Small Animal Critical Care Medicine [3 ed.] 032376469X, 9780323764698

Table of contents :
Dedication
Contributors
Foreword • Bernie Hansen
Contents
Video TOC
Part I: Key Critical Care Concepts
Part II: Respiratory Disorders
Part III: Advanced Respiratory Support
Part IV: Cardiovascular Disorders
Part V: Electrolyte and Acid-Base Disturbances
Part VI: Fluid Therapy
Part VII: Endocrine Disorders
Part VIII: Neurologic Disorders
Part IX: Infectious Disorders
Part X: Hematologic Disorders
Part XI: Intraabdominal Disorders
Part XII: Urogenital Disorders
Part XIII: Nutrition
Part XIV: Trauma
Part XV: Anesthesia and Pain Management
Part XVI: Environmental Emergencies
Part XVII: Miscellaneous Disorders
Part XVIII: Pharmacology
Part XIX: Antimicrobial Therapy
Part XX: Extracorporeal Therapy
Part XXI: Monitoring
Part XXII: Procedures
Part XXIII: Intensive Care Unit Design and Management
Appendices
Index

Citation preview

REFERENCE RANGES FOR SELECT LABORATORY VALUES All readers are urged to use reference values specific for the laboratory or instrumentation device used when interpreting values for individual patients. Reference intervals depend on the region of the world/country, the type of sample (whole blood vs. plasma or serum), and the type of instrument that is being used.

Coagulation Test Reference Ranges (note: point-of-care machines may have markedly different ranges) PT (sec)

Arterial and Venous Blood Gas Values for Normal Cats (at 37°C)a Arterial

Venous

Canine

Feline

pH

7.46 (7.44-7.47)

7.39 (7.38-7.4)

6-11

6-12

PCO2 (mm Hg)

30 (28-32)

37.5 (36-39)

aPTT (sec)

10-25

10-25

Bicarbonate (mmol/L)

21 (20 – 22)

22 (21-24)

FDP (mcg/ml)

,10

,10

97 (94-100)

35 (33-37)

d-dimer

,250

,250

PO2 (mm Hg) (sea level)

(ng/dl)

ACT (sec)

60-125

,165

BMBT (min)

1.7-4.2

1.4-2.4

Fibrinogen (mg/dl)

150-400

150-400

Herbert DA, Mitchell RA. Blood gas tensions and acid-base balance in awake cats. J Appl Physiol 1971;30(3):434-436; Bachmann K, Kutter APN, Schefer RJ, et. al. Determination of reference intervals and comparison of venous blood parameters using standard and non-standard collection methods in 24 cats. J Feline Med Surg 2017;19(8):831-840 a

PT, prothrombin time; aPTT, activated partial thromboplastin time; FDP, fibrinogen degradation products; ACT, activated clotting time; BMBT, buccal mucosal bleeding time.

Normal Adrenal Function Test Values Canine and Feline

Arterial and Venous Blood Gas Values for Normal Dogs (temperature corrected for dog)

Resting cortisol (mcg/dl)

2-6

Arterial

Post-ACTH cortisol (mcg/dl)

6-18

ACTH, adrenocorticotropic hormone.

Venous

pH

7.361 – 7.444

7.345 – 7.433

PCO2 (mm Hg)

27 - 39

40 - 46

Base deficit (mmol/L)

27 to 21.6

–6 to 0.4

Bicarbonate (mmol/L)

17 - 23

19 - 26

Total CO2 (mmol/L)

18 - 24

20 - 27

PO2 (mm Hg) (sea level)

83 - 120

32 - 64

Vanova-Uhrikova I, Rauserova-Lexmaulova L, Rehakova K, et. al. Determination of reference intervals of acid-base parameters in clinically healthy dogs. J Vet Emerg Crit Care 2017;27(3):325-332.

Liver Function Tests Reference Values

Urinalysis Reference Values Canine

Feline

Canine

Feline

Ammonia (mcg/dl)

45-120

30-100

Specific gravity

NH3 post ATT (mcg/dl)

Minimal change from normal

No change from normal

Minimum

1.001

1.001

Maximum

1.060

1.080

Bile acids—fasting (µM)

,10

,2

Usual limits

1.018-1.050

1.018-1.050

Bile acids—2-hour postprandial (µM)

,15.5

,10

Volume (ml/kg/day)

24-41

22-30

Osmolality (mOsm/kg)

369-2416

366-2178

Protein/creatinine ratio

,0.5 5 normal 0.5-1.0 5 gray zone .1.0 5 abnormal

NH3, ammonia; ATT, ammonia tolerance test.

Normal Urinary Fractional Electrolyte Clearance Values (%) Canine

Feline

Sodium

,1

,1

Chloride

,1

,1.3

Potassium

,20

,20

Phosphate

,40

,73

Cerebrospinal Fluid Analysis Reference for Dogs and Cats Value Color

Colorless

Clarity

Transparent, clear

Refractive index

1.3347-1.3350

Protein concentration

Cisternal: ,25 mg/dl Lumbar: ,40 mg/dl

Total cell count

RBC: 0/µl WBC: ,3/µl cisternal ,5/µl lumbar

WBC differential count

Mononuclear cells Small mononuclear cells: 60%-70% Large mononuclear cells: 30%-40% Polymorphonuclear cells Neutrophils: ,1% Eosinophils: ,1% Others Ependymal lining cells: rare Nucleated RBC: rare in lumbar taps

Glucose (mg/dl)

61-116

RBC, Red blood cells; WBC, white blood cells.

Categories of Effusions in Dogs and Cats Transudate

Modified Transudate

Exudate

Hemorrhagic

Chylous*

Specific gravity

,1.017

1.017-1.025

.1.025

N/A

N/A

Total protein (g/dl)

,2.5

2.5-5.0

.3.0

. 2.5

.2.5 Refractometer may be inaccurate

Nucleated cell count (per µl) or PCV

,1000

500-10,000

.5,000

PCV 10% Variable with peripheral PCV

Variable . 3,000

Predominant cell type

Mononuclear Mesothelial

Lymphocytes Monocytes Mesothelial RBCs Neutrophils

Neutrophils Mononuclear cells RBCs

RBCs Neutrophils Lymphocytes Monocytes (no platelets, non-clotting unless actively bleeding)

Small lymphocytes

*Triglycerides .100mg/dl or 1.7mmol/L also supportive of chylous effusion.

Resting Energy Requirement (kcal/24h) and Daily Maintenance Fluid Volume in mL BW0.75 3 70 (BW5body weight in kg) Body Weight (kg)

Daily Maintenance Fluid Volume (ml) and Resting Energy Requirement (kcal/24 hr)

Body Weight (kg)

Daily Maintenance Fluid Volume (ml) and Resting Energy Requirement (kcal/24 hr)

1

70

26

806

2

118

27

829

3

160

28

852

4

198

29

875

5

234

30

897

6

268

31

920

7

301

32

942

8

333

33

964

9

364

34

986

10

394

35

1007

11

423

36

1029

12

451

37

1050

13

479

38

1071

14

507

39

1092

15

534

40

1113

16

560

41

1134

17

586

42

1154

18

612

43

1175

19

637

44

1196

20

662

45

1216

21

687

46

1236

22

711

47

1257

23

735

48

1277

24

759

49

1296

25

783

50

1316

THIRD EDITION

SMALL ANIMAL

Critical Care Medicine Deborah C. Silverstein, DVM, DACVECC Professor of Small Animal Critical Care Medicine Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine University of Pennsylvania Philadelphia, PA

Kate Hopper, BVSc, PhD, DACVECC Professor of Small Animal Emergency and Critical Care University of California, Davis Department of Surgery and Radiological Sciences School of Veterinary Medicine Davis, CA United States

3251 Riverport Lane St. Louis, Missouri 63043

SMALL ANIMAL CRITICAL CARE MEDICINE, THIRD EDITION

ISBN: 978-0-323-76469-8

Copyright © 2023 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2015 and 2009.

Content Strategist: Jennifer Catando Content Development Specialist: Shweta Pant Publishing Services Manager: Deepthi Unni Project Manager: Thoufiq Mohammed Design Direction: Margaret Reid

Printed in India. Last digit is the print number:  9  8  7  6  5  4  3  2  1

D E D I C AT I O N As the saying goes, “Three’s a charm!” Despite the extended pandemic timeline for completion, this third edition of the Small Animal Critical Care Medicine Textbook is by far the best one yet. However, it would not have been possible without the support of so many wonderful people. I want to dedicate this book to my incredible coeditor, Dr. Kate Hopper, and everyone who contributed their writings despite the most challenging of times. The need for cutting-edge, high-quality veterinary critical care medicine has never been greater, and it is exhilarating to be a part of this exciting specialty. The connection between people, animals, and doctors for all species has never felt stronger, and our ability to push the envelope toward new heights of critical care medicine is at our fingertips. I would also like to dedicate this book to my nearest and dearest humans in this world: my husband, Stefan, and my sons, Maxwell and Henry, who keep me grounded, balanced, and fulfilled and have given me never-ending support and unlimited patience as I pursue crazy book editing endeavors. I love you to the moon and back. And lastly, thank you to my dad who was and will always be my greatest inspiration to be the best you can be. Your memory will most definitely always be a blessing. So much to be grateful for. Thank you to all who have made this dream a reality! - Deb I dedicate this book to my family, both Australian and American. In particular, to the next generation of my family, Levi, Jack H, Jack B, Zara, Lucy, and Alex. You bring me so much love and fun and I feel incredibly lucky to have you all in my life. And to my veterinary friends the world over who have enriched my life and have made this career such a wonderful experience. I first met my coeditor, Dr. Deb Silverstein, as a resident mate and she has become the best friend and collaborator one could wish for. Thank you! -Kate

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CONTRIBUTORS Sophie Adamantos, BVSc, CertVA, DACVECC, DECVECC, MRCVS, FHEA

Dominic Barfield, BSc, BVSc, MVetMed, DECVECC, DACVECC

Clinical Director Paragon Referrals Wakefield, England United Kingdom

Senior Lecturer Royal Veterinary College, London Clinical Science and Services Hertfordshire, England United Kingdom

Ashley E. Allen-Durrance, DVM, DACVECC Clinical Assistant Professor University of Florida Department of Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

Ciara A. Barr, VMD, DACVAA

Lillian Ruth Aronson, VMD, DACVS Professor of Surgery University of Pennsylvania Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Associate Professor Emergency and Critical Care University of Melbourne, Melbourne Victoria Australia

Manuel Boller, Dr med vet, MTR, DACVECC

Assistant Professor of Clinical Anesthesiology University of Pennsylvania Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Specialist Central Victoria Veterinary Hospital Victoria, BC Canada

Linda S. Barter, BVSc, PhD, DACVAA

Senior Lecturer in Emergency and Critical Care Murdoch University School of Veterinary and Biomedical Sciences Murdoch, Western Australia Australia

Robert A. Armentano, DVM, DACVIM Internal Medicine Specialist Veterinary Specialty Center Buffalo grove, IL United States

Elise Mittleman Boller, DVM, DACVECC

Professor University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Anthony Barthélemy, DMV, MS, PhD Doctor in ICU & ER Center Hospitalier Vétérinaire HOPia, Guyancourt, France

Corrin Boyd, BSc, BVMS (Hons), GradDipEd, MVetClinStud, MANZCVS, DACVECC

Søren R. Boysen, DVM, DACVECC Associate Professor University of Calgary Veterinary Clinical and Diagnostic Services Calgary, Alberta Canada

Amanda Arrowood, BS, CVT, VTS (ECC) Veterinary Nurse University of Pennsylvania Intensive Care Unit School of Veterinary Medicine Philadelphia, PA United States

Kari Santoro Beer, DVM, DACVECC Emergency and Critical Care Specialist Oakland Veterinary Referral Services Bloomfield Hills, MI United States

Allyson Berent, DVM, DACVIM Anusha Balakrishnan, BVSc, DACVECC Staff Criticalist Cornell University Veterinary Specialists Stamford, CT United States Adjunct Assistant Clinical Professor of Emergency-Critical Care Cornell University College of Veterinary Medicine Ithaca, NY United States

Ingrid M. Balsa, MEd, DVM, DACVS-SA Assistant Clinical Professor University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

vi

Staff Veterinarian; Director Interventional Endoscopy Services The Animal Medical Center Interventional Radiology/Endoscopy New York, NY United States

Rachael Birkbeck, DVM, PGCert, MVetMed, DACVECC, MRCVS Specialist Dick White Referrals Cambridge, England United Kingdom

Amanda K. Boag, MA, VetMB, DECVECC, DACVECC, DACVIM, FHEA, FRCVS Chief Medical Officer IVC Evidensia Keynsham, Bristol United Kingdom

Benjamin M. Brainard, VMD, DACVAA, DACVECC Edward H Gunst Professor of Small Animal Critical Care University of Georgia Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Sara R. Brethel, DVM Cardiology University of Florida College of Veterinary Medicine Gainesville, FL United States

Gareth J. Buckley, MA, VetMB, MRCVS, DACVECC, DECVECC Clinical Associate Professor, Emergency & Critical Care University of Florida Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

CONTRIBUTORS

Yekaterina Buriko, DVM, DACVECC

Dana L. Clarke, VMD, DACVECC

Meredith L. Daly, VMD, DACVECC

Assistant Professor - Critical Care University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Assistant Professor of Interventional Radiology & Critical Care University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Head of Medical Quality Medical Operations Bond Vet New York, NY United States

Jenna H. Burton, DVM, MS, Dip ACVIM (Oncology) Associate Professor, Medical Oncology Colorado State University Clinical Sciences College of Veterinary Medicine Fort Collins, CO United States

Alessia Cenani, DVM, MS, DACVAA Assistant Professor of Clinical Anesthesia University of California, Davis School of Veterinary Medicine Davis, CA United States

Steven J. Centola, BVMS, MRCVS, DACVECC Emergency and Critical Care University of Pennsylvania School of Veterinary Medicine Philadelphia, PA United States

Daniel L. Chan, DVM, DACVECC, DECVECC, DACVIM(Nutrition), FHEA, MRCVS Professor in Emergency and Critical Care The Royal Veterinary College Clinical Sciences and Service Hertfordshire, England United Kingdom

Peter S. Chapman, BVetMed, DECVIMCA, DACVIM, MRCVS Medical Director Internal Medicine Veterinary Specialty and Emergency Center Levittown, PA United States

Dennis J. Chew, DVM, Dipl ACVIM (Internal Medicine) Professor Emeritus The Ohio State University Veterinary Clinical Sciences College of Veterinary Medicine Columbus, OH United States

Melissa A. Claus, DVM, DACVECC Head of Department Emergency and Critical Care Perth Veterinary Specialists, Perth Australia Adjunct Senior Lecturer School of Veterinary Medicine Murdoch University, Perth Australia

vii

Harold Davis, BA, RVT, VTS (ECC) (Anesthesia & Analgesia) Clinical Educational Consultant West Sacramento California United States Former Manager University of California, Davis Small Animal Emergency and Critical Care Service School of Veterinary Medicine Davis, CA United States

Leah A. Cohn, DVM, PhD, DACVIM (SAIM)

Armelle de Laforcade, DVM, DACVECC

Professor, Small Animal Internal Medicine University of Missouri Department of Veterinary Medicine and Surgery College of Veterinary Medicine Columbia, MO United States

Associate Professor Tufts University Clinical Sciences Cummings School of Veterinary Medicine North Grafton, MA United States

Stephen Cole, VMD, MS, DACVM (Bacteriology/Mycology, Immunology)

Sage M. De Rosa, DVM, DACVECC

Assistant Professor of Microbiology University of Pennsylvania School of Veterinary Medicine Philadelphia, PA United States

Assistant Professor University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Edward S. Cooper, VMD, MS, DACVECC Professor—Clinical The Ohio State University Veterinary Clinical Sciences School of Veterinary Medicine Columbus, OH United States

Jamie M. Burkitt Creedon, DVM, DACVECC Assistant Professor of Clinical Small Animal Emergency and Critical Care University of California Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Teresa C. DeFrancesco, DVM, DACVIM, DACVECC Professor of Cardiology and Critical Care North Carolina State University Department of Clinical Sciences College of Veterinary Medicine Raleigh, NC United States

Amy Dixon-Jimenez, DVM, MS, DACVIM Cardiologist Wheat Ridge Animal Hospital Petcardia Wheat Ridge, CO United States

viii

CONTRIBUTORS

Kenneth J. Drobatz, DVM, MSCE, DACVIM, DACVECC Professor and Chief, Section of Critical Care Director, Emergency Service University of Pennsylvania Department of Clinical Studies School of Veterinary Medicine Philadelphia, PA United States

Justin Duval, BSc, DVM, DACVECC Diplomate of the American College of Veterinary Emergency and Critical Care Emergency and Critical Care Veterinary Specialty Center of Seattle Lynnwood, WA United States

Daniel J. Fletcher, PhD, DVM, DACVECC

Giacomo Gianotti, DVM, DVSc, DACVAA

Associate Professor, Emergency and Critical Care Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca NY United States

Associate Professor—Anesthesia University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Thierry Francey, Dr med vet, Dipl ACVIM (SAIM), Dipl ECVIM-CA

Erin A. Gibson, BS, DVM

Head, Nephrology Group (Small Animal Internal Medicine) University of Bern Department of Clinical Veterinary Medicine Vetsuisse Faculty Bern Switzerland

Adam E. Eatroff, DVM, DACVIM (SAIM) Staff Internist and Nephrologist ACCESS Specialty Animal Hospitals Los Angeles, CA United States

Steven E. Epstein, DVM, DACVECC Professor of Clinical Emergency and Critical Care University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Kate S. Farrell, DVM, DACVECC Assistant Professor of Clinical Small Animal Emergency and Critical Care University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Christiana Fischer, BS, VMD, DACVECC Criticalist Emergency and Critical Care Metropolitan Veterinary Associates, Norristown, PA United States

Molly J. Flaherty, DVM, CCRP, CVA, CVPP Rehabilitation Medicine Clinician University of Pennsylvania Department of Clinical Sciences School of Veterinary Medicine Philadelphia, PA United States

Fellow, Minimally Invasive Procedures University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Massimo Giunti, DVM, PhD, DECVECC Mack Fudge, DVM, MPVM, DACVECC Colonel (ret) Veterinary Corps US Army Retired, Helotes Texas United States Director of Medical Research Surgery Hill Country Animal League, Boerne Texas United States

Joao Felipe de Brito Galvao, MV, MS, DACVIM (SAIM) Internal Medicine Specialist VCA Arboretum View Animal Hospital Downers Grove, IL United States

Caroline K. Garzotto, VMD, DACVS, CCRT Surgeon, Department Head Mount Laurel Animal Hospital Mount Laurel, NJ United States

Anna R.M. Gelzer, DMV, PhD, DACVIM (Cardiology), DECVIM-CA (Cardiology) Professor of Cardiology University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Katherine K. Gerken, DVM, MS, DACVECC Assistant Clinical Professor Auburn University Department of Clinical Sciences College of Veterinary Medicine Auburn, AL United States

Associate Professor Alma Mater Studiorum - University of Bologna Department of Veterinary Medical Sciences Bologna Italy

Kris Gommeren, DMV, MSc, PhD, DECVIM-CA, DECVECC Assistant Professor Liege University Small Animal Department Liege Belgium

Jennifer M. Good, DVM, DACVECC, CVA Clinical Assistant Professor of Emergency and Critical Care University of Georgia Small Animal Medicine and Surgery Athens, GA United States

Thomas D. Greensmith, BVetMed, MVetMed, DACVECC, DECVECC, FHEA, MRCVS Lecturer in Emergency and Critical Care Royal Veterinary College Clinical Science and Services Hertfordshire, England United Kingdom

Tamara Grubb, DVM, PhD, DACVAA Adjunct Professor Washington State University Veterinary Clinical Sciences Pullman, WA United States

CONTRIBUTORS

Julien Guillaumin, Docteur Veterinaire, DACVECC, DECVECC Associate Professor Colorado State University Department of Clinical Sciences Fort Collins, CO United States

Rebecka S. Hess, DVM, MSCE, DACVIM Professor University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Timothy B. Hackett, DVM, MS, DACVECC Chair, Department of Clinical Sciences Professor, Emergency and Critical Care Medicine Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca, NY United States

Guillaume Laurent Hoareau, DVM, PhD, Diplomate ACVECC, Diplomate ECVECC

Emergency and Critical Care Clinician Vets Now Manchester Manchester, England United Kingdom

Assistant Professor University of Utah Health Emergency Medicine Division Salt Lake City, UT United States Investigator Nora Eccles-Harrison Cardiovascular Research and Training Institute University of Utah Health, Salt Lake City, UT United States

Bernie Hansen, DVM, MS, DACVECC, DACVIM (Internal Medicine)

Sabrina N. Hoehne, Dr med vet, DACVECC, DECVECC

Associate Professor North Carolina State University Clinical Sciences Raleigh, NC United States

Assistant Professor of Emergency and Critical Care Medicine Department of Veterinary Clinical Sciences Washington State University, Pullman WA United States

Simon P. Hagley, BVSc, DACVECC

Samantha Hart, BVMS (Hons), MS, DACVS, DACVECC ER Veterinarian Veterinary Emergency Group, Edgewater, CO United States

Ralph C. Harvey, DVM, MS, Diplomate ACVAA

Marie K. Holowaychuk, DVM, DACVECC Veterinary Wellbeing Advocate and Small Animal Emergency and Critical Care Specialist Calgary, Alberta Canada

Chair - Veterinary Advisory Board BioTraceIT Corporation Charlottetown, Prince Edward Island Canada Associate Professor, Retired University of Tennessee Small Animal Clinical Sciences Knoxville, TN United States

Kate Hopper, BVSc, PhD, DACVECC

Galina Hayes, BVSc, PhD, DACVECC, DACVS

Dez Hughes, BVSc (Hons), DACVECC

Assistant Professor Cornell University Small Animal Surgery Ithaca, NY United States

Professor of Small Animal Emergency & Critical Care University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Associate Professor and Section Head, Emergency and Critical Care University of Melbourne Faculty of Veterinary and Agricultural Science Werribee, Victoria Australia

ix

Daniel Z. Hume, DVM, DACVIM, DACVECC Medical Director - Critical Care WestVet Boise, ID United States

Karen Humm, MA, VetMB, MSc, CertVA, DACVECC, FHEA, MRCVS Associate Professor in Transfusion Medicine and Emergency and Critical Care The Royal Veterinary College Clinical Sciences and Services London, England United Kingdom

Karl E. Jandrey, DVM, MAS, DACVECC Professor of Clinical Small Animal Emergency & Critical Care Associated Dean of Admissions and Student Programs University of California, Davis School of Veterinary Medicine Davis, CA United States

Tania Perez Jimenez, DVM, MS, PhD, DACVAA Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences College of Veterinary Medicine, Washington State University Washington United States

Lynelle R. Johnson, DVM, MS, PhD, Dipl ACVIM (SAIM) Professor University of California, Davis Department of Medicine & Epidemiology School of Veterinary Medicine Davis, CA United States

Andrea N. Johnston, DVM, PhD Assistant Professor Louisiana State University Veterinary Clnical Sciences School of Veterinary Medicine Baton Rouge, LA United States

Joanna L. Kaplan, DVM Cardiology Resident University of California, Davis Department of Medicine & Epidemiology School of Veterinary Medicine Davis, CA United States

x

CONTRIBUTORS

Iain Keir, BVMS, DACVECC, DECVECC Head of Critical Care Medicine Small Animal Specialist Hospital Sydney, New South Wales Australia

Marie E. Kerl, DVM, MPH, DACVIM (SAIM), DACVECC Chief Medical Officer VCA Animal Hospitals Inc. Medical Operations Los Angeles, CA United States

Marguerite F. Knipe, BA, DVM, DACVIM (Neurology) Health Sciences Clinical Professor University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Kathryn Good, DVM, DACVO Associate Clinical Professor of Veterinary Ophthalmology University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Amie Koenig, DVM, DACVIM (SAIM), DACVECC Professor, Emergency and Critical Care University of Georgia Department of Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Lucy Kopecny, BVSc (Hons) DACVIM (SAIM) Small Animal Internal Medicine Specialist Small Animal Specialist Hospital Sydney, New South Wales Australia

Marc S. Kraus, DVM, Dipl ACVIM (Internal Medicine, Cardiology), DECVIM -CA (Cardiology) Professor University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Catherine E. Langston, DVM, DACVIM Professor - Small Animal Internal Medicine The Ohio State University Columbus, OH United States

Jennifer A. Larsen, DVM, MS, PhD, DACVN Professor of Clinical Nutrition University of California, Davis Department of Molecular Biosciences School of Veterinary Medicine Davis, CA United States

Chai-Fei Li, DVM, DACVIM (Neurology) Assistant Professor University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Ronald H. L. Li, DVM, MVetMed, PhD, DACVECC Associate Professor of Small Animal Emergency and Critical Care University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Ta-Ying Debra Liu, DVM, DACVECC Veterinary Criticalist VCA Orange County Veterinary Specialists Tustin, CA United States

Natalie Kovak, DVM, DACVECC Criticalist Small Animal Emergency and Critical Care Metropolitan Veterinary Associates, Norristown, PA United States

Alex Lynch, BVSc (Hons), DACVECC, MRCVS Assistant Professor North Carolina State University Department of Clinical Sciences College of Veterinary Medicine Raleigh, NC United States

Bridget M. Lyons, VMD, DACVECC Service Head Department of Emergency and Critical Care Cornell University Veterinary Specialists, Stamford, CT United States

Kristin A. MacDonald, DVM, PhD, DACVIM (Cardiology) Veterinary Cardiologist VCA Animal Care Center of Sonoma County Rohnert Park, CA United States

Deborah C. Mandell, VMD, DACVECC Professor, Emergency and Critical Care University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Linda G. Martin, DVM, MS, DACVECC Associate Professor, Emergency and Critical Care Medicine Washington State University Veterinary Clinical Sciences Pullman, WA United States

Karol Mathews, DVM, DVSc, DACVECC Professor Emerita University of Guelph Clinical Studies Ontario Veterinary College Guelph, Ontario Canada

Katie D. Mauro, DVM, DACVECC Assistant Professor of Emergency and Critical Care Medicine Small Animal Clinical Sciences Michigan State University East Lansing, MI, United States

Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC Staff Criticalist Cornell University Veterinary Specialists Department of Emergency & Critical Care Stamford, CT United States Adjunct Associate Clinical Professor Emergency and Critical Care Cornell University Ithaca, NY United States

CONTRIBUTORS

xi

Duana McBride, BVSc, DACVECC, MVMedSc, FHEA, MRCVS

Adam Moeser, DVM, DACVIM (neurology)

Mark A. Oyama, DVM, MSCE, DACVIM-Cardiology

Veterinary Criticalist Southfields Veterinary Specialist Essex, England United Kingdom

Veterinary Neurologist MedVet Commerce, MI United States

Megan E. McClosky, DVM, DACVIM

Bea Monteiro, DVM, PhD, PgDip

Assistant Professor Clinical Medicine and Extracorporeal Therapies University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA United States

Research Advisor Universite de Montreal Department of Clinical Sciences Saint-Hyacinthe, Quebec Canada

Charlotte Newton Sheppard Endowed Chair of Medicine and Professor of Cardiology University of Pennsylvania Department of Clinical Sciences and Advanced Medicine Philadelphia, PA United States

Maureen A. McMichael, DVM, M.Ed., DACVECC Professor Auburn University Department of Clinical Sciences College of Veterinary Medicine Auburn, AL United States Professor Carle-Illinois College of Medicine Department of Biomedical & Translational Science Urbana, IL United States

Margo Mehl, DVM, DACVS Veterinary Surgeon San Franciso Animal Medical Center San Francisco, CA United States

Matthew S. Mellema, DVM, PhD, DACVECC Vice-President for Product Development Applaud Medical Inc. San Francisco, CA United States

Julie M. Menard, DVM, DACVECC Assistant Professor University of Calgary Department of Veterinary Clinical and Diagnostic Services Calgary, Alberta Canada

Vishal D. Murthy, DVM, DACVIM (Neurology) Assistant Professor Washington State University Department of Veterinary Clinical Sciences College of Veterinary Medicine Pullman, WA United States

Sarah E. Musulin, DVM, DACVECC Clinical Associate Professor, Emergency and Critical Care North Carolina State University Molecular Biomedical Sciences Raleigh, NC United States Director of Emergency Services Blood Bank Director NC State Veterinary Hospital

Adesola Odunayo, DVM, MS, DACVECC Clinical Associate Professor of Emergency and Critical Care University of Florida Department of Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

Maureen S. Oldach, DVM, DACVIM (Cardiology) Resident, Cardiology University of California, Davis Department of Medicine and Epidemiology School of Veterinary Medicine Davis, CA United States

Laura Osborne, BVSc Hons, DACVECC Carrie J. Miller, DVM, DACVIM Director of Internal Medicine Virginia Veterinary Specialists Charlottesville, VA United States

Criticalist Western Veterinary Specialist and Emergency Centre Calgary, Alberta Canada

James B. Miller, DVM, MS, DACVIM

Katie E. Osekavage, DVM, DACVECC

Retired Stratford Prince Edward Island Canada

Criticalist Upstate Veterinary Specialists Greenville, SC United States

Carrie A. Palm DVM, MAS, DACVIM (Internal Medicine) Professor University of California, Davis Department of Medicine and Epidemiology School of Veterinary Medicine Davis, CA United States

Romain Pariaut, DVM, DACVIM, DECVIM-CA Associate Professor of Cardiology Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca, NY United States

Medora Pashmakova, DVM, DACVECC Staff Criticalist BluePearl Veterinary Partners Clearwater, FL United States

Simon Platt, BVM&S, FRCVS, Dipl ACVIM (Neurology), Dipl ECVN Professor of Neurology University of Georgia Department of Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Céline Pouzot-Nevoret, DVM, MS, PhD, DECVECC Associate Professor, Head of the ICU (SA-ICU) SIAMU® VetAgro Sup Campus Vétérinaire, Marcy l’Etoile Rhône France

Lisa Leigh Powell, DVM, DACVECC Associate Emergency and Critical Care Clinician Blue Pearl Veterinary Partners Eden Prairie, Minnesota United States

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CONTRIBUTORS

Bruno H. Pypendop, DrMedVet, DrVetSci, DACVAA Professor Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California, Davis, Davis California United States

Jane Quandt, BS, DVM, MS, DACVAA, DACVECC Professor Department of Small Animal Medicine & Surgery University of Georgia, Athens Georgia United States

Jessica M. Quimby, DVM, PhD, DACVIM Associate Professor of Internal Medicine Department of Veterinary Clinical Sciences The Ohio State University, Columbus Ohio United States

Louisa J. Rahilly, DVM, DACVECC Medical Director Cape Cod Veterinary Specialists, Bourne Massachusetts United States

Alan G. Ralph, DVM, DACVECC Staff Criticalist MedVet, Metairie Louisiana United States

Kaitlyn Rank, DVM Resident, Emergency and Critical Care Department of Clinical Sciences Small Animal Emergency & Critical Care North Carolina State College of Veterinary Medicine, Raleigh North Carolina United States

Alan H. Rebar, DVM, PhD, DACVP

Tommaso Rosati, DVM, DACVECC

Emeritus Dean & Emeritus Professor of Veterinary Clinical Pathology College of Veterinary Medicine Purdue University, West Lafayette Indiana United States Former Vice Chancellor for Research and Innovation University Administration North Carolina State University, Raleigh North Carolina United States

Senior Clinician Department of Small Animals University of Zurich Zurich Switzerland

Erica L. Reineke, VMD, DACVECC

Elizabeth Rozanski, DVM, DACVIM (SA-IM), DACVECC

Associate Professor Emergency and Critical Care Medicine Department of Clinical Studies and Advanced Medicine University of Pennsylvania, Philadelphia Pennsylvania United States

Patricia G. Rosenstein, DVM, DACVECC Criticalist Emergency and Critical Care Animal Referral Hospital, Sydney New South Wales Australia

Associate Professor Department of Clinical Sciences Tufts Cummings School of Veterinary Medicine, North Grafton Massachusetts United States

Christin L. Reminga, DVM, DACVECC

Elke Rudloff, DVM, DACVECC, cVMA

Critical Care Specialist, DVM Manager Emergency and Critical Care DoveLewis Animal Emergency and Specialty Hospital, Portland Oregon United States

Staff Criticalist Emergency and Critical Care BluePearl Specialty + Emergency Pet Hospital, Glendale Wisconsin United States

Joris H. Robben, DVM, PhD, Dipl ECVECC, Dipl ECVIM-CA

Jonathan Schaefer, MSc, DVM, DACVECC

Associate Professor, Emergency and Critical Care Medicine Department of Clinical Sciences Faculty of Veterinary Medicine, Utrecht University, Utrecht Netherlands

Narda G. Robinson, DO, DVM, MS, FAAMA

Assistant Teaching Professor Small Animal Emergency and Critical Care University of Missouri College of Veterinary Medicine, Columbia Missouri United States

Michael Schaer, DVM, DACVIM, DACVECC

Founder and CEO Medical Education CuraCore VET, Fort Collins Colorado United States

Emeritus Professor; Adjunct Professor Emergency Medicine and Critical Care Department of Small Animal Clinical Sciences University of Florida, Gainesville Florida United States

Mark P. Rondeau, DVM, DACVIM (SAIM)

Gretchen L. Schoeffler, DVM, DACVECC

Professor of Clinical Medicine Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Clinical Professor Department of Clinical Sciences Cornell University College of Veterinary Medicine, Ithaca New York United States

Shelley C. Rankin, BSc (Hons), PhD Emeritus Professor of Microbiology School of Veterinary Medicine Department of Pathobiology University of Pennsylvania, Philadelphia Pennsylvania United States

CONTRIBUTORS

Sergi Serrano, LV, DVM, DACVECC

Kimberly Slensky, DVM, DACVECC

Staff Criticalist Emergency and Critical Care Veterinary Medical Center or Long Island, West Islip New York United States Chief Operating Officer ECCVET LLC, Norwalk Connecticut United States

Assistant Professor of Clinical Emergency and Critical Care Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Claire R. Sharp, BSc, BVMS, MS, DACVECC Associate Professor School of Veterinary Medicine Murdoch University, Murdoch Western Australia Australia

Ashley N. Sharpe, DVM Cardiology Resident Department of Medicine and Epidemiology University of California, Davis, Davis California United States

Sean D. Smarick, VMD, DACVECC

Rebecca S. Syring, DVM, DACVECC

Adjunct Associate Professor College of Science, Health, Engineering and Education Murdoch University, Murdoch Western Australia Australia Criticalist Small Animal Specialist Hospital, Tuggerah New South Wales Australia

Critical Care Specialist Veterinary Specialty and Emergency Center, Levittown Pennsylvania United States

Nadja E. Sigrist, Dr med vet, FVH, DACVECC, DECVECC

Paulo V. Steagall, MV, MSc, PhD, DACVAA

Meg M. Sleeper, VMD, DACVIM Clinical Professor of Cardiology Department of Small Animal Clinical Sciences University of Florida College of Veterinary Medicine, Gainesville Florida United States

Jane E. Sykes, BVSc (Hons), PhD, MBA, DACVIM

Lisa Smart, BVSc, DACVECC, PhD

Florence Soares-Dabalos, MS, LMFT

Professor of Small Animal Critical Care Medicine Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Doctor Department of Radiological & Surgical Sciences University of California Davis, Davis California United States

Professor Department of Medicine & Epidemiology University of California, Davis, Davis California United States

Assistant Professor, Small Animal Internal Medicine Department of Clinical Sciences Colorado State University, Fort Collins Colorado United States

Deborah C. Silverstein, DVM, DACVECC

Beverly K. Sturges, DVM, MS, MaS, DACVIM (Neurology)

Consultant North Huntingdon Pennsylvania United States

Sarah B. Shropshire, DVM, PhD, DACVIM

CEO and Owner Veterinary Emergency and Critical Care Consulting and Education Affoltern am Albis, Switzerland

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Client Support & Wellness Professional Veterinary Medical Teaching Hospital University of California, Davis, Davis California United States

Associate Professor of Veterinary Anesthesia and Pain Management Department of Clinical Sciences Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe Quebec Canada

Joshua A. Stern, DVM, PhD, DACVIM (Cardiology) Professor of Cardiology & Associate Dean for Veterinary Medical Center Operations Department of Medicine and Epidemiology School of Veterinary Medicine, University of California Davis, Davis California United States

Kelly Tart, BA, DVM, DACVECC Professor Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine, Shoreview Minnesota United States

Vincent J. Thawley, VMD, DACVECC Clinical Asst Professor—Emergency and Critical Care Medicine Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine, University of Pennsylvania, Philadelphia Pennsylvania United States

Isabelle Goy-Thollot, DVM, MS, PhD, DECVECC Project Manager VetAgro Sup Agriculture and Food Ministry, Marcy l’Étoile France

Elizabeth J. Thomovsky, DVM, MS, DACVECC Clinical Associate Professor Department of Veterinary Clinical Sciences Purdue University, West Lafayette Indiana United States

Randolph H. Stewart, DVM, PhD, DACVIM

Jeffrey Michael Todd, DVM, DACVECC

Clinical Professor Department of Veterinary Physiology & Pharmacology Texas A&M University, College Station Texas United States

Associate Professor Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine, St. Paul Minnesota United States

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CONTRIBUTORS

Carissa W. Tong, BVM&S, DACVECC Staff Criticalist VCA Canada CARE Centre Calgary Alberta Canada

Roberta Troia, DVM, PhD, DECVECC Research Fellow Department of Veterinary Sciences University of Bologna, Ozzano dell’Emilia, Bologna Italy

Yu Ueda, DVM, PhD, DACVECC Clinical Assistant Professor Department of Clinical Sciences North Carolina State University, Raleigh North Carolina United States

Kelley M. Varner, DVM, DACVAA Assistant Clinical Professor of Anesthesia Molecular Biomedical Science North Carolina State University, Raleigh, NC United States

Karen M. Vernau, DVM, MAS, DACVIM (Neurology) Clinical Professor of Neurology/ Neurosurgery Department of Surgical and Radiological Sciences University of California Davis, Davis California United States

Cecilia Villaverde, BVSc, PhD, DACVN, DECVCN Consultant Clinical Nutrition Expert Pet Nutrition, Fermoy Cork Ireland

Lance C. Visser, DVM, MS, DACVIM (Cardiology) Associate Professor of Cardiology Department of Medicine & Epidemiology University of California, Davis, Davis California United States

Lori S. Waddell, DVM, DACVECC Clinical Professor, Critical Care Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Orla Mahoney-Wages, MVB, DACVIM, DECVIM Clinical Assistant Professor Department of Clinical Sciences Tufts University, Cummings School of Veterinary Medicine, N. Grafton Massachusetts United States

Jake Wolf, DVM, DACVECC Clinical Assistant Professor Department of Small Animal Clinical Sciences University of Florida, Gainesville, FL United States

Bonnie Wright, DVM, DACVAA Ashley L. Walker, DVM Cardiology Resident Department of Medicine and Epidemiology School of Veterinary Medicine, University of California, Davis, Davis California United States

Cynthia R. Ward, VMD, PhD, DACVIM Meigs Distinguished Teaching Professor Emerita Department of Small Animal Medicine and Surgery University of Georgia College of Veterinary Medicine, Athens Georgia United States

Wendy A. Ware, DVM, MS, DACVIM (Cardiology) Professor Emerita Departments of Veterinary Clinical Sciences and Biomedical Sciences Iowa State University, Ames Iowa United States

Samantha Wigglesworth, VMD, DACVECC Criticalist Red River Animal Emergency Hospital, Fargo, ND United States

Michael D. Willard, DVM, MS, DACVIM Professor Emeritus Department of Small Animal Clinical Sciences Texas A&M University, College Station Texas United States

Kevin Winkler, DVM, DACVS Surgeon BluePearl Veterinary Partners, Atlanta Georgia United States Medical Director BluePearl Veterinary Partners, Atlanta Georgia United States

Associate Colorado Canine Orthopedics and Rehab, Colorado Springs Colorado United States Affiliate Faculty Veterinary Medicine and Biomedical Sciences Colorado State University, Fort Collins Colorado United States CEO Mistral Vet, Johnstown Colorado United States

Kathy N. Wright, DVM, DACVIM (Cardiology and Internal Medicine) Veterinary Cardiologist Cardiology and Small Animal Internal Medicine MedVet Medical and Cancer Centers for Pets, Fairfax, OH United States

Todd A. Green, DVM, MS, DACVIM (Internal Medicine) Internist VCA West Coast Specialty and Emergency Animal Hospital Los Angeles, CA United States

F O R E WO R D It is my great pleasure to introduce you to the third edition of Small Animal Critical Care Medicine. The first two editions established the text as a go-to information source for veterinarians caring for critically ill dogs and cats. This edition will further cement its reputation as a definitive resource for those who strive to improve their understanding of the pathophysiology of critical illness and how to monitor and treat it. The last three decades have witnessed remarkable growth in our capacity to provide intensive care for our sickest patients. Not that long ago, there were only a handful of people doing this, and even in teaching hospitals we sometimes struggled to convince medical and surgical colleagues of the value of collaborating with a specialist in critical care. We often “made do” with used equipment and practiced in relative isolation, relying on a knowledge of physiology and extrapolating from the young specialty in human medicine. Drs. Silverstein and Hopper were trained and mentored by one of the “founding fathers” who brought purpose and credibility to the specialty, Dr. Steve Haskins. Like Steve, they are intellectually curious, clinically gifted, professionally meticulous, and incredibly productive, as evidenced in the pages that follow. They are among the vanguard of a “second wave” of Diplomates in the American College of Veterinary Emergency and Critical Care, and their skill as researchers, teachers, and leaders in the specialty had a positive impact on the entire profession even before the inception of the first edition of this book. As early as the 1990s, many members of the American College of Veterinary Emergency and Critical Care were keen to collaborate to

publish a text that would serve as a guide and resource for the care of critically ill dogs and cats. The challenges and obstacles to success were formidable, and progress faltered. Drs. Silverstein and Hopper took it upon themselves to pick up the slack and, with characteristic efficiency and fortitude, got the job done. Thirteen years on, they prevailed yet again when, barely a year into the creation of this edition, the COVID-19 pandemic landed upon us. Despite the chaos imposed on everyone involved, they successfully guided the project to completion. Deb and Kate not only wrote much (and edited all) of the material in this book, but they also recruited a Who’s Who of experts to author the text and shepherded us through the arduous process of writing the two hundred and twelve (!) chapters contained herein. The result of this hard work is the marvelous resource you see before you. If you are new to the field of critical care (welcome!), this book will provide a very readable in-depth introduction to the pathophysiology of severe illness and how it is monitored and treated. If you are already immersed in emergency and critical care medicine, you will find this edition to be an updated, irreplaceable resource that you’ll come back to time and time again for factual support and expert advice. Bernie Hansen, DVM, MS, DACVECC, DACVIM Raleigh, North Carolina

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CONTENTS Contributors, vi Foreword, xv

PART I  Key Critical Care Concepts 1 Evaluation and Triage of the Critically Ill Patient, 1 Erica L. Reineke

2 Physical Examination and Daily Assessment of the Critically Ill Patient, 9 Timothy B. Hackett

3 Hemostasis, 15 Ronald H. L. Li

4 Cardiopulmonary Resuscitation, 22 Daniel J. Fletcher, Manuel Boller

5 Postcardiac Arrest Care, 30

24 Pneumonia, 138 Amanda K. Boag, Gretchen L. Schoeffler

25 Acute Respiratory Distress Syndrome, 149 Laura Osborne, Kate Hopper

26 Pulmonary Contusions and Hemorrhage, 154 Sergi Serrano

27 Pulmonary Thromboembolism, 161 Vincent J. Thawley

28 Chest Wall Disease, 166 Christiana Fischer, Deborah C. Silverstein

29 Pleural Space Disease, 170 Bridget M. Lyons

30 Respiratory Distress Look-Alikes, 177 Sage M. De Rosa, Deborah C. Silverstein

Manuel Boller, Daniel J. Fletcher

PART III  Advanced Respiratory Support

Armelle de Laforcade, Deborah C. Silverstein

31 High Flow Nasal Oxygen, 181

Kaitlyn Rank, Bernie Hansen

32 Mechanical Ventilation—Core Concepts, 185

Duana McBride

33 Mechanical Ventilation—Advanced Concepts, 193

Lisa Smart, Deborah C. Silverstein

34 Jet Ventilation, 198

James B. Miller

35 Ventilator Waveforms, 201

Randolph H. Stewart

36 Anesthesia and Monitoring of the Ventilator Patient, 212

Matthew S. Mellema

37 Nursing Care of the Ventilator Patient, 219

Galina Hayes, Karol Mathews

38 Discontinuing Mechanical Ventilation, 223

6 Classification and Initial Management of Shock States, 37 7 SIRS, MODS, and Sepsis, 42 8 Oxygen Toxicity, 49

9 The Endothelial Surface Layer, 55 10 Hyperthermia and Fever, 61 11 Interstitial Edema, 67 12 Patient Suffering in the Intensive Care Unit, 72 13 Predictive Scoring Systems in Veterinary Medicine, 75

Iain Keir

Kate Hopper

Kimberly Slensky, Deborah C. Silverstein Bruno H. Pypendop

Matthew S. Mellema

Kimberly Slensky, Ciara A. Barr

Simon P. Hagley, Steven E. Epstein Kate Hopper

PART II  Respiratory Disorders

39 Ventilator-induced Lung Injury, 227

14 Control of Breathing, 80

40 Ventilator-Associated Pneumonia, 232

Kate S. Farrell

15 Oxygen Therapy, 85

Steven E. Epstein

Elisa M. Mazzaferro

Part IV  Cardiovascular Disorders

Steve C. Haskins, Deborah C. Silverstein

41 Mechanisms of Heart Failure, 238

Meredith L. Daly

42 Ventricular Failure and Myocardial Infarction, 243

Dana L. Clarke

43 Feline Cardiomyopathy, 246

16 Hypoxemia, 89

17 Hypoventilation, 95

18 Upper Airway Disease, 101 19 Tracheal Collapse: Management & Indications for Tracheal Stents, 113 Dana L. Clarke

20 Feline Bronchopulmonary Disease, 119 Elizabeth Rozanski, Gareth J. Buckley

21 Lower Airway Disease in Dogs, 122 Lynelle R. Johnson

22 Pulmonary Hypertension, 127 Lance C. Visser, Yu Ueda

23 Pulmonary Edema, 132 Sophie Adamantos, Dez Hughes

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Lisa Smart, Kate Hopper

Mark A. Oyama

Sara R. Brethel, Meg M. Sleeper

Joshua A. Stern, Maureen S. Oldach

44 Canine Cardiomyopathy, 255 Joanna L. Kaplan, Joshua A. Stern

45 Canine Myxomatous Mitral Valve Disease, 260 Ashley N. Sharpe, Lance C. Visser

46 Blunt Cardiac Injury, 266 Maureen S. Oldach

47 Pericardial Diseases, 271 Wendy A. Ware

48 Bradyarrhythmias and Conduction Disturbances, 279 Romain Pariaut

CONTENTS

49 Supraventricular Tachyarrhythmias, 283 Teresa C. DeFrancesco

50 Ventricular Tachyarrhythmias, 291 Romain Pariaut

51 Myocarditis, 296 Sara R. Brethel, Meg M. Sleeper

52 Cardiac Biomarkers, 300 Mark A. Oyama

53 Systemic Hypertension, 304

73 Diabetic Ketoacidosis, 432 Sabrina N. Hoehne

74 Hyperglycemic Hyperosmolar Syndrome, 438 Amie Koenig

75 Hypoglycemia, 444 Amie Koenig

76 Diabetes Insipidus, 451 Melissa A. Claus

Edward S. Cooper

77 Syndrome of Inappropriate Antidiuretic Hormone Secretion, 454

Thomas D. Greensmith, Dominic Barfield

78 Thyroid Storm, 457

54 Cardiopulmonary Bypass, 309

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Kate Hopper

Cynthia R. Ward

PART V  Electrolyte and Acid-Base Disturbances

79 Hypothyroid Crisis in the Dog, 461

55 Sodium Disorders, 316

80 Pheochromocytoma, 465

Jamie M. Burkitt Creedon

56 Potassium Disorders, 326 Samantha Wigglesworth, Michael Schaer

57 Calcium Disorders, 333

Joao Felipe de Brito Galvao, Dennis J. Chew, Todd A. Green

58 Magnesium and Phosphate Disorders, 342

Rebecka S. Hess

Kari Santoro Beer

81 Critical Illness-Related Corticosteroid Insufficiency, 470 Jamie M. Burkitt Creedon

82 Hypoadrenocorticism, 475 Jamie M. Burkitt Creedon

Linda G. Martin, Ashley E. Allen-Durrance

PART VIII  Neurologic Disorders

Kate Hopper

83 Neurological Evaluation of the ICU Patient, 480

Kate Hopper

84 Seizures and Status Epilepticus, 489

Patricia G. Rosenstein, Dez Hughes

85 Intracranial Hypertension, 494

Justin Duval, Kate Hopper

86 Tetanus, 502

59 Traditional Acid-Base Analysis, 350 60 Nontraditional Acid-Base Analysis, 357 61 Hyperlactatemia, 362 62 Urine Osmolality and Electrolytes, 369

Marguerite F. Knipe

Chai-Fei Li, Karen M. Vernau

Chai-Fei Li, Beverly K. Sturges Simon Platt

PART VI  Fluid Therapy 63 Assessment of Hydration, 373

87 Hepatic Encephalopathy, 506 Alex Lynch

Elke Rudloff

Part IX  Infectious Disorders

Søren R. Boysen, Kris Gommeren

88 Hospital-Associated Infections and Zoonoses, 510

64 Assessment of Intravascular Volume, 378 65 Crystalloids and Hemoglobin-Based Oxygen-Carrying Solutions, 386 Ta-Ying Debra Liu, Deborah C. Silverstein

66 Colloid Solutions, 391

Steven J. Centola, Deborah C. Silverstein

67 Daily Intravenous Fluid Therapy, 396 Natalie Kovak, Deborah C. Silverstein

68 Shock Fluids and Fluid Challenge, 402 Anusha Balakrishnan, Deborah C. Silverstein

69 Transfusion Medicine, 409 Sarah E. Musulin

70 Blood Types, Pretransfusion Compatibility, and Transfusion Reactions, 416

Shelley C. Rankin

89 Febrile Neutropenia, 513 Melissa A. Claus

90 Sepsis and Septic Shock, 519 Elise Mittleman Boller, Deborah C. Silverstein

91 Bacterial Infections, 527 Stephen Cole

92 Fungal Infections, 532 Elizabeth J. Thomovsky

93 Viral Infections, 538 Jane E. Sykes

94 Canine Parvovirus Infection, 544 Rachael Birkbeck, Karen Humm

Sarah E. Musulin

95 Infective Endocarditis, 549

Corrin Boyd, Lisa Smart

96 Urosepsis, 557

71 Hemorrhagic Shock, 422

Kristin A. MacDonald, Steven E. Epstein Lillian Ruth Aronson

PART VII  Endocrine Disorders

97 Necrotizing Soft Tissue Infections, 564

72 The Diabetic Patient in the ICU, 429

98 Catheter-Related Bloodstream Infections, 569

Elizabeth Rozanski, Orla Mahoney-Wages

Elke Rudloff, Kevin Winkler Christin L. Reminga

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CONTENTS

  99 Multidrug-Resistant Infections, 576 Steven E. Epstein

100 Infectious Disease Control in the ICU, 580 Timothy B. Hackett

PART X  Hematologic Disorders 101 Hypercoagulable States, 584 Alan G. Ralph, Benjamin M. Brainard

102 Feline Aortic Thromboembolism, 595 Julien Guillaumin

103 Platelet Disorders, 599 Ronald H.L. Li

104 Coagulopathy in the ICU, 608 Alex Lynch

105 Management of the Bleeding Patient in the ICU, 615 Yekaterina Buriko

106 Anemia in the ICU, 619 Alex Lynch

107 Dyshemoglobinemias, 624

PART XIII  Nutrition 124 Nutritional Assessment, 729 Cecilia Villaverde, Jennifer A. Larsen

125 Nutritional Modulation of Critical Illness, 735 Daniel L. Chan

126 Enteral Nutrition, 740 Daniel L. Chan

127 Parenteral Nutrition, 746 Daniel L. Chan

PART XIV  Trauma 128 Traumatic Brain Injury, 751 Rebecca S. Syring, Daniel J. Fletcher

129 Wound Management, 756 Caroline K. Garzotto

130 Thermal Burn Injury, 765 Caroline K. Garzotto

Louisa J. Rahilly, Deborah C. Mandell

PART XV  Anesthesia and Pain Management

Leah A. Cohn

131 Pain Assessment, 770

108 Acute Hemolytic Disorders, 632

Alessia Cenani, Linda S. Barter

PART XI  Intraabdominal Disorders

132 Sedation of the Critically Ill Patient, 776

109 Acute Abdominal Pain, 640

133 Anesthesia in the Critically Ill Patient, 778

Kenneth J. Drobatz

110 Acute Pancreatitis, 644 Jennifer M. Good

111 Acute Cholecystitis, 651 Mark P. Rondeau

112 Hepatitis and Cholangiohepatitis, 655 Mark P. Rondeau

113 Hepatic Failure, 660

Giacomo Gianotti Jane Quandt

134 Analgesia and Constant Rate Infusions, 787 Jane Quandt

135 Physical Rehabilitation for the Critical Care Patient, 795 Molly J. Flaherty

136 Integrative Veterinary Medicine for the Intensive Care Unit Patient, 800 Narda G. Robinson

Allyson Berent

114 Portal Hypertension, 668 Andrea N. Johnston

115 Portosystemic Shunt Management, 675 Margo Mehl

116 Acute Gastroenteritis, 680 Adesola Odunayo

117 Gastrointestinal Hemorrhage, 685 Søren R. Boysen

118 Regurgitation and Vomiting, 691 Peter S. Chapman

119 Diarrhea, 696 Daniel Z. Hume

120 Peritonitis, 701 Kelly Tart

PART XVI  Environmental Emergencies 137 Smoke Inhalation, 804 Tommaso Rosati, Kate Hopper

138 Hypothermia, 810 Jeffrey Michael Todd

139 Heat Stroke, 817 Kenneth J. Drobatz

140 Drowning and Submersion Injury, 822 Lisa Leigh Powell

PART XVII  Miscellaneous Disorders 141 Anaphylaxis, 826 Medora Pashmakova

PART XII  Urogenital Disorders

142 Gas Embolism, 831

121 Acute Kidney Injury, 706

143 Subcutaneous Emphysema, 835

Catherine E. Langston, Adam E. Eatroff

122 Chronic Kidney Disease, 713

Catherine E. Langston, Adam E. Eatroff

123 Kidney Transplantation, 721 Lillian Ruth Aronson

Bonnie Wright

Carissa W. Tong, Anusha Balakrishnan

144 Ocular Disease in the Intensive Care Unit, 840 Kathryn Good

145 Critically Ill Neonatal and Pediatric Patients, 845 Maureen A. McMichael, Katherine K. Gerken

146 Critically Ill Geriatric Patients, 851

Maureen A. McMichael, Katherine K. Gerken

CONTENTS

PART XVIII  Pharmacology

175 Fluoroquinolones, 1001

147 Catecholamines, 855

176 Antifungal Therapy, 1007

Samantha Hart, Deborah C. Silverstein

148 Vasopressin, 861

Deborah C. Silverstein, Samantha Hart

149 Antihypertensives, 867

Jonathan Schaefer, Deborah C. Silverstein Marie E. Kerl

177 Miscellaneous Antibiotics, 1011 Julie M. Menard

Edward S. Cooper

PART XX  Extracorporeal Therapy

Joshua A. Stern, Ashley L. Walker

178 Renal Replacement Therapies, 1017

Thierry Francey

179 Apheresis, 1022

Jessica M. Quimby

180  Extracorporeal Therapies for Blood Purification, 1026

150 Pimobendan, 872 151 Diuretics, 877

152 Appetite Stimulants, 882 153 Gastrointestinal Protectants, 886 Michael D. Willard

154 Antiemetics and Prokinetics, 890

Carrie A. Palm, Lucy Kopecny Carrie A. Palm, Lucy Kopecny

Katie D. Mauro, Megan E. McClosky

Michael D. Willard, Ralph C. Harvey

Part XXI  Monitoring

Ralph C. Harvey

181 Hemodynamic Monitoring, 1030

Ralph C. Harvey

182 Cardiac Output Monitoring, 1037

Bruno H. Pypendop

183 Electrocardiogram Evaluation, 1043

Bea Monteiro, Paulo V. Steagall

184 Oximetry Monitoring, 1049

Tamara Grubb

185 Colloid Osmotic Pressure and Osmolality, 1054

Tania Perez Jimenez

186 Coagulation and Platelet Monitoring, 1059

Ciara A. Barr, Kelley M. Varner

187 Viscoelastic Monitoring, 1064

155 Opioid Agonists and Antagonists, 895 156 Benzodiazepines, 902 157 a2-Agonists and Antagonists, 905 158 Nonsteroidal Antiinflammatory Drugs, 911 159 Gabapentin, 919 160 Tramadol, 922 161 Trazodone, 925

162 Cannabinoid Medicine in Intensive Care Unit Patients, 928 Narda G. Robinson

163 Anticonvulsants, 932 Adam Moeser

164 Antiplatelet Drugs, 937 Benjamin M. Brainard, Sarah B. Shropshire

165 Anticoagulants, 943

Benjamin M. Brainard, Amy Dixon-Jimenez

166 Thrombolytic Agents, 951 Julien Guillaumin

Lori S. Waddell

Edward S. Cooper

Marc S. Kraus, Anna R.M. Gelzer Kate S. Farrell

Lori S. Waddell Claire R. Sharp

Anthony Barthélemy, Céline Pouzot-Nevoret, Isabelle Goy-Thollot

188 Intraabdominal Pressure Monitoring, 1071 Guillaume Laurent Hoareau

189 Point-of-Care Ultrasound in the ICU, 1076 Kris Gommeren, Søren R. Boysen

190 Capnography, 1093 Bruno H. Pypendop

191 Intracranial Pressure Monitoring, 1097 Beverly K. Sturges

192 Urine Output, 1103 Sean D. Smarick

167 Hemostatic Drugs, 956 Katie E. Osekavage, Benjamin M. Brainard

PART XXII  Procedures

Kathy N. Wright

193 Peripheral Venous Catheterization, 1107

Carrie J. Miller

194 Intraosseous Catheterization, 1112

Jenna H. Burton

195 Central Venous Catheterization, 1117

Robert A. Armentano, Michael Schaer

196 Blood Film Evaluation, 1125

168 Antiarrhythmic Agents, 961 169 Inhaled Medications, 967

170 Complications of Chemotherapy Agents, 972 171 Antitoxins and Antivenoms, 978

Harold Davis

Massimo Giunti, Roberta Troia Harold Davis

Alan H. Rebar

PART XIX  Antimicrobial Therapy

197 Endotracheal Intubation and Tracheostomy, 1131

172 Antimicrobial Use in the Critical Care Patient, 983

198 Thoracocentesis, 1137

Steven E. Epstein

173 b-Lactam Antimicrobials, 991 Steven E. Epstein

174 Aminoglycosides, 995 Julie M. Menard

Mack Fudge

Nadja E. Sigrist

199 Thoracostomy Tube Placement and Drainage, 1141 Nadja E. Sigrist

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xx

CONTENTS

Karl E. Jandrey

PART XXIII Intensive Care Unit Design and Management

Elisa M. Mazzaferro

209 Intensive Care Unit Facility Design, 1187

Jake Wolf, Deborah C. Silverstein

210 Management of the Intensive Care Unit, 1196

Teresa C. DeFrancesco

211 Client Communication, Grief, and Veterinary Wellness, 1200

200 Abdominocentesis, 1146 201 Arterial Catheterization, 1149 202 Blood Gas Sampling, 1153 203 Temporary Cardiac Pacing, 1157 204 Cardioversion, 1163 Romain Pariaut

205 Defibrillation, 1166 Gareth J. Buckley

206 Cerebrospinal Fluid Sampling and Interpretation, 1169 Vishal D. Murthy, Beverly K. Sturges

207 Urinary Catheterization, 1175 Sean D. Smarick

208 Urinary Diversion Techniques, 1181 Erin A. Gibson, Ingrid M. Balsa

Joris H. Robben

Amanda Arrowood, Lori S. Waddell Florence Soares-Dabalos

212 Prevention of Compassion Fatigue and Burnout, 1205 Marie K. Holowaychuk

Appendices, 1212 Index, 1218

VIDEO TO C Video 28-1: This video illustrates flail chest in a dog. Video 28-2: This video illustrates Polyradiculoneuritis in a dog with abdominal breathing. Video 83-1: This video illustrates and explains differences between some acute postures seen in patients with neurological injury Video 83-2: This video demonstrates the cranial nerve exam and illustrates related anatomy for interpretation Video 86-1: This video illustrates a 7yr old male neutered mix breed dog with an ‘exercise intolerance’ causing tetraparesis with limited activity. Video 95-1: This video illustrates mitral valve endocarditis in a dog.

