 and 6 years of age [45]. The dosing varies from 1 mg/kg IV once daily to 40 mg/1.73 m2 daily to maintain gastric pH >4 [46]. Adult studies have shown that the combination of bolus

Vasoactive Drugs Early administration of vasoactive therapy prior to endoscopy is recommended for variceal bleeding in children. The Somatostatin analogue Octreotide is used in the treatment of UGI bleeding from varices in children with portal hypertension. It inhibits gastric acid secretion and diminishes splanchnic and azygous blood flow. Infused at 1–2 mcg/kg/h, it stopped UGI bleeding in 71 % of children with portal hypertension in one study; rebleeding after the infusion was discontinued occurred in 50 % of children with portal hypertension [49]. Cramps, nausea, and hyperglycemia are some of the side effects of octreotide. Vasopressin and somatostatin have also been used in the medical management of UGI bleeding. Sucralfate Although the mechanism of action is not totally understood, sucralfate is thought to form a protective barrier when exposed to an acidic environment which is protective for the gastric mucosa. Although there is no data on the addition of sucralfate to a PPI, the combination may be less effective than either medication alone because sucralfate requires an acidic pH to form the protective gel, although this is unproven [50]. Recombinant Activated Factor 7 FDA approved for use in hemophilia, recombinant Factor VIIa is being used for treatment of severe bleeding in other contexts. Factor VII is part of the extrinsic pathway in coagulation. After binding with tissue factor, it can directly activate factor 10, bypassing the intrinsic pathway. It has also been effective in patients with liver disease and GI bleeding. A dose of 90 mcg/kg every 2 h has been used [51]. In addition to the expense of this medication, and the extremely short half-life of only 2–4 h, side effects include thrombosis [52]. The administration of rFVIIa decreases the PT, but there are no established laboratory parameters to guide treatment, and treatment needs to be monitored clinically. As it is off-label use, treatment of GI bleeding with rFVIIa should be after failure of standard therapy [53].

Antibiotic Therapy Antibiotic treatment of infectious diarrhea should be carefully considered. The treatment of E. Coli O157 H7 can

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increase the risk of Hemolytic Uremic Syndrome (HUS) [54] and indiscriminate use of antibiotics may increase the risk of C. difficile colitis and prolonged shedding for salmonella. Absolute indications for the treatment of infectious diarrhea include children with immune compromise, a known etiology that requires treatment (Shigella or C.difficile), or critical illness.

Beta-blockers may be considered for prophylaxis against rebleeding in children with a prior variceal bleed. The benefits of this therapy should be weighed against the risks of beta blockade in the event of bleeding, The inability to mount appropriate tachycardia may lead to poor and delayed recognition of hemodynamic compromise and may interfere with the child’s ability to compensate for hypovolemia in general.

Surgical Therapy

Transjugular Intrahepatic Porto Systemic Shunt

In severe cases of GI bleeding, a surgical consult should be obtained. Massive ongoing blood loss, bleeding Meckels diverticulum, volvulus, malrotation with obstruction, or bowel perforation may be some indications for surgery.

Management of Variceal Bleeding The initial management of variceal bleeding is similar to the therapy of non-variceal UGI bleeding. Vasoactive medications should be started before endoscopy. Endoscopy can be performed safely in children by experienced operators [55]. Endoscopy is mandatory in cases of severe bleeding requiring transfusion or unexplained, recurrent bleeding [56]. While there are no randomized controlled trials addressing the timing of endoscopy in pediatric variceal bleeding, endoscopy should be performed as early as possible after the child has been stabilized. Prophylaxis against intestinal flora with a third-generation cephalosporin is recommended before endoscopy based on adult literature [57]. Endoscopic treatment of variceal bleeding includes endoscopic band ligation (EBL) or sclerothrerapy. A randomized controlled trial on 49 children with variceal bleeding showed that EBL achieved control of bleeding faster, with fewer complications and less rebleeding than sclerotherapy [58]. As an alternative, tissue adhesives like cyanoacrylate can also be injected endoscopically to control bleeding [59]. Sclerotherapy has been shown to be effective in eliminating varices and preventing subsequent bleeding in a RCT and some uncontrolled trials [60]. No survival benefit was detected and serious complications included bleeding prior to obliteration, esophageal perforation, and stricture formation [16, 17]. Balloon tamponade with a Sengstaken- Blakmore tube or a Foley catheter in infants may be used in the PICU setting for uncontrolled bleeding. In a retrospective study of 100 adult patients with variceal bleeding, the SB tube had an overall efficacy of 61 %. Tamponade was more likely to be successful without an increase in the risk of esophageal perforation if it had been preceded by sclerotherapy. Aspiration was the main complication [61]. Overall, inadequate pediatric evidence in the management of variceal bleeding leads to significant variability in the way physicians treat them [62].

For children with end stage liver disease and cirrhosis, one other option is the Transjugular intra-hepatic porto systemic shunt (TIPS) created between the portal vein and the hepatic vein. This can be used as a temporizing therapy prior to transplantation, or as a treatment in itself. The major benefit of the TIPS procedure is that it may replace a surgical shunt with its accompanying risks. The risks of the TIPS procedure include bleeding, and the shunting can cause encephalopathy if all blood bypasses the filtering effect of the liver [63, 64].

Summary and Recommendations 1. Clinically significant GI bleeding is rare in the pediatric population. 2. Initial treatment should focus on stabilization of the patient. 3. Focused physical examination and laboratory work up are essential after resuscitation. 4. Localization of the bleeding, with focused work-up while not always successful, is always beneficial. 5. Parenteral proton-pump inhibitors, H-2 blockers, and endoscopy are the mainstays of therapy of UGIB. 6. Supportive care and colonoscopy are important in managing LGIB. 7. Most bleeding, upper and lower, will resolve spontaneously.

References 1. Teach SJ, Fleisher GR. Rectal bleeding in the pediatric emergency department. Ann Emerg Med. 1994;23(6):1252. 2. Chaibou M, Tucci M, Dugas M, et al. Clinically significant upper gastrointestinal bleeding acquired in a pediatric intensive care unit: a prospective study. Pediatrics. 1998;102(4 Pt 1):933–8. 3. Peters JM. Management of gastrointestinal bleeding in children. Curr Treat Options Gastroenterol. 2002;5(5):399–413. 4. Cochran EB, Phelps SJ, Toiley EA, et al. Prevalence of, and risk factors for upper gastrointestinal bleeding in critically ill pediatric patients. Crit Care Med. 1992;20:1519–23. 5. Gauvin F, Dugas MA, Chaibou M, et al. The impact of clinically significant upper gastrointestinal bleeding acquired in a pediatric intensive care unit. Pediatr Crit Care Med. 2001;2:349–50.

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6. Meyers MA. Treitz redux: the ligament of Treitz revisited. Abdom Imaging. 1995;20(5):421–4. 7. Elta GH. Urgent colonoscopy for acute lower-GI bleeding. Gastrointest Endosc. 2004;59(3):402–8. 8. Stoll BJ. Blood disorders. In: Kliegman RM, Behrman RE, Jenson HG, et al., editors. Nelson’s textbook of pediatrics. Philadelphia: WB Saunders; 2007. p. 766–75. 9. Arain A, Rossi T. Gastrointestinal bleeding in children: an overview of conditions requiring nonoperative management. Semin Pediatr Surg. 1999;8(4):172–80. 10. Lazzaroni M, Petrillo M, Tornaghi R, et al. Upper GI bleeding in healthy full-term infants: a case-control study. Am J Gastroenterol. 2002;97(1):89–94. 11. Grimaldi-Bensouda L, Abenhaim L, Michaud L, et al. Clinical features and risk factors for upper gastrointestinal bleeding in children: a case-crossover study. Eur J Clin Pharmacol. 2010;66(8):831– 7. Epub 2010 May 16. 12. Goenka MK, Kochar R, Chakrabarti A, et al. Candida overgrowth after treatment of duodenal ulcer: a comparison of cimetidine, famotidine and omeprazole. J Clin Gastroenterol. 1996;23(1):7–10. 13. McBane RD, Gross Jr JB. Herpes esophagitis: clinical syndrome, endoscopic appearance and diagnosis in 23 patients. Gastrointest Endosc. 1991;37(6):600–3. 14. Bak-Romaniszyn L, Malecka-Panas E, Czkwianianc E, et al. Mallory-Weiss syndrome in children. Dis Esophagus. 1999;12(1): 65–7. 15. Maksoud-Filho JG, Gonçalves ME, Cardoso SR, et al. Long-term follow-up of children with extrahepatic portal vein obstruction: impact of an endoscopic sclerotherapy program on bleeding episodes, hepatic function, hypersplenism, and mortality. J Pediatr Surg. 2009;44(10):1877–83. 16. Howard ER, Stringer MD, Mowat AP. Assessment of injection sclerotherapy in the management of 152 children with esophageal varices. Br J Surg. 1988;155:404–8. 17. Stringer MD, Howard ER. Longterm outcome after injection scerotherapy for esophagal varices in children with extrahepatic portal hypertension. Gut. 1994;35(2):257–9. 18. Alsarraj A. Prevalence and determinants of colonic polyps in children undergoing colonoscopy: a large hospital-based cross-sectional study (January 1, 2009). Texas Medical Center Dissertations (via ProQuest). Paper AAI1470192 http://digitalcommons.library.tmc. edu/dissertations/AAI1470192. Accessed 17 Aug 2012. 19. Chen SY, Kong MS. Gastrointestinal manifestations and complications of Henoch-Schonlein purpura. Chang Gung Med J. 2004; 27:175–81. 20. Dolezal J, Vizda J. Experiences with detection of the ectopic gastric mucosa by means of Tc-99m pertechnetate disodium scintigraphy in children with lower gastrointestinal bleeding. Eur J Pediatr Surg. 2008;18:258–60. 21. Applegate K. Intussusception in children: imaging choices. Semin Roentgenol. 2008;43(1):15–21. 22. Beasley SW, Auldist AW, Stokes KB. The diagnostically difficult intussusception: its characteristics and consequences. Pediatr Surg Int. 1998;3:135–8. 23. Piper DW, Fenton BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut. 1965;5:506–8. 24. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243–5. 25. Raff T, Germann G, Hartmann B. The value of early enteral nutrition in the prophylaxis of stress ulceration in the severely burned patient. Burns. 1997;23(4):313–8. 26. Bonten MJ, Gaillard CA, Van Tiel FH. Continuous enteral feeding counteracts preventive measures for gastric colonization in intensive care unit patients. Crit Care Med. 1994;22(6):939–44.

11 27. Marik PE, Vasu T, Hirani A, et al. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010;38(11):2222–8. 28. Deerojanawong J, Peongsujarit D, Vivatvakin B, et al. Incidence and risk factors of upper gastrointestinal bleeding in mechanically ventilated children. Pediatr Crit Care Med. 2009;10(1):91–5. 29. Apt KL, Downey WS. Melena neonatorium: the swallowed blood syndrome. J Pediatr. 1955;47:6–9. 30. Bliss D, Silen M. Pediatric thoracic trauma. Crit Care Med. 2002;30(11 Suppl):S409–15. 31. Palamidessi N, Sinert R, Falzon L, et al. Nasogastric aspiration and lavage in emergency department patients with hematochezia or melena without hematemesis. Acad Emerg Med. 2010;17:126–32. 32. Aljebreen AM, Fallone CA, Barkun AN. Nasogastric aspirate predicts high-risk endoscopic lesions in patients with acute upper-GI bleeding. Gastrointest Endosc. 2004;59(2):172–8. 33. Pillai JB, Vegas A, Brister S. Thoracic complications of nasogastric tube: review of safe practice. Interact Cardiovasc Thorac Surg. 2005;4:429–33. 34. Ritter DM, Rettke SR, Hughes RW. Placement of nasogastric tubes and esophageal stethoscopes in patients with documented esophageal varices. Anesth Analg. 1998;67:283–5. 35. Felber S, Rosenthal P, Henton D. The BUN/creatinine ratio in localizing gastrointestinal bleeding in pediatric patients. J Pediatr Gastroenterol Nutr. 1988;7(5):685–7. 36. Chawla S, Seth D, Mahajan P, et al. Upper gastrointestinal bleeding in children. Clin Pediatr (Phila). 2007;46(1):16–21. 37. Long PC, Wilentz KV, Sudlow G, et al. Modification of the Hemoccult slide test for occult blood in gastric juice. Crit Care Med. 1982;10(10):692–3. 38. Daneman A, Navarro O. Intussusception part 2: an update on the evolution of management. Pediatr Radiol. 2004;34:97–108. 39. Padia SA, Bybel B, Newman JS. Radiologic diagnosis and management of acute lower gastrointestinal bleeding. Cleve Clin J Med. 2007;74(6):417–20. 40. Ford PV, Bartold SP, Fink-Bennett DM, et al. Procedure guideline for gastrointestinal bleeding and Meckel’s diverticulum scintigraphy. J Nucl Med. 1999;40(7):1226–32. 41. Loffroy R, Guiu B, Cercueil JP, et al. Refractory bleeding from gastroduodenal ulcers: arterial embolization in high-operative-risk patients. J Clin Gastroenterol. 2008;42(4):361–7. 42. Squires R, Colletti R. Indications for pediatric gastrointestinal endoscopy: a medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 1996;23(2):107–10. 43. Thomson M, Venkatesh K, Elmalik K, et al. Double balloon enteroscopy in children: diagnosis, treatment and safety. World J Gastroenterol. 2010;16:56–62. 44. Ge ZZ, Chen HY, Gao YJ, et al. Clinical application of wireless capsule endoscopy in pediatric patients for suspected small bowel diseases. Eur J Pediatr. 2007;166(8):825–9. Epub 2006 Nov 14. 45. Kearns GL, Winter HS. Proton pump inhibitors in pediatrics- relevant pharmacokinetics and pharmacodynamics. J Pediatr Gastroenterol Nutr. 2003;37(Supl 1):S52–9. 46. Lilatalien C, Theoret Y, Faure C. Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet. 2005;44:441–66. 47. Hung W, Li VKM, Chung C, et al. Randomized trial comparing pantoprazole infusion, bolus and no treatment on gastric pH and recurrent bleeding in peptic ulcers. ANZ J Surg. 2007;77: 677–81. 48. Faure C, Michaud L, Shaghaghi EK, et al. Lansoprazole in children: pharmacokinetics and efficacy in reflux esophagitis. Aliment Pharmacol Ther. 2001;15:1397–402. 49. Eroglu Y, Emerick KM, Whittingo PF, et al. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr. 2004;38:41–7.

12 50. Danesh B, Duncan A, Russell R. Is an acid pH medium required for the protective effect of sucralfate against mucosal injury? Am J Med. 1987;83(3B):11–3. 51. Mathew P. The use of rFVIIa in non-haemophilia bleeding conditions in paediatrics. Thromb Haemost. 2004;92(4):738–46. 52. Winkler M, Alten J, Benner K, et al. Pediatric off-label use of recombinant factor VIIa. Pediatrics. 2009;123:1066. 53. Vilstrup H, Markiewicz M, Biesma D, et al. Recombinant activated factor VII in an unselected series of cases with upper gastrointestinal bleeding. Thromb Res. 2006;118:595–601. 54. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolyticuremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342(26):1930–6. 55. Balsells F, Wyllie R, Kay M, et al. Use of conscious sedation for upper and lower gastrointestinal bleeding in children, adolescents and young adults: a twelve year review. Gastrointest Endosc. 1997;45:375–80. 56. Fox VL. Gastrointestinal bleeding in infants and children. Gastroenterol Clin North Am. 2000;29:37–66. 57. Schenider B, Emre S, Groszmann R, et al. Expert opinion on the report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. Pediatr Transplant. 2006;10:893–907. 58. Sokal EM, Van Hoorebeeck N, Van Obbergh L, et al. Upper gastrointestinal bleeding in cirrhotic children candidates of liver transplantation. Eur J Pediatr. 1992;151:326–8.

B. Whittaker et al. 59. Rivet C, Rovbles-Medranda C, Dumortier J, et al. Endoscopic treatment of gastroesophageal varices in young infants with cyanoacrylate glue: a pilot study. Gastrointest Endosc. 2009;69: 1034–8. 60. Maksoud-Filho J, Gonçalves M, Cardoso S, et al. Long-term follow-up of children with extrahepatic portal vein obstruction: impact of an endoscopic sclerotherapy program on bleeding episodes, hepatic function, hypersplenism, and mortality. J Pediatr Surg. 2009;44:1877–83 61. Pinto-Marques P, Romaozinto M, Ferreira M, et al. Esophageal perforation– associated risk with balloon tamponade after endoscopic therapy. Myth or reality? Hepatogastroenterology. 2006; 53(77):536–9. 62. Gana JC, Valentino PL, Morinville V, et al. Variation in care for children with esophageal varices: a study of physicians’, patients’, and families’ approaches and attitudes. J Pediatr Gastroenterol Nutr. 2011;52(6):751–5. 63. Heyman MB, LaBerge JM, Somberg KA, et al. Transjugular Intrahepatic Portosystemic Shunts (TIPS) in children. J Pediatr. 1997;131(6):914–9. 64. Heyman MB, LaBerge JM. Role of transjugular intrahepatic portosystemic shunt in the treatment of portal hypertension in pediatric patients. J Pediatr Gastroenterol Nutr. 1999; 29(3):240.

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Liver Failure in Infants and Children Ann E. Thompson

Abstract

Liver dysfunction is common in children requiring intensive care and is a common source of morbidity and mortality. Both primary disorders of the liver and complications of other underlying disorders may result in hepatic failure and life-threatening multisystem dysfunction. Slowly progressive liver disease may result from numerous disorders of infancy and childhood. The rate of progression and specific complications vary with the specific disorder, but most ultimately progress to cirrhosis and obstruction to portal venous blood flow, with variceal bleeding, intractable ascites, failed synthetic function, growth failure, severe coagulopathy, encephalopathy, and multiple organ dysfunction. Biliary atresia is the most common, but intrahepatic cholestasis, a variety of familial disorders, chronic viral infection, and parenteral nutrition induced cirrhosis are also relatively frequent. Keywords

Acute liver failure • Fulminant liver failure • Hepatitis • Acetaminophen toxicity • Portal hypertension

Introduction Liver dysfunction is common in children requiring intensive care and is a common source of morbidity and mortality. Both primary disorders of the liver and complications of other underlying disorders may result in hepatic failure and life-threatening multisystem dysfunction. Slowly progressive liver disease may result from numerous disorders of infancy and childhood (Table 2.1). The rate of progression and specific complications vary with the specific disorder, but most ultimately progress to cirrhosis and obstruction to portal venous blood flow, with variceal bleeding, intractable ascites, failed synthetic function, growth failure, severe coagulopathy, encephalopathy, and multiple organ dysfunction. Biliary atre-

A.E. Thompson, MD, MHCPM Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Ave, Pittsburgh, PA 15224, USA e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_2, © Springer-Verlag London 2014

sia is the most common, but intrahepatic cholestasis, a variety of familial disorders, chronic viral infection, and parenteral nutrition induced cirrhosis are also relatively frequent. Acute liver failure (ALF), also called Fulminant hepatic failure (FHF), is classically defined as massive liver necrosis with encephalopathy, developing within 8 weeks of the onset of illness. More recently it has been redefined as encephalopathy beginning less than 2 weeks after the onset of disease in patients without chronic liver disease. In children, FHF is a rare multiorgan system disorder, characterized by severe hepatic dysfunction with hepatocellular necrosis, which occurs in patients without underlying chronic liver disease, with or without encephalopathy [1]. Mortality is high, reported as 60–80 % in most series.

Etiology Causes of fulminant hepatic failure are varied and numerous, and include infectious, metabolic, toxic, vascular, infiltrative, and autoimmune, as well as unknown processes 13

14 Table 2.1 Etiology of chronic liver failure in infants and children Cholestatic liver disease Biliary atresia Intrahepatic cholestasis, including Alagille’s syndrome Familial intrahepatic cholestasis (Byler disease) Sclerosing cholangitis Primary biliary cirrhosis Parenteral nutrition-induced cirrhosis Metabolic diseases (liver-based) α1-Anti-trypsin deficiency Wilson’s disease Tyrosinemia Chronic active hepatitis/cirrhosis Hepatitis B, C Autoimmune Neonatal hepatitis Cryptogenic cirrhosis Cystic fibrosis Other/miscellaneous

(Table 2.2). In infants and children under the age of 2 years, metabolic disorders and infectious causes are most common, especially herpes viruses, adenovirus, and echovirus. Hepatitis A, B, and rarely C are more common, but many other infectious agents can cause fulminant disease. In older children infectious causes predominate, but metabolic and toxic causes remain important. Numerous drugs and environmental agents may be associated with toxic liver injury, either direct or indirect (e.g., hypersensitivity related). In older children, especially adolescents, acetaminophen poisoning is a common cause of FHF. In adolescents it is most commonly the result of suicidal intent, though in younger children it results from accidental ingestion or inadvertent overdose. Of interest, several recent studies have suggested that many cases of FHF previously classified as “idiopathic” may in fact be due to unrecognized acetaminophen poisoning. For example, acetaminophen-containing protein adducts released by dying hepatocytes have been found in 20 % of children and adults with idiopathic FHF [2, 3]. Metabolism of acetaminophen is normally by three different pathways – conjugation with sulfate or glucuronide accounts for approximately 90 % of the metabolism, about 5 % is excreted unchanged in the urine, and 5–10 % is metabolized by cytochrome P450 mixed-function oxidase. The last of these is the primary mechanism of the hepatic toxicity. Acetaminophen is metabolized to N-acetyl-pbenzoquinoneimine (NAPQI) by the cytochrome P450 oxidase, which forms covalent bonds within the hepatocyte. Under normal circumstances, NAPQI is detoxified by addition of sulfhydryl groups, usually through conjugation by glutathione, but stores of glutathione may be exhausted by massive doses, and irreversible injury can occur. Treatment of acetaminophen poisoning is with the specific antidote,

A.E. Thompson

N-acetylcysteine. The initial dose is 140 mg/kg, followed by 70 mg/kg given po or pg every 4 h for 17 doses. Intravenous treatment may be more easily tolerated. Current recommendations are for a bolus dose of 150 mg/kg over 15–60 min, followed by a continuous infusion of 50 mg/kg/dose over 4 h, followed by 100 mg/kg/dose over 16 h. The management of acetaminophen poisoning is discussed further in the chapter on toxic ingestions. Severe liver failure is associated with a microcirculatory disturbance causing tissue hypoxemia. N-acetylcysteine has been noted to have beneficial systemic hemodynamic effects in a variety of critical illnesses, serving as a means of reducing oxidative stress associated with inflammation and overwhelmed antioxidant mechanisms. This has suggested potential benefit in acute hepatic failure from a variety of other causes. A number of small studies have demonstrated improved oxygen consumption and indocyanine green clearance in patients with liver failure treated with N-acetylcysteine [4, 5]. In addition, as previously mentioned above, several studies have shown that many cases of idiopathic liver failure are actually due to acetaminophen poisoning. Given this information, N-acetylcysteine has been proposed as a potential treatment for all patients presenting with FHF. However, a multi-institutional study in children, conducted by the Pediatric Acute Liver Failure Group, unfortunately was unable to shown any improvement in survival at 1 year in non-acetaminophen acute liver failure. Moreover, liver transplant-free survival was significantly lower in the group that was treated with N-acetylcysteine [6]. Therefore, N-acetylcysteine is not currently recommended for treatment of non-acetaminophen acute liver failure in children.

Liver Failure and its Effects on Organ Function Hepatic failure, whether acute or chronic, is associated with dysfunction of multiple organ systems. It is this constellation of system failures that characterizes most patients admitted to intensive care units and which are the most common causes of death [7, 8].

Hepatic Encephalopathy Clinical Manifestations Central nervous system dysfunction occurs in the majority of patients with both acute and chronic liver failure. Its etiology is multifactorial and not fully understood, and appears to differ somewhat between the two [9, 10]. For example, neurologic dysfunction develops rapidly in patients with acute liver failure, often progressing to coma, cerebral edema, and death from elevated intracranial pressure and herniation

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Table 2.2 Causes of acute or fulminant hepatic failure Infectious Hepatitis A, B, B and D, C, E Cryptogenic Herpes simplex Adenovirus Echovirus Epstein-Barr Cytomegalovirus Varicella Parvovirus B19 Toxic (direct or indirect) Acetaminophen Halothane Valproate Carbamazepine Phenytoin Phenobarbital Tricyclic antidepressants Metabolic Galactosemia Fructosemia Tyrosemia Niemann-Pick II (C) Infiltrative Leukemia Hemophagocytic lymphohistiocytosis Hemangioendothelioma Lymphangioendothelioma Ischemic/vascular (rare) Budd-Chiari syndrome Acute circulatory failure Septicemia with shock Heat stroke

Measles Yellow fever Lassa Ebola Marburg Dengue Togaviruses Bacterial septicemia Leptospirosis Malaria Isoniazid Cytotoxic agents Irradiation Copper Amanita phalloides Carbon tetrachloride

Neonatal hemochromatosis Alpha-1 antitrypsin deficiency Wilson’s disease Autoimmune Liver-kidney microsomal type I Ab (+) hepatitis Smooth muscle Ab (+) hepatitis Giant cell hepatitis with hemolytic anemia Undefined

within days or even hours. Seizure activity and muscle twitching are commonly observed prior to the onset of coma. Cerebral edema occurs far more commonly in patients with acute or fulminant hepatic failure than in those with chronic hepatic insufficiency. It occurs in approximately 80 % of patients with acute disease and is a common cause of death [11]. Histological findings are consistent with cytotoxic edema – primarily severe swelling of astrocytes and astrocyte end feet. It is generally a reversible process, i.e. patients who recover spontaneously or undergo transplantation have resolution of the neurologic dysfunction if secondary damage has not occurred. However, secondary damage does occur frequently, and moderate to severe neurologic deficits are common. In contrast, in patients with cirrhosis and chronic liver failure, encephalopathy is much more insidious in both its onset and progression and may wax and wane.

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Episodes of gastrointestinal hemorrhage, sepsis, and sedative administration (among other events) may precipitate deteriorating mental status. Personality changes, motor dyscoordination, and asterixis usually precede the onset of stupor and coma. Histologic findings also reveal astrocytic rather than neuronal abnormalities, specifically Alzheimer type II astrocytosis, with swollen astrocytes, large pale nuclei, prominent nucleoli, and margination of chromatin.

Pathophysiology The pathophysiology of hepatic encephalopathy needs to be further elucidated. Several hypotheses have been proposed to date, including the reduced synthesis (by the liver) of an essential substance for brain function, synthesis by the diseased liver of an encephalopathogenic substance, and/or reduced extraction and metabolism by the liver of encephalopathogenic substances or precursors. As investigation proceeds there is increasing evidence for activation of inflammatory mediators, alteration of gene expression in brain, and the effects of oxidative/nitrosative stress. In addition, multiple neurotoxins and false neurotransmitters, excessive levels of octopamine and serotonin, and deficient norepinephrine and dopamine are hypothesized to play important roles. Accumulation of ammonia plays a major and presumed central role in the pathophysiology of both hepatic encephalopathy and cerebral edema, but is not the exclusive factor. The association between ammonia and hepatic encephalopathy has been recognized for over a century, and recent investigation continues to support its role. Positron emission tomography (PET) reveals increased blood-brain barrier permeability to ammonia as well as increased brain uptake and metabolism of the compound [12]. Excess CNS ammonia has multiple effects on brain function, not fully understood, which affect both excitatory and inhibitory function and contribute to edema formation. Elevated ammonia levels block chloride ion extrusion from post-synaptic neurons and render the inhibitory neurotransmitter ineffective [10]. However, ammonia also inhibits excitatory neurotransmission. The glutamine theory proposes that glutamine, produced in the brain by deamination of ammonia, converting glutamate to glutamine, accumulates in astrocytes, where its osmotic effect is to promote edema formation (Fig. 2.1). It also causes acute egress of potassium, organic osmolytes, and methylamines through a volume activated channel. Magnetic resonance spectroscopy has provided support for the importance of the glutamine hypothesis [13]. Treatment with methionine sulfoximine, which inhibits glutamine synthesis, blocks accumulation of glutamine and water in experimental animals. In cell culture, free radicals form in astrocytes exposed to NH3, leading to mitochondrial dysfunction which can be prevented by inhibition of glutamine synthetase. Inhibition of glutamine synthetase also prevents

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A.E. Thompson

Pre-synaptic neuron

Astrocyte

GLN

GLN NH3 GS

GLU GLU GLU NH3

GLT-1

AM

NMDA

PA/

KA M

Arg

NOS

Cit

Capillary

NO???

NH3

Post-synaptic neuron

Fig. 2.1 Potential mechanisms for development of cerebral edema in acute hepatic failure. Ammonia (NH3) is taken up in abnormal quantities across an abnormally permeable blood brain barrier into the astrocyte. It promotes production of glutamine (GLN) from glutamate (GLU) by the action of glutamine synthase (GS) in the astrocyte. Elevated levels of glutamine lead to excess uptake of water into the astrocyte. Glutamine is pumped out of the astrocyte and taken up by the presynaptic neuron, where it is converted to glutamate. Nerve stimulation

causes release of glutamate into the synaptic cleft where is acts as an excitatory neurotransmitter. Astrocytes rapidly take up glutamate via the glutamate transporter (GLT-1). Ammonia also blocks export of glutamine from the astrocyte which further increases astrocyte glutamine concentration and edema. Stimulation of NMDA receptors by glutamate may also stimulate nitric oxide synthase (NOS) and promote nitric oxide (NO) production with subsequent cerebral vasodilatation

edema formation and death in rats with hepatic failure [14, 15]. However, the effect on water content is not proportionate to the effect on glutamine accumulation, suggesting that other mechanisms are likely to be involved in development of cerebral edema. Oxidative and nitrosative stress may be additional factors contributing to edema formation. Increased gene expression of brain heme oxygenase-1 and reduced expression of Cu/Zn superoxide dismutase are noted in rats in after portocaval shunts, and neuronal NOS is increased. Another theory of edema formation attributes edema formation to gradual vasodilatation, in which failed autoregulation occurs with uncoupling of CMRO2 and CBF, loss of arteriolar tone, and vasogenic edema [16–19]. These two prevailing theories may, in fact, be interrelated. Once glutamine is produced in the astrocyte, it diffuses to presynaptic neurons where it is deaminated to glutamate, a critical excitatory neurotransmitter. The increased levels of glutamate may activate NMDA receptors, stimulating production of nNOS and nitric oxide, promoting vasodilatation and vasogenic edema [9, 14]. In addition to glutamate’s potential effect on vascular tone,

endotoxin and other vasoactive peptides from the gut or necrotic liver may contribute to vasodilation. Measurement of cerebral blood flow (CBF) in patients indicates significant variability. Most appear to have decreased CBF, probably consistent with decreased energy consumption, but some are noted to have elevated flow which is associated with edema and higher mortality. Autoregulation may be impaired in late disease, especially in those with low systemic blood pressure [20], but is restored rapidly after transplantation, or during hypothermia. Limited experimental evidence indicates that both mild hypothermia and indomethacin can reduce CBF and prevent cerebral edema [21]. Brain energy metabolism is decreased in hepatic encephalopathy. The cerebral metabolic rate for glucose and CMRO2 are proportionately decreased, apparently secondary to decreased energy demand [10, 22]. Neurologic dysfunction precedes depletion of high-energy phosphates in models of both acute and chronic encephalopathy, as well as in patients with mild encephalopathy associated with cirrhosis. Elevated CNS ammonia may contribute to cerebral energy failure, although this appears to be a late phenomenon. Its inhibition

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of mitochondrial α-ketoglutarate dehydrogenase prevents pyruvate from entering the Kreb’s cycle and results in excess lactate formation and decreased ATP production. Following the onset of intracranial hypertension, there may be evidence of cerebral hypoxia, probably secondary to the pressurerelated decrease in cerebral blood flow. Decreased energy consumption may be secondary to defects of neurotransmission which are associated with hepatic encephalopathy. Glutamate is the major excitatory neurotransmitter. It is released by the presynaptic neuron and stimulates receptors on postsynaptic cells. It is taken up by astrocytes and metabolized to glutamine by action of glutamine synthetase using ammonia from the circulation. Normally glutamine is actively extruded from the astrocyte and taken up again by the presynaptic neuron for conversion back to glutamate. In the setting of hyperammonemia, numerous alterations in this pathway occur [23]. Expression of multiple enzymes, including glutamine synthetase, is decreased. Nonetheless, elevated ammonia promotes production of glutamine, but impairs its release from astrocytes. The action of the glutamate transporter GLT-1, which is required for inactivation of glutamate in the synapse, is diminished [24]. Elevated levels of CNS glutamate have been noted in fulminant hepatic failure proportional to the degree of neurologic impairment. However, while seizures and hyperexcitability are seen in early acute hepatic encephalopathy and some congenital metabolic disorders, they are not common in patients with encephalopathy associated with chronic liver failure, as would be expected in the setting of excess excitatory neurotransmitters, casting doubt on the glutamate hypothesis as complete. The potential for ammonia to also decrease excitatory transmission, apparently by a post-synaptic mechanism, may partially explain these observations [25]. Glutamate receptors of all types are decreased on post-synaptic neurons, perhaps partially explaining the absence of neurological hyperactivity. The specific receptor most affected seems dependent on whether hepatic failure is acute or chronic. GABA, γ-aminobutyric acid, is an inhibitory neurotransmitter found throughout the CNS. An alternative hypothesis to explain hepatic encephalopathy attributes neurologic dysfunction to excess GABA or heightened sensitivity to it [26, 27]. Increased blood-brain permeability allows increased amounts of GABA, derived from the gut, to enter the brain and bind to its receptor, producing neuronal inhibition and, presumably, hepatic encephalopathy. The GABA receptor is closed linked to the central benzodiazepine receptor (GABAA). Drug-binding as well as binding by related compounds to these receptors enhances neuroinhibition. Furthermore, ammonia facilitates GABA-gated chloride currents and increases agonist ligand binding to the GABAA/ benzodiazepine receptor complex. This hypothesis predicts that patients with hepatic encephalopathy will be exquisitely

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sensitive to the benzodiazepines and endogenous benzodiazepine-like substances (which appears to be the case) and that benzodiazepine-antagonists such as flumazenil will improve the encephalopathy. Flumazenil does appear to decrease neurologic manifestations of chronic liver failure, but its effect is partial and transient, and there is no correlation with benzodiazepine receptor ligands in blood. In addition to the GABA receptors coupled to central benzodiazepine receptors, peripheral-type benzodiazepine receptors (PTBR) on the outer mitochondrial membrane are noted to be increased in patients dying in hepatic coma, as well as in a variety of animal models of hepatic encephalopathy. Increased ammonia levels appear to upregulate astroglial PTBRs with increased production of neurosteroids. These neurosteroids have potent positive modulatory effects on the neuronal GABAA receptor which, combined with an ammonia-induced astroglial defect in GABA uptake may result in enhanced GABAergic tone [28, 29] and dysregulation of brain function through differential effects on neurotransmitter receptors [30]. In addition these substances may induce the morphological changes (Alzheimer type II) characteristic of hepatic encephalopathy [31]. Accumulation of manganese, particularly in the globus pallidus, has been shown to occur in patients with chronic liver failure and correlates with extrapyramidal symptoms in these patients, although not with the grade of encephalopathy [32–35]. MRI reveals signal hyperintensity in the globus pallidus on T1-weighted images, hypothesized to be related to deposition of paramagnetic Mn2+, and autopsy demonstrates elevated tissue levels of manganese in patients dying in hepatic coma. Manganese appears to decrease glutamate uptake by astrocytes and increase glyceraldehydes-3phosphate dehydrogenase, which suggests a role in the glutamatergic system as well as energy metabolism. In addition, its accumulation in astrocytes in non-human primates is associated with development of Alzheimer type II astrocytosis. Reversal of both symptoms and radiologic findings occurs after liver transplantation.

Management Current treatment is very limited. Careful attention to details of general supportive care is essential (Table 2.3). Decreasing serum ammonia levels by administration of lactulose is considered the mainstay of therapy. Determining levels by arterial sampling is important, because arteriovenous difference of ammonia levels can be significant in hepatic failure. By-products of lactulose fermentation by gut flora decrease the pH in the intestinal lumen and trap ammonium in the colon for excretion. The osmotic load promotes rapid evacuation, but risks hypovolemia and hypernatremia. Even this routine approach to management, however, is of questionable value. For example, a recent meta-analysis questioned the beneficial effects of

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non-absorbable disaccharides [36]. Antibiotics, e.g., neomycin or metranidazole, administered enterally alter gut flora and reduce bacterial production of ammonia and may be superior to lactulose [36]. Patients should be cared for with the head of the bed elevated to 30°. Controlled ventilation is indicated for those with absent protective airway reflexes and/or ineffective respiratory effort. Mannitol and loop diuretics are appropriate for patients with intracranial hypertension. Efforts to decrease external stimuli and control patient restlessness are difficult in the PICU setting, but important, and patients should be monitored for seizure activity. Sedation may be desirable in agitated patients, though the risk of exacerbating the encephalopathy must be considered (certainly the benzodiazepines should be avoided in these patients). Hyponatremia may worsen osmolar disequilibrium in the brain and should be corrected. Very limited experience supports use of hypertonic saline and maintenance of serum sodium level of 145–155 mEq/L [37]. Hyperglycemia may also increase intracranial pressure in hepatic failure [38]. Maintenance of normal serum glucose levels is recommended. Intracranial pressure monitoring in these patients is controversial because of patients’ coagulopathy and associated risk of intracranial hemorrhage. However, the correlation between clinical neurologic dysfunction and intracranial hypertension is poor, and numerous centers have reported experience with extradural monitoring devices. While the risk of CNS bleeding is real, the information gained has proved valuable in supporting these patients. It has also been used to help assess a patient’s potential to survive and benefit from transplantation and to provide appropriate intraoperative intervention at the time of transplantation. Accumulated experience indicates that epidural monitoring, while somewhat less reliable, is significantly less risky than other approaches. With epidural monitoring, complications occur in approximately 4 % of patients with fatal hemorrhage in 1 %, as compared with 20 and 4 % with other types of monitors [39]. With the availability of Factor VIIa, it may be possible to further reduce the risk of bleeding in monitored patients [40]. Temperature control should help avoid increased cerebral blood flow and metabolism. In addition, induced hypothermia may be of some value. Several preliminary, small studies suggest that maintaining hypothermia (32–33 °C) may improve cerebral autoregulation and response to CO2, and decrease cerebral edema and intracranial pressure [41–45]. Larger, better controlled studies are necessary, but hypothermia may be helpful in providing additional time to transplantation. The diagnosis, staging, pathophysiology, and management of hepatic encephalopathy is discussed further in the chapter on toxic/metabolic encephalopathy in this textbook.

A.E. Thompson Table 2.3 Hepatic encephalopathy: supportive care Maintain normal serum electrolyte levels Avoid hyponatremia Maintain normoglycemia Maintain hemodynamic homeostasis Normovolemia Normotension Reduce serum ammonia levels Lactulose Non-absorbable antibiotics (e.g. neomycin) Elevate head of bed 15–30° Mechanical ventilation Provide airway protection Maintain mild hyperventilation Consider mild-moderate sedation Consider induction of mild hypernatremia Consider epidural ICP monitor when coma > stage II Maintain INR 50,000 Mannitol (0.25–0.5 g/kg IV) for elevated ICP, or Loop diuretic Consider therapeutic coma (with ICP monitoring) Avoid hyperthermia Consider hypothermia

Acute Kidney Injury Pathogenesis of Hepatorenal Syndrome Acute kidney injury occurs frequently in patients with both acute and chronic liver failure [46, 47]. Hepatorenal syndrome (HRS) is the most common cause of acute kidney injury in this population, but other causes include prerenal azotemia, acute tubular necrosis following episodes of hemorrhagic or septic shock, and direct renal toxicity (e.g. acetaminophen, radiocontrast-induced, hepatitis B or C). Forty to eighty percent of patients with fulminant hepatic failure develop HRS, and it occurs in up to 40 % of patients with cirrhosis and ascites. Two clinical presentations have been described. Type I is rapid in onset and progression, with a doubling of creatinine in less than 2 weeks (to >2.5 mg/dl in adults) and frequently follows an episode of hypovolemia or hypotension. Type II is more indolent with a less dramatic increase in serum creatinine. The primary manifestation is often diuretic-resistant ascites. In both types, onset often appears to be the consequence of an acute change in intravascular volume leading to an unstable renal circulation with cortical vasoconstriction and corticomedullary redistribution of blood flow. Renal histology is normal. Common precipitating events include gastrointestinal losses, hemorrhage, excessive diuresis, paracentesis without albumin replacement, or sepsis, especially spontaneous bacterial peritonitis. Some patients develop HRS in association with progressive hepatic deterioration in the absence of an obvious precipitating event. However, mild systemic hypotension is reliably

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Liver Failure in Infants and Children

present. Multiple circulating vasoactive substances have been implicated in its pathogenesis including renin and angiotensin II, norepinephrine, arginine vasopressin, substance P, endotoxin, octopamine, and prostaglandins E2 and I2, among others. In severe hepatic insufficiency the renal circulation is subject to complex hemodynamic effects of multiple vasoactive mediators [48, 49]. Hepatic failure itself and portal hypertension lead to extreme splanchnic vasodilatation secondary to increased local production (and decreased clearance) of vasodilating substances, especially nitric oxide, but including endotoxin and numerous cytokines. Ultimately systemic vasodilatation also occurs. Vasodilatation results in decreased effective intravascular volume and increased activation of vasoconstrictor mechanisms, especially the reninangiotensin-aldosterone axis and sympathetic nervous system. Exposure to these endogenous vasoconstricting substances shifts the renal autoregulatory curve to the right. Although patients with severe hepatic insufficiency respond to the decrease in splanchnic and systemic vascular resistance with a compensatory increase in cardiac output, increased output is inadequate to normalize blood pressure. The resulting mean arterial pressure is on the pressuredependent portion of the renal autoregulatory curve. Decreased renal blood flow leads to a further intense compensatory increase in renal vasoconstrictor and antinatriuretic mediator release, including renin, angiotensin, aldosterone, norepinephrine, and arginine vasopression, with resulting preglomerular vasoconstriction. Increased production of endothelin-1 in the renal vascular bed likely contributes to renal vasoconstriction [50]. Renal synthesis of nitric oxide and vasodilating prostaglandins is decreased. The observation that renal blood flow is lower in some patients without HRS than in some with the syndrome suggests that mechanisms other than decreased RBF are important. Contraction of glomerular mesangial cells with reduction of the surface area available for glomerular filtration may be another important response to many of these agonists, particularly the endothelins, and an additional factor decreasing renal function [51]. This disturbance in vascular tone leads to hypofiltration, with sodium and water retention, while tubular function is preserved. High levels of circulating antidiuretic hormone further impair excretion of water by promoting reabsorption in the distal nephron. Of great interest is the fact that these derangements are functional: they are reversible after hepatic transplantation. Moreover, the kidneys function if they are transplanted into a recipient without liver dysfunction. There are no specific clinical findings in the hepatorenal syndrome. Diagnosis follows exclusion of other causes of renal failure and absent diuretic response to volume loading (Table 2.4). It is supported by the presence of oliguria, elevated blood urea nitrogen (BUN) and serum creatinine, low

19 Table 2.4 Diagnosis of hepatorenal syndrome, based on International Ascites Club consensus, adapted for children Major criteria Chronic or acute liver disease with advanced hepatic failure and/or portal hypertension Low glomerular filtration rate, as indicated by serum creatinine >2× baseline (normal for age) Absence of shock, ongoing bacterial infection, or current or recent treatment with nephrotoxic agents. Absence of gastrointestinal fluid losses No sustained improvement in renal function following diuretic withdrawal and volume expansion with 20 ml/kg isotonic fluid Proteinuria 10 mmHg were potentially dangerous. Sukhotnik et al. [30] showed that neonates may develop ACS at IAP’s in the range of 9–13 mmHg. Baroncini et al. [31] investigated hemodynamic function in children undergoing laparoscopic procedures and reported substantial cardiopulmonary compromise at very low IAP’s in neonates and at slightly higher levels in older children. They recommend a maximal IAP of 6 mmHg in neonates and of 12 mmHg in older children during laparoscopy. Ejike et al. recently suggested that pediatric ACS should be defined as an IAP of >12 mmHg associated with new dysfunction or failure of two or more organ systems [16] (See Appendix). Again, the IAP value should be considered only as one component of the entire clinical picture. According to its cause and duration, ACS may also be classified as primary, secondary, or recurrent (Table 4.1) [1]. Primary ACS is characterized by the presence of acute or subacute IAH resulting from an intra-abdominal cause (e.g., abdominal trauma, post abdominal surgery, ascites, abdominal tumor). Secondary ACS is caused by extra-abdominal causes, typically in conditions requiring massive fluid resuscitation, such as septic shock and major burns. Recurrent ACS represents a redevelopment of ACS following resolution of an earlier episode of either primary or secondary ACS (a “second-hit” phenomenon) and may occur despite of an open abdomen or as a new ACS episode following definitive closure of the abdominal wall [28].

Incidence Among adult patients, the incidence of IAH is variable, ranging between 18 and 80 % of ICU patients, depending on the definition threshold used and on the type of the patient population [32]. In a 1-day-point prevalence study, Malbrain et al. [33] found that 50.5 % of ICU patients had IAH and 8.2 % had ACS. Among 265 medical/surgical ICU patients, the same group observed a 32.1 % incidence of IAH on ICU admission [34]. Very scant data exist regarding the occurrence of ACS in children. Earlier studies by Beck et al. [11] and Diaz et al. [19] calculated an incidence of severe ACS, requiring decompressive laparotomy (DL) of around 1 % among critically ill children. Ejike at al., defining ACS as an IAP of >12 mmHg associated with new dysfunction or failure of two or more

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organ systems [16], found ACS to be present in 4.7 % of ventilated PICU patients. However, only five of their 294 (1.7 %) eligible patients underwent laparotomy, three of them for ‘bowel perforation’. In a recent study, Pearson et al. [14] described 26 children who have undergone DL for ACS. The occurrence rate was calculated as 0.56 % of the ventilated patients in their PICU (Meyers RB 2012, personal communication). This lack of consensus definition makes the true incidence of ACS among pediatric patients difficult to determine [16]. The higher incidence of ACS – when defined as a certain threshold pressure combined with significant physiological deterioration – has a profound clinical importance as it serves to awaken the critically crucial index of suspicion. If unrecognized – and therefore untreated – this ‘early’ ACS may rapidly evolve and deteriorate to ‘full blown’ ACS requiring emergency DL and resulting in a very high mortality rate. Unfortunately, ACS is still grossly under-recognized by pediatric intensive care personnel [9].

Etiology and Risk factors of ACS Although primarily thought of as surgical diagnoses, IAH and ACS pose a risk to both medical and surgical patients [34, 35]. In principle, two basic mechanisms can lead,

Table 4.2 Conditions associated with IAH and ACS

Increased intraabdominal content

Decreased abdominal wall compliance

Combination of decreased abdominal wall compliance and increased intraabdominal content

independently or in combination, to IAH and ACS. The first is the accumulation of excessive mass within the limited capacity of the abdominal cavity [36]. The second is a tense, low compliant abdominal wall (Table 4.2). Primary ACS derives from intra-abdominal pathology and is most often seen in trauma or in postoperative patients. It has been identified as one of the major causes of morbidity and mortality in patients with a traumatic injury [37–39]. Secondary ACS, associated with an extra-abdominal etiology, is encountered mostly in medical or burn patients [40, 41], usually as a result of edema fluid accumulation. It is often viewed as an “unavoidable” sequelae of aggressive fluid (crystalloid) resuscitation for various etiologies (e.g., sepsis, post trauma, burns) [11, 18, 37, 42–44]. In adults, the most common cause of primary ACS is abdominal injury with intra-abdominal bleeding. Aside from the accumulated blood in the peritoneal or retroperitoneal spaces, the situation may be aggravated by edema formation, bowel distention and tense abdominal wall. Consequently, a damage control approach has become an established routine, consisting of hemorrhage control with or without abdominal packing, leaving of an ‘open abdomen’ and delaying definitive abdominal wall closure (‘staged celiotomy’) [45–48]. Other relatively frequent causes of ACS in adults are major abdominal surgeries such as abdominal aortic surgery, especially if

Hemoperitoneum (blunt or penetrating abdominal trauma) Intra-abdominal or retroperitoneal masses (tumor, hematoma, abscess) Ascites (liver failure, nephrotic syndrome etc.) Peritoneal dialysis Pneumoperitoneum (during laparoscopy) Gastrointestinal tract dilatation Gastroparesis and gastric distention Ileus Volvulus Colonic pseudo-obstruction Necrotizing enterocolitis (NEC) Small bowel perforation Abdominal surgery, especially with tight abdominal closures Abdominal wall bleeding or rectus sheath hematomas Surgical correction of large abdominal hernias, gastroschisis, or omphalocele Major burns (with or without abdominal eschars) Mechanical ventilation, with PEEP >10 cmH2O Prone positioning Massive fluid resuscitation Sepsis, severe sepsis, and septic shock Cardiogenic shock Complicated intra-abdominal infection Obesity Severe acute pancreatitis

ACS abdominal compartment syndrome, IAH intra-abdominal hypertension, PEEP positive end-expiratory pressure

Abdominal Compartment Syndrome in Children

associated with coagulopathies. In contrast to adults, primary ACS due to abdominal trauma has been reported in only a minority of the pediatric cases [11–19], in whom ACS is associated with a diversity of other acquired, non-congenital etiologies, such as enteropathies, intestinal perforation, peritonitis, post abdominal surgery for various conditions and malignancies (Table 4.2). In recent years, the role of massive fluid resuscitation and capillary leak emerges as a major – if not the major – contributor or cause of ACS [37, 42, 49–51]. In the multicenter study by Malbrain et al., massive fluid resuscitation and polytransfusion were used almost twice as frequently among patients who have developed IAH than in patients who did not [34]. In children, ACS was associated with massive fluid resuscitation for the treatment of various etiologies [11, 14, 18, 19, 52]. Marked capillary leak, characterizing conditions such as sepsis, burns or bone marrow transplantation, predispose to the development of secondary ACS [11, 52]. This secondary ACS adds significant morbidity and mortality, and it may be predicted and possibly avoided by more judicious fluid resuscitation [37, 42, 49–51]. Major burns have been increasingly recognized as a risk factor for IAH and ACS due to massive (initial) fluid resuscitation and due to capillary leak leading to ascites, bowel edema and abdominal wall edema [32, 43, 44, 53, 54]. It should be stressed that ACS developed not only in patients with full-thickness circular burns of the abdomen, but also following proper escharotomy or in the absence of any abdominal burns.

43

Normal abdominal pressure

Organ dysfunction

4

0

5

IAH

Abdominal compartment syndrome

10 15 20 25 30 Intra-abdominal pressure (mmHg)

35

40

Fig. 4.1 Distinctions between normal intra-abdominal pressure, intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) in adults, depicted over the abdominal volume-pressure curve. The area illustrating IAH may undergo shifts to the right or left depending on the clinical scenario (Reproduced with permission from the World Society of the Abdominal Compartment Syndrome – www.wsacs.org) Physiologic insult/Critical illness

Ischemia

Systemic inflammatory response

Capillary leak Fluid resuscitation

Pathophysiology of ACS IAP and APP may be considered analogous to the Monro – Kelly doctrine relating to the intra-cranial pressure (ICP) and cerebral perfusion pressure (CPP), respectively (Fig. 4.1). The abdominal pressure – volume curve consists basically of two arms: At low intra-abdominal volumes, the abdominal wall is very compliant and relatively large increases in “pathologic” volumes will lead to only minor increases in IAP [55]. Subsequently, once a critical excessive volume has been attained, compliance of the abdominal cavity decreases abruptly and small changes in volume will lead to large changes in IAP. Further distension beyond this “knee” of the curve will result in a rapid rise in IAP, decreased organ perfusion, development of clinical ACS and, if untreated, in multiple organ failure (MOF) and death. Regardless of the primary initial insult or pathological event, three main processes are always secondarily involved in the pathogenesis of IAH and its progression to ACS: tissue ischemia/hypoxia followed by reperfusion injury, inflammatory response and increased capillary permeability. The combination of these processes is augmented by massive

Tissue edema (including bowel wall and mesenteric edema)

IAH

Fig. 4.2 The vicious cycle of inflammatory response, fluids resuscitation and intra-abdominal hypertension. Abbreviations: IAH intraabdominal hypertension (Adapted and reproduced with permission from AbViser® Medical, LLC, by Dr. Tim Wolfe)

crystalloid resuscitation, which activates a vicious cycle that results in tissue edema – involving both abdominal wall and intra-abdominal tissues and organs, and often in free fluid sequestration and ascites accumulation (Fig. 4.2). The inflammatory response is a predominant component of the primary conditions associated with IAH and ACS (Table 4.2). Inflammation follows tissue ischemia, cellular hypoxia and reperfusion – the hallmark of traumatic shock [56]. It involves, among others, the release of cytokines,

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formation of oxygen free radicals and decreased cellular production of adenosine triphosphate (ATP) [57]. The pro-inflammatory cytokines promote vasodilatation and increase capillary permeability, leading to edema formation [58]. Tissue reperfusion promotes the generation of oxygen free radicals that have a toxic effect on cell membranes. Insufficient oxygen delivery limits ATP production and impedes energy-dependent cellular activities, particularly the sodium-potassium pump. Pump failure causes cellular swelling, lose of membrane integrity and spilling of intracellular contents into the extracellular space, thus promoting further inflammation [57, 59]. Capillary leakage, edematous intestines and accumulation of ascitic fluid elevate IAP that impairs venous return and intestinal lymphatic outflow and thereby increases capillary filtration pressure and worsens gut edema [56, 60, 61]. As pressure mounts, intestinal perfusion is impaired, and the cycle of cellular hypoxia and damage, inflammation and edema formation continues in a vicious cycle [57]. Efforts aimed at restoring abdominal organs’ perfusion with large amounts of crystalloid solutions or blood products further aggravate the clinical condition. Aside from their effect on the capillary filtration pressure, crystalloids decrease plasma protein concentration and reduce plasma oncotic pressure. These combined effects of the Starling forces serve to overwhelm the anti-edema safety factors (lymph flow, plasma oncotic pressure) and the vicious cycle

Total body fluid third spacing/edema

is further augmented by the “futile crystalloid preloading” [32, 62]. Other organ specific pathophysiologic processes are discussed in the relevant sub-sections below.

Organ System Dysfunction and the Clinical Presentation of ACS ACS and IAH affect all critical body systems, most notably the cardiac, respiratory, renal, and neurologic systems, as well as the hepatic and intestinal systems [28, 32] (Fig. 4.3).

Cardiovascular Effects With advancing ACS, the patient presents a rapidly deteriorating clinical picture of profound shock, unresponsive to fluid resuscitation and to vasoactive drugs [11, 52, 63, 64]. Cardiac output (CO) decreases primarily due to decreased venous return: The inferior vena cava (IVC) and the portal vein are compressed by the elevated IAP [38, 64–68]. Cephalad deviation of the diaphragm increases intrathoracic pressure, impedes superior vena cava (SVC) flow and possibly causes direct cardiac compression, reducing ventricular compliance and contractility [28, 64, 66, 67]. In small children undergoing laparoscopy, an IAP of 12 mmHg may lead to regional cardiac

Elevated intra-abdominal pressure due to bowel ischemia

Vena cava compression

Fluid resuscitation for critical illness Intestines: IAP compromise intestinal blood flow resulting in ischemia, necrosis and multisystem organ failure Brain: IAP elevation can directly contribute to ICP elevation

Lung: IAP pushes diaphragms into chest, raising intrathoracic pressure, causing an increase in barotrauma, hypercarbia and hypoxemia. This results increase time on ventilator with increase in VAP

Impact of IAH on capillary blood flow to abdominal organs:

EDEMA MAP > 90 mmHg

If IAP exceeds 15–20 mmHg, capillary blood flow is dramatically reduced leading to anaerobic metabolism, increased cytokine production and capillary leak. At IAP ~ 20 mmHg, venous return to the heart is impaired, reducing cardiac output. This results in tissue ischemia perpetuating the vicious cucle.

CVP > 4–12 mmHg

Heart: Cardiac monitering, including CVP and PAOP, are artificially elevated by IAP making them difficult to interpret in the IAH setting. Multi-system organ dysfunction/failure

Kidneys: Reduced kidney perfusion and urine production results in inability to mobilize fluids and increased rates of renal insufficiency/failure.

Reduced blood flow to organs

Fig. 4.3 The vicious cycle nature of the pathopysiologic processes leading to abdominal compartment syndrome (ACS) and multi-organ system failure. Abbreviations: IAH intra-abdominal hypertension, CVP central venous pressure, MAP mean arterial pressure, PAOP pulmonary

Vena Cava Compression: IAP greater than 8–12 mmHg results in reduced blood flow to the heart (preload)

Reduced cardiac output

Reduced blood flow to heart (preload)

artery occlusion pressure, ICP intra-cranial pressure, VAP ventilator associated pneumonia (Adapted and reproduced with permission from AbViser® Medical, LLC, by Dr. Tim Wolfe)

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Abdominal Compartment Syndrome in Children

45

wall motion abnormalities, especially to septal hypokinesia [69]. Mechanical compression of the abdominal vasculature increases systemic vascular resistance and cardiac afterload. In this setting, straightforward interpretation of hemodynamic data may be misleading, as the elevated intrathoracic pressure ‘falsely’ increases all other manometric measurements, including central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP) and pulmonary artery pressure [24, 38, 68, 70], potentially leading to erroneous management decisions. Therefore, alternative methods of preload evaluation, like the measurement of right ventricular enddiastolic volume by echocardiography, reflect more accurately the intravascular volume status as it is less affected by changes in the intrathoracic pressure [21, 28, 71–74]. Alternatively, the falsely elevated CVP and PAOP can be ‘corrected’ by using the following formula [28, 72]: Corrected CVP = Measured CVP − IAP / 2

(4.1)

Corrected PAOP = Measured PAOP − IAP / 2

(4.2)

The compressed IVC and the impaired venous drainage from the lower extremities promotes the formation of peripheral edema and may place the patient with IAH/ACS at an increased risk for developing of deep vein thrombosis [28, 41, 75].

Respiratory Effects Acute respiratory failure is a major component of ACS. The elevated IAP causes upward displacement of the diaphragms, resulting in increased intrathoracic pressure, compression of the lungs and progressively low compliant, stiffer chest [11, 28, 38, 52, 68, 76, 77]. The resultant pathophysiologic picture is characterized by alveolar atelectasis, decrease in all lung volumes mimicking severe restrictive lung disease, hypoxemia and hypercarbia [11, 28, 38, 52, 64]. Parenchymal compression impairs pulmonary capillary blood flow, leading to increased alveolar dead space and ventilation – perfusion (V/Q) mismatch [78]. In the ventilated patient, progressively higher positive end expiratory pressure (PEEP), peak inspiratory and plateau pressures are required to maintain gas exchange [11]. Mechanical ventilation at high inflation pressures can cause alveolar barotrauma triggering the release of inflammatory mediators that enhance capillary leakage and may aggravate preexisting lung injury [21, 41].

Renal Effects Acute kidney injury (AKI) characterized by oliguria progressing to anuria – both unresponsive to fluid therapy and

diuretics – is one of the hallmarks of ACS and is usually its first clinical manifestation [10, 11, 38, 64, 79]. Location of the kidneys deep within the retroperitoneal space makes them especially vulnerable to the deleterious effects of increased IAP. In adults, oliguria usually develops at IAP’s >15–20 mmHg and anuria at IAP’s >30 mmHg [80, 81]. Parallel values for pediatric patients are not available, though it should be expected that renal impairment will be manifested at lower IAP’s [11]. Oligo-anuria results mainly from the combined effects of reduced renal perfusion and direct compression of both renal parenchyma and the renal veins, leading to severe reduction in the renal filtration gradient (FG) [70, 82–84]: FG is the mechanical force across the glomerulus and is equal to the difference between the glomerular filtration pressure (GFP) and the proximal tubular pressure (PTP). GFP is equal to renal perfusion pressure and is calculated as MAP minus renal venous pressure that equals IAP, while PTP is equal to the IAP. FG = GFP − PTP = ( MAP − IAP ) − IAP = MAP − 2IAP

(4.3)

Thus, elevations in IAP will have a far greater impact on renal function and urine production than that caused by reduction in MAP alone – such as seen in shock states – and the IAH-induced renal dysfunction is responsive to neither volume expansion nor vasopressors and loop diuretics, but rather improves dramatically by prompt release of the increased IAP [4, 11, 81, 85, 86]. Ureteral compression has been excluded as the cause of diminished urine production with IAH since oliguria was not prevented by the placing ureteral stents [80].

Gastrointestinal Effects The gastrointestinal (GI) tract is very sensitive to elevations in IAP. A dog’s model showed that an IAP of 20 mmHg significantly decreases blood flow to the entire GI tract and other intra-abdominal organs with the exception of the adrenal glands that were spared, probably as a survival mechanism supporting catecholamine release in the presence of hypoperfusion [87]. Animal models also showed significant decreases in intestinal mucosal blood flow with the development of tissue ischemia and intra-mucosal acidosis at IAP levels above >20 mmHg [88, 89]. In the setting of hemorrhagic shock and fluid resuscitation, the adverse effects of increased IAP on intra-abdominal organs may manifest even at IAP’s lower than 20 mmHg due to the combined effects of reduced CO and splanchnic vasoconstriction [90]. Moreover, IAH also compresses the mesenteric venous system, causing venous congestion, intestinal edema and ascites, further

46

increasing IAP and worsening intestinal hypoperfusion and ischemia. Intestinal hypoperfusion leads to bacterial translocation and may contribute to the development of sepsis and MOF in patients with ACS [75, 89, 91]. Aside from the markedly swollen, tense abdomen, the GI manifestations of ACS include paralytic ileus, feeding intolerance, systemic lactic acidosis, exacerbation of NEC and not infrequently gut necrosis and significantly increased mortality [11, 30, 34, 44, 92–94]. Lactic acidosis is often the first sign of intestinal ischemia as a result of IAH, and should never be ignored. The abdominal wall blood flow is dramatically reduced by the elevated IAP, resulting in impaired wound healing and high rates of fascial dehiscence or surgical site infection [28, 95].

CNS Effects Increased intracranial pressure (ICP) is a well recognized component of the ACS [41, 96–100]. The elevated IAP increases intra-thoracic pressure that interferes with internal jugular venous drainage, causing intracranial congestion and intracranial hypertension (ICH) [77, 96, 98, 101, 102]. Multiple studies described prompt reductions of ICH following DL [97, 103–105]. It was therefore recommended that IAP monitoring should be considered in all traumatic or nontraumatic patients with non-responsive ICH, and a lower threshold for DL should be considered in patients who have sustained combined abdominal and head trauma [55]. As diagnostic laparoscopy may increase ICP, it should be avoided in evaluating patients with severe head injuries [55].

O. Attias and G. Bar-Joseph

(Table 4.2) should undergo baseline IAP measurement, and if IAH is present, serial IAP measurements should be performed every 4–6 h throughout the patient’s critical course, until IAP remains 20 mmHg and for secondary ACS with IAP >25 mmHg, when accompanied with progressive organ failure or failure to maintain APP ≥60 mmHg despite of all medical measures [106, 141]. No parallel recommendations have been defined for children (See Appendix). A therapeutic algorithm described by Steinau et al. [12] defines ACS as IAP >20 mmHg or IAP >16 mmHg with organ dysfunction, and recommends immediate DL for primary ACS, and delaying DL

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Fig. 4.6 “Makeshift” abdominal drainage catheter (Leader Cath 115.11, Vygon, France): (a) preparation of the catheter: side holes are cut in a swiping motion when the metal guidewire is inserted into the catheter. (b) drainage catheter with four side holes cut along it in a spiral fashion

49

a

b

until medical therapy is exhausted for secondary ACS. Pearson et al. [14] recommend DL in any child with a IAP >20 mmHg, lactate >3 mg/dL, persistent oliguria, elevated ventilatory pressures and an increasing vasopressor score. Our approach – similar to that of 70 % of surveyed members of the Society of Critical Care [20] – is to reach at a decision based on the comprehensive clinical picture combined with the IAP value. In the presence of IAH, when organ functions continue to deteriorate despite of all appropriate medical measures, DL should be considered and performed without additional delays [38, 106, 138]. Techniques of DL: The selection of the optimal technique for DL will be decided by the responsible surgeon. In cases of ACS following a recent abdominal surgery or in a case of recurrent ACS, the existing abdominal incision will usually be re-opened. For primary ACS, a full-thickness, longitudinal midline or subcostal transverse laparatomy will be performed. Temporary abdominal closure (TAC) techniques are used following DL to avoid evisceration and protect the underlying

viscera, to prevent abdominal infection and to allow for faster abdominal wall closure [55, 70, 142]. The most commonly used methods are the placement of a temporary absorbable mesh (e.g. Vicryl) (see Fig. 4.7), the “Bogata bag” [117, 142–145] and the vacuum-assisted closure (VAC) [142, 146]. The “Bogota bag”, consisting of a plastic sheet cut from a sterile infusion fluids bag sewn to the fascia or skin edges [143], is always readily available and allows easy visualization of the abdominal organs – a helpful adjunct in evaluating the patient following DL. Recurrent ACS is possible with any of the TAC techniques, especially if they are applied in a fashion that does not allow continued visceral expansion during resuscitation. Patients who develop “open-abdomen” ACS have a high mortality, and IAP monitoring should be continued after the procedure [147]. If recurrent ACS develops, the abdomen should immediately be reopened. Following the resolution of ACS, definitive abdominal closure should not be delayed, since the incidence of failed

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requirement after DL decreased by 43 % compared to that before DL. On the other hand, urine output continued to be low with no return to normal by 12 h after DL, 11 patients had persistent renal failure and 20 required hemodialysis.

Critical Care Management of the Child with ACS

Fig. 4.7 Temporary abdominal closure (TAC) of the open abdomen with a Vicryl mesh following decompressive laparotomy (DL) for abdominal compartment syndrome (ACS) (Adapted from Steinau et al. [12]. With permission from Springer Science + Business Media)

closure and additional complications increases with time. The time window for successful primary fascial closure is usually 5–7 days [106, 122]. Beyond this time, adhesions and early granulation tissue often preclude fascial closure, resulting in the need for split-thickness skin grafting or cutaneous advancement flaps [11, 106, 122]. In children, however, even with prolonged use of a TAC, skin grafting is only rarely needed [146]. Complications of DL: DL can result in significant fluid and heat losses [70, 148, 149]. Postoperative bleeding and infection are rare [137], although Pearson et al. mentioned that bleeding occurred in 22 of 26 children who have underwent DL [14]. Enterocutaneous fistulas may form due to exposure of the bowel to the specific TAC used, inflammation, and/or infection [150, 151]. Extensive bowel swelling, adhesions between the bowel and the abdominal wall and sustained fistulas can prevent and delay definitive closer of the abdomen [148–150, 152]. Cosmetic concerns and physical and psychological discomfort with the scar area can complicate DL among children [12, 70]. The effects of DL on organs dysfunction: De Waele et al. [150] analyzed 18 adult studies (a total of 250 patients) for the effects of DL: The mean IAP fell from 34.6 mmHg before DL to 15.5 mmHg after DL. The hemodynamic effects of DL were somewhat non-uniform, but in general blood pressure and cardiac output increased, CVP and PAOP decreased significantly following DL. In all of the reviewed studies, PaO2/FIO2 ratios significantly increased and PIP’s significantly decreased following DL. In most – but not in all – reviewed studies, urinary output increased dramatically after DL. Pearson et al. [14], recently analyzed the effects of DL among 26 pediatric patients with ACS: Oxygen index, mean airway pressure and vasopressor score gradually decreased toward normal within 12 h of DL. Lactate levels dropped postoperatively by an average of 56 % and the hourly fluid

Critical care management of the patient with ACS consists of supporting the failing organ systems until definitive therapy is instituted and the patient’s basic problem is brought under control. Cardiovascular function should be supported by judicious use of fluid resuscitation to avoid volume overload and further aggravation of ACS, combined with inotropic support. Traditional measures of preload, such as CVP, may be misleading due to the concomitant elevated intrathoracic pressure. APP may serve as a resuscitation endpoint, though it was not subjected to a prospective clinical trial [106, 122]. In adults, the WSACS recommended APP above 50–60 mmHg as a resuscitation endpoint [106]. No parallel recommendation was published for children, but given their lower physiologic perfusion pressures, APP threshold of 40–50 mmHg may be suggested, with infants at the lower end and adolescents at the upper end of this range. Most patients will require mechanical ventilation, and as IAP rises, higher ventilatory pressures and FiO2 will be required. As IAH and ACS represent an extreme lowcompliance state, pressure regulated, volume controled (PRVC) modes in conjunction with prolongation or reversal of the I/E ratio may help maintaining oxygenation while controlling PIP’s. High PEEP may be required to counteract lungs compression, but should be applied judiciously, as it may further decrease venous return to the heart. Improving renal perfusion with fluid resuscitation and inotropic support and high-dose furosemide (often as continuous intravenous infusion), may preserve urinary output and renal function in mild or early cases of ACS. Acidosis should be corrected, attempting to maintain arterial pH >7.20. These measures, however, will result, at best, in temporary improvement, as they do not alleviate the basic problem. Therefore, treatments directed at resolving ACS are mandatory and should not be delayed.

Outcome of ACS The outcome of patients with ACS depends primarily on the basic clinical situation as well as on the delay in relieving the IAH. In both critically ill adults and children, the occurrence of ACS during ICU stay is an independent predictor of mortality [16, 21]. When left unrecognized and untreated, ACS is almost uniformly fatal. Deaths associated with ACS are usually due to multiple organ failure or sepsis. Mortality

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Abdominal Compartment Syndrome in Children

among adult patients with documented ACS occurred in 10–68 % of patients [3, 39, 79, 140]. The mortality rate of children who underwent DL for ACS ranged between 40 and 60 % [11, 14, 16, 19].

Summary ACS is a clinical syndrome resulting from IAH and characterized by rapidly progressive organ system failure, involveing the cardiac, respiratory, renal, gastrointestinal and central nerve systems. High index of suspicion, timely recognition and prompt intervention can be lifesaving. No specific definitions of IAH and ACS, nor specific treatment guidelines for the pediatric population have been published by the WSACS. Stepwise approach including medical management and DL may alleviate ACS and improve outcome, though the overall mortality even with surgical intervention is still very high (See Appendix).

Appendix Following completion of this Chapter, updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome were published in July 2013 [153, 154]. The Pediatric Sub-Committee of the WSACS reviewed the (adult) main management guidelines in regard to their applicability and suitability for children, but could not make firm recommendations and proposed pediatric specific definitions: 1. ACS in children is defined as a sustained elevation in IAP of greater than 10 mmHg associated with new or worsening organ dysfunction that can be attributed to elevated IAP. 2. The reference standard for intermittent IAP measurement in children is via the bladder using 1 mL/kg as an instillation volume, with a minimal instillation volume of 3 mL and a maximum installation volume of 25 mL of sterile saline. 3. IAP in critically ill children is approximately 4–10 mmHg. 4. IAH in children is defined by a sustained or repeated pathological elevation in IAP >10 mmHg.

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55 153. Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med. 2013;39:1190–206. 154. https://www.wsacs.org/education/algorithms.html

5

Obesity in Critical Illness Michael Hobson and Jennifer Kaplan

Abstract

Obesity continues to be a major health concern facing today’s youths. With the ongoing rise in obesity, clinicians will increasingly care for more obese children struck with critical illness. Clinical management in these patients often becomes complicated, as obesity adversely impacts numerous organ systems. As such, pediatric intensivists should recognize these children as a unique patient population that merit special attention. Keywords

Obesity • Inflammation • Critical illness

Introduction Obesity is one of the most widespread and substantial health concerns facing today’s children. Obesity in adulthood is defined as a body mass index (BMI) of ≥30 kg/m2, whereas pediatric obesity is characterized by a BMI at or above the 95th percentile for age and gender. At present, it is estimated that 17 % of children and adolescents are obese [1]. Furthermore, nearly one-third of youths are overweight, based on a BMI greater than the 85th percentile [1]. As the obesity epidemic rages onward, its economic burden continues to have significant impact [2–4]. It is estimated that the Medicare costs associated with obesity could be as high as $85 billion per year [5]. In 2008, the National Association of Children’s Hospitals and Related Institutions (NACHRI) M. Hobson, MD Division of Critical Care Medicine, Pediatric Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA J. Kaplan, MD, MS (*) Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH 45229, USA e-mail: [email protected]

D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_5, © Springer-Verlag London 2014

convened a group to investigate the needs and barriers to pediatric obesity programs [6]. Executive sponsors of the 47 NACHRI member hospitals that completed an application were invited to complete a survey. Nearly 75 % of the respondents reported that obesity programs were integrated into their hospitals’ strategic plans. Children’s hospital administrators also reported that managing childhood obesity is an integral part of the goal of caring for children. With such an emphasis from hospital administration, the care of the obese child will become more apparent in pediatric hospitals. Furthermore, with the increasing number of obese children being managed at children’s hospitals, the number of critically ill obese children will increase. With the rise in pediatric obesity across society, clinicians must continue to familiarize themselves with the unique challenges that accompany caring for the obese child. Obesity leads to a wide array of comorbidities (Table 5.1), and an understanding of the many medical and surgical pathologies seen in these patients is paramount for their proper care in the critical care setting. At the present time, there is a paucity of literature regarding the care of obese pediatric patients in the ICU, and clinical guidance in large part must be extrapolated from adult studies. This chapter will provide an overview of the care of the critically ill obese child.

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58 Table 5.1 Comorbidities associated with pediatric obesity Cardiovascular: Hypertension Dyslipidemia Early atherosclerotic disease Pulmonary: Obstructive sleep apnea Obesity hypoventilation syndrome Gastrointestinal: Nonalcoholic steatohepatitis Gastroesophageal reflux disease Cholelithiasis Endocrine: Diabetes mellitus, impaired glucose tolerance Metabolic syndrome Hyperandrogenism Accelerated linear growth, early onset of puberty Neurologic: Idiopathic intracranial hypertension Psychosocial: Depression, anxiety, poor self esteem

General Considerations for Dealing with the Critically Ill Obese Patient Difficulties with Routine Bedside Care and Procedures An obvious but important notion is that the sheer size of obese pediatric patients, particularly adolescents, presents challenges for customary medical care. Pediatric hospitals specifically may not be equipped with properly sized blood pressure cuffs, patient beds, imaging modalities and operating room tables. Routine nursing care is made more difficult and often requires additional staff to assist with routine care. Furthermore, the lack of mobility associated with an ill obese patient increases the risk of venous thromboembolism and pressure ulcers [7]. Everyday diagnostic radiologic procedures are also made problematic in obese patients because of a large body habitus. The image quality of radiographs is reduced, particularly with portable x-ray machines, often making it difficult to distinguish between infiltrates and overlying soft tissue. Diagnostic imaging with ultrasound is hindered by a greater distance to be penetrated by the sound waves, and changing patient position to obtain better acoustic windows may be even more difficult in the obese patient. Utilizing CT and MRI studies may be prohibited by patient size, particularly in pediatric hospitals. These same factors may exclude interventional procedures such as ultrasound or CT-guided abscess drainage [8]. Lastly, peripheral intravenous access may not be obtainable in these patients, and central venous access is made more difficult by disruption of the

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normal anatomical landmarks and an increased distance of the vessels from the skin surface. However, the use of ultrasound guidance has increased success of central venous cannulation and decreased complication frequency in obese patients [9].