Video 95-2: This video illustrates concurrent mitral and aortic infective endocarditis in a dog. Video 135-1: This video illustrates passive range of motion (PROM) forelimb. Video 135-2: This video illustrates passive range of motion (PROM) hindlimb. Video 198-1: This video illustrates over-the-needle thoracocentesis in a cat. Video 206-1: This video shows the patient positioning and collection of a cerebellomedullary cisternal CSF sample. Video 206-2: This video shows the patient positioning and collection of a lumbar cistern CSF sample.

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PART I   Key Critical Care Concepts

1 Evaluation and Triage of the Critically Ill Patient Erica L. Reineke, VMD, DACVECC KEY POINTS • Critically ill or hospitalized animals may deteriorate suddenly due to several disease complications or progression of disease. • A systematic approach to a deteriorating critically ill patient includes an initial evaluation of the respiratory, cardiovascular, and neurologic systems to guide immediate stabilizing interventions

followed by a more complete physical examination and medical record review. • Point-of-care blood testing and ultrasound are used alongside the physical examination to determine the cause of the patient’s deterioration and direct additional therapies and diagnostic testing.

INTRODUCTION

animal is assessed. Nurses may also play a vital role in this step by notifying veterinarians of a deteriorating patient, thereby helping to identify and prioritize which critically ill animals may need immediate intervention. The decision regarding which animal should be addressed first is typically based on the recognition of a change in vital signs such as tachypnea, increased respiratory effort, tachycardia, hypotension, change in mentation, or metabolic disturbances such as hypoglycemia or acidemia. Table 1.1 and Table 1.2 illustrate physical examination and diagnostic findings that may be identified in deteriorating patients.

Critical illness, secondary to diseases such as trauma, sepsis, pancreatitis, immune mediated disease, neoplasia and pneumonia, can cause significant metabolic derangements that require intensive care to sustain life or enhance metabolic stability.1 These conditions may result in tissue hypoperfusion and hypoxia, ultimately triggering a cascade of events including severe systemic inflammation that could result in multiple organ dysfunction and death.2 Organ dysfunction that may occur in critically ill animals includes respiratory dysfunction such as acute respiratory distress syndrome and pulmonary thromboembolism; cardiovascular dysfunction such as left ventricular dysfunction, arrhythmias and vasopressor dependent hypotension; gastrointestinal tract dysfunction such as gastric stasis and ileus, hemorrhagic diarrhea and bacterial translocation, hepatic dysfunction, and acute kidney injury; and coagulation abnormalities such as disseminated intravascular coagulation resulting in thrombosis and bleeding.3 As a result of organ dysfunction, progression of underlying disease, or complications of treatment, all hospitalized critically ill animals are at risk for sudden deterioration. A systematic approach to an acutely deteriorating critically ill patient is essential in order to quickly recognize and institute life-saving therapies. This approach consists of a primary survey followed by a more thorough secondary survey (i.e., complete physical examination), which includes a review of available medical records. Point-ofcare ultrasound, blood tests, and other cage side diagnostics are used alongside the primary survey to direct therapeutic interventions and guide additional diagnostic testing. If multiple critically ill patients require evaluation at the same time, as often occurs in a busy intensive care unit, the animal with the most life-threatening abnormalities (e.g., those with impending respiratory failure, hypotension, or severe cardiac arrhythmias) should be assessed first and life-saving interventions initiated (i.e., administration of an intravenous fluid bolus for hypotension or supplementation oxygen administration) before the next

PRIMARY SURVEY The primary survey is a rapid assessment of the animal’s respiratory, cardiovascular, and neurologic systems.4 While this assessment is being performed, a brief patient medical and surgical history, medications, and current nursing concerns can be relayed to the veterinarian.

Respiratory System Evaluation Evaluation of the respiratory system is focused on determining the presence or absence of hypoxemia or hypoventilation. In patients with an increased respiratory rate and effort, the airway should be assessed first followed by thoracic auscultation and evaluation of the chest wall and diaphragm. During the patient evaluation, oxygen supplementation typically via mask or flow-by should be provided until more objective assessments for hypoxemia are made. Although tachypnea can indicate the presence of hypoxemia, it can also be associated with concurrent hypovolemia, metabolic acidosis, pain, and abdominal distension, and other nonrespiratory disease. Therefore, a complete evaluation of the animal, including point-of-care bloodwork and ultrasound (see below), should be performed. If the patient is not breathing, immediate endotracheal intubation should be performed, and positive pressure ventilation should be initiated. A patient with respiratory arrest should also be evaluated for

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PART I  Key Critical Care Concepts

TABLE 1.1  Diagnostic Findings that May

Signal the Deterioration of a Critically Ill Patient

SpO2 ,95% or PaO2 ,80 mm Hg PaCO2 .50 mm Hg SBP ,90 mm Hg Lactate .2.5 mmol/L pH ,7.35 Base deficit ,24 mmol/L (dog) or ,25 mmol/L (cat) BG ,60 mg/dl or .180 mg/dl Na .160 mEq/L or ,130 mEq/L K .6.0 mEq/L or ,3 mEq/L iCa ,0.8 mmol/L Creatinine .2 mg/dl or rise in creatinine by 0.3 mg/dl from baseline or suspected oliguria or anuria Cardiac arrhythmias White blood cell count (3 103) ,6 or .16; .3% bands Thrombocytopenia PT or PTT prolongation of .25%

TABLE 1.2  Physical Examination Findings That May Signal Deterioration During Critical Illness Mentation Mucous membranes Capillary refill time Heart rate

Respiratory rate Temperature Pulse quality

Obtunded, Stuporous, Comatose, or Sudden Change in Mentation Pale pink, white, injected/dark pink or red .2 s or ,1 s Cats: .220 bpm, ,160 bpm Small-breed dogs: .160 bpm Large-breed dogs: .100 bpm .20 breaths/min (dog), .40 breaths/min (cat) Stridor/stertor ,100.58F (38.18C) or .102.58F (39.28C) Absent or weak femoral or pedal pulses Narrow or wide pulse pressure

cardiac arrest and chest compressions initiated depending on the resuscitation status of the patient (i.e., do not resuscitate versus cardiopulmonary resuscitation). The presence of stertor or stridor, along with an increased inspiratory effort, indicates upper airway obstruction.5 Airway obstruction is more likely to occur in brachycephalic dogs, dogs with a history of coughing and diagnosed or suspected to have tracheal or mainstem bronchial collapse, or in dogs with underlying laryngeal dysfunction. Additionally, airway obstruction may also occur in animals that have traumatic injuries to the neck or skull or secondary to orofacial surgery as a result of hemorrhage and/or progressive swelling. Stabilizing interventions for patients with upper airway obstruction may include administration of sedatives, cooling measures if hyperthermic, and antiinflammatory medications. If airway obstruction is severe, endotracheal intubation and tracheostomy may be needed depending on the underlying disease. Next, auscultation of the trachea and thorax should be performed along with an evaluation of the mucous membrane color. It is important to note that cyanotic mucous membranes are a late and severe sign of hypoxemia. Dull lung sounds on thoracic auscultation are most commonly associated with pleural space disease; however, severe consolidation of lung parenchyma can also contribute to dull lung

sounds.5 Pleural effusion may develop in critically ill patients secondary to the systemic inflammatory response syndrome and endothelial damage resulting in leakage of fluid, severe hypoalbuminemia, massive pulmonary thromboembolism and right-sided heart failure, fluid overload in cats, and following thoracic surgery, for example. A pneumothorax may develop spontaneously due to ruptured pulmonary bulla in dogs, secondary to severe asthma in cats, following blunt or penetrating thoracic trauma, postthoracic or diaphragmatic surgery, as a complication of needle thoracocentesis, or due to barotrauma from anesthesia or mechanical ventilation. If pleural space disease is suspected, point-of-care ultrasound and needle thoracocentesis should be performed, if indicated, as soon as possible. Additional diagnostic evaluation, including thoracic radiography, echocardiography, and/or computed tomography could be considered on a case-by-case basis (see Chapter 29, Pleural Space Disease). On thoracic auscultation, increased breath sounds and pulmonary crackles or wheezes are associated with the development of pulmonary parenchymal disease.5 Animals with gastrointestinal dysfunction and neurologic disease and those needing aggressive pain management (especially opioid medications) are at high risk for regurgitation, vomiting, and the development of aspiration pneumonia, which may cause acute respiratory distress. It is not uncommon for regurgitation and aspiration events to be unwitnessed. Other causes of pulmonary parenchymal disease in critically ill patients include acute lung injury and acute respiratory distress syndrome, fluid overload and congestive heart failure, and pulmonary thromboembolism. Identified risk factors in veterinary patients for the development of acute lung injury and acute respiratory distress syndrome include systemic inflammatory response syndrome, sepsis, infection, smoke inhalation, near drowning, and severe trauma.6,7 Point-of-care lung ultrasound at the cage side may help to confirm the presence of parenchymal disease (see Chapter 189, Point of Care Ultrasound in the ICU), but ultimately thoracic radiography will be the first step in diagnosing the underlying cause. Additionally, echocardiography and/or computed tomography may also be necessary. During the respiratory assessment, a noninvasive assessment of oxygenation via pulse oximetry should be obtained. A pulse oximetry reading of at least 95% is normal; values less than 95% (corresponding to a partial pressure of oxygen [PaO2] of less than 80 mm Hg) indicate hypoxemia.8 Arterial blood gas analysis, although more invasive than pulse oximetry, can also be performed to determine if hypoxemia and/or hypoventilation is present. Hypoxemia is defined as a PaO2 ,80 mm Hg when breathing room air whereas hypoventilation is defined as a partial pressure of carbon dioxide (PaCO2) .50 mm Hg (see Chapter 16, Hypoxemia).9 A PaO2 to fraction of inspired oxygen (FiO2) ratio can be calculated in animals receiving oxygen supplementation with ratios of ,300 suggesting acute lung injury and ,200 suggestive of acute respiratory distress syndrome.6 When arterial blood gas analysis cannot be performed, an oxygen saturation (SpO2) to FiO2 ratio can be calculated on spontaneously breathing dogs as a surrogate assessment of hypoxemia.10 Hypoventilation may occur in patients in the immediate postoperative period secondary to anesthesia or in those treated with opioids, benzodiazepines, or other respiratory depressant medications, in patients with cervical myelopathy, thoracic trauma or pain, secondary to intoxications, neuromuscular disease, or central nervous system pathology. If hypoxemia is suspected or confirmed, supplemental oxygen therapy (either by mask, flow-by or cage) should be instituted immediately, if not already provided, and the clinical response to treatment should be evaluated. Supplemental oxygen should be administered to all animals with tachypnea and increased respiratory effort to try and decrease the work of breathing, even if the pulse oximetry reading

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient (.95%) is normal. Additional therapeutics such as administration of a diuretic, bronchodilator, and antibiotics should be made on a caseby-case basis depending on the underlying disease process suspected or confirmed via additional diagnostic evaluation. For patients with hypoventilation, the specific underlying cause should be addressed, e.g., reversal of respiratory depressant medication or administration of analgesic medications to patients with thoracic injury.

Cardiovascular System Evaluation The evaluation of the cardiovascular system is performed to identify poor tissue perfusion resulting in decreased tissue oxygen delivery. Conditions that may develop in critically ill patients and result in poor tissue perfusion include hypovolemia secondary to gastrointestinal dysfunction with fluid and electrolyte losses from vomiting/regurgitation and diarrhea, third space losses of fluid due to systemic endothelial damage and vascular leak, massive urinary losses of fluid (e.g., postobstructive diuresis), hemorrhage, severe hypoalbuminemia, cardiac disease and ventricular dysfunction, cardiac arrhythmias, cardiac tamponade, and vasodilatory states such as sepsis or systemic inflammatory response syndrome (SIRS). Animals identified as having poor tissue perfusion should receive rapid therapy and the underlying cause for the shock identified as soon as possible. Physical examination findings consistent with poor tissue perfusion include pale mucous membranes, prolonged capillary refill time, tachycardia (or bradycardia in cats), tall and narrow pulse profile, and poor or absent peripheral pulses. In vasodilatory states such as sepsis and SIRS, the mucous membranes may be red (primarily in dogs) with a shortened capillary refill time and peripheral pulses may be widened due to a lower diastolic pressure. The absence of peripheral pulses is a specific indicator of hypotension (systolic blood pressure ,90 mm Hg); however the presence of palpable pulses does not rule out hypotension and a blood pressure measurement should be obtained.11,12 Additionally, animals with alterations in systemic perfusion frequently have a dull mentation, heart sounds may be quiet, the body temperature may be low, and the extremities are often cool to the touch (see Table 1.2).13 A rectal-interdigital (temperature taken between the third and fourth digit in the pelvic limb) temperature gradient can be performed; a gradient of 211.6°F is suggestive of shock in dogs.14 It is important for the veterinarian to recognize that animals in the early stages of compensatory shock may only have mild changes in their cardiovascular parameters (i.e., heart rate and pulse quality). It may not be until the late stages of shock (or decompensated shock) that marked changes (i.e., tachycardia, weak pulses) in these cardiovascular parameters are recognized (see Chapter 6, Classification and Initial Management of Shock States). Animals that are assessed in the early stages of shock may initially appear stable and treatment thereby delayed; this could result in patient deterioration and subsequently a worse outcome. Therefore, careful evaluation of the cardiovascular parameters in conjunction with the patient’s clinical history and comparisons to previous measurements should be performed to determine if shock might be present. If there is concern during the primary survey that the patient may be in shock, more objective measurements of the cardiovascular system should be performed and/or therapy should be instituted (such as administration of an intravenous fluid bolus) while the patient’s response to treatment is assessed. Objective assessments of the cardiovascular system during the cardiovascular evaluation may include an electrocardiographic tracing to evaluate for cardiac arrhythmias (both tachycardias and bradyarrhythmias) that may be affecting cardiac output and a noninvasive blood pressure measurement. Cardiac arrhythmias may develop secondary to abnormalities such as hyperkalemia, cardiac ischemia, intraabdominal disease, underlying cardiac disease, and central nervous system disease.

3

A Doppler blood pressure measurement less than 90 mm Hg is considered low and may represent shock in both cats and dogs. Once a blood pressure measurement has been obtained, a shock index (heart rate divided by blood pressure) can be calculated with shock index .1.0 (dogs) or .1.6 (cats) identifying the possible presence of shock. This may be especially useful in patients with early compensatory shock where vital signs and systemic perfusion are not significantly different from normal.15-18 A blood lactate measurement is another useful diagnostic test that can aid in assessing for the presence of poor perfusion to the tissues. Under conditions of hypoxia, cells switch to anerobic metabolism and lactate will be produced. A blood lactate concentration .2.5 mmol/L may be indicative of systemic hypoperfusion, although other conditions such as sepsis may lead to elevated lactate levels (see Chapter 61, Hyperlactatemia).19-21 It is important to note that no single variable, whether subjective or objective, can provide an accurate and consistent estimate of the adequacy of global tissue perfusion, and all variables mentioned to determine the adequacy of systemic perfusion should be assessed within the clinical context of the patient.

Neurologic System Evaluation Evaluation of the animal’s neurologic system should include an evaluation of mentation (level of consciousness), brainstem reflexes (pupil size, pupillary light responses and physiologic nystagmus), and motor ability (see Chapter 83, Neurologic Evaluation of the ICU Patient). A modified Glasgow Coma Scale score can be calculated serially in critically ill patients with neurologic disease allowing for comparison over time.22 Problems affecting the neurologic system that require immediate stabilizing interventions include seizures and altered mental state such as stupor or coma. Patients with known or suspected intracranial disease, such as traumatic brain injury, meningoencephalitis or neoplasia, may develop seizures during hospitalization. In critically ill patients without primary intracranial disease, new onset seizures may occur secondary to a variety of extracranial causes, including rapid decreases in blood glucose causing cerebral edema which may occur in a diabetic patient receiving insulin, secondary to neuroglycopenia (a blood glucose ,60 mg/dl), rapid decreases in blood sodium concentration causing cerebral edema, brain hemorrhage or thrombosis, secondary to hepatic encephalopathy, following congenital portosystemic shunt ligation, or secondary to medication administration such as enrofloxacin or dobutamine. Seizures should be treated immediately since prolonged seizure activity can result in hyperthermia, cerebral edema and irreversible brain injury, regardless of the underlying cause of the seizures (see Chapter 84, Seizures and Status Epilepticus).23 A patient that experiences new onset seizures during hospitalization should have blood glucose and blood electrolytes assessed immediately in addition to a medical chart evaluation to rule out drug-induced seizures. Increased intracranial pressure, which may occur secondary to intracranial disease such as traumatic brain injury, neoplasia, or inflammatory brain diseases or due to extracranial causes such as hepatic encephalopathy, should be suspected in any animal with a severely altered mental status (see Section VIII, Neurologic Disorders). Additionally, disequilibrium syndrome has been documented in animals following hemodialysis or relief of urinary tract obstruction due to rapid changes in plasma osmolality that result in cerebral edema and elevations in intracranial pressure.24,25 On cardiovascular examination, animals with elevations in intracranial pressure may exhibit the Cushing reflex characterized by bradycardia and hypertension. Prolonged elevations in intracranial pressure can lead to ischemia of the brain and herniation through the foramen magnum.23 Therefore, animals with altered mental status should have stabilizing therapies initiated

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PART I  Key Critical Care Concepts

immediately, such as administration of hyperosmotic agents (i.e., mannitol or hypertonic saline) and placement on a slant board to elevate the head and neck 15 to 30 degrees to decrease cerebral blood volume through increased venous drainage. Additionally, as changes in mentation may precede the onset of seizures, point-of-care blood work should be obtained, including an evaluation of blood glucose, electrolytes, and a blood ammonia in animals with suspected hepatic encephalopathy. A blood pressure measurement should be obtained to evaluate for both hypotension and hypertension, which can lead to altered mentation in addition to other neurologic signs. Severely altered mental status can be seen in patients with severe hypotension and impending cardiopulmonary arrest due to cerebral hypoxia, whereas changes in mentation due to systemic hypertension may occur secondary to cerebral hemorrhage, infarction, and edema.26-29 In animals in which acute brain herniation is suspected, such as those with decerebrate rigidity characterized by stupor or coma and extended front and pelvic limbs, tracheal intubation and mechanical ventilation should be instituted to temporarily lower arterial blood carbon dioxide levels in addition to the aforementioned treatment strategies. This will result in cerebral vasoconstriction, thereby lowering intracranial pressure, and could be considered for short-term management of marked elevations in intracranial pressure. Once the initial assessment of the cardiovascular, respiratory, and neurologic systems has been performed and stabilizing therapies instituted, a more thorough secondary assessment of the animal should be undertaken. This more thorough assessment should include a review of the patient history including past medical problems and chart review including medications administered. A more formal and complete physical examination of all body systems should be performed, including but not limited to abdominal palpation to assess for acute abdominal pain and investigation of urine output to assess for the development of oligoanuria or anuria.

SUPPORTING DIAGNOSTICS Point-of-Care Bloodwork In addition to the physical examination, point-of-care blood testing such as a packed cell volume, total solids via refractometry, blood glucose, blood gas analysis, lactate, electrolytes, and creatinine are important parameters for evaluating the acutely deteriorating critically ill animal. Most benchtop venous blood gas analyzers are able to provide this information rapidly and use minimal amounts of blood. These blood values provide useful diagnostic information about the animal and may help guide emergent therapeutic interventions. Additionally, tracking changes in these values may indicate a need to adjust interventions, progression of illness, or the development of complications. For example, a postoperative patient that has a deteriorating cardiovascular status with a new onset fever and hypoglycemia could indicate sepsis; possible sites of infection should be investigated (including surgical and catheter sites), blood cultures obtained, and initiation or adjustments to the antimicrobial therapy should be considered. The packed cell volume can be measured to assess for hemorrhage or severe anemia. Hemorrhage, reflected by a decreasing packed cell volume and total solids, may occur as a complication of major thoracic or abdominal surgery, secondary to disseminated intravascular coagulation, or gastrointestinal hemorrhage resulting from gastrointestinal dysfunction and/or ulceration (see Chapter 71, Hemorrhagic Shock). Gastrointestinal ulceration and hemorrhage are seen most commonly in critically ill patients as a complication of hypoperfusion, in patients administered steroids, secondary to hepatic failure, underlying gastrointestinal tract disease (i.e., severe inflammatory bowel disease or lymphoma), or as a complication of gastrointestinal tract surgery or

portosystemic shunt ligation due to portal hypertension. A decrease in total solids via refractometer, reflecting hypoalbuminemia, may also suggest hemorrhage, losses of albumin from the gastrointestinal tract or urinary system, or decreased albumin production due to hepatic dysfunction. Patients with severe hypoalbuminemia can develop hypovolemia from transvascular fluid movement into the thoracic or abdominal cavity. This is commonly identified on point-of-care ultrasound (see below). Patients with intravascular volume deficits secondary to severe hypoalbuminemia may respond to resuscitation with either canine or human albumin (dogs) and/or plasma products (fresh frozen, frozen, or cryopoor plasma) in addition to intravascular volume resuscitation with isotonic crystalloids or synthetic colloids. The administration of synthetic colloids, such as hydroxyethyl starches, may interfere with refractometer measurements of total solids, and values should be interpreted cautiously in these patients.30,31 Ideally, either a measurement of colloid osmotic pressure or serum albumin in patients receiving synthetic colloids should be performed. A blood glucose measurement should be done to assess for hypo- or hyperglycemia, both of which occur commonly in critically ill patients. Decreasing blood glucose levels and hypoglycemia, in addition to changes in vital signs, may indicate the development of sepsis (see Chapter 75, Hypoglycemia). Sepsis may occur postoperatively in patients that have had major surgery due to leakage of gastrointestinal contents during surgery or dehiscence, due to the development of incisional or surgical site infections, or as a result of aspiration pneumonia, for example. In patients with gastrointestinal tract disease or dysfunction, sepsis may occur as a result of bacterial translocation. Other causes of hypoglycemia include toy breed hypoglycemia, insulinoma or insulin overdose, hepatic failure, and xylitol toxicity. Patients with hypoglycemia (blood glucose ,60 mg/dl) should be treated with a bolus of 0.25–0.5 g/kg of 50% dextrose diluted at least 1:3 with sterile water or isotonic crystalloids for injection and intravenous fluids should be supplemented with 2.5%–5% dextrose. Hyperglycemia (blood glucose .180 mg/dl) is commonly seen in nondiabetic critically ill animals and likely results from a combination of low or normal insulin concentrations, increased counterregulatory hormone secretion, peripheral tissue insulin resistance, and deranged hepatic autoregulatory mechanisms.32 Additionally, hyperglycemia may result from the administration of medications, such as catecholamines and steroids, or from parenteral nutrition. Acute hyperglycemia (blood glucose levels may be over .300 mg/dl) can be seen in patients with severe cardiovascular and/or respiratory dysfunction and may indicate severe impairment in tissue oxygen delivery and impending cardiopulmonary arrest. Generally, mild and acute elevations in blood glucose do not cause acute clinical signs and the underlying disease or identification of complications should be investigated and treated. The acid-base status of a deteriorating patients is an important part of the evaluation. A metabolic acidosis (defined as a pH ,7.34, base deficit ,24 mmol/L [dogs] ,25 mmol/L [cats]) is common in critically ill dogs and cats and often associated with hyperlactatemia (lactate .2.5 mmol/L) due to altered tissue perfusion.33 Normalization of lactate (i.e., serial evaluations of lactate) in response to therapeutic interventions should be assessed in patients with hyperlactatemia; failure to normalize lactate has been associated with a worse outcome in canine studies (see Chapter 61, Hyperlactatemia).34,35 Other common causes of metabolic acidosis in critically ill patients include diabetic ketoacidosis, renal failure, renal tubular acidosis, and loss of bicarbonate from the gastrointestinal tract (typically secondary to diarrhea). Severe metabolic acidosis (pH ,7.2) may affect the cardiovascular system by causing myocardial dysfunction, vasodilation, hypotension, and decreased responsiveness to catecholamines.36 Metabolic alkalosis (pH .7.45) is most commonly seen in hospitalized

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient critically ill patients following furosemide therapy, animals with gastrointestinal tract obstruction, gastric stasis, and/or regurgitation, or secondary to nasogastric tube suctioning due to loss of chloride from the gastrointestinal tract.37 This can be addressed through the administration of 0.9% NaCl, correction of underlying hypokalemia, and administration of prokinetic medications such as metoclopramide. Blood electrolytes, including sodium, potassium and ionized calcium, should also be rapidly evaluated. Rapid increases in sodium (and chloride) may occur in critically ill patients due to hypotonic fluid losses from the respiratory (i.e., secondary to panting) or gastrointestinal systems, skin, or urinary tract. A syndrome of inappropriate antidiuretic hormone (SIADH) secretion leading to hyponatremia may be identified secondary to pneumonia, neoplasia, babesiosis, intracranial disease, or medication administration.38-42 In general, the change in sodium seen with SIADH is slowly progressive, but rapid changes are possible. Marked changes in blood sodium, either increasing rapidly or decreasing rapidly, can be associated with the onset of neurologic signs and seizures as noted above. In addition to managing acute cerebral edema secondary to rapid decreases in sodium concentration, hypernatremia should be addressed through parenteral administration of hypotonic fluids (5% dextrose in water or 0.45% NaCl) or via orally or enterally administered water. Careful monitoring must follow to ensure a safe lowering of blood sodium levels (maximum 0.5–1 mEq/hr) in animals with chronic hypernatremia. Similarly, changes in blood potassium may occur in a critically ill patient. Hyperkalemia may occur secondary to renal failure, urinary tract obstruction, rupture, or urine leakage following urogenital surgery, hypoadrenocorticism, ischemia reperfusion injury (i.e., resolving aortic thromboembolism), or iatrogenically due to oversupplementation of potassium chloride in intravenous fluids. Patients with an elevated blood potassium (.6 mEq/L) on point-of-care blood work should have an electrocardiogram performed (if not already done during the cardiovascular assessment) to assess for cardiac arrhythmias such as bradycardia, tented T-waves, widened QRS, and atrial standstill.43 When cardiac arrhythmias are identified, treatment with intravenous calcium gluconate (50–100 mg/kg IV over 5 minutes)44 is used to stabilize the heart rhythm and additional medications such as treatment with regular insulin (0.2 units/kg IV) and 2.5% dextrose or terbutaline sulfate intravenously (0.01 mg/kg)45 may be considered. The specific underlying cause for the hyperkalemia should be investigated and treated. Hypokalemia (potassium ,3.0 mEq/L) results most commonly from treatment with potassium deficient intravenous fluids and inadequate oral intake. However, a number of conditions are also associated with severe hypokalemia including diabetic ketoacidosis, renal failure, albuterol intoxication, and hyperaldosteronism for example. Blood potassium concentrations between 2.0 mEq/L and 3.0 mEq/L are unlikely to cause severe clinical signs; however, blood potassium concentration falling below 2.0 mEq/L can cause severe muscular weakness leading to hypoventilation and cardiac arrhythmias. Finally, patients receiving massive transfusions should be evaluated for hypocalcemia and hypomagnesemia, which may result from citrate toxicity. In summary, when electrolyte abnormalities are present, veterinarians should diagnose and manage the underlying disease, institute treatments (i.e., potassium supplementation for hypokalemia) to correct these abnormalities or consider altering the current treatment strategies (i.e., discontinuing 0.9% NaCl in a patient that becomes hypernatremic or hyperchloremic). Serial evaluations of creatinine in the critically ill patient may indicate the presence of acute kidney injury indicated by a change of creatinine of 10.3 mg/dl from baseline.46 Along with evaluation of creatinine, an assessment of urine output should be done in patients with a low urine output (,0.5–1 ml/kg/hr). Evaluation of creatinine

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and urine output should be made in light of the intravascular volume status of the patient; for example, in patients with an intravascular volume deficit, urine output may decrease due to a decrease in the glomerular filtration rate. High urine output that exceeds the rate of intravenous fluid therapy rate of administration may be seen in animals following relief of a urinary tract obstruction due to a postobstructive diuresis or recovery from an acute kidney injury.47,48 This can cause hypovolemia if intravenous fluid therapy and/or oral water intake are not adjusted accordingly. A urine specific gravity can be helpful when investigating kidney function at the cage side but should be interpreted cautiously in a patient already treated with fluids; this can lead to medullary washout and inadequate urine concentration (urine specific gravity may be in the isosthenuric or hyposthenuric range) even in conditions of hypoperfusion. Administration of synthetic colloids will artificially increase the urine specific gravity and therefore urine specific gravity in these patients cannot be reliably interpreted.49 However, isosthenuric or hyposthenuric urine, urine specific gravity ,1.008–1.012, may indicate nephrogenic (i.e., secondary to pyelonephritis, pyometra, hypokalemia or hyperkalemia for example) or central diabetes insipidus, liver failure, or secondary to medication administration such as diuretic therapy. In addition to point-of-care blood testing, additional blood should be obtained for a complete blood count, chemistry screen, urinalysis, and coagulation testing depending on the clinical situation. These tests should be performed initially to diagnose the underlying disease process, but serial evaluations, especially in a hospitalized patient that acutely deteriorates, should be performed to diagnose infection and organ failure, which may complicate critical illness. In one study of septic dogs, multiple organ dysfunction including coagulation, renal, and hepatic dysfunction was identified in approximately 50% of dogs.3

Point-of-Care Ultrasound (see also Chapter 189, Point-of-Care Ultrasound in the ICU) A point-of-care ultrasound evaluation, including a thoracic and abdominal focused assessment with sonography, to assess for free abdominal, pleural, and pericardial fluid should be performed following the primary survey in patients with tissue hypoperfusion, respiratory distress, acute abdominal distension, or abdominal pain.50-52 This can be done quickly at the cage side, generally taking less than 5 minutes to perform. The information gained may help guide therapeutic interventions and identify causes for the patient’s deterioration. In patients with suspected pleural effusion, point-of-care thoracic ultrasound can be used to confirm the presence of fluid and guide needle thoracocentesis. This should be performed immediately to relieve respiratory distress and diagnose the underlying cause. The pleural effusion should be evaluated microscopically for bacteria, and a total solids via refractometry can be done to characterize the type of effusion present (i.e., transudate versus exudate). A packed cell volume of the effusion should be evaluated if on visual inspection it appears to be hemorrhagic. Similarly, in patients that are identified to have abdominal effusion or increasing abdominal effusion on point-of-care ultrasound, diagnostic sampling of the effusion should be performed. The fluid should be evaluated visually (i.e., hemorrhagic effusion, serosanguineous or sanguineous effusion) and microscopically for the presence of bacteria or other abnormalities. An evaluation of packed cell volume and refractometer total solid, measurement can be done on hemorrhagic effusions. Septic effusions are characterized by suppurative inflammation with intracellular bacteria (see Chapter 120, Peritonitis). A lactate and glucose measurement in the effusion can be compared with a lactate and glucose in the peripheral blood if septic peritonitis is suspected but intracellular bacteria are not identified. A lactate difference of .2 mmol/L and glucose difference of ,20 mg/dl of the effusion compared with blood may indicate septic

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PART I  Key Critical Care Concepts

peritonitis.53 However, a glucose and lactate comparison of the effusion to blood should not be used to assess for the development of septic peritonitis in dogs following a laparotomy; analysis of intraabdominal drain fluid was found to not reliably detect septic peritonitis.54 In addition to septic peritonitis and hemorrhage, abdominal effusion may occur secondary to a uroperitoneum (i.e., leakage of urine following urinary tract surgery or trauma), bile peritonitis (secondary to biliary mucocele rupture or blunt trauma), pancreatitis, or neoplasia, or may occur secondary to third spacing of fluid as a result of severe hypoalbuminemia. Additional evaluations of the effusion may include an evaluation of the effusion creatinine and potassium as compared with blood for uroperitoneum (effusion creatinine to blood .2:1 or effusion potassium to blood .1.4 [dogs] or 1.9 [cats]: 1)55,56 and total bilirubin levels of effusion compared with blood (effusion total bilirubin to blood .2:1)57. Bile pigments (free green or yellow brown material) or acellular mucinous fibrillar material may be seen microscopically in patients with bile peritonitis.57-60 In addition to the identification of free fluid, thoracic and lung ultrasonography should also be performed in patients with respiratory distress to aid in identifying pneumothorax, diaphragmatic hernia, and interstitial-alveolar disease.51,61 A pneumothorax may be suspected in patients with dull lung sounds on respiratory evaluation and indicated by the absence of a glide sign on lung ultrasound. Once a pneumothorax is diagnosed, immediate needle thoracocentesis should be performed. Thoracostomy tubes may be needed if the patient cannot be managed with intermittent needle thoracocentesis or the air removed via needle thoracocentesis does not stop or decrease. Interstitial-alveolar disease is indicated by the presence of .3 B-lines in more than one lung field on point-of-care lung ultrasound.61 This can be seen secondary to congestive heart failure, fluid overload, and other conditions affecting the lung parenchyma (e.g., pneumonia, non-cardiogenic edema, and acute respiratory distress syndrome). A focused cardiac ultrasound evaluation should be performed next in a patient noted to have B-lines on lung ultrasound to differentiate between cardiac and noncardiac causes of interstitial-alveolar disease. A patient with congestive heart failure or fluid overload should have evidence of left atrial enlargement with a left atrial to aortic diameter of at least 1.5 to 1.62-64 Additionally, an evaluation of cardiac contractility can be done to investigate for left ventricular dysfunction, which may be seen in patients with dilated cardiomyopathy or as a complication of critical illness.1 If fluid overload and/or congestive heart failure is suspected as the cause of respiratory distress based on the results of point-of-care ultrasound, furosemide should be administered, and any intravenous fluids should be discontinued. It is important to note that dogs with mitral valve disease and hospitalized for other conditions may have underlying left atrial enlargement but noncardiac causes of interstitial-alveolar disease. Therefore, point-of-care ultrasound should not replace thoracic radiography and echocardiography, and point-ofcare ultrasound findings should always be confirmed when possible. Differentiating between other cause of interstitial-alveolar edema, such as pneumonia and acute respiratory distress syndrome for example, can only be diagnosed via thoracic radiography or computed tomography and results of additional diagnostic testing such as an endotracheal wash cytology with culture and susceptibility testing results.

SUMMARY Critically ill patients may deteriorate suddenly due to a variety of reasons, and changes in vital signs or metabolic status typically herald the development of complications. Therefore, a systematic approach to a patient with recognized changes to the cardiovascular, respiratory, and neurologic systems should be performed to identify and

address the underlying cause. Point-of-care blood testing and ultrasound should be evaluated alongside the physical examination to help guide acute stabilizing interventions. With this type of approach, organ dysfunction and complications of critical illness can be addressed rapidly, and ultimately disease progression and patient death may be prevented.

SELECTED REFERENCES Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 29:1303-1310, 2010. A retrospective study provides criteria for the diagnosis of multiple organ dysfunction and evaluates association of organ dysfunction and outcome in dogs with sepsis. Boiron L, Hopper K, Borchers A: Risk factors, characteristics and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29(2):173-179, 2019. A retrospective study that identifies risk factors for the development of ARDS including sepsis, SIRS and shock. A grave outcome was identified with a case fatality rate of 84% in dogs and 100% in cats. Thoen ME, Kerl ME: Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system, J Vet Emerg Crit Care 21(6):648-657, 2011. A veterinary acute kidney injury staging system was retrospectively applied to 164 critically ill dogs. Dogs that developed acute kidney injury during hospitalization were less likely to survive to hospital discharge. McMurray J, Boysen S, Chalhoub S: Focused assessment with sonography in nontraumatized dogs and cats in the emergency and critical care setting, J Vet Emerg Crit Care 26(1):64-73, 2016. A prospective study describing the use of focused assessment with sonography to identify thoracic and abdominal effusion in non-traumatized dogs and cats. Free fluid was identified in 75% of cardiovascularly unstable or dyspneic patients compared to only 9% of stable patients.

REFERENCES 1. Nelson OL, Thompson PA: Cardiovascular dysfunction in dogs associated with critical illness, J Am Anim Hosp Assoc 42:344-349, 2006. 2. Aldrich J: Shock fluids and fluid challenge. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, St. Louis, 2009, Saunders Elsevier, pp 276-280. 3. Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 29:1303-1310, 2010. 4. Aldrich J: Global assessment of the emergency patient, Vet Clinic Small Anim 35:281-305, 2005. 5. Sigrist NE, Adamik KN, Doherr MG, et al: Evaluation of respiratory parameters at presentation as clinical indicators of respiratory localization in dogs and cats with respiratory disease, J Vet Emerg Crit Care 21(1): 13-23, 2011. 6. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine consensus definitions: the Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17(4):333-339, 2007. 7. Boiron L, Hopper K, Borchers A: Risk factors, characteristics and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29(2):173-179, 2019. 8. Reeves RB, Park JS, Lapennas GN, Olszowka JA: Oxygen affinity and Bohr coefficients of dog blood, J Appl Physiol 53(1):87-95, 1982. 9. Tobin MJ, editor: Indications for mechanical ventilation, 2nd ed, New York, 2006, McGraw-Hill, pp 129-162. 10. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23(3)280-285, 2013.

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient 11. Ateca LB, Reineke EL, Drobatz KJ: Evaluation of the relationship between peripheral pulse palpation and Doppler systolic blood pressure in dogs presenting to an emergency service, J Vet Emerg Crit Care 28(3):226-231, 2018. 12. Reineke EL, Rees C, Drobatz KJ: Prediction of systolic blood pressure using peripheral pulse palpation in cats, J Vet Emerg Crit Care 26(1): 52-57, 2016. 13. Boag AK, Hughes D: Assessment and treatment of perfusion abnormalities in the emergency patient, Vet Clin Small Anim 35:319-342, 2005. 14. Schaefer JD, Reminga C, Drobatz KJ: Evaluation of the rectal-interdigital temperature gradient as a diagnostic marker of shock in dogs presenting with undifferentiated shock, J Vet Emerg Crit Care 27(S1):S9, 2017. 15. Porter AE, Rozanski EA, Sharp CR, et al: Evaluation of the shock index in dogs presenting as emergencies, J Vet Emerg Crit Care 23(5):538-544, 2013. 16. Peterson KL, Hardy BT, Hall K: Assessment of shock index in healthy dogs and dogs in hemorrhagic shock, J Vet Emerg Crit Care 23(5):545-550, 2013. 17. McGowan EE, Marryott K, Drobatz KJ, Reineke EL: Evaluation of the use of shock index in identifying acute blood loss in healthy blood donor dogs, J Vet Emerg Crit Care 27(5):524-531, 2017. 18. Kenton R, Adamantos S: An evaluation of the shock index in cats with hypoperfusion; a novel, pilot study (abstract), BSAVA Conference Proceedings, 2016. 19. Hughes D, Rozanski ER, Shofer FS, et al: Effect of sampling site, repeated sampling, pH and pCO2 on plasma lactate concentration in healthy dogs, Am J Vet Res 60:521-524, 1999. 20. Redavid LA, Sharp CR, Mitchell MA, Beckel NF: Plasma lactate measurements in healthy cats, J Vet Emerg Crit Care 22(5):580-587, 2012. 21. Reineke EL, Rees C, Drobat KJ: Association of blood lactate concentration with physical perfusion variables, blood pressure and outcome for cats treated at an emergency service, J Am Vet Med Assoc 247:79-84, 2015. 22. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 16(6): 581-584, 2001. 23. Syring RS: Assessment and treatment of central nervous system abnormalities in the emergency patient, Vet Clin Small Anim 35:343-358, 2005. 24. Shi ZW, Wang ZG: Acute cerebral and pulmonary edema induced by hemodialysis, Chin Med J 121(11):1003-1009, 2008. 25. Ostroski CJ, Cooper ES: Development of dialysis disequilibrium-like clinical signs during postobstructive management of feline urethral obstruction, J Vet Emerg Crit Care 24(4):444-449, 2014. 26. Oppenheimer BS, Fishbery AM: Hypertensive encephalopathy, Arch Intern Med 41(2):264-278, 1928. 27. Lowrie M, De Risio L, Dennis R, et al: Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage, Vet Radiol Ultrasound 53:381-388, 2012. 28. Littman MP: Spontaneous systemic hypertension in 24 cats, J Vet Intern Med 8:79-86, 1994. 29. Kyles AE, Gregory CR, Wooldridge JD, et al: Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats, Vet Surg 28:436-441, 1999. 30. Bumpus SE, Haskins SC, Kass PH: Effect of synthetic colloids on refractometric readings of total solids, J Vet Emerg Crit Care 8(1):21-26, 1998. 31. Yam E, Hosgood G, Rossi G, Smart L: Synthetic colloid fluids (6% hydroxyethyl starch 130/0.4 and 4% succinylated gelatin) interfere with total plasma protein measurements in vitro, Vet Clin Pathol 47(4):575-581, 2019. 32. Mizock BA: Alterations in fuel metabolism in critical illness: hyperglycemia, Best Pract Res Clin Endocrinol Metab 15(4):533-551, 2001. 33. Kohen CJ, Hopper K, Kass PH, Epstein SE: Retrospective evaluation of the prognostic utility of plasma lactate concentration, base deficit, pH and anion gap in canine and feline emergency patients, J Vet Emerg Crit Care 28(1):54-61, 2018. 34. Zollo AM, Ayoob AL, Prittie JE, et al: Utility of admission lactate, lactate variables and show index in outcome assessment in dogs diagnosed with shock, J Vet Emerg Crit Care 29(5):505-513, 2019. 35. Cortellini S, Seth M, Kellett-Gregory LM: Plasma lactate concentrations in septic peritonitis: a retrospective study of 83 dogs (2007-2012), J Vet Emerg Crit Care 25(3):388-395, 2014.

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36. Kimmoun A, Novy E, Auchet T, et al: Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside, Crit Care 19(1):175, 2015. 37. Ha YS, Hopper K, Epstein SE: Incidence, nature, and etiology of metabolic alkalosis in dogs and cats, J Vet Intern Med 27(4):847-853, 2013. 38. Kokko H, Hall PD, Afrin LB: Fentanyl-associated syndrome of inappropriate antidiuretic hormone secretion, Pharmacotherapy 22(9):1188-1192, 2002. 39. Barrot AC, Bedard A, Dunn M: Syndrome of inappropriate antidiuretic hormone secretion in a dog with a histiocytic sarcoma, Can Vet J 58(7): 713-715, 2017. 40. Martinez R, Torrente C: Syndrome of inappropriate antidiuretic hormone secretion in a mini-breed puppy associated with aspiration pneumonia, Top Companion Anim Med 32(4):146-150, 2017. 41. Zygner G, Bartosik J, Gorski P, Zygner W: Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in non-azotaemic dogs with babesiosis associated with decreased arterial blood pressure, J Vet Res 63(3):339-344, 2019. 42. De Monaco SM, Koch MW, Southward TL: Syndrome of inappropriate antidiuretic hormone secretion in a cat with a putative Rathke’s cleft cyst, J Feline Med Surg 16(12):1010-1015, 2014. 43. Tag TL, Day TK: Electrocardiographic assessment of hyperkalemia in dogs and cats, J Vet Emerg Crit Care 18(1):61-67, 2008. 44. Calcium gluconate. In Plumb DC, editor: Veterinary drug handbook, 4th ed, Ames, Iowa, 2002, Iowa State Press. 45. Terbutaline Sulfate. In Plumb DC, editor: Veterinary drug handbook, 4th ed, Ames, Iowa, 2002, Iowa State Press. 46. Thoen ME, Kerl ME: Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system, J Vet Emerg Crit Care 21(6):648-657, 2011. 47. Francis BJ, Wells RJ, Rao S, Hackett TB: Retrospective study to characterize post-obstructive diuresis in cats with urethral obstruction, J Feline Med Surg 12(8):606-608, 2010. 48. Frohlich L, Hartmann K, Louis-Sautter C, Dorsch R: Postobstructive diuresis in cats with naturally occurring lower urinary tract obstruction: incidence, severity and association with laboratory parameters on admission, J Feline Med Surg 18(10):809-817, 2016. 49. Smart L, Hopper K, Aldrich J, et al: The effect of hetastarch (670/0.75) on the urine specific gravity and osmolality in the dog, J Vet Intern Med 23(2):388-391, 2009. 50. Boysen SR, Rozanski EA, Tidwell AS, et al: Evaluation of a focused assessment with sonography for trauma protocol to detect free abdominal fluid in dogs involved in motor vehicle accidents, J Am Vet Med Assoc 225(8): 1198-1204, 2004. 51. Lisciandro GR, Lagutchik MS, Mann KA, et al: Evaluation of a thoracic focused assessment with sonography for trauma (TFAST) protocol to detect pneumothorax and concurrent thoracic injury in 145 traumatized dogs, J Vet Emerg Crit Care 18(3):258-269, 2008. 52. McMurray J, Boysen S, Chalhoub S: Focused assessment with sonography in nontraumatized dogs and cats in the emergency and critical care setting, J Vet Emerg Crit Care 26(1):64-73, 2016. 53. Bonczynski JJ, Ludwig LL, Baron LJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats, Vet Surg 32(2):161-166, 2003. 54. Guieu LS, Bersenas AM, Brisson BA: Evaluation of peripheral blood and abdominal fluid variables as predictors of intestinal surgical site failure in dogs with septic peritonitis following celiotomy and the placement of closed-suction abdominal drains, J Am Vet Med Assoc 249(5):515-525, 2016. 55. Schmiedt C, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11(4):275-280, 2001. 56. Aumann M, Worth LT, Drobat KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315-324, 1998. 57. Ludwig LL, McLoughlin MA, Graves TK, Crisp MS: The surgical treatment of bile peritonitis in 24 dogs and 2 cats: a retrospective study (1987-1994), Vet Surg 26:90-98, 1997.

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58. Parchman MB, Flanders JA: Extrahepatic biliary tract rupture: evaluation of the relationship between the site of rupture and the cause of rupture in 15 dogs, Cornell Vet 80:267-272, 1990. 59. Elsheikh TM, Silverman JF, Sturgis TM, Geisinger KR: Cytologic diagnosis of bile peritonitis, Diagn Cytopathol 14:56-59, 1996. 60. Owens SD, Gossett R, McElhaney R, Christopher MM, Shelly SM: Three cases of canine bile peritonitis with mucinous material in the abdominal fluid as the prominent cytologic finding, Vet Clin Pathol 32(3):114-120, 2003. 61. Ward JL, Lisciandro GR, Keen BW, et al: Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea, J Am Vet Med Assoc 250:666-675, 2017.

62. Ward JL, Lisciandro GR, Ware WA, et al: Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress, J Vet Intern Med 32(5):1530-1540, 2018. 63. Ostroski C, Hezzell M, Oyama M, Drobatz K, Reineke EL: Focused cardiac ultrasound and point-of-care NT-proBNP assay in the emergency room improves the differentiation of respiratory and cardiac causes of dyspnea in cats (abstract), J Vet Emerg Crit Care 26:S9, 2016. 64. Hezzell M, Ostroski C, Oyama M, Drobatz K, Reineke EL: Focused cardiac ultrasound in the emergency room improves the differentiation of respiratory and cardiac causes of dyspnea in dogs (abstract), J Vet Intern Med 31:206, 2017.

2 Physical Examination and Daily Assessment of the Critically Ill Patient Timothy B. Hackett, DVM, MS, DACVECC

KEY POINTS • Physical examination of critical patients is essential to detect lifethreatening changes in their condition. • Thorough, efficient physical examination should precede blood tests, electrodiagnostics, or imaging. • Physiologic variables related to oxygen delivery take precedence in evaluating the critical patient. • Veterinarians and support staff should note and record both subjective and objective physical examination parameters as often as

necessary while taking into consideration the patient’s current problems and anticipated complications. • Algorithms and checklists can enhance patient care through targeted, problem-oriented, rapid assessment of key variables. • The ideal monitoring plan allows for early detection of metabolic or physiologic derangements with minimal risks for iatrogenic insult, unnecessary expense to the client, and inappropriate use of intensive care unit resources.

Assessment of the critical patient begins with a thoughtful, historyguided physical examination. The frequency of exams will be guided by patient condition and patient familiarity of the medical team. Thorough exams should be conducted at least daily along with a review of the medical record and the results of recent diagnostics. Thorough physical examinations are the key to detecting subtle changes and establishing a baseline; they are especially important for new veterinarians and support staff to perform at shift changes following patient rounds and repeatedly during each shift. The goal of serial physical examination is to detect problems with organ function in time for targeted interventions that prevent organ failure. Monitoring and record keeping are important, but not as important as the interpretation of the physical examination findings and diagnostics that lead to timely changes in treatment. A monitored variable is useful only if changes in that variable are linked to an intervention or therapy that affects outcome.1 While more frequent, focused examinations may be useful for known problems, the dynamic, multiorgan nature of critical illness demands frequent checks of the whole patient. Available technology helps in the identification of life-threatening problems. Arterial and venous blood gas analysis, oscillometric blood pressure monitors, pulse oximetry, point-of-care ultrasonography, computed tomography, coagulation analysis and other point-of-care tests are some the technologies that have found their way into 24-hour emergency and critical care practice.

better able to measure adequacy of perfusion or degree of hydration than the physical examination. For example, parameters like heart rate and blood pressure provide valuable information, but only when interpreted in conjunction with the physical examination. When a veterinarian reaches for an ultrasound probe or electrocardiogram before looking at and touching the patient with eyes, hands, and stethoscope, readily available information can be left on the table. The physical examination should be both planned and focused for unplanned and emergent changes in patient condition.2 The physical examination of the critically ill patient is approached much the same as the triage and primary survey of the emergency patient. With focus on the efficacy of oxygen delivery, the priority is assessment of the respiratory and cardiac systems. The ABCs (airway, breathing, and circulation) of resuscitation provide a simple systematic approach to the primary survey in both the ICU and emergency room (see Chapter 1, Evaluation and Triage of the Critically Ill Patient).3

PHYSICAL EXAMINATION Serial physical examination is core to the practice of critical care medicine. Physical examination interfaces with, and adds context to, medical technology. Both are necessary. Their appropriate use has improved our ability to provide the best care to our patients. The additional data can be overwhelming, and with reliance on technology, the importance of the practiced and repeated physical examination may be minimized. There is still no readily available technology that is

Airway and Breathing Patients adopt respiration positions and patterns to minimize the work of breathing. Recognition of altered or adaptive breathing patterns is a feature of a complete physical examination. A very slow or apneustic respiratory pattern may be indicative of impending respiratory arrest, and the patient should be rapidly assessed and stabilized as necessary (see Part II: Respiratory Disorders). Similarly, an increase in respiratory rate or effort indicates the need for rapid assessment. Animals with upper airway obstruction, dynamic airway collapse, bronchitis, or other obstructions to airflow will often breathe slower and more deeply to minimize airway resistance. With laryngeal disease or extrathoracic tracheal collapse/obstruction, increased effort will be noted on inspiration. With obstructions or collapse of the intrathoracic airways, there is greater effort on expiration. When there is physical obstruction such as a mass or foreign body, the abnormal effort can be noticed on both inspiration and expiration. Auscultating the entire respiratory tract and finding the point of maximal intensity can help identify the location of the obstruction (see Chapter 18, Upper Airway Disease).

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Animals with pulmonary parenchymal disease or pulmonary fibrosis may adopt a restrictive breathing pattern to overcome increased elastic forces of the pulmonary parenchyma. By minimizing the change in volume and increasing the respiratory rate, they can attempt to maintain alveolar minute ventilation despite decreased pulmonary compliance (see Chapters 20–26). Respiratory failure is not only a failure of gas exchange and hypoxemia but also of ventilation (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively). Hypoventilation is an important cause of hypoxemia and a treatable cause of acidosis. When assessing respiratory rate and pattern, adequacy of ventilation should be estimated. Noting shallow breathing at normal or decreased respiratory rates should be followed by definitive diagnostics. Monitoring of pH and carbon dioxide (CO2) directly through blood gas analysis or indirectly with end-tidal CO2 are the most objective ways to follow trends (see Chapters 59, 60, and 190, Traditional Acid-Base Analysis, NonTraditional Acid-Base Analysis, and Capnography, respectively).

Circulation Alveolar ventilation is the first step in providing oxygen to the tissues. A normal cardiovascular system is then necessary to carry oxygenated blood from the lungs to the body. Physical assessment of the circulatory system relies on palpation of the arterial pulse (for synchrony, quality, and pulse rate), evaluation of venous distention, assessment of mentation and mucous membrane color and capillary refill time, and auscultation of the heart and lungs. Inadequate global perfusion is considered an indicator of circulatory shock and is a clinical diagnosis that can be made from physical examination alone (see Chapter 6, Classification and Initial Management of Shock).4

Heart Rate A normal heart rate indicates that at least one component of cardiac output is normal. A heart rate of 70 to 120 beats/min is considered normal in small dogs, 60 to 120 beats/min in large dogs, and 140 to 200 beats/min in cats. Bradycardia can result in decreased cardiac output and subsequent poor perfusion (see Chapter 48, Bradyarrhythmias and Conduction Disturbances). Cats often develop bradycardia (,120 beats/min) in shock, and this can be associated with imminent cardiac arrest. Bradycardia is an unusual finding in a critically ill patient and can result from electrolyte imbalances (hyperkalemia), neurologic disease (increased intracranial pressure), or conduction disturbances (atrioventricular block, sick sinus syndrome), or can be a side effect of analgesic or anesthetic drugs. An electrocardiogram (ECG) is indicated for full assessment of bradycardia. Sinus tachycardia (dogs .180 beats/min, cats .220 beats/min) is the body’s response to decreased blood volume, pain, anxiety, hypoxemia, and systemic inflammation (see Chapter 49, Supraventricular Tachyarrhythmias). Increasing heart rate will temporarily increase cardiac output and oxygen delivery. However, there are some physiologic limitations to this response. When the heart rate becomes too fast, diastolic filling is compromised and stroke volume is inadequate. Sinus tachycardia often results from circulatory shock or pain. Tachycardia that is irregular or associated with pulse deficits usually indicates an arrhythmia, and an ECG is indicated (see Chapter 50, Ventricular Tachyarrhythmias).

Mucous Membrane Evaluation of mucous membrane color is subjective but can give important information about peripheral capillary perfusion. Pale or white mucous membranes can be indicative of anemia or a vasoconstrictive response to shock. Red mucous membranes suggest vasodilation and

are observed in systemic inflammatory states and hyperthermia. Cyanotic gums indicate severe hypoxemia in the face of a normal packed cell volume because cyanosis will not be clinically evident without adequate hemoglobin levels. A yellow hue (icterus) indicates increased serum bilirubin resulting from hepatic disease, posthepatic disease, or hemolysis. A brown discoloration of the mucous membranes is observed with methemoglobinemia, and a “cherry red” may be observed with carbon monoxide poisoning (see Chapter 107, Dyshemoglobinemia). During examination of the gums, petechiation or bleeding should be noted because petechiae and bruising are clinical signs of platelet deficiency or dysfunction, and thrombocytopenia is an early finding in disseminated intravascular coagulation.

Capillary Refill Time Evaluation of capillary refill time (CRT) provides further information on peripheral perfusion. Used in conjunction with pulse quality, respiratory effort, heart rate, and mucous membrane color, the CRT can help assess a patient’s blood volume and peripheral perfusion and provide information on shock etiology. Normal CRT is 1 to 2 seconds. This is consistent with a normal blood volume and perfusion. A CRT longer than 2 seconds suggests poor perfusion due to peripheral vasoconstriction.5 Peripheral vasoconstriction is an appropriate response to low circulating blood volume and reduced oxygen delivery to vital tissues. Patients with hypovolemic and cardiogenic shock should be expected to have peripheral vasoconstriction. Peripheral vasoconstriction is also commonly associated with cool extremities, assessed by palpation of the distal limbs. Significant hypothermia will also cause vasoconstriction. A CRT of less than 1 second is suggestive of a hyperdynamic state and vasodilation. Hyperdynamic states can be associated with systemic inflammation, distributive shock, and heat stroke or hyperthermia.

Venous Distention Venous distention can be a sign of volume overload, right-sided congestive heart failure, or increased right-sided filling pressure. Palpation of the jugular vein may demonstrate distention, although it may be easier to visualize by clipping hair over the lateral saphenous vein. The patient is positioned in lateral recumbency; if the lateral saphenous vein in the upper limb appears distended, the limb is slowly raised above the level of the heart. If the vein remains distended, it may suggest an elevated central venous pressure. Potential causes of an elevated central venous pressure include volume overload, pericardial effusions, or right-sided congestive heart failure. A patient with pale mucous membranes and a prolonged CRT from vasoconstriction in response to hypovolemia would not be expected to have venous distention. In comparison, cardiogenic shock with biventricular failure is more likely to cause pale mucous membranes, prolonged CRT, and increased venous distention.