Effects of Obesity on Pharmacology Clinicians must also be aware of pharmacologic adjustments which may be needed for obese patients. Many sedative and analgesic agents are extremely fat soluble, and thus their volume of distribution becomes altered in obese patients. An increase in total blood volume, cardiac output and an alteration in plasma protein binding can affect the pharmacokinetic profile of medications in the obese patient [10–12]. Obesity may also cause changes in hepatic and renal function which may modify drug metabolism and clearance [13]. Dosing regimens for obese patients include dosing on total (actual) body weight (TBW), ideal body weight (IBW), percent ideal body weight, adjusted body weight [IBW + 0.4 (TBW − IBW)], body mass index, and body surface area. Another method used to predict the expected normal weight of an obese patient is called the predicted normal weight (PNWT). The PNWT is equal to the sum of an individual’s lean body weight and a fraction of the individual’s excess fat content that represents the predicted normal fat mass [14]. Unfortunately, there is no consensus regarding the appropriate drug dosing method to use in obesity. However, in general, hydrophilic agents should be dosed based on ideal body weight; whereas lipophilic drugs should be dosed based on total body weight. In obese pediatric and adult patients, basing drug dosing on total (actual) rather than ideal body weight may lead to undesired prolonged effects of the medication. For example, when rocuronium was dosed based on total body weight versus ideal body weight, obese patients demonstrated a significant increase in the duration of action of rocuronium [15, 16]. In contrast, Purhinger et al. demonstrated no difference in the duration of action of rocuronium when dosed by total body weight [17]. Still, it is recommended that rocuronium be dosed based on ideal body weight to avoid prolonged duration of action. Alternatively, using an ideal body weight for obese patients may undertreat patients. In a multicenter study evaluating vancomycin dosing, adequate initial dosing was achieved in only 28 % of obese patients compared with 99 % of normal weight patients [18]. In a separate study, actual versus ideal body weight dosing of vancomycin did not result in increased serum trough levels in obese children [19]. Therefore it is recommended that in obese adult and pediatric patients vancomycin dosing should be based on total versus ideal body weight. Total weight based dosing

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was utilized for a study examining cefoxitin kinetics in obese surgical patients in which patients weighing ≥80 kg received a 2 g dose versus a 1 g for patients weighing 40 kg/m2 were more likely to require mechanical ventilation compared with patients with a BMI 30–40 kg/m2 [46]. The mean lengths of mechanical ventilation and ICU stay were longer for morbidly obese patients (7.7 ± 10.6 days and 9.3 ± 13.5 days, respectively) compared to non-obese patients [4.6 ± 7.1 days (p = 0.0004) and 5.8 ± 8.2 days (p = 0.007), respectively] [45].

Acute Lung Injury/ARDS Obese patients with acute lung injury (ALI) or ARDS demonstrate increased morbidity but not increased mortality. Analysis from the ARDS Network found no significant increase in the adjusted odds for mortality in overweight or obese patients suffering acute lung injury [53]. Morris et al. conducted a prospective cohort study of 825 patients with ALI across a range of BMI categories in an adult intensive care unit and demonstrated no mortality difference between overweight and obese patients compared to those with normal weight [54]. However in severely obese patients (BMI > 40 kg/m2) duration of mechanical ventilation and ICU and hospital stays were longer [54]. Data suggests that about 14 % of obese patients require re-intubation after undergoing prolonged (>48 h) mechanical ventilatory support [55]. The use of non-invasive ventilation in obese patients following extubation may improve extubation success rates. In a study of 62 adult obese patients with a BMI ≥ 35 kg/m2 the initiation of post-extubation noninvasive ventilation resulted in a 16 % absolute risk reduction in the rate of respiratory failure. This resulted in shorter ICU and hospital length of stays [55].

Asthma While the prevalence of both obesity and asthma have risen dramatically over the past few decades, the significance of the association between these two diseases is currently unclear [56]. Cross-sectional and prospective studies have established a link between obesity and asthma in both children and adults [57]. Furthermore, these studies have shown that obesity frequently precedes the development of asthma and also increases the risk of childhood asthma persisting into adulthood [57]. A recent meta-analysis investigating the relationship between weight and asthma showed that a high birth weight along with an increased weight through childhood resulted in a higher risk of asthma in adolescence, particularly in females [58]. However, several confounding factors have prohibited a definitive causality between obesity and asthma. For example, the dyspnea on exertion that may

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result from obesity-related deconditioning can potentially be falsely interpreted as exercise-induced asthma. The obese pediatric patient with asthma is at risk for more severe exacerbations relative to non-obese asthmatics. In an inner-city cohort of 1,322 children with asthma, obese patients reported a higher rate of medication use, reported more wheezing, and were more likely to seek care in the emergency department [59]. A recent retrospective study of children admitted to the intensive care unit with status asthmaticus found that obese patients had a longer requirement for continuous albuterol, intravenous corticosteroids, and supplemental oxygen, and thus ultimately a longer stay in the ICU [60]. Several factors have been proposed to explain this phenomenon. As described above, obese patients have a propensity toward mechanical air trapping as well as diminished respiratory system compliance with a subsequent reduction in lung volumes. Under reduced tidal volumes less retraction is exerted on the airways from the surrounding lung parenchyma, thereby allowing the airway smooth muscle to contract more readily when activated by various broncho-constricting stimuli [61]. Despite their worse disease severity, obese patients with asthma have not demonstrated increased airway inflammation or airway hyper-responsiveness [62, 63]. For example, exhaled nitric oxide, a highly reproducible indicator of airway inflammation, is not increased in obese asthmatics [62]. Thus, it appears that the increased severity of disease in obese patients with asthma may be more attributable to mechanical factors than airway inflammation. If this is indeed the case, it is not surprising that bronchodilator and corticosteroid therapies appear less efficacious in this patient population [64].

Obstructive Sleep Apnea Obstructive sleep apnea (OSA) is another condition which may complicate the care of an obese child in the PICU. Children with obesity are four to five times more likely to have sleep disordered breathing [65]. There is a positive correlation between obesity and the apnea index, defined as the number of respiratory events divided by the sleep time [65]. A large neck circumference coupled with an abnormal upper airway results in partial or complete airway obstruction while sleeping, causing intermittent hypoxia, hypercapnia, and sleep fragmentation. Patients with OSA display apnea, snoring, paradoxical chest/abdominal motion, and may suffer from daytime somnolence as well as mild cognitive impairment. Positive pressure ventilation for the correction of OSA in pediatric patients is associated with a decreased apnea index and less severe oxygen desaturations; however, compliance with such therapy has shown to be difficult for children [66]. Obese children with accompanying adenotonsillar hypertrophy have improved sleep physiology and

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improved quality of life following adenotonsillectomy [67]. Children with obesity and severe OSA have an altered ventilatory response to carbon dioxide stimulation, and thus are prone to post-operative respiratory complications [68]. Obese and overweight children who underwent adenotonsillectomy were more likely to be admitted following surgery compared with normal weight children [69]. Furthermore, length of stay positively correlated with BMI. Nafiu et al. demonstrated that overweight/obese children had more frequent peri-operative complications such as desaturation, multiple laryngoscopy, and laryngospasm compared with healthy weight subjects [69]. Therefore, the obese patient undergoing adenotonsillectomy may merit hospital observation with a consideration for ICU-level care on the first postoperative night. The economic implications may be substantial for this patient population, as obese children undergoing tonsillectomy have higher hospital costs compared to normal-weight counterparts [70]. The obesity-hypoventilation syndrome (OHS) is a related but distinct entity from OSA. The classic triad encompassing this condition consists of obesity, daytime hypoxemia, and diurnal hypoventilation [2]. While the exact pathogenesis of OHS remains to be elucidated, contributing factors include abnormal respiratory system mechanics, blunted central chemoresponsiveness to hypoxia and hypercapnia, and neurohormonal abnormalities [71]. Patients with obesity hypoventilation syndrome are more likely to require hospitalization for hypercapnic respiratory failure compared to patients with obesity alone, and the management of this disorder involves titration of noninvasive positive pressure ventilation. Additionally, these patients are prone to other clinical problems such as polycythemia, pulmonary hypertension, and cardiac dysrhythmias. Hospitalized patients with OHS required more ICU admissions (40 % vs. 25 %) compared to eucapnic morbidly obese hospitalized patients [72]. Patients with obesity hypoventilation syndrome have a higher mortality rate and are 2.5 times more likely to die than obese patients lacking this comorbidity [2].

Cardiopulmonary Arrest Recovery after in-hospital cardiopulmonary arrest in obese pediatric patients is worse than in non-obese pediatric patients [73]. Obese pediatric patients who receive cardiopulmonary resuscitation (CPR) following an in-hospital cardiopulmonary arrest are less likely to be successfully resuscitated. In a review of the American Heart Association National Registry of Cardiopulmonary Resuscitation, 213 (17 %) of the 1,268 pediatric patients who suffered inhospital cardiac arrest were obese [73]. The authors noted that obese patients were more often pulseless throughout the event and had a first documented rhythm of asystole

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compared with non-obese patients. Obese patients received more epinephrine doses compared with non-obese groups (4 vs. 3 respectively, p < 0.005). Additionally, obese patients were less likely to receive extracorporeal membrane oxygenation therapy (ECMO). Obesity was independently associated with worse rates of event survival as well as survival to hospital discharge [73]. The reasons for these differences may be explained in the effectiveness of the resuscitation efforts. The authors cite the following as reasons for suboptimal resuscitations in the obese child: deviation in effective team function, difficulties with vascular access, difficulties with airway management, ineffective force and depth of chest compressions, confusion over proper medication dosages, and uncertainty regarding defibrillation energy dosages [73]. Advances in medical simulation involving scenarios with the obese critically ill child may alleviate many of these shortcomings.

Venous Thromboembolic Disease Venous thromboembolic (VTE) disease in children was historically thought to occur infrequently but is becoming more prevalent in the pediatric population [74, 75]. Data obtained from a large retrospective cohort study of children 13 1.5 Reprinted from Mehta [86]. With permission from Society of Critical Care Medicine, Copyright 2011

Protein Goals Once energy goals have been determined, the next step is to ensure adequate protein intake to account for the muscle catabolism and the general trend towards negative protein balance during critical illness (Table 6.2). In a recent review of studies reporting protein balance in mechanically ventilated children, we observed a direct correlation between both protein and energy intake and likelihood of achieving a positive protein balance [42]. In general, protein balance improved as protein intake increased [43–48]. Positive balance was achieved in enterally fed infants with viral bronchiolitis with as little as 1.5 g protein/kg/day [45]. While the lowest protein intake associated with a positive balance was 1.5 g/kg/day, individual and grouped thresholds for protein intake associated with achieving a positive protein balance were varied. In parenterally fed, hypermetabolic subjects an intake of 2.8 g protein/kg/day was required to achieve positive nitrogen balance [49, 50]. Severely ill, catabolic patients may be unable to maintain protein balance even with increasing amounts of protein and energy intake during the early and most critical stages of illness [48, 51]. Provision of nutrients during this time is often technically challenged by fluid restriction, interruptions or intolerance to feeding, and difficulty in obtaining enteral or parenteral feeding access [52, 53]. Due to the fixed protein: energy ratio of available enteral nutrition formula, failure to deliver nutritional prescription results in cumulative deprivation of both energy and protein, and anthropometric deterioration. In a recent multicenter study of nutrition practice in mechanically ventilated children, average enteral protein intake in the first 10 days in the PICU was less than 50 % of prescribed [54]. Lean body mass loss from cumulative negative protein balance is particularly concerning in children with pre-existing malnutrition, patients with compromised respiratory reserves and muscle function, and preterm infants with low reserves. Based on our review, protein intake for critically ill infants and children should reach a minimum of 1.5 g/kg/day, which is consistent with the recommendation in the recent American Society for Parenteral and Enteral Nutrition pediatric critical care nutrition guidelines [34]. Groups with a positive protein balance reported a minimum energy intake of 57 kcal/kg/day. The association between energy intake and protein balance in these studies might be

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independent of protein intake. However, existing studies lack uniform study design, consistent methodology for measuring protein balance, and as such, do not allow meaningful interpretation from pooled data. There is an urgent need for studies with clearly defined interventions, larger samples, uniform and reproducible methodology, and longitudinal data points. Future research should consider the effect of increased protein provision on measures of lean body mass, while accounting for energy balance.

Nutrient Delivery in the PICU Enteral Nutrition: Practical Considerations The preferred route of nutrient delivery in critically ill children and adults is via a functional gastrointestinal tract [55]. Enteral nutrition (EN) is recommended in patients with hemodynamic stability and is generally considered to be more physiologic, cost-effective, and with a lower risk of nosocomial infection compared to parenteral nutrition (PN). In adult critically ill patients, EN is associated with beneficial effects on intestinal mucosal permeability, a lower rate of infectious complications, and decreased length of hospital stay [56–58]. To realize the potential benefits of EN in the PICU, both early initiation and maintenance of enteral feeding is recommended. Although the perceived benefits of early EN have not been backed by randomized control trials, it has been uniformly promoted by consensus-based guidelines in pediatric populations, mainly by extrapolation from adult literature [55, 59].

Role of Transpyloric Enteral Feeding in the PICU The optimal site of enteral feeding (gastric vs. postpyloric) remains unclear. In general, gastric feedings are preferred because of ease of administration and reduced costs and expertise required in comparison to transpyloric feedings. In patients with poor gastric emptying or in cases where a trial of gastric feeding has failed, transpyloric or postpyloric (small bowel) feeding may be used to decrease the risk of aspiration and to improve EN tolerance [60]. However, there is no evidence of benefit for routine use of small bowel feeding in all patients admitted to the PICU. In a study examining the role of small bowel feeding in 74 critically ill children randomized to either gastric or postpyloric feedings, there was no significant difference in the incidence of microaspiration, tube displacement, and feeding intolerance between the two groups [61]. The study was not powered to detect differences in mortality. Although caloric goals were only met in a small percentage of the population studied, the proportion of

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subjects who achieved their daily caloric goal was higher in the small bowel group compared with the gastric fed group. The evidence for benefits of postpyloric feeding remains equivocal, even in the adult critical care population [62]. It may be prudent to consider postpyloric feedings in selected patients who do not tolerate gastric feeding or those who are at a high risk of aspiration. Patients with depressed mental status, absent or depressed gag reflexes, severe respiratory distress, recurrent emesis, gastroesophageal reflux, history of aspiration, and delayed gastric emptying are deemed at high risk of aspiration [63]. Successful placement of transpyloric tubes requires the availability of experienced and expert operators, and backup support from radiologists in case bedside placement cannot be achieved. A variety of procedural techniques for transpyloric feeding tube placement have been described, including the use of modified tubes; air insufflation; videoscopic, echocardiographic, or external magnet assistance; and pH-assisted and spontaneous passage with or without promotility agents [64–67]. No single method has been shown to be superior and centers use techniques based on available local experience and expertise. The advent of percutaneously placed gastric and jejunal tubes has minimized cost, time, and morbidity [68]. Tube tip malposition is frequently encountered with any of these devices either at placement or during the course of use [69, 70]. Bedside screening methods for achieving correct tip position range from auscultation during air insufflation to ultrasound-guided tip localization. However, feedings should be held when malposition of tip is suspected, and when in doubt, radiographic confirmation of correct tip position must be obtained before recommencing feedings. Overall, transpyloric feeding is well tolerated in critically ill children and may allow early goal caloric intake by improving tolerance in carefully selected patients [61]. The benefit of transpyloric enteral feeding compared with PN, in terms of decreased complications and costs, must be further examined [71].

Barriers to EN in the PICU Prospective cohort studies and retrospective chart reviews have reported the inability to achieve daily caloric goal in critically ill children. The most common reasons for suboptimal enteral nutrient delivery in these studies are fluid restriction, interruptions to EN for procedures, and EN intolerance due to hemodynamic instability. The percent of estimated energy expenditure actually administered to these subjects was remarkably low. In a study examining the endocrine and metabolic response of children with meningococcal sepsis, goal nutrition was achieved in only 25 % of the cases [12]. Similar observations have been made in a group of 95 children in a PICU where patients received a median of 58.8 % (range 0–277 %) of their estimated energy requirements. In this

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Table 6.3 Barriers to optimal EN and suggested management Barriers to enternal nutrition (EN) in the PICU Barrier Interruptions to EN

Reason Intolerance Procedures Enteral access issues

Fluid restriction

Patients with cardiac or renal conditions

Patient on vasoactive drug(s)

Concerns for gut ischemia

Delayed EN initiation

Failure to prioritize

General reluctance to address nutrition delivery

Failure to prioritize nutrition support

Suggested approach Apply uniform definition, algorithmic guideline Review fasting guidelines for procedures Resume feeding if procedure delayed, canceled or complete Request specialized team for enteral access, radiology collaboration, prompt replacement of displaced enteral tubes Consider concentrated formulae Review other fluids Anticipate and plan with dietitian Prudent to hold EN when actively resuscitating with fluid, hemodynamics worsening or multiple vasoactive drugs required Consider EN if no fluid resuscitation for over 12 h and on single or stable vasoactive support Monitor closely while advancing feeds Educate, develop institution-specific, uniform guidelines for nutrition delivery Create nutrition support teams Request dietitian dedicated to the ICU Involve key stakeholders and develop multiprofessional consensus for nutritional therapy goals

Reprinted from Mehta [86]. With permission from Society of Critical Care Medicine, Copyright 2011

review, EN was interrupted on 264 occasions for clinical procedures. In another review of nutrition intake in 42 patients in a tertiary-level PICU over 458 ICU days, actual energy intake was compared with estimated energy requirement. Only 50 % of patients were reported to have received full estimated energy requirements after a median of 7 days in the ICU [53]. Diagnostic and therapeutic interventions in the PICU often require a fasting state, and hence compete with EN delivery goals. In addition, a significant number of eligible patients are deprived of EN during critical illness because of avoidable factors such as suboptimal nutrient prescription, failure to initiate EN early, and prolonged interruptions to enteral feeding [53, 72, 73]. Delayed initiation and subsequent interruptions contribute to suboptimal EN administration in the PICU. Patients with avoidable EN interruptions in one study experienced significant delays in reaching the prescribed caloric goal and were more likely to be exposed to the higher cost, infectious risks, and other morbidities associated with PN use [52]. Following initiation, EN was interrupted in 24 (30 %) patients at an average of 3.7 ± 3.1 times per patient (range, 1–13), for a total of 88 episodes, accounting for 1,483 h of EN deprivation in this study. A majority of EN interruptions in this study were deemed as avoidable, and nearly a third of the patients did not receive any EN during their PICU course. Fasting for procedures and intolerance to EN were the most common reasons for prolonged EN interruptions. Interventions aimed at optimizing EN delivery must be designed after examining existing barriers to EN and directed at high-risk individuals who are most likely to benefit from these interventions (Table 6.3). In some patients, EN may not be feasible, especially due to intolerance or hemodynamic instability during acute illness.

EN is generally initiated once hemodynamic stability has been achieved. In most centers, ongoing fluid resuscitation, escalating vasopressor medications, and worsening shock may be contraindications for initiating EN. The administration of EN in patients on single vasoactive medications for hemodynamic support in the PICU is probably safe [74]. The interaction between nutrient administration in patients receiving vasoactive and inotropic infusions on gut mucosal perfusion and the risk of mucosal ischemia are complex. In an effort to minimize the likelihood of intestinal ischemic necrosis, EN administration in this group of patients requires a thoughtful approach and robust monitoring for early signs of intolerance. EN intolerance is another challenging bedside dilemma in the PICU. The condition is variably defined, and the use of markers of intolerance such as gastric residual volume (GRV) is not based on sound evidence. The absence of bowel sounds, abdominal distension, vomiting, diarrhea and discomfort are other markers that are used to assess for intolerance to EN. Bedside practice is heterogeneous and EN is interrupted due to perceived intolerance in a large proportion of patients [52].

Strategies to Optimize Macronutrient Intake in the PICU In a large multicenter study of mechanically ventilated children in the PICU, lower energy and protein delivery in relation to estimated requirements was significantly associated with increased mortality [54]. The use of protocolized nutrient delivery was associated with decreased acquired infections in this group. Protocols that provide

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guidelines for early initiation, rapid advancement and maintenance of EN in the PICU have been shown to improve the ability to reach nutrition goals in several cen-

ters [75, 76]. These protocols guide bedside management of intolerance and provide surveillance for safe delivery of enteral nutrients. Figure 6.1 shows an example of a step-

Oral route unavailable OR Unable to protect airway

CONSTIPATION (For age > 1 month / non-nuetropenic)

Nutrition assessment, Weight on admission Identify caloric goal6 HEAD OF BED elevated 30° unless contraindicated7 EVALUATE FOR RISK OF ASPIRATION7 (Depressed gag/cough, altered sensorium, delayed gastric emptying, GE reflux, severe bronchospasm, history of reflux (−) NO ASPIRATION RISK

(+) ASPIRATION RISK

NASOGASTRIC / Gastric Tube FEEDINGS BS BS present / No gastric distension

TRANSPYLORIC (Nasojejunal / Gastrojejunal) FEEDINGS with gastric decompression

Continuous Feedings

NO STOOL AFTER 48 HOURS OF EN Day#1 Prune juice Day#2 Glycerin supp. Docusate (< 3 years: PO 10 mg BID) (3–6 years: PO 20 mg BID) (6–12 years: PO 50 mg BID) (≥12 years: PO 100 mg BID) Senna (Discontinue after 2 normal stools) (1 month–2 years: PO 2.5 mL BID) (2−5 years: PO 3.75 mL BID) (5−12 years: PO 7.5 mL BID) (≥12 years: PO 1 Tab BID)

(−) (+) ABNORMAL GASTRIC NORMAL GASTRIC EMPTYING EMPTYING Fleet Enema (for age > 2 years) - Pediatric Fleets enema: 2 –12 years Bolus Feedings (66 mL/bottle)1 enema - Adult Fleet enema: ≥12 years DIARRHEA (>4 Loose stools/24 h) GOAL CALORIES

GOAL CALORIES TROPHIC FEEDING START: 1–2 mL/kg/h (max 25 mL/h) (or 0.5 mL/kg/h if risk of gut ischemia) ADVANCE: 1 yr: 5–20mL/h q4h until goal reached.

1–2 mL/kg/h or 20 mL/h Full-strength formula or breast milk

START: ½ Goal volume (Full-strength feeding volume required to reach caloric goal). Bolus feedings divided q 3 h (if 6 months of age). If volume intolerant, try smaller volumes more frequently or continuous feedings. ADVANCE: Increase each feeding by 25 % volume until goal reached.

Discontinue laxatives (senna) and stool softenerns (docusate) Discontinue any sorbital-containing medication Review osmolarity of formula Consider withdrawal from opiates Consider change in formula, or hold tube feedings until diarrhea resolves Stool viral studies / Clostridia (C.) difficile Stool C. difficile toxine and culture (if on antimicrobials).

ENTERAL FEEDING INTROLERANCE gastic residual volumes (GRV) recorded prior to each bolus feed or q 4 hrs in patients on continuous gastric feedings with abdominal discomfort, distension or emesis. If GRV > 150 mL; or 5 ml/kg, or >½ volume of previous feeding; or > total 2 hourly infusion rate in patients on continuous feeding-hold feedings and repeat GRV after 2 h. If repeat GRV is elevated, hold feedings and monitor GRV of 4 h. If abdominal distension, (abdominal girth incresed for 2 consecutive measurements) or abdominal discomfort or emesis × 2 -hold feedings for 4 h and reassess.

Fig. 6.1 Approach to EN paper (NCP) – CHB EN algorithm (Reprinted from Mehta [87]. With permission from SAGE Publications)

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wise algorithm for delivering EN in the PICU. In addition, educational intervention and practice changes targeted at high-risk patients and addressing institution-specific deficiencies in practice may decrease the incidence of avoidable interruptions to EN in critically ill children. The role of transpyloric feeding especially in children at risk of aspiration or those who have failed an attempt at gastric feeding has been discussed earlier. Some centers use continuous gastric feeds in an effort to increase tolerance, and the strategy is generally well tolerated [77]. There is not enough evidence to recommend the use of prokinetic medications or motility agents (for EN intolerance or to facilitate enteral access device placement), prebiotics, probiotics, or synbiotics in critically ill children. The use of PN to supplement suboptimal EN in select patients with unavoidable EN interruptions may be reasonable [78]. The safety and efficacy of a mixed EN and PN strategy to reach nutrition goals in critically ill children need to be examined. A recent study in critically ill adults did not show any benefit of early PN introduction in the ICU population, which was associated with higher complication rates when compared to the group where PN was initiated only after 7 days [79]. Optimal enteral delivery of nutrients can only be realized with multidisciplinary commitment to prioritize EN and a specialized nutrition support team has been shown to benefit this goal [80, 81].

Immunonutrition in the PICU The potential of specific nutrients as modulators of the inflammatory or immune response has generated great enthusiasm in employing them in the critically ill population. The properties of nutrients such as arginine, glutamine, aminopeptides, ω -3 fatty acids and antioxidants, have promoted the concept of immunonutrition and elevated nutrition in the ICUs from a supportive to a therapeutic strategy. Unfortunately, several RCTs examining the role of immunonutrition in adult critically ill patients have shown conflicting results. These studies tested immune enhancing diets as a combination of a variety of nutrients administered to heterogeneous patient populations. As a result, the studies do not allow meaningful interpretation of the safety or efficacy of individual nutrients and fail to detect significant differences in relevant clinical outcomes. Systematic reviews of immunonutrition studies in adults seemed to suggest a beneficial role for parenteral glutamine in patients receiving parenteral nutrition, and enteral glutamine in burn and trauma patients [82]. Antioxidants, particularly selenium, have also generated some interest [83]. However, in a recent international trial in critically ill adults, glutamine supplementation was associated with worse outcomes. In this blinded, 2 × 2 factorial trial, 1,223 critically ill adults from

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40 centers were randomized to receive glutamine, antioxidants, both or a placebo within 24 h of admission to the intensive care unit. Patients on mechanical ventilatory support and with multi-organ failure were eligible for enrollment. The results revealed a trend towards higher 28-day mortality in the group receiving glutamine versus those that did not receive glutamine (32.4 % vs. 27.2 %; adjusted odds ratio, 1.28; 95 % confidence interval [CI], 1.00–1.64; P = 0.05). Furthermore, there was a significant increase in mortality while in the hospital and at 6 months, in the glutamine group. Early provision of antioxidants did not improve outcomes in this study. The results of this study are compelling and preclude any attempts to supplement glutamine in high doses early in the course of critical illness. Enteral formulas enriched with fish oils are recommended in patients with acute respiratory distress syndrome. The role of arginine-supplemented diets is controversial and not recommended in septic patients. In general, the data are insufficient to make recommendations on the optimal route, timing, duration and dosage of each nutrient. The role of immune-enhancing EN in children during critical illness has not been extensively studied. Briassoulis et al. randomized mechanically ventilated children in the PICU to receive either a formulation containing glutamine, arginine, ω -3 fatty acids, and antioxidants or standard ageappropriate formulation [43]. No difference in outcome was noted in the 25 children in each arm, although a trend toward a decrease in nosocomial infection rates and positive gastric aspirate culture rates in the treatment arm was noted. The use of a specialized adult immune modulating enteral formula in pediatric burn victims has been associated with improvement in oxygenation and pulmonary compliance in a retrospective review [84]. The immunologically active formulae used in these studies were not specifically tailored for children. A recent RCT of glutamine supplementation in critically ill pediatric population was terminated for futility [85]. In this comparative effectiveness trial, 293 critically ill pediatric patients were randomized to receive a combination of enteral glutamine (0.3 g/kg/day), zinc, selenium and intravenous metoclopramide (GZSM); or enteral whey protein. There were no differences between the groups with respect to time until acquiring nosocomial infection or sepsis (13.2 days whey protein vs. 12.1 days GZSM; p = 0.29). Future pediatric studies in this field might need to focus on examining the effects of single (vs combination of) nutrients, in large (multicenter) trials, on homogeneous PICU populations designed to detect differences in important outcome measures. The adult trials, especially the recent glutamine and antioxidant trial, are cautionary and perhaps hint at a careful investigative approach. The temptation to adopt these strategies prematurely in the heterogeneous PICU population should be avoided, pending a definite evidence of safety and benefit [86, 87].

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Conclusions

Optimizing nutrition therapy is a low cost intervention with potential for improved outcomes during critical illness in children. Increased awareness of the role of nutrition during critical illness and a multidisciplinary effort will ensure that nutrition goals are reached in the PICU population. There is increasing evidence that failure to reach nutrition goals during critical illness is associated with poor patient outcomes. Screening on admission to detect patients who are either malnourished or at risk of nutritional deterioration is the first step. Accurate and sequential assessment of energy and protein requirements, delivery of nutrients early via enteral route when feasible and attention to common hurdles, are prudent measures to ensure optimal nutrient delivery. In recent years, the possibility of modulating immune response by the specific functions of individual nutrients has sparked widespread interest. Future studies must use sound clinical design and multicenter collaboration to elucidate the impact of immunonutrients on outcomes from pediatric critical illness. Other areas needing urgent clarification include, defining and managing intolerance to EN, role of energy balance on clinical outcomes, protein supplementation and balance, and the indications as well as benefits of small bowel feeding. Protocols that provide guidelines for early initiation, rapid advancement and maintenance of EN in the PICU have been shown to improve the ability to reach nutrition goals and their use is associated with improved clinical outcomes. In the interim, it is important to adhere to prudent nutrition practices at the bedside derived by consensus. Nutrition must be recognized as a critical component of care, a discrete discipline, in which all intensivists should reach a minimum level of competence.

8. 9.

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14. 15. 16.

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19. 20.

21.

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6

Nutrition in the PICU

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Part II The Endocrine System in Critical Illness and Injury Jefferson P. Piva

7

Diabetic Ketoacidosis Jefferson P. Piva, Pedro Celiny Ramos Garcia, and Ricardo Garcia Branco

Abstract

The current concepts of physiopathology, diagnosis and treatment of diabetic ketoacidosis (DKA) in childhood, as well as preventive measures to avoid cerebral edema are reviewed in this chapter. Based on the reviewed literature and on the author’s experience, the most efficient and recommended measures for DKA management are presented. Among the main findings we would remark: (a) Normal saline solution (NaCl 0.9 %) remains as the preferred hydration solution. Hypotonic (diluted) solutions are avoided in the treatment of DKA. (b) there is a consensus regarding the contraindication of sodium bicarbonate administration to repair metabolic acidosis in DKA. (c) Regular insulin should be used as continuous infusion (0.1 IU/kg/h) without the need of a loading dose. In small babies with KAD and new onset diabetes, low insulin infusion rates (0.05 IU/kg/h) has been associated with few hypoglycemic episodes as well as with lower impact on the osmolarity, being protective for cerebral edema; (d) For fast corrections of glucose oscillations during DKA treatment, a practical scheme using two bags of electrolytic solutions is presented. (e) Cerebral edema, associated with DKA is a multifactorial process with different pathophysiological mechanisms. Depending on the associated risk for cerebral edema the most efficient treatment measures are reviewed. In conclusion: continuous infusion of regular insulin associated with adequate water and electrolyte replacement using isotonic solutions, besides being an effective treatment for DKA, preserves plasma osmolarity and prevents cerebral edema. Keywords

Diabetes in children ketoacidosis • Hyperglycemia and cerebral edema

J.P. Piva, MD, PhD (*) Pediatric Emergency and Critical Care Department, Hospital de Clinicas de Porto Alegre-Brazil Rua Ramiro Barcelos, 2350 – 10 andar, Porto Alegre (RS), CEP 90035-903, Brazil Department of Pediatrics, School of Medicine, Universidade Federal do Rio Grande do Sul (UFGRS), Rua Ramiro Barcelos, 2350 Porto Alegre (RS), CEP 90035-903, Brazil e-mail: [email protected], [email protected] P.C.R. Garcia, MD, PhD Pediatric Department, Hospital São Lucas da PUCRS Av Ipiranga 6690. H. São Lucas da PUCRS – 5 andar, Porto Alegre, RS 90.610-000, Brazil D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_7, © Springer-Verlag London 2014

Pediatric Intensive Care Unit, H. São Lucas da PUCRS Av Ipiranga 6690–5 andar, Porto Alegre (RS), CEP 90.610-000, Brazil Department of Pediatrics, School of Medicine, Pontificia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil e-mail: [email protected], [email protected] R.G. Branco, MD, PhD Department of Pediatric Intensive Care Unit, Addenbrookes Hospital, Hills road, Cambridge, Cambridgeshire CB2 0QY, UK e-mail: [email protected] 83

84

J.P. Piva et al.

Introduction Diabetic ketoacidosis (DKA) is a frequent cause of admission to the Pediatric Intensive Care Unit (PICU). DKA is a life-threatening condition affecting patients with Diabetes Mellitus (DM) type 1 and less frequently in patients with DM type 2, manifested by hyperglycemia (generally higher than 200 mg/dL), acidosis (pH 1.30 ↓ Rate by 10 mL/h 1.10–1.30 No change 0.90–1.10 ↑ Rate by 10 mL/h ↑ Rate by 20 mL/h 1.5 g/kg/ day of protein. Maxvold et al. compared amino acid losses and nitrogen balance in critically ill pediatric patients requiring CVVH and CVVHD who were receiving similar dialysate or replacement fluid rates and total parenteral nutrition [80]. They noted that amino acid loss was slightly greater with CVVH than with CVVHD and that these losses accounted for approximately 12 and 11 %, respectively, of the total daily protein intake. Micronutrients also are removed by both diffusive and convective CRRT. A negative net balance of selenium, copper, and thiamine while having a slightly positive net balance of zinc has been shown to occur with hemodialfiltration [81]. Trace element supplementation with selenium, and other micronutrients that are water soluble, may be necessary in situations of prolonged CRRT.

Medication Errors Adverse drug events and medication errors are usually due to errors in dialysis fluid or anticoagulation. A study by Barletta based on a survey sent to CRRT clinicians (prior to the use of standardized solutions) reported 50 % errors being harmful, either a prolonged hospital stay, near death event or death [82].

S.S. Sreedhar et al.

CRRT Survival Large scale survival reports with the use of CRRT in the modern era of pediatric critical care remain limited. In 2001, Goldstein et al. at Texas Children’s Hospital retrospectively reported on 21 pediatric patients receiving CVVH therapy, taking into account the patient’s severity of illness by using the PRISM2 score [83]. These authors identified the percentage of fluid overload as a significant predictor of mortality after controlling for severity of illness. Shortly after this report, the ppCRRT was established in order to collect multicenter data on CRRT in pediatric patients at 12 pediatric institutions across the United States. In their initial report of 273 pediatric patients, the ppCRRT found an overall survival rate of 58 %, with patients having hepatic failure or a hepatic transplant having the lowest survival rate (37 %) and those with drug intoxication having the highest survival rate (100 %) [84].

Intermittent Hemodialysis Hemodialysis (HD) is less often used in the PICU situation but has a role in the areas of AKI, in born error or metabolism and in intoxications [85]. HD can be performed for solute clearance only (e.g. urea clearance), or ultrafiltration only or a combination of both. As compared to CRRT (CVVH) or PD, the solute clearance on HD is significantly greater due to a high volume of dialysate turn over (30–50 l/h). HD treatment is often performed within a 2–4 h period of time. Often the goal of fluid removal is achieved easily in that period of time. Due to this need to large ultrafiltration to be achieved in a relatively short period of time, HD is less hemodynamically stable during ultrafiltration removal as compared to CVVH or PD.

Hemodialysis Equipment Vascular access of acute HD is similar to that of CVVH and has been discussed elsewhere. The machines used in HD have the flexibility of variable blood flow rate and dialysate flow rate. Further, the machines generate their own dialysate utilizing a reverse osmosis (RO) system that blends the RO water with an “acid” and a “base” solution that results in an isotonic physiologic ultrapure dialysate solution. As compared to CVVH and PD the cost of dialysate for HD is significantly cheaper. The machines have the capability of modeling up or down the sodium or bicarbonate if needed in some clinical situations. The machines have the ability to turn up or down the temperature of the dialysate to add to cooling or warming of the child. The extracorporeal volume of the HD circuit is made of up the blood lines and the hemodialysis filter. As a rule this total extracorporeal volume should be less than 10 % of the child’s intravascular volume. In some cases, blood priming may be needed to minimize

18 Renal Replacement Therapy

hemodynamic instability at the initiation of HD. Beware that blood bank blood is acidotic (pH of 6.2), hypocalcemic (ionized calcium of 0.04 mmol/l) and hyperkalemic (as great as 40 meq/bag of blood), therefore this needs to be considered at the time of blood priming. Data to date does not identify the “best membrane” used in AKI therapies.