Pulse Quality The femoral pulse should be palpated while listening to the heart or palpating the cardiac apex beat. A strong pulse that is synchronous with each heartbeat is normal and consistent with adequate blood volume and cardiac output. Digital palpation of pulse quality is largely a reflection of pulse pressure. Pulse pressure equals the difference between the systolic and diastolic arterial blood pressures. A normal pulse pressure may be felt despite abnormal systolic and diastolic pressures. Global markers of anaerobic metabolism like base deficit and lactate, along with low mixed venous oxygen saturation, are more sensitive indicators of perfusion than blood pressure or physical examination parameters. If other indicators suggest inadequate perfusion, the patient should be evaluated for pathologic hyperdynamic conditions

CHAPTER 2  Physical Examination and Daily Assessment of the Critically Ill Patient such as sepsis or causes of a low diastolic pressure. For example, the presence of a holosystolic murmur with normal to increased pulse pressure can indicate diastolic runoff through a patent ductus arteriosus. Both the femoral and dorsal pedal pulses should be palpated. At least one study suggests a palpable dorsal pedal arterial pulse indicates a systolic blood pressure less than 90 mm Hg,6 although experienced clinicians will find they are able to feel these pulses in hypotensive patients. An irregular pulse or one that is asynchronous with cardiac auscultation is a sign of a significant cardiac arrhythmia. An ECG can confirm the arrhythmia and help determine the best treatment. Weak pulses are a common finding in the critically ill and can be due to decreased cardiac output as a result of either low stroke volume or decreased contractility, peripheral vasoconstriction, or decreased pulse pressure. The simultaneous evaluation of pulse pressure and response to intravenous fluid therapy will help distinguish the common causes of shock.

Auscultation Cardiac and pulmonary auscultation is an essential part of the physical examination. Clinicians and critical care technicians should perform serial auscultation throughout a patient’s hospitalization. Patient care staff and clinicians should auscultate the heart and pulmonary sounds at least twice during a shift. Subtle changes in respiratory noise may identify potential fluid overload or early pulmonary dysfunction. The respiratory system should be evaluated from the nasal cavity, larynx, and trachea to all lung fields. Stertor and wheezes in the upper airways and quiet crackles in the lungs may be an early sign of fluid overload.7 Inspiratory stridor can be heard with laryngeal paralysis, whereas expiratory wheezes suggest small airway collapse and bronchitis. Crackles can be heard with pneumonia, pulmonary edema, pulmonary hemorrhage, and small airway disease. Aspiration pneumonia often affects the cranioventral lung fields, with normal breath sounds giving way to adventitious sounds in these areas. Pulmonary edema may begin in the perihilar lung fields. Decreased lung sounds may be heard with pulmonary consolidation, pneumothorax, and pleural effusion. With pleural effusion, a fluid line may be detected by auscultating the patient’s chest while the patient is standing or held in sternal recumbency. Changes in lung sounds may be an indication for further examination by thoracic radiography or ultrasound (see Chapter 29, Pleural Space Disease). Critically ill patients with evidence of pulmonary dysfunction should have their oxygenating ability evaluated with pulse oximetry or arterial blood gas measurement. Any change in respiratory character or sounds should prompt immediate reevaluation of oxygenation status (see Chapter 16, Hypoxemia). Cardiac auscultation should be repeated at least once daily. As mentioned with pulse quality, the pulse should be palpated while listening to the heart. New murmurs or asynchronous pulses should be noted and investigated. Cardiac arrhythmias in the critically ill are an early sign of cardiac dysfunction. As with the failure of any organ system, these abnormalities should be investigated and underlying metabolic or oxygen delivery abnormalities corrected.

Level of Consciousness The patient’s level of consciousness and response to surroundings should be assessed frequently (see Chapter 83, Neurological Evaluation of the ICU Patient). If the patient appears normal, alert, and responsive, overall neurologic and metabolic status is likely normal. Patients that are obtunded or less responsive to visual and tactile stimuli may be suffering from a variety of complications and illnesses. Patients with stupor can be aroused only with painful stimuli. Stupor is a sign of severe neurologic or metabolic derangements. Coma and seizures are signs of abnormal cerebral electrical activity from either

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primary neurologic disease or severe metabolic derangements such as hepatic encephalopathy. One of the most concerning issues in the critically ill patient is any decrease in the gag reflex. This may be a result of a general decrease in the level of consciousness or a primary neurologic deficit. A decrease in the gag reflex places the animal at high risk of aspiration pneumonia, a potentially fatal complication. Oral intake should be withheld in animals with a compromised gag reflex, and if the gag reflex is absent, immediate endotracheal intubation to protect the airway is indicated.

Temperature Body temperature should be monitored frequently, if not continuously, in the critically ill patient. Environmental hyperthermia should be differentiated from primary hyperthermia. Hospitalized animals may develop hyperthermia from cage heat or heating pads. Primary hyperthermia or true fever should be investigated quickly because systemic inflammation and infectious complications are common sequalae of critical illness. Hypothermia is also common in critically ill animals. Many have difficulty maintaining their body temperature and require external heat supplementation. Passive warming with a dry blanket is safer than active warming with external heat sources. Active warming should take care to prevent burns and iatrogenic hyperthermia. Circulating hot air systems are an excellent source for active rewarming. Heat may be supplied by circulating hot water blankets or by placing warm water-filled gloves or bottles in towels next to the animal. A warming waterbed can be made by placing a thick plastic bag over an appropriate-size container filled with warm water. A towel placed under the animal will prevent the patient’s nails from perforating the plastic. Blankets placed on top of the animal will prevent heat from escaping. Heating pads should be used with caution, using both a low temperature setting and insulating the animal with a blanket or fleece pad. Heat lamps should be used from a distance of more than 30 inches to prevent burns. Electric cage dryers or handheld blow dryers are useful if the animal is wet. Intravenous fluids warmed to body temperature can be beneficial when rapid administration rates are used but are not effective at maintenance fluid rates.8 To prevent overwarming, body temperature should be monitored at regular intervals and warming measures discontinued when the body temperature reaches 100°F. Animals should be monitored carefully to prevent iatrogenic hyperthermia or thermal burns.

Hydration Whereas perfusion parameters such as mucous membrane color, CRT, and heart rate are measures of intravascular volume, hydration status is a subjective measure of interstitial fluid content. It is important to assess intravascular and interstitial fluid compartments separately and individualize fluid plans according to needs in both spaces. Day-to-day changes in body weight reflect fluid balance; therefore, daily body weight is the most objective way to monitor hydration. A dehydrated patient should gain weight as fluid volumes are restored. Overhydration is associated with progressive increases in body weight. Evaluating skin turgor or skin elasticity is used to assess hydration. With dehydration, skin turgor is decreased and skin tenting becomes prolonged. With overhydration, skin turgor increases and the subcutaneous tissues gain a “jelly-like” consistency. Serous nasal discharge, peripheral edema, and chemosis are additional supporting signs of overhydration. Peripheral edema can also indicate vasculitis or decreased oncotic pressure such as that seen with hypoproteinemia. Skin turgor is affected by the amount of subcutaneous fat, making it difficult to assess in cachectic and obese animals. Clinicians should be wary of third-space fluid accumulation. Third-space fluid loss is fluid collection within a body cavity that does

12

PART I  Key Critical Care Concepts

not contribute to circulation. Pleural and abdominal effusions can lead to increases in body weight or maintenance of body weight in a patient that is becoming hypovolemic. Daily, or more often when appropriate, assessment of fluid balance is essential in critically ill animals. This requires accurate measurement of all fluid intake and output to include food and water consumption, urine, vomit, and any drain fluid production. Discrepancies in the volume of intake versus output require reevaluation of the patient and alteration of the fluid plan.

Abdominal Palpation and Gastrointestinal Assessment The abdominal examination is necessary due to the hidden nature of many important organ systems and their association with many infectious complications. Serial, gentle abdominal palpation can help localize tenderness. Measurement of the abdominal circumference at the last rib can provide objective serial data for the early detection of abdominal distension. The gastrointestinal (GI) tract may be difficult to evaluate on physical examination but is very important as GI problems are often seen with circulatory shock and critical illness. Thorough abdominal palpation is an important part of a complete physical examination. Clinicians and technicians should evaluate the patient’s abdomen for effusion, organ size, and location and localize any discomfort. Contents of the intestinal tract can be evaluated by both gentle palpation and digital rectal examination. The frequency, character, and volume of GI losses should be monitored. If fresh or digested blood is observed, GI protectants and antibiotics may be indicated.

POINT-OF-CARE ULTRASOUND It has been over 15 years since the introduction of a focused assessment with sonography for trauma protocol in canine patients following motor vehicle accidents.9 Since then, point-of-care ultrasound (POCUS) has seen expanded application and has been the focus of intense study. The availability of compact, high-resolution ultrasound units has made the technology available across all aspects of veterinary medicine. Used in conjunction with physical examination and previously described monitoring parameters, POCUS has found acceptance in many aspects of acute and critical care. Detailed discussion on the utility of POCUS in augmenting emergency and serial assessment, its limitations, and responsible training can be found in Chapter 189, Point-of-Care Ultrasound in the ICU.

MONITORING AND LABORATORY DATA The use of checklists has been promoted to enhance care for critically ill patients.10 By combining aspects of the physical examination with the most essential diagnostic tests, patient status is reviewed in a systematic manner, minimizing the chance of missing significant changes in condition. Kirby’s Rule of 20, a list of monitoring parameters for septic small animal patients, predates much of the current human literature on the use of checklists.11 Box 2.1 lists these 20 parameters and provides an excellent initial approach to monitoring most critically ill animals. This work provided the groundwork for critical care monitoring of the septic patient and has been adapted for most critical veterinary patients. Optimal care is provided when information collected by physical examination and clinical observation is integrated with the results of ancillary tests and technologically derived data. Fluid balance; oxygenation; mentation; perfusion and blood pressure; heart rate, rhythm, and contractility; GI motility; mucosal integrity; and nursing care have all been discussed in the physical examination section of this chapter. The remainder of this checklist makes up the daily monitoring and laboratory assessment recommended for most critical patients.

BOX 2.1  Kirby’s Rule of 20 for Monitoring

the Critically Ill Patient8

• Fluid balance • Oncotic pull • Glucose • Electrolyte and acid-base balance • Oxygenation and ventilation • Mentation • Perfusion and blood pressure • Heart rate, rhythm, and contractility • Albumin levels • Coagulation • Red blood cell and hemoglobin concentration • Renal function • Immune status, antibiotic dosage and selection, and WBC count • GI motility and mucosal integrity • Drug dosages and metabolism • Nutrition • Pain control • Nursing care and patient mobilization • Wound care and bandage change • Tender loving care GI, gastrointestinal; WBC, white blood cell count.

Oncotic Pull, Total Protein, and Albumin Hypoproteinemia is a common finding in critically ill patients. Total protein should be monitored at least daily, and serum albumin should be monitored every 24 to 48 hours. Hypoalbuminemic animals may require support with synthetic or natural colloids. Although albumin levels less than 2 mg/dl have been associated with increased mortality in human patients, albumin transfusions to increase serum levels have not resulted in increased survival.12 Colloid osmotic pressure (COP), the osmotic pressure exerted by large molecules, serves to hold fluid within the vascular space. It is normally the role of plasma proteins, primarily albumin, that stay within the vasculature. Inadequate COP can contribute to vascular volume loss and peripheral edema. The COP can be measured directly with a colloid osmometer; however, it is not commonly available, so most clinicians will base assessment of oncotic pressure on serum total protein (see Chapter 185, Colloid Osmotic Pressure and Osmolality). The limitation to the use of serum total protein is that the correlation between the refractive index of infused synthetic colloids and COP is not reliable.13

Glucose Hyper and hypoglycemia can occur rapidly in critically ill patients. Blood glucose concentration should be monitored routinely. The frequency of measurement will depend on the severity of illness and the nature of the underlying disease. The development of hypoglycemia in a critically ill adult patient should prompt the consideration of sepsis. Studies of human ICU patients have also demonstrated increased morbidity and mortality associated with hyperglycemia.14 The 2016 Surviving Sepsis guidelines recommend targeted treatment for hyperglycemia in patients with an upper blood glucose level of 180 mg/dl.15 A veterinary study of 660 dogs presenting to an emergency room with a blood glucose concentration measured within 6 hours of presentation found hyperglycemia (.120 mg/dl) in 40.1% of dogs. Hypoglycemia was detected in 9.0%, and the mortality rates were significantly higher in hyper- and hypoglycemic patients (33.3% and 44.6%, respectively), compared with those with normoglycemia (24.9%).16

CHAPTER 2  Physical Examination and Daily Assessment of the Critically Ill Patient

Electrolyte and Acid-Base Balance Abnormalities in serum electrolytes are common in critically ill patients. Serum sodium, chloride, potassium, phosphorous, magnesium, and calcium should be monitored and maintained within the normal ranges through appropriate supplementation and crystalloid fluid choices. Measurement of acid-base status has become routine, and both arterial and venous samples can be evaluated. Interpretation of acidbase abnormalities can be aided by the measurement of lactate and electrolyte concentrations (see Chapters 59–61, Traditional and NonTraditional Acid-Base Analysis and Hyperlactatemia, respectively).

Oxygenation and Ventilation In addition to the physical examination described for the respiratory system, additional monitoring is recommended to objectively assess respiratory function. Respiratory failure can be a failure of oxygenation, resulting in hypoxemia, or a failure of ventilation, resulting in hypercapnia (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively). Pulse oximetry, end-tidal CO2 measurement, and arterial and venous blood gases can all be used to assess oxygenation and ventilation.

Red Blood Cell and Hemoglobin Concentrations The oxygen content of arterial blood is mostly bound to hemoglobin, making anemia an easily identified cause of reduced arterial oxygen content. Daily assessment of hemoglobin concentration is one important variable in a clinician’s understanding of a patient’s oxygen delivery. Human and canine studies have attempted to establish an optimal hematocrit value, or transfusion trigger, for oxygen transport with reported values ranging from 30% to 60%.17 With many interfering factors and adaptive mechanisms, it becomes more important to assess daily changes in patient hematocrit along with other individual variables affecting oxygen delivery in order to determine the need for transfusions of whole blood, packed red blood cells, or hemoglobincontaining solutions.

Blood Pressure Blood pressure can be measured indirectly by Doppler or oscillometric techniques or directly via an indwelling arterial catheter. Blood pressure should be measured at least daily in critically ill patients. Continuous blood pressure monitoring may be indicated for hemodynamically unstable patients (see Chapter 181, Hemodynamic Monitoring).

Coagulation Coagulation abnormalities often occur in critically ill patients. They can result from primary diseases such as vitamin K antagonist intoxication or hepatic disease, a coexisting problem such as von Willebrand disease, or nonsteroidal antiinflammatory drug administration, or because of an acquired problem such as dilutional coagulopathy or disseminated intravascular coagulation. The choice of coagulation test will depend on the patient’s history, primary disease process, and available tests. Practices should be able to evaluate platelet number, function, and clotting factor function (see Chapters 104 and 186, Coagulopathy in the ICU and Coagulation and Platelet Monitoring, respectively).

13

disease are at risk of acute kidney injury. Critical patients often receive potentially nephrotoxic drugs. Normal urine output in a well-perfused, normally hydrated patient is 1 to 2 ml/kg/hr. In both oliguric and polyuric patients, measurement of fluid intake and GI and urinary losses can be used to facilitate fluid therapy. Indwelling urinary catheters are often used in the critically ill patient to maintain normal bladder size and prevent urine scald. Because they allow for frequent checks of urine output, indwelling urinary catheters should also be considered a simple monitoring technique. With careful attention to cleanliness, these can be very effective tools without significant risk of ascending urinary tract infection.18 Serum creatinine and blood urea nitrogen levels should be monitored daily during a crisis period. Urine should be evaluated daily for evidence of renal tubular casts or glucosuria.

Immune Status, Antibiotic Dosage and Selection, and White Blood Cell Count Bacterial infection is a common complication in ICU admissions (see Part IX: Infectious Disorders). Empiric broad-spectrum, parenteral antibiotic therapy is often initiated based on knowledge of common pathogens and results of Gram staining of appropriate specimens. Culture and sensitivity results should be reviewed when available and empiric antibiotic choices adjusted accordingly. White blood cell count and differential should be monitored frequently for evidence of new or nonresponsive infections.

DRUG DOSAGES AND METABOLISM Drug dosages should be reviewed daily. Animals with renal and hepatic dysfunction or neonatal patients may have altered metabolism and/or distribution, and dosages may need to be adjusted. Interactions among drugs should be considered in animals receiving multiple therapies.

NUTRITION GI dysfunction can present in many ways, from nausea, changes in appetite, and anorexia to more the serious loss of intestinal mucosal integrity, hemorrhagic diarrhea, enteric bacterial translocation, septicemia, and death. Attention to total food intake, nausea behaviors, stomach size and GI motility via POCUS, and digital rectal examination for GI bleeding and stool character are all points to assess regularly. Symptomatic treatment of the GI complications associated with critical illness can be an important consideration in these patients. Examples of these treatments include antiemetics, antiulcer strategies, motility modifying drugs, and antibiotics. Once a patient is hemodynamically stable, caloric intake becomes an important monitoring variable and treatment goal (see Chapter 124, Nutritional Assessment). Nutrition is an essential yet commonly overlooked component of successful management of the critical patient. Patients that develop a negative energy and protein balance may develop a loss of host defenses, loss of muscle strength, visceral organ atrophy and dysfunction, GI barrier breakdown, pneumonia, sepsis, and death. Enteral malnutrition is a predisposing factor in bacterial translocation and secondary sepsis, making enteral feeding the preferred route when possible (see Chapters 126 and 127, Enteral and Parenteral Nutrition, respectively).

Renal Function and Urine Output

NURSING CARE

Urine output should be monitored in critically ill patients (see Chapter 192, Urine Output). Decreased urine output can reflect inadequate renal perfusion or acute renal failure. Patients who have experienced hypotension during anesthesia or secondary to their underlying

Recumbent patients require attentive nursing care to prevent secondary complications. Patients should be turned every 4 to 6 hours through both laterals and sternal recumbency and encouraged to take deep breaths to prevent pulmonary atelectasis. The skin should be

14

PART I  Key Critical Care Concepts

assessed often. Pressure points over bony protuberances should be evaluated regularly to prevent decubitus ulcers. Moisture from urine, feces, or other draining fluids should be identified early to prevent scalding of the skin. Urine output and bladder size should be monitored frequently. This is especially true in animals at risk for renal failure or in patients with neurologic disease that prevents normal micturition. Frequent assessment of patient comfort is subjective but important (see Chapter 131, Pain Assessment). Appropriate pain control should always be provided (see Chapter 134, Analgesia and Constant Rate Infusions). Hands-on contact with the patient is invaluable in highquality clinical assessment and monitoring. Mental health is as important as physical health. Comfortable, dry bedding, gentle handling by staff members, and visits from owners are important. If possible, normal circadian rhythms should be maintained, with lights out or dimmed at night. Owner visits may improve the attitude of the patient and provide insights that may not be appreciated with the physical examination alone.

REFERENCES 1. Prittie J: Optimal endpoints of resuscitation and early goal-directed therapy, J Vet Emerg Crit Care 16:329, 2006. 2. Illuzzi E, Gillespie M. Physical Examination in the ICU. In: Oropello JM, Pastores SM, Kvetan V. eds. Critical Care. McGraw Hill. Accessed June 29, 2022. https://accessmedicine-mhmedical-com.proxy.library.upenn.edu/ content.aspx?bookid=1944§ionid=143515966 3. Aldrich J: Global assessment of the emergency patient, Vet Clin North Am Small Anim Pract 35:281, 2005. 4. Kittleson MD: Signalment, history and physical examination. In Kittleson MD, Kienle RD, editors: Small animal cardiovascular medicine, St. Louis, 1998, Mosby. 5. Chalifoux N, Spielvogel CF, Stefanovski D, Silverstein DC: Standardization and reliability of capillary refill time in hospitalized dogs, J Vet Emerg Crit Care 31(5):545-674, 2021.

6. Ateca LB, Reineke EL, Drobatz KJ: Evaluation of the relationship between peripheral pulse palpation and Doppler systolic blood pressure in dogs presenting to an emergency service, J Vet Emerg Crit Care (San Antonio) 28(3):226-231, 2018. doi:10.1111/vec.12718. 7. Kotlikoff MI, Gillespie JR: Lung sounds in veterinary medicine. Part I. Terminology and mechanisms of sound production, Comp Cont Educ Pract Vet 5:634, 1984. 8. Chiang V, Hopper K, Mellema MS: In vitro evaluation of the efficacy of a veterinary dry heat fluid warmer, J Vet Emerg Crit Care 21(6):639-647, 2011. 9. Boysen SR, Rozanski EA, Tidwell AS, et al: Evaluation of a focused assessment with sonography for trauma protocol to detect free abdominal fluid in dogs involved in motor vehicle accidents, J Am Vet Med Assoc 225(8):1198-1204, 2004. 10. Winters BD, Gurses AP, Lehmann H, Sexton CJ, Pronovost PJ: Clinical review: checklists—translating evidence into practice, Crit Care 13:1, 2009. 11. Kirby R: Septic shock. In Bonagura JD, editor: Current veterinary therapy XII, Philadelphia, 1995, Saunders, pp 139-146. 12. Mazzaferro EM, Rudloff E, Kirby R: The role of albumin replacement in the critically ill veterinary patient, J Vet Emerg Crit Care 12:113, 2002. 13. Bumpus SE, Haskins SC, Kass PH: Effect of synthetic colloids on refractometric readings of total solids, J Vet Emerg Crit Care 8:21-26, 1998. 14. Krinsley JS: Effect of an intensive glucose management protocol on the mortality of critically ill adult patient, Mayo Clin Proc 79:992, 2004. 15. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43:304-377, 2013. 16. Hagley SP, Hopper K, Epstein SE: Etiology and prognosis for dogs with abnormal blood glucose concentrations evaluated in an emergency room, J Vet Emerg Crit Care 30(5):567-573, 2020. doi:10.1111/vec.12996. 17. Winfield WE: The transfusion trigger. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, WY, 2002, Teton NewMedia. 18. Smarick SD, Haskins SC, Aldrich J, et al: Incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit, J Am Vet Med Assoc 224:1936, 2004.

3 Hemostasis Ronald H. L. Li, DVM, MVetMed, PhD, DACVECC

KEY POINTS • The initial interactions between platelets and the injured endothelium play a key role in initiating thrombus formation. • Elaborate connections between coagulation factors, the cell surface, and the immune system occur in vivo, which can be explained by the cell-based model of coagulation. • Dysregulation of the negative feedback mechanisms for controlling thrombin generation can lead to excessive fibrin deposition and spontaneous clot formation.

• Appropriate fibrinolysis has an essential role in hemostasis, while excessive fibrinolysis can lead to bleeding, and inadequate fibrinolysis promotes thrombosis. • Immunothrombosis is an important component of innate immunity mediated by the formation of neutrophil extracellular traps.

The hemostatic system, which comprises circulating blood, endothelium, and subendothelial matrixes, is necessary to maintain blood flow to organs and tissues in the face of dynamic pathophysiologic conditions. Under normal physiologic conditions, a delicate balance between antithrombotic and prothrombotic properties is constantly maintained. In response to damage to the vasculature, the hemostatic system rapidly responds to limit excess blood loss and tissue destruction. However, many critically ill animals have underlying disease processes that disrupt the dynamic balance of hemostasis, clinically manifested by either bleeding or thrombosis. This chapter focuses on the fundamental concepts in the physiology of hemostasis, including platelet physiology, their interactions with the humoral coagulation network, and many of the feedback mechanisms that regulate the hemostatic system.

per platelet. The seven-transmembrane receptor family is the major agonist receptor family that includes thrombin receptors (protease activation receptors [PAR]), ADP receptors (P2Y1 and P2Y12), thromboxane receptors, and prostacyclin (PGI2)/prostaglandin (PGE2) receptors. Lastly, platelets contain unique membrane-bound granules within the cytoplasm. a-Granules are unique to platelets and contain a variety of membrane/soluble proteins that are integral to hemostasis/ thrombosis, inflammation, angiogenesis, host defense, and mitogenesis. Platelet dense granules, a subtype of lysosome-related organelle, contain high concentrations of cations, polyphosphates, adenosine nucleotides, and bioactive amines like serotonin and histamine. Granular contents are released following platelet activation.

OVERVIEW OF PLATELET STRUCTURE AND FUNCTION Platelets, which are anuclear, discoid-shaped, subcellular fragments of megakaryocytes, are the primary effector cells of hemostasis. The peripheral zone of a platelet consists of the plasma membrane, receptors, integrins, surface-connected open canalicular system, and dense tubular system. The open canalicular system consists of membrane-lined invaginations that extend deep within the cytoplasm, providing passages for secretory products as well as uptake or transfer of products from plasma. The platelet plasma membrane, with its asymmetrical composition, plays a significant role in cell signaling and thrombin generation. Lipid rafts, a subdomain of the phospholipid bilayer consisting of high concentrations of cholesterol and glycosphingolipids, carry signaling molecules such as integrins and glycoproteins along the plasma membrane to initiate signal transduction.1 Abrupt disturbance of these lipid rafts can lead to unnecessary cell signaling and platelet activation. Platelet integrins are heterodimeric receptors consisting of transmembrane a and b subunits that mediate cell–cell interaction and cell–matrix interactions. Integrins must undergo conformational changes from their low-affinity to high-affinity states, leading to firm adhesion to extracellular matrix or fibrinogen and, subsequently, robust cell signaling and activation (outside-in signaling).2 Of these, aIIbb3 is the most abundant integrin with 80,000 to 100,000 copies

PRIMARY HEMOSTASIS AND THE THREE-STAGE MODEL OF PLATELET ACTIVATION Primary hemostasis comprises the endothelium, the inner lining of blood vessels, platelets, and extracellular matrix components of the endothelium. The initial interactions between platelets and the injured blood vessels play a key role in initiating thrombus formation. The end goal of primary hemostasis is the formation of platelet aggregates that facilitate thrombus growth and stabilization. In pathological conditions, dysregulation of these interactions results in hemorrhage or thrombotic vascular occlusion. The initial platelet plug formation in flowing blood, commonly described as the three-stage model of platelet activation, is summarized in Fig. 3.1.

1. Initiation: Vascular injury leads to exposure of subendothelial collagen complexes, fibronectin, laminin, and von Willebrand factor (vWF), a multimeric glycoprotein.3 Of these, vWF and collagen play a key role in platelet adhesion. vWF, stored within the Weibel–Palade bodies of endothelial cells and the platelet a-granules, is also secreted into plasma upon activation of endothelial cells and platelets, respectively. The pathological level of shear stress results in conformational changes of vWF and its receptor, glycoprotein GP1ba (subunit of GP1b-IX-V), thus increasing their binding affinity to each other.4 Plasma vWF, once cleaved and immobilized on collagen, forms multimers that capture

15

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PART I  Key Critical Care Concepts

Fig. 3.1  A schematic diagram summarizing the three-stage model of platelet activation demonstrating initiation, extension, and stabilization of the initial platelet plug formation in flowing blood.

platelets at vascular lesions. The initial binding of vWF and platelet glycoprotein (GP1ba) results in tethering and rolling of platelets along the endothelium.5 As the velocity of rolling decreases, bonds between vWF and GP1ba increase and strengthen, leading to adhesion and formation of a platelet monolayer. The binding of platelets to collagen and vWF triggers platelet activation (Fig. 3.1).6

2. Extension: Extension of the adhered platelet monolayer on injured vessels undergoes further activation resulting in secretion, shape change, formation of the procoagulant membrane, and integrin activation.7 Local accumulation of thrombin and secretion of agonists such as thromboxane A2 and ADP act as autocrine and paracrine factors to recruit and

CHAPTER 3  Hemostasis activate nearby platelets. Agonists then trigger inside-out signaling, which activates integrins, of which the most essential is the binding of fibrinogen to aIIbb3, to initiate platelet aggregation. The activation of integrin, as a result of inside-out signaling, facilitates conformational changes from a low-affinity to high-affinity state.2 (Fig. 3.1).

Stabilization: Firm adhesion to fibrinogen via platelet integrins results in outside-in signaling, a cascade of events that occur downstream of integrins, and leads to the clustering of the platelet integrin within the lipid rafts and protein complexes that are linked to the actin/myosin filaments.2 Mechanical forces generated by contraction of actin/myosin filaments in platelet further strengthen platelet-to-platelet interactions by narrowing the gap between platelets and preventing the diffusion of activators away from the platelets, hence fostering a local procoagulant microenvironment. This also causes clot retraction when fibrin is deposited, thereby further stabilizing the platelet plug while minimizing premature disaggregation (Fig. 3.1).

SECONDARY HEMOSTASIS The end goal of secondary hemostasis is the formation of a stable fibrin clot. A series of enzymatic reactions activates thrombin (factor II). The coagulation cascade, which is initiated by two distinct pathways (extrinsic and intrinsic), leads to activation of the common pathway (factors X, V, prothrombin, and fibrinogen) (Fig. 3.2). The theory that secondary hemostasis exists as three arbitrary pathways remains conceptually important to this day as it is helpful for clinicians to interpret results of coagulation assays such as prothrombin time or activated partial thromboplastin time for the screening of clotting factors deficiencies. It is important to note, however, that this model of the coagulation cascade does not occur in vivo as it neglects the elaborate connections between coagulation factors, the cell surface, and the immune system.8

Cell-based Model of Coagulation In vivo, secondary hemostasis takes place on phospholipids on the external leaflet of intact cells, including fibroblasts, platelets, leukocytes and microparticles, which are subcellular membrane-bound particles. Phospholipids provide docking sites for the assembly of coagulation complexes to form. For this to occur, two important events must take place: 1. Disruption of membrane asymmetry and exposure of negatively charged phospholipids. Phosphatidylserine (PS) plays a key role in coagulation complex formations during secondary hemostasis. The localization of PS is dynamic, capable of moving between the cytoplasmic and exoplasmic (outer) leaflets of the cell membrane. This is mediated by the coordinated actions of the transmembrane enzymes flippase, floppase and scramblase. 9 During homeostasis, PS is largely maintained in the cytoplastic membrane leaflets of the cell membrane by flippase. Increased activity of scramblase in apoptotic cells and activated platelets facilitates the exposure of PS on the cell surface, providing necessary docking sites for the assembly of tenase (factors IXa-VIIIa) and prothrombinase complexes (factors Xa-Va) on cells.10 A good example of the importance of membrane topology in hemostasis is the congenital disorder Scott syndrome, which is caused by a mutation of the gene affecting scramblase function and production. Despite normal platelet function and clotting factors, dogs with Scott syndrome have bleeding diathesis that resembles the phenotypes of hemophilia (see Chapter 103, Platelet Disorders).11 2. Gamma-carboxylation of glutamic acid of clotting factors. Clotting factors must first undergo posttranslational modification enabling

17

them to interact with negatively charged phospholipids. The process of g-carboxylation is carried out by vitamin K-dependent carboxylase, which facilitates the addition of an extra negative charge on glutamic acid on clotting factors X, IX, VII, II, protein C, and protein S; hence the name “vitamin K-dependent coagulation factors.” This allows clotting factors to bind to calcium, resulting in a conformational change that enables them to interact with PS on the cell surface (Fig. 3.2). The drug warfarin disrupts the vitamin K cycle to stop g-carboxylation of glutamic acid on clotting factors to achieve its anticoagulant property. The cell-based model of coagulation comprises four phases (initiation, amplification, propagation, and termination) and not only emphasizes the contribution of the cell membrane to thrombin generation but also highlights the feedback mechanisms that amplify the coagulation cascade while preventing excessive fibrin formation. Fig. 3.3 summarizes the cell-based model of coagulation.

Initiation: Factor VII and tissue factor (TF) are considered the main initiator of secondary hemostasis. Factor VII, produced by the liver as a zymogen, is converted to a serine protease, factor VIIa, by minor proteolysis in the blood. Factor VIIa (FVIIa) has little enzymatic activity in the absence of TF, a transmembrane glycoprotein, which is mainly synthesized in adventitial fibroblasts. Upon vascular injury, the exposure of TF-bound fibroblasts to FVIIa facilitates the assembly of the FVIIa-TF complex, which activates small amounts of factors IX and X. Activated factor X (FXa) activates FV to form the prothrombinase complex (FXa-FVa) converting small amounts of prothrombin (FII) to thrombin (FIIa).12,13 This is essential for the continuation to the next phase, amplification. It is believed that the initiation phase is continuously occurring outside the blood vessels in the absence of vascular injury.

Amplification: Upon vascular injury, platelets, which play a dominant role in primary hemostasis, leave the vasculature and bind to extracellular matrixes such as collagen to form the initial platelet plug, where it provides procoagulant membrane surfaces for clotting factors to bind to. In addition, activated platelets also release partially activated factor V. The small amount of thrombin generated during the initial phase has several important functions. First, thrombin, as a potent platelet agonist, maximizes platelet aggregation and formation of procoagulant membrane. Second, thrombin activates factors XI, V, and VIII, which become dissociated from vWF (Fig. 3.3B).14 Factors attached on the surface of platelets lead to the propagation phase.

Propagation: This phase is characterized by the production of a substantial amount of thrombin via formations of the tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets (Fig. 3.3C).14 In addition to the FIXa generated during the initiation phase, more FIXa is generated by FXIa bound on platelets. The formation of tenase complex facilitates the generation of large amounts of FXa, which results in prothrombinase complex formation leading to activation of large amounts of FIIa (thrombin). Thrombin is responsible for cleaving fibrinogen into fibrin monomers that eventually polymerize to form a fibrin clot. Factor XIII, which is activated by thrombin, is responsible for the crosslinking of fibrin monomers to further stabilize fibrin clots.

Termination: An essential feature of the coagulation system is its ability to regulate fibrin formation so that a stable clot is formed without excessive thrombosis within the vasculature. In general, there are several negative

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PART I  Key Critical Care Concepts

Fig. 3.2  Traditional model of the coagulation cascade divided into extrinsic, intrinsic/contact, and common pathways. Vitamin K-dependent coagulation factors FVII, FX, FIX, and FII undergo g-carboxylation, which facilitates the binding of calcium and complex formations on phospholipids, and are outlined in red here. Prothrombin time (PT) is sensitive to the deficiencies in coagulation factors in the extrinsic and common pathway (excluding tissue factor) while activated partial thromboplastin time (APTT) and activated clotting time (ACT) allow assessment of deficiencies of clotting factors in the intrinsic and common pathways. HMWK, high molecular weight kininogen.

feedback mechanisms for controlling thrombin generation. First, the endothelium produces and secretes tissue factor pathway inhibitor (TFPI), which regulates coagulation through inhibition of a quaternary complex of TPFI, FVIIa, FXa, and TF. The natural anticoagulant antithrombin (AT), which is produced by the liver, inhibits thrombin generation by forming molar complexes with thrombin, FIXa, FXa, FXIa, and FXIIa and is facilitated by the glycosaminoglycans, heparin, and heparin sulfate by inducing conformational changes to AT. Animals deficient in AT due to protein-losing nephropathy or enteropathy are at increased risk for thrombosis.15 Protein C and protein S are vitamin K-dependent natural anticoagulants that play an essential role in controlling excessive coagulation. Protein C is activated by thrombin bound to thrombomodulin (TM), which is a transmembrane protein expressed on endothelial cells. This process can be further augmented by endothelial cell protein C receptor, which is another endothelial transmembrane protein. Activated protein C, once bound with its cofactor, protein S, inhibits coagulation by causing proteolysis of factors Va and VIIIa (Fig. 3.3D).16

OVERVIEW OF FIBRINOLYSIS Following healing of the vascular lesion, the fibrin clot must be dissolved to allow the reestablishment of blood flow. This process, termed

fibrinolysis, is a highly regulated system maintained by a dynamic equilibrium between proteolytic and inhibitory proteins; excessive breakdown of fibrin results in bleeding, whereas inadequate fibrinolytic activity may exacerbate the extension of thrombus formation. Fig. 3.4 summarizes the intricate balance of fibrinolysis.

Activators of Fibrinolysis Plasminogen, a zymogen form of plasmin that is predominantly produced by the liver and is present in tissues such as kidneys and brain, plays a key role in fibrinolysis. Fibrinolysis occurs when plasminogen is cleaved to plasmin by two physiologic activators, tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), to generate a two-chain molecule linked by disulfide bonds. tPA is constituently expressed in the endothelium and is also stored in vesicles of various cell types such as neuroendocrine and adrenal chromaffin cells. tPA is rapidly released into the circulation upon stimulation by agonists from the coagulation cascade such as thrombin and FXa, and beta-adrenergic agents, histamine, and bradykinin. Plasminogen is only readily activated by tPA in the presence of fibrin via the formation of a tertiary complex (Fig. 3.4).17 The amino acid lysine on fibrin binds to the lysine-binding sites on plasminogen. These lysine residues are crucial for facilitating tPA-catalyzed plasminogen activation.18 In fact, the antifibrinolytic drugs tranexamic acid and

CHAPTER 3  Hemostasis

19

Fig. 3.3  A summary of the cell-based model of coagulation. A, Initiation: Tissue factor (TF)-bearing cells come into contact with FVIIa, which facilitates the formation of small amounts of thrombin (FIIa). B, Amplification: Thrombin activates platelets to degranulate and externalize phosphatidylserine, which facilitates their adhesion to subendothelial matrixes and activates other factors (FXI, V and VIII). C, Propagation: Formation of tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets propagates massive formation of thrombin. D, Termination: Thrombin generation is countered by endogenous anticoagulants including tissue factor pathway inhibitor (TFPI), protein C (PC), protein S (PS), and antithrombin.

aminocaproic acid are synthetic derivatives of lysine, which irreversibly binds to the lysine-binding sites on plasminogen, thereby preventing its interaction with fibrin and its activation to plasmin.19 uPA, also known as urokinase, is activated from single-chain urinary plasminogen activator by plasmin and does not require fibrin as a cofactor. Instead, it binds to the specific uPA receptor on certain cell types, which enhances the activation of cell-bound plasminogen.

Inhibitors of Fibrinolysis The two most important inhibitors of fibrinolysis are plasminogen activator inhibitor 1 (PAI-1) and alpha-2 antiplasmin. Platelets are the main source of circulating PAI-1, although it is produced in many other cell types such as endothelial and smooth muscle cells, cardiac myocytes, hepatocytes, and adipocytes.20 PAI-1 inhibits fibrinolysis by formation of non-covalent complexes with tPA and uPA.17 Alpha-2 antiplasmin, produced by the liver, inhibits fibrinolysis by either binding noncovalently to plasminogen or crosslinking to fibrin, thus preventing plasmin and tPA from binding to fibrin (Fig. 3.4). Thrombin-activatable fibrinolysis inhibitor (TAFI), also produced by the liver, is a zymogen that is activated by the thrombin/TM complex and plasmin. Once activated, TAFI removes the lysine residues, which are crucial for the binding of plasminogen to fibrin and

fibrinolysis. Alpha-2 macroglobulin, C1-inhibitor, and lipoprotein(a) are other minor inhibitors of fibrinolysis.

IMMUNOTHROMBOSIS The innate immune system functions as an active initiator of thrombosis through the activation of neutrophils, monocytes, and dendritic cells to propagate clot formation and activate platelets. For example, inflammatory cytokines such as tissue necrosis factor and interleukins can upregulate TF expression on endothelial cells and macrophages. On the other hand, coagulation factors can also bind to protease-activated receptors on immune cells to facilitate the release of cytokines.21 Increased fibrin formation within the vasculature in the face of pathogen invasion is an important first line of defense as it prevents systemic dissemination of pathogens via the circulation. This protective mechanism known as immunothrombosis can become dysregulated in diseases resulting in excessive clot formation or consumptive coagulopathy. Neutrophil extracellular traps (NETs), which are web-like scaffolds of cell-free DNA (cfDNA) decorated with neutrophil granular proteins, are key players in the genesis of immunothrombosis. Recently, NETs have been found to be structural components of human and feline arterial thrombi, highlighting the multifaceted abilities of NETs to stimulate thrombus generation.22,23 First, cell-free double-stranded

20

PART I  Key Critical Care Concepts

Fig. 3.4  The primary initiators of fibrinolysis are tissue plasminogen activator (tPA) and urinary-type plasminogen activator (uPA). The formation of a tertiary complex, tPA, in the presence of fibrin converts plasminogen to plasmin, which cleaves fibrin to fibrin degradation products (FDPs). Fibrinolysis is mainly inhibited by plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, and alpha2-antiplasmin (a2-AT). Once activated by the thrombin-thrombomodulin (T-TM) complex, thrombin activable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by removing the lysine residues on fibrin.

DNA, which forms the architectural structure of NETs, facilitates binding of factor XII and other contact activation factors such as high- molecular weight kininogen to activate the contact pathway of coagulation. The web-like structure of cfDNA also fortifies clots by binding to circulating erythrocytes, platelets, and clotting factors, including TF and fibrin.24 Moreover, histones on NETs can activate platelets and increase thrombin generation.25 Histones exhibit further prothrombotic effects by modulating the activation of the natural anticoagulant protein C. NETs can also impede fibrinolysis by the formation of ternary complex of DNA, plasmin, and fibrin.23

SUMMARY Hemostasis is a complex and balanced process facilitated by a network of zymogens, proteins, phospholipids, platelets, immune cells, and the endothelium. It is also meticulously regulated via intricate negative feedback mechanisms. There are numerous interactions between innate immunity and the coagulation system. Excessive innate immune response seen in sepsis or systemic inflammation can lead to dysregulation of hemostasis, causing thrombotic or consumptive coagulopathy via NETs production or an extensive crosstalk between inflammation and coagulation.

REFERENCES 1. Komatsuya K, Kaneko K, Kasahara K: Function of platelet glycosphingolipid microdomains/lipid rafts, Int J Mol Sci 21:5539, 2020. 2. Durrant TN, van den Bosch MT, Hers I: Integrin IIb3 outside-in signaling, Blood 130:1607-1619, 2017. 3. Nagy M, Heemskerk JWM, Swieringa F: Use of microfluidics to assess the platelet-based control of coagulation, Platelets 28:441-448, 2017. 4. Kim J, Zhang CZ, Zhang X, et al: A mechanically stabilized receptor- ligand flex-bond important in the vasculature, Nature 466:992-995, 2010. 5. Dopheide SM, Maxwell MJ, Jackson SP: Shear-dependent tether formation during platelet translocation on von Willebrand factor, Blood 99: 159-167, 2002. 6. Ruggeri ZM, Orje JN, Habermann R, et al: Activation-independent platelet adhesion and aggregation under elevated shear stress, Blood 108: 1903-1910, 2006. 7. Goggs R, Poole AW: Platelet signaling-a primer, J Vet Emerg Crit Care (San Antonio) 22:5-29, 2012. 8. Hoffman M: A cell-based model of coagulation and the role of factor VIIa, Blood Rev 17(Suppl 1):S1-S5, 2003. 9. Suzuki J, Umeda M, Sims PJ, et al: Calcium-dependent phospholipid scrambling by TMEM16F, Nature 468:834-838, 2010. 10. Tzima E, Walker JH: Platelet annexin V: the ins and outs, Platelets 11: 245-251, 2000.

CHAPTER 3  Hemostasis 11. Jandrey KE, Norris JW, Tucker M, et al: Clinical characterization of canine platelet procoagulant deficiency (Scott syndrome), J Vet Intern Med 26:1402-1407, 2012. 12. Bouchama A, Al-Mohanna F, Assad L, et al: Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon, Crit Care Med 40:1229-1236, 2012. 13. Butenas S, van ‘t Veer C, Mann KG: Evaluation of the initiation phase of blood coagulation using ultrasensitive assays for serine proteases, J Biol Chem 272:21527-21533, 1997. 14. Negrier C, Shima M, Hoffman M: The central role of thrombin in bleeding disorders, Blood Rev 38:100582, 2019. 15. Jacinto AML, Ridyard AE, Aroch I, et al: Thromboembolism in dogs with protein-losing enteropathy with non-neoplastic chronic small intestinal disease, J Am Anim Hosp Assoc 53:185-192, 2017. 16. Esmon CT: The protein C pathway, Chest 124:26S-32S, 2003. 17. Thelwell C, Longstaff C: The regulation by fibrinogen and fibrin of tissue plasminogen activator kinetics and inhibition by plasminogen activator inhibitor 1, J Thromb Haemost 5:804-811, 2007. 18. Voskuilen M, Vermond A, Veeneman GH, et al: Fibrinogen lysine residue A alpha 157 plays a crucial role in the fibrin-induced acceleration of

21

plasminogen activation, catalyzed by tissue-type plasminogen activator, J Biol Chem 262:5944-5946, 1987. 19. McCormack PL: Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis, Drugs 72:585-617, 2012. 20. Brogren H, Karlsson L, Andersson M, et al: Platelets synthesize large amounts of active plasminogen activator inhibitor 1, Blood 104:3943-3948, 2004. 21. Kranzhofer R, Clinton SK, Ishii K, et al: Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes, Circ Res 79:286-294, 1996. 22. Duler L, Nguyen N, Ontiveros E, et al: Identification of neutrophil extracellular traps in paraffin-embedded feline arterial thrombi using immunofluorescence microscopy, J Vis Exp (157), 2020. 23. Ducroux C, Di Meglio L, Loyau S, et al: Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke, Stroke 49:754-757, 2018. 24. Martinod K, Wagner DD: Thrombosis: tangled up in NETs, Blood 123:2768-2776, 2014. 25. Semeraro F, Ammollo CT, Morrissey JH, et al: Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4, Blood 118:1952-1961, 2011.

4 Cardiopulmonary Resuscitation Daniel J. Fletcher, PhD, DVM, DACVECC, Manuel Boller, Dr med vet, MTR, DACVECC

KEY POINTS • Early recognition of cardiopulmonary arrest (CPA) and rapid initiation of cardiopulmonary resuscitation (CPR) are crucial for patient survival. • Basic life support, consisting of high-quality chest compressions at a rate of 100–120 per minute, a depth of one-third to one-half the width of the chest, and delivered in uninterrupted cycles of 2 minutes, as well as ventilation at a rate of 10 breaths per minute, is arguably the most important aspect of CPR. • Monitoring priorities during CPR include electrocardiography to obtain a rhythm diagnosis and end-tidal carbon dioxide monitoring

to evaluate the effectiveness of chest compressions and as an early indicator of return of spontaneous circulation. • Advanced life support interventions for asystole and pulseless electrical activity include vasopressor therapy and parasympatholytic therapy, especially in cases of bradycardic arrest due to high vagal tone. • The most effective advanced life support therapy for ventricular fibrillation is electrical defibrillation. Only a single shock should be delivered initially, followed by a full 2-minute cycle of basic life support before administering an additional shock in refractory ventricular fibrillation.

Cardiopulmonary arrest (CPA) in cats and dogs is a highly lethal condition, with rates of survival to discharge of only 6%–7%.1 Widespread training targeted to standardized cardiopulmonary resuscitation (CPR) guidelines in human medicine has led to substantial improvements in outcome after in-hospital CPA from 13.7% in 2000 to 22.3% in 2009.2 An exhaustive literature review completed by the Reassessment Campaign on Veterinary Resuscitation (RECOVER) initiative in 2012 generated the first evidence-based, consensus veterinary CPR guidelines.3 The evidence evaluation and guidelines were distributed among five domains: preparedness and prevention,4 basic life support (BLS),5 advanced life support,6 monitoring,7 and postcardiac arrest care.8 The goal of this chapter is to summarize the most important treatment recommendations from the first four domains. Chapter 5 discusses the postcardiac arrest care guidelines.

patient. In nonanesthetized patients, a diagnosis of CPA should be highly suspected in any unconscious patient that is not breathing. A brief assessment lasting no more than 10–15 seconds based on evaluation of airway, breathing, and circulation (ABC) will efficiently identify CPA. If CPA cannot be definitively ruled out, CPR should be initiated immediately rather than pursuing further diagnostic assessment. The rationale for this aggressive approach includes: (1) pulse palpation is an insensitive test for CPA in people, and this may also be the case in dogs and cats; (2) even short delays in starting CPR in pulseless patients reduce survival rates; and (3) starting CPR on a patient not in CPA carries minimal risks.18,19 Therefore, there should be no delay in starting CPR in any patient in which there is a suspicion of CPA.

PREPAREDNESS AND PREVENTION

BLS includes chest compressions to restore blood flow to the tissues and the pulmonary circulation and ventilation to provide oxygenation of the arterial blood and removal of carbon dioxide from the venous blood. BLS should be initiated as quickly as possible once a diagnosis of CPA has been made using the treatment mnemonic CAB (circulation, airway, breathing). More than any other CPR intervention, highquality BLS focused first on chest compressions followed by ventilation likely has the most significant impact on outcome.18 However, given the higher incidence of primary respiratory arrest in dogs and cats than in people, early airway management and ventilation are strongly recommended. In multiple rescuer CPR, an airway should be established simultaneously with the initiation of chest compressions.

It has been long understood that early recognition of and response to CPA are critical if survival rates are to be improved. Both didactic training targeted at establishing a baseline CPR knowledge base and hands-on practice for psychomotor skill development in training programs improve CPR performance and outcomes.9,10 Once baseline training has been completed, refresher training at least every 6 months is recommended for personnel likely to be involved in CPR attempts to reduce decline of skills and knowledge.11,12 A centrally located, routinely audited crash cart containing all necessary drugs and equipment should be maintained in the practice. Readily available cognitive aids, such as algorithm and dosing charts, improve adherence to guidelines as well as individual performance during CPR.13–15 Staff should be trained on the use of these aids regularly. Short post-event debriefing sessions where team performance is discussed and critically evaluated can help improve future performance and serve as refresher training at the same time.16,17 A standardized assessment leading to early recognition of CPA is crucial and should be applied immediately to any acutely unresponsive

22

BASIC LIFE SUPPORT

Circulation — Chest Compressions Tissue hypoxia and ischemic injury occur rapidly in patients with untreated CPA, an immediate consequence of which is the exhaustion of cellular energy stores. Altered cellular membrane potentials and organ dysfunction follow rapidly, and longer duration of ischemia primes the system for more severe reperfusion injury when tissue blood flow resumes. Administration of high-quality chest compressions can provide

CHAPTER 4  Cardiopulmonary Resuscitation vital blood flow to tissues, decreasing ischemic injury and blunting the reperfusion injury set in motion with return of spontaneous circulation (ROSC). Chest compressions are targeted at two main goals: (1) restoration of pulmonary CO2 elimination and oxygen uptake by providing pulmonary blood flow; and (2) delivery of oxygen to tissues to restore organ function and metabolism by providing systemic arterial blood flow. Even well-executed chest compressions produce only approximately 30% of normal cardiac output; therefore, meticulous attention to chest compression technique is essential. Any delay in starting high-quality chest compressions or excessive pauses in compressions reduce the likelihood of ROSC and survival to discharge. During ventricular systole in the spontaneously beating heart, coronary blood flow is negligible and at times may be retrograde; several mechanisms have been proposed to explain this finding, including backward pressure waves, the intramyocardial pump theory, coronary systolic flow impediment, and cardiac compression.20,21 This same phenomenon has been described during CPR using external chest compressions.22,23 Therefore, it is important to consider that the majority of myocardial perfusion during CPR occurs during the decompression phase of chest compressions and is predominantly determined by coronary perfusion pressure (CPP, also known as myocardial perfusion pressure), which is defined as the difference between aortic diastolic pressure (ADP) and right atrial diastolic pressure (RADP) (CPP 5 ADP – RADP). There is strong evidence that higher CPP during CPR is associated with better success in both humans and dogs, leading to the use of CPP as a primary marker of CPR quality.24,25 Unfortunately, little experimental or clinical data are available to guide chest compression technique in dogs and cats, but anatomical principles suggest that chest compressions may be delivered with the patient in either left or right lateral recumbency,26 with a compression depth of one-third to one-half the width of the chest and at a rate of 100–120 compressions per minute regardless of animal size or species. An experimental study in dogs showed that higher compression rates lead to higher CPP and coronary blood flow velocity, but because anterograde flow occurred only during chest decompression, net coronary blood flow decreased at compression rates above 120 per minute, so faster rates should be avoided.27 To ensure the correct compression frequency, the use of cues such as a metronome or a song with the correct tempo (e.g., the Bee Gees’ “Staying Alive”) is recommended. Leaning on the chest between compressions will reduce filling of the heart by preventing full elastic recoil of the chest and must be avoided. Compressions should be delivered without interruption in cycles of 2 minutes to optimize development of adequate CPP, as it takes approximately 60 seconds of continuous chest compressions before CPP reaches its maximum.28 CPP is the primary determinant of myocardial blood flow, and higher CPP is associated with a higher likelihood of ROSC. Electrocardiogram analysis to diagnose the arrest rhythm and pulse palpation to identify ROSC require pauses in chest compressions, and should be accomplished during a brief cessation (2–5 seconds) of compressions at the end of each 2-minute BLS cycle. To minimize compressor fatigue, a new team member should take over chest compressions during this planned pause. The generation of blood flow to the tissues during CPR occurs in fundamentally different ways than in a patient with a spontaneously beating heart. There are two models explaining the mechanisms of forward flow during external chest compressions, and based upon these models, it is likely that the most effective technique for chest compressions will depend upon patient size and chest geometry. The cardiac pump theory proposes that direct compression of the left and right ventricles increases ventricular pressure, opening the pulmonic and aortic valves and allowing blood flow to the lungs and the tissues respectively.29 Thoracic elastic properties allow the chest to recoil

23

between compressions, creating a subatmospheric intrathoracic pressure that draws venous blood into the ventricles prior to the subsequent compression. In contrast, an increase in overall intrathoracic pressure during a chest compression forcing blood from the thorax into the systemic circulation is proposed in the thoracic pump theory. Rather than as a pump, the heart acts simply as a conduit for blood flow.30 Taking these two theories into account and which is more likely to be most exploitable given an individual patient’s thoracic shape and size, recommendations can be made for rescuer hand position during chest compressions. Table 4.1 specifies the recommended approach to chest compressions in dogs and cats based upon size and thoracic conformation. It should be noted that although animals of the same breed tend to have similar chest conformations, each individual should be evaluated independently and the most appropriate technique applied regardless of breed. Medium to large dogs with round chest conformations (lateral width similar to dorsal-ventral height) are likely best compressed in lateral recumbency using the thoracic pump theory by placing the hands over the widest portion of the chest (the highest point when laying in lateral recumbency). In contrast, similarly sized dogs with deeper, keel-chested conformations (lateral width significantly smaller than dorsal-ventral height) are likely to be more effectively compressed using a cardiac pump approach, with the hands placed directly over the heart. In markedly flat-chested dogs (such as many English Bulldogs) with dorsoventrally compressed chests similar to humans (lateral width significantly larger than dorsal-ventral depth), the cardiac pump theory may be maximally employed by positioning the hands over the sternum with the patient in dorsal recumbency. In medium to large dogs with low chest compliance, considerable compression force is necessary for CPR to be effective. The compressor’s posture has a significant impact on efficacy; the compressor should lock the elbows with one hand on top of the other and position the shoulders directly above the hands. Engaging the core muscles rather than the biceps and triceps by using this posture will allow the compressor to maintain optimal compression force and reduce fatigue. The use of a step stool is recommended if the patient is on a table and the elbows cannot be locked. Alternatively, the compressor can kneel over the patient by climbing onto the table or placing the patient on the floor. Chest compressions should be done directly over the heart in most cats and small dogs. These patients tend to have highly compliant, predominantly keel-shaped chests that favor the cardiac pump mechanism. Either the same two-handed technique as described above for large dogs or a single-handed technique with the hand wrapped around the sternum and compressions achieved by squeezing the chest can be used. Circumferential compressions of the chest using both hands may also be considered.

Airway and Breathing — Ventilation Dogs and cats in CPA should be ventilated as soon as possible after chest compressions are started. Patients should be intubated immediately if the equipment is available. Intubation should occur in lateral recumbency without interrupting chest compressions. In intubated patients, chest compressions and ventilation are done simultaneously. The inflated endotracheal tube cuff prevents gastric insufflation with air, allows pulmonary inflation during chest compressions, and minimizes interruptions in chest compressions. The following ventilation targets should be used during CPR: ventilation rate of 10 breaths per minute, a short inspiratory time of approximately 1 second, and a tidal volume of approximately 10 ml/kg. This low minute ventilation is adequate during CPR because pulmonary blood flow is reduced. Because low arterial CO2 tension causes cerebral vasoconstriction leading to decreased cerebral blood flow and oxygen delivery, hyperventilation

24

PART I  Key Critical Care Concepts

TABLE 4.1  Chest Compression Approaches Conformation

Breed Examples

Predominant Theory

Technique

Medium and large breed round-chested dogs

• Labrador Retriever • Golden Retriever • Rottweiler • German Shepherd • American Pitbull Terrier

Thoracic pump

Lateral recumbency, two-hand technique, hands over the widest part of the chest (highest point in lateral recumbency)

Medium and large breed keel-chested dogs

• Greyhound • Doberman Pinscher

Cardiac pump

Lateral recumbency, two-hand technique, hands directly over the heart

Flat-chested dogs

• English Bulldog • French Bulldog

Cardiac pump

Dorsal recumbency, two-hand technique, hands directly over the sternum

Cats and small dogs in average body condition • All cats • Chihuahua • Yorkshire Terrier • Maltese • Shih Tzu

Cardiac pump

Lateral recumbency, (a) one-hand technique, hand wrapped around sternum over heart (2) twohand technique, hands directly over the heart, take care not to over-compress the chest

Obese cats and small dogs

Cardiac pump

Lateral recumbency, two-hand technique, hands over the heart (if chest is keel-shaped) or the widest part of the chest (if chest if roundshaped)

or Thoracic pump

must be avoided. In addition, increased intrathoracic pressure due to positive pressure ventilation will impede venous return to the chest, reducing effectiveness of chest compressions and reducing CPP. Therefore, limiting the ventilation rate to reduce the mean intrathoracic pressure will improve cardiac output. Mouth-to-snout ventilation is an alternative breathing strategy and will provide sufficient oxygenation and CO2 removal but should only be used if endotracheal intubation is not possible. Firmly close the animal’s mouth with one hand while extending the neck to align the snout with the spine. The rescuer should then make a seal over the patient’s nares with his/her mouth and inflate the lungs by blowing firmly into the nares while visually inspecting the chest during the procedure, continuing the breath until a normal chest excursion is accomplished. An inspiratory time of approximately 1 second should be targeted. Because ventilation cannot be accomplished simultaneously with chest compressions in nonintubated patients, rounds of 30 chest compressions should be delivered, immediately followed by two short breaths. Compressions and mouth-to-snout breaths at a ratio of 30:2 should be continued for 2-minute cycles, and the rescuers rotated every cycle to prevent fatigue. This technique necessitates pauses in chest compressions and should only be employed when endotracheal intubation is impossible due to lack of equipment or trained personnel.

MONITORING Because of motion artifact and the lack of adequate pulse quality during CPR, many monitoring devices are of limited use, including pulse oximeter and indirect blood pressure monitors such as Doppler and oscillometric devices. However, electrocardiography (ECG) and capnography are two useful monitoring modalities during CPR and their use is recommended.

to minimize pauses in chest compressions, the only time the ECG should be evaluated is between 2-minute cycles of BLS while compressors are being rotated. The team leader should clearly announce the rhythm diagnosis and invite other team members to express agreement or dissent to minimize misdiagnosis. In the event of differing opinions on the rhythm diagnosis, chest compressions should be resumed immediately, and discussion should proceed into the next cycle. The three most common arrest rhythms leading to CPA in dogs and cats are: asystole, pulseless electrical activity (PEA), or ventricular fibrillation (VF).1,31,32

Capnography End-tidal CO2 (ETCO2) monitoring is safe and feasible during CPR, and is resistant to motion artifact regardless of technology.33,34 Detection of measurable ETCO2 suggests (but is not definitive for) correct endotracheal tube placement, especially in the CPA patient with poor pulmonary blood flow.35 ETCO2 can also be used as an indicator of chest compression efficacy because when minute ventilation is held constant, ETCO2 is proportional to pulmonary blood flow. A very low ETCO2 value during CPR (e.g., ,10–15 mm Hg) has been associated with a reduced likelihood of ROSC in dogs and humans.1,36 ETCO2 substantially increases upon ROSC and therefore is a valuable early indicator of ROSC during CPR.

ADVANCED LIFE SUPPORT ALS, including drug therapy and electrical defibrillation, is initiated once BLS procedures have been started. It should be emphasized that in the absence of high-quality BLS interventions, ALS procedures are unlikely to be successful; therefore, all ALS interventions should be implemented so as to minimize any impact on BLS quality.

Electrocardiography

Drug Therapy

Many important decisions about advanced life support (ALS) therapy are dependent upon the ECG rhythm diagnosis. However, it is important to note that the ECG is highly susceptible to motion artifact and cannot be interpreted during ongoing chest compressions; therefore,

During CPR, drug therapy should preferentially be administered by the intravenous or intraosseous route, and early placement of a peripheral venous, central venous, or intraosseous catheter is recommended. Cutdown procedures to obtain peripheral venous access are

CHAPTER 4  Cardiopulmonary Resuscitation commonly required. Note that BLS should not be paused during vascular access procedures. Vasopressors, parasympatholytics, and/or antiarrhythmics may be indicated in dogs and cats with CPA, depending on the underlying arrest rhythm. Depending on the type of arrest, the duration, and predisposing factors, other potentially useful ALS therapies may include reversal agents, intravenous fluids, and alkalinizing drugs. Table 4.2 summarizes the doses of drugs that may be of use during CPR. As part of preparedness for CPR, a drug dose chart should be in plain view in the ready area of the hospital. CPR algorithms and drug dose charts produced as part of the RECOVER initiative are available at http://www.veccs.org.

Vasopressors Because cardiac output during CPR is generally 30% or less of normal, increasing peripheral vascular resistance to redirect blood flow from the periphery to the core can be useful regardless of the arrest rhythm. The best-studied vasopressor during CPR is epinephrine, a catecholamine that causes peripheral vasoconstriction via stimulation of a1 receptors but also acts on b1 and b2 receptors. The a1 effects have been shown to be the most beneficial during CPR,37 and these vasoconstrictive effects predominate in the periphery, while sparing the coronary and cerebral vasculature and preserving blood flow to these core organs.38 A meta-analysis showed that low-dose epinephrine (0.01 mg/kg IV/IO every other cycle of CPR) was associated with

25

higher rates of survival to discharge in people than high-dose epinephrine (0.1 mg/kg IV/IO every other cycle of CPR).39 A metaanalysis of human clinical trials confirmed that the use of epinephrine was associated with increased rates of survival to discharge and with increased rates of poor neurologic outcome, possibly due to increased survival rates among more severely ill patients in the epinephrine groups.40 However, a more recent large scale, placebo-controlled clinical trial in humans showed improved survival to 30 days in the group receiving epinephrine with no difference in functional neurologic outcome.41 Therefore, early in CPR, low-dose epinephrine is recommended. However, after prolonged CPR, a higher dose (0.1 mg/ kg IV/IO every other cycle of CPR) may be considered due to evidence that this dose is associated with a higher rate of ROSC, but only with the understanding that the use of high-dose epinephrine may lead to a lower likelihood of survival to discharge, and should be avoided in patients with acute, reversible causes of CPA. Intratracheal (IT) administration of epinephrine is also possible (0.02 mg/kg low dose; 0.2 mg/kg high dose) and should be accomplished by feeding a long catheter through the tube and diluting the epinephrine 1:1 with isotonic saline or sterile water.42 Although still considered a mainstay of therapy for asystole and PEA, there is controversy regarding the utility of epinephrine during CPR. Despite evidence of increased ROSC rates with its use, no consistent long-term survival or functional outcome effect has been demonstrated.43

TABLE 4.2  CPR Drugs and Doses Arrest

Drug

Common Concentration Dose / Route

Comments

Epinephrine (low dose)

1 mg/ml (1:1000)

0.01 mg/kg IV/IO 0.02–0.1 mg/kg IT

Every other basic life support cycle for asystole/pulseless electrical activity Increase dose 2–103 and dilute for IT administration

Epinephrine (high dose)

1 mg/ml (1:1000)

0.1 mg/kg IV/IO/IT

Consider for prolonged (.10 minutes) cardiopulmonary resuscitation

Vasopressin

20 U/ml

0.8 U/kg IV/IO 1.2 U/kg IT

Every other basic life support cycle Increase dose for IT use

Atropine

0.4 mg/ml

0.04 mg/kg IV/IO

Every other basic life support cycle during cardiopulmonary resuscitation Recommended for bradycardic arrests / known or suspected high vagal tone Increase dose for IT use

0.15–0.2 mg/kg IT

Antiarrhythmic

Reversals

Defibrillation (may increase dose once by 50%–100% for refractory VF/pulseless VT)

Bicarbonate

1 mEq/ml

1 mEq/kg IV/IO

For prolonged cardiopulmonary resuscitation/ PCA phase when pH ,7.0 Do not use if hypoventilating

Amiodarone

50 mg/ml and 1.8 mg/ml

5 mg/kg IV/IO

For refractory ventricular fibrillation/pulseless ventricular tachycardia Associated with anaphylaxis in dogs

Lidocaine

20 mg/ml

2 mg/kg slow IV/IO push (1–2 minutes)

For refractory ventricular fibrillation/pulseless ventricular tachycardia only if amiodarone is not available

Naloxone

0.4 mg/ml

0.04 mg/kg IV/IO

To reverse opioids

Flumazenil

0.1 mg/ml

0.01 mg/kg IV/IO

To reverse benzodiazepines

Atipamezole

5 mg/ml

100 mg/kg IV/IO

To reverse a2 agonists

Monophasic External

4–6 J/kg

Monophasic Internal

0.5–1 J/kg

Biphasic External

2–4 J/kg

Biphasic Internal

0.2–0.4 J/kg

IT, intratracheal; PCA, post cardiac arrest

26

PART I  Key Critical Care Concepts

An alternative to epinephrine is vasopressin (0.8 U/kg IV/IO every other cycle of CPR), a vasopressor that acts via activation of peripheral V1 receptors. It may be used interchangeably or in combination with epinephrine during CPR. Unlike epinephrine, it is efficacious in acidic environments in which a1 receptors may become unresponsive to epinephrine. It also lacks the inotropic and chronotropic b1 effects that may worsen myocardial ischemia in patients that achieve ROSC.44 Like epinephrine, vasopressin may be administered endotracheally as described above. See Chapter 148, Vasopressin.

Parasympatholytics Atropine is a parasympatholytic drug and has been extensively studied in CPR.45–47 Its administration may be considered during CPR in all dogs and cats (0.04 mg/kg IV/IO every other cycle of CPR), and it may be especially useful in patients with asystole or PEA associated with increased vagal tone, such as occurs with chronic or severe, acute gastrointestinal, respiratory, or ocular disease. Endotracheal administration is also possible (0.08 mg/kg).48 Although the guidelines state that it may be repeated every 3–5 minutes during CPR, given its long halflife, it may be judicious to repeat only once or twice.

Antiarrhythmic Drugs Patients with VF refractory to electrical defibrillation (discussed in the next section) may benefit from treatment with the antiarrhythmic drug amiodarone at a dose of 2.5–5 mg/kg IV/IO.49 There are reports of anaphylactic reactions in dogs, so close monitoring for signs of anaphylaxis is warranted once ROSC is achieved, and if noted, they should be treated appropriately (see Chapter 141, Anaphylaxis). Lidocaine (2 mg/kg slow IV/IO push) is a less effective alternative to amiodarone for patients with refractory VF. Although lidocaine has been shown to increase the energy required for successful electrical defibrillation in dogs in one study, others have shown that this drug is beneficial.50,51

Reversal Agents If any reversible sedative drugs were administered to the patient before CPA, reversal agents may be beneficial and are unlikely to cause harm. Commonly available reversal agents include naloxone (0.04 mg/kg IV/ IO) for opioids, flumazenil (0.01 mg/kg IV/IO) for benzodiazepines, and atipamezole (0.1 mg/kg IV/IO) or yohimbine (0.1 mg/kg IV/IO) for a2 agonists.

Intravenous Fluids Administration of IV fluid boluses during CPR may be harmful to euvolemic or hypervolemic patients because they tend to increase central venous (and hence right atrial) pressure rather than arterial blood pressure in patients in CPA. This elevation in right atrial pressure can compromise perfusion of the brain and heart by decreasing CPP and cerebral perfusion pressure. Conversely, patients with documented or suspected hypovolemia will likely benefit from IV fluids, which will help to restore adequate preload, and may increase the efficacy of chest compressions and improve arterial systolic and diastolic pressures, leading to increased cerebral perfusion pressure and CPP.

Corticosteroids Most studies have shown no definitive evidence of benefit or harm from corticosteroid administration during CPR, although most were confounded by coadministration of other drugs.52,53 One prospective observational study in dogs and cats showed an increased rate of ROSC in dogs and cats, but the type and dose of steroids administered were highly variable, and a causative effect could not be inferred due to the study design.1 It is well known that significant gastrointestinal ulceration can develop from a single high dose of corticosteroids.54–56

In addition, immunosuppression and reduced renal perfusion due to decreased renal prostaglandin production are known side effects. Because of this nonadvantageous risk:benefit ratio, the routine use of corticosteroids is not recommended during CPR.

Alkalinizing Agents Severe metabolic acidosis can develop with prolonged CPA (greater than 10–15 minutes), leading to inhibition of normal enzymatic and metabolic activity as well as severe vasodilation. Administration of sodium bicarbonate (1 mEq/kg, once, diluted IV) may be considered in these patients. It should be remembered that these metabolic disturbances may resolve rapidly after ROSC; therefore, bicarbonate therapy in patients with prolonged CPA should be reserved for those with severe acidemia (pH ,7.0) of metabolic origin.

Electrical Defibrillation Electrical defibrillation is the cornerstone of therapy for VF and pulseless ventricular tachycardia (VT). Guidelines for the approach to electrical defibrillation during CPR have recently been modified due to data suggesting a three-phase model of ischemia during VF in the absence of CPR. The initial electrical phase during the first 4 minutes is characterized by minimal ischemia and continued availability of cellular energy stores to maintain metabolic processes. The subsequent 6 minutes, constituting the circulatory phase, are characterized by reversible ischemic injury due to depletion of cellular ATP stores. After 10 minutes, the metabolic phase begins, and potentially irreversible ischemic damage begins to occur. Based on this model, if the duration of VF is known or suspected to be of duration of 4 minutes or less, chest compressions should be continued only until the defibrillator is charged and the patient should then be defibrillated immediately. However, one full cycle of CPR should be done before defibrillating if the patient has been in VF for more than 4 minutes. This allows for blood flow and oxygen delivery to the myocardial cells, which can then generate ATP and restore normal membrane potentials, making the cells more likely to respond favorably to electrical defibrillation.57 Two types of defibrillators are available. Monophasic defibrillators deliver current in one direction between the paddles and across the patient’s chest, while biphasic defibrillators deliver current in one direction before reversing polarity and delivering a current in the opposing direction. Biphasic defibrillators have been shown to successfully defibrillate patients at a lower energy output, leading to less myocardial damage, and are therefore recommended over monophasic devices. Dosing for monophasic defibrillators begins at 4–6 J/kg, while biphasic defibrillation dosing starts at 2–4 J/kg. The second dose may be increased by 50%, but subsequent doses should not be further increased (see Chapter 205, Defibrillation). Regardless of the technology used, ALS algorithms no longer recommend three stacked shocks. Instead, chest compressions should be resumed immediately after a single defibrillation attempt without a pause for rhythm analysis. A full 2-minute cycle of BLS should then be administered before reassessing the ECG. If the patient is still in VF, defibrillation should be repeated at the end of this cycle of BLS.58,59

OPEN-CHEST CPR The International Liaison Committee on Resuscitation consensus on science does not currently provide any recommendations on openchest CPR (OCCPR) due to the lack of controlled clinical trials.60 However, there are a number of experimental studies in dogs and clinical studies in people showing improvements in hemodynamic variables, CPP and cerebral perfusion pressure, and outcome when

CHAPTER 4  Cardiopulmonary Resuscitation comparing OCCPR with closed-chest CPR.61,62 There is also evidence that delays in starting OCCPR lead to poorer outcomes, and that after 20 minutes of closed-chest CPR in dogs, OCCPR is unlikely to be effective.63 Although significantly more invasive and costly than closedchest CPR, the prevailing evidence suggests that improved outcomes from CPA are likely with OCCPR compared with closed-chest CPR, and in cases in which owner consent has been obtained and no underlying diseases that would be contraindications to OCCPR are present (such as thrombocytopenia or coagulopathy), the procedure should be employed as soon as possible after diagnosis of CPA. To perform OCCPR, a left lateral thoracotomy in the fourth to fifth intercostal space is performed with the animal in right lateral recumbency, and Finochietto retractors are used to open the chest for access to the heart. The pericardium may be removed in all cases to facilitate compressions but should always be removed in patients with pericardial effusion or other pericardial disease. The ventricles can then be directly compressed using either a two-hand technique with the right ventricle cupped in the left hand and the fingers of the right hand placed over the left ventricle or a one-hand technique with the fingers of the right hand placed over the left ventricle and the heart compressed against the sternum.64 Care should be taken to compress the ventricles from apex to base to maximize forward blood flow. If ROSC is achieved, intensive postcardiac arrest care will be required after the thoracotomy is closed and a chest tube placed to reduce the risk of pneumothorax. Although OCCPR may be employed in any patient in CPA, for some conditions leading to CPA, it is likely the only viable option. Conditions making external chest compressions futile include pleural space disease, pericardial effusion, and penetrating thoracic injuries. In addition, it is likely that closed-chest CPR will be ineffective in giant breed dogs with round or flat-chested conformation, and OCCPR is preferable. Finally, patients already in surgery that experience CPA should likely have OCCPR rather than closed-chest CPR. In patients undergoing abdominal surgery, the heart is easily accessible via an incision in the diaphragm, so thoracotomy is not required. A recent experimental study found that a transdiaphragmatic approach to OCCPR took the same time for initiation of cardiac compressions as a lateral thoracotomy in a nonsurgical scenario, suggesting it is a possible alternative beyond the abdominal surgery setting.65

PROGNOSIS There are limited data on prognosis in dogs and cats after CPA. It is likely, however, that the cause of the arrest is an important prognostic indicator, as evidenced by several retrospective studies of dogs and cats with CPA. In one, the authors found that of 15 dogs and 3 cats that survived to hospital discharge, only 3/18 had significant underlying chronic disease, whereas all other patients had acute disease leading to CPA.31 It is likely that patients experiencing CPA as a consequence of severe, untreatable, or progressive chronic diseases are less likely to survive to hospital discharge, even though these outcomes are confounded by euthanasia. Patients that arrest in the perianesthetic period have a markedly better prognosis, as high as 47% survival to discharge in one prospective observational veterinary study, than patients that arrest due to other etiologies.1 A more recent prospective, observational study of 172 dogs and 47 cats that underwent CPR at a tertiary referral facility showed that cats had a 19% survival to discharge rate and were almost five times as likely to survive than dogs, and that animals that experienced CPA under the care of the anesthesia service were almost 15 times as likely to survive as animals that arrested in other parts of the hospital.66,67 CPR efforts in the population of cats and dogs with acute, treatable disease, especially when incited by an anesthetic event, are warranted, and should be aggressive and persistent if the owner consents.

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REFERENCES 1. Hofmeister EH, Brainard BM, Egger CM, Kang S: Prognostic indicators for dogs and cats with cardiopulmonary arrest treated by cardiopulmonary cerebral resuscitation at a university teaching hospital, J Am Vet Med Assoc 235(1):50-57, 2009. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/19566454. 2. Girotra S, Nallamothu BK, Spertus JA, et al: Trends in survival after inhospital cardiac arrest, N Engl J Med 367(20):1912-1920, 2012. Available at: http://www.nejm.org/doi/abs/10.1056/NEJMoa1109148. 3. Fletcher DJ, Boller M, Brainard BM, et al: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 7: Clinical guidelines, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S102-S131, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676281. 4. McMichael M, Herring J, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 2: Preparedness and prevention, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S13-S25, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676282. 5. Hopper K, Epstein SE, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 3: Basic life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S26-S43, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676283. 6. Rozanski EA, Rush JE, Buckley GJ, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 4: Advanced life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S44-S64, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676286. 7. Brainard BM, Boller M, Fletcher DJ: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 5: Monitoring, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S65-S84, 2012. Available at: http://www.ncbi. nlm.nih.gov/pubmed/22676287. 8. Smarick SD, Haskins SC, Boller M, Fletcher DJ: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 6: Post-cardiac arrest care, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S85-S101, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676288. 9. Noordergraaf GJ, Van Gelder JM, Van Kesteren RG, Diets RF, Savelkoul TJ. Learning cardiopulmonary resuscitation skills: does the type of mannequin make a difference? Eur J Emerg Med 4(4):204-209, 1997. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9444504. 10. Cimrin AH, Topacoglu H, Karcioglu O, Ozsarac M, Ayrik C: A model of standardized training in basic life support skills of emergency medicine residents, Adv Ther 22(1):10-18, 2005. Available at: http://www.ncbi.nlm. nih.gov/pubmed/15943217. 11. Isbye DL, Meyhoff CS, Lippert FK, Rasmussen LS: Skill retention in adults and in children 3 months after basic life support training using a simple personal resuscitation manikin, Resuscitation 74(2):296-302, 2007. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17376582. 12. Mpotos N, Lemoyne S, Wyler B, et al: Training to deeper compression depth reduces shallow compressions after six months in a manikin model, Resuscitation 82(10):1323-1327, 2011. Available at: http://www.ncbi.nlm. nih.gov/pubmed/21723028. 13. Royse AG: New resuscitation trolley: stages in development, Aust Clin Rev 9(3-4):107-114, 1989. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/2486036. 14. Schade J: An evaluation framework for code 99, QRB Qual Rev Bull 9(10):306-309, 1983. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/6417586. 15. Dyson E, Smith GB: Common faults in resuscitation equipment—guidelines for checking equipment and drugs used in adult cardiopulmonary resuscitation, Resuscitation 55(2):137-149, 2002. Available at: http://www. ncbi.nlm.nih.gov/pubmed/12413751. 16. Edelson DP, Litzinger B, Arora V, et al: Improving in-hospital cardiac arrest process and outcomes with performance debriefing, Arch Intern Med 168(10):1063-1069, 2008. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/18504334. 17. Dine CJ, Gersh RE, Leary M, Riegel BJ, Bellini LM, Abella BS: Improving cardiopulmonary resuscitation quality and resuscitation training by combining audiovisual feedback and debriefing, Crit Care Med 36(10):2817-2822, 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18766092.

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PART I  Key Critical Care Concepts

18. Rittenberger JC, Menegazzi JJ, Callaway CW: Association of delay to first intervention with return of spontaneous circulation in a swine model of cardiac arrest, Resuscitation 73(1):154-160, 2007. Available at: http://www. ncbi.nlm.nih.gov/pubmed/17223246. 19. Dick WF, Eberle B, Wisser G, Schneider T: The carotid pulse check revisited: what if there is no pulse? Crit Care Med 28(11 Suppl):N183-N185, 2000. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11098941. 20. Tyberg JV: Late-systolic retrograde coronary flow: an old observation finally explained by a novel mechanism, J Appl Physiol 108(3):479-480, 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20075268. 21. Khouri EM, Gregg DE, Rayford CR: Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog, Circ Res 17(5):427-437, 1965. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/5843879. 22. Kern KB, Hilwig R, Ewy GA: Retrograde coronary blood flow during cardiopulmonary resuscitation in swine: intracoronary Doppler evaluation, Am Heart J 128(3):490-499, 1994. Available at: http://www.ncbi.nlm.nih. gov/pubmed/8074010. 23. Andreka P, Frenneaux MP: Haemodynamics of cardiac arrest and resuscitation, Curr Opin Crit Care 12(3):198-203, 2006. Available at: http://www. ncbi.nlm.nih.gov/pubmed/17241498. 24. Kern KB, Ewy GA, Voorhees WD, Babbs CF, Tacker WA: Myocardial perfusion pressure: a predictor of 24-hour survival during prolonged cardiac arrest in dogs, Resuscitation 16(4):241-250, 1988. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/2849790. 25. Paradis NA, Martin GB, Rivers EP, et al: Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation, JAMA 263(8):1106-1113, 1990. Available at: http://www.ncbi.nlm. nih.gov/pubmed/2386557. 26. Maier GW, Tyson GS, Olsen CO, et al: The physiology of external cardiac massage: high-impulse cardiopulmonary resuscitation, Circulation 70(1):86-101, 1984. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/6723014. 27. Wolfe JA, Maier GW, Newton JR, et al: Physiologic determinants of coronary blood flow during external cardiac massage, J Thorac Cardiovasc Surg 95(3):523-532, 1988. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3343860. 28. Kern K, Hilwig R, Berg R, Sanders A: Importance of continuous chest compressions during cardiopulmonary resuscitation, Circulation 105(5):645-649, 2002. Available at: http://circ.ahajournals.org/content/105/5/645.short. 29. Kouwenhoven WB, Jude JR, Knickerbocker GG: Closed-chest cardiac massage, JAMA 173:1064-1067, 1960. Available at: http://www.ncbi.nlm.nih. gov/pubmed/14411374. 30. Niemann JT, Rosborough J, Hausknecht M, Ung S, Criley JM: Blood flow without cardiac compression during closed chest CPR, Crit Care Med 9(5):380-381, 1981. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/7214963. 31. Waldrop JE, Rozanski EA, Swanke ED, O’Toole TE, Rush JE: Causes of cardiopulmonary arrest, resuscitation management, and functional outcome in dogs and cats surviving cardiopulmonary arrest, J Vet Emerg Crit Care 14(1):22-29, 2004. Available at: http://doi.wiley. com/10.1111/j.1534-6935.2004.04006.x. 32. Plunkett SJ, McMichael M: Cardiopulmonary resuscitation in small animal medicine: an update, J Vet Intern Med 22(1):9-25, 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18289284. 33. Grmec S, Klemen P: Does the end-tidal carbon dioxide (EtCO2) concentration have prognostic value during out-of-hospital cardiac arrest? Eur J Emerg Med 8(4):263-269, 2001. Available at: http://www.ncbi.nlm.nih. gov/pubmed/11785591. 34. Pokorná M, Necas E, Kratochvíl J, Skripský R, Andrlík M, Franek O: A sudden increase in partial pressure end-tidal carbon dioxide (P(ET)CO(2)) at the moment of return of spontaneous circulation, J Emerg Med 38(5): 614-621, 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19570645. 35. Li J. Capnography alone is imperfect for endotracheal tube placement confirmation during emergency intubation, J Emerg Med 20(3):223-229, 2001. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11267809.

36. Kolar M, Krizmaric M, Klemen P, Grmec S: Partial pressure of end-tidal carbon dioxide successful predicts cardiopulmonary resuscitation in the field: a prospective observational study, Crit Care 2008 12(5):R115. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid525927 43&tool5pmcentrez&rendertype5abstract. 37. Bassiakou E, Xanthos T, Papadimitriou L: The potential beneficial effects of beta adrenergic blockade in the treatment of ventricular fibrillation, Eur J Pharmacol 616(1-3):1-6, 2009. Available at: http://www.ncbi.nlm. nih.gov/pubmed/19555681. 38. Koehler RC, Michael JR, Guerci AD, et al: Beneficial effect of epinephrine infusion on cerebral and myocardial blood flows during CPR, Ann Emerg Med 14(8):744-749, 1985. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/4025969. 39. Vandycke C, Martens P: High dose versus standard dose epinephrine in cardiac arrest - a meta-analysis, Resuscitation 45(3):161-166, 2000. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10959014. 40. Loomba RS, Nijhawan K, Aggarwal S, Arora RR: Increased return of spontaneous circulation at the expense of neurologic outcomes: is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? J Crit Care 30(6):1376-1381, 2015. 41. Perkins GD, Ji C, Deakin CD, et al: A randomized trial of epinephrine in out-of-hospital cardiac arrest, N Engl J Med 379(8):711-721, 2018. 42. Manisterski Y, Vaknin Z, Ben-Abraham R, et al: Endotracheal epinephrine: a call for larger doses, Anesth Analg 95(4):1037-1041, 2002. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12351290. 43. Callaway CW: Epinephrine for cardiac arrest, Curr Opin Cardiol 28(1): 36-42, 2013. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23196774. 44. Biondi-Zoccai GGL, Abbate A, Parisi Q, et al: Is vasopressin superior to adrenaline or placebo in the management of cardiac arrest? A meta- analysis, Resuscitation 59(2):221-224, 2003. Available at: http://linkinghub.elsevier.com/retrieve/pii/S030095720300234X. 45. Blecic S, Chaskis C, Vincent JL: Atropine administration in experimental electromechanical dissociation, Am J Emerg Med 10(6):515-518, 1992. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1388375. 46. DeBehnke DJ, Swart GL, Spreng D, Aufderheide TP: Standard and higher doses of atropine in a canine model of pulseless electrical activity, Acad Emerg Med 2(12):1034-1041, 1995. Available at: http://www.ncbi.nlm.nih. gov/pubmed/8597913. 47. Coon GA, Clinton JE, Ruiz E: Use of atropine for brady-asystolic prehospital cardiac arrest, Ann Emerg Med 10(9):462-467, 1981. Available at: http://www.annemergmed.com/article/S0196-0644(81)80277-6/abstract. 48. Paret G, Mazkereth R, Sella R, et al: Atropine pharmacokinetics and pharmacodynamics following endotracheal versus endobronchial administration in dogs, Resuscitation 41(1):57-62, 1999. Available at: http://www. ncbi.nlm.nih.gov/pubmed/10459593. 49. Anastasiou-Nana MI, Nanas JN, Nanas SN, et al: Effects of amiodarone on refractory ventricular fibrillation in acute myocardial infarction: experimental study, J Am Coll Cardiol 23(1):253-258, 1994. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/8277089. 50. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A: Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation, N Engl J Med 346(12):884-890, 2002. Available at: http://www.ncbi. nlm.nih.gov/pubmed/11907287. 51. Dorian P, Fain ES, Davy JM, Winkle RA: Lidocaine causes a reversible, concentration-dependent increase in defibrillation energy requirements, J Am Coll Cardiol 8(2):327-332, 1986. Available at: http://linkinghub.elsevier.com/retrieve/pii/S073510978680047X. 52. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al: Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest, Arch Intern Med 169(1):15-24, 2009. Available at: http://archinte.ama-assn.org/cgi/ content/abstract/169/1/15. 53. Smithline H, Rivers E, Appleton T, Nowak R: Corticosteroid supplementation during cardiac arrest in rats, Resuscitation 25(3):257-264, 1993. Available at: http://www.sciencedirect.com/science/article/pii/03009572 93901238. 54. Levine JM, Levine GJ, Boozer L, et al: Adverse effects and outcome associated with dexamethasone administration in dogs with acute thoracolumbar

CHAPTER 4  Cardiopulmonary Resuscitation intervertebral disk herniation: 161 cases (2000-2006), J Am Vet Med Assoc 232(3):411-417, 2008. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/18241109. 55. Dillon AR, Sorjonen DC, Powers RD, Spano S: Effects of dexamethasone and surgical hypotension on hepatic morphologic features and enzymes of dogs, Am J Vet Res 44(11):1996-1999, 1983. Available at: http://www. ncbi.nlm.nih.gov/pubmed/6650953. 56. Rohrer CR, Hill RC, Fischer A, et al: Gastric hemorrhage in dogs given high doses of methylprednisolone sodium succinate, Am J Vet Res 60(8):977-981, 1999. 57. Weisfeldt ML, Becker LB: Resuscitation after cardiac arrest a 3-phase time-sensitive model, J Am Med Assoc 288(23):3035-3038, 2002. 58. Cammarata G, Weil MH, Csapoczi P, Sun S, Tang W: Challenging the rationale of three sequential shocks for defibrillation, Resuscitation 69(1):23-27, 2006. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/16517041. 59. Tang W, Snyder D, Wang J, et al: One-shock versus three-shock defibrillation protocol significantly improves outcome in a porcine model of prolonged ventricular fibrillation cardiac arrest, Circulation 113(23):26832689, 2006. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16754801. 60. Shuster M, Lim SH, Deakin CD, et al: Part 7: CPR techniques and devices: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with treatment recommendations, Circulation 122(16 Suppl 2):S338-S344, 2010. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/20956255.

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61. Alzaga-Fernandez AG, Varon J: Open-chest cardiopulmonary resuscitation: past, present and future, Resuscitation 64(2):149-156, 2005. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15680522. 62. Benson DM, O’Neil B, Kakish E, et al: Open-chest CPR improves survival and neurologic outcome following cardiac arrest, Resuscitation 64(2):209-217, 2005. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15680532. 63. Kern KB, Sanders AB, Ewy GA: Open-chest cardiac massage after closedchest compression in a canine model: when to intervene, Resuscitation 15(1):51-57, 1987. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3035670. 64. Barnett WM, Alifimoff JK, Paris PM, Stewart RD, Safar P: Comparison of open-chest cardiac massage techniques in dogs, Ann Emerg Med 15(4):408-411, 1986. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3954173. 65. Jack MW, Wierenga JR, Bridges JP, et. al: Feasibility of open-chest cardiopulmonary resuscitation through a transdiaphragmatic approach in dogs, Vet Surg 48:1042-1049, 2019. 66. Hoehne SN, Hopper K, Epstein SE: Prospective evaluation of cardiopulmonary resuscitation performed in dogs and cats according to the RECOVER guidelines. Part 2: patient outcomes and CPR practice since guideline implementation, Front Vet Sci 6:1-11, 2019. 67. Hoehne SN, Epstein SE, Hopper K: Prospective evaluation of cardiopulmonary resuscitation performed in dogs and cats according to the RECOVER guidelines. Part 1: prognostic factors according to Utstein-style reporting, Front Vet Sci 6:1-10, 2019.

5 Postcardiac Arrest Care Manuel Boller, Dr med vet, MTR, DACVECC, Daniel J. Fletcher, PhD, DVM, DACVECC

KEY POINTS • The systemic response to ischemia and reperfusion, anoxic brain injury, postresuscitation myocardial dysfunction, and persistent precipitating pathologic conditions define post-cardiac arrest care measures needed for each individual patient. • Immediate post-cardiac arrest care focuses on prevention of rearrest by ensuring optimal ventilation, oxygenation, and tissue perfusion, as well as identifying and correcting reversible causes of cardiopulmonary arrest. • Early hypoxemia and hyperoxemia after return of spontaneous circulation (ROSC) should be prevented by controlled reoxygenation with a target SaO2/SpO2 of 94% to 98% or a PaO2 of 80 to 100 mm Hg.

• Hemodynamic optimization measures after ROSC include administration of intravenous fluids, pressors, inotropes, and blood products to reach a mean arterial pressure (MAP) of 80 mm Hg or higher, an ScvO2 of 70% or more, and a lactate of less than 2.5 mmol/L. • Targeted temperature management (32°C to 36°C) for 24 to 48 hours is recommended in patients that remain comatose after ROSC and if advanced critical care capability is available. • Additional neuroprotective strategies include permissive hypothermia, slow rewarming (0.25°C to 0.5°C/hr), osmotic therapy, and seizure prophylaxis. • Critically ill survivors should be referred to veterinary critical care centers for post-cardiac arrest care.

Ahead of his time, the Russian resuscitation scientist and physician Vladimir Negovsky stated in 1972 that “after the first step in resuscitation when heart function and respiration have been restored, the second step in resuscitation arises—the more complicated problems of treating the after-effects of a general hypoxia.”1 Since then, postcardiac arrest (PCA) care has been increasingly emphasized as a critical part of cardiopulmonary resuscitation (CPR). Current CPR guidelines in both human and veterinary medicine devote entire sections to the care of those patients that achieved return of spontaneous circulation (ROSC) after cardiopulmonary arrest (CPA).2,3 The rationale behind this is twofold. First, epidemiologic studies in people show that twothirds of in-hospital cardiac arrest (IHCA) patients who achieve stable ROSC do not survive to hospital discharge.4 In veterinary medicine, 79% of dogs or cats with any ROSC are euthanized or die before hospital discharge.5 Thus optimization of PCA care has the potential to save many lives. Second, new effective PCA therapies have been discovered. Foremost, strong evidence of the neuroprotective potential of controlled postresuscitation hypothermia boosted the field of PCA care. Human epidemiologic data suggest that recent improvement in outcomes achieved after IHCA is in part due to increased postresuscitation survival.6 PCA arrest care is now considered the final essential link of a comprehensive treatment strategy to improve outcomes from CPA. There are two paradigms of care during the PCA phase. One targets the pathophysiologic processes that occur in the postresuscitation phase, namely (1) ischemia and reperfusion (IR) injury, (2) PCA brain injury, (3) PCA myocardial dysfunction, and (4) persistent precipitating pathologic conditions (Fig. 5.1). The second paradigm of care responds to a shift in treatment prioritization with time. Immediately after ROSC, the focus is on preventing the recurrence of cardiac arrest

and limitation of organ injury. Later care emphasizes treatment of the underlying disease processes, prognostication, and rehabilitation.

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PROPAGATING SUSTAINED ROSC The majority of dogs and cats that are initially successfully resuscitated die within the first few hours because of rearrest.7 In a recent observational study, 41% of the animals achieved any ROSC, and 15% of these animals rearrested within 20 minutes (Fig. 5.1).5 In people, 24% of patients with sustained ROSC (i.e., ROSC 20 minutes) rearrested after a median duration of 5.4 h.8 The goal immediately after ROSC is to sustain spontaneous circulation and perfusion of vital organs, such as the brain and the myocardium, attenuating further injury and preventing rearrest. Although patient monitoring options are limited during CPA (see Chapter 4), common monitoring such as noninvasive blood pressure measurement and pulse oximetry provide useful information after ROSC. Identification of any reversible cause of CPA needs to be proactively pursued. If not already addressed during advanced life support, it is important to assess for abnormalities in electrolytes, glucose, acid-base status, hematocrit, arterial oxygenation, and ventilation soon after ROSC. Abnormalities such as hypoxemia, severe anemia, hypotension, and hyperkalemia or hypocalcemia must be corrected. The incidence of rearrest rhythms has not been systematically reported in veterinary patients, but in people, one study (n5381) reported that the majority (76%) of first identified rhythms were nonshockable.8 If ventricular tachycardia persists, treatment with lidocaine (2 mg/kg intravenous [IV] bolus, followed by a 30 to 50 µg/kg/min continuous rate infusion [CRI]) is recommended. Shortly after ROSC, epinephrine [0.1 to 0.5 µg/kg/min CRI]) may be necessary to maintain vascular tone and adequate blood pressure, as adrenal function may be

CHAPTER 5  Postcardiac Arrest Care

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Post–cardiac arrest syndrome

Systemic ischemiareperfusion response

Post–cardiac arrest brain injury

Post–cardiac arrest myocardial dysfunction

• SIRS

Pathophysiology

• Impaired vasoregulation • Increased coagulation • Adrenal suppression • Impaired tissue oxygen delivery and utilization

• Impaired cerebrovascular autoregulation • Cerebral edema (limited) • Postischemic neurodegeneration

• Right and left ventricular dysfunction (myocardial stunning)

Potential treatments

Clinical manifestations

• Impaired resistance to infection

• Ongoing tissue hypoxia– ischemia

• Delirium, stupor, coma

• Hypotension

• Seizures

• Hypotension

• Pyrexia (fever)

• Myoclonus

• Arrhythmias

• Hyperglycemia

• Cognitive dysfunction

• Multiorgan failure

• Cortical blindness

• Ongoing tissue hypoxiaischemia

• Infection

• Brain death

• Early hemodynamic optimization

• Targeted temperature management

• Intravenous fluids

• Early hemodynamic optimization

• Early hemodynamic optimization

• Airway protection and mechanical ventilation

• Inotropes

• Seizure control

• Targeted temperature management

• Vasopressors • Temperature control • Glucose control • Antibiotics for documented infection

• Controlled reoxygenation (SaO2 94% to 98%)

Persistent precipitating pathology

• Infection (sepsis, pneumonia) • Upper airway obstruction • Cardiovascular disease (cardiomyopathy) • Pulmonary disease (CHF, ARDS) • Thromboembolic disease (PTE) • CNS disease • Toxicological (overdose, poisoning) • Hypovolemia (hemorrhage, dehydration) • MODS

• Reduced cardiac output • Specific to cause • Complicated by concomitant PCA syndrome

• Disease-specific • Guided by patient condition and concomitant PCA syndrome

• Supportive care

Fig. 5.1  Flowchart summarizing pathophysiology, clinical manifestations, and potential treatments for the four major components of post-cardiac arrest syndrome. ARDS, Acute respiratory distress syndrome; CHF, congestive heart failure; CNS, central nervous system; MODS, multiorgan dysfunction syndrome; PCA, post-cardiac arrest; PTE, pulmonary thromboembolism; SIRS, systemic inflammatory response syndrome. (Modified with permission from Boller M, Boller EM, Oodegard S, et al: Small animal cardiopulmonary resuscitation requires a continuum of care: proposal for a chain of survival for veterinary patients, J Am Vet Med Assoc 240[5]:540-554, 2012.)

insufficient after ROSC.9 This can then be replaced with more targeted catecholamine use (e.g., norepinephrine for vasodilation; dobutamine for left ventricular dysfunction) once a more refined understanding of the patient’s physiology is acquired. Positive inotropic support (i.e., dobutamine, 5–10 µg/kg/min CRI) can mitigate postischemic left

ventricular systolic dysfunction, and response to treatment can be assessed with repeat cardiovascular point-of-care ultrasound. Ventilatory assistance is commonly required during the immediate PCA phase and may be provided by either manual or mechanical ventilation with a target PaCO2 of 32 to 43 mm Hg in dogs and 26 to 36 mm Hg

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PART I  Key Critical Care Concepts

in cats.10 Once sustained ROSC has been achieved for 20 to 40 minutes, the priorities are the mitigation of further organ injury that arises as a consequence of IR and the titration of supportive care adapted to the needs of the patient.

SYSTEMIC RESPONSE TO ISCHEMIA AND REPERFUSION: SEPSIS-LIKE SYNDROME ROSC after the global ischemic event of CPA leads to a whole-body IR syndrome that Negovsky characterized as “postresuscitation disease” nearly 50 years ago.1 The syndrome shares many characteristics with severe sepsis, specifically in regard to inflammation, coagulation, and endothelial injury. After observing neutrophil and endothelial activation paired with high concentrations of circulating cytokines (tumor necrosis factor a [TNF-a], interleukin 6 [IL-6], IL-9, IL-10) in the PCA phase in humans, Adrie et al. coined the term sepsis-like syndrome to describe the phenotype of post-cardiac arrest abnormalities.11 Thus the PCA patient may demonstrate characteristics that are similar to sepsis and multiorgan dysfunction syndrome. With that in mind, therapeutic concepts involving (1) early hemodynamic optimization, (2) glycemic control, and (3) critical illness-related corticosteroid insufficiency (CIRCI) are being examined in human medicine and may have relevance to veterinary PCA care. Naturally, treatment is highly individualized, with each element of care titrated to the patient’s needs.

Hemodynamic Optimization Early goal-directed therapy (EGDT) was studied by Rivers et al. 20 years ago as a strategy for hemodynamic optimization in patients with severe sepsis and septic shock.12 EGDT uses an algorithm in which single interventions are started or discontinued based on the achievement of predefined physiologic endpoints with an emphasis on early resuscitation. In human medicine, the EGDT approach has been implemented for PCA care as an early hemodynamic optimization protocol.13 Included interventions are those used to optimize tissue oxygen delivery (fluid administration, vasopressors/inotropes, red blood cell transfusion, oxygen supplementation) and decrease tissue oxygen demand (sedation, mechanical ventilation, neuromuscular blockade, temperature control). A veterinary PCA hemodynamic optimization algorithm has been published by the RECOVER initiative.10 Resuscitation endpoints are a high-normal mean arterial pressure (MAP) (80 to 120 mm Hg) and perfusion parameters (central venous oxygen saturation [ScvO2] .70 %; lactate ,2.5 mmol/L). The blood pressure target is higher than in septic patients, as cerebrovascular autoregulation can be absent, and perivascular edema and intravascular clot formation can compromise PCA cerebral blood flow. Markers of vasodilation, such as injected mucous membranes or shortened capillary refill time, pulse quality, and echocardiographic determination of left ventricular function should also be included in a comprehensive hemodynamic assessment. Such monitoring will guide effective yet safe treatment with fluids, vasopressors, and inotropes (see Chapters 8 and 183).

Glycemic Control Hyperglycemia commonly occurs after cardiac arrest in humans, dogs, and cats and has been associated with worse outcomes.5,14 Mild to moderate hyperglycemia combined with a total plasma insulin decrease of 60% was observed in experimental research in dogs early after ROSC.15 In dogs, hyperglycemia after ROSC worsens ischemic brain injury.16 In humans, iatrogenic hypoglycemia occurred in 18% of PCA patients treated with tight glycemic control (4.4 to 6.1 mmol/L; 80 to 110 mg/dl). There is no evidence that strict glucose control provides additional benefits over a less stringent target, and no specific

target range is currently recommended in humans.2 Insulin administration to control severe hyperglycemia while avoiding iatrogenic hypoglycemia is reasonable in dogs and cats. Implementation of glycemic control with intravenous insulin administration follows the recommendation for patients with severe sepsis (see Chapter 6).

Adrenal Dysfunction Steroids are essential to the physiologic response to severe stress and are important for the regulation of vascular tone and endothelial permeability. CIRCI, or relative adrenal insufficiency, after ROSC was identified in several human clinical studies and has been associated with increased mortality.17 Low-dose steroid administration for septic shock remains controversial, and direct evidence supporting corticosteroid administration during PCA care is lacking. Because of this and the risk for infection and peptic ulcer and the exacerbation of postischemic neurologic injury associated with corticosteroid administration, routine administration of corticosteroids during PCA care is not recommended.10 However, administration of low-dose hydrocortisone (1 mg/kg IV followed by either 1 mg/kg IV q6h or an intravenous infusion of 0.15 mg/kg/hr) in dogs and cats with vasopressor-dependent shock after CPA, with or without documented CIRCI, may be considered.10

POST-CARDIAC ARREST BRAIN INJURY In humans, cerebral dysfunction after cardiac arrest is the single greatest concern and the most common single cause of death. In one study, neurologic injury was the cause of death in two-thirds of patients after out-of-hospital cardiac arrest (OHCA) and one-fifth after IHCA.18 In small animals, PCA brain injury has been described in experimental and clinical reports, but little is known about its epidemiology. PCA brain injury results from global cerebral IR.19 Although the process is complex and not understood in its entirety, some aspects of cerebral IR injury are clear: 1. Most of the injury is sustained during reperfusion and not during ischemia, affording the clinician the opportunity to intervene after ROSC is achieved. 2. Cytosolic and mitochondrial calcium overload leads to the activation of proteases that may lead to neuronal death and production of reactive oxygen species (ROS). 3. A burst of ROS occurs during reperfusion, leading to oxidative alterations of lipids, proteins, and nucleic acids, propagating injury of neuronal cell components and limiting the cells’ protective and repair mechanisms. 4. Hypothermia after ROSC is proven to reduce PCA cerebral dysfunction.20

Brain Injury Sustained During Ischemia Versus During Reperfusion Much of the injury sustained after CPA evolves during reperfusion rather than ischemia. By optimizing the reperfusion process, extended durations of ischemia can be tolerated. Nevertheless, IR is a continuum that is initiated during cellular ischemia. A sudden decline in oxygen delivery occurs upon onset of CPA. Glycolysis allows for limited continued energy production, but cerebral adenosine triphosphate (ATP) stores are depleted within 2 to 4 minutes. In contrast, 20 to 40 minutes are required for the same event to occur in the intestines and the myocardium. Once ATP is depleted, cellular membrane potentials are rapidly lost. Clinically, any cardiac electrical activity as detected by electrocardiogram (ECG) provides evidence that the global myocardial membrane potential has not yet subsided or has been reestablished during reperfusion. Large amounts of sodium, chloride, and

CHAPTER 5  Postcardiac Arrest Care calcium enter the cells, followed by cellular edema and membrane disruption. It is believed that the combined influences of increased exposure to calcium, oxidative stress, and energy depletion lead to mitochondrial injury, finally leading to more ROS production upon reperfusion and to apoptosis and necrosis. Therefore, protective reperfusion strategies (e.g., reperfusion with cardiopulmonary bypass) include tolerance of mild hypocalcemia and avoidance of hyperoxemia.21,22 Experimental studies in swine have demonstrated neurologically intact survival using these strategies even after 30 minutes of warm cerebral ischemia.23

Controlled Reoxygenation Large amounts of ROS are generated after ROSC. Becker and Neumar summarized in detail the pathobiology of ROS produced by IR in the PCA period.24,25 Excessive production of ROS in the presence of exhausted protective mechanisms results in elaboration of highly reactive free radicals, namely hydroxyl radicals (•OH) and peroxynitrite (ONOO•), which in turn cause cell membrane damage, lipid peroxidation, DNA damage, and protein alterations. Rapid reoxygenation following prolonged global ischemia is an implied goal of CPR and essential for saving lives after cardiac arrest. However, the absolute requirement of reintroducing oxygen conflicts with the toxic potential of oxygen as substrate for ROS. Much evidence suggests that arterial hyperoxemia soon after ROSC increases oxidative brain injury, increases neurodegeneration, worsens functional neurologic outcome, and negatively affects overall survival. Retrospective clinical studies in humans demonstrated an association between post-ROSC hyperoxemia and in-hospital mortality and documented a linear relationship between the degree of hyperoxemia and nonsurvival.26 In a canine experimental study, titration of oxygen supplementation to an SpO2 of 94% to 96% compared with a consistent FiO2 of 1 led to superior functional neurologic outcomes and a reduction in neuronal degeneration in vulnerable brain regions.27 The inspired oxygen concentration, especially early after ROSC, should therefore be titrated to normoxemia (PaO2 80 to 100 mm Hg; SpO2 94% to 98%), avoiding both hypoxemia and hyperoxemia.10

Targeted Temperature Management Targeted temperature management (TTM), an intervention originally known as mild therapeutic hypothermia, describes the therapeutic control of the core body temperature in the range of 32–36°C (89.6°F– 96.8°F).28 Mechanistically, the protective effect of hypothermia from global IR injury is well established and has been shown to occur via many pathways, including mitochondrial protection, decreased cerebral metabolism, impediment of cellular calcium influx, reduced neuronal excitotoxicity, reduced elaboration of ROS, attenuated apoptosis, and control of seizure activity.20 Unlike other interventions that target just a single pathway of injury, the combined effects of these mechanisms may be responsible for the robust benefit observed in a large number of experimental animal studies across species and models. Taking all animal data together, we can surmise that (1) mild hypothermia reduces anoxic brain injury; (2) hypothermia during arrest has the most profound and long-lasting effect; (3) after reperfusion, any delay in hypothermia reduces the beneficial effect; (4) long duration of hypothermia improves the protective effect, and (5) long duration of hypothermia can “rescue” the loss of effect due to delayed onset of cooling. The first human PCA guidelines recommending hypothermia in 2005 reflected the findings of the two pivotal randomized controlled studies and recommended that adult unconscious patients with ROSC after OHCA should be cooled (32°C–34°C) for 12–24 hours, if the initial rhythm was ventricular fibrillation.29-31 With more clinical data,

33

the 2015 American Heart Association guidelines include a more liberal temperature target (33°C–36°C) for patients after OHCA and IHCA and irrespective of the arrest rhythm but emphasize the importance of constant temperature maintenance within that target range for at least 24 hours.2 The 2012 RECOVER guidelines suggest that in dogs or cats that remain comatose after CPA, hypothermia to a core temperature of 32°C–34°C should be instituted as quickly as possible and be maintained for 24–48 hours.10 It is possible that a less stringent temperature window will be recommended in the upcoming revision to the RECOVER guidelines, with an emphasis on avoiding rapid rewarming and hyperthermia. A rewarming rate of 0.25°C to 0.5°C (0.45°F to 0.9°F) per hour should be targeted. In reality, most small-animal PCA patients will be hypothermic when they achieve ROSC, and prevention of rapid rewarming rather than induction of hypothermia is the goal. As the TTM target refers to core temperature, the use of an esophageal thermocouple is preferred over a rectal probe, especially in cases with active surface cooling as a significant temperature differential between rectal and core temperature may be present. Patient management and monitoring efforts may be considerable during TTM and are likely similar to that needed for mechanical ventilation. Clinical application of TTM requires managing the side effects. Cooling induces increased muscle tone and shivering, which in turn leads to increased oxygen consumption, metabolic rate, and respiratory and heart rates and requires sedation, endotracheal intubation, and ventilation. Cooling without sedation may abolish the protective effect of TTM.20 Other physiologic disturbances can occur, including changes in metabolism, acid-base status, electrolytes, ECG, drug elimination, coagulation, and immune function, and the clinician should be familiar with those alterations when using PCA cooling. However, adverse effects associated with PCA hypothermia in humans with OHCA were found to be on par with normothermic care and did not affect mortality.32 Nevertheless, the side effect profile may be different in other species such as dogs and cats and after IHCA, where sepsis and coagulopathy are more common. If either of these conditions is present, the benefit of TTM must be carefully weighed against the risk, and a higher (e.g., 35°C) as opposed to lower (e.g., 33°C) temperature target may be indicated. Many small animals are spontaneously hypothermic after CPA. Allowing these patients to remain hypothermic and slowly rewarming them to normal core temperature over many hours after ROSC (i.e., permissive hypothermia) offers an alternative to TTM. Even though the entire potential of TTM may not be realized with this approach, it may attenuate the well-documented harmful effects of a rapid increase in brain temperature after ischemia. It is reasonable to target a rewarming rate of 0.25°C to 0.5°C (0.45°F to 0.9°F) per hour.10 In addition, it is important to prevent fever or hyperthermia after CPA as this may worsen neurologic outcome.2

Other Neuroprotective Treatment Strategies Although epidemiologic data are lacking, clinical experience suggests that PCA seizures can occur in dogs and cats. In humans, the occurrence of seizures during the first 3 days after CPA is associated with worse outcome. Nonconvulsive status epilepticus (i.e., only identified by electroencephalography) commonly occurs in humans who remain comatose after ROSC.33 Seizure activity leads to a drastic increase in cerebral metabolism and oxygen demand, possibly outstripping oxygen supply. Thus, patients should be monitored for seizures and treated accordingly if they occur (see Chapter 84). Prophylactic administration of anticonvulsants may also be considered.10 This is particularly relevant in animals that remain comatose or are sedated because nonconvulsive seizure activity may be present and difficult to diagnose.

34

PART I  Key Critical Care Concepts

Cytotoxic and vasogenic cerebral edema have been described after CPA and are associated with poor neurologic outcome in people. In contrast, intracranial hypertension (ICH) does not commonly occur, but if it does it can compromise cerebral perfusion pressure and thus cerebral blood flow. In dogs, hypertonic fluid administration after 14 minutes of anoxic brain injury decreased cerebral edema but did not affect survival or functional neurologic outcome.34 In general, the use of hypertonic solutions such as mannitol or hypertonic saline for the reduction of cerebral edema after cardiac arrest has not been well examined, and the few studies available demonstrate neither benefit nor harm.3 Thus the use of mannitol or hypertonic saline can be considered if the presence of cerebral edema is suggested by clinical signs, such as coma, stupor, or decerebrate posture.10 Unfortunately, the clinical signs of ICH overlap with the neurologic deficits caused by brain ischemia during CPA. Induction of supranormal cerebral perfusion pressure during the PCA phase is beneficial, indicating that a clinically relevant increase of intracranial pressure or resistance to blood flow exists. In dogs after 12.5 minutes of untreated ventricular fibrillation, more than 50% of the brain remained below baseline blood flow 1 to 4 hours after resuscitation but not in animals with hypertensive hemodilution with a hematocrit of 20% and a MAP of 140 mm Hg.35 Similar results were found in other animal studies of optimized brain perfusion after prolonged cardiac arrest. In addition to increased intracranial pressure, perivascular edema, intravascular coagulation, and a loss of blood flow, autoregulation may also be responsible for the beneficial effect of supranormal cerebral perfusion pressures after prolonged cardiac arrest. It is likely that these mechanisms are of less importance during shorter durations of CPA, and thus a less aggressive perfusion pressure goal may be sufficient in most clinical veterinary cases.10 Experimental evidence suggests that the CO2 responsiveness of cerebral arteries is disturbed for the first several hours after prolonged ischemia such that arterial vasodilation in response to increasing PaCO2 is abolished.36 In contrast, with shorter durations of cerebral ischemia or later after reperfusion, CO2 responsiveness was maintained or restored such that hyperventilation after ROSC reduced cerebral blood flow and worsened neurologic outcomes compared with normoventilation. Similarly, the decreased tissue pH associated with hypoventilation could be harmful. It is therefore reasonable to avoid both hypoventilation and hyperventilation after ROSC and to control ventilation such that normocapnia is achieved (dog: PaCO2 32 to 42 mm Hg; cat: PaCO2 26 to 36 mm Hg).10

NEUROLOGIC ASSESSMENT AND PROGNOSTICATION Assessing the patient’s PCA neurologic status is relevant for treatment decisions and prognostication. Complete neurologic examinations should be undertaken directly after ROSC and initially every 2 to 4 hours. Care should be taken to interpret the findings in light of factors that confound the neurologic examination, such as sedation, neuromuscular blockade, seizures, and postictal status. Neurologic deficit scoring systems that include metrics of consciousness, motor and sensory function, and behavior have been used in clinical and experimental studies in dogs.37,38 Alternatively, the Modified Glasgow Coma Scale (MGCS), originally developed for dogs with traumatic brain injury, can be used to systematically assess and track the patient’s overall PCA neurologic status, although it has not been validated for this indication. The MGCS assesses function of the brainstem (cranial nerve reflexes) and cerebral cortex (motor response and level of consciousness). In principle, any signs of normal neurological function early after ROSC (e.g., spontaneous ventilation, gag reflex, pupillary light reflex

[PLR]) likely support a favorable prognosis despite the lack of evidence in the veterinary literature. Predicting neurologic futility is more complicated. Studies of unconscious human CPA survivors (i.e., those that remain comatose shortly after ROSC) substantiate that clinical neurological examination alone is a poor predictor of functional outcome during the first 72 hours after ROSC.2 Some of the delay is due to therapeutic hypothermia and the sedation required for the duration of TTM. A prognostication algorithm has been devised by the European Resuscitation Council that describes the integrated use of a series of examination modalities.39 The algorithm first prescribes up to 48 hours of TTM followed by slow rewarming as recommended for all unconscious survivors from CPA. No conclusive prognostic assessment is made until 72 hours after ROSC, by which time sedation (for TTM) is expected to be weaned without any residual effects. Findings from five modes of examination are then assessed: (1) clinical examination, (2) electroencephalography (EEG), (3) somatosensory evoked potential (SSEP), (4) imaging, and (5) circulating markers. Poor neurologic outcome is predicted if a clinical examination after 72 hours shows the absence of response to a noxious stimulus and bilaterally absent PLRs and corneal reflexes. The absence of SSEP in an unconscious patient is likewise highly predictive of a poor outcome. If neither of these highly sensitive indicators of poor prognosis (PLR or SSEP) are available, a set of less sensitive signs should be considered, but not until another 24 hours after the 72-hour assessment. These include (1) high levels of circulating neurospecificity enolase, a commonly used biomarker of neuronal injury after CPA; (2) diffuse anoxic injury on brain computed tomography/magnetic resonance imaging; (3) unreactive burst-suppression or status epilepticus on EEG, or (4) status myoclonus. The presence of at least two of these less reliable factors suggests that a poor outcome is highly likely. In the absence of these poor prognostic indicators, treatment should continue, and the patient be reevaluated in regular intervals. It is likely that adult animals and humans with CPA-related anoxic brain injury recover along a similar timeline. Thus, allowing 24–72 hours after ROSC before making a euthanasia decision is reasonable unless financial constraints are a factor. Depending on comorbidities, this may require costly PCA care before a definitive poor neurologic outcome can be established. Clinical assessment of unconsciousness (i.e., absence of response to painful stimulus), PLR and corneal reflexes may be useful as they are in humans. Experimental and limited clinical evidence in dogs and cats demonstrates the significant potential for neurological recovery, provided adequate supportive care is provided.40 Waldrop et al. (2004) documented that neurologic abnormalities after ROSC (i.e., dullness, ataxia, circling, seizures, and blindness) resolved in 90% of CPA survivors before hospital discharge.40 Unfortunately, veterinary data are sparse, and more evidence is needed to determine the specifics of PCA prognostication in dogs and cats.