253

can be a detriment (e.g. in elevated urea states) but is often seen as a positive in HD. Excessive ultrafiltration can occur in HD, but in the hands of skilled clinician, the ultrafiltration rate is easily controllable avoiding this complication. Mediation clearance will be more efficient in HD that will result in a greater attention to medication dosing when HD is utilized. Conclusions

Anticoagulation Classically anticoagulation in HD is with heparin with the risk of heparinization of the child during HD therapy. Often, anticoagulation free HD treatments can be performed by using high blood flow rates and short duration treatments.

Hemodialysis Use in Clinical Situations Due to the large volume of dialysate use per hour HD is superior to other forms of RRT when rapid solute clearance is needed. In situations of high potassium, in born error of metabolism and in intoxications, HD is the first line RRT. In situations of a high osmolar state (elevated BUN, elevated sodium, elevated glucose) HD is the least preferred due to the risk of “dialysis disequilibrium” which is a term that describes seizures due to rapid osmolar shifts in a short period of time primarily noted in times of BUNs greater the 100 mg/dl [86]. Inborn error of metabolism and intoxications are similar in their clinical requirements that RRT is used in the face of no AKI but the need for rapid removal of toxins. In these settings it is imperative that the dialysis solution be normal physiologically in potassium and phosphorous to avoid rapid clearance that could result in cardiac or respiratory compromise. In both of these clinical situations HD is preferred as the first therapy of choice due to the rapid clearance of solute. In situations of in born error of metabolism or in certain “two compartment “ drug intoxications (e.g. vancomycin) the serial use of HD followed by CVVH or CVVHD will allow for the initial high clearance then the clearance of the ammonia or intoxicant that will rebound until the clinical situation is resolved.

Renal replacement therapy has evolved over the past 30 years as an efficient and safe treatment for AKI, intoxications and for inborn error of metabolism in pediatric patients. Whether it is CRRT, PD or HD the choice of the RRT is best decided upon by the local skills and experience of the program. The mainstay in the PICU has come front and center to be CRRT. For CRRT, over the last decade advances in new dialysate and replacement fluid solutions are available using bicarbonate as the buffer minimizes cardiovascular instability. The nutritional effects of CRRT are numerous, and include the effects of the dialysate or replacement fluids’ dextrose content, the dextrose content of citrate anticoagulation, and the diffusive and/or convective clearance of amino acids and trace minerals. Data would suggest that targeting a lower limit of carbohydrate intake while maximizing amino acids to around >2 g/kg/day may improve glycemic control and improve outcome. The effect of CRRT clearance of trace elements is unclear at this time, but protracted CRRT treatments may result in clinically significant disorders. Anticoagulation for maintenance of the CRRT circuit is critical to providing adequate fluid and electrolyte therapy in the pediatric patient with AKI, and citrate anticoagulation appears to have multiple benefits over heparin anticoagulation. Vascular access is critical for proper functioning of a CRRT circuit, and ideally should be the largest catheter possible with a targeted blood flow rates as high as 400 mL/min/1.73 m2. Finally, CRRT is a useful therapy in many special situations, including hyperosmolality, intoxications; hematopoietic cells transplantation, tumor lysis syndrome prevention, extracorporeal hepatic support, and can be coupled with plasmapheresis.

Outcome in Hemodialysis

References Little HD pediatric specific literature exists for the treatment of AKI or inborn error of metabolism but more in intoxications. This form of RRT remains one more form of RRT needed in the critical care arena for the care of complicated patients.

Complications of Hemodialysis As mentioned early, as compared to CVVH or PD, thermic control is easier to achieve in HD. Excessive solute clearance

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254 5. Zappitelli M, Bernier PL, Saczkowski RS, et al. A small postoperative rise in serum creatinine predicts acute kidney injury in children undergoing cardiac surgery. Kidney Int. 2009;76(8):885–92. 6. Devarajan P. Biomarkers for the early detection of acute kidney injury. Curr Opin Pediatr. 2011;23(2):194–200. Review. 7. Haase M, Devarajan P, Haase-Fielitz A, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57(17):1752–61. 8. Askenazi D. Evaluation and management of critically ill children with acute kidney injury. Curr Opin Pediatr. 2011;23:201–7. 9. Shilliday IR, Quinn KJ, Allison ME. Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebocontrolled, randomized study. Nephrol Dial Transplant. 1997;12: 2592–6. 10. Lameire N, Vanholder R, Van Biesen W. Loop diuretics for patients with acute renal failure: helpful or harmful? JAMA. 2002;288:2599–601. 11. Cerda J, Sheinfeld G, Ronco C. Fluid overload in critically ill patients with acute kidney injury. Blood Purif. 2010;29(4):331–8. 12. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis. 2010;55:316–25. 13. Hayes LW, Oster RA, Tofil NM, Tolwani AJ. Outcomes of critically ill children requiring continuous renal replacement therapy. J Crit Care. 2009;24:394–400. 14. Foland JA, Fortenberry JD, Warshaw BL. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med. 2004;32(8):1771–6. 15. Goldstein SL. Advances in pediatric renal replacement therapy for acute kidney injury. Semin Dial. 2011;24(2):187–91. 16. DiCarlo JV, Alexander SR, Agarwal R, Schiffman JD. Continuous veno-venous hemofiltration may improve survival from acute respiratory distress syndrome after bone marrow transplantation or chemotherapy. J Pediatr Hematol Oncol. 2003;25(10):801–5. 17. Flores FX, Brophy PD, Symons JM, et al. Continuous Renal Replacement Therapy (CRRT) after stem cell transplantation. A report from the prospective pediatric CRRT Registry Group. Pediatr Nephrol. 2008;23:625–30. 18. Ansari N. Peritoneal dialysis in renal replacement therapy for patients with acute kidney injury. Int J Nephrol. 2011;2011:739794. Epub 2011 Jun 8. 19. Katz A, Kashtan CE, Greenberg LJ, et al. Hypogammaglobulinemia in uremic infants receiving peritoneal dialysis. J Pediatr. 1990; 117:258–61. 20. Bunchman TE, Wood EG, Lynch RE. Hydrothorax as a complication of pediatric peritoneal dialysis. Perit Dial Bull. 1987;7:237–9. 21. Forni LG, Hilton PJ. Continuous hemofiltration in the treatment of acute renal failure. N Engl J Med. 1997;336(18):1303–9. 22. Jenkins R, Harrison H, Chen B, Arnold D, Funk J. Accuracy of intravenous infusion pumps in continuous renal replacement therapies. ASAIO J. 1992;38(4):808–10. 23. Hackbarth R, et al. The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry. Int J Artif Organs. 2007;30:1116–21. 24. Davenport A, Will EJ, Davison AM. Hyperlactatemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron. 1991;59:461–5. 25. Davenport A, Aulton K, Payne RB, Will EJ. Hyperlactatemia and increasing metabolic acidosis in hepatorenal failure treated by hemofiltration. Ren Fail. 1990;12:99–101. 26. Thomas AN, Guy JM, Kishen R, Geraghty IF, Bowles BJM, Vadgama P. Comparison of lactate and bicarbonate buffered haemofiltation fluids: use in critically ill patients. Nephrol Dial Transplant. 1997;12:1212–7.

S.S. Sreedhar et al. 27. Zimmerman D, Cotman P, Ting R, Karanicolas S, Tobe SW. Continuous veno-venous haemodialysis with a novel bicarbonate dialysis solution: prospective cross-over comparison with a lactate buffered solution. Nephrol Dial Transplant. 1999;14:2387–91. 28. Maxvold NJ, Flynn JT, Smoyer WE, et al. Prospective, crossover comparison of bicarbonate vs lactate-based dialysate for pediatric CVVHD. Blood Purif. 1999;17:27. 29. Barenbrock M, Hausberg M, Matzkies F, de la Motte S, Schaefer RM. Effects of bicarbonate- and lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients. Kidney Int. 2000; 58:1751–7. 30. McLean AG, Davenport A, Cox D, Sweny P. Effects of lactatebuffered and lactate-free dialysate in CAVHD patients with and without liver dysfunction. Kidney Int. 2000;58:1765–72. 31. Bunchman TE, Maxvold NJ, Barnett J, Hutchings A, Benfield MR. Pediatric hemofiltration: Normocarb® dialysate solution with citrate anticoagulation. Pediatr Nephrol. 2002;17:150–4. 32. Bunchman TE, Maxvold NJ, Brophy PD. Pediatric convective hemofiltration (CVVH): Normocarb replacement fluid and citrate anticoagulation. Am J Kidney Dis. 2003;42:1248–52. 33. Manns M, Sigler MH, Teehan BP. Continuous renal replacement therapies: an update. Am J Kidney Dis. 1998;32:185–207. 34. O’Shea SI, Oftel TL, Kovalik EC. Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia. Sem Dial. 2003;16:61–7. 35. Mehta RL, McDonald BR, Aguilar MM, Ward DM. Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int. 1990;38:976–81. 36. Chadha V, Garg U, Warady BA, Alon US. Citrate clearance in children receiving continuous venovenous renal replacement therapy. Pediatr Nephrol. 2002;17:819–24. 37. Meier-Kriesche HU, Gitomer J, Finkel K, Dubose T. Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med. 2001;29: 748–52. 38. Monchi M, Berghams D, Ledoux D, Canivet JL, Dubois B, Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med. 2004;30:260–5. 39. Brophy PD, Somers MJG, Baum MA, et al. Multi-centre evaluation of anticoagulation in patients receiving Continuous Renal Replacement Therapy (CRRT). Nephrol Dial Transplant. 2005;20: 1416–21. 40. Heney D, Essex-Cater A, Brocklebank JT, Bailey CC, Lewis IJ. Continuous arteriovenous haemofiltration in the treatment of tumor lysis syndrome. Pediatr Nephrol. 1990;4:245–7. 41. Saccente SL, Kohaut EC, Berkow RL. Prevention of tumor lysis syndrome using continuous veno-venous hemofiltration. Pediatr Nephrol. 1995;9:569–73. 42. Lin JJ, McKenney DW, Price C, Morrison RR, Novotny WE. Continuous venovenous hemodiafiltration in hypernatremic hyperglycemic nonketotic coma. Pediatr Nephrol. 2002;17:969–73. 43. McBryde KD, Bunchman TE, Kudelka TL, Pasko DA, Brophy PD. Hyperosmolar solutions in continuous renal replacement therapy for hyperosmolar acute renal failure: a preliminary report. Pediatr Crit Care Med. 2005;6:220–5. 44. Hingorani SR, Guthrie K, Batchelder A, et al. Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors. Kidney Int. 2005;67:272–7. 45. Borkan SC. Extracorporeal therapies for acute intoxications. Crit Care Clin. 2002;18:393–420. 46. Bunchman TE, Ferris ME. Management of toxic ingestions with the use of renal replacement therapy. Pediatr Nephrol. 2011;26(4): 535–41. 47. Mokhlesi B, Leikin JB, Murray P, Corbridge TC. Adult toxicology in critical care: part II: specific poisonings. Chest. 2003;123: 897–922.

18 Renal Replacement Therapy 48. Goebel J, Ananth M, Lewy JE. Hemodiafiltration for vancomycin overdose in a neonate with end-stage renal failure. Pediatr Nephrol. 1999;13:423–5. 49. Meyer RJ, Flynn JT, Brophy PD, et al. Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis. 2001;37:1044–7. 50. Christiansson LK, Kaspersson KE, Kulling PE, Ovrebo S. Treatment of severe ethylene glycol intoxication with continuous arteriovenous hemofiltration dialysis. J Toxicol Clin Toxicol. 1995;33:267–70. 51. Domoto DT, Brown WW, Bruggensmith P. Removal of toxic levels of N-acetylprocainamide with continuous arteriovenous hemofiltration or continuous arteriovenous hemodiafiltration. Ann Intern Med. 1987;106:550–2. 52. Okada S, Teramoto S, Matsuoka R. Recovery from theophylline toxicity by continuous hemodialysis with filtration. Ann Intern Med. 2000;133:922. 53. Pasko DA, Grio M, Thomas S, Mottes T, Brophy PD. Methotrexate transmembrane clearance during albumin based continuous venovenous hemodialysis. Blood Purif. 2005;23:149–74. 54. Jalan R, Sen S. Extracorporeal albumin dialysis for intoxication from protein-bound agents. Crit Care Med. 2004;32:1436–7. 55. Askenazi DJ, Goldstein SL, Chang IF, Elenberg E, Feig DI. Management of a severe carbamazepine overdose using albuminenhanced continuous venovenous hemodialysis. Pediatrics. 2004;113:406–9. 56. Churchwell MD, Pasko DA, Smoyer W. Enhanced valproic acid dialytic clearance with an albumin-based dialysate in continuous venovenous hemodialysis. Blood Purif. 2005;23:149–74. 57. Braun MC, Welch TR. Continuous venovenous hemodiafiltration in the treatment of acute hyperammonemia. Am J Nephrol. 1998;18:531–3. 58. Jouvet P, Poggi F, Rabier D, et al. Continuous venovenous haemodiafiltration in the acute phase of neonatal maple syrup urine disease. J Inherit Metab Dis. 1997;20:463–72. 59. Wong KY, Wong SN, Lam SY, Tam S, Tsoi NS. Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration. Pediatr Nephrol. 1998;12:589–91. 60. Picca S, Dionisi-Vici C, Abeni D, et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol. 2001;16:862–7. 61. Deodato F, Boenzi S, Rizzo C, et al. Inborn errors of metabolism: an update on epidemiology and on neonatal-onset hyperammonemia. Acta Paediatr Suppl. 2004;445:18–21. 62. Bunchman TE, Barletta GM, Winters JW, et al. Phenylacetate and benzoate clearance in a hyperammonemic infant on sequential hemodialysis and hemofiltration. Pediatr Nephrol. 2007;22(7):1062–5. 63. Eding DM, Jelsma LR, Metz CJ, et al. Innovative techniques to decrease blood exposure and minimize interruptions in pediatric continuous renal replacement therapy. Crit Care Nurse. 2011;31(1): 64–71. 64. Proulx F, Fayon M, Farrell CA, Lacroix J, Gauthier M. Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest. 1996;109:1033–7. 65. Askenazi DJ, Ambalavanan N, Hamilton K, Cutter G, Laney D, Kaslow R, Georgeson K, Barnhart DC, Dimmitt RA. Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011;12(1):e1–6. 66. Goldstein SL, Symons JM, Somers MJG, et al. Pediatric CRRT for multiorgan dysfunction syndrome (MODS): a prospective pediatric (ppCRRT) CRRT registry group report. Blood Purif. 2005;23: 149–74. 67. Bunchman TE. Plasmapheresis and renal replacement therapy in children. Curr Opin Pediatr. 2002;14:310–4.

255 68. Ponikvar R, Kandus A, Urbančič A, Kornhauser AG, Primožič J, Ponikvar JB. Continuous renal replacement therapy and plasma exchange in newborns and infants. Artif Organs. 2002;26:163–8. 69. Symons JM, Brophy PD, Gregory MJ, et al. Continuous renal replacement therapy in children up to 10 kg. Am J Kidney Dis. 2003;41(5):984–9. 70. Paden ML, Warshaw BL, Heard ML, Fortenberry JD. Recovery of renal function and survival after continuous renal replacement therapy during extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011;12(2):153–8. 71. Meyer RJ, Brophy PD, Bunchman TE, et al. Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration. Pediatr Crit Care Med. 2001;2(3):238–42. 72. Brophy PD, Mottes TA, Kudelka TL, et al. AN-69 membrane reactions are pH-dependent and preventable. Am J Kidney Dis. 2001;38(1):173–8. 73. Parshuram CS, Cox PN. Neonatal hyperkalemic-hypocalcemic cardiac arrest associated with initiation of blood-primed continuous venovenous hemofiltration. Pediatr Crit Care Med. 2002;3(1):67–9. 74. Pasko DA, Mottes TA, Mueller BA. Pre dialysis of blood prime in continuous hemodialysis normalizes pH and electrolytes. Pediatr Nephrol. 2003;18:1177–83. 75. Hackbarth RM, Eding D, Smith CG, Koch A, Sanfilippo DJ, Bunchman TE. Zero-balance ultrafiltration (Z-BUF) in bloodprimed CRRT circuits achieves electrolyte and acid-base homeostasis prior to patient connection. Pediatr Nephrol. 2005;20:1328–33. 76. Joy MS, Matzke GR, Armstrong DK, Marx MA, Zarowitz BJ. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother. 1998;32:362–75. 77. Monaghan R, Watters JM, Clancey SM, Moulton SB, Rabin EZ. Uptake of glucose during continuous arteriovenous hemofiltration. Crit Care Med. 1993;21:1159–63. 78. Frankenfield DC, Reynolds HN, Badellino MM, Wiles 3rd CE. Glucose dynamics during continuous hemodiafiltration and total parenteral nutrition. Intensive Care Med. 1995;21:1016–22. 79. Fiaccadori E, Lombardi M, Leonardi S, Roteli CF, Tortorella G, Borghetti A. Prevalence and clinical outcomes associated with preexisting malnutrition in acute renal failure: a prospective cohort study. J Am Soc Nephrol. 1999;10:581–93. 80. Maxvold NJ, Smoyer WE, Custer JR, Bunchman TE. Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med. 2000;28: 1161–5. 81. Berger MM, Shenkin A, Revelly JP, et al. Copper, selenium, zinc, and thiamine balances during continuous venovenous hemodiafiltration in critically ill patients. Am J Clin Nutr. 2004;80:410–6. 82. Barletta JF, Barletta GM, Brophy PD, et al. Medication errors and patient complications with continuous renal replacement therapy. Pediatr Nephrol. 2006;21:842–5. 83. Goldstein SL, Currier H, Graf JM, Cosio CC, Brewer ED, Sachdeva R. Outcomes in children receiving continuous venovenous hemofiltration. Pediatrics. 2001;107:1309–12. 84. Goldstein SL, Somers MJ, Baum MA, et al. Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int. 2005;67(2):653–8. 85. Donckerwolcke RA, Bunchman TE. Hemodialysis in infants and small children. Pediatr Nephrol. 1994;8(1):103–6. 86. Bunchman TE, Hackbarth RM, Maxvold NJ, et al. Prevention of dialysis disequilibrium by use of CVVH. Int J Artif Organs. 2007; 30(5):441–4. 87. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73:391–8.

Part IV The Hematologic System in Critical Illness and Injury Jacques Lacroix

Transfusion Medicine

19

Marisa Tucci, Jacques Lacroix, France Gauvin, Baruch Toledano, and Nancy Robitaille

Abstract 

Anemia is common in pediatric intensive care units (PICU). Severe anemia can s­ ignificantly increase the risk of death. Only a red blood cell (RBC) transfusion can rapidly treat a severe anemia. In stable PICU patients, RBC transfusion is probably not required if the hemoglobin concentration is above 7 g/dL, unless the patient has a cyanotic cardiac condition. The trigger or goal that should be used to direct RBC transfusion therapy in unstable critically ill children remains undetermined, although some data suggest that RBC transfusion may help in the early treatment of unstable patients with sepsis if their ScvO2 is below 70 % after mechanical ventilation, fluid challenge, and inotropes/vasopressors perfusions have been initiated. Plasma and platelets are used to prevent or to treat hemorrhage attributable to a coagulopathy, thrombocytopenia or platelet dysfunction. The risks and benefits of plasma and platelet concentrates in PICU patients are discussed. There is almost no evidence at the present time that might permit a strong recommendation with regard to the use of plasma and platelets in PICU. Good knowledge of transfusion reactions is required in order to appropriately estimate the cost/benefit ratio of transfusion. Nowadays, non-infectious serious hazards of transfusion (NISHOT) are more frequent and more challenging for pediatric intensivists than transfusion-transmitted infectious diseases. The decision to prescribe a ­transfusion must be tailored to individual needs and repeated clinical evaluation of each critically ill child. Keywords 

Anemia • Erythrocyte • Plasma • Platelets • Transfusion

M. Tucci, MD Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, 3175 Cote Sainte-Catherine, Montreal, QC H3T 1C5, Canada e-mail: [email protected] J. Lacroix, MD (*) Department of Pediatrics, Sainte-Justine Hospital 3175 Cote Sainte-Catherine, Montreal, QC H3T 1C5, Canada e-mail: [email protected] F. Gauvin, MD, FRCPC, MSc • B. Toledano, MD, FRCPC, MSc Division of Pediatric Critical Care Medicine, Department of Pediatrics, Faculté de Médecine, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada N. Robitaille, MD, FRCPC Division of Hematology-Oncology, Department of Pediatrics, Faculté de Médecine, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_19, © Springer-Verlag London 2014

Transfusion of Red Blood Cells Anemia in the PICU Anemia—defined as a hemoglobin (Hb) concentration below the “normal” range for age—has been reported to occur up to 74 % of critically ill children with a pediatric intensive care unit (PICU) stay longer than 2 days. Indeed, anemia is already present at the time of PICU admission in 33 % of children, and an additional 41 % develop anemia during their PICU stay [1]. Patients who become anemic gradually over a long period of time and who are chronically anemic are more tolerant of their anemic state than those who develop anemia acutely. The main symptoms and signs of acute anemia are 259

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not specific and include pallor, tachycardia, lethargy and weakness. An increased blood lactate level and elevated oxygen (O2) extraction ratio (>40 %) can also be observed in severe cases [2]. The etiology of anemia may be attributable to: (1) blood loss, (2) decreased bone marrow production, which may in part be secondary to a disturbed bone marrow response to erythropoietin [3], (3) decreased RBC survival [4], and (4) anemia due to underlying diseases such as cancer and congenital hemoglobinopathies. However, blood loss is the most important cause of anemia acquired in the PICU. Blood draws account for 70 % of all blood loss (0.32 mL/kg/day in PICU), and procedures and hemorrhage are other causes of blood loss [1]. In healthy animals undergoing acute hemodilution, evidence of heart dysfunction appears only once the Hb concentration drops below 3.3–4 g/dL [5, 6]. However, animals with 50–80 % coronary artery stenosis can show evidence of ischemic insult to the heart with a Hb concentration as high as 7–10 g/dL [7]. In human beings, Carson et al. [8] studied the outcome after surgery in 1,958 patients who declined transfusion for religious reasons; the odds ratio for death started to increase in those with prior ischemic heart disease when their pre-operative Hb concentration decreased below 10 g/dL. Carson et al. [9] also studied the outcome after surgery in 300 patients without prior ischemic heart disease who declined transfusion for religious reasons. The odds ratio for death started to increase when the post-operative Hb concentration dropped below 4 g/dL. There are some data describing the relationship between anemia in severely ill children and mortality. A prospective cohort study in Kenya of 1,269 hospitalized children with malaria showed that RBC transfusions decreased death rate if anemia was severe (Hb level < 4 g/dL) or if some dyspnea was associated with a Hb level < 5 g/dL [10]. In another study conducted in Kenya, Lackritz et al. [11] followed 2,433 hospitalized children younger than 12 years with chronic or acute anemia among which 20 % received RBC transfusions. Some benefit was observed when a RBC transfusion was given to patients with a Hb level below 4.7 g/dL, and if there were signs and symptoms of respiratory disease. Given these results, guidelines were written suggesting that a RBC transfusion should be given to all children with a Hb level < 5 g/dL hospitalized in this Kenyan hospital. Subsequently, Lackritz et al. [12] undertook a prospective study in 1,223 consecutively hospitalized children. The Hb level was 5 g/dL; none of the latter children with a Hb level > 5 g/dL received a

M. Tucci et al.

RBC transfusion. Overall mortality was 30 % in the 303 children with a Hb level < 5 g/dL and 19.5 % in those with a Hb level > 5 g/dL (p  70%, SVC flow > 40 mL/Kg/min & Cl 3.3 L/m2/min

shock not reversed? Refractory shock: Rule out & correct pericardial effusion, pneumothorax, Use hydrocortisone for absolute adrenal insufficiency, and T3 for hypothyroidism. Begin pentoxifylline if VLBW newborn. Consider closing PDA if hemodynamically significant.

antibiotic administration. For example, Gaieski and colleagues showed that mortality significantly increased when antibiotics were delayed beyond 1 h in critically ill adults presenting to the ED with severe sepsis and septic shock [280]. A study by Kumar and colleagues showed that only 50 % of patients received antibiotics within 6 h of documented hypotension, which was associated with increased risk for mortality [267]. A protocolized approach to the management of sepsis has been shown to improve the time to administration of antibiotics in several studies involving both children [281–283] and adults presenting to the ED [284– 289]. Indeed, this kind of approach has even been successful in resource-poor countries. For example, studies conducted in a rural population in India showed that home administration of oral and injectable antibiotics to neonates with perinatal-acquired sepsis resulted in significant reductions in

shock not reversed? ECMO

sepsis-related neonatal mortality – sustained over a 10-year period [290, 291]. Early source control and antibiotic administration have also been emphasized in the highly successful Surviving Sepsis Campaign (SSC) [292], a joint collaboration between the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine. The resuscitation bundle for managing critically ill adults with sepsis calls for broad-spectrum antibiotics to be administered within 3 h of ED admission and/or 1 h of ICU admission [293–295]. Notably, the SSC (discussed further below) enrolled over 15,022 patients from 165 centers from January, 2005 through March, 2008. Compliance with the resuscitation and management bundles was associated with a significant reduction in hospital mortality [296].

30 Sepsis

Early Reversal of Shock Early reversal of the shock state with aggressive resuscitation targeted at rational therapeutic endpoints represents the third pillar in the management of pediatric sepsis. While it has been known for several years that early reversal of shock improves outcomes in critically ill children [54, 269, 297], the concept known as early goal-directed therapy (EGDT) was initially popularized following the publication of the study by Rivers and colleagues, which showed that EGDT significantly improved outcomes [298]. All patients had arterial and central venous catheters placed in the ED, and therapy was protocolized to achieve a CVP 8–12 mmHg with fluid resuscitation, MAP >65 mmHg and 65 mmHg and 5 mL/kg/h. In-hospital mortality was significantly lower in the EGDT group compared to the conventional therapy group (30.5 % vs. 46.5 %, respectively, p = 0.009). Differences in outcomes were noted despite the fact that the groups received the same treatment after the initial 6 h of therapy. The EGDT trial is one of only a few studies that have been published to date that have shown a reduction in mortality from sepsis and highlights the importance of early recognition and aggressive resuscitation of shock. A subsequent meta-analysis of 21 randomized, controlled trials of sepsis by Kern and Shoemaker [299] further highlights the importance of early, goal-directed therapy, demonstrating that when patients with acute critical illness are treated early to achieve optimal goals before the development of organ failure, significant reductions in mortality are achieved [294, 300]. In addition, there are currently three prospective, multicenter, randomized clinical trials going on in the United Kingdom, U.S., and Australia that are further testing the overall validity of this concept in critically ill adults with severe sepsis/septic shock. The Surviving Sepsis Campaign conducted a multicenter, international, prospective, collaborative involving over 15,000 patients worldwide. Increasing compliance with a 6-h resuscitation bundle (focused on early antibiotics and rapid reversal of shock) and maintenance bundle (focused more on lung-protective ventilation, stress ulcer prophylaxis, glucose control, corticosteroids for vasopressor-refractory shock, activated protein C) was associated with significant reductions in mortality at participating hospitals [296]. There has since been significant controversy regarding both the use of activated Protein C and “tight glucose control” in critically ill patients with severe sepsis and septic shock. A similar quasi-experimental study in Spain showed that compliance with the resuscitation bundle was more important than the maintenance bundle [301].

469 Table 30.5 Surviving Sepsis Campaign (SSC) bundles To be completed within 3 h 1. Measure lactate level 2. Obtain blood cultures prior to administration of antibiotics 3. Administer broad spectrum antibiotics 4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L To be complete within 6 h 1. Apply vasopressors (for fluid-refractory hypotension) to maintain a mean arterial blood pressure ≥65 mmHg (adult) 2. If the patient remains hypotensive despite fluid resuscitation or initial lactate ≥4 mmo/L (a) Measure central venous pressure (CVP) (b) Measure central venous oxygen saturation (SCVO2) Remeasure lactate if initial lactate was elevated

Based on these results and the aforementioned controversies, the Surviving Sepsis Campaign has changed the bundles to de-emphasize care beyond 6 h (see the Surviving Sepsis Campaign website at http://www.survivingsepsis.org/ Bundles/Pages/default.aspx) (Table 30.5). Preliminary studies suggest that EGDT may be beneficial in select groups of critically ill children with sepsis [54, 282, 283, 302, 303]. Additionally, investigators at St. Mary’s Hospital-London developed a protocol for managing critically ill children with meningococcal sepsis [297] and were able to demonstrate a dramatic reduction in mortality from 23 % in 1993 to 2 % in 1997 [266]. This protocol similarly emphasized early recognition and has been modified [269] and adapted into a National Institute for Health and Clinical Excellence (NICE) guideline in the United Kingdom [304]. Based upon the studies published above, it is imperative that resuscitation should begin as soon as the sepsis syndrome is recognized, usually in the ED, and should not be delayed until admission to the PICU [54, 57, 305, 306]. During the first 6 h the aim is to achieve the following goals: 1. Capillary refill 70 % 5. Declining lactate and base deficit 6. Improved level of consciousness

Fluid Resuscitation Critically ill children with severe sepsis and/or septic shock almost universally have decreased effective intravascular volume for a variety of reasons. Many of these children have had poor oral intake of fluid for a period of time prior to developing sepsis. With the development of increased vascular permeability, intravascular volume has been lost due to third spacing. Finally, peripheral vasodilation related to excessive NO production (see above) results in an abnormally

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increased vascular capacitance, decreasing the effective circulating volume. Aggressive fluid resuscitation with crystalloids or colloids is therefore essential to increase survival of septic shock in children. This goal can be reached by administering 20 mL/kg boluses over 5-10 min, repeated as necessary to achieve the hemodynamic goals stated in the preceding paragraph [305, 306]. Large fluid deficits are typically encountered, requiring 60 mL/kg volume resuscitation or occasionally much higher amounts [305]. Transfusion of packed red blood cells should be considered to maintain hemoglobin levels at levels consistent with adequate oxygen delivery, though the optimal hemoglobin for infants and children with septic shock is not currently known. The available evidence suggests that the different types of intravenous fluid available for fluid resuscitation are similar in terms of efficacy, both in pediatric [307–310] and adult studies [311–313]. There is perhaps one caveat, in that there is some preliminary data suggesting a mortality benefit with colloid compared to crystalloid in critically ill children with severe sepsis secondary to malaria [314, 315]. In recent years, several studies have shown a correlation between fluid overload and increased mortality in critically ill children requiring renal replacement therapy [316–319]. Fluid overload has also been shown to correlate with impaired oxygenation, longer duration of mechanical ventilation, and increased PICU and hospital length of stay (LOS), even in critically ill children who do not require renal replacement therapy [320]. Preliminary data from our group suggests that fluid overload is associated with worse outcomes in critically ill children with a low initial probability of mortality, but not in children with an intermediate-risk or high-risk of mortality (Wong, personal communication). The recently published FEAST trial has led to further questions on the utility of fluid resuscitation in critically ill children with severe sepsis and septic shock. In this prospective, randomized, controlled study, children presenting to the hospital (in Uganda, Kenya, or Tanzania) with a severe febrile illness received one of three treatments: 20–40 mL/kg 5 % albumin, 20–40 mL/kg 0.9 % saline, or no fluid bolus. There were no differences in mortality at 48 h between the saline (110/1,047 children, 10.5 %) and albumin (111/1,050 children, 10.6 %) groups, though mortality was lowest (76/1,044 children, 7.3 %) in the control group that did not receive a fluid bolus. These results were consistent across all sub-group analyses [321]. A follow-up analysis of these results showed that excess mortality occurred as a result of cardiovascular collapse and not fluid overload (pulmonary edema, neurologic deterioration, etc.) [322]. Given the accumulation of several decades of experience with intravenous fluid resuscitation, it would seem premature to abandon (or even temper) this therapy without additional data. In addition, it should be noted that the FEAST study and the majority of the aforementioned studies comparing crystalloid to colloid in children were performed in patient populations (e.g., dengue fever, severe malaria, severe malnutrition,

J.L. Wynn et al.

etc.) that are quite different from the majority of critically ill children with shock in the developed world. Whether these findings can be generalized to different populations around the world remains an area of active study. In light of the remaining questions and available data, the usual practice in most PICUs is to initiate volume resuscitation with crystalloid fluids as a first line and follow with colloid if needed. Collectively, these data further strengthen the concept of carefully titrating fluid resuscitation and other therapies to rational therapeutic endpoints in a protocolized fashion, consistent with the American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock [67]. Again, reliable implementation of these guidelines has resulted in improved outcomes in at least a few published reports [54, 302, 303].

Hemodynamic Support While the principles of hemodynamic monitoring and support have been discussed elsewhere in this textbook, a brief discussion here is justified. In the case of fluid refractory shock, inotropic or vasoactive support should be started without delay. Again, the most common hemodynamic derangements observed in critically ill children with septic shock are low cardiac output and high systemic vascular resistance (i.e., socalled cold shock). Dopamine has traditionally been the initial agent of choice for infants and children with septic shock [306], though the choice of additional agents will be determined by the clinical condition of the child. For example, dobutamine or epinephrine may be preferable in children with low cardiac output and poor peripheral perfusion (cold shock), especially given the association of dopamine with increased morbidity and mortality in several studies [323]. In addition, there have been some observational studies in both critically ill children and adults suggesting that dopamine may be associated with an increased risk of morbidity and mortality [324–326]. Norepinephrine is the preferred agent for children with normal cardiac output and bounding peripheral pulses (warm shock). A type III phosphodiesterase inhibitor such as milrinone may also improve perfusion in children with cold shock, who are adequately volume resuscitated, though hypotension is always a risk with this agent. Regardless of the vasoactive regimen chosen, close monitoring of the oxygen delivery, as assessed by end-organ function, mixed venous oxygen saturation and a falling lactate levels, is necessary to tailor ongoing treatment. Finally, extracorporeal life support (ECLS) may be necessary and lifesaving in select patients [327–332].

Supportive Care Children with sepsis may have poor nutrition prior to presentation and are often not fed in the first few days of illness. Because of increased metabolic rate and poor nutrition,

30 Sepsis

septic patients are frequently catabolic and at risk for the development of protein calorie malnutrition [333]. Intestinal ischemia in association with the loss of the mucosal barrier from malnutrition has been associated with translocation of bacteria and endotoxin from the intestine into the blood stream [334, 335]. Use of enteral feeding in critical illness has been shown to improve survival and decrease hospital stay [336]. The benefit of enteral feeding should be balanced with the risk of stressing the intestinal function in the face of poor splanchnic perfusion, especially in the presence of vasopressors such as epinephrine and norepinephrine [337, 338]. Regardless of the mode of feeding, adequate nutrition and nitrogen balance is important for maintaining adequate host immune function and achieving homeostasis. Malnutrition may adversely affect the immune function and the ability to have an appropriate immune response [339]. Finally, in the absence of enteral feedings, protection from stress-related gastrointestinal bleeding is advised.

Corticosteroids High pharmacologic doses of corticosteroids were used in the past in an attempt to turn off the systemic inflammatory response associated with sepsis. However, most of the studies suggested that high-dose corticosteroids did not improve survival in septic patients and may even have worsened outcome by increasing the incidence of secondary infection [340]. However, more recent data suggests that patients, who are critically ill, in persistent shock, requiring vasopressors and mechanical ventilation, might benefit from physiological doses of corticosteroids [341]. This finding has not been confirmed in other studies [342]. Some investigators have postulated that some patients with sepsis may have a relative adrenal insufficiency despite normal serum cortisol levels, because of desensitization of corticosteroid responsiveness [343, 344]. This has been shown in critically ill children with meningococcal sepsis [345] and in other forms of sepsis [343]. Unfortunately, there have been no randomized, controlled studies of corticosteroid replacement in critically ill children with severe sepsis or septic shock. The most recent Surviving Sepsis Campaign guidelines [300] recommend corticosteroids only if the patient remains refractory to vasoactive medications. In addition, use of the ACTH stimulation test to discern between relative and absolute adrenal insufficiency is not necessary. The pediatric version of these guidelines suggests starting stress-dose hydrocortisone (50–100 mg/m2/day hydrocortisone) in critically ill children with fluid-refractory and catecholamine-resistant septic shock and suspected or proven absolute adrenal insufficiency (i.e., after appropriate diagnostic workup with a random/basal serum cortisol level followed by an ACTH stimulation test). The diagnosis and treatment of adrenal insufficiency is discussed in great detail in other chapters of this textbook.

471

Conclusion

Sepsis remains a significant problem in pediatrics. The diagnosis remains a clinical one, and early recognition is absolutely critical. Additional treatment depends upon early source control and antibiotic administration, as well as early reversal of shock.

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Thrombocytopenia-Associated Multiple Organ Failure Syndrome

31

Trung C. Nguyen, Yong Y. Han, James D. Fortenberry, Zhou Zhou, Miguel A. Cruz, and Joseph A. Carcillo Jr.