MYOCARDIAL DYSFUNCTION Myocardial dysfunction (MD) is well described after cardiac arrest in experimental studies and in humans and has been the subject of one veterinary case report.41,42 MD occurs even in cases free of coronary artery disease and, like brain injury, is attenuated by hypothermia. The mechanisms of injury are not fully understood and are multifactorial. Myocyte dysfunction results from cellular processes associated with cellular IR comparable to those evolving in the nervous system. Thus, the severity of MD depends on the duration and extent of myocardial ischemia as well as the conditions under which reperfusion occurs (e.g., presence or absence of hypothermia and hyperoxia). Second, a lack of capillary blood flow during PCA (myocardial no-reflow) may occur. Microvascular obstruction or plugging may occur subsequent to

CHAPTER 5  Postcardiac Arrest Care endothelial cell activation and swelling, neutrophil–endothelial cell interactions, activation of coagulation, and platelet aggregation.43 Pericapillary edema will further impede microvascular blood flow. With alterations in capillary permeability, the subsequent increase in microvascular hematocrit and total protein and the associated rheologic properties can impair tissue blood flow. Moreover, postischemic red blood cells may have reduced deformability and have a tendency toward endothelial cell adhesion and formation of erythrocyte plugs. Third, factors associated with worse MD include intraarrest administration of epinephrine and high energy and monophasic waveform defibrillation.44 Clinically, PCA MD is characterized by increased central venous and pulmonary capillary wedge pressure, reduced left- and right-sided systolic and diastolic ventricular function with increased end-diastolic and end-systolic volume, and reduced left ventricular ejection fraction and cardiac output. These changes may be further complicated by ventricular tachyarrhythmia and lead to cardiogenic shock in severe cases. MD is reversible and typically resolves within 48 hours. This reversibility in the absence of cell necrosis is the basis for the term myocardial stunning. Diagnosis and monitoring of progression and resolution of MD during the PCA phase are best accomplished noninvasively via serial echocardiography. Dobutamine administration at typical clinical doses used in dogs and cats was shown to effectively improve left ventricular function and cardiac output in humans and swine.41 Cardiac arrhythmias should be addressed commensurate to their significance (see the Cardiac Disorders section).

PERSISTENT PRECIPITATING PATHOLOGY IHCA, the most common CPA scenario confronting the small-animal clinician, may be triggered by preexisting disease processes, such as severe sepsis, trauma, or respiratory failure. These pathologic conditions will likely persist after ROSC. They will affect the specific PCA care provided and influence the prognosis. Precipitating processes and preexisting comorbidities add considerable variability to the PCA patient population. Limited information is available about what these precipitating factors are in small-animal patients. In one veterinary study in a tertiary referral facility including 204 dogs and cats, causes of CPA were identified as hypoxemia (36%), shock (18%), anemia (13%), arrhythmia (8%), multiple organ dysfunction syndrome (MODS) (6%), traumatic brain injury (5%), anaphylaxis (1%), or other causes (21%).7 Another study suggests that trauma is a more common clinical feature in cats compared with dogs with CPA.45 It should be noted that in many veterinary general practice settings, CPA is likely most commonly associated with anesthesia, and multiple veterinary studies have documented significantly better rates of ROSC and survival to discharge in these patients.5,7 Meaney et al. evaluated the causes of CPA in 51,919 human patients with IHCA and found the following: hypotension (39%), acute respiratory failure (37%), acute myocardial infarction (10%), and metabolic/electrolyte disturbances (10%).46 A validated prognostic tool used in early human survivors from IHCA found that age, initial arrest rhythm, prearrest neurologic function, and duration of CPR were predictors of CPA, as well as the presence of preexisting disease, including mechanical ventilation, renal and hepatic insufficiency, sepsis, malignancy, and hypotension.47 Accordingly, the cause of death in adults with sustained ROSC after IHCA was comorbid withdrawal of care (36%), refractory hemodynamic shock (25%) and sudden cardiac arrest (11%).48 Neurologic withdrawal of care occurred in only 27% of people after IHCA, while the same was true in 73% of OHCA cases. A larger veterinary data set is required to acquire similar information in dogs and cats.49 The PCA population encountered after IHCA is influenced by a plethora of preexisting conditions. These demand an individualized

35

patient approach using critical care principles to support oxygenation, ventilation, circulation, and metabolism in order to realize the animal’s potential for a positive, meaningful outcome.

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21. Allen BS, Castella M, Buckberg GD, Tan Z: Conditioned blood reperfusion markedly enhances neurologic recovery after prolonged cerebral ischemia, J Thorac Cardiovasc Surg 126(6):1851-1858, 2003. 22. Hazelton JL, Balan I, Elmer GI, et al: Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death, J Neurotrauma 27(4):753-762, 2010. 23. Allen BS, Ko Y, Buckberg GD, Tan Z: Studies of isolated global brain ischaemia: II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischaemia - the importance of perfusion pressure, Eur J Cardiothor Surg 41(5):1147-1154, 2012. 24. Neumar RW: Optimal oxygenation during and after cardiopulmonary resuscitation, Curr Opin Crit Care 17(3):236-240, 2011. 25. Becker LB: New concepts in reactive oxygen species and cardiovascular reperfusion physiology, Cardiovasc Res 61(3):461-470, 2004. 26. Kilgannon JH, Jones AE, Parrillo JE, et al: Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest, Circulation 123(23):2717-2722, 2011. 27. Balan IS, Fiskum G, Hazelton J, et al: Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest, Stroke 37(12):3008-3013, 2006. 28. Brodeur A, Wright A, Cortes Y: Hypothermia and targeted temperature management in cats and dogs, J Vet Emerg Crit Care 27(2):151-163, 2017. 29. American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 7.5: postresuscitation support, Circulation 112(suppl 24):IV-84-88, 2005. 30. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia, N Engl J Med 346(8):557-563, 2002. 31. Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest, N Engl J Med 346(8):549-556, 2002. 32. Nielsen N, Sunde K, Hovdenes J, et al: Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia, Crit Care Med 39(1):57-64, 2011. 33. Rittenberger JC, Popescu A, Brenner RP, et al: Frequency and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest subjects treated with hypothermia, Neurocrit Care 16(1):114-122, 2012. 34. Kaupp HA Jr, Lazarus RE, Wetzel N, Starzl TE: The role of cerebral edema in ischemic cerebral neuropathy after cardiac arrest in dogs and monkeys and its treatment with hypertonic urea, Surgery 48(2):404-410, 1960.

35. Leonov Y, Sterz F, Safar P, et al: Hypertension with hemodilution prevents multifocal cerebral hypoperfusion after cardiac arrest in dogs, Stroke 23(1):45-53, 1992. 36. Nemoto EM, Snyder JV, Carroll RG, Morita H: Global ischemia in dogs: cerebrovascular CO2 reactivity and autoregulation, Stroke 6(4): 425-431, 1975. 37. Buckley GJ, Rozanski EA, Rush JE: Randomized, blinded comparison of epinephrine and vasopressin for treatment of naturally occurring cardiopulmonary arrest in dogs, J Vet Intern Med 25(6):1334-40, 2011. 38. Safar P, Xiao F, Radovsky A, et al: Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion, Stroke 27(1):105-113, 1996. 39. Cronberg T: Assessing brain injury after cardiac arrest, towards a quantitative approach, Curr Opin Crit Care 25(3):211-217, 2019. 40. Waldrop JE, Rozanski EA, Swanke ED, et al: Causes of cardiopulmonary arrest, resuscitation management, and functional outcome in dogs and cats surviving cardiopulmonary arrest, J Vet Emerg Crit Care 14(1): 22-29, 2004. 41. Bougouin W, Cariou A: Management of postcardiac arrest myocardial dysfunction, Curr Opin Crit Care 19(3):195-201, 2013. 42. Nakamura RK, Zuckerman IC, Yuhas DL, et al: Postresuscitation myocardial dysfunction in a dog, J Vet Emerg Crit Care 22(6):710-715, 2012. 43. Niccoli G, Burzotta F, Galiuto L, Crea F: Myocardial no-reflow in humans, J Am Coll Cardiol 54(4):281-292, 2009. 44. Kern KB: Postresuscitation myocardial dysfunction, Cardiol Clin 20(1): 89-101, 2002. 45. Kass PH, Haskins SC: Survival following cardiopulmonary resuscitation in dogs and cats, J Vet Emerg Crit Care 2(2):57-65, 1992. 46. Meaney PA, Nadkarni VM, Kern KB, et al: Rhythms and outcomes of adult in-hospital cardiac arrest, Crit Care Med 38(1):101-108, 2010. 47. Chan PS, Spertus JA, Krumholz HM, et al: A validated prediction tool for initial survivors of in-hospital cardiac arrest, Arch Intern Med 172(12):947-953, 2012. 48. Witten L, Gardner R, Holmberg MJ, et al: Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest, Resuscitation 136:93-99, 2019. 49. Boller M, Fletcher DJ, Brainard BM, et al: Utstein-style guidelines on uniform reporting of in-hospital cardiopulmonary resuscitation in dogs and cats. A RECOVER statement, J Vet Emerg Crit Care 26(1): 11-34, 2016.

6 Classification and Initial Management of Shock States Armelle de Laforcade, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Shock is defined as inadequate cellular energy production and most commonly occurs secondary to poor tissue perfusion from low or unevenly distributed blood flow. This leads to a critical decrease in oxygen delivery (DO2) to the tissues. • There are numerous ways to classify shock, and many patients suffer from more than one type of shock simultaneously. A common classification scheme includes hypovolemic, distributive, cardiogenic, and obstructive, although metabolic and hypoxic causes of shock are also well recognized.

• For most forms of shock, the mainstay of therapy involves rapid vascular access and administration of isotonic crystalloid fluids. Studies have not shown a clear benefit of one type of fluid over another; however, failure to administer an appropriate volume of fluids may contribute significantly to mortality. • Endpoints of resuscitation such as normalization of heart rate and blood pressure, improved pulse quality and mentation, and resolution of lactic acidosis are necessary to tailor therapy to the individual patient.

Shock is defined as a severe imbalance between oxygen supply and demand, leading to inadequate cellular energy production, cellular death, and multiorgan failure. It most commonly occurs secondary to poor tissue perfusion from low or unevenly distributed blood flow that causes a critical decrease in oxygen delivery (DO2) relative to oxygen consumption (V˙O2). Although metabolic disturbances (e.g., cytopathic hypoxia, hypoglycemia, toxic exposures) and decreased arterial oxygen content (e.g., severe anemia, pulmonary dysfunction, methemoglobinemia/carbon monoxide poisoning) can lead to shock, it more commonly results from a reduction in DO2 secondary to one of four major mechanisms: loss of intravascular volume (hypovolemic shock), maldistribution of vascular volume (distributive shock), obstruction to diastolic filling (obstructive shock), or failure of the cardiac pump (cardiogenic shock). Box 6.1 lists all the functional classes of shock. There are numerous ways to classify shock and no gold standard exists; variations merely reflect the various ways of categorizing the different mechanisms and treatments. Multiple forms of shock can and often do occur concurrently. Early recognition of shock based on a combination of physical examination findings and point-of-care testing are all that is necessary to initiate therapy. Rapid, aggressive therapy and appropriate monitoring, along with the removal of any underlying causes, are necessary to optimize the chance for a successful outcome.

primary mechanisms of circulatory shock (e.g., hypovolemic, distributive, cardiogenic, and obstructive), although other types of shock do exist (metabolic, hypoxic) and further details can be found elsewhere (see Chapters 16, 75, 106, and 107; Hypoxemia, Hypoglycemia, Anemia in the ICU, and Dyshemoglobinemias, respectively).

PATHOPHYSIOLOGY Inadequate cellular energy production leads to cell membrane ion pump dysfunction (e.g., Na-K ATPase), intracellular edema, leakage of intracellular contents extracellularly, and the inability to regulate intracellular pH. This ultimately leads to systemic acidemia, endothelial dysfunction, and activation of inflammatory and antiinflammatory cascades. Therefore, rapid recognition and appropriate treatment of patients in shock are key to prevent irreversible organ damage and possible death. The information below focuses on the

Hypovolemic Shock Hypovolemic shock occurs secondary to a loss of intravascular fluid volume causing inadequate organ perfusion. Insufficient oxygen delivery causes a shift from aerobic to anaerobic metabolism with accumulation of lactate, hydrogen ions, and oxygen free radicals. Damage associated molecular patterns (DAMPs) consisting of mitochondrial DNA, histones, heat shock proteins, and other mediators rise in response to damaged or dying cells. DAMPs activate the innate immune system by interacting with pattern recognition receptors and triggering a pathologic systemic inflammatory response.1,2 Prolonged oxygen deprivation at the cellular level ultimately causes cellular necrosis and apoptosis, followed by end-organ damage and multiple organ dysfunction. Compensatory mechanisms aimed at preserving intravascular volume begin within minutes of an acute drop in venous return and cardiac output. Baroreceptors function to keep arterial blood pressure constant by communicating with the brain via the glossopharyngeal nerve and vagus nerve to the nucleus of the solitary tract in the brainstem. There is a decrease in impulse firing to the medulla oblongata in response to low pressure or stretch in the carotid sinuses or aortic arch; this enables (disinhibits) sympathetic activation while inhibiting parasympathetic activation. The resultant response to shock-induced hypotension includes increased arteriolar and venous tone, cardiac contractility, and heart rate. Peripheral chemoreceptors are located in the aortic and carotid bodies and respond to changes in CO2, hydrogen ions (decreased pH), and to a lesser extent, the partial pressure of O2. Stimulation of these chemoreceptors causes both vasoconstriction and increased minute ventilation. Central chemoreceptors in the respiratory

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PART I  Key Critical Care Concepts

BOX 6.1  Functional Classifications and

Examples of Shock

Inadequate Oxygen Delivery Hypovolemic: Decrease in Circulating Blood Volume Hemorrhage Severe dehydration Trauma Distributive: Marked Decrease or Increase in Systemic Vascular Resistance or Maldistribution of Blood Sepsis Anaphylaxis Catecholamine excess (pheochromocytoma, extreme fear) Cardiogenic: Decrease in Forward Flow from the Heart Congestive heart failure Cardiac arrhythmia Drug overdose (e.g., anesthetics, b-blockers, calcium channel blockers) Obstructive: Reduced Diastolic Filling and Preload Gastric dilatation–volvulus Obstruction of the vena cava or aorta Tension pneumothorax Pericardial tamponade High positive end-expiratory pressure mechanical ventilation Hypoxic: Decreased Oxygen Content in Arterial Blood Anemia Severe pulmonary disease Carbon monoxide toxicity Methemoglobinemia Inappropriate Use of Oxygen by Tissues Metabolic: Deranged Cellular Metabolic Machinery Hypoglycemia Cyanide toxicity Mitochondrial dysfunction Cytopathic hypoxia of sepsis

tissue injury resulting in worsened microvascular dysfunction, endothelial injury, and vasomotor tone derangements. Gastrointestinal bleeding, coagulopathies, and vascular erosion are examples of nontraumatic causes of hemorrhagic shock. Traumatic hypovolemic shock (without hemorrhage) can occur following large surface burns and deep skin lesions. Hypovolemic shock without hemorrhage results from a severe imbalance between fluid intake and fluid loss and can occur secondary to severe vomiting and diarrhea, uncompensated renal losses, or large volume fluid sequestration.

Distributive Shock Distributive shock refers to a state of relative hypovolemia due to the pathologic redistribution of fluid caused by changes in vascular tone or increased vascular permeability. Subcategories of distributive shock include septic, anaphylactic, and neurogenic shock. Sepsis is defined as life-threatening organ dysfunction in response to infection, and persistent hypotension requiring vasopressor therapy indicates septic shock (see Chapter 90, Sepsis and Septic Shock). Central to the pathophysiology of sepsis is cytokine-mediated endothelial dysfunction, which causes both increased endothelial permeability and vasodilation. The result is both a relative decrease in vascular filling and a shift of volume from the intravascular to the interstitial space. Histamine-induced vasodilation characterizes anaphylaxis (see Chapter 141, Anaphylaxis). Vasodilation seen in neurogenic shock (typically traumatic brain or spinal cord injury) results from abnormally low sympathetic tone and unopposed parasympathetic stimulation of vascular smooth muscle.

Cardiogenic Shock Unlike hypovolemic or distributive shock, cardiogenic shock is characterized by systolic or diastolic cardiac dysfunction resulting in hemodynamic abnormalities that include increased heart rate, decreased stroke volume, decreased cardiac output, decreased blood pressure, increased peripheral vascular resistance, and increased right atrial, pulmonary arterial, and pulmonary capillary wedge pressures (see Chapter 41, Mechanisms of Heart Failure). These pathologic changes result in diminished tissue perfusion and increased pulmonary venous pressures, resulting in pulmonary edema and increased respiratory effort.

Obstructive Shock center of the medulla oblongata sense an increase in CO2 or decrease in pH of the cerebrospinal fluid and cause an increase in respiratory rate and tidal volume. Other changes associated with severe hypotension include an increase in circulating catecholamines and b endorphin release, which reduces perception to pain. Over a period of hours, reduced capillary pressure results in a net shift in fluid from the interstitial to the intravascular compartment, although the significance of this shift has been questioned (see Chapter 11, Interstitial Edema). Other factors, such as the osmotic effect of hyperglycemia, may also contribute to intravascular volume replacement during shock. Reduced renal blood flow activates the renin-angiotensin-aldosterone system, which leads to an increase in norepinephrine and angiotensin II-mediated vasoconstriction as well as sodium and water retention via the release of both aldosterone and antidiuretic hormone, respectively. Subclassifications of hypovolemic shock have been proposed to account for slight differences in pathophysiology and include hemorrhagic shock, traumatic hemorrhagic shock, hypovolemic shock without hemorrhage, and traumatic hypovolemic (nonhemorrhagic) shock. Both hemorrhagic shock and traumatic hemorrhagic shock are characterized by an acute drop in circulating red blood cells causing tissue hypoxia; however, traumatic hemorrhagic shock is further complicated by the inflammatory response that accompanies severe soft

Compression of the heart or a great vessel compromises venous return, diastolic filling, and cardiac preload and is referred to as obstructive shock. Causes include severe gastric dilation (with or without volvulus) decreasing preload and tension pneumothorax or cardiac tamponade, reducing diastolic filling. High positive end-expiratory pressure ventilation can also negatively affect venous return and cardiac output. As with other forms of shock, reduced cardiac output results in reduced perfusion and oxygen delivery, ultimately resulting in tissue hypoxia and organ failure.

CLINICAL PRESENTATION OF CIRCULATORY SHOCK Compensatory responses increase tissue perfusion and intravascular volume such that the clinical signs of shock maybe initially subtle. Animals with compensated shock commonly exhibit mild to moderate mental depression, tachycardia, normal or prolonged capillary refill time, cool extremities, fair to moderate pulse quality, tachypnea, and a normal blood pressure (see Chapter 64, Assessment of Intravascular Volume). With ongoing compromise of systemic perfusion, compensatory mechanisms are no longer adequate and often begin to fail. Pale mucous membranes, poor peripheral pulse quality, depressed mentation, and a drop in blood pressure become apparent as the animal

CHAPTER 6  Classification and Initial Management of Shock States progresses to decompensated shock. Ultimately, if left untreated, reduced organ perfusion results in end-organ failure (e.g., oliguria) and ultimately death. Dogs with sepsis or systemic inflammatory response syndrome (SIRS) may show clinical signs of hyperdynamic or hypodynamic shock (see Chapters 7 and 90, SIRS, MODS, and Sepsis and Sepsis and Septic Shock, respectively). The initial hyperdynamic phase of sepsis or SIRS is characterized by tachycardia, fever, bounding peripheral pulse quality, and hyperemic mucous membranes secondary to cytokinemediated peripheral vasodilation (e.g., nitric oxide). This is often referred to as vasodilatory shock. If septic shock or SIRS progresses unchecked, a decreased cardiac output and signs of hypoperfusion often ensue secondary to cytokine effects on the myocardium or myocardial ischemia. Clinical changes may then include tachycardia, pale (and possibly icteric) mucous membranes with a prolonged capillary refill time, hypothermia, poor pulse quality, and a dull mentation. Hypodynamic septic shock is the decompensatory stage of sepsis and without intervention will result in organ damage and death (see Chapter 7, SIRS, MODS, and Sepsis). Lastly, the gastrointestinal tract is the shock organ in dogs, so shock often leads to ileus, diarrhea, hematochezia, and melena. The hyperdynamic phase of shock is rarely recognized in cats. Also, in contrast to dogs, changes in heart rate in cats with shock are unpredictable; they may exhibit tachycardia or bradycardia. In general, cats typically present with pale mucous membranes (and possibly icterus), weak pulses, cool extremities, hypothermia, and generalized weakness or collapse. In cats, the lungs are vulnerable to damage during shock or sepsis, and signs of respiratory dysfunction are common in this species.3-5 Although the classifications of shock are useful in understanding the underlying mechanism of cardiovascular instability, different forms of shock can occur simultaneously in the same patient. A dog with gastric dilatation–volvulus, for example, will often have a component of hypovolemic shock secondary to fluid pooling in the stomach and blood loss associated with rupture of the short gastric vessels, in addition to obstructive shock with compromised cardiac output from great vessel compression. Dogs with septic peritonitis may experience tissue hypoxia as a result of cytokine-mediated mitochondrial dysfunction (metabolic shock), cytokine-mediated cardiac dysfunction (cardiogenic shock), and vasodilation (distributive shock) and a relative hypovolemia, and absolute hypovolemia as well if severe cavitary effusions or protracted vomiting/diarrhea are present.

DIAGNOSTICS AND MONITORING Some basic diagnostic tests should be completed for all patients in shock to assess the extent of organ injury and identify the etiology of the shock state. A venous or arterial blood gas with lactate measurement, a complete blood cell count, blood chemistry panel, coagulation panel, blood typing, urinalysis, and point-of-care ultrasound should be performed (see Chapters 202 and 189, Blood Gas Sampling and Point-of-Care Ultrasound in the ICU, respectively). Thoracic and abdominal radiographs, abdominal ultrasound, and echocardiography may be indicated once the patient is stabilized. Additional monitoring techniques that are essential in the diagnosis and treatment of the shock patient include continuous electrocardiographic monitoring, blood pressure measurement, and pulse oximetry (see Monitoring section below and Chapter 181, Hemodynamic Monitoring). Gradual resolution of tachycardia (and hypotension), as well as mental alertness, often signals successful return of cardiovascular stability, whereas persistent tachycardia and mental depression indicate ongoing cardiovascular instability. It is important to note that

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the best form of monitoring is a thorough physical examination, and frequent patient assessment will also provide important clues regarding response to therapy.

Monitoring Tissue Perfusion and Oxygen Delivery The magnitude of the oxygen deficit is a key predictor of outcome in shock patients. Therefore, optimizing oxygen delivery and tissue perfusion is the goal of treatment, and sufficient monitoring tools are necessary to achieve this objective. A well-perfused patient possesses the following characteristics: central venous pressure between 0 and 6 cm H2O; urine production of at least 1 ml/kg/hr; mean arterial pressure between 70 and 100 mm Hg; normal body temperature, heart rate, heart rhythm, and respiratory rate; and moist, pink mucous membranes with a capillary refill time of less than 2 seconds. Monitoring these parameters is the tenet of patient assessment. Additional monitoring tools that may prove beneficial include the measurement of blood lactate, indices of systemic oxygenation transport, and mixed venous oxygen saturation, as discussed below.

Blood Lactate Levels Critically ill patients with inadequate oxygen delivery, oxygen uptake, or tissue perfusion often develop hyperlactatemia and acidemia that are reflective of the severity of cellular hypoxia. A lactic acidosis in human patients carries a greater risk for developing multiple organ failure, and these people demonstrate a higher mortality rate than those without an elevated lactate concentration.6 High blood lactate levels may also aid in predicting mortality in dogs.7-9 The normal lactate concentration in adult dogs and cats is less than 2.5 mmol/L; lactate concentrations greater than 7 mmol/L are severely elevated.7 However, normal neonatal and pediatric patients may have higher lactate concentrations.10 In addition, sample collection and handling procedures can affect lactate concentration.11 Serial lactate measurements taken during the resuscitation period help to gauge response to treatment and evaluate resuscitation end points; the changes in lactate concentrations are a better predictor of survival than single measurements (see Chapter 61, Hyperlactatemia).

Cardiac Output Monitoring and Indices of Oxygen Transport The measurement of indices of systemic oxygen transport is a direct method of assessing the progress of resuscitation in shock patients, although it is rarely utilized in clinical patients due to its invasive nature, potential risks, and questionable benefit. A right-sided cardiac catheter or pulmonary artery catheter (PAC, also termed Swan-Ganz catheter or balloon-directed thermodilution catheter) is typically used to monitor these parameters (see Chapters 182 and 184, Cardiac Output Monitoring and Oximetry Monitoring, respectively). The PAC enables the measurement of central venous and pulmonary arterial pressure, mixed venous blood oxygen parameters (PvO2 and SvO2), pulmonary capillary wedge pressure, and cardiac output. With this information, further parameters of circulatory and respiratory function can be derived (i.e., stroke volume, end-diastolic volume, systemic vascular resistance index, pulmonary vascular resistance index, arterial oxygen content, mixed venous oxygen content, DO2 index, V˙O2 index, and oxygen extraction ratio). Although cardiac output is typically determined using thermodilution methods, other less invasive techniques are available (see Chapter 182, Cardiac Output Monitoring).

Mixed Venous Oxygen Saturation and Central Venous Oxygen Saturation Changes in the global tissue oxygenation (oxygen supply to demand) can be assessed using mixed venous oxygen saturation

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PART I  Key Critical Care Concepts

(SvO2) measurements. Assuming V˙ O2 is constant, SvO2 is determined by cardiac output, hemoglobin concentration, and SaO2. SvO2 is decreased if DO2 decreases (i.e., low CO, hypoxemia, severe anemia) or if V˙O2 increases (i.e., fever, seizure activity). With conditions such as the hyperdynamic stages of sepsis and cytotoxic tissue hypoxia (e.g., cyanide poisoning), SvO2 is increased. A reduction in SvO2 may be an early indicator that the patient’s clinical condition is deteriorating. In addition, SvO2 may be an alternative to measuring cardiac index during resuscitative efforts. Ideally, venous oxygen saturation is measured in a blood sample from the pulmonary artery. However, in animals that do not have a PAC, venous oxygen saturation can be measured from the central circulation, using a central venous catheter in the cranial or proximal caudal vena cava. This is termed central venous oxygen saturation (ScvO2). Although the ScvO2 values are generally higher than SvO2 in critically ill patients with circulatory failure, the two measurements closely parallel each other in patients with less severe disease. Therefore, a pathologically low ScvO2 likely indicates an even lower SvO2. A prospective, randomized study comparing two algorithms for early goal-directed therapy in human patients with severe sepsis and septic shock showed that maintenance of a continuously measured ScvO2 above 70% (in addition to maintaining central venous pressure above 8 to 12 mm Hg, mean arterial pressure above 65 mm Hg and urine output above 0.5 ml/kg/hr) resulted in a 15% absolute reduction in mortality compared with the same treatment without ScvO2 monitoring.12 A study of dogs with severe sepsis and or septic shock evaluated changes in tissue perfusion parameters in response to goal-directed hemodynamic resuscitation.13 In this study, resuscitation was aimed at restoring parameters related to tissue perfusion, including capillary refill time, central venous pressure, blood pressure, lactate, base deficit, and ScvO2. A higher ScvO2 was associated with a lower risk of death, highlighting the importance of microcirculatory and macrocirculatory dysfunction in severe sepsis and septic shock.14 Similarly, in a prospective study of dogs with pyometra-induced sepsis or septic shock, ScvO2 and base deficit had prognostic value, with a higher ScvO2 and a lower abnormal base deficit at admission to the ICU associated with a lower risk of death.15 Until these parameters are more extensively studied in naturally occurring shock in dogs, early recognition of shock followed by aggressive goal-driven resuscitation is likely crucial to a successful outcome.

TREATMENT Treatment of circulatory shock hinges on early recognition of the condition and rapid restoration of the cardiovascular system so that DO2 to the tissues is normalized as soon as possible. The mainstay of therapy for all forms of circulatory shock except cardiogenic shock is based on rapid administration of intravenous fluids to restore an effective circulating volume and tissue perfusion.16 Vascular access is essential for successful treatment of shock but can be difficult as a result of poor vascular filling and a collapsed cardiovascular state; short, large-bore catheters should be placed in a central or peripheral vein for initial resuscitation. When intravenous access is difficult or delayed because of cardiovascular collapse, a cutdown approach or intraosseous catheterization may be necessary (see Chapters 194 and 195, Intraosseous and Central Venous Catheterization, respectively). The type of fluid selected for the treatment of shock may vary (see Chapter 68, Shock Fluid Therapy). Replacement isotonic crystalloids such as lactated Ringer’s solution, 0.9% sodium chloride, or Normosol R are the mainstay of therapy for shock, administered rapidly and titrated to effect with total doses up to one blood volume (90 ml/kg for the dog, 50 ml/kg for the cat). The administered fluid rapidly spreads

into the extracellular fluid compartment so that only approximately 25% of the delivered volume remains in the intravascular space 30 minutes after infusion;17 some animals will therefore require additional resuscitation at this time point. Hypotensive resuscitation (to a mean arterial pressure of approximately 60 mm Hg) may prove beneficial in treatment of hemorrhagic shock since aggressive fluid therapy prior to definitive control may worsen bleeding and outcome (see Chapter 71, Hemorrhagic Shock).18 The “shock doses” of crystalloids serve as useful guidelines for fluid resuscitation of the shock patient; however, the actual volume administered should be titrated according to the patient’s clinical response in order to prevent volume overload, endothelial damage, and interstitial edema (see Chapter 11, Interstitial Edema). Additional fluid therapy options in patients with complicated shock states include synthetic colloid solutions, hypertonic saline, blood products, and hemoglobin-based oxygen carrying solutions (see Chapters 66 and 68, Colloid Solutions and Shock Fluid Therapy, respectively). Concerns regarding potential adverse effects of synthetic colloids have limited their use in human patients, although similar research in dogs and cats remains limited.19-22 The use of human albumin for treatment of circulatory shock is commonly used in people, but a risk:benefit analysis should be performed in dogs due to potential immune reactions.18,23-25 Lyophilized canine albumin may provide a less antigenic natural colloid alternative.26-27 The use of 7% to 7.5% sodium chloride (hypertonic saline) can be lifesaving in the emergency setting (see Chapter 65, Crystalloid Solutions). Combinations of hypertonic saline and synthetic colloid solutions may provide more rapid improvement in hemodynamic status and with lower overall crystalloid requirements than when crystalloids are used alone.19,20 Blood component therapy is often used during resuscitation of the shock patient with severe hemorrhage (see Chapters 69 and 71, Transfusion Medicine and Hemorrhagic Shock, respectively). Shock patients that remain hypotensive despite intravascular volume resuscitation often require vasopressor or inotrope therapy. There is increasing evidence in people to suggest that early vasopressor use may decrease fluid overload and improve outcome, especially with septic shock.30 Because oxygen delivery to the tissue is dependent on both cardiac output and systemic vascular resistance, therapy for hypotensive patients includes maximizing cardiac output with fluid therapy, as discussed earlier, and inotropic drugs or modifying vascular tone with vasopressor agents (see Chapters 6, 147, and 148, Pathophysiology and Mechanisms of Shock, Catecholamines, and Vasopressin, respectively). Commonly used vasopressors include catecholamines (epinephrine, norepinephrine, dopamine), positive inotropic agents, and the sympathomimetic drug phenylephrine. In addition, vasopressin, corticosteroids, and glucagon have been used as adjunctive pressor agents. Unlike hypovolemic or distributive shock, patients with cardiogenic shock experience a combination of cardiovascular changes that result in diminished tissue perfusion and increased pulmonary venous pressures, resulting in pulmonary edema and dyspnea. Supplemental oxygen therapy and minimal handling are extremely important to avoid further decompensation in patients with cardiogenic shock. A brief physical examination combined with point-of-care ultrasound may be very helpful in differentiating heart failure from other causes of dyspnea (see Chapter 189, Point-of-Care Ultrasound in the ICU). The diuretic furosemide administered intravenously or intramuscularly is the mainstay of therapy for congestive heart failure (see Part IV, Cardiovascular Disorders). Animals that fail to show clinical signs of improvement after repeated doses of diuretics may require more specific therapy targeting the underlying cardiac abnormality (e.g., systolic dysfunction, diastolic failure, arrhythmias). Ultimately, the dyspneic

CHAPTER 6  Classification and Initial Management of Shock States patient in cardiogenic shock that fails to respond to therapy should either be treated with high flow nasal oxygen or be anesthetized, intubated, and positive pressure ventilated with 100% oxygen to stabilize the animal and allow the clinician to perform a thorough physical examination and pursue further diagnostics such as thoracic radiographs and echocardiography. Early recognition and initiation of therapy are essential for successful treatment of the shock patient. Therapy for the shock patient is complicated by the need for rapid decision making in the absence of a complete medical history or diagnostic tests. In all forms of shock other than cardiogenic shock, intravenous fluid administration is the mainstay of therapy. Although under-resuscitation or delayed onset of therapy could clearly contribute to a negative outcome, excessive or overaggressive resuscitation may also have undesirable consequences, including a dilutional coagulopathy and pulmonary edema. The combination of breed, signalment, and physical examination findings will help the emergency clinician identify the type of shock present, and serial evaluation with clearly defined endpoints of resuscitation is essential for successful management of the shock patient.

REFERENCES 1. Chen GY, Nunez G: Sterile inflammation: sensing and reacting to damage, Nat Rev Immunol 10(12):826-837, 2010. 2. Nakahira K, Hisata S, Choi AMK: The roles of mitochondrial damage-associated molecular patterns in diseases, Antioxid Redox Signal 23(17):1329-1350, 2015. 3. Schutzer KM, Larsson A, Risberg B, et al: Lung protein leakage in feline septic shock, Am Rev Respir Dis 147:1380, 1993. 4. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217:531, 2000. 5. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990-2001), J Am Vet Med Assoc 225:897, 2004. 6. Nguyen HB, Rivers EP, Knoblich BP, et al: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock, Crit Care Med 32:1637, 2004. 7. Boag A, Hughes D: Assessment and treatment of perfusion abnormalities in the emergency patient, Vet Clin North Am Small Anim Pract 35:319, 2005. 8. dePapp E, Drobatz KJ, Hughes D, et al: Plasma lactate concentration as a predictor of gastric necrosis and survival among dogs with gastric volvulus: 102 cases (1995-1998), J Am Vet Med Assoc 215:49, 1999. 9. Nel M, Lobetti RG, Keller N, et al: Prognostic value of blood lactate, blood glucose and hematocrit in canine babesiosis, J Vet Intern Med 18:471, 2004. 10. McMichael MA, Lees GE, Hennessey J, et al: Serial plasma lactate concentration in 68 puppies aged 4 to 80 days, J Vet Emerg Crit Care 15:17, 2005. 11. Hughes D, Rozanski ER, Shofer FS, et al: Effect of sampling site, repeated sampling, pH, and PCO2 on plasma lactate concentration in healthy dogs, Am J Vet Res 60:521, 1999. 12. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock, N Engl J Med 345:1368, 2001.

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13. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22(4):409-418, 2012. 14. Trzeciak S, McCoy JV, Dellinger RP, et al: Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis, Intensive Care Med 34(12):2210-2217, 2008. 15. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22(4):409-418, 2012. 16. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010), J Vet Emerg Crit Care 22(6):666-673, 2012. 17. Silverstein DC, Aldrich J, Haskins SC, et al: Assessment of changes in blood volume in response to resuscitative fluid administration in dog, J Vet Emerg Crit Care 15:185, 2005. 18. Stern SA, Wang S, Mertz M, et al: Under-resuscitation of near-lethal uncontrolled hemorrhage: effects on mortality and end-organ function at 72 hours, Shock 15:16, 2001. 19. Martin GS, Bassett P: Crystalloids vs. colloids in the intensive care unit: a systematic review, J Crit Care 50:144-154, 2019. 20. Sigrist NE, Kalin N, Dreyfus A: Changes in serum creatinine concentration and acute kidney injury (AKI) grade in dogs treated with hydroxyethyl starch 130/0.4 from 2013 to 2015, J Vet Intern Med 31(2):434-441, 2017. 21. Sigrist NE, Kalin N, Dreyfus A: Effects of hydroxyethylstarch 130/0.4 on serum creatinine concentration and development of acute kidney injury in nonazotemic cats, J Vet Intern Med 31(6):1749-1756, 2017. 22. Hayes G, Benedicenti L, Mathews K: Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010), J Vet Emerg Crit Care 26(1):35-40, 2016. 23. Cohn LA, Kerl ME, Dodam JR, et al: Clinical response to human albumin administration in healthy dogs, Am J Vet Res 68:657, 2007. 24. Francis AH, Martin LG, Haldorson GJ, et al: Adverse reactions suggestive of Type III hypersensitivity in six healthy dogs given human albumin, J Am Vet Med Assoc 230(6):873-879, 2007. 25. Martin LG, Luther TY, Alperin DC, et al: Serum antibodies against human albumin in critically ill and healthy dogs, J Am Vet Med Assoc 232(7):1004-1009, 2008. 26. Craft EM, Powell LL: The use of canine-specific albumin in dogs with septic peritonitis, J Vet Emerg Crit Care 22(6):631-639, 2012. 27. Enders B, Musulin S, Holowaychuk M, et al: Repeated infusion of lyophilized canine albumin safely and effectively increases serum albumin and colloid osmotic pressure in healthy dogs, J Vet Emerg Crit Care 28(S1):S5, 2018. 28. Shertel ER, Allen DA, Muir WW, et al: Evaluation of a hypertonic sodium chloride/dextran solution for treatment of traumatic shock in dogs, J Am Vet Med Assoc 208:366, 1996. 29. Fantoni DT, Auler JO Jr, Futema F, et al: Intravenous administration of hypertonic sodium chloride solution with dextran or isotonic sodium chloride solution for treatment of septic shock secondary to pyometra in dogs, J Am Vet Med Assoc 215:1283, 1999. 30. Ospina-Tascón GA, Hernandez G, Alvarez I: Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis, Crit Care 24(1):52, 2020.

7 SIRS, MODS, and Sepsis Kaitlyn Rank, DVM, Bernie Hansen, DVM, MS, DACVECC, DACVIM (Internal Medicine)

BACKGROUND The term systemic inflammatory response syndrome (SIRS) was coined in 1992 by participants of the joint American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference and published in a concerted effort to standardize the terminology used to describe the clinical syndromes of systemic inflammation, sepsis, and septic shock.1,2 Their goal was to create a conceptual framework characterizing sepsis (and the inflammatory response that accompanies it) in order to both improve individual patient management and to better define illness severity in patients enrolled in clinical research. Conference participants created a working definition of SIRS that required the presence of any two of the four clinical findings of hyper/hypothermia, tachycardia, tachypnea (or hyperventilation), and leukocyte count abnormalities in the absence of other known causes such as exercise or chemotherapy (Table 7.1). They also recommended specific definitions for sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). MODS was defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, and sepsis was defined as SIRS caused by an infectious agent. The consensus conference recommendations were a milestone in the history of medicine, encouraging clinicians to abandon meaningless terms like “septicemia” and creating a mechanism to stratify patients with infectious disease within a continuum that was anchored by infection without systemic illness on one end, and septic shock on the other. Sepsis became, by definition, infection accompanied by two or more of the four SIRS criteria. Adoption of the consensus definitions of SIRS and sepsis as screening tools for sick companion animals was proposed separately by Purvis3 in 1994 and Hardie4 in 1995, using rectal temperature and heart rate criteria that were empirically modified for dogs and cats. The diagnostic utility of using these criteria to identify bacterial sepsis (defined as SIRS due to infection) was first tested by Hauptman in 1997, who applied institution-specific normal range cutoffs (Table 7.1) prospectively to 350 hospitalized dogs and required at least two of the four criteria to be abnormal for a diagnosis of sepsis.5 The sensitivity of this SIRS schema to identify sepsis in dogs with confirmed infection and “systemic illness” (n 5 30) was 97%, but over one-third of the 320 dogs without infection met the “2 of 4” criteria and were erroneously classified as septic. Because their goal was to evaluate the SIRS criteria as a screening test for sepsis, the authors did not consider the utility of the criteria as a diagnostic or prognostic tool. A similar approach was retrospectively applied by Brady et al. to cats with severe sepsis confirmed at necropsy. Clinical findings obtained within 12 hours of death were used to generate feline-specific cutoff values for these criteria in 29 cats that were ill enough to

42

die or be euthanized in response to a poor prognosis.6 In that study, severe sepsis was defined as postmortem evidence of multiorgan involvement with bacterial thrombi or multifocal necrosis in cats that had clinical features of grave illness. All 15 cats that had a complete blood count (CBC) performed fulfilled three of the four SIRS criteria, prompting the authors to recommend “3 of 4” as the threshold for a clinical diagnosis of SIRS in cats. These two studies served as the basis for classification of animals as SIRS-positive or SIRS-negative in several subsequent investigations. More recently, Alves et al. applied SIRS criteria (using cutoffs only slightly different from Hauptman’s) to dogs with laboratory-confirmed canine parvovirus infection to establish the accuracy of SIRS criteria to classify dogs with this viral infection, a disorder frequently complicated by bacterial sepsis.7 Results of that study suggested improved accuracy when the “2-of-4” criteria approach was combined with assessment for abnormalities of the mucous membranes (Table 7.1). The association of MODS with mortality in critically ill dogs was formally described in 2010 by Kenney et al. in a retrospective study of 114 dogs undergoing surgery for septic peritonitis.8 The authors included cases of confirmed abdominal sepsis that had sufficient laboratory data to evaluate renal, cardiovascular, respiratory, hepatic, and coagulation function. Arbitrary thresholds, based on direct extrapolation from the human Sequential Organ Failure Assessment (SOFA) score (see below) and Multiple Organ System Dysfunction Score, were used to determine the presence or absence of organ dysfunction.9 The thresholds included hypotension requiring pressor support (cardiovascular), oxygen supplementation (respiratory), an increase in serum creatinine of 0.5 mg/dl from preoperative values (renal), a serum bilirubin concentration 0.5 mg/dl (hepatic), and a prothrombin time or activated partial thromboplastin time 25% higher than reference range or a platelet count #100,000/µl (coagulation). Each category was treated as binary (present or absent) with no weighted scores applied to indicate severity, and MODS was diagnosed if there were two or more organ systems affected. Although there was no effort to quantify the severity of dysfunction of any organ, the mere presence of any organ system dysfunction had a significant association with outcome. When compared with dogs with no organ system dysfunction, the odds ratio of death in dogs with organ dysfunction ranged from 6.73 (one organ) to 18.7 (four or five organs involved).

EVOLUTION OF DEFINITIONS With time, several limitations to the 1992 consensus definitions became apparent. First and foremost were the lack of specificity of SIRS criteria for infection in hospitalized patients and the lack of sensitivity of SIRS criteria to predict severity of illness and prognosis. These observations reinforced the evidence accumulating from

TABLE 7.1  Examples of SIRS Schemes Proposed for Companion Animals. The Four Clinical Characteristics that Comprise the SIRS Criteria are Numbered at the Top 4 Leukocyte Abnormalities Leukocytosis Leukopenia Bandemia (%) (3 103/mm3) (3 103/mm3)

Criteria

.38°C (100.4°F) ,36°C (96.8°F)

.90

.20

,32

.12

,4

.10

Any 2 of 4

Opinion

.39.7°C (103.5°F) ,37.8°C (100°F)

.160 (dog) .250 (cat)

.20

,32

.12

,4

.10

Any 2 of 4

Dog/cat

Opinion

.40°C (104°F) ,38°C (100.4°F)

.120 (dog) .140 (cat)

.20

,30 (dog) ,28 (cat)

.18

,5

.5

Any 2 of 4

1997

Dog

Observational study

.39°C (102.2°F) ,38°C (100.4°F)

.120

.20

3

.16

,6

.3

Any 2 of 4

Brady6

2000

Cat

Retrospective study

.39.7°C (103.5°F) ,37.8°C (100°F)

.225 or ,140

.40

3

.19.5

,5

.5

Any 3 of 4

Alves7

2020

Dog

Observational study

.39.4°C (102.9°F) ,37.8°C (100°F)

.140

.30

,32

.16

,6

.3

Any 2 of 4, 1 prolonged CRT or abnormal MM color

1 Temperature

ACCP/SCCM1

1992

Human

Consensus

Purvis3

1994

Dog/cat

Hardie4

1995

Hauptman5

CHAPTER 7  SIRS, MODS, and Sepsis

2 Heart Rate (BPM) 3 Respiration Respiratory pCO2 (mm Hg) rate (BrPM)

First author Year Species Method

43

44

PART I  Key Critical Care Concepts

experimental and clinical research that progression of critical illnesses, especially sepsis, has more to do with dysregulated host responses and organ dysfunction than it does with the presence of inflammation alone.10-13 An attempt to address this at the 2001 Sepsis-2 conference led to the recommendation to adopt the PIRO scheme (Predisposition, Insult/infection, Response, Organ dysfunction) to try to better incorporate the clinical features of organ dysfunction in an approach that was modelled on the TMN classification scheme used for staging many cancers.14 With time, scoring systems based on the PIRO concept were developed, but the approach remained tethered to the requirement for some SIRS criteria of inflammation, and a rigorous scoring system remained elusive for well over a decade.15 Growing awareness of the limitations, imposed by defining sepsis in terms of SIRS ultimately led to the revisions drafted by the third sepsis consensus conference (Sepsis-3) published in 2016, defining sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection.13 The specific phrase multiple organ dysfunction syndrome was not reviewed or redefined in the conference proceedings, but the participants emphasized progressive organ dysfunction as a keystone event in the development of critical illness. Organ dysfunction, rather than clinical features of inflammation, was recognized as a hallmark feature of sepsis syndrome, and it can be characterized clinically by various scoring systems. The SOFA score and the quick SOFA (qSOFA) score were identified as the most clinically useful methods.

ASSESSMENT OF MODS SEVERITY The SOFA score was developed in the 1990s as an evaluation tool for organ dysfunction in any ICU patient (septic or not), but was revalidated as an assessment tool for septic patients in conjunction with the work of the Sepsis-3 conference task force.16 The score is based on the combined clinical assessment of cardiopulmonary (blood pressure, P/F ratio), neurologic (Glasgow Coma Score), renal (serum creatinine), hepatic (serum bilirubin), and coagulation (platelet count) system functions, with deviations from normal scored on a 5-point scale (Fig. 7.1). The score (from 0 to 4) assigned to a patient is the value of the highest subscore in the schema. Patients are assumed to have a baseline score of 0 unless there is known preexisting disease. A score of 2 is accompanied by at least a 10% mortality risk in humans hospitalized with infection, and a score of 2 or an increase in the score by a value of 2 in infected patients has defined human sepsis since the Sepsis-3 conference.17 Application of the SOFA score to a small group of hospitalized dogs was described by Ripanti in 2012.18 The authors slightly modified the human SOFA score and used it to prospectively evaluate a convenience sample of 45 dogs admitted to the ICU for three consecutive days. Forty dogs survived to complete data collection; all dogs

met two of the four SIRS criteria using cutoffs only slightly different from Hauptman’s. As might be expected, 19/20 of the dogs whose SOFA scores increased during those three days died, and 19/20 dogs with stable or decreasing SOFA scores survived. Half of the dogs had confirmed infection and were therefore classified as septic based on the combination of meeting SIRS criteria and infection. There was no difference in survival or time to discharge between septic and nonseptic dogs, suggesting that it was the severity and progression of organ dysfunction, not the presence of infection, that had the greatest impact on survival. The same Sepsis-3 study that evaluated the predictive value of the SOFA score examined the simplified qSOFA.16 This scoring system uses three elements (altered mentation, systolic blood pressure #100 mm Hg, respiratory rate of 22) to create a scale of 0–3, with each abnormality assigned 1 point. Because there is good agreement between qSOFA and SOFA and because qSOFA does not require laboratory tests and may be quickly and repeatedly applied, the Sepsis-3 conference recommendations include using this as a screening tool for sepsis outside of the ICU. A qSOFA score 2 increases the likelihood of a poor outcome and warrants further investigation to rule out sepsis. As of this writing, there are only two published studies of the utility of the qSOFA score in dogs. As reported in 2021,19 Ortolani and Bellis retrospectively applied the unedited human criteria to 267 dogs hospitalized in an ICU with a variety of diseases, including sepsis, to determine whether there was an association with mortality. Using those human scoring parameters patient qSOFA scores were not associated with survival. Adding blood lactate concentration to the assessment improved the sensitivity of the instrument to predict mortality, but this was not superior to measurement of lactate alone. Possible explanations for this apparent lack of utility are that the blood pressure and respiratory rate cutoffs appropriate for humans do not work for dogs, and identifying significant change in mentation in this species may be more difficult. Similarly, the second study retrospectively applied the same human criteria to dogs with sepsis. Sepsis was defined by finding at least two of the four SIRS criteria and a documented site of infection requiring surgical source control.20 When applied to dogs with sepsis, a qSOFA score of 2 was associated with a sevenfold higher risk of death and an increased duration of both postoperative complications and length of hospitalization. Thus, the qSOFA tool may have more value for animals with sepsis as opposed to other causes of severe illness, but accurate assessment of the tool’s utility to identify either will require prospective trials.

THE APPLE SCORE To date, the most comprehensive validated illness severity scoring system to characterize organ dysfunction and risk of death in dogs and cats is the Acute Patient Physiologic and Laboratory Evaluation

Fig. 7.1  The Sequential Organ Failure Assessment (SOFA) score. Adapted from reference 17.

CHAPTER 7  SIRS, MODS, and Sepsis (APPLE) score developed by Hayes et al. and reported in 201021 (dogs) and 201122 (cats). Both instruments were developed via analysis of physiological data acquired within 24 hours of hospital admission using the LOWESS approach23 to parse continuous physiological data into discrete categories. Each categorized variable was then screened via univariate logistic regression, and suitable candidate variables were assessed using a multivariate logistic regression model to identify the association between each variable and mortality outcome. Out of 55 preliminary variables evaluated for dogs and 41 for cats, the models were reduced to 10 (APPLEfull) or 5 (APPLEfast) variables in dogs (Fig. 7.2) and 8 or 5 variables in cats (Fig. 7.3). The individually weighted scores add up to a maximum possible score of 80 (APPLEfull) or 50 (APPLEfast). When applied to a cohort of ICU patients with high mortality rates (18.4% in dogs and 25.8% in cats), the accuracy of the APPLEfull score to predict survival in the authors’ validation groups was strong, with an area under the receiver operator curve (AUROC) value of .91 for dogs and .88 for cats. The APPLEfast scores performed nearly as well when predicting survival, with AUROC values of .85 in dogs and .76 in cats. Multiple investigators have subsequently used the APPLE score instruments to categorize animals for studies of critical illness from sepsis, trauma, and other disorders. Summers et al. retrospectively applied APPLEfull, APPLEfast, and an older classification system (Survival Prediction Index) to 37 dogs with septic shock and a very high

45

(81.1%) mortality rate. Of the three classification schema, only the APPLEfull had good predictive value, with an AUROC value of 0.8 across the range of calculated scores.24 In an overlapping retrospective study using some of the same subjects, higher APPLEfull scores were found in septic dogs treated with hydrocortisone for suspected relative adrenal insufficiency, consistent with clinical assessment that those dogs were sicker than dogs not treated with hydrocortisone. In critically ill dogs meeting SIRS criteria, APPLE scores were generally higher in nonsurvivors across several studies.25-28 Higher APPLEfull scores also predict mortality following traumatic injury in both cats29 and dogs;30: in the canine study, an APPLEfull score of 31 was 90% sensitive and 84.6% specific for nonsurvival with an AUROC of 0.912. Although some of the predictive variables in the APPLE scheme (age, body cavity fluid, temperature, and blood glucose) do not directly represent organ dysfunction, most of the included variables are directly related to the neurologic, cardiopulmonary, hepatic, renal, and hemostatic systems and thus provide an assessment for multiple organ dysfunction. As with other scoring systems, the weights assigned to different categorical variables do not necessarily correlate with clinical severity. For example, in the canine APPLEfull model, hyperglycemia (blood glucose concentration .273 mg/dl) is weighted at 0 and a normal blood glucose concentration (84-102) is weighted with a score of 8 (Fig. 7.2). Similarly, both the APPLEfull and APPLEfast instruments

Fig. 7.2  The canine APPLEfull and APPLEfast score.21

46

PART I  Key Critical Care Concepts

assign an item score of 0 for marked anemia (packed cell volume (PCV) ,11% or ,16%, respectively) and a score of 14 or 9, respectively, to cats with an admission PCV of 40% (Fig. 7.3). Such counterintuitive score assignments are likely due to a combination of multivariate effects in the model plus the nature of underlying disease in animals used for instrument development. For example, cats with marked anemia and dogs with marked hyperglycemia may have survived to discharge following transfusion or treatment with insulin.

ASSESSMENT OF ANIMALS WITH SIRS OR MODS Although the 2016 redefinition of sepsis was stripped of its original association with SIRS, the clinical identification of systemic inflammation remains a foundational screening tool for severe illness due to infectious and noninfectious disease in humans, dogs, and cats. Hyper/hypothermia, unexplained sinus tachy- or bradycardia, and tachypnea are significant features of critical illness in companion animals, particularly when accompanied by other physical examination findings such as depressed mentation or abnormal mucus membrane color, skin temperature, and femoral pulse quality. Discovery of physical evidence of SIRS criteria should trigger immediate investigation to localize the cause additional testing such as hematology (necessary to complete the SIRS evaluation), serum biochemistry panel, blood lactate, arterial blood pressure, pulse oximetry, cytology, bacteriological culture, and diagnostic imaging. The low specificity of SIRS criteria for predicting outcome means that a prognosis should not be offered based on the presence of the syndrome alone. Additionally, a majority of animals meeting SIRS criteria may ultimately have no evidence of an infectious cause, as these criteria are not specific for sepsis. However, if an infectious cause is suspected, the appropriate steps for diagnosing (collecting blood, urine, and/or site-specific cultures) and treatment (starting broad spectrum antibiotics) should be

initiated. When the source of suspected infection is not immediately apparent, ancillary testing should include point-of-care or comprehensive ultrasound examination of the thorax and abdomen, with aspirates of any body cavity fluid or abnormal masses for cytology and bacterial culture and susceptibility testing. The urogenital system should be examined for evidence of pyelonephritis, pyometra, or prostatitis and a urine sample collected aseptically for analysis and microbial culture with susceptibility testing. Thoracic radiographs should be obtained to rule out pneumonia or pulmonary masses; if heavy lung infiltrate suggests severe pneumonia, an airway wash to collect a respiratory fluid sample for culture may be warranted. A CBC may reveal changes supportive of infection, such as leukocytosis, leukopenia, or a left shift, and examination of a blood smear may reveal neutrophil toxic change or evidence of intracellular or extracellular organisms. Serologic testing may be indicated for agents such as Rickettsia ricketsii or other causes of systemic illness. If no localized source of infection is evident, or if bacterial endocarditis is suspected, blood cultures (including Bartonella alphaproteobacteria growth medium culture) should be obtained. Additional testing is patientspecific, and could include diagnostics such as an echocardiogram if a new murmur is auscultated, arthrocentesis if joints are effusive or painful, cerebrospinal fluid tap and/or spinal radiographs if evidence of neck or back pain. Empiric therapy with antimicrobials should be based on clinical suspicion and informed by local experience, organ involvement, apparent virulence, and when available, cytology and Gram stain results. Treatment of suspected bacterial sepsis should utilize intravenous antibiotics administered at the upper end of the therapeutic dosage range, adhering to principles of time- or concentrationdependent drug administration. Time-dependent antibiotics may best be administered as a loading dose followed by a continuous rate intravenous infusion to maintain tissue concentrations above the

Fig. 7.3  The feline APPLEfull and APPLEfast score.22

CHAPTER 7  SIRS, MODS, and Sepsis minimal inhibitory concentration for the target organism. Although many drugs in widespread use may be effective in animals with no recent antibiotic exposure (e.g., fluoroquinolones for Escherichia coli infection), animals recently treated with antibiotics for other illnesses likely are at a higher risk of multidrug resistant infections and may need escalated therapy at the onset of treatment. In contrast to SIRS criteria, comprehensive screening for multiple organ dysfunction is more complex because its quantification requires more than just a physical examination combined with a CBC. At present, there is no reliable cage-side prediction tool that adequately characterizes multiple organ dysfunction or estimates mortality risk in animals as well as the qSOFA score does in humans. The APPLEfast and APPLEfull scores are the best validated of the companion animal illness severity assessments, and in cats the APPLEfast score can be estimated rather quickly with a combination of physical examination and pointof-care testing (see Chapter 13, Predictive Scoring Systems in Veterinary Medicine). However, both of the canine APPLE scores and the feline APPLEfull score require a biochemistry profile in addition to an ultrasound examination of both body cavities, and therefore may be more useful as an objective tool to characterize illness severity and predict prognosis rather than a triage screening instrument. It is important to recognize that mortality estimates provided by the APPLE scores are based on data obtained from one hospital between 2007 and 2009, and treatment strategies that affect mortality may be very different now. Therefore, the APPLE score should be folded into the overall clinical assessment of the patient, and not mistaken for an objective way to quantify absolute mortality risk for any individual patient. An interactive APPLE score calculator is available for download31 this point-and-click template simplifies the computation of either APPLE score.

SUMMARY The systemic inflammatory response is a common reaction to both sepsis and noninfectious critical illness. Its presence should alert the clinician to the likelihood that something serious is going on. SIRS criteria and other features of inflammation such as altered skin temperature, changes to mucous membrane color and/or capillary refill time, and abnormal behavior may be quickly identified via physical examination and basic hematology. Possible causes such as trauma, burns, or cellulitis may be obvious during initial examination. However, when the cause is not quickly apparent, identifying SIRS criteria in a dog or cat should prompt diagnostic testing to rule out bacterial sepsis, viral, protozoal, or rickettsial infections, pancreatitis, immunemediated disease, or neoplasia. In conjunction with additional diagnostic testing and application of scoring indices such as APPLE, the identification of MODS carries more important and accurate implications for outcome. However, treatment decisions and prognosis for each patient are clinically complex and should never be based solely on any illness severity index.

REFERENCES 1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Crit Care Med 20(6):864-874, 1992. 2. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Chest 101(6):1644-1655, 1992. 3. Purvis D, Kirby R: Systemic inflammatory response syndrome: septic shock, Vet Clin North Am Small Anim Pract 24(6):1225-1247, 1994.

47

4. Hardie EM: Life-threatening bacterial infection, Compend Contin Educ Pract Vet 17(6):763-778, 1995. 5. Hauptman JG, Walshaw R, Olivier NB: Evaluation of the sensitivity and specificity of diagnostic criteria for sepsis in dogs, Vet Surg 26(5):393-397, 1997. 6. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217(4):531-535, 2000. 7. Alves F, Prata S, Nunes T, et al: Canine parvovirus: a predicting canine model for sepsis, BMC Vet Res 16(1):199, 2020. 8. Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 236(1):83-87, 2010. 9. Marshall JC, Cook DJ, Christou NV, et al: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome, Crit Care Med 23(10):1638-1652, 1995. 10. Kaukonen KM, Bailey M, Pilcher D, et al: Systemic inflammatory response syndrome criteria in defining severe sepsis, N Engl J Med 372(17): 1629-1638, 2015. 11. Fernando SM, Tran A, Taljaard M, et al: Prognostic accuracy of the quick sequential organ failure assessment for mortality in patients with suspected infection: a systematic review and meta-analysis, Ann Intern Med 168(4):266-275, 2018. 12. Ghnewa YG, Fish M, Jennings A, et al: Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction, Med Klin Intensivmed Notfmed 115(Suppl 1):10-14, 2020. 13. Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3), J Am Med Assoc 315(8):801-810, 2016. 14. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/ SIS international sepsis definitions conference, Crit Care Med 31(4): 1250-1256, 2003. 15. Marshall JC: The PIRO (predisposition, insult, response, organ dysfunction) model: toward a staging system for acute illness, Virulence 5(1): 27-35, 2014. 16. Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3), J Am Med Assoc 315(8):762-774, 2016. 17. Lambden S, Laterre PF, Levy MM, et al: The SOFA score-development, utility and challenges of accurate assessment in clinical trials, Crit Care 23(1):374, 2019. 18. Ripanti D, Dino G, Piovano G, et al: Application of the sequential organ failure assessment score to predict outcome in critically ill dogs: preliminary results, Schweiz Arch Tierheilkd 154(8):325-330, 2012. 19. Ortolani JM, Bellis TJ: Evaluation of the quick sequential organ failure assessment score plus lactate in critically ill dogs, J Small Anim Pract 62(10):874-880, 2021. 20. Stastny T, Koenigshof AM, Brado GE, et al: Retrospective evaluation of the prognostic utility of quick sequential organ failure assessment scores in dogs with surgically treated sepsis (2011-2018): 204 cases, J Vet Emerg Crit Care 32(1):68-74, 2022. 21. Hayes G, Mathews K, Doig G, et al: The acute patient physiologic and laboratory evaluation (APPLE) score: a severity of illness stratification system for hospitalized dogs, J Vet Intern Med 24(5):1034-1047, 2010. 22. Hayes G, Mathews K, Doig G, et al: The Feline Acute Patient Physiologic and Laboratory Evaluation (Feline APPLE) Score: a severity of illness stratification system for hospitalized cats, J Vet Intern Med 25(1):26-38, 2011. 23. Cleveland WS: Robust locally weighted regression and smoothing scatterplots, J Am Stat Assoc 74(368):829-836, 1979. 24. Summers AM, Vezzi N, Gravelyn T, et al: Clinical features and outcome of septic shock in dogs: 37 cases (2008-2015), J Vet Emerg Crit Care 31(3):360-370, 2021. 25. Langhorn R, Oyama MA, King LG, et al: Prognostic importance of myocardial injury in critically ill dogs with systemic inflammation, J Vet Intern Med 27(4):895-903, 2013. 26. Giunti M, Troia R, Bergamini PF, et al: Prospective evaluation of the acute patient physiologic and laboratory evaluation score and an extended clinicopathological profile in dogs with systemic inflammatory response syndrome, J Vet Emerg Crit Care 25(2):226-233, 2015.

48

PART I  Key Critical Care Concepts

27. Heilmann RM, Grutzner N, Thames BE, et al: Serum alpha1-proteinase inhibitor concentrations in dogs with systemic inflammatory response syndrome or sepsis, J Vet Emerg Crit Care 27(6):674-683, 2017. 28. Köster LS, Fosgate GT, Suchodolski J, et al: Comparison of biomarkers adiponectin, leptin, c-reactive protein, s100a12, and the Acute Patient Physiologic and Laboratory Evaluation (APPLE) score as mortality predictors in critically ill dogs, J Vet Emerg Crit Care 29(2):154-160, 2019.

29. Murgia E, Troia R, Bulgarelli C, et al: Prognostic significance of organ dysfunction in cats with polytrauma, Front Vet Sci 6:189, 2019. 30. Goggs R, Letendre JA: High mobility group box-1 and pro-inflammatory cytokines are increased in dogs after trauma but do not predict survival, Front Vet Sci 5:179, 2018. 31. https://docs.google.com/spreadsheets/d/1bQ_iaUHeILWn3NpGxFi1 Ewvbp8zEiwKAn0SvsOc0VRI/copy

8 Oxygen Toxicity Duana McBride, BVSc, DACVECC, MVMedSc, FHEA, MRCVS KEY POINTS • Oxygen is a stable molecule that is metabolized to water during a three-stage reduction. Hyperoxia or pathological states can result in the incomplete reduction of oxygen, producing reactive oxygen and nitrogen species (RONS). • RONS cause oxidative injury by inducing damage to lipids (via lipid peroxidation), nucleic acids, and proteins, resulting in cellular injury. • Hyperoxia can result in cellular injury that predominantly affects the respiratory, central nervous, and cardiovascular systems.

• Hyperoxia is associated with worse outcome in critically ill people, including patients with sepsis, those receiving mechanical ventilation, and postcardiac arrest patients. • Antioxidants are endogenous or exogenous compounds that can delay or prevent the oxidation of substrates into RONS, which are important mechanisms in protecting cells against oxidative injury.

PATHOPHYSIOLOGY The oxygen molecule (O2) consists of a pair of oxygen atoms bound together with two unpaired electrons in the outer shell (known as a biradical [Box 8.1]). Unpaired electrons are considered free radicals and are typically highly reactive.1 However, oxygen is unique in that the unpaired electrons orbit around the oxygen atom in parallel, and therefore it is not highly reactive. Reactive oxygen and nitrogen species (RONS) are natural byproducts of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis.1,2 Excess accumulation of RONS is limited by the body’s capacity to convert RONS into stable molecules via antioxidants. When oxidative injury occurs due to endogenous or exogenous sources (Box 8.2), the body’s capability to metabolize RONS becomes exhausted, resulting in dangerous levels of RONS production (Fig. 8.1).

Three-stage Reduction of Oxygen The three-stage reduction of oxygen involves the reduction of 90%– 95% of oxygen to water when there are no pathological stresses on the body.1,2 The remaining 5% of oxygen only partially undergoes reduction, and the intermediate products leak into the cytosol and outside the cell and cause oxidative injury. Initially, oxygen is reduced to the superoxide anion (• O22), which is a precursor of most other reactive oxygen species (ROS). The superoxide anion is one of the most reactive ROS; however, it is rapidly metabolized due to the presence of superoxide dismutase and glutathione peroxidase. Dismutation of • O22 produces hydrogen peroxide (H2O2), which is not a free radical as it has no unpaired electrons, but it is highly toxic. Hydrogen peroxide is then reduced to water through a reaction catalyzed by catalase (Fig. 8.1).

Fenton/Haber–Weiss Reaction The Fenton reaction, also known as the Haber–Weiss reaction, is the most cytotoxic of all oxidative pathways. The reaction is dependent on the availability of H2O2, iron, and copper.1,2 The products of this

BOX 8.1  Definitions Oxygen molecule: A pair of oxygen atoms bound together with two unpaired electrons in the outer shell. Hyperoxia: An excess of oxygen supply in tissues or organs.2,3 Hyperoxemia: Partial pressure of oxygen in arterial blood (PaO2) above normal values.2,3 Free radical: Reactive atom or group of atoms that has one or more unpaired electrons.1,2 Reactive oxygen and nitrogen species (RONS): Chemically reactive species containing oxygen or nitrogen.1,2 Antioxidant: Compound that inhibits oxidation.1,2 Oxygen toxicity/oxidative injury: Where excessive tissue oxygen or pathological states can result in the transformation of a stable oxygen molecule to highly toxic substances, causing damage to nucleic acids, proteins, and lipids.2,3

BOX 8.2  Sources of Oxygen Toxicity Endogenous

Exogenous

Aerobic respiration Excessive oxygen in the tissues compared with antioxidant defence mechanisms Free electron production from NADPH in neutrophils and macrophages during phagocytosis Ischemic reperfusion injury Iron Copper Oxidation of hemoglobin to methemoglobin

Ionizing radiation Environmental background radiation Ultraviolet radiation Pollution Paraquat toxicity Bleomycin toxicity

NADPH, nicotinamide adenine dinucleotide phosphate.

49

50

PART I  Key Critical Care Concepts

•HO + OH– + 1O2 Cu/Fe2+ 2e– 2O2

2H+ 2•O2–

Fenton/Haber-Weiss reaction 2e– 2H+

O2

Superoxide dismutase/ glutathione peroxidase

H2O2

O2

Catalase

Three-stage reduction of oxygen

2H2O

2HOCI Myeloperoxidase reaction 2CI–

2NO•

2ONO2– Reactive nitrogen species Fe2+

Fe3+

Fig. 8.1.  ​Three-stage reduction of oxygen and reactive oxygen/nitrogen species production. 1O2, singlet oxygen molecule; Cl, chloride; Cu, copper; e2, electron; Fe, iron; H2O, water; H2O2, hydrogen peroxide; HOCl, hypochlorous acid; O2, dioxygen; • O22, superoxide anion; OH2, hydroxyl anion; • OH, hydroxyl free radical; ONO22, peroxynitrite. R (PUFA)

reaction are the hydroxyl free radical (• OH), which is one of the most toxic ROS; the hydroxyl anion (OH2); and the singlet oxygen molecule (1O2). The 1O2 is a free radical and ROS formed by internal rearrangement of unpaired electrons from the dioxide oxygen molecule (O2) (Fig. 8.1).

–

ONO

or •HO H2O •R (lipid radical)

Myeloperoxidase Reaction

O2

Hydrogen peroxide can react with chloride to form hypochlorous acid (HOCl), which occurs in the phagocytic vesicles of neutrophils and is important in killing bacteria (Fig. 8.1).1,2 Hypochlorous acid is not a free radical. It is a ROS and a precursor to free radicals.

R (PUFA) + •RO2 (peroxyl radical)

ROOH (lipid peroxide)

Reactive Nitrogen Species Nitric oxide (NO •) is a potent endogenous vasodilator, cell messenger, and platelet inhibitor and can have cytotoxic effects in large quantities (e.g., during ischemia-reperfusion injury [IRI]).1,2 Nitric oxide can react with O• 22 to produce peroxynitrite (ONO22), which is a reactive nitrogen species that can initiate lipid peroxidation (Fig. 8.1). Peroxynitrite can also rearrange itself into nonreactive molecules and has a role as an antioxidant.

2

Fe2+ •RO (ocoxyl radical)

Fig. 8.2.  ​Lipid peroxidation. • HO, hydroxyl free radical; ONO22, peroxynitrite; PUFA, polyunsaturated fatty acid.

CELLULAR EFFECT OF OXIDATIVE INJURY

backbone. There are endogenous DNA repair mechanisms that prevent mutagenesis; however, DNA and RNA mutations can result if these repair mechanisms are overwhelmed.4

Lipid Peroxidation

Proteins

Lipids are the most susceptible to oxidative injury due to their relatively unstable double bonds and high prevalence in cell membranes. Lipid peroxidation is a major source of cellular injury, resulting in increased cell membrane permeability; inhibition of normal cellular enzyme processes; damage to proteins, intracellular membranes, capillaries, and alveoli; and inactivation of lung surfactant. The two main free radicals that can initiate lipid peroxidation are • OH and ONO22, although many other free radicals and RONS can also initiate lipid peroxidation. Polyunsaturated fatty acid is the major target of lipid peroxidation, and injury to polyunsaturated fatty acids results in a chain reaction of the generation of other ROS (Fig. 8.2).

Proteins are affected during oxidative stress due to decreased production secondary to inhibition of ribosomal translation, and direct reversible and irreversible oxidative injury. The most susceptible amino acid residues are cysteine and methionine; oxidation of the sulfhydryl groups results in the formation of disulphide bridges, which can inactivate a range of proteins. As a result, impairment of cellular signaling and metabolism can occur.

Nucleic Acids Oxidative stress can cause DNA and RNA damage, including mutations, and is therefore one of the contributing factors in mutagenesis, carcinogenesis, and aging. Hydroxyl radicals can react with DNA molecules, damaging purine and pyrimidine bases and the deoxyribose

Role of Inflammation During Oxidative Injury In addition to necrosis and apoptosis, oxidative injury can result in release of damage-associated molecular pattern molecules (DAMPS).2 DAMPS are recognized by pattern recognition receptors of the innate immune system and activate polymorphonuclear neutrophils (PMNs), thus contributing to the release of cytokines and the recruitment of monocytes and additional neutrophils. PMNs stimulate the inflammatory response and contribute to further RONS production, which in turn causes a vicious cycle of oxidative injury.2

CHAPTER 8  Oxygen Toxicity

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CLINICAL EFFECTS OF HYPEROXIA

ISCHEMIA-REPERFUSION INJURY IRI can be a source of oxidative injury in critically ill patients. It has been associated with myocardial infarction, thrombolytic therapy, aortic cross-clamping, cardiac bypass surgery, and organ transplantation in people.5 In veterinary medicine, IRI has been documented to occur in dogs with gastric dilation and volvulus, in dogs with myocardial injury, and in cats with arterial thromboembolism.6-8 During ischemia, anaerobic metabolism occurs, leading to the accumulation of intracellular lactate and hydrogen ions. There is decreased ATP available for ATP-dependent cell membrane pumps, resulting in a net efflux of potassium, and an influx of sodium, calcium, and chloride, leading to cell swelling. The high intracellular calcium concentration plays a large part in early IRI, causing cell apoptosis and necrosis, and contributes to the activation of the xanthine oxidoreductase system (Fig. 8.3). Activation of nuclear factor-kB occurs, increasing inflammatory mediators, resulting in leukocyte adhesion at the site of ischemia and during the reperfusion process. As oxygen is required for NO•  production, ischemia results in NO•  depletion and subsequent vasoconstriction, decreased perfusion, and cellular injury. During reperfusion, there is an increase in NO•  production, which is cytotoxic and causes severe nonresponsive vasodilation. Concurrently, there is release of ROS, which can inactivate NO •. In addition, NO •  and • O22 combine to produce ONO22 and cause further cellular injury. One of the most significant causes of cellular injury during IRI is the xanthine oxidoreductase system (Fig. 8.3). During ischemia, ATP is degraded to adenosine diphosphate, then to adenosine followed by inosin, and finally to hypoxanthine. In addition, the increased intracellular calcium catalyzes the metabolism of xanthine dehydrogenase to xanthine oxidase, which initiates the xanthine oxidoreductase system when reperfusion occurs. Upon reperfusion, there is a sudden increase in oxygen delivery, and in combination with oxidized nicotinamide adenine dinucleotide (NAD1), causes xanthine and uric acid production. This process occurs 10–30 seconds after the onset of reperfusion. During this process, NAD1 is reduced to NADH, and H2O2 and • O22 production occurs. The endothelium and gastrointestinal mucosa have the greatest amount of xanthine oxidase and, as a result, are highly susceptible to IRI. The most common clinical signs associated with IRI are hyperkalemia, acidemia, and associated cardiac arrhythmias; the “no reflow” phenomenon (where despite the occlusion being resolved, there is decreased perfusion due to leukocyte adhesions, platelet–leukocyte aggregation, and decreased endothelium-dependent vasorelaxation); myocardial stunning; central nervous system changes; gastrointestinal signs; and multiple organ dysfunction syndrome.

Hyperoxia and the Lungs The lungs are the organ most affected by hyperoxia due to high exposure levels compared with other tissues. Despite protective mechanisms (e.g., high antioxidant activity), hyperoxia can result in apoptosis and necrosis of pulmonary parenchymal cells, inflammation, noncardiogenic pulmonary edema, impaired gas exchange, and fibrosis, for which the underlying causes are multifactorial.1 The NO•  pathway plays a key role in the lungs, with the increased production of NO•  resulting in ONO22 formation in epithelial and endothelial cells.1 Vacuolation and thinning of the pulmonary capillary endothelium can result in increased permeability and pulmonary interstitial edema. Release of DAMPs and activation of PMNs result in inflammation, which leads to systemic inflammatory response syndrome, pulmonary inflammation, and a subsequent increase in alveolar–capillary permeability.9 Eventually, type I pneumocytes of the alveolar epithelium are lost and replaced by type II, which are surfactant-secreting pneumocytes that are relatively resistant to oxygen and also contribute to a thicker alveolar/capillary membrane, leading to diffusion impairment and eventually pulmonary fibrosis. Hyperoxia can lead to alveolar collapse by multiple mechanisms. First, nitrogen, an important molecule in preventing pulmonary atelectasis, is displaced by administration of 100% oxygen, thus resulting in absorptive atelectasis.9 Increased alveolar oxygen concentration results in a marked alveolar to arterial oxygen gradient, resulting in rapid diffusion of oxygen from the alveoli to the pulmonary circulation, also contributing to atelectasis.1 In addition, hyperoxia can induce surfactant impairment due to the downregulation of surfactant-associated proteins.9 Overall, atelectasis results in decreased alveolar capacity, decreased tidal volume, and ventilationperfusion mismatch; these affect both oxygenation and ventilation.1 Hyperoxia decreases mucociliary clearance and alters the pulmonary microbial flora and immune function, causing a predisposition to secondary infections.1,10,11 The duration of hyperoxia in people ranges from as little as 3 hours of 100% oxygen delivery to cause decreased mucociliary clearance and up to 30 hours to result in a decrease in vital capacity and gas diffusion. However, the effects of hyperoxia on the lungs are species-specific, with no available data in dogs or cats, and confounding illness factors must be taken into account in the clinical setting.

Hyperoxia and the Cardiovascular System Hyperoxia results in increased systemic vascular resistance and vasoconstriction secondary to decreased NO • bioavailability. ROS, most notably • O22, inhibits NO • via multiple mechanisms by reducing12,13

Inosine Hypoxanthine NAD+ + O2 Xanthine oxidase H2O2 NADH + O2– SOD Protease Xanthine Xanthine Ca2+ + dehydrogenase NAD + O2 Xanthine oxidase H2O2 NADH + O2– SOD Uric acid Fig. 8.3.  ​Xanthine oxidoreductase system. Ca21, calcium; H2O2, hydrogen peroxide; NAD1, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; O2, oxygen; O22, superoxide anion; SOD, superoxide dismutase.

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PART I  Key Critical Care Concepts

1) L-arginine levels (a precursor of NO •); 2) nitric oxide synthase, which catalyzes the reaction of L-arginine to NO •; and 3) the offloading of NO • from the hemoglobin molecule.13 Other proposed mechanisms of hyperoxia-induced vasoconstriction include a reduction in other vasodilators, including prostaglandin, alterations in ATP secretion (which can alter NO • production), and alterations in the morphology of erythrocytes that modulate vasomotor tone.13 In addition, NO•  is released in response to a decrease in oxyhemoglobin saturation; hence, hyperoxia may counteract this response.12 Because of the vasoconstrictive effects, baroreceptors respond by decreasing the heart rate with no change in stroke volume, resulting in a decrease in cardiac output. Additionally, the difference between arterial and venous oxygen content of blood is also reduced due to reduced oxygen consumption.1,2 Therefore, despite hyperoxia, oxygen delivery to cells is actually unchanged.1,2 Deleterious effects of hyperoxia on the cardiovascular system result from the vasoconstrictive effects that lead to decreased perfusion to vital organs, predominantly the myocardium and brain,12 as well as skeletal muscle, retina, and skin.13 Hyperoxic vasoconstriction has some beneficial effects, including its ability to reduce intracranial pressure; counterbalance the vasodilatory effects of septic shock; preserve perfusion to the sublingual, hepato-splanchnic, pulmonary systems; and improve renal circulation in experimental studies.3,2,12,14

Hyperoxia and the Central Nervous System Hyperoxia can result in decreased cerebral blood flow secondary to hypoxic vasoconstriction, though this same vasoconstrictive effect also decreases intracranial pressure.3 Hyperoxia may also lead to increased cerebral excitotoxicity, thus attenuating secondary brain injury.15

HYPEROXIA IN THE CRITICALLY ILL Although oxygen supplementation is often prescribed in the critically ill, hyperoxia has been associated with worse outcomes in critically ill people.1,16-18 Subgroup analysis in various meta-analyses has shown that hyperoxia in postcardiac arrest patients, those that require extracorporeal membrane oxygenation, or those that suffer from ischemic stroke or traumatic brain injury (TBI) is associated with a higher mortality rate.16,17,19

Oxygen Targets in the Mechanically Ventilated Although there is evidence that there is a time- and dose-dependent association of hyperoxia with mortality,20 there is conflicting evidence regarding the outcome when comparing liberal versus conservative (SpO2 targets of 98% vs. 88%) oxygen treatment strategies in the critically ill.18,21,20,22-24 The current recommendation for patients requiring mechanical ventilation is to target a SpO2 of 88%–92% or a PaO2 of 55–80 mm Hg.9

Hyperoxia in Sepsis Hyperoxia in the presence of sepsis can exacerbate the vicious cycle of hyperoxia and inflammation.3 Subgroup analysis of patients with sepsis exposed to hyperoxia in a meta-analysis showed no difference in mortality.17,25 However, one recent randomized controlled trial was terminated upon finding that patients exposed to hyperoxia had a higher risk of mortality and serious adverse events.26

Hyperoxia Following Cardiac Arrest Cardiopulmonary arrest can result in severe hypoxemia and reperfusion injury after return of spontaneous circulation (ROSC).1 Several studies found an association between hyperoxia after ROSC and mortality and worse neurological outcomes, although some studies have

conflicting results.1 The current recommendation is to minimize hyperoxia in postcardiac arrest care.

Hyperoxia in Traumatic Brain Injury Subgroup analysis from a meta-analysis found an increased mortality rate with hyperoxia in people with TBI.16,17,19 However one study demonstrated improved outcome with a combined use of hyperbaric oxygen therapy (HBOT) and normobaric oxygen therapy in patients with TBI.27 At the time of this publication, there has been no clear benefit of hyperbaric or normobaric oxygen therapy for treatment of TBI.

HYPERBARIC OXYGEN THERAPY HBOT is the therapeutic use of pressurized 100% oxygen, above 1.5– 3.0 atmosphere absolute in a closed chamber.28-30 This therapy increases the oxygen content in the blood by increasing PaO2 beyond the saturable oxygen capacity of the hemoglobin molecule. The principle of HBOT is based on the gas laws described in Box 8.3. Dalton’s Law states that in a mixed gas, each element exerts a pressure proportional to its partial pressure.28,29 Boyle’s Law states that the volume of gas decreases as pressure increases. Therefore, as the partial pressure of oxygen in alveoli (PAO2) increases, gas volume decreases, thus allowing more oxygen to enter the alveoli.29 Based on Henry’s Law and Fick’s Law, diffusion of gas occurs from a high to low concentration gradient. Therefore, increasing the PAO2 causes a greater pressure gradient between the alveoli and pulmonary capillary bed, increasing the rate of diffusion.28,29 As hemoglobin becomes completely saturated with oxygen, further diffusion of oxygen into the circulation will increase PaO2. Oxygen unbound to hemoglobin diffuses much more readily into tissues and can provide oxygen in areas that are not accessible to hemoglobin.28,29 Boyle’s Law plays another important role in reducing unwanted volumes of gas in blood and tissues (i.e., treatment of decompression sickness and air embolism).29 HBOT can also have potential antimicrobial, immunomodulatory, angiogenic, and vasoconstrictive effects.29,30 Indications for the use of HBOT in people include treatment of gas embolization, decompression sickness, carbon monoxide toxicity, cyanide toxicity, ischemic or burn injuries, severe crush injuries, gas gangrene, diabetic wounds, radiation injuries, and compartment syndrome.13 Although HBOT has been used for TBI and ischemic brain injury, there is no strong evidence for its use. Complications associated with HBOT include barotrauma, decompression sickness, pulmonary oxygen toxicity, and seizures. Seizures occur secondary to decreased cerebral metabolism, leading to decreased levels of g-aminobutyric acid, an inhibitory neurotransmitter. Another proposed mechanism is the denaturation of DNA secondary to RONS. A recent prospective clinical trial in 230 hyperbaric oxygen treatments in dogs and cats found no major adverse effects and

BOX 8.3  Gas Laws Involved in Hyperbaric

Oxygen Therapy

Dalton’s Law PTotal 5 P1 1 P2 Boyle’s Law P1V1 5 P2V2 Henry’s Law Conc 5 P(sol) Fick’s Law Vgas 5 A/T • D(P1 – P2) D 5 sol/MW A, area; Conc, concentration; D, diffusion constant; MW, molecular weight; P, pressure; sol, solubility; T, thickness; V, volume.

CHAPTER 8  Oxygen Toxicity 76 minor adverse effects of no clinical significance.30 HBOT is contraindicated in patients with pneumothorax; it should be avoided or used with extreme caution in patients with bulla, pulmonary lesions, history of thoracic or ear surgery, pyrexia, pregnancy, or upper respiratory tract infections.

ANTIOXIDANTS Antioxidants include any compound that can delay or prevent the oxidation of a substrate, thus helping to protect cells against oxidative injury.1 They are important in minimizing oxidative injury, DNA mutations, malignant transformation, and cell damage.1 Antioxidant depletion can occur with chronic kidney disease,31 cardiac disease,1,32 hepatic disease,33 diabetes mellitus, neoplasia, and in the critically ill.1 Antioxidants can be classified into three categories: endogenous antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase, catalase), endogenous nonenzymatic antioxidant compounds (glutathione, albumin, ferritin, transferrin, ceruloplasmin, haptoglobin, bilirubin, uric acid, coenzyme Q, lipoic acid, vitamin C, vitamin E, glutathione, selenium, lycopene, melatonin), and exogenous antioxidants (vitamin C, vitamin E, beta-carotene, phenolics, acetylcysteine, selenium, zinc).1 The endogenous antioxidant enzymes play an important role in preventing oxidative injury by catalyzing the pathways of oxygen metabolism, therefore minimizing production of intermediate ROS products. SOD production is stimulated by hyperoxia and by inflammatory cytokines such as interferons, tumor necrosis factor, interleukins, and lipopolysaccharides. There are three forms of SOD: extracellular SOD, cytoplasmic SOD containing manganese, and mitochondrial SOD containing copper and zinc. SOD has a very short half-life and is relatively unstable in circulation due to rapid renal excretion. Therefore, therapeutic use has been limited, although there have been recent advances in SOD mimetics. Catalase catalyzes the decomposition of H2O2 to water and oxygen. As with SOD, catalase is found in the extracellular space, cytoplasm, and mitochondria, with particularly high concentrations in the liver and erythrocytes. Glutathione peroxidase contains selenium and scavenges ROS and reactive species formed during lipid peroxidation.1

PREVENTION AND TREATMENT OF OXYGEN TOXICITY It is important to prevent oxygen toxicity by titrating oxygen supplementation to the desired levels of oxygenation, although this value is still debatable. Mild to moderate hypoxemia (PaO2 of 60–80 mm Hg or SpO2 of 90%–95%) may be well tolerated in some patients. When deciding on minimally acceptable oxygen levels, the overall clinical condition of the patient should be considered while considering all determinants of oxygen delivery to the tissues, including cardiac output and hemoglobin concentration of the patient. As antioxidant depletion has been described in some critically ill conditions, it is logical to consider the use of exogenous antioxidant supplementation in critically ill patients at risk of oxidative injury. These supplements include ascorbic acid, vitamin E, N-acetylcysteine, silymarin, and S-adenosylmethionine.1 However, if the balance is reversed to reduce RONS, the vital roles of RONS (i.e., cell signaling) may be inhibited. In addition, exogenous antioxidants may not have the same effects as endogenous antioxidants.2 Currently, there is no evidence for the use of antioxidants in the critically ill. Investigative therapies that might decrease oxidative stress include modulation of protein kinases and transcription factors, as well as

53

manipulation of chemokines, cytokines, growth factors, receptors, and DAMPs, although clinical applications have not yet been described.2 Future advances are likely to change the recommended treatment strategies for the modulation of the inflammatory system.

REFERENCES 1. Pisoschi AM, Pop A: The role of antioxidants in the chemistry of oxidative stress: a review, Eur J Med Chem 97:55-74, 2015. 2. Damiani E, Donati A, Girardis M: Oxygen in the critically ill: friend or foe? Curr Opin Anaesthesiol 31:129-135, 2018. 3. Helmerhorst HJF, Schultz MJ, van der Voort PHJ, et al: Bench-to bedside review: the effects of hyperoxia during critical illness, Crit Care 19: 284-296, 2015. 4. Poff AM, Kernagis D, D’Agostino DP: Hyperbaric environment: oxygen and cellular damage versus protection, Compr Physiol 7:213-234, 2017. 5. McMichael M, Moore R: Ischemia-reperfusion injury pathophysiology, part I, J Vet Emerg Crit Care 14(4):231-241, 2014. 6. Vajdovich P: Free radicals and antioxidants in inflammatory processes and ischemia-reperfusion injury, Vet Clin North Am Small Anim Pract 38:31-123, 2008. 7. Guillaumin J, Gibson RMB, Goy-Thollot I, Bonagura JD: Thrombolysis with tissue plasminogen activator (TPA) in feline acute aortic thromboembolism: a retrospective study of 16 cases, J Feline Med Surg 21(4): 340-346, 2019. 8. Welch KM, Rozanski EA, Freeman LM, Rush JE: Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism, J Feline Med Surg 12:122-128, 2010. 9. Pannu SR: Too much oxygen: hyperoxia and oxygen management in mechanically ventilated patients, Semin Respir Crit Care Med 37:16-22, 2016. 10. Patel VS, Sitapara RA, Gore A, et al: High Mobility Group Box-1 mediates hyperoxia-induced impairment of Pseudomonas aeruginosa clearance and inflammatory lung injury in mice, Am J Respir Cell Mol Biol 48(3):269-270, 2013. 11. Kennedy TP, Nelson S: Hyperoxia, HMGB1, and ventilator-associated pneumonia: reducing risk by practicing what we teach, Am J Respir Cell Mol Biol 48(3):269-270, 2013. 12. Brugniaux JV, Coombs GB, Barak OF, et al: Highs and lows of hyperoxia: physiological, performance, and clinical aspects, Am J Physiol Regul Integr Comp Physiol 315:R1-R27, 2018. 13. Sjoberg F, Singer M: The medical use of oxygen: a time for critical reappraisal, J Intern Med 274:505-528, 2013. 14. He X, Su F, Xie K, et al: Should hyperoxia be avoided during sepsis? An experimental study in ovine peritonitis, Crit Care Med 45:e1060-e1067, 2017. 15. Quintard H, Patet C, Suys T, et al: Normobaric hyperoxia is associated with increased cerebral excitotoxicity after severe traumatic brain injury, Neurocrit Care 22:243-250, 2015. 16. Damiani E, Adrario E, Girardis M, et al: Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis, Crit Care 18:711, 2014. 17. You J, Fan X, Bi X, et al: Association between arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis, J Crit Care 47:260-268, 2018. 18. Helmerhorst HJF, Schultz MJ, van der Voort PH, et al: Effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in critically ill patients: a before and after trial, Crit Care Med 44:554-563, 2016. 19. Ni YN, Wang YM, Liang BM, Liang ZA: The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis, BMC 19:53-66, 2019. 20. Barbateskovic M, Schjorring OL, Krauss SR, et al: Higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit, Cochrane Database Syst Rev 2019(11):CD012631, 2019.

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21. Girardis M, Busani S, Damiani E, et al: Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. The oxygen-ICU randomized clinical trial, JAMA 316(15): 1583-1589, 2016. 22. Suzuki S, Eastwood GM, Goodwin MD, et al: Atelectasis and mechanical ventilation mode during conservative oxygen therapy: a before-and-after study, J Crit Care 30:1232-1237, 2015. 23. Panwar R, Hardie M, Bellomo R, et al: Conservative versus liberal oxygen targets for mechanically ventilated patients – a pilot multicentre randomized controlled trial, Am J Respir Crit Care Med 193:43-51, 2016. 24. Mackle D, Bellomo R, Bailey M, et al: Conservative oxygen therapy during mechanical ventilation in the ICU, N Engl J Med 382:989-998, 2020. 25. Helmerhorst HJF, Arts D, Schultz MJ, et al: Metrics of arterial hyperoxia and associated outcomes in critical care, Crit Care Med 45:187-195, 2017. 26. Asfar P, Schortgen F, Boisrame-Helms J, et al: Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised clinical trial, Lancet Respir Med 15:180-190, 2017. 27. Rockswold SB, Rockswold GL, Zaun DA, Liu J: A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and

normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury, J Neurosurg 118:1317-1328, 2013. 28. Poff AM, Kernagis D, D’Agostino DM: Hyperbaric environment: oxygen and cellular damage versus protection, Compr Physiol 7:213-234, 2017. 29. Braswell C, Crowe T: Hyperbaric oxygen therapy, Compend Contin Educ Vet 34(3):E1-5, 2012. 30. Birnie GL, Fry DR, Best MP: Safety and tolerability of hyperbaric oxygen therapy in cats and dogs, J Am Anim Hosp Assoc 54(4):188-194, 2018. 31. Daenen K, Andries A, Mekahli D, et al: Oxidative stress in chronic kidney disease, Pediatr Nephrol 34:975-991, 2019. 32. Genga J, Qiana J, Weijun S, et al: The clinical benefits of perioperative antioxidant vitamin therapy in patients undergoing cardiac surgery: a meta-analysis, Interact Cardiovasc Thorac Surg 25(6):966-974, 2017. 33. Vandeweerd J, Cambier C, Gustin P: Nutraceuticals for canine liver disease: assessing the evidence, Vet Clin Nort Am Small Anim Pract 43: 1171-1179, 2013.

9 The Endothelial Surface Layer Lisa Smart, BVSc, DACVECC, PhD, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • The endothelial surface layer plays many important roles that are vital to the blood-to-vessel and vessel-to-interstitium interfaces. • Damage or modification of the endothelial surface layer affects vascular permeability, vasomotor tone, inflammation, and coagulation. • Animals with critical illness are at increased risk for endothelial surface layer damage and shedding; organ dysfunction may result from this damage.

• Measurement of circulating endothelial glycocalyx biomarkers and videomicroscopic estimation of the perfused boundary region are commonly used to detect and monitor this damage. • Therapeutic restoration of the endothelial surface layer and repair of the glycocalyx are areas of active investigation.

INTRODUCTION

in the coming years that may alter interventions used in veterinary critical care medicine.

The endothelial surface layer (ESL) on the luminal side of blood vessels comprises a gel-like glycocalyx with an immobile plasma layer. The ESL plays many important roles in the blood-to-blood vessel and vessel-to-interstitium interfaces, for example, modulating inflammation, coagulation, vasomotor tone, and vessel wall permeability. There has been a large amount of research in this area in the last 10 to 15 years, most of which cannot be covered in detail in this chapter. Instead, this chapter reviews broad concepts of the ESL, with references to detailed, or focused, reviews or key studies provided as examples. Two terms are frequently used throughout this chapter: ESL and the endothelial glycocalyx (EG). The ESL refers to the entire endothelial layer itself, whereas the EG refers to only the glycocalyx structure within the ESL. This difference is subtle but important to distinguish.

THE IMPORTANCE OF THE ESL IN CRITICAL ILLNESS Damage or modification of the ESL affects vascular permeability, vasomotor tone, inflammation, and coagulation. A better understanding of the barrier role of the ESL has led to modification of the traditional Starling hypothesis for fluid movement. This has had a particular impact on our understanding of fluid distribution and fueled the debate on ideal fluid types for fluid resuscitation. It is well established that critical illness, especially illness involving a systemic inflammatory response or ischemia, causes shedding of the ESL. This may increase the risk of interstitial edema, propagation of inflammation, and thrombosis and decrease vasomotor function. Interventions common in the intensive care unit have also been shown to modify the ESL, such as rapid intravenous fluid administration. It is not yet known if protecting the ESL by modifying our treatment approaches, or using interventions specifically to repair the ESL, affects clinical outcome. However, it is prudent to be aware of the pathophysiological consequences of endothelial damage and dysfunction. This is a burgeoning area of research in critical care medicine, and new therapies are likely to emerge

STRUCTURE AND FUNCTION The ESL has been an elusive structure that is hard to visualize or preserve. Traditional preparation of the endothelium for high-resolution microscopy reveals only bare luminal surfaces. More recent methods for preserving this delicate structure of the ESL in situ have revealed a furry or fuzzy layer of varying thickness (Fig. 9.1).1 Further developments in real-time in vivo microscopy techniques have revealed two areas of the intravascular space: a central column of traveling red blood cells, white blood cells, and an immobile perimeter of cell-free plasma (Fig. 9.2). This outer perimeter is the domain of the ESL. At a systemic level, the volume of plasma residing in this cell-free space has been estimated to be 15% of circulating plasma volume.2 The measured thickness of the ESL varies with location and imaging technique. Our understanding of the structures within the ESL has developed over time. Most methods for discovery have relied on first culturing endothelial cells in vitro, then labeling certain molecules to detect their presence or absence. This has revealed a forest-like structure of proteoglycans and attached glycosaminoglycan chains (Fig. 9.3). These individual elements of the ESL have been reviewed in detail elsewhere.3-5 Briefly, the proteoglycans include syndecans and glypican-1, with sulfated glycosaminoglycan chains extending from their intraluminal segments, or ectodomains. The sulfated glycosaminoglycans include heparan, chondroitin, and dermatan sulfate; the first of these is the most abundant. Hyaluronan, a long glycosaminoglycan chain, weaves its way along the forest floor directly attached to the endothelium or associated with chondroitin sulfate. Moving within this basic structure are proteins such as albumin, uromucoids and anticoagulants, and phospholipids, such as sphingosine-1 phosphate. The presence of these additional molecules within the EG structure is thought to be important for maintaining ESL thickness and barrier function. The ESL provides a barrier to the interstitial tissues through the physical nature of the gel-like layer (preventing adhesion, rolling or

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Fig. 9.1  ​The endothelial glycocalyx stained with Alcian blue 8GX and visualized with electron microscopy. The Alcian blue stains the glycosaminoglycans since they are acidic polysaccharides.1

A

B

Median RBC column width

PBR

PBR

Perturbed ESL

PBR

Healthy ESL

PBR

56

Median RBC column width

Fig. 9.2  ​Sidestream darkfield (SDF) imaging to measure the perfused boundary region (PBR) in the sublingual capillary bed. A, Recordings from the sublingual capillary bed made with the SDF camera (left). Capillaries are automatically recognized and analyzed after various quality checks (right). Based on the shift in red blood cell (RBC) column width in time, the PBR can be calculated. B, Model of a blood vessel showing the PBR in a healthy situation (left). The endothelial glycocalyx (EG) prevents the RBC from approaching the endothelial cell; thus, a small PBR is measured. In a disease situation (right) or after enzymatic EG breakdown in an animal model, the damaged EG allows the RBCs to approach the endothelium more often. This results in a higher variation in RBC column width reflected by a high PBR.1 ESL, endothelial surface layer.

CHAPTER 9  The Endothelial Surface Layer

57

Endothelial surface layer

Flowing plasma

Immobile plasma

Endothelial cell

Interstitium KEY Syndecan

Glypican-1

CD44 (green) and hyaluronan (orange)

Heparan sulfate

Chondroitin sulfate

Albumin

Fig. 9.3  ​Basic structure of the endothelial surface layer. The scaffold of the endothelial glycocalyx, within the endothelial surface layer, is provided by proteoglycans: syndecans (four subtypes) and glypican-1. Glycosaminoglycans are attached to proteoglycans (e.g., heparan sulfate) or the endothelial surface (hyaluronan). Molecules suspended in the plasma of the endothelial surface layer include proteins such as albumin. These proteins create a protein-poor subglycocalyx area that is important for transvascular colloid osmotic pressure balance. For simplicity, structures within the interendothelial cleft are not represented. (Reproduced with permission from Smart L, Hughes D: The effects of resuscitative fluid therapy on the endothelial surface layer, Front Vet Sci 8:661660, 2021. doi: 10.3389/fvets.2021.661660)

migration of large cells such as white blood cells), maintaining an electrostatic charge (repelling positively charged ions), and having a relatively protein-free fluid space (thereby creating an oncotic pressure gradient favoring intravascular fluid retention) between the clefts of the endothelial cells.6 It also contains anticoagulants, such as antithrombin and tissue factor pathway inhibitor, discouraging thrombosis of the endothelium.3,7 Other roles include detection of changes in shear stress and modulation vasomotor tone. For example, removal of glycosaminoglycans leads to loss of shear-induced nitric oxide production, which would normally cause compensatory vasodilation.5

FLUID MOVEMENT ACROSS THE ENDOTHELIUM One of the pivotal roles of the ESL that is currently under investigation is its influence on transvascular fluid flux (see also Chapter 11, Interstitial Edema). Recent developments in this area have led to some researchers challenging the traditional Starling principle for fluid movement (see Chapter 185, Colloid Osmotic Pressure and Osmolality Monitoring).8,9 The original concept was that the direction of fluid movement was determined by the balance of hydrostatic pressure and colloid osmotic pressure (COP) between the vascular space and interstitium.10 Added factors

include the reflection coefficient and permeability of the blood vessel concerned. In the revised Starling principle, based on controlled benchtop experiments, the opposing forces of COP belong to the intravascular space and the protein-poor subglycocalyx space.8,9,11 This means that interstitial proteins have little influence on transvascular fluid movement, as previously described in the classic Starling principle. The revised theory states that fluid is never reabsorbed into capillaries except during an acute, large decrease in intravascular hydrostatic pressure, and that this reversal is very brief before net filtration of fluid is reestablished. The period of fluid resorption is brief as proteins back diffuse into the subglycocalyx space, increasing the subglycocalyx COP, and reducing the influence of the COP gradient between the capillary and the subglycocalyx space. This new principle challenges the concept that fluid can be reabsorbed, including after infusion of hyperoncotic fluids, except for this brief deviation during extreme hypotension. However, some authors have challenged this new Starling principle, as the “no absorption rule” is not consistent with clinical experience.12 There is still much to be elucidated for in vivo fluid dynamics, including transvascular fluid flux in the presence of a denuded, ESL-free endothelium. This question is highly relevant to patients with critical illness that likely experience shedding or modification of the ESL.

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SHEDDING OF THE ESL The ESL is shed, modified, or compacted by many factors relevant to critical care, which includes tissue trauma, inflammation, hyperglycemia, hemodilution, and hypervolemia.13,14 Inflammatory cytokines have a direct shedding effect on the ESL, which allows for exposure of adhesion receptors and margination of leukocytes into tissue.15 This is an adaptive response to local inflammation but can become, presumably, maladaptive in critical illness. Inflammatory cytokines also upregulate components of the EG within the ESL, which may lead to increased turnover and, subsequently, increased circulating concentrations of these molecules.16-18 Increased turnover becomes relevant when interpreting EG biomarker concentrations in clinical studies (discussed further below). Shedding of the ESL by mechanisms other than inflammation can also stimulate inflammation. For example, enzymatic removal of the EG leads to increased leucocyte adhesion and inflammatory cytokine production,19-21 and some components of the EG that are released into circulation, such as soluble heparan sulfate and low molecular weight hyaluronan, can also stimulate inflammation.22,23 Other conditions related to severe inflammation, such as ischemia– reperfusion injury and oxidative stress, can also cause shedding of the EG.24,25 Also relevant to any severe inflammatory process is the effect of coagulation proteins on the EG. Both thrombin and plasmin, which are increased in severe inflammation, have been shown to cleave syndecan ectodomains from endothelial cells.26 Relevant to sepsis, or any process that causes bacteremia, is the effect of bacterial fragments on the ESL. Lipopolysaccharide, contained within the wall of Gramnegative bacteria, not only accelerates shedding of syndecans but also upregulates their expression on endothelium.27,28 Another example is the bacterial peptide formylmethionyl-leucyl-phenylalanine, which has been shown to shed glycosaminoglycans from the EG.25 Mild hyperglycemia due to critical illness, or stress hyperglycemia, is another common condition in the small animal intensive care unit.29 Given the evidence of ESL thinning in people with diabetes mellitus, several studies have investigated the direct impact of glucose on the shedding of the ESL. In healthy human volunteers who had hyperglycemia induced to ∼288 mg/dl (16 mmol/L), there was reduced estimated ESL volume, increased plasma hyaluronan concentration, and decreased flow-mediated dilation, a measurement of endothelial function.30 Shedding of the EG after the addition of glucose has also been shown in an endothelial cell culture model, which mimicked clinically relevant hyperglycemic conditions of 200 mg/dl (11 mmol/L).31 Therefore, the presence of hyperglycemia in critically ill animals, especially those with diabetes mellitus, may contribute to ESL shedding, and subsequently a proinflammatory and procoagulative state. Resuscitation fluid therapy can cause ESL shedding by several proposed mechanisms, including dilution of plasma proteins and secretion of natriuretic peptides. These proposed mechanisms have been reviewed in detail elsewhere.32 Plasma proteins have a stabilizing effect on the ESL, therefore dilution of plasma proteins with crystalloid fluid likely causes ESL shedding. Rodent models have shown that infusion of albumin solution or plasma maintains the ESL better than infusion of a clear fluid, such as a crystalloid.33,34 Rapid infusion of large volumes of crystalloid fluid may also lead to natriuretic peptide release, due to the stretch of cardiac chambers. Natriuretic peptides have a direct shedding effect on the ESL35 and have been shown to rise in concert with biomarkers of EG shedding after fluid administration in people.36,37 A canine hemorrhagic shock model was unable to demonstrate this relationship; however, small sample size or assay sensitivity may have precluded being able to detect significant changes in atrial natriuretic peptide.38

The consequences of ESL shedding may include worsening inflammation, promotion of coagulation, an increase in endothelial permeability, and interference with the normal regulation of vasomotor tone. It may also contribute to microcirculatory dysfunction or lack of hemodynamic coherence, whereby improvement of macrohemodynamics does not improve microcirculatory flow.39 This family of problems is well recognized in patients with a systemic inflammatory response, especially in those with sepsis, and is likely on the pathophysiological continuum to multiple organ dysfunction. Measures of ESL shedding in critically ill people, such as those with sepsis or severe traumatic injury, have been associated with increased severity of illness and worse clinical outcome. Other illnesses relevant to critical care that have been associated with increased EG biomarkers are reviewed in detail elsewhere.13 There has been a bevy of research in this area in the last decade identifying these biomarkers, investigating their prognostic ability, and using these biomarkers to assess the effect of interventions on the ESL.

METHODS FOR DETECTION OF ESL SHEDDING The two most frequently used methods for detecting ESL shedding in clinical studies are measurement of circulating EG biomarkers and videomicroscopic estimation of the perfused boundary region (PBR). Shedding of the ESL releases both glycosaminoglycans (e.g., hyaluronan) and proteoglycan ectodomains (e.g., syndecan-1) into circulation, which can be measured in the plasma or serum by a range of laboratory techniques. There are some limitations to the use of EG biomarkers for quantifying ESL shedding. The first limitation is that there may be other sources of these biomarkers in critical illness.14 The elements are not unique to the EG; they are present on all cells in the body to varying degrees. Some of these molecules are also present throughout the interstitium, especially hyaluronan, which may be flushed into circulation via lymphatic flow after intravenous fluid therapy. Second, it is known that some EG biomarkers are upregulated on the surface of the endothelium in response to changes within the blood, such as inflammation. Third, measurement of these biomarkers relies on research-grade assays that may have varying sensitivity and reproducibility. Finally, there is a limitation of validated commercial assays for measurement of these biomarkers in dogs and cats, with hyaluronan currently being the only known exception. The direct relationship between increased biomarkers of ESL shedding, thinning of the ESL, and endothelial dysfunction in the clinical setting requires further research. The second potential method used for detection of ESL damage is measurement of the PBR using sidestream darkfield imaging (SDF) with specialized software for bedside evaluation. This technique uses videomicroscopy to determine lateral red blood cell movement within the vessels (the PBR) of the microcirculation (diameter 5–25 µm). The PBR is normally regulated by the ESL barrier to maintain separation from the RBCs (Fig. 9.2).39 When the ESL is damaged or thinned, the RBCs penetrate more deeply towards the endothelium and the PBR increases. Studies in people have found that critical illness results in a thinner ESL, as measured by SDF microscopy.40 Experimental animal models have also used this technique to quantify the effect of certain diseases and therapeutic interventions on ESL thickness.41 Use of SDF microscopy for estimation of the ESL in dogs and cats is still in the early stages; however, reference values for healthy dogs and cats have been published in abstract form42,43 and continued research is underway. These studies have laid the groundwork for an additional study evaluating the jejunal microvasculature of healthy dogs44 and another study in healthy cats examining the effect of a single bolus of isotonic crystalloids

CHAPTER 9  The Endothelial Surface Layer or synthetic colloids on the PBR; there were no significant differences compared with controls (abstract only).45 Further studies in critically ill animals are warranted, although the need for general anesthesia limits the clinical application of this technology.

ESL SHEDDING IN DOGS AND CATS Two studies in dogs comparing fluid therapy strategies have measured hyaluronan concentration as a marker of ESL shedding. In an atraumatic hemorrhagic shock model, dogs received either 80 ml/kg of balanced isotonic crystalloid, or 20 ml/kg of either fresh whole blood, 4% succinylated gelatin or low molecular weight hydroxyethyl starch (n 5 6 per group), given intravenously over 20 minutes.38 Although hyaluronan concentration increased at various time points in all four groups after fluid resuscitation, the most marked changes were after crystalloid or gelatin fluid. The group that received crystalloid fluid also had significantly greater inflammatory biomarker concentrations after fluid resuscitation. In a study comparing healthy dogs that received an intraoperative infusion of 5 ml/kg/hr or 10 ml/kg/hr of lactated Ringer’s solution (n 5 19 per group), there was a significant rise in plasma hyaluronan concentration at the end of fluid therapy, compared with at induction of anesthesia, for both groups.46 However, there was no significant difference between groups. Several abstracts have been published assessing markers of ESL shedding in critically ill small animals: three in dogs, one in cats. In dogs with sepsis and multiple organ dysfunction (n 5 18), serum hyaluronan concentration was significantly higher than healthy controls (n 5 20), as were concentrations of other endothelial activation biomarkers.47 In 8 dogs with septic peritonitis, serum hyaluronan concentration was associated with serum interleukin-6 concentration and daily intravenous fluid volume.48 In 27 dogs meeting systemic inflammatory response syndrome (SIRS) criteria, only 5 had detectable serum concentrations of canine syndecan-1, compared with none of the 20 healthy dogs.49 A human syndecan-1 kit was also trialed with a subset of these dogs, and higher concentrations in dogs with SIRS than healthy dogs were found. There was no significant difference in serum hyaluronan concentration between dogs with SIRS and healthy dogs. Finally, PBR was estimated in 30 cats that received 10 ml/kg of either lactated Ringer’s solution or hydroxyethyl starch, or no fluid, under propofol anesthesia.45 No significant difference was detected either between groups or over time.

PROTECTION OF THE ESL IN DISEASE Therapeutic restoration of the ESL and repair of the glycocalyx are areas of active investigation. Numerous potential agents have been shown to ameliorate vascular leak, decrease markers of glycocalyx degradation, and improve survival in experimental animal models of disease. In addition to albumin and plasma administration as mentioned above, additional promising future treatments include disintegrin and metalloprotease 17 inhibitor,50 sphingosine-1 phosphate,51 heparin,52 intravenous hyaluronan, chondroitin sulfate, and sulodexide,53 among others. Changes to fluid therapy strategies, such as limiting crystalloid fluid volume and slowing down fluid administration, may also be useful for mitigating ESL shedding;32 however, this needs further investigation.

CONCLUSION There is strong evidence from benchtop and laboratory animal research that conditions of critical illness cause shedding of the ESL, which in turn has pathophysiological consequences that likely contribute to organ dysfunction. Clinical evidence from human critical care

59

has demonstrated a relationship between biomarkers of EG shedding and severity of illness; however, this research is still in the early stages and causal relationships have not been confirmed. There are still several limitations of the ability to assess ESL shedding in veterinary medicine. As research progresses in this field, changes to critical care interventions to provide better protection or repair of the ESL are likely to emerge.

REFERENCES 1. Dane MJ, van den Berg BM, Lee DH, et al: A microscopic view on the renal endothelial glycocalyx, Am J Physiol Renal Physiol 308:F956-F966, 2015. 2. Hahn RG: Water content of the endothelial glycocalyx layer estimated by volume kinetic analysis, Intensive Care Med Exp 8:29, 2020. 3. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG: The endothelial glycocalyx: composition, functions, and visualization, Pflugers Arch 454:345-359, 2007. 4. Zeng Y, Zhang XF, Fu BM, Tarbell JM: The role of endothelial surface glycocalyx in mechanosensing and transduction, Adv Exp Med Biol 1097:1-27, 2018. 5. Tarbell JM, Simon SI, Curry FR: Mechanosensing at the vascular interface, Annu Rev Biomed Eng 16:505-532, 2014. 6. Becker BF, Chappell D, Jacob M: Endothelial glycocalyx and coronary vascular permeability: the fringe benefit, Basic Res Cardiol 105:687-701, 2010. 7. Bashandy GM: Implications of recent accumulating knowledge about endothelial glycocalyx on anesthetic management, J Anesth 29:269-278, 2015. 8. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovas Res 87:198-210, 2010. 9. Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br J Anaesth 108:384-394, 2012. 10. Starling EH: On the absorption of fluids from the connective tissue spaces, J Physiol 19:312-326, 1896. 11. Weinbaum S, Cancel LM, Fu BM, Tarbell JM: The glycocalyx and its role in vascular physiology and vascular related diseases, Cardiovasc Eng Technol 12(1):37-71, 2021. 12. Hahn RG, Dull RO, Zdolsek J: The Extended Starling principle needs clinical validation, Acta Anaesthesiol Scand 64:884-887, 2020. 13. Gaudette S, Hughes D, Boller M: The endothelial glycocalyx: structure and function in health and critical illness, J Vet Emerg Crit Care 30:117-134, 2020. 14. Smart L: Endothelial glycocalyx biomarkers in sepsis and trauma: associations with inflammation, organ failure and fluid bolus therapy, Dissertation, 2020, University of Western Australia. 15. Lipowsky HH: The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases, Ann Biomed Eng 40: 840-848, 2012. 16. Ramnath R, Foster RR, Qiu Y, et al: Matrix metalloproteinase 9-mediated shedding of syndecan 4 in response to tumor necrosis factor alpha: a contributor to endothelial cell glycocalyx dysfunction, FASEB J 28:4686-4699, 2014. 17. Rops AL, van den Hoven MJ, Baselmans MM, et al: Heparan sulfate domains on cultured activated glomerular endothelial cells mediate leukocyte trafficking, Kidney Int 73:52-62, 2008. 18. Klein NJ, Shennan GI, Heyderman RS, Levin M: Alteration in glycosaminoglycan metabolism and surface charge on human umbilical vein endothelial cells induced by cytokines, endotoxin and neutrophils, J Cell Sci 102(Pt 4):821-832, 1992. 19. McDonald KK, Cooper S, Danielzak L, Leask RL: Glycocalyx degradation induces a proinflammatory phenotype and increased leukocyte adhesion in cultured endothelial cells under flow, PLoS One 11:e0167576, 2016. 20. Lygizos MI, Yang Y, Altmann CJ, et al: Heparanase mediates renal dysfunction during early sepsis in mice, Physiol Rep 1:e00153, 2013.

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21. Constantinescu AA, Vink H, Spaan JA: Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface, Arterioscler Thromb Vasc Biol 23:1541-1547, 2003. 22. Wrenshall LE, Stevens RB, Cerra FB, Platt JL: Modulation of macrophage and B cell function by glycosaminoglycans, J Leuk Biol 66:391-400, 1999. 23. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR: Hyaluronan fragments act as an endogenous danger signal by engaging TLR2, J Immunol 177:1272-1281, 2006. 24. Kurzelewski M, Czarnowska E, Beresewicz A: Superoxide- and nitric oxidederived species mediate endothelial dysfunction, endothelial glycocalyx disruption, and enhanced neutrophil adhesion in the post-ischemic guinea-pig heart, J Physiol Pharmacol 56:163-178, 2005. 25. Mulivor AW, Lipowsky HH: Inflammation- and ischemia-induced shedding of venular glycocalyx, Am J Physiol Heart Circ Physiol 286:H1672H1680, 2004. 26. Schmidt A, Echtermeyer F, Alozie A, Brands K, Buddecke E: Plasmin- and thrombin-accelerated shedding of syndecan-4 ectodomain generates cleavage sites at Lys(114)-Arg(115) and Lys(129)-Val(130) bonds, J Biol Chem 280:34441-34446, 2005. 27. Strand ME, Aronsen JM, Braathen B, et al: Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice, J Mol Cell Cardiol 88:133-144, 2015. 28. Strand ME, Herum KM, Rana ZA, et al: Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan-4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure-overloaded heart, FEBS J 280:2228-2247, 2013. 29. Torre DM, deLaforcade AM, Chan DL: Incidence and clinical relevance of hyperglycemia in critically ill dogs, J Vet Intern Med 21:971-975, 2007. 30. Nieuwdorp M, van Haeften TW, Gouverneur MC, et al: Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo, Diabetes 55:480-486, 2006. 31. Diebel LN, Diebel ME, Martin JV, Liberati DM: Acute hyperglycemia exacerbates trauma-induced endothelial and glycocalyx injury: an in vitro model, J Trauma Acute Care Surg 85:960-967, 2018. 32. Smart L, Hughes D: The effects of resuscitative fluid therapy on the endothelial surface layer, Front Vet Sci 8:661660, 2021. Available at: https://doi. org/10.3389/fvets.2021.661660. 33. Torres LN, Sondeen JL, Dubick MA, Filho IT: Systemic and microvascular effects of resuscitation with blood products after severe hemorrhage in rats, J Trauma Acute Care Surg 77:716-723, 2014. 34. Torres Filho IP, Torres LN, Salgado C, Dubick MA: Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids, Am J Physiol Heart Circ Physiol 310:H1468-H1478, 2016. 35. Jacob M, Saller T, Chappell D, Rehm M, Welsch U, Becker BF: Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability, Basic Res Cardiol 108:347, 2013. 36. Chappell D, Bruegger D, Potzel J, et al: Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx, Crit Care 18:538, 2014.