Abstract

Thrombocytopenia-associated multiple organ failure (TAMOF) is a clinical syndrome often managed by critical care physicians. It is characterized by new onset thrombocytopenia in the setting of evolving multiple organ failure. TAMOF is an entity within the family of thrombotic microangiopathies, a spectrum of mixed coagulopathies and thrombotic disorders that include thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/ HUS) on one end of the spectrum and disseminated intravascular coagulation (DIC) on the other. Autopsies performed in patients who have succumbed to DIC, TTP and HUS reveal disseminated microvascular thromboses with distinct findings that help to differentiate these three entities. Furthermore, our biologic and molecular understanding of the pathophysiologic processes governing DIC, TTP and HUS have significantly expanded and allow better laboratory delineation among these three entities. Tissue factor plays a pivotal role in the initiation and propagation of DIC. Von Willebrand factors and deficient ADAMTS-13 (a.k.a von Willebrand factor-cleaving proteinase) drive the pathology in TTP. Shiga toxins and the complement pathway drive the pathology in HUS. With better understanding of the biology of TAMOF syndrome, innovative therapies are currently being evaluated with the hope of reversing this destructive pathology. Keywords

Thrombocytopenia-associated multiple organ failure • TAMOF • DIC • TTP • HUS • Thrombocytopenia • Platelets • Fibrin • VWF • ADAMTS-13 • Alternative complement pathway • Thrombotic microangiopathy • Disseminated microvascular thrombosis • Plasma exchange

T.C. Nguyen, MD (*) Department of Pediatrics, Texas Children’s Hospital/ Baylor College of Medicine, 6621 Fannin St WT 06-006, Houston, TX 77030, USA e-mail: [email protected]

Z. Zhou, MD, PhD State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei Li Shi Lu #167, Xi Cheng District, Beijing, PR 100037, People’s Republic of China e-mail: [email protected]

Y.Y. Han, MD Department of Critical Care Medicine, Children’s Mercy Hospital and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA e-mail: [email protected]

M.A. Cruz, PhD Medicine/Cardiovascular Research Section, One Baylor Plaza, N1319, Houston, TX 77030, USA e-mail: [email protected]

J.D. Fortenberry, MD, MCCM, FAAP Department of Pediatric Critical Care, Children’s Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Road NE, Atlanta, GA 30322, USA e-mail: [email protected]

J.A. Carcillo Jr., MD Pediatric Intensive Care Unit, Children’s Hospital of Pittsburgh of UPMC, 4401 Forbes Avenue, FP2118, Pittsburgh, PA 15224, USA e-mail: [email protected]

D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_31, © Springer-Verlag London 2014

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Introduction Thrombocytopenia-associated multiple organ failure syndrome (TAMOF) is a clinical syndrome not infrequently encountered by critical care physicians in the intensive care unit. It is characterized by new onset thrombocytopenia (often with platelet counts dropping to less than 100,000/mm3) in the setting of emerging or evolving multiple organ (systems) failure. The acute drop in platelet count in this syndrome suggests pathologic involvement of platelets as they form microvascular thromboses in the vascular beds of tissues and organs, leading to regional ischemia and injury and ultimately resulting in the observed multiple organ failure. Autopsies performed on patients who have died with TAMOF demonstrate widespread microvascular thromboses in all vital organs. Mortality from TAMOF syndrome remains high ranging from 5 to 80 % with current management strategy [1–10]. Pathophysiologically, TAMOF is an entity within the family of thrombotic microangiopathies (TMA’s), a spectrum of mixed coagulopathies and thrombotic disorders that include disseminated intravascular coagulation (DIC) on one end of the spectrum and thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) on the other. Over the past decade, our biologic and molecular understanding of the pathophysiologic processes governing DIC, TTP and HUS have expanded considerably, allowing better laboratory delineation between these three distinct forms of TMA. This new knowledge has provided some analogous mechanistic insight into TAMOF pathophysiology that has motivated TAMOF investigators to explore innovative new therapeutic strategies with the hope of improving outcome in patients with TAMOF. However, more than 60 % of critically ill patients in the intensive care unit with TAMOF do not have overt clinical and biomarker evidence of DIC, TTP or HUS, underscoring our incomplete mechanistic understanding of TAMOF biology. In this chapter, we will review the TMA’s, describing our current understanding of DIC, TTP, and HUS. We then discuss TAMOF and the different approaches to this syndrome.

Thrombotic Microangiopathy (TMA) Thrombotic microangiopathies (TMA’s) are a family of syndromes characterized by mixed coagulopathies and thrombotic abnormalities with a common clinical presentation of new onset thrombocytopenia. When severe, they are often associated with the development of multiple organ failure. The classification of TMA has been revised and updated as investigators learned more about the mechanisms of these syndromes. Classically, TMA has been categorized into primary or secondary, based on etiology or trigger [11,12]. TTP has been considered as primary TMA because its etiology is

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idiopathic. DIC has been considered as secondary TMA because an underlying trigger is usually identified such as sepsis, cancer, trauma, or other insults. Recently, the European Paediatric Research Group for HUS proposed a new classification for HUS, TTP and related disorders [13]. This group proposed to divide the classification into two parts. Part 1 includes etiologies that are reasonably advanced, which include infection-induced, disorders of complement regulation, ADAMTS-13 deficiency, defective cobalamine metabolism, and quinine-induced. Part 2 includes etiologies that are unknown but associated with certain clinical conditions such as human immunodeficiency virus infection, cancer, calcineurin inhibitors usage, pregnancy, systemic lupus erythematosus, glomerulopathy, and familial etiologies not included in Part 1. Part 2 also includes unclassified etiologies. Reclassification of TMA’s will surely continue as investigators uncover new pathologic mechanisms. Autopsies performed in patients who have succumbed to DIC, TTP and HUS reveal distinct findings that help to differentiate these three entities. Patients who die from DIC characteristically have fibrin-rich microthrombi throughout the body, whereas patients who die from TTP characteristically have von Willebrand factor (VWF)/platelet-rich microthrombi [14–16]. Patients who die from HUS have predominantly fibrin-rich microthrombi, but a subgroup also has VWF/platelet-rich microthrombi [16,17]. TTP has a significant involvement of myocardial arteries, whereas HUS has a striking involvement of the kidneys [15,17,18]. Thus, immunohistochemistry affirms that the molecular mechanisms within the spectrum of TMA can be rather distinct.

Disseminated Intravascular Coagulation (DIC) DIC is usually triggered by an underlying pathology (Table 31.1). Autopsies performed in patients who have died from DIC reveal fibrin-rich microthrombi in small and midsize vessels in all organs [14,15,19]. The cornerstone of treatment for DIC is treating the underlying inciting disease or problem. In 2001, the Scientific Subcommittee on DIC of the International Society of Thrombosis and Haemostasis (ISTH) proposed a consensus definition of DIC as “an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction” [20]. To facilitate recognition of DIC, the ISTH recommended measuring platelet counts, fibrin-related marker (soluble fibrin monomers/fibrin degradation products), prothrombin time, and fibrinogen level [20]. The abnormalities of these global coagulation tests are tabulated to form the DIC score (Table 31.2). If the DIC score is ≥5,

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Table 31.1 Clinical conditions associated with disseminated intravascular coagulation 1. Sepsis 2. Cancer 3. Trauma/burns 4. Obstetric complications 5. Toxins exposure 6. Vascular abnormalities

Table 31.2 Disseminated intravascular coagulation score by the International Society of Thrombosis and Haemostasis 1. Platelet count (>100 K/mm3 = 0; 105 of no more than two organisms, or between 103 and 105 organisms if symptoms are present and there is an abnormal urinalysis [2]. Compared to previous guidelines, a major change has been removal of asymptomatic bacteriuria (ASB). ASB can be considered evidence of a true UTI if identical uropathogens are grown from blood cultures in addition to the positive urine culture.

Pathogenesis The pathogenesis of urinary catheter-related UTI is similar in some ways to the process described with indwelling vascular catheters. Most microorganisms causing CAUTI derive from the patient’s own perineal flora or from the hands of healthcare personnel. The entry of a urinary catheter bypasses the normal host defenses at the urinary meatus. This allows the entry of pathogens into the bladder and also allows for the formation of a biofilm, similar to the process in vascular catheters [93]. Organisms gain access to the bladder by one of two main routes. The principle route of acquisition is the extraluminal route. Colonization occurs either early, at the time of catheter insertion, or late due to colonization of the meatus and the ascent of microorganisms from the perineum along the surface of the catheter. The second pathway for microorganisms to enter the bladder is the intraluminal route. This occurs by reflux of organisms from a contaminated drainage bag (e.g. handling by healthcare workers) or by a break in the closed drainage system (e.g. irrigation of the bladder without proper asepsis). The contaminated urine can ascend from the bag into the catheter by capillary action or when the bag is raised above the level of the bladder (e.g. during transport) [54, 93].

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Management and Prevention Careful fluid input and output monitoring requires the use of indwelling urinary catheters; they are an integral part of the management of many critically ill infants and children. This is especially true for ICU patients with organ failure, complex congenital heart repairs, and severe sepsis. The need for continued catheterization must be balanced against the increased risk of catheter-related urinary tract infection. At the top of the list of effective strategies for prevention of CAUTI is the least “novel” of technologies: risk factor modification. Minimizing the duration of catheterization may be the single most important modifiable variable. Application of basic principles of infection control and using a closed drainage system will prevent many infections. Table 33.1 lists items that are useful in device-associated urinary tract infection control strategies. Numerous trials in adult patients evaluating oral antibiotics, urinary acidifying agents, antimicrobial bladder washes, antimicrobial drainage bag solutions, and topical disinfectants all point to the same conclusion: bacteriuria and UTI can be suppressed temporarily, but resistant flora eventually appear [54, 90]. Antibiotic- and silver alloy-impregnated urinary catheters are a novel therapy and the current focus of many clinical trials. They appear to decrease the incidence of ASB in adults catheterized for short periods of hospitalization, but there was no clear indication if this reduced the risk of CAUTI compared to standard catheters in a large metaanalysis of adult patients [98]. Thus, a firm recommendation cannot yet be made for their use. Another possible new therapy is the technique of bacterial interference, or the use of benign non-pathogenic bacteria to prevent colonization and symptomatic infection with pathogenic organisms. Clinical trials in the pediatric population have not yet been published.

Surgical Site Infections Scope of the Problem Post-operative patients make up an important subset of all pediatric intensive care unit patients. Surgical site infections (SSIs) are those infections that occur in the surgical patient within 30 days of an operation or within 1 year of the operation if an implant was placed and meets specific criteria as defined by the NNIS system. SSIs are classified as: (1) superficial incisional (superficial to fascia/muscle), (2) Deep incisional (within fascia/muscle), or (3) organ/space (deep to fascia/muscle). Infections are further classified by risk index category as determined by the American Society of Anesthesiologists (ASA) preoperative assessment score, the degree, if any, of surgical field contamination, and the duration of the surgical procedure. The degree of contamination

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is categorized as follows: Class I (clean), class II (cleancontaminated), class III (contaminated), and class IV (dirtyinfected) [99]. The NHSN system now monitors SSIs and reports rates of SSI for specific surgical procedures and risk categories. SSIs are an increasingly common clinical issue, accounting for 14–16 % of all nosocomial infections among hospitalized patients [99]. It is estimated that SSIs occur in at least 2 % of all hospitalized patients who undergo surgical procedures [100]. However, the largest to date prospective multicenter study of pediatric SSIs in the United States in 1998 revealed a 4.4 % incidence of SSI in 846 general pediatric surgery patients at three large children’s hospitals [101]. Of note, that study did not include cardiothoracic, orthopedic, or neurosurgical procedures. Analysis of data from hospitals participating in the NNIS system indicates that, among the 98,987 deaths (adults and children included) caused by or associated with HAIs in 2002, 8,000 were surgical site infections (SSIs) [100]. In the pediatric ICU specifically, during the years 1992–1997, between 6 and 10 % of NIs were SSIs [5]. The most common infections were skin infections, followed in most age groups by intra-abdominal abscesses and soft tissue infections. Mediastinitis was an important SSI in children and infants less than 5 years of age, due to early surgery for congenital heart defects. The most frequent types of preceding surgical procedures were chest surgery, including cardiovascular surgery (41 %); gastrointestinal surgery (24 %); neurosurgery (13 %); transplant surgery (8 %); orthopedic surgery (5 %); vascular surgery (3 %); and head and neck surgery (3 %) [5].

Risk Factors Several pediatric-specific studies have examined risk factors for SSI. Both host factors and procedural risk factors appear to play roles in the development of SSIs in infants and children. The youngest patients, particularly neonates, are at greater risk for SSI. A large Spanish prospective study of 3,700 postoperative children identified eight risk factors associated with SSI: (1) use of a peripheral venous catheter, (2) higher degree of wound contamination, (3) use of a central venous catheter, and (4) urologic surgery (vs. general surgery), (5) having >1 diagnoses, (6) use of a urinary catheter, (7) duration of surgery, and (8) postoperative length of stay [102]. Other independent risk factors that have been shown to be associated with SSI are African-American race, implantable device placement, and postoperative admission to the intensive care unit [103]. The microbiology of SSIs often varies according to the type of surgical procedure. Most organisms originate from the patient’s own flora, although some pathology may arise from other sources, including surgical equipment, operating room personnel, and implanted devices [99]. A recent study

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which examined over 8,000 patients who were re-admitted with a culture-confirmed SSI between the years 2003 and 2007 found that methicillin-sensitive Staph. aureus was the most commonly cultured organism, followed by MRSA and CONS. Together, Staphylococci species accounted for approximately 50 % of infections. The authors found that MRSA became increasingly common during the course of their study and was often a component of polymicrobial infections. The most commonly encountered gram-negative species was Pseudomonas aeruginosa, found in 2.1 % of cultures. Polymicrobial infections were common, accounting for approximately 33 % of infections [104]. Among pediatric patients, MSSA was also the most commonly cultured single organism, followed by MRSA. Polymicrobial infections accounted for 21 % of infections, and monomicrobial gram-negative cultures accounted for 6 % of infections [103]. In the largest PICU-specific study of nosocomial surgical infections, staphylococcus species were the most commonly isolated organisms, although Pseudomonas aeruginosa was the most commonly isolated pathogen in gastrointestinal surgery [5]. In addition to contributing to morbidity and mortality, SSIs increase hospital length of stay and hospital costs. Older adult studies have estimated costs between $3,000 and $29,000 per SSI [105]. However, a recent matched cohort study of pediatric patients with SSIs revealed that on average, length of hospital stay was increased by 10.6 days and costs were increased by greater than $27,000 for each patient with a SSI [106].

Management and Prevention The 1999 Guidelines for Prevention of SSI published by the Hospital Infection Control Practices Advisory Committee serves as the basis of SSI prevention efforts and detail evidence-based interventions targeted toward the perioperative and operative milieu [99]. In addition, the recommendations for the Institute for Healthcare Improvement (IHI) 100,000 Lives campaign have been extended to pediatric patients. In general, antimicrobial prophylaxis should be administered intravenously within 0–60 min prior to surgical incision and redosed during the procedure, depending on the length of the operation. A large multicenter study in adult surgical patients showed a strong relationship between the timing of antibiotic administration and SSI risk, with a trend toward lower risk occurring when prophylaxis with cephalosporins and other antibiotics with short infusion times were administered within 30 min prior to incision. Antibiotics with longer infusion times such as vancomycin should be administered within 60 min and no longer than 2 h prior to incision [107]. Antibiotics should be selected based on the surgical site and common pathogens related to specific operations. Antibiotic use as “prophylaxis” after 24 postoperative

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hours is not efficacious, seldom warranted, and should be discouraged.

Specific SSIs Commonly Encountered in the PICU Cardiothoracic Surgery The post-operative cardiothoracic surgery patient in the ICU is at risk for SSI, including wound infection, sternal osteomyelitis, and mediastinitis. In pediatric cardiac surgical patients, the rates of reported SSI range from 1.7 to 8 per 100 cases [108–114]. Multiple studies have examined risk factors for SSI in pediatric cardiac surgery patients and have identified age younger than 1 month, the diagnosis of a genetic syndrome, preoperative hospitalization for greater than 48 h, higher ASA score, intraoperative hypothermia, need for multiple procedures during the same operation, duration of surgery, hypoplastic left heart syndrome, femoral catheter presence, postoperative receipt of total parenteral nutrition, and presence of temporary pacing wires for >3 days as risk factors for SSI [108, 112–115]. A 2009 study of patients with cardiac SSI found that independent risk factors for any type of SSI were age younger than 1 year and duration of cardiopulmonary bypass greater than 105 min [116]. Although relatively infrequent, mediastinitis is the most serious of SSIs associated with pediatric cardiac surgery and carries a high risk of morbidity and mortality. Mediastinitis is infection involving the mediastinum or sternum and meets the CDC criteria for organ/space SSI. To meet criteria for mediastinitis, the patient has to meet at least one of the following criteria: (1) have organisms cultured from mediastinal tissue or fluid, (2) evidence of mediastinitis seen during a surgical operation or histopathologic examination, (3) have fever, chest pain, or sternal instability and at least one of the following: purulent discharge from the mediastinum, bacteremia or organisms cultured from mediastinal wound discharge, or mediastinal widening on chest radiograph. Various studies have found incidence rates for mediastinitis in pediatric cardiac surgery patients of 0.2–3.9 % [117–121]. The largest study of mediastinitis in congenital heart surgery patients found that gram-positive organisms were present in 67 % of cases and gram negative organisms were present in 30 % of cases. Concurrent bacteremia was very common and found in over 50 % of cases. Delayed sternal closure has been found to be an independent risk factor for the development of gram negative mediastinitis [120].

Craniofacial Surgery Surgical site infections following craniofacial surgery can be difficult to treat and can change both medical and cosmetic outcomes. While mortality associated with pediatric craniofacial surgery performed at experienced centers is low, factors such as implanted materials used in procedures as well as the

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common need for multiple procedures to address complex malformations increase infection risk in these patients [122]. Two relatively recent studies with large numbers of patients reveal an SSI rate of 2.5–3.2 % [122, 123]. Pseudomonas aeruginosa and Candida albicans are the most frequent pathogens in craniofacial SSIs, although polymicrobial infections are common [122, 123]. Risk factors for SSIs in craniofacial surgery include: (1) complicated preoperative diagnoses such as genetic syndromes, (2) long duration of surgery (3) closure of skin under tension, (4) more than four surgeons present during surgery, (5) PICU stay longer than 2 days, and (6) use of a ventilator after surgery [122]. Tracheostomies and ventriculoperitoneal shunts have not been identified as a risk factor for infection [122, 123]. Antibiotic prophylaxis with first-generation cephalosporins is used most commonly, with some centers dosing for 24 h for cranial vault remodeling and others continuing antibiotics until drain removal. Significant infections often require aggressive surgical management for drainage and debridement.

Neurosurgery Nosocomial central nervous system infections usually involve a surgical site or presence of a foreign body such as a ventriculoperitoneal shunt, intracranial pressure monitor, or externalized ventricular drain (EVD). For combined adult and pediatric patients from 2006 to 2008, the pooled mean rates for craniotomy-associated SSIs are 2.15 for low risk patients and 4.66 per 100 operations for higher risk patients. For ventricular shunts, the pooled mean rates for SSIs are 4.0–5.9 per 100 operations [124]. When all shunt infections are considered, rates are between 5 and 15 %. This increase reflects the fact that many of these shunts become infected over a year after insertion [125]. Ventricular shunt infections contribute to a significant number of PICU hospitalizations yearly because of these patients’ needs for close monitoring of their mental status as well as the complexities of care involved. Shunt infections accounted for the most hospital charges outside of the neonatal period and increased length of stay significantly [126]. Shunt infections have been associated with complications such as seizures and electrolyte disturbances [127]. An older, but to this date unreplicated, retrospective 20 year study of shunt infections found associations between shunt infections and decreased intellectual performance and overall increased mortality [128]. Independent risk factors for ventriculoperitoneal shunt infection include premature birth, previous shunt infections, intraoperative use of the neuroendoscope, postoperative CSF shunt leak, and intraoperatively breached gloves [125, 129]. Most commonly, organisms found as skin flora, including CONS, Staphylococcus aureus, and proprionibacterium are cultured from infected shunts [130, 131]. Management strategies for infected ventricular shunts vary. A 2001 survey of pediatric neurosurgeons found that most surgeons remove

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the infected shunt and place an external ventricular drain, while others externalize the shunt itself. Duration of antibiotic therapy was also found to vary, with treatment lengths ranging from 5 to 24 days [132]. A multicenter study of a standardized protocol for ventricular shunt procedures showed an absolute risk reduction of 3.15 % and a relative risk reduction of 36 % with utilization of the protocol. Significant components of the protocol included routine administration of pre-operative and peri-operative antibiotics, double-gloving to prevent contamination of shunt with skin flora, and injecting the shunt reservoir with vancomycin and gentamycin prior to closure [133]. The use of antibiotic impregnated ventricular shunts and external ventricular drains remains controversial, but may decrease incidence of shunt infection [134]. Infection of intracranial pressure monitors and external ventricular drains is a complication in the treatment of both traumatic brain injury and hydrocephalus. The use of prophylactic antibiotics, while common, is controversial and may increase the incidence of resistant gram-negative pathogens [135–137]. Further data is needed to determine the best practice regarding antibiotic prophylaxis for intracranial pressure monitors and external ventricular drains.

Orthopaedic Surgery Spinal fusions for idiopathic or neuromuscular kyphoscoliosis are common admissions to the PICU. While many of these procedures fall into the low risk index categories, some procedures are performed on patients with complex medical histories resulting in higher risk. The pooled infection rate means for spinal fusions (adults and children) vary from 0.7 to 4.15, depending on risk category. Wound infections develop more commonly in patients with neuromuscular scoliosis compared to idiopathic scoliosis [138]. Wound infections following spinal surgery result in pseudoarthrosis as well as prolonged hospital stay and recovery [139]. Deep infections often require surgical debridement, drainage, and possibly removal of hardware [140]. Significant risk factors for deep SSI after spine surgery include: previous spinal surgery, presence of complex underlying medical condition, younger age, greater than ten vertebrae fused, higher intraoperative blood loss, and the presence of a ventriculoperitoneal shunt [141]. In addition, as with many other SSIs, inappropriate timing of preoperative antibiotic prophylaxis has been found to be a significant independent risk factor for deep SSI in spinal fusion [141].

Transplant Surgery Solid organ transplants have some of the highest SSI rates among all surgical procedures. Immunosuppression as well as debilitated pre-operative states contribute to increased risks of SSIs. Pooled mean infection rates for solid organ transplants are 3.28 per 100 heart transplants, regardless of

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risk category, with lower infection rates following kidney transplants, and significantly higher rates following liver transplants [124]. In addition to standard pre- and perioperative infection control measures, increased compliance with strict hand washing and the use of gown and glove isolation in the PICU have been found to be associated with a significant reduction in nosocomial infections in children undergoing solid organ transplantation [142]. Active surveillance to detect SSI is also important in preventing poor outcomes in solid organ transplant patients.

Infection Control in the PICU Infection control measures within the PICU are increasingly important. The U.S. Department of Health and Human Services estimates that health-care-associated infections affect 5 % of patients hospitalized each year in the United States [143]. Knowledge of risk factors, prevalence and infection control bundles is vital to the developent of pediatric intensivists. Nosocomial infection rates are now routinely monitored both as benchmarks for assessing the quality of patient care and for reimbursement. Morbidity and mortality from hospital-acquired infections is known to be both preventable as well as a significant contributing factor to spiraling health care costs in the United States. Multiple sources within the PICU for nosocomal infections are well-established. Within the PICU, utilization of medical devices such as central vascular catheters, mechanical ventilation, and urinary catheters is a well-recognized factor that influences the development of hospital-acquired infections. Other factors also play a role, including the environment (humidity, air quality, distance between patients), adherence to hand hygiene by health care workers, immune and nutritional status of the host, use of antimicrobial therapy, and length of stay [144]. Since most hospital-acquired infections in the PICU are associated with the use of intravascular catheters, mechanical ventilation, or urinary catheters, most infection control measures are focused on use of proper sterile barrier techniques, use of sterile water in ventilator humidifiers, proper timing for ventilator circuit changes, prompt removal of devices, and proper preparation and handling of intravenous fluids. Multiple disease outbreaks have been implicated with environmental factors [144, 145]. Unit design is especially important. While large open areas (“open wards”) provide access to patients, they pose great problems for infection control. Distance between patients greatly influences some hospital-acquired infection rates. Transmission between patients could be possible because of close proximity or as a consequence of absence of barriers between patients. As an example, patients with respiratory infections caused by influenza or respiratory syncytial viruses can transmit virus to

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individuals within the recognized “drop zone” of large droplets (~3 ft). Units with separate rooms for patients are optimal, allowing isolation when necessary. During the annual respiratory season observed in the northern United States, cohorting patients with bronchiolitis symptoms can be considered as an added infection control measure. Whenever possible, PICU nursing staff caring for patients with respiratory viral illnesses should not care for patients who are either high-risk or immunocompromised. High-risk immunocompromised patients are frequently admitted in the PICU. These patients are at risk of opportunistic infections by organisms such as Aspergillus. Ideally, immunocompromised patients are placed in private rooms with positive-pressure or positive-air flow. Many transplant or cancer units have high-efficiency particulate air (HEPA) handling with high number of air changes per hour (ACH) in their “protective environment” rooms. Most PICUs do not require this type of air handling. However, if available, rooms in the PICU should have at least six ACH. Every PICU needs to be capable of caring for patients with airborne-transmitted pathogens such as tuberculosis, measles, and varicella. Units must have an adequate number of “airborne infection isolation” rooms. These rooms must have negative-pressure or negative-air flow air handling (air flows into the room from the adjacent space or corridor when the door is opened). These rooms should have a minimum of six ACH if construction of room was done before the year 2001 or 12 ACH if built after 2001. The air from these rooms must be vented out of the hospital and not re-circulated unless filtered [146]. Patients colonized with resistant organisms such as methicillin-resistant Staphylococcus aureus or vancomycinresistant Enterococci pose special problems for isolation. Many hospitals have reported outbreaks within itensive care units with these organsms. Conventional wisdom holds that nosocomial infections manifesting in the ICU represent microorganisms acquired from within this high-risk environment. This is not necessarily true. The contribution of the patient’s own flora was highlighted in an elegant study from the United Kingdom. The investigators demonstrated that the majority of infections (59.8 %) diagnosed during prolonged PICU stays (≥4 ICU days) were actually due to microorganisms imported into the ICU from the patient’s own flora and predominantly occurred in the first week of PICU stay. Microorganisms associated with the microbial ecology of the ICU caused the other 38.9 % of infections [147]. Numerous clinical studies and reviews have consistently demonstrated that appropriate hand disinfection or washing remains the single most effective measure to decrease the spread of nosocomial infections [142, 144–146, 148]. The importance of proper hand hygiene cannot be overemphasized. Hand hygiene can be greatly improved if access to hand washing facilities and antiseptic hand sanitizer

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dispensers can be facilitated and encouraged. At least one hand washing station should be provided for every three patient beds in an open area floor plan. These should be equipped with hands-free operable controls [148]. In units with separate rooms, each room should have a sink and soap and hand sanitizer dispensers. Since not all health care workers prefer to use hand sanitizers, sinks provide an appropriate alternative. The CDC has published guidelines for hand hygiene. In a nationwide survey concerning routine hand washing, significantly more positive attitudes toward the practice guidelines were found among staff in pediatric as compared with adult ICUs [149]. Further, nursing staff had more positive attitudes toward hand hygiene guidelines when compared with physicians. Inadequate hand washing (and use of artificial fingernails) has been associated with multiple outbreaks within ICUs [150]. Hand hygiene is clearly an area in many PICUs where simple education and vigilance will pay enormous dividends. Strict gown and glove use has been shown to decrease nosocomial infections in the PICU [151]. However, it appears to be no more effective than strict hand washing and it is difficult to maintain increased compliance. When utilized together, gown and glove use and hand washing have an additive protective effect in decreasing nosocomial infections in immunocompromised patients within the PICU. Maintaining routine use of barrier precautions among ICU staff is difficult. While use of barrier methods such as gloves, gowns and masks clearly minimize transmission, adherence to their proper use often deteriorates over time [142]. Proper disinfection of PICU rooms is critical, especially when a patient is colonized or infected with resistant organisms. Organisms such as RSV may survive on hard surfaces and fomites for hours, allowing for the transmission between patients. Bacteria such as vancomycin-resistant enterococci (VRE) and MRSA can survive even longer. Inappropriately cleaned rooms have been implicated in the transmission of resistant organisms [146, 152, 153]. Since patient’s colonization status with resistant organisms is often unknown, proper room cleaning is imperative after discharge of all PICU patients. The frequency of isolation of resistant organisms such as VRE, MRSA and extended-spectrum-lactamase (ESBL)producing gram-negative rods varies between institutions [154]. Unfortunately, they are being isolated in greater frequency. Each PICU should have information about their hospital and unit’s prevalence. Knowledge of unit-specific susceptibility antibiograms can assist clinicians greatly in selecting the most appropriate empiric antimicrobial therapy for patients with suspected hospital-acquired infections [155, 156]. Antimicrobial resistance can be reduced only if the PICU physician uses antimicrobial therapies more appropriately. Access to molecular assays such as pulsedgel field electrophoresis is critical in determining the extent

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of outbreaks and the need for special infection control measures [157]. Appropriate nursing-to-patient ratio has been found to be important in the prevention of hospital-acquired infections, especially ventilator-associated pneumonias [158]. Low nurse to patient staffing levels as well as the presence of nonpermanent or “float” nurses have been shown to increase the risk of CLABSI [159, 160]. Patient-nurse ratios are often detemined by patient acuity, but in general should not exceed 1:2. When nursing staffs are forced to “ration” care due to heavy workload assignments or when PICU nursing personnel are reduced, the risk of PICU nosocomial infections increases [158, 161]. PICU staffing is a growing problem, with both nationwide nursing shortages in the United States, as well as increasing hospital bugetary constraints. The prevention of PICU-acquired infections is a complex endeavor that requires a thorough adherence to well designed practices and engineering controls. In most hospitals, colaboration is crucial. Hospital infection control programs have active surveillance measures in place to detect infections in a timely manner. They will typically contact the clinician and are helpful in instituting necessary preventive measures. The sharing of information between infection control practitioners, unit nursing staff, and medical directors generally results in the identification of problems and their resolution. Lapses in compliance may result in preventable hospitalacquired infections, which may have devastating consequences. Adoption of healthcare ordersets or “bundles” for VAP and CLABSI have become the focus of quality improvement efforts in many pediatric facilities. Specific measures within the PICU such as antibiotic rotation, selective decontamination of the gastrointestinal tract, or antibioticimpregnated catheters are also currently being investigated, but are not recommended yet for nationwide implementation [151, 162, 163]. Conclusion

Nosocomial infections in the PICU remain a significant but potentially preventable source of morbidity and mortality. The risk of infection in PICU patients remains high because invasive devices allow organisms to bypass normal host defenses. Additionally, PICU patients often have coexisting organ system dysfunctions or degrees of immunocompromise. While blood stream infections are the most common nosocomial problem in the PICU, ventilator-associated pneumonias have the highest mortality. The overall attributable mortality due to nosocomial infections within the PICU is estimated at 11 % [6]. The mortality associated with nosocomial infections is multifactorial. Clearly the patient population, underlying disease, number of organ systems affected, need for invasive therapies, and the microorganisms responsible all contribute to the risk of developing a hospital-acquired infection.

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Nosocomial infections have a significant economic impact on the United States healthcare system. The patient population within the PICU is unique. They tend to not have the chronic diseases noted in the adult ICU population and are more likely to have a sequelae-free recovery. Thus, PICU nosocomial infections have a potentially enormous effect on productive years of life lost. Nosocomial infections add an additional four billion dollars annually to US health care expense both in direct costs and future wages lost [164]. Additionally, a majority of prospective payment systems refuse to pay the additional reimbursement caused as a consequence of treating a nosocomial infection [165, 166]. Even the most conservative estimates suggest that one third of all nosocomial infections in the US could be prevented by following established infection control programs. In a recent study in adults, strict compliance with hand washing, sterile procedures, hospital and national infection control policies, and empowering the ICU nursing staff to stop the procedure essentially stopped the occurrence of BSIs [167]. Use of infection control bundles directed at improving compliance with infection control policies is having a dramatic effect on ICUacquired nosocomial infections. In 2001, the Centers for Disease Control and Prevention reported an estimated 43,000 CLABSIs cases in adult and pediatric ICUs in the United States. By 2009, this number had decreased to 18,000 [20]. The best current approach for preventing PICUacquired infections centers on strict adherence to infection control policies, early discontinuation of invasive devices, and appropriate isolation strategies. Insight into the organisms and sensitivites of PICU-related infections is a crucial component in the success of any hospital infection control guidelines. Research into best preventive strategies is ongoing and likely to significantly alter our practice of intensive care medicine in the near future.

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Anaphylaxis Shilpa K. Shah and Erika L. Stalets

Abstract

Anaphylaxis is a life-threatening systemic hypersensitivity reaction caused by the release of mediators, most notably histamine, from mast cells and basophils. The underlying mechanism may be immunologically mediated, non-immunologic, or idiopathic. These mediators lead to deleterious effects on multiple organ systems and symptoms occur within seconds to minutes after exposure to a trigger. The epidemiology and pathophysiology of anaphylaxis will be reviewed in this chapter, as will the clinical presentation and management. Given the rising incidence of pediatric anaphylaxis, it is becoming increasingly important for child healthcare providers to recognize and rapidly treat this disease process. Symptoms may be relatively benign or severe and fatal. They can include classic allergic symptoms such as sneezing, hives, and angioedema, but also dizziness, blurred vision, chest pain, abdominal pain, or acute respiratory arrest. Immediate treatment with epinephrine and isotonic volume resuscitation can be life-saving for patients with anaphylaxis. Additional interventions and therapies are discussed in the chapter, including the management of cardiopulmonary arrest due to anaphylaxis. A key component of anaphylaxis treatment is prevention, which requires identification of the causative agent and avoidance whenever possible. Additionally, given the rapid onset of symptoms and the risk for severe morbidity and mortality, patient and family education, prescription of an epinephrine auto-injector device, and referral to an allergist are equally important in preventing anaphylaxis. Keywords

Anaphylaxis • Anaphylactic shock • Food allergy • Histamine

Introduction The term anaphylaxis is derived from the Modern Latin terms ana, meaning against, and phylaxis, meaning guarding or protection [1]. The World Allergy Organization defines anaphylaxis as a “severe, life-threatening generalized or systemic hypersensitivity reaction” [2]. Knowledge of the pre-

S.K. Shah, DO • E.L. Stalets, MD (*) Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA e-mail: [email protected]; [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_34, © Springer-Verlag London 2014

sentation, causes, mechanisms and treatment of anaphylaxis is imperative for the pediatric intensivist.

Epidemiology Accurate incidence of anaphylaxis is difficult to ascertain secondary to inconsistent definitions and inadequate data. A recent review of the literature found reported lifetime prevalence of anaphylaxis to range from 0.05 to 2 % [3]. However, correlating with an increase in the incidence of allergy, the incidence of anaphylaxis, especially for children, is rising worldwide. Incidence is particularly increasing for food-induced anaphylaxis [4–6]. Risk factors for anaphylaxis include asthma, 531

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history of atopy, previous history of anaphylaxis, and mastocytosis [3, 7, 8]. One study found that the use of angiotensin converting enzyme (ACE) inhibitors was associated with an increased risk of severe reactions to insect sting in adults [9]. Interestingly, some investigators have found a correlation between higher latitude and increased incidence of anaphylaxis, especially in children. This has led some to postulate that vitamin D deficiency may be a risk factor for anaphylaxis [5]. A person’s gender also plays a role. In children, males appear to have a greater incidence of anaphylaxis, but this ratio changes in adulthood, with females having a higher incidence later in life [4, 7, 10–12]. Despite the increase in anaphylaxis incidence, anaphylaxis death rates remain stable. A notable exception is the significant increase in deaths from drug-induced anaphylaxis beyond the increased incidence of drug-induced anaphylaxis. In studies of fatalities, drugs are implicated in up to 50–60 % of cases, insect stings in about 20 %, and food in 10–20 %. Risk factors for death from anaphylaxis include active asthma, peanut or tree nut allergy, delayed or lack of use of epinephrine, and previous history of severe reactions [4, 13–17].

Pathophysiology Anaphylaxis is classified by underlying mechanism: immunologic, non-immunologic, or idiopathic. Terms such as anaphylactoid and pseudoanaphylaxis are no longer recommended; all fall under the umbrella of anaphylaxis (Fig. 34.1) [3, 18–20]. The most common immunologic mechanism of anaphylaxis is an IgE mediated reaction to an allergen. The allergen elicits IgE antibody production. IgE then binds to the high affinity IgE receptors (Fcε(epsilon)RI) on mast cells and basophils. Upon re-exposure to this allergen, crosslinking and subsequent aggregation of these bound antibodies triggers mast cell and basophil degranulation causing release of mediators. This mechanism is responsible for the majority of anaphylaxis cases. Triggers are myriad and include food, drugs, insect stings (i.e. from hymenoptera venom), latex, seminal fluid, animal dander, plant pollen, and in some cases, radiocontrast media [3, 19–21]. Immunologic mechanisms independent of IgE have been described but are incompletely understood. Although rare, both IgG and complement-mediated mechanisms, including activation via immune complexes, have been implicated. The end result is still mast cell and basophil degranulation with release of mediators. Dextran, monoclonal antibodies such as infliximab, and radiocontrast media have all been reported to trigger non-IgE mediated anaphylaxis [3, 19, 20]. Non-immunologic mechanisms underlie anaphylaxis triggered by agents and physical stimuli that cause direct mediator release. Examples include opiates, ethanol, cold, sunlight

S.K. Shah and E.L. Stalets Human Anaphylaxis

Immunologic

Non-Immunologic Idiopathic

lgE, FcεRI food, venoms, drugs,latex

Non-lgE, FcεRI dextran, OSCS contaminants in heparin

Physical exercise, cold

Other drugs

Fig. 34.1 Mechanisms underlying human anaphylaxis. Anaphylaxis is commonly mediated through an immune IgE-dependent mechanism. Rarely, it occurs through another immune mechanism. Uncommonly, it occurs through direct (non-immune) activation of mast cells. Idiopathic anaphylaxis, currently a diagnosis of exclusion, presents opportunities for identification of previously unrecognized triggers, elucidation of pathophysiologic mechanisms, and identification of patients with mastocytosis or clonal mast cell disorders. FcεRI high affinity IgE receptor, OSCS oversulfated chondroitin sulfate (Reprinted from Simons [18]. With permission from Elsevier)

and exercise. Additionally, activation of the contact system can occur when blood is exposed to dialysis membranes or when radiocontrast media is administered. Aspirin and other NSAIDs may contribute to anaphylaxis via abnormalities in arachidonic acid metabolism. Some cases of anaphylaxis may be idiopathic which should lead one to consider exposure to an unknown or unrecognized allergen or possibly a mast cell disorder [3, 19, 20]. The non-IgE mediated mechanisms of anaphylaxis were previously encompassed in the category of “anaphylactoid” reactions, but this term is no longer used [3, 19, 20] It should also be noted that some agents can cause anaphylaxis via more than one mechanism, e.g. radiocontrast media [3].