37. Belavic´ M, Sotošek Tokmadžic´ V, Fišic´ E, et al: The effect of various doses of infusion solutions on the endothelial glycocalyx layer in laparoscopic cholecystectomy patients, Minerva Anestesiol 84:1032-1043, 2018. 38. Smart L, Boyd CJ, Claus MA, Bosio E, Hosgood G, Raisis A: Large-volume crystalloid fluid is associated with increased hyaluronan shedding and inflammation in a canine hemorrhagic shock model, Inflammation 41:1515-1523, 2018. 39. Lee DH, Dane MJ, van den Berg BM, et al: Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion, PLoS One 9:e96477, 2014. 40. Donati A, Damiani E, Domizi R, et al: Alteration of the sublingual microvascular glycocalyx in critically ill patients, Microvasc Res 90:86-89, 2013. 41. Cui N, Wang H, Long Y, Su L, Liu D: Dexamethasone suppressed LPSinduced matrix metalloproteinase and its effect on endothelial glycocalyx shedding, Mediators Inflamm 2015:912726, 2015. 42. Londono L, Bowen CM, Buckley GJ: Evaluation of the endothelial glycocalyx in healthy anesthetized dogs using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 28:S7, 2018. 43. Millar KK, Yozova Y, Londono L, Monday JS, Thomson N, Sano H: Evaluation of the endothelial glycocalyx in healthy anesthetized cats using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 29:S11, 2019. 44. Mullen KM, Regier PJ, Londono L, Millar KK, Groover J: Evaluation of jejunal microvasculature of healthy anaesthetized dogs with sidestream dark field video microscopy, Am J Vet Res 81:888-893, 2020. 45. Yozova ID, Londono L, Sano H, Thomson N, Munday J, Cave N: Assessment of the endothelial glycocalyx after a fluid bolus in healthy anesthetized cats using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 30:S27, 2020. 46. Beiseigel M, Simon BT, Michalak C, Stickney MJ, Jeffery U: Effect of perioperative crystalloid fluid rate on circulating hyaluronan in healthy dogs: a pilot study, Vet J 267:105578, 2021. 47. Gaudette S, Smart L, Hughes D, et al: Biomarkers of endothelial activation are increased in dogs with severe sepsis, J Vet Emerg Crit Care 28:S14, 2018. 48. Shaw K, Bersenas A, Bateman S, Blois S, Guieu LV, Wood R: Evaluation of hyaluronic acid as a marker of glycocalyx degradation in dogs with septic peritonitis, J Vet Emerg Crit Care 30:S33, 2020. 49. Briganti A, Di Franco C, Meucci V: Endovascular shedding markers in critically ill patients, J Vet Emerg Crit Care 29:S36, 2019. 50. Palau V, Riera M, Soler MJ: ADAM17 inhibition may exert a protective effect on COVID-19, Nephrol Dial Transplant 35:1071-1072, 2020. 51. Zeng Y, Adamson RH, Curry FR, Tarbell JM: Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding, Am J Physiol Heart Circ Physiol 306:H363-H372, 2014. 52. Yini S, Heng Z, Xin A, Xiaochun M: Effect of unfractionated heparin on endothelial glycocalyx in a septic shock model, Acta Anaesthesiol Scand 59:160-169, 2015. 53. Song JW, Zullo JA, Liveris D, Dragovich M, Zhang XF, Goligorsky MS: Therapeutic restoration of endothelial glycocalyx in sepsis, J Pharmacol Exp Ther 361(1):115-121, 2017.

10 Hyperthermia and Fever James B. Miller, DVM, MS, DACVIM KEY POINTS • Thermoregulation is controlled by the preoptic region of the hypothalamus. It responds to thermoreceptors in the brain and peripheral nervous system to maintain a narrow range of body temperature by increasing or decreasing heat production or loss. • Hyperthermia describes any elevation in core body temperature above accepted normal values. • A true fever is the body’s normal response to infection, inflammation, or injury and is part of the acute-phase response. It is controlled by the thermoregulatory center in the hypothalamus. • Other forms of hyperthermia are a result of an imbalance between heat production and heat loss. Nonfebrile hyperthermic patients are approached differently from those with a fever, both diagnostically and therapeutically. • A fever may be beneficial to the host by decreasing bacterial growth and inhibiting viral replication. Most fevers and other forms of hyperthermia are not a threat to life unless body temperature exceeds 107°F (41.6°C).

• A fever will increase water and caloric requirements, and this must be considered when treating the febrile patient. • In most cases an accurate diagnosis should be obtained before initiating nonspecific therapy for a fever unless the fever exceeds 107°F (41.6°C). • Nonsteroidal antiinflammatory drugs and glucocorticoids will reduce a fever, but the latter will also block the acute-phase inflammatory response. • Total body cooling may be counterproductive and is usually reserved for afebrile hyperthermia or when fevers approach 107°F (41.6°C). • Antimicrobial therapy should not be used empirically for fever management unless there is a documented or strongly suspected indication of infection. Treatment should be based on culture and susceptibility testing, as indicated.

Obtaining a body temperature measurement is important in the evaluation of all patients, especially the critically ill patient. A rectal temperature higher than 102.5°F (39.2°C) is considered elevated in the unstressed dog or cat. The method of measurement must also be taken into account because ear, axillary, or toe web measurements will be lower than rectal temperatures. An intravascular thermistor is considered the most accurate but is usually impractical in the clinical setting. It is tempting for the veterinarian to associate any elevation in body temperature with true fever. The assumption is often made that the fever is caused by an infectious agent, even if there is no obvious cause. If the patient’s fever resolves after antimicrobials are administered, the assumption is made that it was caused by a bacterial infection. A normal body temperature is often assumed to indicate the absence of infectious disease. This approach to fever, hyperthermia, or normothermia can be misleading and result in inaccurate diagnoses and inappropriate, or even lack of, therapy. In one French study, almost half the 50 febrile dogs that were retrospectively examined had a noninfectious cause for the increased body temperature.1 This is less than human ICU patients where up to 70% are due to sepsis.2

Changes in ambient and core body temperatures are sensed by the peripheral and central thermoreceptors, and information is conveyed to the AH via the nervous system. The thermoreceptors sense that the body is below or above its normal temperature (set point) and subsequently cause the AH to stimulate the body to increase heat production and reduce heat loss through conservation if the body is too cold or to dissipate heat if the body is too warm (Fig. 10.1). Through these mechanisms, the dog and cat can maintain a narrow core body temperature range in a wide variety of environmental conditions and activity levels. With normal ambient temperatures, most body heat is produced by muscular activity, even while at rest. Cachectic or anesthetized patients, or those with severe neurologic impairment, may not be able to maintain a normal set point or generate a normal response to changes in core body temperature. Neonatal dogs and cats have a poorly developed thermoregulatory center and lack significant muscle mass. They require higher ambient temperatures to maintain normal body temperature.

THERMOREGULATION

Hyperthermia is the term used to describe any elevation in core body temperature above the accepted normal range for that species. When heat is produced or stored in the body at a rate greater than it is lost, hyperthermia results.4 The term fever is reserved for those hyperthermic animals in whom the set point in the AH has been reset to a higher temperature. In hyperthermic states other than fever, temperature elevation is not a result of the body attempting to raise its temperature

Thermoregulation is the balance between heat loss and heat production. Metabolic, physiologic, and behavioral mechanisms are used by homeotherms to regulate heat loss and production. The thermoregulatory control center for the body is located in the central nervous system in the preoptic area of the anterior hypothalamus (AH).3

HYPERTHERMIA

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Anterior hypothalamic area of the brain

Monoamines

Cutaneous and deep receptors

Heat gain mechanisms

Increased production Decreased loss Catecholamines Vasoconstriction Thyroxine Piloerection Shivering Postural changes Seeking warm environment

Heat loss mechanisms Panting Vasodilation Postural changes Seeking cool environment Perspiration Grooming (cat)

Fig. 10.1  Schematic representation of normal thermoregulation. (From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.)

but is due to the physiologic, pathologic, or pharmacologic changes that cause heat gain to exceed heat loss. Box 10.1 outlines the various classifications of hyperthermia.

TRUE FEVER True fever is the normal response of the body to invasion or injury and is part of the acute-phase response.5 Other parts of the acute-phase response include increased neutrophil numbers and phagocytic ability, enhanced T and B lymphocyte activity, increased acute-phase protein production by the liver, increased fibroblast activity, and increased sleep. Fever and other parts of the acute-phase response are initiated by exogenous pyrogens that lead to the release of endogenous pyrogens (Fig. 10.2).6

Exogenous Pyrogens True fever may be initiated by a variety of substances, including infectious agents or their products, immune complex formation, tissue inflammation or necrosis, and several pharmacologic agents. Collectively, these substances are called exogenous pyrogens. Their ability to directly affect the thermoregulatory center is probably minimal and they primarily cause the release of endogenous pyrogens by the host. Box 10.2 lists some of the more important known exogenous pyrogens.

Endogenous Pyrogens In response to stimulation by an exogenous pyrogen, proteins (cytokines) released from cells of the immune system trigger the febrile response. Macrophages are the primary immune cells involved, although T and B lymphocytes and other leukocytes may play significant roles. The proteins produced are called endogenous pyrogens or fever-producing cytokines. Although interleukin 1, interleukin 6, and tumor necrosis factor-a are considered the most important fever-producing cytokines, at least 11 cytokines are capable of initiating a febrile response (Table 10.1). Some neoplastic cells are also capable of producing cytokines that lead to a febrile response. The cytokines travel via the bloodstream to the AH, where they bind to the vascular endothelial cells within the AH

BOX 10.1  Classification of Hyperthermia True Fever Production of endogenous pyrogens Inadequate Heat Dissipation Heat stroke Hyperpyrexic syndromes Exercise-Induced Hyperthermia Normal exercise Hypocalcemic tetany (eclampsia) Seizure disorders Pathologic or Pharmacologic Origin Lesions in or around the anterior hypothalamus Malignant hyperthermia Hypermetabolic disorders Monoamine metabolism disturbances From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.

and stimulate the release of prostaglandins (PGs), primarily PGE2 and possibly PGF2a.7,8 The set point is raised, and the core body temperature rises through increased heat production and conservation. The body also produces cytokines in response to insult or injury that are cytoprotective with increased body temperature. They are called heat shock proteins and provide protection against a variety of insults, including heat.2

INADEQUATE HEAT DISSIPATION Heat Stroke Heat stroke is a common result of inadequate heat dissipation (see Chapter 139, Heat Stroke). Exposure to high ambient temperatures

CHAPTER 10  Hyperthermia and Fever

63

Fever Increased “set point” Anterior hypothalamus (Chemical mediators−−prostaglandins) Circulation Neoplastic cell

Endogenous pyrogen (IL-1, others) Activated immune cell

Exogenous pyrogen

Immune cell (macrophage, lymphocytes)

Fig. 10.2  Schematic representation of the pathophysiology of fever. IL-1, interleukin 1.  (From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 10, St Louis, 2010, Saunders.)

BOX 10.2  Exogenous Pyrogens Infectious Agents Bacteria (Live and Killed) Gram positive Gram negative Bacterial Products Lipopolysaccharides Streptococcal exotoxin Staphylococcal enterotoxin Staphylococcal proteins Fungi (Live and Killed) Fungal products Cryptococcal polysaccharide Cryptococcal proteins

Nonmicrobial Agents Soluble Antigen-Antibody Complexes Bile Acids Pharmacologic Agents Bleomycin Colchicine Tetracycline Hydromorphone (cats) Levamisole (cats) Tissue Inflammation and Necrosis

Viruses Rickettsial disease Protozoa From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.

may increase heat load at a faster rate than it can be dissipated from the body. This is especially true in large breed dogs and obese or brachycephalic animals. Heat stroke may occur rapidly, especially in closed environments with poor ventilation (e.g., inside a car with the windows closed on a moderately hot day). Environmental temperatures inside a closed car exposed to direct sun may exceed 120°F (48°C) in less than 20 minutes, even when the outside temperature is only 75°F (24°C). Death may occur in less than an hour, especially in the predisposed animal types described earlier. Severely affected animals may have peripheral blood nucleated red blood cells; these dogs have a 50% mortality rate despite aggressive therapy.9 A prospective study in 83 human heat stroke patients during a heat wave in France found a death rate of 52% at 28 days and 71% at 2 years.10

TABLE 10.1  Proteins with Pyrogenic Activity Endogenous Pyrogen

Principal Source

Cachectin (TNF-a) Lymphotoxin (TNF-b) IL-1a IL-1b Interferon a

Macrophages Lymphocytes (T and B) Macrophages and many other cell types Macrophages and many other cell types Leukocytes (especially monocytes/ macrophages) Fibroblasts T lymphocytes Many cell types Macrophages

Interferon b Interferon g IL-6 Macrophage inflammatory protein 1 a Macrophage inflammatory protein 1 b IL-8

Macrophages Macrophages

IL, interleukin; TNF, tumor necrosis factor. From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders. Adapted from Beutler B, Beutler SM: The pathogenesis of fever. In Bennett JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders.

Heat stroke will not respond to antipyretics used for the management of a true fever. The severely hyperthermic patient must undergo immediate total body cooling to prevent organ damage or death. Mechanisms of heat loss from the body include the following: radiation (electromagnetic or heat exchange between objects in the environment), conduction (between the body and environmental objects that are in direct contact with the skin, as determined by the relative temperatures and gradients), convection (the movement of fluid, air, or water over the surface of the body), and evaporation (disruption of heat by the energy required to convert the material from a liquid to a gas, as with panting). There are numerous strategies for cooling the

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BOX 10.3  Cooling Options for the

Hyperthermic Patient

Oxygen and Intravenous Isotonic Fluid Therapy Surface Cooling Techniques Clip fur if indicated Tepid water applied to skin or whole body (manually or via bath) Fan Ice packs over areas with large vessels (neck, axilla, inguinal region) Combination of above techniques Internal Cooling Techniques Rectal administration of cool isotonic fluids Gastric lavage Open body cavity Peritoneal dialysis Extracorporeal Techniques Antipyretic Drugs Antiprostaglandins Dantrolene Dipyrone Aminopyrine COX-2 inhibitors Glucocorticoids Additional NSAIDs COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal antiinflammatory drugs.

hyperthermic patient (Box 10.3), and the techniques chosen should be based on the severity of the animal’s condition, temperature, and response to therapy. In most veterinary patients, total body cooling is best accomplished by administering intravenous fluids (see Chapter 68, Shock Fluid Therapy), providing water baths and rinses using tepid water, and placing a fan near the animal. If the water applied to the animal is too cold, there is a tendency for peripheral vasoconstriction that will inhibit radiant heat loss and slow the cooling process. Cooling should be discontinued when body temperature approaches normal (approximately 103°F [39.4°C]) to prevent iatrogenic hypothermia.

Hyperpyrexic Syndrome Hyperpyrexic syndrome is associated with moderate to severe exercise in hot and humid climates. This syndrome may be more common in hunting dogs or dogs that “jog” with their owners. In humid environments, evaporative cooling via panting is minimal. In addition, heavy exercise may lead to vasodilation to increase blood flow to skeletal muscles but simultaneous vasoconstriction of cutaneous vessels, thus compromising peripheral heat loss. Many hunting dogs and dogs that run with their owners will continue to work or run until they become weak, stagger, and collapse. In suspected cases of hyperpyrexic syndrome, owners should measure the dog’s rectal temperature if the dog shows any signs of becoming weak or not wanting to continue. Owners should be instructed that rectal temperatures above 106°F (41°C) require immediate total body cooling and temperatures above 107°F (41.6°C) may lead to permanent organ damage or death.

Exercise-Induced Hyperthermia The body temperature will rise with sustained exercise of even moderate intensity because of heat production associated with muscular

activity. Even when extreme heat and humidity are not factors, dogs will occasionally reach temperatures that require total body cooling. This is especially true in dogs that do not exercise frequently, have thick undercoats, are overweight, or have respiratory disease. Eclampsia results in extreme muscular activity that can lead to significant heat production and result in severe hyperthermia. Total body cooling should be initiated if the patient is hyperthermic, in conjunction with therapy for the eclampsia. Seizure disorders from organic, metabolic, or idiopathic causes are encountered often in small animals (see Chapter 84, Seizures and Status Epilepticus). Hyperthermia associated with increased muscular activity can result, especially if the seizures are prolonged or occur in clusters. The first treatment priority should be to stop the seizures, but when significant hyperthermia is present, total body cooling is also recommended as soon as possible.

Pathologic and Pharmacologic Hyperthermia The pathologic and pharmacologic causes of hyperthermia encompass several disorders that will impair the heat balance equation. Hypothalamic lesions may obliterate the thermoregulatory center, leading to impaired responses to both hot and cold environments. Malignant hyperthermia has been reported in dogs and cats. It leads to a myopathy and subsequent metabolic heat production secondary to disturbed calcium metabolism that is initiated by pharmacologic agents such as inhalation anesthetics (especially halothane) and muscle relaxants (e.g., succinylcholine). Extreme muscle rigidity may or may not be present. Removal of the offending causative agent and total body cooling may prevent death. Dantrolene sodium, a muscle relaxant, is a specific and effective therapy for malignant hyperthermia and acts by binding to the ryanodine receptor to depress excitation-contraction coupling in skeletal muscle. It is dosed at 1 to 3 mg/kg IV or 1 to 5 mg/kg PO. Hypermetabolic disorders may also lead to hyperthermic states. Endocrine disorders such as hyperthyroidism and pheochromocytoma can lead to an increased metabolic rate or vasoconstriction, resulting in excess heat production, decreased ability to dissipate heat, or both. These conditions rarely lead to severe hyperthermia that requires total body cooling. Recent evidence suggests that thyroid hormone may also act directly on the hypothalamic set point resulting in a true fever as part of the hyperthermia.2 The use of opioids, especially as a preanesthetic, may lead to hyperthermia. Both retrospective and prospective studies have been done in cats using opioids as a preanesthetic.11,12 In both studies, most cats had significant elevations (.40°C) in body temperature between 1 and 5 hours after recovery from anesthesia. The highest temperature was 42.5°C (108.5°F). Studies in guinea pigs with opioid-induced hyperthermia showed that the hyperthermia was centrally mediated. It did not appear to be related to prostaglandins since it was not responsive to nonsteroidal antiinflammatory drugs (NSAIDs) but could be reversed with naloxone.13 Cats given opioids as a preanesthetic should be monitored following recovery for hyperthermia and treated with naloxone or total body cooling, if indicated.

BENEFITS AND DETRIMENTS OF FEVER Benefits Fever is part of the acute-phase response and is a normal response of the body. Even poikilotherms such as fish and reptiles will respond to a pyrogen by seeking higher environmental temperatures to raise their body temperatures.14 It is logical to think that a true fever is beneficial to the host. Most studies have shown that a fever will reduce the duration of morbidity and decrease mortality from many infectious diseases. A fever decreases the ability of many bacteria to use iron, which

CHAPTER 10  Hyperthermia and Fever is necessary for them to live and replicate.14 Use of NSAIDs to block fever in rabbits with Pasteurella infections significantly increases mortality rates. Many viruses are heat sensitive and cannot replicate in high temperatures. Raising the body temperature in neonatal dogs with herpesvirus infections significantly reduces the mortality rate. Most studies in human ICU patients with infection found that the prognosis is better when fever is present. In contrast, fever in patients with noninfectious diseases such as traumatic brain injury may carry a worse prognosis.2

Detriments Hyperthermia increases tissue metabolism and oxygen consumption, thus raising both caloric and water requirements by approximately 7% for each degree Fahrenheit (0.6°C) above accepted normal values. In addition, hyperthermia leads to suppression of the appetite center in the hypothalamus; the thirst center usually remains unaffected. Animals that have sustained head trauma or a cerebrovascular accident may suffer more severe brain damage if coexisting hyperthermia is present; total body cooling may therefore be beneficial in these patients. Body temperatures above 107°F (41.6°C) often lead to increases in cellular oxygen consumption that exceed oxygen delivery, resulting in the deterioration of cellular function and integrity. This may lead to disseminated intravascular coagulation (DIC) (see Chapters 101 and 105, Hypercoagulable States and Management of the Bleeding Patient in the ICU, respectively), with thrombosis and bleeding, or cause serious damage to organ systems, including the brain (cerebral edema and subsequent confusion, delirium, obtundation, seizures, coma); heart (arrhythmias); liver (hypoglycemia, hyperbilirubinemia); gastrointestinal tract (epithelial desquamation, endotoxin absorption, bleeding); and kidneys (acute kidney injury). Additional abnormalities might include hypoxemia, hyperkalemia, skeletal muscle cytolysis, tachypnea, metabolic acidosis, tachycardia, tachypnea, and hyperventilation. Exertional heat stroke and malignant hyperthermia may lead to severe rhabdomyolysis, hyperkalemia, hypocalcemia, myoglobinemia, myoglobinuria, and elevated levels of creatine phosphokinase. Fortunately, true fevers rarely lead to body temperatures of this magnitude and are usually a result of other causes of hyperthermia that should be managed as medical emergencies.

CLINICAL APPROACH TO THE HYPERTHERMIC PATIENT The evaluation of the hyperthermic patient should be approached in a logical manner to avoid making erroneous conclusions.4 A complete history and physical examination should be performed unless the patient is unstable or severely hyperthermic (temperature higher than 106°F [41°C]). In such cases, stabilization and immediate total body cooling should be initiated. In stable patients, a thorough physical examination and specific questions concerning previous injuries or infections, exposure to other animals, disease in other household pets, previous geographic environment, and recent or current drug therapy may be beneficial. This approach enables the clinician to decide if the elevated body temperature is a true fever. Temperatures less than 106°F (41°C), unless prolonged, are usually not life threatening, and antipyretic therapy should not be administered before performing a proper clinical evaluation.

NONSPECIFIC THERAPY FOR FEBRILE PATIENTS Mild to moderate elevations in body temperature (,107°F) are rarely fatal and may be beneficial to the body. As stated before, hyperthermia

65

may inhibit viral replication, increase leukocyte function, and decrease the uptake of iron by microbes (which is often necessary for their growth and replication). If a fever exceeds 107°F (41.6°C), there is a significant risk of permanent organ damage and DIC. The benefits of nonspecific therapy versus its potential negative effects should be considered before initiating such management. As stated earlier, fever associated with traumatic brain injury should be addressed to improve outcome. Nonspecific therapy for true fever usually involves inhibitors of prostaglandin synthesis. The compounds most commonly used are the NSAIDs (see Chapter 158, Nonsteroidal Antiinflammatory Drugs). These products inhibit the chemical mediators of fever production and allow normal thermoregulation. They do not block the production of endogenous pyrogens.4 These drugs are relatively safe in stable animals, although acetylsalicylic acid is potentially toxic to the cat (cyclooxygenase-2 [COX-2] inhibitors are relatively safe) and animals with gastrointestinal ulceration or renal disease should not receive these drugs. Consensus guidelines have been published on the use of NSAIDS in cats.15 Dipyrone, an injectable NSAID sometimes used in cats, may lead to bone marrow suppression, especially with prolonged use. Total body cooling with water, fans, or both in a febrile patient will reduce body temperature; however, the thermoregulatory center in the hypothalamus will still be directing the body to increase the body temperature. This may result in a further increase in metabolic rate, oxygen consumption, and subsequent water and caloric requirements. Unless a fever is life threatening, this type of nonspecific therapy is counterproductive. Glucocorticoids block the acute-phase response, fever, and most other parts of this (adaptive) response. In general, their use should be reserved for those patients in whom the cause of the fever is known to be noninfectious and blocking the rest of the acute-phase response will not be detrimental (and may prove beneficial). The most common indications include some immune-mediated diseases in which fever plays a significant role and glucocorticoid therapy is often part of the chemotherapeutic protocol (e.g., immune-mediated hemolytic anemia, immune-mediated polyarthritis). Phenothiazines can be effective in alleviating a true fever by depressing normal thermoregulation and causing peripheral vasodilation. The sedative qualities of the phenothiazines and their potential for hypotension should be considered before administration to the febrile patient.

THE FEBRILE INTENSIVE CARE PATIENT Fever is a common problem in critically ill veterinary patients. The clinician must attempt to exclude noninfectious causes and then determine the infection site and likely pathogens (see Chapter 7, SIRS, MODS and Sepsis). Intensive care patients often have both infectious and noninfectious causes of fever, necessitating a systematic and comprehensive diagnostic approach. Altered immune function, indwelling catheter devices, and more invasive monitoring and treatment approaches put these patients at high risk for inflammation and nosocomial infections. Noninfectious causes of fever in intensive care patients commonly include phlebitis or thrombophlebitis, postoperative inflammation, posttransfusion reactions, post trauma, pancreatitis, hepatitis, cholecystitis, aspiration pneumonitis, acute respiratory distress syndrome, and neoplastic processes. Nosocomial infection in critically ill patients is an important cause of new-onset fevers. Although incidence studies have not been performed in veterinary patients, the reported range in people is 3%

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to 31%. Commonly implicated sources include the lungs (aspiration or ventilator-associated pneumonia), the bloodstream, catheters, incisions, and the urinary tract (see Chapter 98, Catheter-Related Bloodstream Infection). An initial diagnostic evaluation might include a complete blood cell count, thoracic and abdominal imaging, and close inspection of all catheter sites or incisions. Additional diagnostic tests that might be indicated include culture and susceptibility testing of blood, urine, airway fluid, pleural or peritoneal effusions, postoperative incisions, cerebrospinal fluid, joint fluid, nasal discharge, and diarrhea. Antimicrobial therapy is indicated for the febrile patient only when a specific pathogen is known or strongly suspected.4 The use of antimicrobials in these patients without knowledge that a microbial agent is causing the fever can lead to bacterial resistance (see Chapter 172, Antimicrobial Use in the Critical Care Patient). Dogs with evidence of a systemic inflammatory response syndrome have a higher mortality rate,16 and the source should be rapidly identified and treated. However, if an infectious cause is not suspected and the patient is not deteriorating or neutropenic, antimicrobial additions or changes should be delayed until more definitive information is obtained.

REFERENCES 1. Chervier C, Chabanne L, Godde M, et al: Causes, diagnostic signs, and the utility of investigations of fever in dogs: 50 cases, Can Vet J 53(5):525, 2012. 2. Walter E, Hanna-Jumma S, Forni L: The pathophysiological basis and consequences of fever, Critical Care 20(1):200, 2016. 3. Cunningham JG: Textbook of veterinary physiology, ed 2, St Louis, 1997, Saunders.

4. Mackowiac PA: Approach to the febrile patient. In Humes HD, editor: Kelley’s textbook of internal medicine, ed 4, Philadelphia, 2000, Lippincott Williams & Wilkins. 5. Dinarella CA: The acute phase response. In Bennet JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders. 6. Beutler B, Buetler SM: The pathogenesis of fever. In Bennet JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders. 7. Steiner AA, Ivanov AI, Serrats J, et al: Cellular and molecular bases of the initiation of fever, PLoS Biol 4(9):E284, 2006. 8. Esikilsson A, Matsuwaki T, Shionoya K, et al: Immune-induced fever is dependent on local but not generalized Prostaglandin E2 synthesis in the brain, J Neurosci 37(19):5035-5044, 2017. 9. Bruchim Y, Horowitz M, Aroch I: Pathophysiology of heatstroke in dogs – revisited, Temperature (Austin) 4(4):356-370, 2017. 10. Argaud L, Tristan F, Le QH, et al: Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France, Arch Intern Med 167(20):2177-2183, 2007. 11. Niedfeldt RL, Robertson SA: Postanesthetic hyperthermia in cats: a retrospective comparison between hydromorphone and buprenorphine, Vet Anaesth Analg 33(6):384-389, 2006. 12. Posner LP, Pavuk AA, Rokshar JL, et al: Effects of opioids and anesthetic drugs on body temperature in cats, Vet Anaesth Analg 37(1)35-43, 2010. 13. Kandasamy SB, Williams BA: Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig, Neuropharmacology 22(5):321-328, 1983. 14. Berlin MT, Abeche AM: Evolutionary approach to medicine, South Med J 94:26, 2001. 15. Sparkes AH, Heiene R, Lascelles BD, et al: ISFM and AAFP consensus guidelines, long-term use of NSAIDs in cats, J Feline Med Surg 12(7):521, 2010. 16. DeClue AE: Biomarkers for sepsis in small animals. In Proceedings of the annual meeting of the ACVP/ASVCP, Seattle, WA, December 2012.

11 Interstitial Edema Randolph H. Stewart, DVM, PhD, DACVIM KEY POINTS • Interstitial fluid is formed by filtration of fluid out of microvessels and removed via the lymphatic system or transudation across the serosal surface of the organ. • Interstitial edema, or increased interstitial fluid volume, commonly forms in response to increased microvascular pressure, hypoproteinemia, increased microvascular permeability, and inflammatory or immune-mediated changes in mechanical relationships within the interstitial space.

• Interstitial edema impairs tissue function by impeding oxygen diffusion to cells and altering the mechanical properties of the affected tissue (e.g., pulmonary compliance or intestinal motility). • Management of interstitial edema requires an understanding of the forces and tissue properties involved in interstitial fluid volume regulation.

Interstitial edema formation, or an increase in interstitial fluid volume, is a common clinical condition observed in conjunction with heart failure, venous thrombosis, protein-losing disorders, excessive crystalloid administration, anaphylaxis, burns, and inflammatory disease/ systemic inflammatory response syndrome. Interstitial edema can negatively affect many organ systems, such as the skin, lung, intestine, brain, skeletal muscle, kidney, and heart. The presence of edema in these organs impairs proper oxygen delivery and cellular function in addition to altering the mechanical properties of the tissue (e.g., pulmonary compliance). Because each organ system possesses a unique set of tissue properties, the specific manner in which individual organs respond to an edemagenic challenge is necessarily organ-specific. However, a common set of principles and mechanisms govern interstitial volume, pressure, and flow in all organs. Interstitial fluid volume is determined by the balance between filtration of fluid out of capillaries and venules into the interstitial space and lymphatic removal of that interstitial fluid. In organs located within body cavities—the heart, lungs, liver, and intestines—transudation of interstitial fluid across the organ’s serosal surface into the surrounding space provides an additional avenue for interstitial fluid removal. The variable primarily responsible for mediating the balance between microvascular filtration and the two interstitial outflows is the interstitial fluid pressure.1 An increase in interstitial pressure acts to inhibit filtration and simultaneously promote lymph flow and serosal transudation. The interstitial fluid volume depends on interstitial fluid pressure and the current interstitial pressure–volume relationship.

microvessels and interstitial space, respectively; sd is the osmotic reflection coefficient; and Pp and Pint are the colloid osmotic pressures exerted by plasma and interstitial fluid, respectively.2 A revised view of the Starling-Landis principle has been proposed based on two related ideas: (1) the endothelial glycocalyx is the primary barrier to microvascular filtration and (2) the colloid osmotic pressure of the fluid on the interstitial side of the glycocalyx and within the endothelial clefts, termed Pg, has a more direct effect on filtration than that of bulk interstitial fluid (Pint). The glycocalyx is a complex of glycoproteins, proteoglycans, and glycosaminoglycans that form a layer attached to the luminal surface of vascular endothelial cells.2 Because of the combined effects of protein sieving by the glycocalyx and the convective flow of filtered fluid through the clefts, the colloid osmotic pressure of this filtered fluid can be lower than that of bulk interstitial fluid.2 The Starling-Landis equation shows that the direction of microvascular filtration depends on the sum of the hydrostatic and colloid osmotic pressure gradients, whereas the magnitude of filtration is the product of the hydraulic conductivity, surface area, and net pressure gradient. Pmv in most organs is between 7 and 17 mm Hg. That pressure is opposed by Pint, which, in many tissues, such as subcutaneous tissue, lung, and resting skeletal muscle, is subatmospheric because of the active removal of interstitial fluid by the lymphatic system. This establishes a hydrostatic pressure gradient (Pmv 2 Pint) favoring filtration out of the microvessels into the interstitial space. The colloid osmotic pressure gradient, however, opposes filtration and favors retention of fluid within the microvasculature. Colloid osmotic pressure of plasma and interstitial fluid is a consequence of the concentration of proteins, particularly albumin, as well as the redistribution of permeable ions induced by the presence of charges on those proteins. The colloid osmotic pressure of plasma is predictably higher than that of interstitial fluid; however, the interstitial fluid protein concentration and colloid osmotic pressure are not as low as commonly reported. Using lymph albumin concentration as an indicator of interstitial fluid albumin concentration, values of the lymph-to-plasma albumin concentration ratio have been reported to be 0.86 (dog heart), 0.90 (sheep lung), 0.81 (dog lung) and 0.92 (dog intestine).3-6 However, according to the revised Starling-Landis principle described above, the effective

MICROVASCULAR FILTRATION The microvascular filtration rate is determined by forces and tissue properties modeled in the Starling-Landis equation: JV 5 LpA [(Pmv 2 Pint) 2 sd(Pp 2 Pint)]

Equation 1

where JV is the microvascular filtration rate; Lp is the hydraulic conductivity (a measure of water permeability); A is the filtration surface area; Pmv and Pint are the hydrostatic pressures within the

67

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colloid osmotic pressure of the interstitial fluid may be much lower than that drained by the lymphatic system. This effect is hypothesized to be the result of protein passing from plasma to the interstitial space directly through endothelial cells via vesicular transport, thus bypassing the endothelial clefts.2 The colloid osmotic pressure gradient in Equation 1, Pp 2 Pint, is modified by sd. This coefficient is a function of the protein permeability of the microvascular barrier and possesses a value between 0 (indicating a membrane that is freely permeable to protein) and 1 (for a membrane that is impermeable to protein). The fraction of the colloid osmotic pressure gradient that is expressed across the microvascular barrier is represented by sd. Its value is close to 1 for the blood–brain barrier, and it approaches 0 for the sinusoids of the liver. In most microvascular beds, there is a small net pressure gradient favoring filtration. The commonly reported view that filtration occurs at the arteriolar end of the capillary and reabsorption occurs at the venular end is not supported by experimental or theoretical analysis. Current evidence indicates that all the microvascular filtrate is removed by lymphatic drainage or trans-serosal flow, and little or no microvascular reabsorption occurs under normal conditions in most tissues.2 Relevant studies have demonstrated that as Pmv decreases, filtration into the interstitial space (JV) decreases, but, at steady state, JV does not reverse to absorb fluid, even at very low microvascular pressures.2,7 Reduction in the rate of microvascular filtration as seen with decreasing capillary pressures is accompanied by two changes that limit continued decreases in JV. First, a decrease in JV is accompanied by an increase in protein concentration of the filtered fluid in the endothelial clefts and, thus, Pg.2 Second, at normal interstitial volumes, the interstitial compliance in most tissues is low; therefore, small decreases in interstitial volume are accompanied by large decreases in interstitial hydrostatic pressure (Pint).8 The increase in Pg and decrease in Pint both act to maintain filtration out of the capillary despite the fall in capillary hydrostatic pressure.

strength and frequency of lymphatic contractions, while increased lymph flow results in a shear-mediated relaxation.10,11 This shearmediated response has a beneficial but counterintuitive effect. Following edema-induced elevations in lymph flow, the reduction in lymphatic pumping caused by increased lymph flow and shear stress further enhances flow because when lymphatic inlet pressure exceeds outlet pressure, passive flow can exceed the pumping capacity of the vessel.12 Pleural fluid and peritoneal fluid are removed by lymphatic drainage and returned to the venous circulation. These fluids exit these cavities through direct connections called lymphatic stomata into lymphatic vessels within the diaphragm and body wall.13 The lymphatic system drains into the great veins of the neck; therefore, systemic venous pressure is the downstream pressure against which lymph must flow (see Equation 2). Because of this arrangement, elevations in venous pressure can diminish lymph flow and thereby contribute to edema formation. This effect, however, is usually modest in unanesthetized animals. The lymphatic circulation is normally more sensitive to changes in the interstitial pressure upstream than it is to changes in the systemic venous pressure downstream. In other words, although lymph flow generally increases markedly in response to interstitial edema formation, it does not usually decrease markedly in response to venous hypertension. This is because lymphatic vessels respond to increased outflow pressure by increasing pumping activity via increases in the strength and frequency of contractions. However, in the presence of interstitial edema caused by increased microvascular filtration, increased venous pressure in the neck may significantly impede lymph flows and, thereby, exacerbate edema formation.14 In addition, many anesthetic agents significantly reduce lymphatic pumping and thus increase lymphatic sensitivity to venous hypertension. This means that the sensitivity to edemagenic challenges such as intravenous crystalloid administration is exaggerated in anesthetized patients.

LYMPHATIC DRAINAGE

SEROSAL TRANSUDATION

The lymphatic system removes interstitial fluid and returns it to the venous blood. This system begins with terminal lymphatic vessels within the interstitial space, converges to progressively larger vessels through lymph nodes, and eventually terminates in the venous system. The determinants of lymph flow have been modeled on a modification of Ohm’s law as given here:

In organs suspended within potential spaces, such as the heart, lung, liver, and intestine, interstitial fluid may be removed, in part, via transudation across the serosal surface into the surrounding space. This process is driven by hydrostatic and colloid osmotic pressure gradients like those seen in Equation 1. Edema-induced increases in interstitial hydrostatic pressure will increase the rate of transudation and may result in effusion within the surrounding cavity.15

QL 5 (Pint 1 Ppump – Psv)/RL

Equation 2

where QL is lymph flow, Pint is the interstitial hydrostatic pressure, Ppump is the effective driving pressure generated by the cyclic intrinsic contraction and extrinsic compression of the lymphatic vessels working in concert with one-way valves, Psv is systemic venous pressure, and RL is the effective resistance to lymph flow.9 Most lymphatic vessels possess intramural smooth muscle and contain one-way valves at regular intervals. Spontaneous phasic contraction and extrinsic compression of these vessels propel lymph antegrade. Lymphatic pumping explains why lymph is able to flow from an interstitial space with subatmospheric pressure to the systemic venous blood where the pressure is 2 to 5 mm Hg. In addition, lymphatic pumping is the prime reason that interstitial hydrostatic pressure can be maintained below atmospheric pressure. Lymph flow is regulated by multiple factors. The strength and frequency of lymphatic contractions are modified by numerous vasoactive mediators, including prostaglandins, thromboxane, nitric oxide, epinephrine, acetylcholine, substance P, and bradykinin. In addition, increased stretch of lymphatic vessels stimulates increased

ANTIEDEMA MECHANISMS When confronted with an edemagenic insult, interstitial edema formation is moderated by a set of antiedema mechanisms. These intrinsic interdependent mechanisms include (1) increased interstitial hydrostatic pressure, (2) increased lymph flow, (3) decreased interstitial colloid osmotic pressure, and (4) increased trans-serosal flow in organs within potential spaces. Increased interstitial pressure opposes microvascular filtration and promotes lymph flow and trans-serosal flow. In response to increased microvascular pressure and subsequent interstitial fluid accumulation, lymph flow can increase tenfold in many tissues. Increased microvascular filtration is characterized by an increase in water filtration that exceeds the increase in protein filtration. The resulting decrease in the protein concentration of the filtrate results in a decrease in colloid osmotic pressure within the endothelial clefts, which acts to lessen microvascular filtration.2,7 In addition, serosal transudation is enhanced by the combined effects of increased Pint and decreased Pint.

CHAPTER 11  Interstitial Edema

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These self-regulating mechanisms are efficient because they incur little energy cost and are effective because they respond rapidly to edema formation; however, their effectiveness diminishes in the presence of continued challenge. Therefore, a patient that has responded to an edemagenic stress, such as hypoproteinemia, is at increased risk of edema development in response to additional challenge, such as crystalloid infusion.

challenges. However, because the protective mechanisms are already engaged, even moderate hypoproteinemia can make the patient particularly susceptible to further edemagenic challenge (e.g., crystalloid infusion). In an experimental canine study, a 55% decrease in total plasma protein over 3 hours resulted in myocardial interstitial edema formation of sufficient magnitude to impair left ventricular function.17

MECHANISMS OF EDEMA FORMATION The pathophysiology of interstitial edema formation involves changes in the factors responsible for interstitial fluid formation and removal (Table 11.1). However, edemagenic diseases commonly result in perturbations of more than one of these factors. In addition, therapeutic measures, such as intravenous fluid administration, may exacerbate these perturbations. In fact, because the pathogenesis of edemagenic diseases may be quite complex, it is perhaps more beneficial clinically to emphasize the degree to which the sensitivity of the fluid balance system has been changed rather than the specific effects of changes in microvascular pressure, permeability, etc. The degree to which the sensitivity of the system to edemagenic challenge, termed edemagenic gain, can be changed has been illustrated for histamine and endotoxin.16 Five basic edemagenic conditions are discussed next and shown in Table 11.1. It should be noted that, although clinical assessment of interstitial edema is often limited to the lungs and subcutaneous tissue, other organs, such as the heart, liver, kidney and intestines, may also be significantly affected.

According to Equation 1, apparent changes in microvascular permeability may involve changes in water permeability (Lp), microvascular surface area (A), and protein permeability (sd). Experimentally, it is very difficult to differentiate between changes in Lp and changes in A. If Lp or A increase, the microvascular filtration rate will be greater for any given transmembrane pressure gradient. If protein permeability increases, the microvascular filtration rate increases because the effectiveness with which the plasma-to-interstitium colloid osmotic pressure gradient restrains fluid filtration is diminished. This increase in protein permeability also impairs the effectiveness of the decrease in interstitial colloid osmotic pressure to serve as an antiedema mechanism. There is growing evidence that a contributing factor leading to increased microvascular permeability in disease states involves damage to the endothelial glycocalyx layer (see Chapter 9, Endothelial Glycocalyx). In experimental preparations of mesenteric (rat and frog) and coronary (pig) microvessels, enzyme-induced damage to the glycocalyx resulted in increased permeability to water and protein.18-20 Preclinical and clinical studies implicate glycocalyx degradation in the pathogenesis of both sepsis and hemorrhagic shock.21,22

Venous Hypertension

Impaired Lymph Flow

Elevations in venous pressure seen with heart failure and venous obstruction (e.g., thrombosis or mass effect) reliably cause regional increases in microvascular hydrostatic pressure. The resulting increase in microvascular filtration (Equation 1) expands interstitial fluid volume in the tissues drained by the affected veins. The severity of the edema is directly proportional to the magnitude of the venous pressure increase. In addition, hypertension of the central veins can retard lymph flow, particularly in anesthetized patients, because it increases lymphatic outflow pressure.

In the short term, lymphatic obstruction or functional impairment generally results in only mild edema formation caused by the diminished interstitial fluid removal. However, the combination of impaired lymph flow with any additional edemagenic challenge can result in profound edema. This is true not only because increased lymph flow is a very important antiedema mechanism but because the effectiveness of the other antiedema mechanisms—decreased interstitial colloid osmotic pressure and increased trans-serosal flow—is dependent on adequate lymph flow. Recall that the inhibitory effect of systemic venous hypertension on lymph flow is increased in anesthetized patients and patients with preexisting interstitial edema.

Hypoproteinemia An acute decrease in plasma colloid osmotic pressure resulting from hypoproteinemia, particularly hypoalbuminemia, results in increased microvascular filtration (see Equation 1). The relationship between the degree of hypoproteinemia and the resulting edema formation is nonlinear such that mild to moderate protein deficits cause little edema formation. This nonlinearity is likely caused by the engagement of antiedema mechanisms that readily compensate for mild to moderate

Increased Microvascular Permeability

Inflammatory Edema Inflammation is characterized by the elaboration of numerous proinflammatory substances mediated, in part, by neutrophils.23-25 This process impacts interstitial fluid balance by increasing microvascular pressure and surface area via vasodilation, increasing microvascular permeability to fluid and protein, and altering

TABLE 11.1  Edemagenic Conditions with Related Mechanisms and Example Disease Processes Condition Venous hypertension

Mechanism Increased microvascular pressure and filtration

Relevant Disease Process Examples Heart disease, venous thrombosis

Hypoproteinemia

Decreased plasma colloid osmotic pressure, increased filtration

Protein-losing enteropathy and nephropathy

Increased microvascular permeability

Increased filtration, diminished influence of plasma-interstitial fluid colloid osmotic pressure gradient

Inflammation, infection

Impaired lymph flow

Vessel obstruction or damage, pharmacologic impairment of pump mechanism

Trauma, surgical damage, systemic venous hypertension, anesthesia

Increased negativity of interstitial fluid pressure

Shift in interstitial pressure–volume relationship, decreased interstitial pressure

Inflammation, anaphylaxis, burn injury, frostbite

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PART I  Key Critical Care Concepts

Interstitial pressure

lymphatic function.4,26-30 The net effect of these changes is to increase the edemagenic gain, that is, the volume of interstitial edema that forms in response to a 1-mm Hg increase in microvascular pressure. In experimental sheep studies, histamine and endotoxin increased edemagenic gain in the lung approximately twofold and sixfold, respectively.16 This change in sensitivity to microvascular pressure in affected patients makes them much more susceptible to further edemagenic challenges such as intravenous fluid administration. An additional mechanism of edema formation identified in skin and tracheal mucosa involves changes in the interstitial pressure–volume relationship that manifest as increased negativity of interstitial fluid pressure. This phenomenon has been reviewed by the investigators primarily responsible for its elucidation.31-33 Under normal conditions, interstitial pressure increases predictably with increases in interstitial volume. However, in response to inflammation, this mechanical relationship can shift markedly in a short period.31-33 A consequence of this shift is a sudden fall in interstitial pressure and a consequent rapid increase in microvascular filtration and interstitial volume (Fig. 11.1). This edema formation can occur with no significant changes in microvascular pressure or permeability. This phenomenon appears to be the result of a structural rearrangement of the extracellular matrix modulated by alterations in the attachment of cells, particularly fibroblasts, to collagen fibers. Collagen fibers in the interstitial space act to restrain or compress interstitial volume. This effect is actuated by fibroblasts exerting tension on multiple collagen fibers via integrin-mediated connections, thus contracting the extracellular matrix.31,32 Inflammation and immunemediated phenomena appear to disrupt this fibroblast-collagen bond. This change in the interstitial pressure–volume relationship has been reported in skin and tracheal mucosa in select experimental models of inflammation, direct tissue damage of burns and freezing, ischemia-reperfusion, neurogenic inflammation induced by vagal nerve stimulation, and anaphylaxis.31-34 This condition has been experimentally created by induction of mast cell degranulation, exposure to lipopolysaccharides, complement activation, and antigen

0 A

C

B Interstitial volume Fig. 11.1  ​A proposed mechanism of inflammatory change in the interstitial pressure–volume relationship. Baseline interstitial pressure and volume values (A) lie along the normal pressure–volume relationship (solid line). With the induction of inflammatory or immune-mediated disease, this relationship may change rapidly (dashed line). In experimental preparations in which microvascular filtration is hindered, interstitial pressure drops (B). More commonly, the fall in interstitial pressure promotes microvascular filtration resulting in marked interstitial edema formation (C).

exposure as well as by introduction of inflammatory mediators, including tumor necrosis factor a (TNF-a), platelet activating factor, interleukin-1b (IL-1b), IL-6, and prostaglandins E1, E2, and I2.31,32 Several agents have been shown experimentally to prevent or reverse the fall in interstitial pressure, including prostaglandin F2a, corticotropin releasing factor, a-trinositol, platelet-derived growth factor BB, insulin, and vitamin C.31,32

CHRONIC EDEMAGENIC CONDITIONS When evaluating chronic disease states, a difficulty arises when trying to ascribe the magnitude, persistence, or absence of edema to the mechanisms described earlier. Assessment of the mechanisms responsible for acute edema depends on parameters having relatively constant values (e.g., Lp and sd in Equation 1, Ppump and RL in Equation 2) and variables with values that can change readily (e.g., Pmv, Pint, Pp). However, the interstitial fluid balance system is not only complex but also adaptive. Chronic increases in interstitial volume, pressure, or flow induce adaptive changes in the values of those previously “constant” parameters.35-38 These might include changes in microvascular permeability to water and protein, interstitial compliance, lymphatic contractile function, and serosal permeability as well as lymphangiogenesis, the growth of new lymphatic vessels. In addition, interstitial edema affecting the heart or lung lasting for more than a few days induces development of interstitial fibrosis.37,39,40 To add to the complexity, an adaptive change in one dimension, such as microvascular permeability, alters the signal for change in another dimension, such as lymphatic pumping. These multiple interdependent responses have the effect of changing both the magnitude of interstitial volume at equilibrium and the edemagenic gain, the sensitivity of the system to edemagenic challenge. These adaptive changes in fluid balance parameters make it difficult to predict the occurrence and severity of interstitial edema in chronic conditions.

CONCLUSION Disease conditions characterized by interstitial edema development can best be understood via changes in the factors responsible for interstitial fluid balance—increased venous and microvascular pressures, decreased plasma colloid osmotic pressure, increased microvascular permeability, impaired lymphatic function, and altered interstitial compliance. However, these cases can often be difficult to manage for two reasons. First, more than one mechanism of edema formation is often involved. For example, inflammatory disease may alter lymphatic pumping, microvascular permeability to water and protein, and the interstitial pressure–volume relationship simultaneously. Second, disease conditions that last for more than 1 to 2 days can induce adaptive responses in the interstitial fluid balance system that diminish clinical predictive accuracy. Preliminary evidence exists for several therapeutic interventions specific to the treatment of interstitial edema. In a rodent model of intestinal edema induced by mesenteric venous hypertension and crystalloid infusion, hypertonic saline treatment significantly reduced interstitial edema formation.41 This effect appeared to be the result of fluid redistribution leading to increased urine production, intestinal luminal fluid volume, and peritoneal fluid volume.41 In a model of anaphylaxis in albumin-sensitized rats, a-trinositol, an isomer of the intracellular messenger inositol trisphosphate, abolished the fall in tracheal interstitial fluid pressure induced by albumin administration, whereas hydrocortisone had no effect.42 a-Trinositol also successfully prevented edema formation and the decrease in interstitial pressure when used as a pretreatment in

CHAPTER 11  Interstitial Edema experimentally induced ischemia-reperfusion.34 Perhaps more promising, platelet-derived growth factor with 2 subunits (BB) was shown to be effective after treatment to speed resolution of the anaphylaxisinduced drop in dermal interstitial pressure.43,44 Clinical trials demonstrating the effectiveness of these and related therapies remain to be performed.

REFERENCES 1. Dongaonkar RM, Laine GA, Stewart RH, Quick CM: Balance point characterization of interstitial fluid volume regulation, Am J Physiol Regul Integr Comp Physiol 297(1):R6-R16, 2009. doi:10.1152/ajpregu.00097.2009. 2. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovasc Res 87(2):198-210, 2010. doi:10.1093/cvr/cvq062. 3. Stewart RH, Geissler HJ, Allen SJ, Laine GA: Protein washdown as a defense mechanism against myocardial edema, Am J Physiol Heart Circ Physiol 279(4):H1864-H1868, 2000. 4. Brigham KL, Woolverton WC, Blake LH, Staub NC: Increased sheep lung vascular permeability caused by pseudomonas bacteremia, J Clin Invest 54(4):792-804, 1974. 5. Parker JC, Falgout HJ, Grimbert FA, Taylor AE: The effect of increased vascular pressure on albumin-excluded volume and lymph flow in the dog lung, Circ Res 47:866-875, 1980. 6. Laine GA, Granger HJ: Permeability of intestinal microvessels in chronic arterial hypertension, Hypertension 5:722-727, 1983. 7. Michel CC, Phillips ME: Steady state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries, J Physiol 388:421-435, 1987. 8. Aukland K, Reed RK: Interstitial-lymphatic mechanisms in the control of extracellular fluid volume, Physiol Rev 73(1):1-78, 1993. 9. Drake RE, Laine GA, Allen SJ, Katz J, Gabel JC: A model of the lung interstitial-lymphatic system, Microvasc Res 34(1):96-107, 1987. 10. Shirasawa Y, Benoit JN: Stretch-induced calcium sensitization of rat lymphatic smooth muscle, Am J Physiol Heart Circ Physiol 285(6): H2573-H2577, 2003. 11. Gashev AA, Davis MJ, Zawieja DC: Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct, J Physiol 540 (Pt 3):1023-1037, 2002. 12. Quick CM, Venugopal AM, Gashev AA, Zawieja DC, Stewart RH: Intrinsic pump-conduit behavior of lymphangions, Am J Physiol Regul Integr Comp Physiol 292(4):R1510-R1518, 2007. 13. Wang ZB, Li M, Li JC: Recent advances in the research of lymphatic stomata, Anat Rec 293(5):754-761, 2010. 14. Drake RE, Abbott RD: Effect of increased neck vein pressure on intestinal lymphatic pressure in awake sheep, Am J Physiol Regul Integr Comp Physiol 262(5 Pt 2):R892-R894, 1992. 15. Stewart RH, Rohn DA, Allen SJ, Laine GA: Basic determinants of epicardial transudation, Am J Physiol Heart Circ Physiol 273(3 Pt 2): H1408-H1414, 1997. 16. Dongaonkar RM, Quick CM, Stewart RH, et al: Edemagenic gain and interstitial fluid volume regulation, Am J Physiol Regul Integr Comp Physiol 294(2):R651-R659, 2008. 17. Miyamoto M, McClure DE, Schertel ER, et al: Effects of hypoproteinemiainduced myocardial edema on left ventricular function, Am J Physiol Heart Circ Physiol 274(3):H937-H944, 1998. 18. Adamson RH: Permeability of frog mesenteric capillaries after partial pronase digestion of the endothelial glycocalyx, J Physiol 428(1):1-13, 1990. 19. Huxley VH, Williams DA: Role of a glycocalyx on coronary arteriole permeability to proteins; evidence from enzyme treatments, Am J Physiol Heart Circ Physiol 278(4):H1177-H1185, 2000. 20. Betteridge KB, Arkill KP, Neal CR, et al: Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function, J Physiol 595(15):5015-5035, 2017. 21. Uchimido R, Schmidt EP, Shapiro NI: The glycocalyx: a novel diagnostic and therapeutic target in sepsis, Critical Care 23(1):16, 2019. doi:10.1186/ s13054-018-2292-6.

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22. Halbgebauer R, Braun CK, Denk S, et al: Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma, J Crit Care 44:229-237, 2018. 23. Aziz M, Jacob A, Yang W, Matsuda A, Wang P: Current trends in inflammatory and immunomodulatory mediators in sepsis, J Leukoc Biol 93:329-342, 2013. 24. Lord JM, Midwinter MJ, Chen Y, et al: The systemic immune response to trauma: an overview of pathophysiology and treatment, Lancet 384: 1455-1465, 2014. 25. Ma Y, Yang X, Chatterjee V, et al: Role of neutrophil extracellular traps and vesicles in regulating vascular endothelial permeability, Front Immunol 10:1037, 2019. doi:10.3389/fimmu.2019.01037. 26. Drake RE, Gabel JC: Effect of histamine and alloxan on canine pulmonary vascular permeability, Am J Physiol Heart Circ Physiol 239(8):H96-H100, 1980. 27. Gabel JC, Hansen TN, Drake RE: Effect of endotoxin on lung fluid balance in unanesthetized sheep, J Appl Physiol 56(2):489-494, 1984. 28. Korthuis RJ, Wang CY, Spielman WS: Transient effects of histamine on the capillary filtration coefficient, Microvasc Res 28:322-344, 1984. 29. Johnston MG, Gordon JL: Regulation of lymphatic contractility by arachidonate metabolites, Nature 293(5830):294-297, 1981. 30. Ferguson MK, Shahinian HK, Michelassi F: Lymphatic smooth muscle responses to leukotrienes, histamine and platelet activating factor, J Surg Res 44:172-177, 1988. 31. Reed RK, Liden A, Rubin K: Edema and fluid dynamics in connective tissue remodeling, J Mol Cell Cardiol 48(3):518-523, 2010. doi:10.1016/j. yjmcc.2009.06.023. 32. Reed RK, Rubin K: Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix, Cardiovasc Res 87(2):211-217, 2010. doi:10.1093/cvr/cvq143. 33. Wiig H, Rubin K, Reed RK: New and active role of the interstitium in control of interstitial fluid pressure: potential therapeutic consequences, Acta Anaesthesiol Scand 47(2):111-121, 2003. 34. Nedrebø T, Reed RK, Berg A: Effect of alpha-trinositol on interstitial fluid pressure, edema generation, and albumin extravasation after ischemia- reperfusion injury in rat hind limb, Shock 20(2):149-153, 2003. 35. Laine GA: Microvascular changes in the heart during chronic arterial hypertension, Circ Res 62(5):953-960, 1988. 36. Gashev AA, Delp MD, Zawieja DC: Inhibition of active lymph pump by simulated microgravity, Am J Physiol Heart Circ Physiol 290(6): H2295-H2308, 2006. 37. Desai KV, Laine GA, Stewart RH, et al: Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema, Am J Physiol Heart Circ Physiol 294(6):H2428-H2434, 2008. doi:10.1152/ ajpheart.00860.2007. 38. Dongaonkar RM, Nguyen TL, Quick CM, et al: Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure, Am J Physiol Heart Circ Physiol 305(2):H203-H210, 2013. doi:10.1152/ajpheart. 00677.2012. 39. Davis KL, Laine GA, Geissler HJ, et al: Effects of myocardial edema on the development of myocardial interstitial fibrosis, Microcirculation 7(4):269-280, 2000. 40. Drake RE, Doursout MF: Pulmonary edema and elevated left atrial pressure: four hours and beyond, News Physiol Sci 17:223-226, 2002. 41. Radhakrishnan RS, Shah SK, Lance SH, et al: Hypertonic saline alters hydraulic conductivity and up-regulates mucosal/submucosal aquaporin 4 in resuscitation-induced intestinal edema, Crit Care Med 37(11):2946-2952, 2009. doi:10.1097/CCM.0b013e3181ab878b. 42. Woie K, Westerberg E, Reed RK: Lowering of interstitial fluid pressure will enhance edema in trachea of albumin-sensitized rats, Am J Respir Crit Care Med 153(4 Pt 1):1347-1352, 1996. 43. Rodt S, Åhlén K, Berg A, Rubin K, Reed RK: A novel physiologic function for platelet-derived growth factor-BB in rat dermis, J Physiol 495(Pt 1): 193-200, 1996. 44. Lidén Å, Berg A, Nedrebø T, Reed RK, Rubin K: Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on b3 but not b1 integrins, Circ Res 98(5):635-641, 2006.

12 Patient Suffering in the Intensive Care Unit Matthew S. Mellema, DVM, PhD, DACVECC KEY POINTS • Suffering is “an experience of unpleasantness and aversion associated with the perception of harm or threat of harm in an individual.” • Pain is far from the only unpleasant sensation critically ill animals are likely to experience.

• Relief of as many forms of patient suffering as possible is likely to lead to improved outcomes.