Triggers Many triggers are listed above according to the mechanism by which they induce anaphylaxis. Depending on the population studied, the most commonly reported anaphylaxis trigger is food, accounting for 20–60 % of cases. Drugs account for 5–50 % of cases, insect stings in 11–30 %, and exercise in 3–9 %, with other causes being less frequent [3, 12, 22–26]. Interestingly, food-dependent exercisedinduced asthma, which is exercised-induced anaphylaxis that occurs in proximity to consumption of certain foods, is more commonly reported in Asian countries, with a frequency as high as 14 % [4].

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As the most frequent triggers of anaphylaxis, special attention should be given to food and drug allergies. The incidence of food allergy is increasing. As noted above, almost any food can cause anaphylaxis. Common foods causing anaphylaxis include peanuts, tree nuts, eggs, dairy products, seafood and fruits. Peanuts and shellfish are increasingly implicated, with a slower increase in cow’s milk and egg-triggered anaphylaxis [13]. A new legume, lupin, is becoming more widely used in Europe and has been implicated in both allergy and anaphylaxis [4]. Crosssensitization among foods can occur, as well as cross-sensitization between latex and certain foods, including banana, kiwi, papaya, avocado, potato and tomato [3]. The incidence of drug anaphylaxis appears to be increasing as is the number of deaths attributed to drug anaphylaxis. Of particular concern is the rise in perioperative anaphylaxis. While almost all drugs are capable of inducing an anaphylactic reaction, two classes of drugs are most commonly implicated: beta-lactam antibiotics and anesthetic agents [27]. Non-steroidal anti-inflammatory drugs and radiocontrast agents are the most commonly implicated triggers for nonimmunologic anaphylaxis [4]. Monoclonal antibodies and immunotherapy allergens are increasingly utilized and have a higher incidence of anaphylaxis [3].

Mechanism of Symptoms Whatever the mechanism leading to anaphylaxis, the symptoms are caused by release of mediators from activated mast cells and basophils. The signaling mechanisms and subsequent release of mediators from these cells is complex and still not fully understood. Mediators such as histamine, tryptase, carboxypeptidase A and proteoglycans are released from mast cells and basophils, triggering phospholipase A2 activation. Phospholipase A2 activity results in production of arachidonic acid, which is modified by cyclooxygenases and lipoxygenases. This results in the production of cytokines and inflammatory mediators, including prostaglandins, leukotrienes, platelet activating factor, and TNF-α, among others. These mediators induce vasodilation, increased vascular permeability, increased heart rate, glandular secretion, bronchoconstriction, pulmonary and coronary vasoconstriction and recruitment of other inflammatory cells including neutrophils. This complex process leads to the signs and symptoms observed in anaphylaxis [3, 19, 20].

Clinical Presentation Part of the difficulty in the diagnosis of anaphylaxis can be attributed to the difference in diversity and severity of symptoms manifested by those affected. No single symptom is

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diagnostic and various organ systems may be affected. Skin and/or mucous membrane manifestations are the most common and are present in 70–90 % of cases. Cutaneous symptoms include urticaria or hives, pruritus, flushing, and swelling (angioedema) [3, 10–12, 22, 25, 26, 28]. Other affected organ systems may include the respiratory, cardiovascular, gastrointestinal and neurologic systems. Respiratory symptoms are present in up to 70–80 % of cases, and include shortness of breath, stridor or bronchospasm depending on the location of inflammation in the airway, hypoxemia/cyanosis, and even respiratory arrest. Other respiratory system symptoms may include rhinitis, sneezing, hoarse voice, or cough. Cardiovascular symptoms can range from hypotension to cardiovascular collapse and occur in 25–80 % of reported cases, with reviews from Asia reporting a higher incidence of cardiovascular symptoms. Gastrointestinal symptoms include cramping, vomiting and diarrhea, and are reported in up to 20–45 % of cases [3, 10–12, 22, 25, 26, 28]. Neurologic symptoms can include headache, dizziness, anxiety, or a feeling of impending doom [3, 10, 28, 29]. Infants and small children cannot describe symptoms, and signs may be nonspecific or difficult to interpret in this age group. In addition to those signs listed above, others may include drooling, spitting up, somnolence, irritability, crying, or abrupt changes in behavior, e.g. sudden cessation of play [30]. Biphasic or late phase reactions, in which anaphylaxis symptoms recur, have been reported in up to 20 % of adult cases and 6–11 % of pediatric cases. They may occur as late as 72 h after the initial symptoms have resolved, although the majority happen within 8 h. Clinical predictors for biphasic reactions in children include delayed epinephrine administration or needing more than one epinephrine dose or fluid bolus during the first episode of anaphylaxis. The second reaction may be the same, less severe, or more severe than the initial reaction and can be fatal. Given the incidence of biphasic reactions and the potential for significant morbidity and mortality, a 24 h observation period has been recommended following an anaphylaxis episode. The pathogenesis of this biphasic response is unclear and may involve delayed synthesis or release of mediators, or delayed recruitment of inflammatory cells [12, 31–33].

Differential Diagnosis The differential diagnosis of anaphylaxis includes entities that mimic the cardiovascular, respiratory, gastrointestinal, neurologic and cutaneous symptoms of anaphylaxis, especially those that involve sudden onset of symptoms and/or a proximate response to a stimulus such as drug or food. These disorders can be classified by either symptoms or etiology; both paradigms are useful.

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Table 34.1 Clinical criteria for diagnosing anaphylaxis Anaphylaxis is highly likely if any one of the following three criteria are fulfilled 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula) And At Least One Of The Following (a) Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) (b) Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours) (a) Involvement of the skin-mucosal tissues (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula) (b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) (c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) (d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 3. Reduced BP after exposure to known allergen for that patient (minutes to several hours) (a) Infants and children: low systolic BP (age specific) or greater than 30 % decrease in systolic BPa (b) Adults: systolic BP of less than 90 mmHg or greater than 30 % decrease from that person’s baseline Reprinted from Sampson et al. [29]. With permission from Elsevier PEF Peak expiratory flow, BP blood pressure a Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 × age]) from 1 to 10 years, and less than 90 mmHg from 11 to 17 years

Perhaps the best mimickers are those disorders caused by an excess of histamine, either endogenous, via mast cell degranulation, or from exogenous sources. Examples include mastocytosis and other disorders of mast cells or basophils, red-man syndrome, and scombroidosis, the histamine poisoning one may get from eating spoiled fish. Similar to those of anaphylaxis, skin and mucous membrane symptoms can be seen in acute urticaria, oral allergy syndrome, and nonallergic angioedema, e.g. hereditary angioedema. Alcohol, carcinoid syndrome, or other agents and disorders that cause flushing of the skin are also in the differential of anaphylaxis. Monosodium glutamate ingestion, also known as “Chinese restaurant syndrome”, is related temporally to food ingestion and can cause nausea, vomiting, flushing, and chest pain, similar to anaphylaxis [34]. Differential diagnoses that show predominantly respiratory symptoms include acute asthma, vocal cord dysfunction, and foreign body aspiration. Cardiovascular mimickers include syncope and sudden catastrophic cardiovascular events such as a saddle pulmonary embolus, distributive shock or septic shock. Panic attacks, seizures, strokes, and disorders of autonomic regulation may manifest similarly to the neurologic symptoms of anaphylaxis [3, 19].

Diagnosis Prompt recognition of anaphylaxis is critical given the potential for rapid deterioration and death. Unfortunately anaphylaxis lacks a universal hallmark for diagnosis. Clinical criteria for the likely diagnosis of anaphylaxis have been proposed by expert consensus but need to undergo testing and validation. These criteria are designed to facilitate the rapid recognition of anaphylaxis based on systemic organ system

involvement, onset of symptoms, and exposure to allergen, be it known, likely or unknown. Table 34.1 outlines the diagnostic criteria [29]. Particularly important elements of the history include thorough review of known and/or likely exposure(s), and the timing and evolution of symptoms. Although no single laboratory test can make the diagnosis of anaphylaxis, elevated plasma histamine level or serum tryptase level can help confirm the diagnosis. Neither test is specific for anaphylaxis so results must be interpreted in the clinical context. The plasma histamine level rises early (5–15 min) and normalizes quickly. Thus, histamine is ideally measured within 1 h after the onset of symptoms. Additionally, the half-life of histamine is only 2 min and it is falsely elevated with cell injury (e.g. hemolysis). Thus, the sampling method is crucial for an accurate result, i.e. the sample should be drawn with a wide-bore needle, kept cold, and processed promptly. Measurement of histamine or histamine metabolites may also be performed on a 24-h urine sample [3, 35]. Tryptase is another protein secreted by mast cells, and to a lesser extent, by basophils. Total tryptase concentration does not always increase in anaphylaxis, but is more likely to be elevated in severe allergic reactions compared with mild reactions. Tryptase is also less likely to be elevated in foodinduced anaphylaxis. This is thought to be secondary to a combination of findings: a slower onset and more sustained duration of symptoms in food induced-anaphylaxis, more localized, versus systemic, mast cell degranulation and activation of basophils, and less tryptase in mucosal mast cells. Various tryptases have been described, including inactive pro-β tryptase and active mature forms of α tryptase and β tryptase. Mature serum β tryptase may be more specific for anaphylaxis and hence more useful in a situation like

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mastocytosis in which baseline levels of pro-β tryptase are elevated. Tryptase should be measured within 3 h of symptom onset, and compared to a baseline level that is obtained 24 h after resolution of symptoms or from stored serum obtained prior to the anaphylaxis episode [3, 36, 37]. Research regarding more sensitive and specific tests to confirm the diagnosis of anaphylaxis is underway [38]. Additional testing can be more helpful to identify and confirm triggers for the patient with an episode of anaphylaxis. This testing can be done in several ways with variable accuracy, including skin tests, allergen-specific IgE measurements, and trigger-challenge tests. The details of these tests are beyond the scope of this chapter, but are an important part in the identification of triggers, risk assessment, and most importantly, the prevention of future anaphylaxis episodes by avoidance of known triggers.

Treatment Effective treatment of anaphylaxis requires a high index of suspicion with early recognition and immediate institution of therapy. As with any critical illness, standard measures of attention to airway, breathing and circulation is essential, however prompt institution of specific pharmacologic measures can be lifesaving. One consensus statement suggests the following guide for order of therapies and interventions: Epinephrine, patient positioning, oxygen, fluids, inhalational therapy, vasopressors, antihistamines, corticosteroids, and then other agents [39].

Epinephrine Epinephrine is the mainstay of lifesaving therapy for anaphylaxis and thus should be prioritized above all other therapies or interventions [39–41]. The evidence for the use of epinephrine consists of uncontrolled studies, fatality studies, cohort studies, clinical observations and expert opinion; however, given the likelihood of death from anaphylaxis in the absence of treatment, it would be unethical to perform a placebo controlled randomized controlled trial [42, 43]. Minimal delay for the administration of epinephrine in the setting of anaphylaxis is crucial in preventing mortality. One review of fatal anaphylaxis cases found the median time from contact with allergen to respiratory or cardiovascular arrest to be 5–30 min, depending on trigger (iatrogenic, venom or food), with a range of 1–360 min. Most did not receive epinephrine before arrest [44].

Mechanism of Action Epinephrine is an endogenous catecholamine that exerts its effects via binding of α and β adrenergic receptors found in nearly all tissues. Exogenous epinephrine has an identical

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mechanism of action. Epinephrine’s most important actions relevant to the treatment of anaphylaxis include its effects on the cardiovascular and respiratory systems. Stimulation of α-1 and β-1 receptors causes systemic vasoconstriction and increases inotropy and chronotropy, respectively, with the net result being increased blood pressure and coronary blood flow. Vasoconstriction may also decrease mucosal edema. The β-2 receptor mediates bronchodilation and inhibition of mast cell release of histamine and other inflammatory mediators. Vasodilation via β-2 receptors is more pronounced in skeletal muscle than in other tissues, including the skin and subcutaneous tissues where the α-1 effect of vasoconstriction is more prominent. This is particularly relevant for route of administration. Adverse effects originate from actions on the same receptors and include increased myocardial oxygen demand, increased myocardial excitability and therefore arrhythmia, and CNS symptoms including headache, palpitations, tremor, and anxiety [45]. Rarely, the cardiovascular effects of epinephrine can lead to death, e.g. acute myocardial infarction or fatal arrhythmia. Usually, however, this has been reported in the setting of overdose or inappropriate administration. No absolute contraindication to the administration of epinephrine exists in the context of true anaphylaxis [44].

Modes of Administration For the treatment of anaphylaxis, epinephrine has traditionally been administered by the subcutaneous, intramuscular (IM), or intravenous (IV) routes. Enteral epinephrine is rapidly metabolized in the gastrointestinal tract and liver, so is ineffective and not recommenced as a viable therapy [45]. Sublingual epinephrine is currently being studied as a potentially effective route of administration, but is not standard practice [46, 47]. Inhaled racemic epinephrine can be used for localized mucosal swelling of the upper airway, but for treatment of anaphylaxis, it is unreliable. Intramuscular injection is the most recommended and preferred route given the more rapid onset of action and peak effects compared with subcutaneous administration. These differences in time to peak concentration may be due in part to epinephrine-mediated vasodilation in skeletal muscle allowing faster absorption of the drug versus the vasoconstriction it causes in subcutaneous tissues which can impede absorption [45, 48–50]. Multiple doses may be needed therefore close clinical monitoring is essential. Though reports are lacking, anywhere from 6 to 36 % of cases of anaphylaxis reported in the literature required two or more doses of epinephrine. [51–56]. The appropriate time interval between repeated doses of epinephrine has not been studied. One guideline suggests re-dosing every 5 min with the recommendation that it may be repeated more frequently based on clinician judgment [39]. The IV route is preferred in a patient in arrest or with profound shock given the lack of circulation in muscle and peripheral

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tissues. It can also be given via continuous infusion. In a canine model of anaphylactic shock, continuous IV infusion was the most effective mode of administration in regards to recovery and maintenance of adequate hemodynamics when compared to bolus IV or IM dosing [57]. Additionally, a prospective trial of 19 adult patients experiencing anaphylaxis in response to a diagnostic sting challenge demonstrated consistent and rapid clinical improvement when epinephrine was titrated for symptoms via continuous infusion [58]. The IV route has the greatest potential for adverse effects due to improper administration, so care should be taken when prescribing this route [59]. Patients who are at known risk for anaphylaxis or serious allergic reaction should be prescribed an auto-injector of epinephrine for administration in the community setting. See Table 34.2 for medications used in the treatment of anaphylaxis and their recommended doses.

Patient Positioning Patients with anaphylaxis, especially those with hemodynamic compromise, should be placed in the supine position with elevation of the lower extremities. This will assist with venous return in a system with abnormally high peripheral capacitance and increased vascular permeability from vasodilation. Care should be taken to keep the patient in a supine position until hemodynamics have been stabilized and symptoms have resolved. Cardiovascular compromise and even death have been reported with a change to an upright position in a symptomatic patient [39, 83].

Oxygen Administration and Fluid Resuscitation High flow oxygen is considered standard therapy for any patient with symptoms of anaphylaxis, especially when the reaction is prolonged or when hypoxemia is present. Fluid resuscitation with isotonic crystalloid or colloid solution should be infused rapidly for signs of hemodynamic compromise, such as tachycardia or hypotension. This will expand the intravascular volume in a system with both a higher than normal capacitance secondary to vasodilation as well as relative hypovolemia secondary to increased vascular permeability and capillary leak [39, 65, 84].

Inhaled β-agonists In the setting of anaphylaxis with bronchospasm, inhaled β-2 agonists such as albuterol or levalbuterol can be useful in relieving bronchospasm. β-2 selective agonists exert effects on both β-1 and β-2 receptors, but act predominantly at the

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β-2 receptor. When administered via the inhalational route, they cause bronchodilation through smooth muscle relaxation [45]. They may also inhibit the release of inflammatory mediators from mast cells (e.g. histamine). Beta agonists should be given in conjunction with epinephrine, not as primary therapy [39, 65, 84]. They have been reported to be useful in the setting of bronchospasm with anaphylaxis unresponsive to epinephrine in patients taking β blockers [85]. Similarly, for airway edema, inhaled epinephrine can be utilized [39, 65].

Histamine Blockers Established guidelines for the treatment of anaphylaxis advise the use of H1 receptor blockers, and most also advocate the use of H2 receptor blockers in conjunction [39, 65, 84]. Histamine, in addition to other inflammatory mediators, is released from mast cells and basophils as part of the immediate sensitivity response to a trigger and is the principle cause of anaphylaxis symptoms. Histamine effects are mediated by H1, H2, H3, and H4 receptors. The majority of anaphylaxis symptoms arise from stimulation of the H1 and H2 receptors, which will be the focus of discussion herein. H1 and H2 receptors are widely expressed on several cell types. Among others, H1 receptors are found on smooth muscles cells, endothelial cells, and neurons in the central nervous system, and promote vasodilation, bronchoconstriction and GI motility. They are also responsible for the cutaneous itch associated with histamine release. H2 receptors are found in gastric parietal cells, smooth muscle and cardiac muscle cells, mast cells and in the central nervous system. H2 activation leads to gastric acid secretion, vasodilation, and bronchial mucus production. Of note, H2 receptors on bronchial smooth muscle cells can mediate a degree of bronchodilation. Both H1 and H2 receptors cause increased vascular permeability and vasodilation, but H1 receptors cause immediate and rapid vasodilation, and promote increased fluid transudation causing edema. H2 receptors mediate a slower, longer lasting vasodilator effect. Both receptors are responsible for direct cardiac effects, including increased heart rate, shorter diastolic depolarization and slowed AV conduction [86, 87]. The recommendation for antihistamine use in anaphylaxis is largely from clinical use, basic science and animal research, and biologic plausibility. There is a paucity of quality, clinical evidence for the use of antihistamines in anaphylaxis [88]. However, more evidence exists regarding the effectiveness of antihistamines in less severe allergic disorders such as acute urticaria and allergic rhinitis. It is in these less severe allergic disorders that the combination of H1 and H2 blockers is variably more effective in controlling and resolving symptoms than H1 receptor blockers alone [89]. It is unclear how much benefit patients obtain, if any, from use

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Table 34.2 Drugs used in the treatment of anaphylaxis Drug Epinephrine [60, 61] Intramuscular (IM) 1:1,000 solution

Auto-injectors [62–64]

Intravenous (IV) 1:10,000 solution

Corticosteroids [29, 39, 65–67]

Pediatric dose

Adult dose

Notes

0.01 mg/kg IM

0.2–0.5 mg IM

Manufacturers’ recommendation: 25 kg, 0.3 mg IM 0.1 mg IV, over 5 min

The IM route is recommended over the subcutaneous route. Fastest onset when given via IM route in the antero-lateral thigh [48, 49] Can be repeated every 5–15 min Auto-injectors are dosed as either 0.15 mg or 0.3 mg dose vials only

Antihistamines [29, 61, 66] Diphenhydramine 1–2 mg/kg IV/IM/ H1 blockers – 1st generation PO, up to 50 mg Hydroxyzine 0.5–1 mg/kg IM every 4–6 h as needed; or 2 mg/kg/day PO divided every 6–8 h Cetirizine 6 month–2 year: 2.5 mg; H1 blockers – 2nd generation 2–5 year 2.5–5 mg; 6+ yrs: 5–10 mg PO Fexofenadine 6 month-2 year: 15 mg; 2–11 year, 30 mg; 12 + yrs: 60 mg PO Loratidine 2–5 year: 5 mg, 6+ yrs: 10 mg PO Ranitidine 1.25 mg/kg IV; 2 mg/kg H2 blocker PO

Vasopressin [61]

Norepinephrine [61] Glucagon [29, 71, 72]

Isoproterenol [61]

Methylene blue [74–81]

Continuous infusion for shock states, titrate to effect 0.01–0.48 units/kg/h IV 0.05–1 mcg/kg/min IV, up-titrate to effect 20–30 mcg/kg IV (max 1 mg)

Continuous infusions may be preferable to frequent bolus doses in severe or refractory reactions [58]

Continuous infusion: 1–4 mcg/min IV. Up-titrate to shock doses to reach desired effect Methylprednisolone 50–120 mg IV Corticosteroids are not useful in the acute management of anaphylaxis; Hydrocortisone 100–500 mg IM/IV no evidence to support the theory that corticosteroids prevent Dexamethasone 4–20 mg IM/IV protracted or biphasic reactions Prednisone 50 mg PO [29, 31, 33, 39] Diphenhydramine 25–50 mg IV/ IM/PO Hydroxyzine 25–50 mg IM/PO every 6–8 h as needed

Common examples in each category, not an exhaustive list

Cetirizine 5–10 mg PO

Second generation H1 blockers are not available in IV formulation

Fexofenadine 60 mg PO

Loratidine 10 mg PO Ranitidine 125 mg PO; 50 mg IV

Used alone, H2 blockers have the theoretical risk of potentiation of bronchoconstriction via unopposed H1 effect [68] Bolus dose treatment of anaphylaxis resistant to epinephrine described in adults: 2–5 units [60, 69, 70]

Continuous infusion for shock states, titrate to effect 0.6– 2.4 units/h IV 0.05–1 mcg/kg/min IV, up-titrate to effect 1–5 mg IV over 5 min followed by May be useful to reverse continuous infusion, 5–15 mcg/ bronchospasm and hypotension min, titrated to response refractory to standard therapy in patients taking beta blockers. May cause emesis Usual dose for brady-arrhythmias Usual dose for brady-arrhythmias Use described in one pediatric and AV nodal block:0.05–2 mcg/kg/ and AV nodal block: 2–20 mcg/min patient on beta blockers for min IV, titrated to response IV, titrated to response epinephrine-refractory anaphylaxis to aprotinin during cardiac surgery. Dose used, 1.7 mcg/kg [73] 0.5–2 mg/kg (most commonly 0.5–2 mg/kg (most commonly Used in epinephrine refractory 1.5 mg/kg) bolus dose over 1.5 mg/kg) bolus dose over anaphylaxis. Use caution in patients 5–20 min, sometimes followed by 5–20 min, sometimes followed by with G6PD deficiency due to risk of continuous infusion of 0.5–1.5 mg/kg continuous infusion of 0.5–1.5 mg/ methemoglobinemia over 1 h kg over 1 h Cardiac angina and anaphylaxis has been reported after methylene blue use [82]

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of both in anaphylaxis [43, 90]. Additionally, publications from the 1980s report resolution of refractory anaphylaxis with the H2 blocker, cimetidine. However, it is not clear that this was a cause/effect relationship, and in fact, an H2 blocker alone has the theoretical risk of potentiation of bronchoconstriction via unopposed H1 effect [68, 91–93]. A variety of different antihistamine agents are available for use. First generation H1 blockers tend to have more adverse effects, especially sedation, but the non-sedating H1 blockers are not available in intravenous form. H2 blockers are available in both enteral and intravenous preparations.

Corticosteroids While ineffective in the acute treatment of anaphylaxis, corticosteroids are another adjunctive treatment and may, in theory, help alleviate protracted symptoms. There is, however, no evidence supporting the concept that their use will prevent a biphasic reaction [31, 33, 39]. The exact mechanisms of the anti-inflammatory effects of corticosteroids are not completely elucidated. They directly affect transcription, thereby inhibiting enzymes that facilitate the production of inflammatory mediators, including prostaglandins, leukotrienes and other cytokines [94]. As with other drugs used for anaphylaxis, quality, clinical evidence supporting corticosteroid use for the alleviation of anaphylactic symptoms is lacking [43, 95]. However, short term use is associated with fewer side effects, and the current guidelines recommend consideration of their use. Given the protracted onset of effect, more immediate and potentially lifesaving treatment, namely epinephrine and fluid resuscitation, should never be delayed by administration of corticosteroids [39, 65, 84].

Other Vasopressors In a number of reported cases of anesthetic related, epinephrine resistant anaphylactic shock, vasopressin, terlipressin, norepinephrine, or the pure α1 agonists metaraminol and methoxamine have been used successfully when epinephrine failed [39, 60, 69, 96–100]. Vasopressin has been reported as successful treatment in cases of anaphylaxis secondary to insect sting [101]. Administration of these agents may be indicated in the setting of circulatory compromise/vasodilation unresponsive to multiple doses of epinephrine.

Other Agents Patients receiving β blocker therapy have a greater risk of more severe and prolonged symptoms, especially hypotension and bradycardia [102]. In these patients, epinephrine, the mainstay

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of anaphylaxis therapy, will primarily result in α-adrenergic effects with little inotropy or chronotropy due to lack of β-adrenergic activation. This phenomenon has been reported in patients receiving therapy with non-selective β blockers as well as those taking cardio-selective β-1 blocker agents. Isoproterenol and glucagon have both been used successfully to increase cardiac output, heart rate, and blood pressure in patients under β blockade. Isoproterenol, a non-selective β agonist, competitively activates β-adrenergic receptors, even in the presence of β blockers. Glucagon bypasses the adrenergic receptors altogether and increases cardiac contractility and heart rate via activation of adenylate cyclase [73, 103–105]. Methylene blue has been reported as effective for treating refractory hypotension, especially in the context of anesthesia induced anaphylaxis as well as cases of idiopathic and contrast induced anaphylaxis [74–78]. Additionally, it has been used successfully for children with persistent vasodilation, or vasoplegic syndrome, following cardiopulmonary bypass. The vasoactive effect of methylene blue is thought to be identical in both entities) [106]. The mechanism by which it treats catecholamine refractory vasodilation is thought to be via inhibition of guanylyl cyclase and nitric oxide synthase [107]. Doses that have been used in published cases are shown in Table 34.2.

Treatment of Cardiorespiratory Arrest in the Management of Anaphylaxis A patient who has progressed to cardiorespiratory arrest from anaphylaxis should receive resuscitation consistent with the standard basic and advanced pediatric life support guidelines, with a focus on simultaneously managing and reversing the effects of anaphylaxis [108]. At any sign of airway edema, including hoarseness, stridor, visible swelling of the tongue or oropharynx, the clinician should prepare for the potential need for advanced airway management. This includes, but is not limited to, controlling the airway early or electively, anticipating a smaller airway and gathering appropriate equipment, summoning the help of anesthesia colleagues, and being prepared to rapidly obtain a surgical airway if indicated. The administration of epinephrine should not be delayed; if an epinephrine auto injector is available, the dose should be used immediately. As noted above, however, in a state of shock or cardiac arrest, absorption may be delayed. Thus intravenous or intraosseous doses should be given as soon as access is obtained with consideration to a continuous infusion. Other vasopressors can be considered as discussed above. Given the degree of vasodilation and vascular permeability associated with anaphylactic shock, fluid resuscitation should be rapid and large in volume as capillary leak leading to relative hypovolemia and decreased preload may have contributed to the state of cardiovascular collapse. Early consideration of

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extracorporeal membrane oxygenation (ECMO), especially in the case of in-hospital arrest should be considered, given the reversible nature of anaphylaxis [108].

Prevention Prevention of anaphylaxis is the best treatment and involves two strategies: diagnosis and avoidance of known triggers and/or immunomodulation to desensitize the individual to the offending agent. In individuals with recurrent idiopathic anaphylaxis, prophylaxis with steroids, histamine blockers and/or anti-IgE antibody preparations may be indicated. Equally important, however, are strategies to reduce the risk of death from anaphylaxis. This includes instruction to avoid the trigger or probable trigger, referral to an allergist for further work-up, and appropriate prescribing of epinephrine auto-injectors to those at known risk. Education about the epinephrine auto-injector for caregivers and patients is necessary and should include instructing them about the proper use of the device and to always carry it in a readily available way. It is important to be aware of the clinically relevant limitations of such “epi pens.” They are available in either 0.15 or 0.3 mg doses. This presents an imperfect dosing strategy for pediatric patients with widely varying weights, and also poses great potential for over- or underdosing. Given the length of the auto-injector needles, they may be too short for adequate intramuscular administration in obese patients. Additionally, the auto-injectors cannot be stored in extremes of temperature and have a short shelf life, thus replacement of them every 12–24 months, or more frequently, is necessary [62]. Parents and patients should also seek medical care anytime they utilize their auto-injector.

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77. Oliveira Neto AM, Duarte NM, Vicente WV, Viaro F, Evora PR. Methylene blue: an effective treatment for contrast mediuminduced anaphylaxis. Med Sci Monit. 2003;9(11):CS102–6. 78. Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PR. Methylene blue for clinical anaphylaxis treatment: a case report. Sao Paulo Med J. 2007;125(1):60–2. 79. Bauer CS, Vadas P, Kelly KJ. Methylene blue for the treatment of refractory anaphylaxis without hypotension. Am J Emerg Med. 2013;31(1):264 e263–265. 80. Evora PR, Roselino CH, Schiaveto PM. Methylene blue in anaphylactic shock. Ann Emerg Med. 1997;30(2):240. 81. Stocche RM, Garcia LV, Reis MP, Klamt JG, Evora PR. Methylene blue to treat anaphylaxis during anesthesia: case report. Rev Bras Anestesiol. 2004;54(6):809–14. 82. Giladi AM, Kasten SJ. Anaphylactic-like reaction to methylene blue: case report and review of perioperative hypersensitivity reactions. Plast Reconstr Surg. 2012;130(1):98e–105. 83. Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol. 2003;112(2):451–2. 84. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005;112(24 Suppl):IV1–203. 85. Lundin AP, Pilkington B, Delano BG, Friedman EA. Response to inhaled beta-agonist in a patient receiving beta-adrenergic blockers. Arch Intern Med. 1984;144(9):1882–3. 86. Simons FE. Advances in H1-antihistamines. N Engl J Med. 2004;351(21):2203–17. 87. Skidgel RA, Kaplan AP, Erdos EG. Histamine, bradykinin, and their antagonists. In: Goodman LS, Brunton LL, Chabner B, Knollmann BC, editors. Goodman & Gilman’s pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011. p. 2084. 88. Movat HZ, Di Lorenzo NL, Taichman NS, Berger S, Stein H. Suppression by antihistamine of passive cutaneous anaphylaxis produced with anaphylactic antibody in the guinea pig. J Immunol. 1967;98(2):230–5. 89. Lin RY, Curry A, Pesola GR, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med. 2000;36(5):462–8. 90. Sheikh A, ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis with and without shock. Cochrane Database Syst Rev. 2007;1, CD006160. 91. De Soto H, Turk P. Cimetidine in anaphylactic shock refractory to standard therapy. Anesth Analg. 1989;69(2):264–5. 92. Mayumi H, Kimura S, Asano M, Shimokawa T, Au-Yong TF, Yayama T. Intravenous cimetidine as an effective treatment for systemic anaphylaxis and acute allergic skin reactions. Ann Allergy. 1987;58(6):447–50. 93. Yarbrough JA, Moffitt JE, Brown DA, Stafford CT. Cimetidine in the treatment of refractory anaphylaxis. Ann Allergy. 1989;63(3): 235–8.

541 94. Schimmer BP, Funder JW. ACTH, adrenal steroids, and pharmacology of the adrenal cortex. In: Goodman LS, Brunton LL, Chabner B, Knollmann BC, editors. Goodman & Gilman’s pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011. p. 2084. 95. Choo KJ, Simons FE, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev. 2010;3, CD007596. 96. Higgins DJ, Gayatri P. Methoxamine in the management of severe anaphylaxis. Anaesthesia. 1999;54(11):1126. 97. McBrien ME, Breslin DS, Atkinson S, Johnston JR. Use of methoxamine in the resuscitation of epinephrine-resistant electromechanical dissociation. Anaesthesia. 2001;56(11):1085–9. 98. Heytman M, Rainbird A. Use of alpha-agonists for management of anaphylaxis occurring under anaesthesia: case studies and review. Anaesthesia. 2004;59(12):1210–5. 99. Schummer W, Schummer C, Wippermann J, Fuchs J. Anaphylactic shock: is vasopressin the drug of choice? Anesthesiology. 2004;101(4):1025–7. 100. Rocq N, Favier JC, Plancade D, Steiner T, Mertes PM. Successful use of terlipressin in post-cardiac arrest resuscitation after an epinephrine-resistant anaphylactic shock to suxamethonium. Anesthesiology. 2007;107(1):166–7. 101. Kill C, Wranze E, Wulf H. Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol. 2004;134(3):260–1. 102. Lang DM. Do beta-blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy Asthma Rep. 2008;8(1):37–44. 103. Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on betablockers. Emerg Med J. 2005;22(4):272–3. 104. Compton J. Use of glucagon in intractable allergic reactions and as an alternative to epinephrine: an interesting case review. J Emerg Nurs. 1997;23(1):45–7. 105. Jacobs RL, Rake Jr GW, Fournier DC, Chilton RJ, Culver WG, Beckmann CH. Potentiated anaphylaxis in patients with druginduced beta-adrenergic blockade. J Allergy Clin Immunol. 1981;68(2):125–7. 106. Leyh RG, Kofidis T, Struber M, et al. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg. 2003;125(6): 1426–31. 107. Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH. Methylene blue and vasoplegia: who, when, and how? Mini Rev Med Chem. 2008;8(5):472–90. 108. Vanden Hoek TL, Morrison LJ, Shuster M, et al. Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3): S829–61.

Rheumatologic Disorders in the PICU

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Steven W. Martin and Michael R. Anderson

Abstract

Rheumatologic diseases in children compromise a small but sometimes perplexing portion of patients admitted to the Pediatric Intensive Care Unit. Systemic Lupus Erythematosus (SLE) is the most variable and indiscriminate vasculitis affecting children. SLE may cause devastating injury to virtually any organ system and therefore must often be included in the differential diagnosis of critically ill children. Juvenile Idiopathic Arthritis (JIA) does not commonly require admission to the ICU in itself, but is associated with macrophage activation syndrome (MAS). MAS is a spectrum of hemophagocytic lymphohistiocytosis (HLH) which often calls for intensive care and aggressive therapies. Henoch-Schoenlein Purpura is a small vessel vasculitis affecting children commonly associated with intussusception, but may also give rise to significant cardioplulmonary complications. Kawasaki Disease is the most common vasculitis in children and the recently described Kawasaki Disease Shock Syndrome may require invasive monitoring and therapies. Antiphospholipid Antibody Syndrome, Goodpasture Disease, and Wegener’s Granulomatosis while not common, give rise to complications which also may necessitate critical care. The following chapter discusses these disease entities and other rheumatologic illness affecting children and common complications arising from them which may indicate critical care. Included in the discussion are the most widely accepted diagnostic approaches and therapies, and supporting evidence is described. Keywords

Systemic Lupus Erythematosus • Juvenile Idiopathic Arthritis • Macrophage Activation Syndrome • Kawasaki Disease • Kawasaki Disease Shock Syndrome • Antiphospholipid Antibody Syndrome • Infliximab • Henoch-Schoenlein Purpura • Goodpasture Disease Churg-Strauss Syndrome • Juvenile Dermatomyositis • Systemic Sclerosis

Introduction

S.W. Martin, MD Department of Pediatrics, Sparrow Hospital Children’s Center, Lansing, MI, USA M.R. Anderson, MD, FAAP (*) University Hospitals Case Medical Center, 11100 Euclid Avenue, LKS 5006, Cleveland, OH 44106, USA e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_35, © Springer-Verlag London 2014

In the general pediatric population, rheumatologic diseases vary greatly in their features and presentation. Thus, despite their infrequency, these disorders often must be included in the differential diagnosis when evaluating a critically ill child. It has been estimated that between 5 and 10,000 children within the United States carry the diagnosis of systemic lupus erythematosus [1], the most common connective tissue disease. In addition, 30,000–50,000 children suffer 543

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Table 35.1 Systemic lupus erythematosus Selected manifestations Central nervous system

Pathophysiology High affinity pathogenic IgG autoantibodies (anti-dsDNA, anti-Sm, etc.) bind to autoantigens and cause direct damage via complement activation [6] Ischemic stroke Circulating immune complexes overwhelm clearance mechanisms and deposit in tissues due to their net anionic Hemorrhagic stroke Cerebral vein thrombosis charge and/or binding to autoantigens by the antibodies in the complex. These complexes lead to complement Seizure activation and subsequent tissue damage [6] Psychosis Delirium Depression Cardiac Myocarditis Cardiomyopathy Pericarditis Endocarditis Pulmonary Pneumonitis Pulmonary hemorrhage Renal Glomerulonephritis Hematological Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia Thromboembolism

from juvenile idiopathic arthritis (JIA) [2], the most common rheumatologic disease. The most common vasculitis in childhood, Henoch-Schonlein Purpura (HSP), has an estimated incidence of nine per 100,000 children [3, 4]. More rare rheumatologic diseases affecting children include antiphospholipid antibody syndrome (APS), juvenile dermatomyositis (JDM), Goodpasture disease, Wegener granulomatosis, Churg-Strauss syndrome, and scleroderma. The pediatric intensivist cares for rheumatology patients for varying reasons, related to the primary disease process, adverse effects of treatment for the underlying disease, and/ or illnesses that are complicated by the underlying disease [5]. In the following sections, we will examine selected rheumatologic diseases affecting children, and will review their presentation, pathophysiology, complications, and management.

Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus (SLE) (Table 35.1) is the prototypic, and most variable rheumatologic disease described to date, affecting all organ systems. SLE affects patients of all ethnicities and ages, but 15–20 % of patients are diagnosed in the first two decades of life [8]. SLE is extremely variable

Laboratory abnormalities Positive anti-dsDNA antibody

Positive anti-Sm antibody Positive antiphospholipid antibodies Positive ANA Low C3 Low C4 Low CH50 Positive anti-centromere antibody Positive anti-SSa antibody Positive anti-SSb antibody Proteinuria Urinary casts (red cell, hemoglobin, granular, tubular, or mixed) [7]

in presentation, organ system involvement, and disease progression [9, 10]. Patients with SLE are hospitalized in the intensive care setting for a wide array of diagnoses. One retrospective study of adult SLE patients requiring intensive care unit admission found that the primary diagnosis was infection in 41 % of admissions (the majority of which were diagnosed with septicemia), renal disease in 21 %, cardiovascular disease in 16 %, and coagulopathy (both thrombotic and hemorrhagic) in 14 % [11]. The pathogenesis of SLE differs depending on which tissues are examined and is best described in renal disease, which shows inflammation, cellular proliferation, and immune complex deposition affecting the glomerular basement membrane (GBM). Deposition of circulating immune complexes or de novo synthesis of immune complexes on the GBM activates the complement cascade, leading to cellular damage, cellular proliferation, and matrix deposition [12]. Tissue classification of lupus nephritis is complex secondary to the variability of disease expression among patients and among various glomeruli within one tissue biopsy [12]. The World Health Organization (WHO) has established a classification scheme based on light microscopy, immunofluorescence, and electron microscopy, which divides lupus nephritis into six classes. Findings range from class I with normal glomeruli by light microscopy,

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immunofluorescence, and electron microscopy, to class VI where >90 % of observed glomeruli are sclerotic [12]. The cardiovascular system, including both the heart and blood vessels, shows pathologic changes due to the ongoing autoimmune process as well. Inflammation is seen in the pericardium, myocardium, and endocardium. Immunofluorescence studies have shown complement and immune complex deposition within the myocardial vessels as well as the myocardium itself [13].

CNS Complications of SLE Approximately 20–30 % of children will develop CNS involvement, or neuropsychiatric lupus (NPS), during the course of their SLE, with 75–85 % of these developing during the first year [14, 15]. The term neuropsychiatric lupus describes 19 clinical situations seen in SLE patients, which may be the consequence of ongoing CNS vasculitis, peripheral nervous system involvement, or stroke due to associated antiphospholipid antibodies [16, 17]. Symptoms range from headache or memory impairment to psychosis, paralysis, seizures, and coma. When considering serious or life-threatening CNS lupus only (including seizures, stroke, major cognitive disorder, chorea, psychosis, major depression, and acute confusional state) Sibbit and colleagues found that 76 % of the patients in their series were affected during the 6-year study period [18]. A similar case series from Spinosa and colleagues reports nearly 62 % of patients with SLE diagnosed before age 16 years had NPS syndromes as defined by the American College of Rheumatology during their 14 year study period [19]. CNS disease has been reported as the initial presentation of SLE in 16–28 % of pediatric patients [15, 20, 21]. However, before CNS symptoms are attributed to the SLE, other entities such as infection, mass, or hemorrhage must be evaluated thoroughly.

Seizures Seizure has been reported as the most common serious CNS complication of pediatric SLE, occurring in up to 51–61 % of patients [15, 18, 20, 22]. Seizures may be the initial presentation of disease [15, 18, 20, 22] and may portend a more severe disease course when present at diagnosis of SLE [23]. Seizures associated with SLE are usually easily controlled with standard antiepileptic therapy and remit with control of SLE, although status epilepticus has been reported [24]. Mecarelli and colleagues reported a case of SLE induced status epilepticus requiring barbiturate coma [25].

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when there is a severe unremitting headache, especially when the patient has known antiphospholipid antibodies [26]. Head CT images are often normal in the presence of a CVT, but abnormalities are sometimes identified. The most common CT finding is the delta sign which appears as a central dark area in the torcula, corresponding to thrombus, surrounded by enhancing contrast representing flowing blood [27]. With early consideration of the diagnosis, imaging, and treatment, reported outcomes have been favorable [26]. Delays in diagnosis and/or therapy have been associated with progressive neurological deficits, and death [26]. Supportive medical and neurologic care, including hydration and seizure control, are the cornerstones of therapy for CVT in children [27]. Anticoagulation is considered by some to be appropriate therapy, but remains controversial, and the most appropriate agent remains unclear. Many studies have shown the safe use of anticoagulation in adult and pediatric patients with sinovenous thrombosis, but none has clearly shown significant benefit [28, 29]. In the acute phase, intravenous infusions of heparin have been most widely used [28, 30], but safe and effective use of low-molecular weight heparin has also been reported in pediatric patients without evidence of preceding intracranial hemorrhage [31–33]. Continued or intensified therapy for the underlying vasculitis is also appropriate [14]. Data regarding the use of thrombolytics in children with CVT are sparse. Studies regarding the use of thrombolytics for other forms of thromboses in children have shown effectiveness but with a low therapeutic index [34].

Stroke Stroke has been reported in 3.4–12 % of pediatric patients with SLE [15, 20, 22] and in 20–40 % of patients with neuropsychiatric lupus [20, 22]. Strokes seen in pediatric SLE may be arterial ischemic strokes or sequelae of cerebral vein thrombosis. Most reports of stroke with pediatric SLE identify the concurrent presence of antiphospholipid antibodies (anti-cardiolipin antibody or lupus anticoagulant) [30]. Treatment of stroke in SLE patients is largely supportive, aiming at maintaining normothermia, hydration, and normal hemodynamics [30]. Anticoagulation is becoming accepted practice although the ideal agent remains controversial, but should be considered in these patients. Patients with antiphospholipid antibodies, particularly lupus anticoagulant, have a high risk of recurrent cerebrovascular disease [30, 35, 36] and therefore may be more likely to benefit from anticoagulation. Therapy should also include ongoing or intensified immunosuppressive therapy provided the absence of a contraindication [14].

Cerebral Vein Thrombosis Cerebral vein thrombosis (CVT), usually seen in association with antiphospholipid antibodies, has been associated with pediatric SLE more commonly than in adults [8]. The presence of a CVT in pediatric patients should be considered

Psychosis, Delirium, and Depression Although children who present with depression, psychosis, delirium, or movement disorders secondary to SLE often have normal CSF findings and non-focal CT and MRI

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studies, discrete lesions can sometimes be seen on CT and MRI [37]. If abnormalities are seen on MRI, they are usually diffuse gray and white matter lesions that dramatically improve or resolve with aggressive SLE treatment [38]. There are also reports of single photon emission computed tomography (SPECT) scan abnormalities in the parietal and frontal lobes [39], as well as diffuse small areas of decreased uptake [40]. Other than possibly supporting the diagnosis of neuropsychiatric lupus, the clinical utility of SPECT scan abnormalities remains unclear as they usually persist despite clinical improvement [8, 39–41] and may be present in pediatric SLE patients without clinical CNS disease [40]. Favorable outcome of neuropsychiatric SLE in both pediatric and adult patients has been reported after treatment with intravenous methylprednisolone and cyclophosphamide [16, 38, 42, 43].

Pulmonary Complications of SLE Pulmonary involvement in adults with SLE is common, with infection being the most frequent complication [44]. The incidence of pulmonary involvement in children with SLE is difficult to estimate as the literature is limited primarily to case reports and small series; however published figures place the incidence anywhere between 5 and 67 % during the course of the disease, and acute lupus pneumonitis may be the first manifestation of disease [45]. Pulmonary hypertension, diffuse interstitial disease, pulmonary hemorrhage, pneumothorax, acute lupus pneumonitis, and shrinking lungs have all complicated SLE in pediatric patients [45].

SLE Pneumonitis Acute lupus pneumonitis is difficult to clinically differentiate from an infectious process, and must be a diagnosis of exclusion [44, 45]. Mortality in adult patients with acute lupus pneumonitis is approximately 50 % [44]. Presenting symptoms include fever, dyspnea, tachypnea, hypoxia, cough, and occasionally hemoptysis [45]. On blood gas analysis, hypoxemia and a respiratory alkalosis are often seen [44]. Initial therapy should consist of corticosteroids; cyclophosphamide, plasmapheresis, or intravenous immunoglobulin may be added if there is no clinical response [44, 46]. One must be cognizant of the fact that treatment with cyclophosphamide has been linked with an increased risk for opportunistic infections and mortality [11, 47]. Pulmonary Hemorrhage Pulmonary hemorrhage in SLE is an uncommon, but often deadly occurrence, with mortality approaching 80 % [45]. Symptoms associated with pulmonary hemorrhage are similar to those seen in pneumonitis, with cough, dyspnea, tachypnea, and hypoxia seen most commonly, in association with

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a sudden drop in hematocrit. Hemoptysis is an unreliable indicator of the presence or absence of pulmonary hemorrhage [44, 45]. Chest radiography will usually reveal patchy alveolar infiltrates, particularly in the lower lobes; however, infiltrates are not universally present [44]. Reported therapies consist of pulse methylprednisolone with or without cytotoxic agents [45, 48]. Respiratory failure associated with SLE and pulmonary hemorrhage requires aggressive ventilatory and hemodynamic support, and extracorporeal life support has been used successfully in conjunction with ongoing immunosuppressive therapy [49].

Cardiac Complications of SLE SLE Pericarditis Pericarditis is the most common cardiac complication of pediatric SLE; throughout the disease process, pericarditis is seen in up to 25 % of SLE patients, and can rarely be the first manifestation of disease [50, 51]. In adult patients, pericarditis is present in 6–45 % of SLE patients, and in autopsy series, as many as 60–80 % of patients have pericardial lesions [52]. Pericardial tamponade is a rare, life-threatening, but usually early complication of SLE [52], occurring in less than 4 % of pediatric patients [50, 53]. Pericardial fluid in SLE serositis is an inflammatory exudate consisting of fibrinous debris and inflammatory cells, which can mimic bacterial pericarditis [54]. An ANA titer of >1:160 in the pericardial fluid has been shown to be a sensitive, but not specific, indicator of underlying SLE [55]. While the presence of lupus erythematosus cells (phagocytic cells which have ingested the nucleus of another cell) in a pericardial aspirate has been shown to have high sensitivity and specificity [54, 55]. Therapy for SLE pericarditis is guided by severity. In pediatric SLE, pericarditis is usually mild, and effusions small [50]. In this setting, treatment is aimed at the underlying disease and consists of monitoring, steroids, antimalarials, and other immune modulators [50, 56]. The presence of a large pericardial effusion is an indication for ICU monitoring, and may warrant aspiration, particularly when present with diminished cardiac function or cardiovascular instability.

SLE Endocarditis Verrucous endocarditis (Libman-Sacks endocarditis) describes the valvar vegetations seen in association with SLE. Most commonly these involve the mitral valve, but also involve the aortic, pulmonic, and tricuspid valves in order of decreasing incidence [50]. The lesions consist of deposits of immune complexes, cellular debris, and fibrin [57, 58]. In autopsy series, these nodular lesions have been found uniformly in SLE patients [59]. However, lesions detectable by echocardiography occur

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generally in older adolescents and adults [50]. Rarely, heart failure from mitral insufficiency can be the clinical presentation in SLE, and require mitral valve replacement in childhood [60].

SLE Myocarditis and Cardiomyopathy Although cardiac processes in association with SLE are widely recognized, clinically apparent acute myocarditis is a rare complication of SLE, particularly in infants and children [61, 62]. Even so, acute myocarditis has been reported as the initial presentation of SLE [63]. The literature regarding lupus-associated myocarditis is limited owing to the rarity of this clinical entity. Therefore, there is no consensus on the best management of SLE myocarditis [62]. The literature contains reports of poor responses of SLE myocarditis to steroid therapy [62, 64]; however, James et al. [62] state that further immunosuppression seems a reasonable approach in light of the underlying autoimmune process. In the adult literature, high dose intravenous corticosteroids are the norm, with anecdotal reports of other immunosuppressive agents (azathioprine and cyclophosphamide) and intravenous immune globulin providing some benefit [13, 65]. Data from Johns Hopkins suggest that the mortality of myocarditis associated with SLE is greater than that of primary myocarditis [66].

Infectious Complications of SLE The most frequent complication, reason for admission to the ICU, and cause of death among SLE patients is infection [11, 67–72]. The rate of infectious complications in these patients is increased by therapy for the underlying disease [71, 73, 74], although SLE intrinsically increases the risk of serious infection [70, 73]. Localized infections are usually related to the underlying disease, while systemic infections are generally caused by immunosuppression from therapy, in particular corticosteroids [70]. Glucocorticoid therapy has multiple effects on immunity, including suppressing phagocytic function, cellmediated immunity, and humoral immunity [70, 74]. As a result, the offending agents in infections related to glucocorticoid therapy are diverse. Defective phagocytic function places the patient at risk for gram-positive, gram-negative, and fungal infections [71, 74]. Ineffective cell-mediated immunity places the patient at risk for organisms such as Mycobacterium, Listeria monocytogenes, Salmonella, and Nocardia, as well as Histoplasma, Coccidiodes, and Cryptococcus [74]. Protozoal (Pneumocystis, Toxoplasma, and Strongyloides) and viral (cytomegalovirus, EpsteinBarr virus, and Varicella-zoster virus) infections are also related to defective cell-mediated immunity [74]. Multiple studies have reported that patients maintained on high dose

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corticosteroids, particularly more than 20 mg per day, are at increased risk for serious infections [75, 76]. In fact, one series reported that 90 % of infected patients on more than 40 mg per day of prednisone were bacteremic [76]. Although even lower doses have been shown to increase the risk [75]. Bacterial pathogens account for more than 90 % of infections in SLE patients [70], and the most frequently isolated organisms are S. aureus and enteric gram-negative bacteria [70, 71, 74]. Gram-negative sepsis or bacteremia was the cause of death in 32 % of SLE-related deaths in one series of 544 patients [71]. Patients with SLE have been found to be at increased risk for pneumococcal infections secondary to functional hyposplenism, hypocomplementemia, impaired chemotaxis, and defects in opsonization, all secondary to SLE itself [75].

Renal Complications of SLE Two-thirds of children and adolescents with SLE will develop nephritis during the course of their illness, and in 90 % of these, the renal disease is present within 1 year of diagnosis [8], with diffuse proliferative glomerulonephritis being the most common form. Unfortunately this form of nephritis is the form most likely to progress to end-stage renal disease and/or death [8]. In patients with SLE admitted to the intensive care unit, renal failure has been associated with increased mortality [67].

Juvenile Idiopathic Arthritis (JIA) Juvenile idiopathic arthritis (JIA) (Table 35.2), formerly known as juvenile rheumatoid arthritis (JRA), is a common rheumatic disease of childhood, responsible for significant morbidity. The underlying cause of JIA remains unclear, but an underlying immunogenetic susceptibility is likely required to react to an external stimulus thereby inducing disease [77]. Approximately 113/100,000 children currently carry the diagnosis of JIA, with an annual incidence of approximately 13.9/100,000 children 15 years old or younger [77]. Three types, or onset forms of JIA are currently described:, oligoarthritis (pauciarticular), polyarthritis, and systemic onset disease [77]. While oligoarthritis generally affects the large joints of the lower extremities, polyarthritis affects both large and small joints, often with 20–40 individual joints involved [77]. Systemic onset disease is characterized by a cyclical fever which may exceed 39 °C, in conjunction with a faint salmon-colored evanescent macular rash [77]. Hepatomegaly, splenomegaly, and lymphadenopathy are present with arthritis. Serositis in the form of pericardial effusion may be present as well [77].

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Table 35.2 Juvenile idiopathic arthritis Selected manifestations Central nervous system Cerebral vasculitis Uveitis Cardiac Pericarditis

Pathophysiology Unknown etiology, but likely represents an exaggerated immune response to an infectious trigger in predisposed children [77]

Endocarditis Myocarditis/ cardiomyopathy Pulmonary Diffuse interstitial fibrosis Gastrointestinal Hemorrhage Hepatomegaly Hepatitis Hematological Hemolytic anemia Anemia of chronic disease Macrophage activation syndrome Splenomegaly

Laboratory abnormalities Leukocytosis (WBC 30,000–50,000/mm3) Thrombocytosis Elevated ESR Elevated CRP Elevated complement components Occasionally RF positive ANA sometimes positive (usually homogenous or speckled pattern) [78]

Although the overall mortality of JIA is low, when comparing affected individuals to non-affected individuals, the diagnosis of JIA does impart an increase in age-adjusted mortality [2]. Approximately two-thirds of deaths attributable to JIA are in patients with systemic onset JIA, which compromises only 10–20 % of all patients with JIA [2]. Deaths due to JIA are most likely secondary to infections, cardiac complications, and macrophage activation syndrome [2].

Infectious Complications of JIA Similar to SLE, infections in patients with JIA are usually a complication of therapy for the underlying disease. The disease modifying drugs used most commonly in JRA include steroids and methotrexate. Other medications, including azathioprine, cyclosporine, and etanercept, have also been used. Although these medications have the potential for significant improvement in the daily function of patients with JIA, several of these medications carry risks of serious infectious complications. As discussed previously, steroid therapy has multiple effects on immunity, and sustained therapy, particularly at high doses, is associated with increased infection rates. With other disease modifying drugs available, steroids

are generally reserved for severe systemic onset disease or life threatening complications of JIA [2]. Anti-TNF therapy is the newest class of medications currently being used for the treatment of JIA. Etanercept (Enbrel; Amgen Inc.) and infliximab (Remicade; Centocor Inc.) are two such medications. Etanercept is a human fusion protein of Fc IgG1 and the p75 TNF receptor which has been FDA approved for use in rheumatoid arthritis and psoriatic arthritis. Its use has proven to provide improvement in patient functionality and pain, as well as slowed disease progression [79]. In children, etanercept has been shown to be well tolerated and effective in the treatment of JIA, particularly those with pauciarticular or polyarticular JIA [80]. Placebo controlled trials found no increase in the rate of serious infections between treatment and control groups [81, 82]. However, post-marketing reports of serious bacterial infections have been published. Patients who are prescribed etanercept with concurrent steroid therapy are at particular risk [83] and in patients with active sepsis etanercept has been shown to increase mortality [84]. Infliximab (Remicade; Centocor Inc.) is a monoclonal anti-TNF-α antibody which has also shown beneficial in the management of inflammatory arthritis [79], but is not currently labeled for use in JIA. In placebo controlled studies evaluating anti-TNF therapy, several studies have shown a similar incidence of serious bacterial infections (lifethreatening or requiring hospitalization) to that of placebo [81, 82]. In post-marketing reports, anti-TNF therapy, infliximab in particular, has been associated with development of active tuberculosis. This most likely represents activation of a latent infection and patients should be screened prior to initiation of infliximab therapy [85].

Cardiac Complications of JIA Pericarditis is a common complication of JIA, and may be present at diagnosis, or precede the development of arthritis [86], although usually not clinically significant [78]. Pericarditis occurs in as many as 30 % of patients, and in autopsy series, as many as 45 % [87]. Pericardial effusions seen with JIA are usually small and clinically insignificant, but cardiac tamponade requiring pericardiocentesis or pericadiectomy has been reported [88, 89]. Non-steroidal anti-inflammatory medications and intensification of anti-inflammatory therapy are usually effective [88, 90]. Valvar disease is a well known, but uncommon complication of JRA [91, 92]. The aortic valve is the most commonly involved; however, the mitral valve may also be diseased [93]. In a recent study of patients with HLA-B27-associated juvenile arthritis, 10 % were found to have aortic regurgitation of varying degrees after a mean of 3 years of illness, compared with none of the healthy control patients [93].

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Table 35.3 Common features of macrophage activation syndrome Clinical Hepatomegaly Lymphadenopathy Splenomegaly Hemorrhage Persistent continuous fevera Central nervous system dysfunction Laboratory Falling platelet counta Hyperferritinemiaa Hemophagocytosis on bone marrow examinationa Elevated liver enzymesa Falling leukocyte counta Falling ESRa Hypofibrinogenemiaa Hypertrigyceridemiaa Prolonged clotting times Increased D-dimer Based on data from Davi et al. [97] a Denotes proposed diagnostic criteria

Generally, the severity of valvar disease correlates with articular disease and the degree of aortic regurgitation may be such that valve replacement is warranted [92]. Recently, the presence of rheumatoid nodules in the diseased valve has been described in a patient without other rheumatoid nodules [92]. Myocarditis is a commonly cited but rarely seen complication of JIA. It occurs with much less frequency than pericarditis, but carries higher mortality and severe sequelae. Patients who recover may be left with residual dilated cardiomyopathy [94].

Macrophage Activation Syndrome Macrophage activation syndrome (MAS), also known as hemophagocytic syndrome, is an uncommon life-threatening complication of JIA (usually systemic JIA), brought about by an infection, medications (gold salts, NSAID’s, or methotrexate), or autologous stem cell transplant [2, 95, 96]. MAS is a form of hemophagocytic lymphohistiocytosis (HLH) characterized by sudden onset of sustained fever, generalized lymphadenopathy, hepatosplenomegaly, and coagulopathy [2] (Table 35.3). Encephalopathy, respiratory distress or failure, and/or renal failure may develop [95, 98] with a mortality rate between 11 and 60 % [99, 100]. Laboratory studies which may suggest or support the diagnosis of MAS are a falling ESR, pancytopenia, elevated transaminases, increased triglyceride levels, elevated serum ferritin, and studies suggestive of a consumptive coagulopathy (elevated D-Dimers, PT, and PTT, decreased fibrinogen, and fibrin split products) [2, 98]. Bone marrow aspirates in MAS provide

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pathognomonic findings consisting of well differentiated macrophage proliferation with active phagocytosis of hematopoetic elements of the marrow [98]. Similar infiltration may also be seen in organs such as the liver and spleen [98, 100]. Differentiation of MAS from systemic JIA is important as therapy should be initiated early to prevent sequelae and death. The fever pattern seen with systemic JIA is usually cyclical with daily or twice daily spikes, whereas with MAS, the fever is high and unremitting [95, 98]. In MAS, the ESR falls precipitously, as opposed to systemic JIA, where it will be elevated. Also with MAS, there is a sudden drop in all hematologic cell lines, in contrast to systemic JIA, which is commonly accompanied by leukocytosis and thrombocytosis [95, 98]. Hypertriglyceridemia is another feature present in MAS which is not generally associated with systemic JIA [95]. First line therapy of MAS includes withdrawal of NSAID’s, disease-modifying antirheumatic drugs and/or immunosuppressives, and early initiation of high dose steroid therapy (methylprednisolone). Despite initiating therapy, the disease may still progress [99]. Because cyclosporine has been useful in a familial form of HLH, it has been investigated in MAS as well. Mouy and colleagues [95] reported the use of cyclosporine in five children with systemic JIA and MAS with good outcome, and recommended its use with high dose parenteral steroids. Other authors recommend cyclosporine for MAS as well, particularly in patients unresponsive to steroids alone [99]. The prevailing current treatment protocols contain steroids and cyclosporine, but other disease modifying agents are gaining evidence for effective use in JIA and MAS. Etanercept (Enbrel; Immunex), a TNF-α blocker, has been used in JIA with good disease control, and its use for MAS has been reported with good outcome [101]. Others, however, have reported a possible link between etanercept therapy and the development of MAS [102]. Anakinra (Kineret; Amgen), an IL-1 receptor antagonist, is becoming widely used for maintenance therapy and has been reported as a treatment of MAS, capable of inducing rapid disease [103, 104]. Tocilizumab (Actemra; Roche), and IL-6 receptor antibody has been shown safe, effective, and well-tolerated in a phase III randomized, placebo-controlled trial in children with JIA and may prove to be an effective therapy in MAS complicating JIA [105, 106]. Tocilizumab is currently pending FDA approval is only available for compassionate use in the United States.

Henoch-Schoenlein Purpura (HSP) Henoch-Schoenlein Purpura (HSP) (Table 35.4), the most common cause of purpura in children with normal platelet counts, is an idiopathic vasculitis syndrome involving the small vessels of the skin, gut, and glomeruli most commonly

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Table 35.4 Henoch-Schoenlein purpura Selected manifestations Central nervous system Cerebral vasculitis Seizure Coma Intracerebral hemorrhage

Pathophysiology Unknown etiology, IgA complex mediated small vessel vasculitis usually seen following a viral infection [3]

Subarachnoid hemorrhage Chorea Cardiac Myocarditis Myocardial necrosis Pericarditis Pulmonary Pulmonary hemorrhage Interstitial pneumonia Gastrointestinal Hemorrhage Intussusception Bowel perforation Esophagitis Obstruction Pancreatitis Renal Glomerulonephritis Nephrotic syndrome

Laboratory abnormalities Thrombocytosis Leukocytosis Elevated ESR Elevated CRP Antiphospholipid antibodies occasionally Cryoglobulins occasionally Microscopic hematuria Urinary casts Albuminuria Sterile pyuria [3, 12]

seen following a viral or streptococcal infection [3, 107, 108]. One study has shown a stronger correlation between an elevated serum Bartonella henselae antibody titer and HSP than with elevated ASO or anti-DNase B [109] titers, but this correlation is as yet unsubstantiated. HSP nephritis may represent a variant of IgA nephropathy [108]. Serious complications of HSP are uncommon, but include neurologic (seizure, intracranial hemorrhage, coma) [110– 113], gastrointestinal (intussusception, obstruction, perforation, hemorrhage) [114], and renal (nephritis) [108]. There are two reported cases of myocardial necrosis associated with HSP, although there is some question as to whether another underlying diagnosis may have been present in at least one of the two cases [115, 116].

CNS Complications of HSP Most believe that the incidence of neurologic involvement, from headaches to intracranial hemorrhages, with HSP lies

somewhere between 2 and 10 %, but estimates have been as high as 20 % [110, 117]. More than 50 % of patients reported to have had neurologic complications had seizures, and most of these were generalized [110]. The etiology of the neurologic complications is unclear. Multiple possible causes, such as hypertensive encephalopathy, uremic encephalopathy, steroids, cytotoxic drugs, cerebral vasculitis and electrolyte imbalances are often simultaneously present in HSP [110]. Magnetic resonance imaging of patients with HSP who manifest seizures and/or encephalopathy has shown lesions consistent with demyelination in the posterior parieto-temporal region that resolve with clinical improvement [118–120]. Intracranial hemorrhage has been reported in less than ten patients [121, 122]. Most of the reported cases are intraparenchymal and parieto-temporal in location [121]. It is thought that in most cases, the vasculitis itself leads to a friability of vessels, allowing the hemorrhage. However, studies have linked HSP to a decrease of factor XIII, possibly contributing to hemorrhage. One recent report documented a low factor XIII level in a patient with HSP complicated by intracerebral hemorrhage [123].

Pulmonary Complications of HSP A rare, but striking and potentially fatal complication of HSP is pulmonary hemorrhage. A recent retrospective analysis reported two of 136 patients with HSP experienced pulmonary hemorrhage [124]. Without rapid diagnosis and institution of treatment, pulmonary hemorrhage can progress to death [113, 125]. A review of the literature demonstrates that mortality in patients with HSP complicated by pulmonary hemorrhage approaches 50 % [113], but other authors suggest that mortality may depend on age, with lower mortality seen in younger children [126]. The treatment regimen reported by many authors for pulmonary hemorrhage in HSP includes aggressive ventilatory support, glucocorticoids, and occasionally cyclophosphamide, although no controlled trial has shown clear benefit of immunosuppressives [113, 127].

Gastrointestinal Complications of HSP Intussusception is the most common, and best described, abdominal complication of HSP. The lead point is edematous bowel wall secondary to intramural vasculitis and hemorrhage [128]. Unlike spontaneous intussusception, which is usually ileocolic, intussusception in HSP usually involves entirely small bowel. This distinction is important as contrast enema is not useful when the pathology is proximal to the ileocecal valve. Bowel perforation is rare, and has decreased dramatically with earlier diagnosis [128]. Gastrointestinal

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hemorrhage has been reported as a common abdominal complication of HSP, occurring in approximately 50 % of patients. The bleeding is usually minimal and self-limited, but may occasionally be massive and lead to hypovolemic shock [128–131].

Nephritis in HSP Nepritis is the most common serious, long-term complication of HSP, affecting 85–90 % of children within 1 month of diagnosis and nearly all children within 6 months to varying degrees [132]. Rarely does nephritis warrant PICU admission, however patients with nephrotic range proteinuria may require admission for correction of fluid and electrolyte abnormalities. Standard therapy consists of glucocorticoids, but those resistant to steroids and more severely ill have been treated with ACE inhibitors, urokinase, plasmapheresis, cyclosporine A, cyclophosphamide, azathioprine, and mycophenolate in various regimens [133, 134]. The outcome of HSP nephritis is generally good with 1–2 % of all patients with HSP nephritis developing chronic renal disease [132] however, those with more severe disease may be at increased risk for the development of chronic renal disease and even end stage renal disease.

551 Table 35.5 Kawasaki disease Selected manifestations Pathophysiology Central nervous system Unknown etiology, but may represent an exaggerated immune response to an infectious trigger in predisposed children [135] Irritability/mental Subendothelial and status changes medial edema in affected vessels Sensorineural precedes neutrophil hearing loss and then Uveitis mononuclear, plasma Cardiac cell, and lymphocytic Myocarditis infiltration. Cellular Pericarditis infiltration results in Mitral insufficiency the destruction of the Coronary aneurysms internal elastic lamina which causes Coronary rupture fibroblast proliferation and Myocardial eventual fibrosis infarction [135]

Laboratory abnormalities Anemia

Leukocytosis Elevated ESR Elevated CRP Abnormal plasma lipids Hypoalbuminemia Hyponatremia Thrombocytosis Sterile pyuria Elevated serum transaminases Elevated serum gamma glutamyl transpeptidase CSF pleocytosis, [135]

Kawasaki Disease

Hematologic Macrophage activation syndrome Gastrointestinal Hydrops of gall bladder

First described in Japan in 1967, Kawasaki disease (Table 35.5) is an acute, self-limited vasculitis affecting infants and children of all races. It is characterized by high fever, conjunctival injection, erythema of the oral mucosal, strawberry tongue, peripheral edema, cervical lymphadenopathy, and variable rash [135, 136]. Kawasaki disease (KD) affects approximately 3,000–4,000 children annually in the United States [135, 136]. The incidence of KD is approximately 112/100,000 in Japanese children 10 %), mono- or polyneuropathy, infiltrates on CXR, paranasal sinus abnormalities, and extravascular eosinophils on blood vessel biopsy [176]. Published reports have implicated a causative role for leukotriene modifiers in CSS, while others have found no such link [177]. A post-marketing analysis confirmed an association between leukotriene modifier therapy (alone or in combination with other asthma therapies) and CSS, but could not speculate on causality [178].

Cardiac Complications of CSS Pericarditis or cardiomyopathy and congestive heart failure may also be present at diagnosis of CSS [173, 179, 180]. Cardiomyopathy secondary to coronary artery vasculitis is common in adult CSS patients, occurring in 22–26 % of patients, and corresponds to advanced disease [179].

Pulmonary Complications of CSS The literature contains multiple reports of serious pulmonary hemorrhage in patients with CSS [181, 182]. Without treatment CSS is fatal within months, secondary to pulmonary disease. Widespread use of corticosteroids has significantly improved survival and become accepted as first-line therapy [183]. While some authors consider a combination of corticosteroids with another immuno-suppressive (cyclophosphamide) to be first-line [179], others reserve cyclophosphamide for those patients who fail corticosteroids alone or have severe disease [183].

Gastrointestinal Complications of CSS While abdominal complaints are common, serious abdominal involvement is rare. Small bowel perforation and peritonitis in association with CSS has been reported [184].

Juvenile Dermatomyositis (JDM) Juvenile dermatomyositis (JDM) (Table 35.8) is a rare autoimmune inflammatory muscle disease with an incidence of 1.7–3.1 per million children, affecting twice as many females

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Table 35.8 Juvenile dermatomyositis Selected manifestations Central nervous system Seizures Pseudoseizures

Psychosis Infarction Cardiac Myocarditis Pericarditis Congestive heart failure Cardiac tamponade Myocardial infarction Arrhythmia Pulmonary Restrictive lung disease Interstitial lung disease Recurrent aspiration Gastrointestinal Hemorrhage Esophageal dysmotility

Pathophysiology Endothelial activation by the class II HLA antigen DQA1*0501 and/or circulating immune complexes activates complement leading to microvascular occlusion and local ischemia [185]

Laboratory abnormalities Elevated creatine kinase Elevated aldolase Elevated lactate dehydrogenase Elevated ESR Elevated CRP Lymphopenia [185]

as males [185–188]. JDM is characterized by proximal muscle weakness, heliotrope rash, and elevated serum levels of skeletal muscle enzymes such as creatinine phosphokinase (CPK), aldolase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) [186, 189]. Muscle biopsy specimens reveal complement-mediated microvascular endothelial damage, which leads to local hypoperfusion and perifascicular atrophy [187]. Overall mortality rate among children with JDM is approximately 1.5 % [185].

CNS Complications of JDM Although extremely rare, CNS complications of JDM are serious and life threatening. CNS involvement likely represents manifestation of severe, uncontrolled disease [188, 190]. Reported manifestations include visual disturbances, seizures, pseudoseizures, psychosis, and brainstem infarction [186, 190]. Seizures are likely the most common manifestation, but are much less common in JDM than in other vasculitides such as SLE [186]. Immunosuppressive therapy

has been used with these complications, and has improved symptoms [190].

Pulmonary Complications of JDM The most common pulmonary manifestations of JDM are those secondary to muscle weakness. Asymptomatic restrictive lung disease has been reported in up to 40 % of JDM patients at presentation [188]. Decreased ventilatory capacity may occur in up to 78 % of JDM patients throughout the course of the illness secondary to respiratory muscle weakness and decreased chest wall compliance [186]. Dysphagia secondary to esophageal dysmotility and pharyngeal weakness is a common symptom in JDM [186, 188], and may lead to pathologic aspiration severe enough to require parenteral nutrition and tracheostomy [186, 191]. Interstitial lung disease (ILD) is a well known complication of dermatomyositis, occurring in up to 65 % of adults [189, 192]. In children, interstitial lung disease has been less well described in association with JDM, however, it has been associated with anti-Jo-1 antibody positive patients [188], and may be detected early as a decrease in diffusion capacity [188]. Unfortunately, JDM-associated interstitial lung disease is often severe and rapidly progressive, with a high mortality [192]. Interstitial lung disease in children with JDM has been reported to occur early in the illness, particularly in patients whom the biochemical markers of ongoing disease (AST, ALT, aldolase, etc.) do not normalize with steroid therapy [189, 192]. Interstitial lung disease associated with DM has been treated with cyclosporine in both adults and children with promising results [192, 193]. Currently, however, the pediatric literature is limited to a few case reports and small series [192]. Cyclosporine is generally reserved for steroid resistant ILD or rapidly progressive ILD [189, 192].

Cardiac Complications of JDM Clinically important cardiac involvement is rare; however, reports have been published of fatal cardiac vasculitis and cardiac tamponade with JDM [186]. Non-specific ECG abnormalities and pericarditis have also been reported in conjunction with JDM, although all of these are primarily associated with adult DM [188].

Systemic Sclerosis Juvenile scleroderma is an autoimmune disease of unknown etiology characterized by hard skin with an onset before the age of 16 years. Two broad categories have been defined,

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morphea (localized skin sclerosis), and systemic sclerosis (skin sclerosis with diffuse internal organ involvement) [194]. Systemic sclerosis (SSc) is rare in children, with only 10–17 % of patients with SSc patients accounted for by those less than 20 years of age [194, 195]. Mononuclear cell infiltration is a key component of the lesions of scleroderma. Cytokine liberation by these mononuclear cells leads to immune activation, increased collagen production, and endothelial damage. Ultimately fibrosis occurs and microvascular disease results in localized tissue ischemia [194]. Management of SSc has been challenging, and no therapy as yet has been shown to have significant benefit without significant risk [194, 196]. Methotrexate trials have had mixed results and steroids have generally been ineffective. Stem cell transplantation has been studied in adults, with disease improvement in 70 % of patients, but 19 % of patients had further disease progression and 17 % died from complications of the transplant itself [194]. One series describing the use of etanercept in ten adults with SSc published in abstract form showed no clinically important improvements [196].

Cardiopulmonary Complications of Systemic Sclerosis Clinically insignificant cardiac disease is common in SSc, but severe cardiopulmonary involvement may be a major cause of morbidity and mortality among SSc patients [194, 195]. Involvement may come in the form of myocardial fibrosis leading to cardiomyopathy or arrhythmia, valvar insufficiency, or pericardial disease [194, 197]. Systolic [198] and diastolic [197, 199] dysfunction have been reported with SSc. Pulmonary hypertension with or without pulmonary fibrosis is another well-known complication of SSc [194, 200]. Autopsy series including both children and adults have shown myocardial fibrosis to be common in patients with SSc [201]. Myocardial fibrosis may lead to cardiomyopathy and arrhythmias including atrioventricular block, supraventricular tachycardia, and ventricular tachycardia [194, 197]. Frank cardiomyopathy is uncommon in pediatric systemic sclerosis, although dilated cardiomyopathy may be more common in children who have myositis in addition to systemic sclerosis [202]. Rokicki reported finding diastolic dysfunction among SSc patients without cardiac symptoms, as well as increased left ventricular mass without overt hypertrophy [197]. Steroid therapy has proven generally ineffective for the management of SSc, except in early muscle involvement or the edematous phase of cutaneous disease, and may be

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associated with renal crisis [194]. Nevertheless, given the autoimmune component of this disease, authors have reported the use of glucocorticoids in SSc cardiomyopathy [203]. In 32 adult patients with scleroderma and secondary myocardial dysfunction, prednisolone treatment was shown to increase LVEF, particularly in patients with the SSc form [198]. Subclinical pericardial disease has been reported as a common occurrence in autopsy series of SSc patients, found in 33–72 % of specimens [201]. Clinical pericardial involvement has been reported in 7–20 % of patients during the disease course [201]. However, Rokicki and colleagues evaluated 43 children with various forms of scleroderma and found no pericardial disease by clinical exam or echocardiography [197]. Rokiciki implied that pericardial disease may be a component of adult SSc as opposed to juvenile SSc [197]. Conduction abnormalities may occur in up to 60 % of adult patients with SSc, particularly in patients with concurrent myositis [204]. These patients are at high risk for sudden death; Follansbee and colleagues found retrospectively that 12 of 25 adult patients with SSc and myositis experienced sudden cardiac deaths [204]. Conduction system disease is often asymptomatic with the first manifestations being slight resting tachycardia and a decrease in heart rate variability attributable to dysautonomia [205]. Pulmonary fibrosis with pulmonary vascular disease has been reported as the most common cause of death among adult patients with SSc [200]. In adults, these two entities generally occur in simultaneously. While this may be the case in children, isolated pulmonary vascular disease is more common in young patients with scleroderma, in particular with SSc [194]. Unfortunately, this isolated pulmonary vascular disease has a much worse prognosis [194]; also, for reasons that remain unclear, pulmonary arterial hypertension (PAH) in scleroderma patients carries a higher risk of death than similarly affected patients with primary pulmonary hypertension [206]. In SSc patients as a whole, PAH likely has a prevalence of 12–15 %, but values as high as 50 % have been published [207–209]. The pulmonary vascular disease associated with SSc is similar in pathology and management to primary pulmonary hypertension [206, 209, 210]. Pathologic evaluation shows prominent intimal proliferation, medial hypertrophy, and adventitial fibrosis [206]. Prostacyclin analogues iloprost [Ventavis®, CoTherix] [211], epoprostenol [Flolan®, GlaxoSmithKline] [209], and treprostinil [Remodulin®, United Therapeutics] [212] have all been evaluated in adults with pulmonary hypertension secondary to the scleroderma. Improvements in exercise tolerance were seen with all; however the greatest improvement in pulmonary hemodynamics was seen with epoprostenol. Epoprostenol is currently considered the

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“gold standard” for management of pulmonary hypertension unresponsive to acute vasodilators [213]. Further studies with treprostinil at optimal doses may show similar efficacy with greater ease of administration (subcutaneous infusion) and elimination of the need for indwelling venous catheters. Systemic sclerosis patients with pulmonary hypertension which does not respond to prostacyclin analogues have been treated with concurrent burst cyclophosphamide with marked improvement in hemodynamic measurements [214]. Endothelin-1 is a potent vasoactive peptide which acts through two receptors, “A” and “B”, and has been implicated in various forms of pulmonary hypertension. Bosentan (Tracleer®, Actelion Pharmaceuticals) is the first orally available non-selective endothelin receptor antagonist approved for use in severe pulmonary hypertension. Channick and colleagues [215] reported significant improvements in pulmonary hemodynamics and exercise tolerance in adults with scleroderma and pulmonary arterial hypertension after 3 months of bosentan therapy. The same group reported after 1 year of treatment that these improvements had been sustained with ongoing bosentan therapy [216]. Initial monotherapy for pulmonary hypertension complicating SSc in adults is generally endothelin blockade [210] and successful use of endothelin blockade in pediatric SSc associated pulmonary hypertension has been reported [217]. In adult patients with systemic sclerosis and severe lung disease unresponsive to medical management, lung transplantation has been performed. Several case series have found that the outcomes of patients with scleroderma who undergo lung transplantation for severe pulmonary disease (both with and without pulmonary hypertension) have similar outcomes to individuals with primary lung disease in the absence of rheumatologic disease [218–220].

Scleroderma Renal Crisis Scleroderma renal crisis is the abrupt onset of severe hypertension and rapidly worsening oliguric renal failure occurring in the setting of scleroderma [221]. It is usually accompanied by left ventricular failure and microangiopathic hemolytic anemia [221]. The pathophysiology is as yet unclear; however it likely involves vascular disease of the small arteries and arterioles of the kidney. This vascular disease causes decreased perfusion, which in turn leads to angiotensin-II mediated hypertension [221]. Some authors have implicated the recent addition of high dose steroids or non-steroidal anti-inflammatory medications in the development of scleroderma renal crisis [221]. Scleroderma renal crisis occurs in 14–18 % of adult patients with SSc during the course of their disease [ 221, 222]. With a mortality rate approaching 35 % despite aggressive antihypertensive management [221, 222 ],

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Scleroderma renal crisis is the most common cause of death in adult patients with SSc. Survivors usually have permanent renal damage, and may be dialysis dependent [221 ]. Management consists of aggressive antihypertensive therapy, and the use of ACE inhibitors (specifically captopril) has proven to improve survival in adult patients [221].

Behcet’s Disease Behcet’s disease (BD) is a multisystem vasculitis of unknown etiology characterized by recurrent oral ulcers, genital ulcers, and uveitis [223, 224]. A positive pathhergy test (formation of a papule or pustule 48 h after skin pinprick or intradermal saline injection) supports the diagnosis of BD but is not required [223]. In Japanese and Middle Eastern patients, HLA-B51 has been associated with BD, although this association does not hold true for Western patients [223, 224]. Behcet’s disease is uncommon in childhood, generally diagnosed in adults in the third decade of life, and is most prevalent in Japan, Turkey, Iran, and Mediterranean countries [223]. Systemic involvement with BD includes nearly all organ systems, and a wide range of severity. Central nervous involvement associated with BD includes headaches, aseptic meningitis, mild intracranial hypertension [225], organic psychiatric disturbances, seizures, hemiparesis, and sinovenous thrombosis [223]. Pulmonary involvement may include pleuritis [225], hemoptysis, parenchymal infarction, and pulmonary vasculitis with inflammatory aneurysms [223, 226]. Rupture of pulmonary artery aneurysms has resulted in hemorrhage and death [223, 226]. Cardiac involvement can include myocarditis, arrhythmia [223], myocardial fibrosis, or endocardial fibrosis [226]. Arterial and venous vascular thromboses are associated with BD, although more commonly in adult patients [225]. Multiple thromboses may be present and can lead to death [223]. Gastrointestinal manifestations of BD include colicky abdominal pain, diarrhea, bloody stools, and ulcerative colitis [223, 225]. Supportive medical care with corticosteroids is the mainstay of therapy for acute exacerbations or complications of BD [227]. Conclusion

Children with rheumatologic diseases require admission to the PICU for a multitude of diagnoses, affecting all organ systems. In addition to the broad spectrum of disease, the limited number of pediatric trials makes caring for these patients challenging. Supportive care remains the cornerstone of therapy in these patients while disease specific therapies (Table 35.9) continue to evolve. Continuing research into the pathophysiology of these diseases and new therapies will improve patient care and patient outcomes.

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Table 35.9 Selected rhematologic medications Medication Class ® Abciximab (Reopro , Platelet inhibitor Lilly, Eli and Company)

Azathioprine (Imuran®, Prometheus Inc.; others)

Immunosuppressive

Cyclophosphamide (Cytoxan®, BristolMyers Squibb; others)

Alkylating agent, chemotherapeutic agent

Cyclosporine (Sandimmune®, Novartis; others)

Immunosuppressive

Potential adverse effects Serious bleeding Intracranial hemorrhage Alveolar hemorrhage Thrombocytopenia Hypotension [228] Leukopenia Thrombocytopenia Bone marrow suppression Bacterial infections Fungal infections Viral infections Hepatotoxicity Malignancy-AML and lymphoma Interstitial pneumonitis [228] Urinary bladder malignancy Lymphoproliferative malignancy Myeloproliferative malignancy Leukopenia Hemorrhagic cystitis Hemorrhagic myocarditis Hemorrhagic colitis Congestive heart failure Opportunistic infections Interstitial pneumonitis Interstitial pulmonary fibrosis [228]

Nephrotoxicity Hepatotoxicity Lymphoma Hypertension Seizures Sepsis [215]

Reported use Kawasaki disease Acute disease with large coronary aneurysms [147]

Systemic lupus erythematosus Myocarditis [13, 44] Pericarditis [229] Peripheral neuropathy [230] Catastrophic antiphospholipid syndrome [164] Juvenile dermatomyositis Interstitial lung disease [231]

Systemic lupus erythematosus Neuropsychiatric lupus [16, 39, 43, 232] Peripheral neuropathy [230] Transverse myelitis [44] Alveolar hemorrhage [44] Myocarditis [13, 44, 64, 229] Pneumonitis [229] Interstitial lung disease [229] Wegener’s granulomatosis Central nervous system vasculitis [233] Kawasaki disease Treatment resistance [234] Henoch-Schonlein purpura Severe nephritis [173] Antiphospholipid syndrome Catastrophic antiphospholipid syndrome [164] Behcet’s disease Inflammatory aneurysms [235] Juvenile dermatomyositis Interstitial lung disease [231, 236] Churg-Strauss syndrome Steroid resistance [237] Cardiac disease [237] Gastrointestinal disease [237] Central nervous system disease [237] Wegener granulomatosis Acute therapy [173] Maintenance therapy after remission [237] Goodpasture’s syndrome Central nervous system vasculitis [169] Glomerulonephritis [167, 169] Juvenile rheumatoid arthritis Macrophage activation syndrome [95, 99] Catastrophic antiphospholipid syndrome [95, 164] Behcet’s disease Uveitis [238, 239] Vascular complications (aneurysm, obstruction, etc.) [238] Juvenile dermatomyositis Acute fibrinous organizing pneumonia [240] Interstitial lung disease [192, 193] (continued)

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Table 35.9 (continued) Medication Etanercept (Enbrel®, Immunex)

Class TNF modulator

Infliximab (Remicade®, Centocor)

TNF modulator

IVIG

Immune globulin

Potential adverse effects Serious bacterial infections-including sepsis Demyelinating disorders Lymphoma Aplastic anemia [215] Demyelinating disorders Tuberculosis (including disseminated) Upper respiratory infections [215]

Transmitted blood borne disease Acute renal failure Acute tubular necrosis Proximal tubular nephropathy Volume overload Congestive heart failure [228]

Methylprednisolone Corticosteroid (Solu-Medrol®, Upjohn; others)

Sodium retention Congestive heart failure Hypertension Fluid retention Potassium loss Gastric ulcer Pancreatitis Ulcerative Esophagitis Hepatotoxicity Hyperglycemia Glaucoma Negative nitrogen balance [228]

References 1. King KK, Kornreich HK, Bernstein BH, et al. The clinical spectrum of systemic lupus erythematosus in childhood. Arthritis Rheum. 1977;20:287. 2. Schneider R, Passo MH. Juvenile rheumatoid arthritis. Rheum Dis Clin N Am. 2002;28:503–30. 3. Miller ML, Pachman LM. Vasculitis syndromes. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004. p. 826–31.

Reported use Treatment resistant associated uveitis [240] Behcet’s disease Uveitis [241] Kawasaki disease [149] Treatment resistance Behcet’s disease Neruo-Behcet’s [242] Uveitis [241, 243, 244] Catastrophic antiphospholipid syndrome [164, 245] Kawasaki disease [135] Henoch-Schonlein purpura [108] Juvenile dermatomyositis Interstitial lung disease [192] Juvenile rheumatoid arthritis Macrophage activation syndrome [99] Systemic lupus erythematosus Neuropsychiatric lupus [15, 16, 26, 39, 232, 246] Myelopathy [247] Peripheral neuropathy [230] Carditis/myocarditis [13, 16, 64] Pericarditis [50, 56, 229] Pneumonitis [44, 229] Alveolar hemorrhage [44, 45] Abdominal vasculitis [44] Juvenile dermatomyositis GI ulceration [50] Interstitial lung disease [192, 193, 231] Henoch-Schonlein purpura Severe nephritis [173] Kawasaki Treatment resistance [135] Antiphospholipid syndrome Catastrophic antiphospholipid syndrome [164, 165, 245] Churg-Strauss syndrome Acute therapy [237] Juvenile rheumatoid arthritis Macrophage activation syndrome [99] Wegener granulomatosis Acute therapy [173, 237] Goodpasture’s syndrome Nephritis [167]

4. Schärer K, Krmar R, Querfeld U, et al. Clinical outcome of Schönlein-Henoch purpura nephritis in children. Pediatr Nephrol. 1999;13(9):816–23. 5. Janssen NM, Karnad DP, Guntupalli KK. Rheumatologic disease in the intensive care unit : epidemiology, clinical approach, management, and outcome. Crit Care Clin. 2002;18:729–48. 6. Hahn BH, Karpouzas GA, Tsa BP. Pathogenesis of systemic lupus erythematosus. In: Harris ED, Budd RC, Genovese MC, Firestein GS, Sargent JS, Sledge CB, editors. Kelley’s textbook of rheumatology. 7th ed. Philadelphia: Saunders; 2005. p. 1174–201.

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187. Chitnis T, Khoury SJ. Immunologic neuromuscular disorders. J Allergy Clin Immunol. 2003;111:S659–68. 188. Compeyrot-Lacassagne S, Feldman BM. Inflammatory myopathies in children. Pediatr Clin N Am. 2005;52:493–520. 189. Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med. 2004;25: 549–59. 190. Elst EF, Kamphuis SS, Prakken BJ, et al. Case report: severe central nervous system involvement in juvenile dermatomyositis. J Rheumatol. 2003;30:2059–63. 191. Iester A, Puleo MG, Buzzanca C, Debbia C, Callegarini L, Alpigiani MG. A case of organic psychosis in dermatomyositis. Etiopathogenetic hypothesis. Minerva Pediatr. 1994;46:565–8. 192. Kobayashi I, Yamada M, Takahashi Y, et al. Interstitial lung disease associated with juvenile dermatomyositis: clinical features and efficacy of cyclosporine A. Rheumatology. 2003;43:371–4. 193. Miyake S, Ohtani Y, Sawada M, et al. Usefulness of cyclosporine A on rapidly progressive interstitial pneumonia in dermatomyositis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:128–33. 194. Zulian F. Scleroderma in children. Pediatr Clin N Am. 2005;52: 521–45. 195. Foeldvari I, Zhavanial M, Birdi N, et al. Favorable outcome in 135 children with juvenile systemic sclerosis: results of a multinational survey. Rheumatology. 2000;39:556–9. 196. Ellman MH, MacDonald PA, Hayes FA. Etanercept as treatment for diffuse scleroderma: a pilot study. Arthritis Rheum. 2000; 43:S392. 197. Rokicki W, Dukalska M, Rubisz-Brzezinska J, Gasior Z. Circulatory system in children with localized scleroderma. Pediatr Cardiol. 1997;18:213–7. 198. Antoniades L, Sfikakis PP, Mavrikakis M. Glucocorticoid effects on myocardial performance in patients with systemic sclerosis. Clin Exp Rheumatol. 2001;19:431–7. 199. Isaeva LA, Deliagin VM, Bazhenova LK. Main manifestations of carditis in diffuse connective tissue diseases in children. Cor Vasa. 1988;30:211–7. 200. Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis. 1998;57:682–6. 201. Byers RJ, Marshall DA, Freemont AJ. Pericardial involvement in systemic sclerosis. Ann Rheum Dis. 1997;56:393–4. 202. Quartier P, Bonnet D, Fournet JC, et al. Severe cardiac involvement in children with systemic sclerosis and myositis. J Rheumatol. 2002;29:1767–73. 203. Moore EC, Cohen F, Farooki Z, Chang CH. Focal scleroderma and severe cardiomyopathy. Patient report and brief review. Am J Dis Child. 1991;145:229–31. 204. Follansbee WP, Zerbe TR, Medsger Jr TA. Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. Am Heart J. 1993;125:194–203. 205. Wranicz J, Zielinska M, Cygankiewicz I, DziankowskaBartkowiak B, Sysa-Jedrzejowska A. Early cardiovascular involvement in patients with systemic sclerosis (SSc). Med Sci Monit. 2002;8:CR78–82. 206. Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 2003;123:344–50. 207. Denton CP, Black CM. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin N Am. 2003;29:335–49. 208. MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology. 2001;40:453–9. 209. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med. 2000;132:425–34.

565 210. Opitz C, Klein-Weigel PF, Riemekasten G. Sestemic Sclerosis – a systematic overview: part 2 – immunosuppression, treatment of SSC-associated vasculopathy, and treatment of pulmonary arterial hypertension. Vasa. 2011;40(1):20–30. 211. de la Mata J, Gomez-Sanchez MA, Aranzana M, Gomez-Reino JJ. Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis Rheum. 1994;37:1528–33. 212. Oudiz RJ, Schilz RJ, Barst RJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004;126:420–7. 213. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol. 2004;38:2–22. 214. Cossio M, Menon Y, Wilson W, deBoisblanc BP. Life-threatening complications of systemic sclerosis. Crit Care Clin. 2002;18: 819–39. 215. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet. 2001;358:1119–23. 216. Sitbon O, Badesch DB, Channick RN, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension. Chest. 2003;124:247–54. 217. Shimizu M, Hashida Y, Ueno K, et al. Successful treatment with bosentan for pulmonary hypertension and reduced peripheral circulation in juvenile systemic sclerosis. Pediatr Cardiol. 2011;32: 1040–2. 218. Levine SM, Anzueto A, Peters JI, Calhoon JH, Jenkinson SG, Bryan CL. Single lung transplantation in patients with systemic disease. Chest. 1994;105:837–41. 219. Pigula FA, Griffith BP, Zenati MA, Dauber JH, Yousem SA, Keenan RJ. Lung transplantation for respiratory failure resulting from systemic disease. Ann Thorac Surg. 1997;64:1630–4. 220. Rosas V, Conte JV, Yang SC, et al. Lung transplantation and systemic sclerosis. Ann Transplant. 2000;5:38–43. 221. Walker JG, Ahern MJ, Smith MD, et al. Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment. Intern Med J. 2003;33:216–20. 222. Steen VD, Medseger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43: 2437–44. 223. Kone-Paut I, Yurdakul S, Barbari S, et al. Clinical features of Behcet’s disease in children: an international collaborative study of 86 cases. J Pediatr. 1998;132:721–5. 224. Dedeoglu F, Sundel RP. Vasculitis in children. Pediatr Clin N Am. 2005;52:547–72. 225. Krause I, Uziel Y, Guedj D, et al. Childhood Behcet’s disease clinical features and comparison with adult onset disease. Rheumatology. 1999;38:457–62. 226. Cohle SD, Colby T. Fatal hemoptysis from Behcet’s disease in a child. Cardiovasc Pathol. 2002;11:296–9. 227. Barrit R, Shannon KM. Autoimmune and inflammatory disorders. In: Goetz CG, editor. Textbook of clinical neurology. 2nd ed. Philadelphia: Saunders; 2003. p. 1124–6. 228. Abernathy DR, Arnold GJ, Azarnoff D, et al., editors. Mosby’s drug consult. 15th ed. St. Louis: Mosby; 2002. 229. Beresford MW, Cleary AG, Sills JA, Couriel J, Davidson JE. Cardio-pulmonary involvement in juvenile systemic lupus erythematosus. Lupus. 2005;14:152–8. 230. Harel L, Mukamel M, Brik R, Blau H, Straussberg R. Peripheral neuropathy in pediatric SLE. Pediatr Neurol. 2002;27:53–6. 231. Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002;47:614–22. 232. Hajj-Ali RA, Chamande S, Calabrese LH, Arroliga AC. Central nervous system vasculitis in the intensive care unit. Crit Care Clin. 2002;18:897–914.

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Infectious Disease-Associated Syndromes in the PICU

36

Isaac Lazar and Clifford W. Bogue

Abstract

In this chapter, we discuss some of the more serious syndromes associated with infectious diseases that are encountered by clinicians in the PICU. The syndromes discussed include necrotizing fasciitis, hemorrhagic shock and encephalopathy, Rocky Mountain spotted fever and Lemierre’s syndrome. All of these conditions are serious, potentially life-threatening syndromes for which early recognition and treatment is critical to obtaining a positive outcome for the patient. We discuss the history and epidemiology, pathogenesis, clinical manifestations and management of each condition with the goal of providing clinicians with the most current information about each syndrome. Keywords

Necrotizing fasciitis • Hemorrhagic shock and encephalopathy • Rocky Mountain spotted fever • Lemierre’s syndrome • Erhlichiosis

Introduction There may be no more common trigger of pathology in pediatric critical care than that initiated by an offending pathogen. Numerous pathogens – bacterial, viral, fungal, and rickettsial – are responsible for a myriad of infectious diseases, often resulting in multi-organ disease necessitating supportive critical care. While a comprehensive review is beyond the scope of this current chapter, herein we review some of the more common and important infectious diseases faced by practicing intensive care personnel. By highlighting the epidemiology, pathogenesis, clinical presentations, and treatment principles of these important entities, we hope to arm the practitioner

I. Lazar, MD Pediatric Intensive Care Unit, Soroka Medical Center, Beer Sheva 84101, Israel e-mail: [email protected] C.W. Bogue, MD (*) Department of Pediatrics, Yale School of Medicine, 333 Cedar Street, 208064, New Haven, CT 06520-8064, USA e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6416-6_36, © Springer-Verlag London 2014

with the knowledge to rapidly diagnose and provide timely therapy for these most challenging infectious diseases.

Necrotizing Fasciitis Necrotizing fasciitis (NF) is a progressively destructive infectious process that involves the deep fascia and its surrounding fat. If left untreated, or if a prompt aggressive surgical debridement is not done, the mortality rate is extremely high.

History and Epidemiology NF was first clinically described in the USA in 1871 by Jones who called it “hospital gangrene.” Wilson first used the term NF in 1951, and the term has remained in use since that time [1]. Although medical and surgical treatment has improved over the years, NF remains a true surgical emergency. NF carries a high mortality and survivors frequently suffer from the disfiguring results of extensive surgical debridement. Skin grafting and reconstructive plastic surgeries are often needed to improve a patient’s quality of life. NF can be classified into two 567

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subgroups based on the microbiological etiology of the disease [2]. Type I includes infection caused by mixed species of anaerobes, most commonly Bacteroides and Peptostreptococcus species, facultative anaerobes such as non-group A [beta]hemolytic streptococci, and enteric gram negative species. Type I is most commonly seen in patients with predisposing medical conditions such as immune deficiencies (primary and secondary), morbid obesity, and diabetes mellitus. Type II NF is caused by Gram positive aerobic bacteria – almost exclusively Group A Streptococcus (GAS) and Staphylococcus Aureus [3]. Some authors also mention a Type III NF that is caused by a marine vibrio (gram negative organism) entering the fascial space through a sharp fish bone injury, sting, infected wound or insect bite [4]. Overall, a wide range of different bacteria have been isolated from NF patients [3]. Review of the pediatric NF literature reveals many individual case reports and small case series with few publications that include large numbers of patients. Because the disease is relatively rare in the pediatric population (0.5–2.9/1,000,000/year) [2, 5, 6], some of the data described in this chapter is taken from the adult medical and surgical literature where the disease is more common.

Pathogenesis Understanding the pathophysiology of necrotizing fasciitis may prompt early diagnosis. The disease process starts at the superficial fascia and, although the portal of entry for bacterial infection can vary, direct invasion of the offending pathogen occurs in most pediatric cases. Minor blunt or penetrating trauma, a surgical wound or instrumentation site, or a secondary varicella lesion infection, are among the most commonly associated injuries [7, 8]. The bacterial inflammatory process spreads within the superficial fascia and to the surrounding adipose tissue. Enzymes and toxins elaborated by the bacteria enable the organisms to spread through the fascia causing thrombosis, further microbial invasion and liquefaction necrosis of the superficial fascia. Histologically, areas of necrosis are seen within the superficial fascia with leukocytes (mainly polymorphonuclear neutrophils) infiltrating the deep dermis and fascia. Thrombosis of blood vessels within and surrounding the fascia is accompanied by suppuration and destruction of the fascia. As this process progresses, occlusion of perforating nutrient vessels to the skin causes skin ischemia responsible for the cutaneous manifestations of necrotizing fasciitis. As the condition evolves, ischemic necrosis of the skin ensues with gangrene of the subcutaneous fat, dermis and epidermis [9].

Diagnosis Establishing the diagnosis of NF can be difficult and a high index of suspicion is necessary. Patients who present with

I. Lazar and C.W. Bogue

chronic, debilitating medical conditions (e.g. diabetes mellitus, complications of premature birth, immune suppression, or morbid obesity) or who present with the breakdown of skin integrity (e.g. IV drug abuse, recent varicella disease, trauma or surgery), together with non-specific soft tissue complaints, should be carefully evaluated for NF. One of the largest studies published on pediatric NF was published by Fustes-Morales et al. [7]. Their 30-year retrospective review of 39 NF pediatric patients admitted to a single medical center in Mexico found a similar disease distribution between boys and girls with the mean age of onset being 4.4 years (range 10 days–15 years). Presenting symptoms were mostly non-specific and non-localizing and included fever (92 %), vomiting (54 %), hypotension and irritability (33 %), physical exhaustion (28 %), altered mental status (15 %), and impaired peripheral perfusion (13 %). Interestingly, in this series, more than 20 % of the patients with NF had no predisposing conditions that would identify them as having increased risk of developing NF [6]. Certain clinical signs can help raise the index of suspicion of a diagnosis of NF. Initial signs and symptoms may include local erythema and swelling with disproportionate pain over the site. Signs of systemic inflammatory such as fever, tachycardia, hypotension and shock may develop. Once the infection progresses, more typical signs and symptoms can be observed, including tense edema outside the area of compromised skin, discoloration (ecchymosis), blisters/bullae and necrosis. Crepitus and/or subcutaneous gas can often be palpated. Because NF is hard to diagnose, even in the hands of an experienced clinician, clinical and laboratory tools have been used to help differentiate NF from other soft tissue infections. Wong analyzed the results of laboratory tests routinely performed for the assessment of a wide range of severe soft tissue infections from cellulitis to NF [9]. The laboratory results they analyzed included complete blood count, electrolytes, erythrocyte sedimentation rate and C-reactive protein. A numerical score based on the relative contribution of the laboratory parameters for distinguishing necrotizing fasciitis from other soft tissue infections was established. This laboratory-based risk score predicting the presence of necrotizing fasciitis was termed the “LRINEC Score” (Table 36.1). The score is calculated by totaling up each of the six predictive factors. A score of six or greater was found to have a positive predictive value of 92.0 % (95 % CI 84.3–96.0) and negative predictive value of 96.0 % (95 % CI 92.6–97.9). A score of eight or more is strongly predictive of necrotizing fasciitis (positive predictive value 93.4 %, 95 % CI 85.5–97.2) [9]. Unfortunately, the LRINEC Score has not been validated in children. Plain radiography, ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) all have been used to help diagnose NF. Plain radiographs

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Infectious Disease-Associated Syndromes in the PICU

Table 36.1 Laboratory Risk Indicators for Necrotizing Fasciitis (LRINEC score) Value C- reactive protein, mg/L 150 WBC count, cells/mm3 25 Hemoglibin level, g/dl >13.5 11–13.5 135 3 mg/dl below admission value) Falling platelet count (< 150 × 109/L) Prolonged prothrombin time, partial thromboplastin time and thrombin time Low fibrinogen level Elevated fibrin degradation products Elevated urea and creatinine plasma concentration Elevated alanine aminotransferase and aspartate aminotransferase plasma concentrations Metabolic acidosis Known infection or metabolic disorder. Reye’s syndrome Toxic shock syndrome

Clinical Manifestations The diagnosis of HSES is difficult to make because there is no single laboratory test to confirm diagnosis. Diagnosis is based on a combination of clinical and laboratory data along with the exclusion of etiologies that can give a similar clinical presentation. Levin et al. published the case definition criteria in 1989 (Table 36.2) based on their large population study [16]. The usual age at presentation varies from infants (2 months) to children (14 years) [16, 19] and most affected children had a history of an upper respiratory tract infection or gastroenteritis 2–5 days prior to admission. The disease course is illustrated in Fig. 36.1 [20]. In most reported cases, the child was found, within a few hours of being put to bed, with severe neurological impairment such as coma and/or seizures. HSES usually presents abruptly with high fever (above 39 °C), hypovolemic shock, coma, seizures, watery diarrhea that develops into bloody lower GI bleeding, profound coagulopathy and oliguria. The hallmark of the disease is severe neurologic deterioration beyond what would be expected from the shock. Brain imaging studies show diffuse cerebral edema and areas of focal bleeding and infarcts. In the report, all patients were admitted to the pediatric ICU and were intubated and ventilated for long periods of time. Based on the constellation of clinical findings, a number of other diseases/syndrome should be considered, including viral hemorrhagic fever, sepsis syndrome, hemolytic uremic syndrome, Reye’s syndrome or toxic shock syndrome.

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Infectious Disease-Associated Syndromes in the PICU

Fig. 36.1 Clinical picture and time course of symptoms of HSES (Adapted from Ince et al. [20]. With permission from Wolter Kluwers Health)

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Hyperthermia Shock Coma Seizures Spasticity

Hypotonia Cerebral Edema Bleeding + DIC Acidosis Diarrhea Elevated transaminases

0

1

2

3

4 Days

Laboratory Findings Laboratory studies are consistent with a clinical diagnosis of shock and hypoperfusion. Metabolic acidosis and decreased hemoglobin and platelet levels develop within a few hours of hospital admission and are associated with shock and DIC. Hypernatremia and hyperkalemia are common and are due to renal injury. Altered liver function is evidenced by markedly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels; however, there are usually only mild elevations in bilirubin and ammonia. Serum CPK may be disproportionately elevated. In general, the laboratory abnormalities peak at 24–48 h after presentation and return to normal level by 7 days [21].

Management Unfortunately, there is no specific therapy available for this syndrome. General supportive measures should be undertaken until the disease process runs its course. Because of the uncertainty of the etiology and the possibility of viral or bacterial infection, bacterial and viral cultures should be drawn and broad-spectrum antibiotic treatment should be initiated. The patient should be placed in isolation and precautions for possible viral hemorrhagic fever should be employed until the diagnosis can be ruled out. Cardiovascular support is usually necessary and fluid resuscitation and/or inotropic medication was utilized in all reported cases. Anemia and coagulopathy usually necessitate frequent blood product replacement. Oliguria and renal failure are usually due to

5

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7

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9 Months - years

pre-renal azotemia and while traditional renal replacement therapy has been used, there is one case report suggesting there may be some benefit from plasma exchange with continuous hemofiltration [22]. Overall, disease outcome seems to be related to the severity of the neurologic impairment on admission and is worse if the patient has prolonged coma or status epilepticus. Aggressive attempts should be taken to control seizure activity and, if signs of increased intracranial pressure (ICP) are present, to control ICP as well. The majority of the patients showed early signs of cerebral edema that often progresses to diffuse brain injury. The theoretical advantage of invasive intracranial pressure monitoring should be weighed against the possible complications in a high-risk patient with systemic coagulopathy. No data regarding benefit from invasive ICP monitoring is present. Mortality is high and ranges between 50 and 80 % with severe neurological disability in the survivors [16, 19].

Rocky Mountain Spotted Fever History and Epidemiology Rocky Mountain spotted fever (RMSF) is a tick-borne disease that has been recognized in North America for more than a century. RMSF was first described in the Rocky Mountain region of the United States in the late 1800s and is caused by the obligate intracellular coccobacillus Rickettsia rickettsii. RMSF is the most common fatal tick-borne illness in the United States. An estimated 612 deaths were attributable to RMSF in the United States during 1983–1998, and

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approximately 12 % of reported deaths occurred in children aged less than 10 years [23]. A recent publication summarizes the annual incidence of RMSF from 2000 to 2007 and shows a worrisome increase in the incidence of the disease from 1.7 cases to 7.0/1,000,000 person in the USA [24]. The authors speculate that some of the increase may be related to the newly-developed ELISA test that was introduced during the study period. Nearly two-thirds of RMSF cases occur in children younger than age 15 years (peak age, 5–9 years). The case-fatality ratio of untreated RMSF across all age groups combined approaches 25 % [25] and 3–5 % in treated patients [26, 27]. While RMSF was initially seen in the Northern Rocky Mountain and Pacific States, today it has been reported in almost every state in the continental United States except Maine and Vermont. Most cases that have been reported are from the South Atlantic Region, Pacific Region, and the West South Central Region. From 1994 to 2003, 54 % of the reported cases were from five states: North Carolina, Tennessee, Oklahoma, South Carolina, and Arkansas. The disease is transmitted by the American dog tick (Dermacentor variabilis), a relatively common and broadly distributed tick in the Eastern United States, and by the wood tick (Dermacentor andersoni) in the Rocky Mountain States. A clear spring-summer distribution of cases is an invariant feature of this illness and attests to the association of RSMF with peak occurrences of Dermacentor tick bites. Currently, the disease is in the midst of its third resurgence since 1920, following epidemiologic peaks from 1939–1949 to 1974–1984. The reasons for the cyclical waxing and waning are not understood but it does underscore the fact that little is known about the virulence mechanisms associated with R. rickettsii and that it remains an important and prevalent disease [28]. It is possible that the new resurgence of the disease is secondary to changes in the vectors of the tick-borne disease as suggested by a recent report of R. rickettsii being transmitted by a new vector, the common brown dog tick R. sanguineus [29].

Pathogenesis Ticks become infected with R. rickettsii either transovarially or by feeding on infected mammals. Once infected, the ticks are not killed by the infection, thus allowing them to serve as both a reservoir and a vector of R rickettsii. The organisms are usually transmitted to humans through the saliva of a tick while it is feeding, although infections may occur following exposure to crushed tick tissues, fluids, or feces. Following the bite of an infected tick, R. rickettsii multiply within the endothelial cells of the small blood vessels, which then become widely disseminated resulting in the pathologic lesion of widespread vasculitis of the small blood vessels. The precise mechanism of the invariant endothelial injury

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is not known. However recent in vitro studies suggest that NF-κB activation may play a prominent role [30, 31]. Focal areas of endothelial proliferation and perivascular mononuclear cell infiltration lead to thrombosis and leakage of red blood cells into the surrounding tissue. These latter changes create the characteristic petechial rash. These vascular lesions also appear to account for most of the prominent clinical manifestations including fever, headache, rash, myalgias, and central nervous system changes.

Clinical Manifestations In its early stages, RMSF can resemble many other infectious and non-infectious conditions and can be difficult to diagnose. A history of tick bite is elicited in only 50–60 % of patients, especially in rural areas where children often remove ticks without telling their parents. The incubation period after a tick bite is approximately 7 days, with a range of 2–14 days. The larger the initial inoculum, the shorter the incubation period is. The initial symptoms of infection are non-specific and may mimic a number of conditions, including viral syndrome. These symptoms include high fever, nausea, vomiting, severe headache, anorexia and malaise. Other non-specific signs or symptoms include myalgia (especially bilateral calf pain), photophobia, and abdominal pain. Meningoencephalitis, myocarditis, and pulmonary involvement are all integral aspects of the syndrome that are also seen in other vasculitis syndromes such as toxic shock syndrome and toxic strep syndrome. While the classic triad of RMSF symptoms is fever, rash, and headache, this combination is not always present when the patient initially presents. The rash usually appears between the second and fifth day of illness and is a blanching, erythematous macular rash that initially begins on the wrists and ankles and typically involves the palms and soles. The rash quickly spreads to the trunk and head within hours and usually transforms into the characteristic petechial rash of RMSF somewhere between the days 6 and 10 of illness. However, rash occurs in only 35–60 % of patients and as many as 10–15 % of patients with RSMF never develop a rash [32]. Other manifestations of the disease are related to the extensive vasculitis that occurs and include changes in mental status and/or meningismus. There are reports of disease progression in the central nervous system that includes coma, seizures, cranial nerve palsies, central deafness, and cortical blindness. Other manifestations of the vasculitis include conjunctivitis, periorbital edema, congestive heart failure, myocarditis, shock, hepatosplenomagly, and jaundice. The respiratory system is also frequently involved and patients can develop severe pneumonia and/or acute respiratory distress syndrome.

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Table 36.3 Case definition from the centers for disease control and prevention for Rocky Mountain spotted fever Laboratory criteria for diagnosis Fourfold or greater rise in antibody titer to R rickettsii in acute- and convalescent-phase specimens ideally taken >3 weeks apart, or Positive polymerase chain reaction assay to R rickettsii, or Demonstration of positive immunofluorescence of skin lesion (biopsy) or organ tissue (autopsy), or Isolation of R rickettsii from a clinical specimen Case classification Probable: a clinically compatible case with a single indirect immunofluorescence assay serologic titer >64 or >16 with single complement fixation titer or other supportive serology (eg, >128 by latex agglutination, microagglutination, or indirect hemagglutination test) Confirmed: a clinically-compatible case that is confirmed by laboratory findings

Laboratory Findings The classic laboratory abnormalities that help increase the index of suspicion for this diagnosis include hyponatremia (≤ 130 mEq/l) and thrombocytopenia (