Patient suffering is a difficult topic to discuss in the clinical setting. A common perception is that the topic of animal suffering has been coopted (some might say hijacked) by animal welfare advocates, including those perceived as extremist in their viewpoints. This perception seems to have led to a reactive pushback and reluctance to address the topic by many small animal clinicians. If this is the case, then it is unfortunate and also incompatible with the veterinarian’s oath, which includes a mandate to use our training in “the prevention and relief of animal suffering.” Another factor that may limit clinician consideration of patient suffering is the perception that if there are larger, more acutely life-threatening aspects of critical illness that require our attention, then patient suffering is a minor issue in the grander scheme of things and can be underevaluated or undertreated. Suffering in animals is challenging to define because of the inability of the patients to verbalize their perception of their sense of well- being. One definition of suffering is that it is “the state of undergoing pain, distress, or hardship;” however, this definition is overly focused on pain and provides little guidance to clinicians. A more useful definition might be that suffering is “an experience of unpleasantness and aversion associated with the perception of harm or threat of harm in an individual.” The author prefers this definition because it can more easily be tied to the physiology of homeostasis in vertebrates. It captures the key concept that suffering is linked to the perception of both genuine harm and potential harm. It also offers the flexibility of treating harm as a multidimensional parameter rather than equating it to a single unpleasant sensation (e.g., pain). This definition allows for the consideration of the different forms of suffering that may be either physical or mental in nature and that there is a continuous range in the intensity of suffering rather than just a binary state (e.g., mild, moderate, severe versus a present/absent model). If one adopts the authors’ preferred definition of suffering, then it can be put into a larger physiologic context that has relevance to critical illness and patient assessment. By focusing on patient perception of real or potential harm, one is led directly to the consideration of how animals monitor their body systems for harm and how their behavior changes in response to harm surveillance signals. Vertebrates have a range of what some have called “primal alert signals” that appear to be highly conserved across species. These signals are linked to the fundamental needs required by animals to maintain homeostasis. Further, these signaling systems are designed to alert the animal to threats to

these needs being met and drive both aversive and adaptive behaviors. The responses to these alarm signals can occur at the cortical and subcortical levels. The best understood of these primal alert signals is pain. Pain is the alert signal tied to tissue integrity surveillance. Real or perceived threats to tissue integrity will be monitored by nociceptive fibers, conveyed by associated transmission pathways, and processed at brainstem and cortical centers. Activation of these receptors will lead to both aversive and adaptive behavioral responses. For example, if a child places his or her finger into a flame, then nociception will result in the reflex withdrawal of the finger (aversive response) and then the child will know not to repeat the process in the future based on the pain perception (adaptive behavior). Although pain is an important alarm signal with great relevance to both animal suffering and clinical practice, there are several others and some evidence to suggest that pain is not the most unpleasant among them.

72

MASLOW’S HIERARCHY OF NEEDS AND PRIMAL ALERT SIGNALS A consideration of animal suffering is inextricably linked to the consideration of their behavior. Indeed, ill animals have such a consistent clustering of disease manifestations when they are ill that the term sickness behavior has arisen to describe the four most common clinical signs associated with illness (i.e., fever, lethargy, anorexia, cachexia).1 Psychologists have long sought to develop an understanding of what drives human behavior. One widely influential model was proposed by Abraham Maslow in 1934 and has come to be known as Maslow’s hierarchy of needs model.2 In Maslow’s framework, much of human (and perhaps animal) behavior is attributed to the perpetual drive to meet specific needs. These drives are akin to instincts. What was unique about Maslow’s work was that he explicitly described a hierarchy and a continuum of dependencies. That is to say, Maslow considered that not all needs are of equal importance and proposed that humans will not exhibit behaviors designed to meet higher order needs (e.g., personal achievement) unless basic needs (e.g., food, water, shelter) are first adequately met. Maslow arranged the needs that may drive human behavior into a pyramid with the most important or essential needs at the bottom (Fig. 12.1). The needs were arranged into several tiers (physiologic, safety, love/belonging, esteem, and self-actualization). Physiologic needs were assigned preeminence.

73

CHAPTER 12  Patient Suffering in the Intensive Care Unit Physiologic need

Sleep

Selfactualization Morality, creativity, spontaneity, acceptance, experience purpose, meaning and inner potential

Nutrient intake

Water balance

Self-esteem Confidence, achievement, respect of others, the need to be a unique individual

Toxin avoidance/clearance

Love and belonging Friendship, family, intimacy, sense of connection

Tissue integrity preservation

Safety and security Health, employment, property, family and social stability

Air; alveolar ventilation

Physiologic needs Breathing, food, water, shelter, clothing, sleep Fig. 12.1  Maslow’s original hierarchy of human needs. Highest priority needs are at the bottom of the pyramid. These needs must be met for needs in a tier lying above them to receive priority. Few would dispute that most of the highest priority needs are shared between humans and animals (excluding clothing, which in some cases may actually lead to patient suffering via humiliation; see also “dogs in sweaters”).

Although sociology and psychology have moved on to embrace attachment theory as an alternative explanation of human behaviors, Maslow’s hierarchy of needs remains better suited to application in veterinary clinical practice. Each of the physiologic needs may be linked to a primal alert signal that provides input regarding whether that need is being met or is under potential threat. Pain may be considered the alert signal linked to threats to tissue integrity. Dyspnea is considered the signal linked to alveolar ventilation adequacy. Thirst and hunger herald threats to water and nutrient balance, respectively. Hunger may be a more nuanced signal that can be altered to drive behaviors geared toward meeting fairly specific nutrient requirements (e.g., cravings, pica). Nausea is likely tied to toxic threats or waste excretion and drives both aversive behaviors (vomiting) and adaptive behaviors (food aversion). Not all the primal alert signals are clearly evident as distinct or unique sensations, yet behavioral changes are still evident. Sleep is a fundamental need of vertebrate species and yet to date no specific, unique sensation linked to sleep inadequacy has been described. Feelings of drowsiness are nonspecific and may be elicited in subjects that have little or no sleep debt under some conditions (e.g., postprandial somnolence). Because primal alert signals linked to procreation have little or no relevance to critical care, the authors have elected to exclude them from this chapter. Some researchers have expanded Maslow’s hierarchy into subhierarchies. For example, physiologic needs are not all given equal priority (Fig. 12.2). The available evidence indicates that the need for air is assigned the top priority. This proposed relationship comes from the finding in human hospice patients with both pain and dyspnea where these patients report that dyspnea is the more unpleasant sensation of

Primal alert signal

Drowsiness

Hunger

Thirst

Nausea

Pain

Dyspnea

Fig. 12.2  A second subhierarchy of the basic physiologic needs and the primal alert signals used to herald real or perceived threats to meeting those needs.

the two.3 In laboratory-induced models of pain and dyspnea, one finds that concurrent dyspnea makes pain less noticeable, whereas the converse is not true (i.e., pain does not make dyspnea less unpleasant). Animal studies have compared how unpleasant dyspnea is versus hunger and find that in most species animals will remain starved rather than seek out food that is made available in an environment that will result in sensations of dyspnea (e.g., argon-filled chamber). Consideration of some, but perhaps not all, of these primal alert signals is a routine part of critically ill patient assessment. In the present era, it would be assumed by the authors that clinicians are frequently monitoring patients for evidence of pain. Signs of respiratory distress are often equated with sensations of dyspnea in veterinary practice. Periodic assessment of hunger, thirst, and nausea may also be performed. Patients may be considered to have a significant sleep debt when microsleeps become apparent. Microsleeps are brief (1- to 60-second) periods of involuntary sleep that occur regardless of what the patient is doing (e.g., briefly falling asleep while sitting upright). Increases in the delta state effectively shut down the brain for a brief period in response to a large sleep debt. Surveillance for the evidence of activation of these primal alert signals is a routine part of clinical practice whether it is done with a recognition of this conceptual framework or not. One entire specialty of medical practice (i.e., palliative care) is devoted to the recognition and alleviation of these symptoms/clinical signs, but all clinicians share a responsibility to monitor for these signs of basic needs not being met in their patients. As described earlier, pain research has dominated the field of patient suffering research. This has clearly been to the patients’ benefit, but much work remains to be done in expanding our understanding of other unpleasant sensations and how they may be alleviated. A growing body of evidence from human intensive care medicine suggests that even at the finest institutions symptom relief is far from optimal. In a study by Denise Li and colleagues out of the University of California at San Francisco, the prevalence of unaddressed symptoms (i.e., unpleasant sensations interfering with a sense of well-being) was 100%.4 All patients reported some degree of dyspnea (i.e., shortness of

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PART I  Key Critical Care Concepts

r  0.74 Tiredness

Generalized discomfort r  0.52

r  0.79

Thirst

r  0.79 r  0.54 Anxiety

r  0.58

Dyspnea

r  0.52 Feelings of depression

Hunger Fig. 12.3  Correlation between symptoms in critically ill human patients.4

breath). Prevalence rates were also quite high for most of the other symptoms that were evaluated (thirst, tiredness, anxiety, hunger, generalized discomfort, pain, dyspnea, depressed feelings, and nausea). Interestingly, this study found that there was a high degree of correlation between some symptoms and others (Fig. 12.3). These associations may be of use in veterinary intensive care. For example, in Fig. 12.3 one finds a high correlation among thirst, tiredness, general discomfort, and anxiety. This suggests that in patients that appear anxious and uncomfortable, providing greater opportunity for rest and meeting water intake needs may have a crossover benefit that translates to less sedative and analgesic need. A similar study by Nelson et al., which focused on cancer patients in the ICU setting, identified prevalence rates of greater than 50% for six different symptoms (all at a moderate to severe level).5 The six symptoms that had these high prevalence rates were discomfort, unsatisfied thirst, difficulty sleeping, anxiety, pain, and unsatisfied hunger. Depression and dyspnea were also identified in 34% to 39% of patients at moderate to severe levels. These same authors also investigated symptom burden in a population of chronically critically ill human patients, and in this group prevalence rates of greater than 50% were identified for all 16 symptoms assessed (weight loss, lack of energy, inappetence, pain, dry mouth, hunger, drowsiness, dyspnea in two settings, insomnia, nausea, difficulty communicating, thirst, worried, sad, and nervous).6 Clearly, some but not all of these symptoms may be relevant to small animal patients. For example, although human patients expressed distress over weight loss, it strains credibility to think that dogs are overly concerned with body image. However, this study does raise some interesting points. Human patients appeared to find dry mouth distressing and unpleasant. Although mucous membrane hydration is frequently assessed in small animal patients, the authors’ impression is that little or no effort is made to maintain membrane moisture as a therapeutic goal.

Impact of Symptom Relief Data would suggest that clinicians are far more likely to consider palliative relief as an important goal in and of itself when such measures can be tied to clinical outcomes. There is evidence that failure to address symptoms in humans and animal models can be linked to both outcomes and physiologic derangements. The ICU can be a noisy environment, and sleep patterns may be frequently disrupted by the chaos and commotion that can occur at unpredictable intervals. Studies in dogs in which their sleep was frequently disrupted by an alarm sounding have demonstrated that such sleep fragmentation leads to systemic hypertension. Considering the number of equipment alarms

(e.g., ventilators, fluid pumps, syringe pumps) that may go off on a typical overnight shift in a busy veterinary ICU, it is not implausible to consider that this noise burden may contribute to cardiovascular instability in some cases. An industry-academia summit was convened recently to address “alarm fatigue” in the human ICU setting.7 Addressing the human toll of alarm signals and hospital noise was the major focus of this meeting. Moreover, it has been shown that symptom experience is an independent predictor of important outcomes in human critically ill patients. Symptom distress has also been associated with unfavorable outcomes including higher mortality rates. Conversely, reduction of symptom burden may promote favorable outcomes such as physiologic stability and reduced resource expenditures. Taken together, the available evidence suggests that greater attention to relief of clinical signs may yield improved outcomes even when clinicians don’t consider palliative measures to be their own reward.

Palliative Measures Some aspects of palliative care may appear self-evident and represent current standard of care, whereas others might require a revision of patient care protocols. Addressing thirst, hunger, and pain in a proactive manner can be easily justified. Consideration should be given to offering small amounts of oral liquids to maintain membrane moisture (even when oral intake should be limited) and increase patient comfort. Providing adequate opportunity for uninterrupted sleep should also be a primary goal. Clustering treatments to minimize patient awakenings is advised. Providing quiet periods with reduced lighting overnight is recommended whenever feasible. Greater vigilance for signs of nausea and earlier intervention may be warranted based on the human ICU experience. Serial monitoring using validated pain scoring systems is advised as well. Nebulized furosemide may provide symptomatic relief from dyspnea, as may opioid administration. It is advised to encourage owner visitations and to make efforts to get patients outside for a portion of each day whenever such measures would not represent an undue risk. Providing opportunities for patients to express normal behaviors may enhance comfort and reduce anxiety. In summary, pain is far from the only unpleasant sensation critically ill animals are likely to experience. The application of a broader definition of animal suffering in the hospital environment may lead to more comprehensive palliative care being provided and to improved outcomes. Increased patient comfort is likely to also lead to improved workplace safety and reduction in negative patient–caregiver interactions as patient tolerance of handling is enhanced.

REFERENCES 1. Tizard I: Sickness behavior, its mechanisms and significance, Anim Health Res Rev 9(1):87, 2008. 2. Zalenski RJ, Raspa R: Maslow’s hierarchy of needs: a framework for achieving human potential in hospice, J Palliat Med 9(5):1120, 2006. 3. Banzett RB, Gracely RH, Lansing RW: When it’s hard to breathe, maybe pain doesn’t matter, J Neurophysiol 97:959, 2007. 4. Li DT, Puntillo K: A pilot study on coexisting symptoms in intensive care patients, Appl Nurs Res 19(4):216, 2006. 5. Nelson JE, Meier DE, Oei EJ, et al: Self-reported symptom experience of critically ill cancer patients receiving intensive care, Crit Care Med 29(2):277, 2001. 6. Nelson JE, Meier DE, Litke A, et al: The symptom burden of chronic critical illness, Crit Care Med 32(7):1527, 2004. 7. Improving clinical alarms: fall summit aims to develop action plan, Biomed Instrum Technol (Suppl 7), 2011.

13 Predictive Scoring Systems in Veterinary Medicine Galina Hayes, BVSc, PhD, DACVECC, DACVS, Karol Mathews, DVM, DVSc, DACVECC

KEY POINTS • Scoring systems objectively quantify an individual patient’s risk of experiencing a defined medical event. • Scoring systems can be used to triage, assist medical decision making, and trend patient progression over time. • In clinical research, scoring systems can facilitate analytic control when observational study associations are confounded by illness

severity and can also be used to demonstrate equivalence of treatment groups. • It is important to assess the predictive accuracy of any score in a patient population distinct from that which was used to derive the score weightings.

DEFINITION

negatively impact a patient. For example, a risk probability should not be used, at least in isolation, to justify withdrawal of care. In general terms, the utility of severity scores is lower when applied to individual patients compared with clinical research populations. However, severity scores can provide an objective measure to assist prognostication and supplement clinical judgment. This may help ensure that owner consent is appropriately informed and that expectations are realistic. Daily score calculation has been used to facilitate objective patient trending1 and decide on the appropriate location of care, such as inpatient versus outpatient.2 Scores indicating high risk can be used to prompt modification of interventions (i.e., high American Society of Anesthesiologists physical status classifications may prompt different drug selections and monitoring protocols for animals undergoing anesthesia). Some examples of veterinary clinical scoring systems and their modeled outcomes are shown in Table 13.1. In general terms, however, at the individual patient level, the utility of any score is an adjunct to, rather than replacement for, the clinical judgment of the primary clinician. This acknowledges the ability of an individual patient to confound any algorithm, no matter how sophisticated.

A scoring system is an algorithm applied to a patient’s characteristics that generates a numeric value. This value reflects the probability of the modeled diagnosis or outcome. Similar to the flow of any clinical assessment, scoring systems typically assign various weights to combinations of clinical signs, components of the medical history, and diagnostic test results to generate a prognosis or guide a treatment decision. However, unlike an individual clinician’s assessment, the risk prediction generated by a scoring system is repeatable both within and between patients and clinicians, is uncolored by recent experience, and is generated from clinical components that have been identified to be statistically associated with outcome in large numbers of patients. In the ideal approach, a clinician synthesizes an individual patient’s plan by integrating probabilistic information generated by a score with their own medical knowledge and acumen.

OUTCOME PROBABILITY VS. CLINICAL DECISION AID TOOLS Scoring systems typically generate a risk probability for a specific modeled outcome, such as death, survival duration, need for a specific intervention, or final diagnosis. Although it may be tempting to employ score cut-offs to prompt specific interventions, such as increased monitoring for dogs at higher risk of complications after airway surgery, the desired reduction in risk resulting from this type of change in practice cannot be assumed to occur until demonstrated in appropriately designed clinical trials.

APPLICATIONS IN CLINICAL PRACTICE Severity scores can provide an objective tool that can be used to assist baseline patient assessment at admission or some other defined time point. However, the confidence interval that surrounds a risk probability for an individual is inherently substantially wider than that generated for a population risk probability. For this reason, it is considered inappropriate to use a severity score as a sole measure to prompt an intervention that might

APPLICATIONS IN HOSPITAL MANAGEMENT Quantification of unit workload may be necessary to appropriately manage staffing, equipment, and workspace needs. Case numbers alone can lack sophistication as a surrogate measure of workload, particularly when cases are complex. Workload may be more accurately quantified as the sum of the total illness severity burden. Similarly, when comparing care unit treatment outcomes, allowance should be made for the average illness severity of the cases managed by that unit. Outcomes will always be better when illness severity is lower, and case illness severity should not be assumed to be homogenous between treatment centers.

APPLICATIONS IN RESEARCH Descriptive Studies Reporting a score that has a known and previously validated association with illness severity provides important contextual information in purely

75

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PART I  Key Critical Care Concepts

TABLE 13.1  Select Veterinary Clinical Scoring Systems and their Modeled Outcomes Score

Patient Group

Modeled Outcome

Score Range

Publication Reference

American Society of Anesthesiologists Physical Status Score (ASA PS) Canine Acute Patient Physiologic and Laboratory Evaluations (APPLE) score Feline Acute Patient Physiologic and Laboratory Evaluations (APPLE) score Animal Trauma Triage (ATT) score

Dogs and cats undergoing general anesthesia Dogs admitted to ICU

Perianesthetic death

I to V 1/2 E

Death or euthanasia over the period of hospitalization

0–80 (APPLEfull)

Bille, Auvigne, Libermann, Vet Anesth Analg 2012; 39:59-68 Hayes, Mathews, Doig, J Vet Intern Med 2010; 24:1034-1047

Death or euthanasia over the period of hospitalization

0–80 (APPLEfull)

Survival 7 days post trauma

0–18

Death or disease associated euthanasia at 30 d post admission Survival 48 hr later

0–18

3–18

Platt SR, Radaelli ST, McDonnell JJ. The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs. J Vet Intern Med. 2001 Nov-Dec;15(6):581-4. doi: 10.1892/ 0891-6640(2001)0152.3.co;2. PMID: 11817064.

Composite of need for postoperative oxygen support for .48 hr, need for a postoperative tracheostomy, or death Survival at 24 hr after birth

0–10

Tarricone, Hayes, Singh, Vet Surg 2019; 48(7):1253-1261

0–10

Survival to discharge and dialysis free at 30 d post discharge Hemangiosarcoma diagnosis

1.11–42.15

Veronesi, Panzani, Faustini, Theriogenology 2009; 72:401-407 Segev, Kass, Francey, J Vet Intern Med 2008; 22:301-308

Diagnosis of hypoadrenocorticism

Probability of diagnosis

Cats admitted to ICU

Canine Acute Pancreatitis Severity (CAPS) score

Dogs and cats following trauma Dogs with acute pancreatitis

Modified Glasgow Coma Scale (mGCS)

Dogs admitted after acute head trauma

Brachycephalic Risk (BRisk) score

Brachycephalic dogs undergoing airway surgery

Apgar score

Puppies at 5 min after birth Dogs with AKI undergoing hemodialysis

Hemodialysis outcome score (model B) Hemangiosarcoma Likelihood Prediction (HeLP) score Hypoadrenocorticism prediction model

Dogs with spontaneous hemoabdomen Dogs with suspect hypoadrenocorticism based on clinical signs

0-50 (APPLEfast)

0-50 (APPLEfast)

0–100

Hayes, Mathews, Doig, J Vet Intern Med 2011; 25:26-38 Rockar, Drobatz, Shofer, J Vet Emerg Crit Care 1994; 4(2):77-83 Fabres, Dossin, Reif, J Vet Intern Med 2019; 33:499-507

Schick, Hayes, Singh, J Vet Emerg Crit Care 2019; 29:239-245 Borin-Crivellenti, Garabed, Moreno-Torres, Am J Vet Res 2017; 78:1171-1181

AKI, acute kidney injury.

descriptive studies such as case reports or case series, giving observations greater interpretability and external validity.3 High external validity allows study findings to be better generalized to the wider population.

Observational Studies The ability to select the most efficacious treatment, or form an accurate prognosis, may be impeded in the absence of well-designed observational studies or randomized controlled trials. Case series and retrospective observational studies make up a substantial proportion of the veterinary literature. These often rely on case accrual over several years and are subject to many pitfalls including lack of case homogeneity and lack of defined control groups. The findings of observational studies may be hampered by confounders, defined as the presence of an extraneous factor distorting the relationship between the outcome and the variable under study.4 Control of confounders minimizes erroneous conclusions about the relationships between exposure and outcome. A common confounder of the relationship between treatment and outcome is illness severity; a clinician-induced selection bias occurs when a treatment is applied with greater frequency in the more severely ill, and this bias may create an inappropriate association between the treatment and mortality that is a result of confounding by illness severity. Objective quantification of illness

severity facilitates analytical control of this variable and can improve the quality of observational studies. In one approach, a minimum or maximum illness score can be set as a predefined criterion for study entry. Alternatively, illness severity can be entered as a covariable with treatment in a regression analysis of treatment effect on outcome. This approach will allow the effect of treatment on outcome to be estimated, while controlling for illness severity. It may also be useful to demonstrate equivalent illness severity among treatment or exposure groups, despite lack of formal randomization. With the increasing availability of appropriately validated scores in veterinary medicine, research use is likely to increase.

DEMONSTRATION OF EFFECTIVE OR INEFFECTIVE RANDOMIZATION IN RANDOMIZED CONTROLLED TRIALS The process of randomization in controlled trials is intended to equally distribute potential confounding factors such as age or degree of illness severity among treatment groups and thus eliminate the effects of confounding. However, when case numbers are small or confounding factors are numerous or variable, randomization may

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CHAPTER 13  Predictive Scoring Systems in Veterinary Medicine not be successful in achieving this goal, and inaccurate estimates of a treatment effect can result. Delineating the severity of illness of animals assigned to treatment and control groups allows for both documentation and analytical control of ineffective randomization, decreasing the risk of an important treatment effect being missed or wrongly assessed.5

basis can be challenging due to the lack of practicality or appropriateness of in-depth owner questioning at a time of emotional stress. Clinician subjectivity and clinician misconceptions can also be sources of error.9 Handling of euthanized patients in veterinary models varies from complete exclusion10 through exclusion of some subsets11 to complete inclusion.12

REDUCTION OF REQUIRED SAMPLE SIZES

CRITICAL APPRAISAL

Illness severity scores are an effective tool by which to improve power and decrease the sample size required to detect a significant difference between treatment or exposure groups in clinical research. Stratifying patients by severity of illness to ensure patient group homogeneity can decrease the sample size required to measure an effect.6 Multivariable regression can be thought of conceptually as the ultimate form of stratified analysis. In this context, the overall sample size required to identify a statistically significant measure of effect between a variable and outcome is decreased when an additional variable that explains a significant degree of the data variation is introduced.7

The key test of any prediction system is not how it performs in the training data set from which it was derived but whether it retains its predictive value in another test data set. While many studies report score performance characteristics only on the training data, these estimates of accuracy must be viewed with caution.13 The theoretically ideal score will hold its predictive utility when applied to a noncontemporary population at a different treatment center. It is up to the potential score user to critically assess the test and validation populations for similarity or otherwise. A number of statistical techniques are available to summarize predictive accuracy. Score discrimination is assessed using the area under the receiver operator characteristic (AUROC). This is a plot of the sensitivity versus the specificity of the score for predicting the outcome of interest in the population being assessed. Typically, a score probability of .0.5 is set as the threshold for predicting the outcome to occur, although this can be adjusted to prioritize sensitivity over specificity and vice versa. Predicted positive and negative outcomes are assessed against true positive and negative outcomes. The ideal discriminator will have a curve which touches the upper left-hand corner of the graph, and the area under the curve would be 1.0 (see Fig. 13.1). In comparison, a discriminator no better than chance alone will have a diagonal line running from bottom left to top right, and an AUROC of 0.5. An example of interpretation for a mortality outcome score with an AUROC of 0.8 would be that for two animals, one of which survived, and one did not, the score had an 80% likelihood of identifying the animal at higher risk. One caveat to be aware of when assessing a

0.

85

=

0.

95

1.0

A

75

0.8

0.

50

0.6

0.

Development of a scoring system has been well described8 but typically begins with defining the outcome of interest (e.g., intraoperative death) and then collecting patient data on a number of variables that might reasonably be hypothesized to be associated with that outcome (e.g., intraoperative hemorrhage). In the ideal situation, patient data are collected from two groups with the same selection criteria but that are receiving treatment at two independent centers or groups of centers. Once data collection is complete, the variables most strongly associated with outcome are identified, and data from one center is used to provide the weightings for score calculation. The accuracy of the score at predicting the outcome is then tested against the data from the second center. While the process of deriving the weightings (typically from a regression analysis) requires some statistical skill, the calculation of the score is generally straightforward requiring only adding or subtracting, together with looking up a reference table or graph. When constructing a score of this type, several key points are worth emphasizing. First, the variable weightings have to be “trained” on a reasonable number of outcomes to perform robustly; as a general rule at least 10 of the outcomes of interest (i.e., at least 10 deaths, if deaths are being modeled) are needed per variable in the score, and the more the better. Too many variables and too few outcomes risk overfitting the model and poor prospective performance. Second, variable selection needs to be pragmatic; if very few centers have the ability to measure the variable being used, then score uptake is likely to be poor. Thirdly, many medical parameters have a biologically nonlinear association with risk outcomes. For example, both very high and very low heart rates may be associated with increased mortality risk, and this needs to be accounted for in the modeling process. Finally, if mortality is used as the modeled outcome, then the way in which euthanized animals are to be handled needs to be considered. The performance and timing of euthanasia reflects multiple factors, including severity of patient illness, owner financial and emotional status, diagnosis of a disease anticipated to be terminal at some future point, subjective assessments of degree of suffering, and individual clinician perspective. If all euthanized patients are excluded from the model development data set, available patient data may be limited and biased. If all patients are included regardless of euthanasia status, the significance of a particular variable as a risk factor for death may be masked by patients euthanized for financial reasons. Attempting to determine the exact reason for euthanasia and discriminate among patient subsets on that

True-positive proportion

CONSTRUCTION OF SCORING SYSTEMS

0.4

0.2

0 0

0.2

0.4

0.6

0.8

False-positive proportion Fig. 13.1  Area under the receiver operator characteristic curve.

1.0

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PART I  Key Critical Care Concepts

40

.6

0

0

.2

20

.4

No dogs

Negative outcome risk

60

.8

1

78

0

2

4

6 BRisk score

Predicted negative outcome risk

8

10

Measured negative outcome risk per BRisk category

No. dogs per BRisk score category Fig. 13.2  Relationship between the number of dogs in each BRisk score group in the study population (n 5 283), the measured negative outcome risk for each of those groups, and the outcome predicted using the BRisk score. BRisk, brachycephalic risk. From Tarricone J, Hayes G, Singh A, Davis G: Development and validation of a brachycephalic risk (BRisk) score to predict the risk of complications in dogs undergoing surgical treatment of brachycephalic obstructive airway syndrome, Vet Surg 48(7):1253-1261, 2019.

score performance by an AUROC value alone is that when the outcome event is rare, the proportion of false positives, and thus specificity, will drive accuracy. For example, in an ICU with a mortality risk of 5%, a score that predicted 100% survival for every patient would have an AUROC of 0.95, and yet it clearly has no utility as a classifier. AUROC generates excessively optimistic estimates of discriminative performance when the frequency of nonevents greatly exceeds the frequency of events.14 A complementary, and often more informative, measure of score performance is calibration. In a perfectly calibrated model, 8 of 10 animals with an 80% predicted probability of mortality would die, and 2 of 10 would survive. Conversely, 99 of 100 animals with a 1% risk would survive. Well-calibrated models estimate individual event probabilities that reflect the true distribution of risk in the population. A useful graphic (see Fig. 13.2) for examining this capacity of a score is a plot of predicted risk outcomes versus observed risk outcomes over the range of the score; a superimposed histogram showing the number of test animals contributing to each risk category can also be helpful in giving the reader a sense of the stability of the risk estimates. This score characteristic can be tested formally in the context of a logistic regression model using the Hosmer–Lemeshow test.15

CONCLUSION In conclusion, predictive scoring systems can be used to complement the clinician’s clinical judgment, provide objective trends of patient progression, and assist in the triage of patients to different levels of care or intervention. In the research setting, they can enable analytic

control of disease severity and demonstrate the effectiveness of randomization for achieving treatment group equivalence at baseline. Critical appraisal of scores is important before choosing to employ them routinely in clinical practice, and seeking evidence of external validation of the score is an important component of this.

REFERENCES 1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL: Serial evaluation of the SOFA score to predict outcome in critically ill patients, J Am Med Assoc 286(14):1754-1758, 2001. 2. Meneghini RM, Ziemba-Davis M, Ishmael MK, Kuzma AL, Caccavallo P: Safe selection of outpatient joint arthroplasty patients with medical risk stratification: the Outpatient Arthroplasty Risk Assessment Score, J Arthroplasty 32(8):2325-2331, 2017. 3. Le Gall JR: The use of severity scores in the intensive care unit, Intensive Care Med 31:1618-1623, 2005. 4. Dohoo I, Martin W, Stryhn H: Confounder bias: analytic control and matching. In McPike M, editor: Veterinary epidemiologic research, Charlottetown, PEI, Canada, 2007, VER Inc., pp 235-270. 5. Higgins TL: Severity of illness indices and outcome prediction. In Fink MP, Abraham E, Vincent JL, Kochanek PM, editors: Textbook of critical care, Philadelphia, 2005, Elsevier Saunders, pp 2195-2206. 6. Higgins TL: Quantifying risk and benchmarking performance in the adult intensive care unit, J Intensive Care Med 22:141-156, 2007. 7. Greenland S: Introduction to regression models. In Rothman KJ, Greenland S, Lash TL, editors: Modern epidemiology, Philadelphia, 2008, Lippincott Williams, pp 381-417.

CHAPTER 13  Predictive Scoring Systems in Veterinary Medicine 8. Zhang Z, Zhang H, Khanal MK: Development of scoring systems for risk stratification in clinical medicine: a step by step tutorial, Ann Transl Med 5(21):436, 2017. 9. Rockar RA, Drobatz KS: Development of a scoring system for the veterinary trauma patient, J Vet Emerg Crit Care 4:77-82, 1994. 10. Brewer BD, Koterba AM: Development of a scoring system for the early diagnosis of equine neonatal sepsis, Equine Vet J 20:18-22, 1988. 11. Segev G, Kass PH, Francey T, Cowgill LD: A novel clinical scoring system for outcome prediction in dogs with acute kidney injury managed by hemodialysis, J Vet Intern Med 22:301-308, 2008.

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12. Rohrbach BW, Buchanan BR, Drake JM, et al: Use of a multivariable model to estimate the probability of discharge in hospitalised foals that are seven days of age or less, J Am Vet Med Assoc 228:1748-1756, 2006. 13. Seymour DG, Green M, Vaz FG: Making better decisions: construction of clinical scoring systems by the Spiegelhalter-Knill-Jones approach, Br Med J 300:223-226, 1990. 14. Leisma D: Rare events in the ICU: an emerging challenge in classification and prediction, Crit Care Med 46:418-424, 2018. 15. Hosmer DW, Lemeshow S: Assessing the fit of the model. In Shewhart WA, Wilks SS, Hosmer DW, Lemeshow S, editors: Applied logistic regression, New York, 2000, Wiley and Sons, pp 143-202.

PART II  Respiratory Disorders

14 Control of Breathing Kate S. Farrell, DVM, DACVECC KEY POINTS • The medulla is considered the respiratory center, and it is the site responsible for the generation of the respiratory pattern and coordination of voluntary and involuntary input that can alter breathing activity. • Within the medulla is a collection of neurons known as the central pattern generator, which acts as a group pacemaker system that produces the basic rhythm of breathing. • Other areas of the central nervous system, including the pontine respiratory group, the cortex, and other higher centers, can alter the respiratory pattern.

Breathing is automatically initiated by the central nervous system (CNS) and occurs largely without conscious awareness. The respiratory center in the fetal brainstem develops early in pregnancy and continues throughout life to generate spontaneous cycles of inspiration and exhalation.1,2 While neurons in the medulla initiate and coordinate control of breathing without conscious input, the automatic cycle of inspiration and exhalation can be altered or interrupted by commands from higher centers of the brain (such as the cortex and hypothalamus), by involuntary actions (such as swallowing, coughing, or sneezing), and by feedback from multiple sensors, including central chemoreceptors, peripheral chemoreceptors, and receptors in the lung parenchyma and airways. Ultimately, this neuronal network controls activity of the motor neurons that innervate the respiratory muscles, resulting in changes in ventilation. In this regard, there can be finetuning of gas exchange in the lungs to meet metabolic demands of the body, allowing O2 and CO2 to be maintained within a narrow range in the normal patient.

CENTRAL CONTROL OF BREATHING The respiratory center of the brain resides in the medulla, where complex collections of neurons form a group pacemaker system known as the central pattern generator (CPG). While the medullary respiratory center is considered essential for generation of the basic rhythm of breathing, influences from other regions of the CNS, including the pontine respiratory group, the cortex, and other higher centers, can alter this pattern. Each of these regions is discussed in more detail below.

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• Central chemoreceptors sense changes in carbon dioxide and pH, while peripheral chemoreceptors also sense changes in oxygenation, and the combined input from these receptors can alter the respiratory pattern to help return blood gases to normal. • Carbon dioxide has a major influence on breathing in health, whereas the partial pressure of oxygen must generally fall to less than 50–60 mm Hg to induce large changes in ventilation. • Receptors in the lungs and airways and other sensory receptors are also involved in reflex mechanisms that can modify the respiratory pattern.

Respiratory Central Pattern Generator To produce a spontaneous respiratory rhythm, collections of associated neurons within the medulla generate intrinsic recurring bursts of neuronal activity. This complex network of neurons acts as a group pacemaker system and is known as the CPG. While neurons involved in this group pacemaker activity are spread throughout the medulla, they are concentrated in a region known as the pre-Bötzinger complex (discussed below). Multiple groups of neurons with intrinsic firing patterns are recognized to contribute to this pacemaker activity, and they can be classified into categories based on shape (augmenting, decrementing, or constant/plateau) and phase of respiration.1,3-5 The resulting respiratory cycle consists of three phases.1,4,5 The first is the inspiratory phase, characterized by a sudden onset of activity of early inspiratory neurons and a ramp increase in inspiratory augmenting neurons, resulting in motor discharge to inspiratory muscles and airway dilators. The next phase is the postinspiratory phase or expiratory phase I, characterized by declining motor discharge to inspiratory muscles and passive exhalation. Expiratory decrementing neurons decrease in activity, resulting in a decline in laryngeal adductor muscle tone that functions as a mechanical brake to expiratory flow. In the final stage, expiratory or expiratory phase II, there is no inspiratory muscle activity. During quiet normal breathing, exhalation is almost entirely passive. During active exhalation, such as during exercise, voluntary forced exhalation, or high minute volumes, expiratory augmenting neurons support expiratory muscle activity. This CPG functions automatically and generates periodic firing to produce respiratory rhythmogenesis. The spontaneous activity

CHAPTER 14  Control of Breathing exhibited by these respiratory neurons is dependent on intrinsic membrane properties and neurotransmitters required for excitatory and inhibitory feedback mechanisms. Similar to cardiac pacemaker cells, multiple types of sodium, potassium, and calcium ion channels are required for the generation of intrinsic membrane activity.4,5 Key neurotransmitters involved in synaptic interactions in the CPG include glutamate (typically excitatory), and GABA and glycine (inhibitory). Additionally, acetylcholine, monoamines, and various neuropeptides act as neuromodulators that, while not essential to rhythmogenesis, can exert significant influence on the CPG.5

Medullary Respiratory Center Located within the brainstem, the medulla is considered the respiratory center and is the region responsible for the generation of the respiratory pattern and coordination of respiratory activity. There are many neuronal connections into and out of the medulla. Neurons related to respiratory function are mostly clustered in two anatomic locations known as the dorsal and ventral respiratory groups. Dorsal respiratory group. The function of the dorsal respiratory group (DRG) is primarily timing of the respiratory cycle.1 The DRG is composed of mostly inspiratory neurons that project to the contralateral spinal cord. These neurons initiate activity in the phrenic nerves, which innervate the diaphragm. Positioned bilaterally in the medulla, the DRG lies in close relation to the nucleus tractus solitarius at the termination of visceral afferents from cranial nerves IX (glossopharyngeal) and X (vagus).1 These nerves carry sensory information that may influence control of breathing, including pH and arterial partial pressures of O2 and CO2 (from carotid and aortic chemoreceptors) and systemic arterial blood pressure (from carotid and aortic baroreceptors).6 The vagus nerve also transmits information from stretch receptors and other sensors in the lungs. Given the location of the DRG, it may serve as a site for the integration of cardiopulmonary reflexes that can alter the pattern of breathing.6 Ventral respiratory group. The ventral respiratory group (VRG) consists of inspiratory and expiratory neurons located in four main collections: the caudal ventral respiratory group (including the nucleus retroambigualis and nucleus paraambigualis), the rostral ventral respiratory group (mostly comprised of the nucleus ambiguus), the pre-Bötzinger complex, and the Bötzinger complex (within the nucleus retrofacialis).1 The caudal respiratory group has expiratory function and governs the force of contraction of inspiratory muscles; the rostral ventral respiratory group controls airway dilator functions of the larynx, pharynx, and tongue; and the Bötzinger complex has extensive expiratory functions. As discussed above, the pre-Bötzinger complex is thought to be essential for pacemaker activity that is responsible for central pattern generation.

Pontine Respiratory Group The pontine respiratory group (PRG) is a collection of neurons located in the pons that functions to fine-tune the breathing pattern via multisynaptic connections to the medullary respiratory center.1 This region corresponds to what was formerly called the “pneumotaxic center”.1,3,6 While the PRG is no longer considered essential for respiratory rhythm generation, the activity of its neurons does act to influence the timing of the respiratory phases, stabilize the breathing pattern, and alter the respiratory rhythm.3 In particular, increased activity of neurons in this region can promote termination of inspiration, and experimental lesions in the PRG have been shown to cause an increase in the duration of inspiration.3 There are many central afferent pathways that connect with the PRG, including those from the cortex, hypothalamus, and nucleus tractus solitarius, suggesting that the pons

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serves as a coordinating center for input from the CNS, peripheral sensors, and cardiovascular reflexes.1 The “apneustic center” is a region located in the caudal pons that has also classically been described in animals and is involved in coordination of speed of inspiration and exhalation. Excitatory impulses from this center to the inspiratory area of the medulla tend to prolong inspiration.7 Experimental lesions in animals disconnecting this region from the PRG, along with vagal transection, result in an abnormal pattern of breathing called apneusis, which is characterized by prolonged gasping inspiratory efforts punctuated by brief inefficient expiratory efforts.3,6 The exact role that this region plays in normal breathing has not been fully elucidated.

Cortex and Other Higher Centers Breathing can occur under voluntary control with input from the cerebral cortex and other suprapontine structures, though interruptions and alterations to the breathing pattern are limited primarily by changes in arterial blood gases. Neuronal input from the cerebral cortex can override impulses from the brainstem or may completely bypass the respiratory center to directly innervate respiratory muscle lower motor neurons.1 In addition to voluntary changes in the respiratory pattern, numerous involuntary suprapontine reflexes alter breathing during actions such as vocalization, sneezing, coughing, swallowing, mastication, vomiting, and hiccupping. There is also experimental and clinical evidence from disease states that other suprapontine structures, such as the hypothalamus and amygdala, can exert strong modulating influence on the normal respiratory pattern generated in the brainstem.8,9 These higher centers can influence respiratory responses during hypoxia, hypercapnia, exercise, thermal changes, pain, and responses to other stressors (e.g., fear, anxiety, defense response).8,9

DESCENDING PATHWAYS Ultimately, axons originating in the brainstem, cerebral cortex, and other suprapontine structures descend along pathways in the white matter of the spinal cord to directly affect lower motor neurons to different groups of respiratory muscles. The respiratory muscles primarily involved in inspiration include the diaphragm, chest wall muscles, and some neck muscles. Active exhalation requires muscles of the abdominal and chest walls. Muscles of the pharynx and larynx also help control upper airway resistance.10

CHEMORECEPTORS AND RESPONSE TO BLOOD GASES While the medulla is the center for initiating and coordinating breathing, regulation of the respiratory pattern is a complex process that involves feedback loops from multiple types of sensors in the body (Fig. 14.1). A chemoreceptor is a type of sensory receptor that responds to alterations in the chemical composition of blood or fluid in which it is immersed. Afferent information from central chemoreceptors (located primarily in the medulla) and peripheral chemoreceptors (located in the aortic and carotid bodies) is transmitted to the respiratory center and provides input that affects automatic regulation of breathing. Central chemoreceptors are responsible for the majority of the response to changes in CO2 and pH, whereas peripheral chemoreceptors exclusively respond to hypoxemia and are also influenced by CO2 and pH. Ultimately, changes in the body’s partial pressure of CO2 (PCO2), pH, and partial pressure of O2 (PO2) trigger alterations in alveolar ventilation that return these variables to their target values.

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PART II  Respiratory Disorders

Medullary respiratory center

Higher brain centers (+⁄–)

Pontine respiratory center (+⁄–)

Central chemoreceptors (+) CO2, H+

Carotid body peripheral chemoreceptors (+) O2, CO2, H+

Aortic arch peripheral chemoreceptors (+) O2, CO2, H+

Pain, temperature, and touch receptors (+)

Muscle and joint receptors (+)

Respiratory muscles

Pulmonary stretch receptors (–) Irritant receptors (+) J receptors (+)

+ : Stimulus increases rate/depth of breathing – : Stimulus decreases rate/depth of breathing

Fig. 14.1  The medulla is considered the center for control of breathing and is the location for the generation of the respiratory rhythm. The medullary respiratory center receives input from other centers in the brain, the central and peripheral chemoreceptors, and multiple other types of receptors in the body that can alter the central respiratory pattern and affect neuronal output to the respiratory muscles. (Illustration by Chrisoula Toupadakis Skouritakis, PhD.)

Central Chemoreceptors Central chemoreceptors are primarily located on the ventrolateral surface of the medulla, close to the origins of the glossopharyngeal and vagus nerves. Many other areas of the CNS, including locations within the brainstem, cerebellum, hypothalamus, and midbrain, show increased neural activity with CO2 stimulation and are proposed as additional central chemosensitive areas; however, their contribution to respiratory control remains unclear.11 Central chemoreceptors are sensitive to changes in brain interstitial fluid pH, which mainly results from changes in PCO2 but is influenced to some degree by cerebral blood flow and brain metabolism.11 Central chemoreceptors do not respond to changes in PO2. While it was historically believed that the respiratory center itself reacted to changes in CO2, it is now recognized that central chemoreceptors are anatomically separate from respiratory neurons of the medulla. Neurons in the

region of the central chemoreceptors have connections to the nearby CPG and thereby function to modify ventilation.1 The PCO2 of blood ultimately helps to regulate ventilation by affecting the pH of the extracellular fluid surrounding central chemoreceptors. Because this interstitial fluid in the brain is in contact with cerebrospinal fluid (CSF), changes in the pH of the brain interstitial fluid and CSF affect ventilation. When arterial PCO2 rises, it causes a concurrent elevation in the PCO2 of venous blood, brain interstitial fluid, and CSF, which are typically 5–10 mm Hg higher than arterial PCO2.1,6 While the blood brain barrier is relatively impermeable to hydrogen and bicarbonate ions, CO2 molecules diffuse freely across this barrier. CO2 that diffuses into the CSF and brain interstitium becomes hydrated and forms carbonic acid, which rapidly dissociates to H1 and HCO3- ions. As the brain interstitium and CSF lack much of the buffering capability of blood due to considerably lower protein

CHAPTER 14  Control of Breathing levels, an elevation in arterial PCO2 results in a significant rise in H1 concentration (and therefore decrease in pH) of the brain extracellular fluid and CSF.7 Furthermore, an increase in arterial PCO2 is accompanied by cerebral vasodilation, and this enhances the diffusion of CO2 into the brain interstitium. This change in pH as a result of altered CO2 levels is believed to affect central chemoreceptors, though the exact mechanism by which this occurs remains disputed.1,11 Following a rise in arterial PCO2 and subsequent decline in brain interstitial pH, respiratory rate and depth are altered to allow return of PCO2 to normal. After several hours, if PCO2 remains elevated, the pH of extracellular fluid in the brain is partially corrected by compensatory changes in bicarbonate concentration, which ultimately restores ventilation to normal, blunting the response to CO2 over time.1

Peripheral Chemoreceptors Peripheral chemoreceptors lie within the carotid bodies close to the bifurcation of the common carotid arteries and within the aortic bodies located along the aortic arch. It is almost exclusively the carotid bodies that are responsible for the respiratory response, whereas the aortic bodies have a greater influence on circulation.1 Peripheral chemoreceptors respond rapidly, within 1–3 seconds, to a decline in PaO2, a rise in PaCO2, an increase in H1 concentration, or hypoperfusion.1 It has been suggested that stimulation of peripheral chemoreceptors is related to decreased PaO2 rather than decreased oxygen content, resulting in little stimulation due to anemia or dyshemoglobinemias.1 However, controversy remains on this subject, and there is some evidence to suggest direct peripheral chemoreceptor stimulation secondary to anemia.12 While the response to PCO2 is more rapid in peripheral chemoreceptors, the change is quantitatively less than that produced on the central chemoreceptors. An increase in blood temperature can also stimulate peripheral chemoreceptors and enhances the ventilatory responses to changes in O2 and CO2. Other drugs and chemical stimulants are known to affect peripheral chemoreceptors as well. Oxygen sensing occurs in specialized cells called type I (glomus) cells that compose the highly vascularized chemoreceptors. Potassium channels in these cells are inhibited either directly by hypoxia or by hypoxia-induced molecules such as reactive oxygen species, carbon monoxide, or hydrogen sulfide.1 This results in modulation of neurotransmitter release from glomus cells. Afferent information from these cells is transmitted to the respiratory center via the carotid sinus nerves (branches of the glossopharyngeal nerve from the carotid bodies) and vagus nerve (from the aortic bodies), resulting in increased rate and depth of breathing. In addition to these effects, stimulation of peripheral chemoreceptors can also result in other consequences, including bradycardia, hypertension, increased bronchiolar tone, and adrenal secretion of catecholamines.1

Integration of Responses to O2, CO2, and pH Through input from central and peripheral chemoreceptors that is assimilated in the respiratory center, alterations in PCO2, pH, and PO2 result in changes to the respiratory pattern that return these variables to their normal values. In the healthy individual, PCO2 is the most important factor affecting control of breathing. Central chemoreceptors have been attributed to account for approximately 60%–80% of the response to CO2, as compared to peripheral chemoreceptors.1,13 One study in awake dogs demonstrated that central chemoreceptors accounted for 63% of the steady-state response to increases in arterial PCO2, though there was significant dog-to-dog variability.14 Because central chemoreceptors appear to rely on extracellular pH within the brain, they are considered

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monitors of steady-state arterial PCO2 and cerebral tissue perfusion, while peripheral chemoreceptors detect and react to rapid and shortterm changes in arterial PCO2, though the response to peripheral chemoreceptors results in less profound changes in ventilation.1 Overall, an increase in PaCO2 results in a nearly linear increase in alveolar ventilation.1,6 This increase in ventilation is amplified by hypoxemia and metabolic acidosis. As opposed to PCO2, variations in oxygenation play a minimal role in health, and progressive hypoxemia results in a hyperbolic increase in ventilation. Hypoxemia causes changes in ventilation primarily through the stimulation of peripheral chemoreceptors, but it has no effect on central chemoreceptors; hypoxemia may also cause changes in ventilation at higher integrating sites. When PaO2 is near the normal range, a decrease in its value to less than 100 mm Hg results in a small increase in alveolar ventilation, whereas a large change in alveolar ventilation does not occur until PaO2 falls below 50–60 mm Hg.1,6,7 Conversely, if there is concurrent elevation of PCO2, changes in ventilation occur with only minimal decreases in PaO2. Exercise and metabolic acidosis also enhance the ventilatory response to hypoxemia, even without elevations in PCO2. In patients with chronic respiratory diseases resulting in hypercapnia, the response to elevated PCO2 is diminished, and hypoxemia becomes the principal stimulus for ventilation. While rare in veterinary medicine, administration of oxygen to these patients can result in a reduced ventilatory drive and severe hypercapnia.15 This is most classically seen in human patients with chronic obstructive pulmonary disease.

OTHER SENSORY RECEPTORS In addition to afferent input from chemoreceptors, information is transmitted from many receptors located in the lungs, airways, cardiovascular system, muscles, tendons, joints, skin, and viscera, all of which can generate reflexes that contribute to control of breathing (Fig. 14.1).

Lung and Airway Receptors Multiple receptors in the lungs and airways contribute to feedback loops that can alter respiratory rate and tidal volume, and some of these are discussed below. Pulmonary stretch receptors. Pulmonary stretch receptors, also known as slowly adapting pulmonary stretch receptors, are present in the smooth muscles of the airways. These receptors are activated in response to excessive and sustained distention of the lung and transmit information to the respiratory center (inspiratory area in the medulla and apneustic center of the pons) via large myelinated vagal fibers. Stimulation of these receptors causes inhibition of inspiratory discharge and slowing of the respiratory rate, resulting in the protective feedback loop known as the Hering–Breuer inflation reflex.1,6,7 An opposite response, known as the deflation reflex, initiates inspiratory activity with deflation of the lungs. Irritant receptors. Located in the epithelium of the nasal mucosa, upper airways, tracheobronchial tree, and possibly the alveoli, irritant receptors are activated by noxious gases, inhaled dust, cold air, and other mechanical and chemical stimuli.1,6,7 The receptors in the larger airways respond to stretch as well and are also referred to as rapidly adapting pulmonary stretch receptors. Irritant receptors transmit information largely via myelinated vagal afferent fibers, and their activation can result in bronchoconstriction, cough, laryngeal spasm, mucus secretion, and increased rate, and depth of breathing. Afferent pathways from receptors in the nasal mucosa send impulses via the trigeminal and olfactory tracts and can result in sneezing.6 J receptors. J receptors, or juxtacapillary receptors, are located in the pulmonary interstitium in close proximity to the pulmonary

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capillaries. These receptors are stimulated by pulmonary capillary distension, interstitial edema, and chemicals in the pulmonary circulation. Information is transmitted to the respiratory center via slowly conducting nonmyelinated C fibers of the vagus nerve, leading to a rapid, shallow breathing pattern or even apnea in extreme circumstances. J receptors are thought to result in the sensation of dyspnea in patients with diseases such as left-sided congestive heart failure and interstitial lung disease.

activates peripheral chemoreceptors and stimulates the medullary respiratory center. Additional respiratory stimulants include aminophylline/theophylline, caffeine, and progesterone. In addition to iatrogenic causes, intrinsic diseases can result in abnormalities in breathing. Causes of hypoventilation (see Chapter 17) and abnormal respiratory patterns witnessed with brain injury and intracranial hypertension (see Chapter 86) are discussed elsewhere.

Other Sensory Receptors

REFERENCES

In addition to those located within the respiratory system, receptors located in other regions of the body can help to adjust breathing patterns under certain circumstances. Arterial baroreceptors. The arterial baroreceptors are predominantly involved in regulation of the cardiovascular system, but they can also mediate ventilatory changes that occur with significant fluctuations in blood pressure.16 A marked decrease in arterial blood pressure sensed by the aortic and carotid sinus baroreceptors can result in reflex hyperventilation, while a substantial increase in blood pressure can cause hypoventilation. Muscle, tendon, and joint receptors. Somatic receptors located in muscles, tendons, and joints can also influence ventilation.6 For instance, receptors in muscles of respiration and rib joints respond to changes in length and tension of respiratory muscles and provide feedback regarding lung volume and work of breathing. Afferent fibers from the musculoskeletal system also likely play a large role in the hyperventilation induced by exercise. Pain and temperature. Receptors that detect pain, temperature, touch, and proprioception send information along ascending pathways of the spinal cord and can influence breathing. Painful stimuli detected by nociceptors can cause initial apnea followed by hyperventilation. An increase in temperature detected on the skin can also induce hyperventilation.

ABNORMALITIES IN THE CONTROL OF BREATHING The complex system that controls breathing is exquisitely fine-tuned and allows for moment-to-moment adjustments in ventilation to meet the metabolic demands of the body. However, drugs and diseases that affect the central and peripheral mechanisms that control respiration can have substantial effects on ventilation and the ability to maintain blood gases. Any drug that causes CNS depression may also result in respiratory depression, and almost all general anesthetic agents produce a dose-related decrease in ventilation. Opioids and benzodiazepines have been well documented to cause dose-dependent respiratory depression and impaired ventilatory response to hypoxemia and hypercapnia.1 Doxapram, on the other hand, is a CNS stimulant that

1. Lumb AB, editor: Control of breathing. In Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 51-72. 2. Blanco CE: Maturation of fetal breathing activity, Biol Neonate 65 (3–4):182-188, 1994. 3. Nogués MA, Roncoroni AJ, Benarroch E: Breathing control in neurologic diseases, Clin Auton Res 12(6):440-449, 2002. 4. Richter DW, Smith JC: Respiratory rhythm generation in vivo, Physiol 29(1):58-71, 2014. 5. Bianchi AL, Denavit-Saubie M, Champagnat J: Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters, Physiol Rev 75(1):1-45, 1995. 6. Levitsky MG, editor: Control of breathing. In Pulmonary physiology, ed 9, New York, 2018, McGraw Hill, pp 206-233. 7. West JB, Luks AM, editor: Gas transport by the blood. In West’s respiratory physiology: the essentials, ed 10, Philadelphia, 2016, Wolters Kluwer, pp 87-107. 8. Horn EM, Waldrop TG: Suprapontine control of respiration, Respir Physiol 114(3):201-211, 1998. 9. Kinkead R, Tenorio L, Drolet G, Bretzner F, Gargaglioni L: Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing, Respir Physiol Neurobiol 204:3-13, 2014. 10. Lumb AB, editor: Pulmonary ventilation. In Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 73-88. 11. Nattie E, Li A: Central chemoreceptors: locations and functions, Compr Physiol 2(1):221-254, 2012. 12. Hatcher JD, Chiu LK, Jennings DB: Anemia as a stimulus to aortic and carotid chemoreceptors in the cat, J Appl Physiol 44(5):696-702, 1978. 13. Cloutier MM, Thrall RS: Control of respiration. In Koeppen BM, Stanton BA, editors: Berne & Levy physiology, ed 7, Philadelphia, 2018, Elsevier, pp 489-497. 14. Smith CA, Rodman JR, Chenuel BJA, Henderson KS, Dempsey JA: Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors, J Appl Physiol 100(1):13-19, 2006. 15. Lumb AB, editor: Airway disease. In Lumb AB, editor: Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 389-405. 16. McMullan S, Pilowsky PM: The effects of baroreceptor stimulation on central respiratory drive: a review, Respir Physiol Neurobiol 174(1-2): 37-42, 2010.

15 Oxygen Therapy Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC

KEY POINTS • Tissue hypoxia occurs in a variety of critical illnesses. Oxygen supplementation can improve oxygen delivery and decrease the incidence of lactic acidosis. • Supplemental oxygen administration should be provided whenever a patient’s PaO2 is less than 70 mm Hg or their oxygen saturation (SpO2) is less than 93% on room air. • Noninvasive means of oxygen supplementation, including flow-by, mask, hood, high-flow nasal cannula and oxygen cages, are simple ways to provide an oxygen-enriched environment to a critical patient.

• High-flow nasal oxygen cannula and machines are available from human medical supply sources for use in veterinary patients and can improve oxygenation in severely hypoxemic animals. • Tracheal oxygen supplementation provides a higher FiO2 than nasal or noninvasive means of oxygen therapy, but it is technically slightly more difficult and has greater inherent risks to the patient.

In clinical medicine the term hypoxia is defined as a decrease in the level of oxygen supply to the tissues, whereas hypoxemia strictly refers to inadequate oxygenation of arterial blood and is defined as a PaO2 less than 80 mm Hg (at sea level) (see Chapter 16, Hypoxemia). Because hypoxemia reduces the oxygen content of the arterial blood (CaO2), it may result in tissue hypoxia. Oxygen delivery to the tissues (DO2) is dependent on the product of cardiac output and CaO2 (Box 15.1); as such, increases in cardiac output can prevent tissue hypoxia in hypoxemic patients. Hypoxemia can occur as a result of hypoventilation, ventilation– perfusion mismatch, diffusion impairment, decreased oxygen content of inspired air, and intrapulmonary shunt (see Chapter 16, Hypoxemia). Global oxygen delivery is often reduced in systemic illnesses such as sepsis, systemic inflammatory response syndrome, anemia, and acid-base imbalances.

indicated in patients with a PaO2 less than 70 mm Hg or SaO2 less than 93% on room air or if the patient’s effort at breathing is increased and at risk of respiratory fatigue.1 Oxygen supplementation is also indicated in patients with other causes of low DO2 such as cardiovascular instability or anemia in an effort to prevent tissue hypoxia. Oxygen therapy can be divided into noninvasive and somewhat invasive administration techniques. The type of oxygen supplementation method of delivery is largely dependent on each patient’s individual needs and tolerance, patient size, the degree of hypoxemia, the level of fraction of inspired oxygen (FiO2) desired, the anticipated length of oxygen supplementation required, clinical experience and skill, and equipment and monitoring available.2

ARTERIAL OXYGEN CONTENT

A variety of methods for oxygen supplementation exist. Ideally, all methods include some kind of humidification source in order to avoid drying and irritation of the nasal mucosa and airways if long-term oxygen therapy is required. The administration of nonhumidified oxygen for more than several hours will result in drying and dehydration of the nasal mucosa, respiratory epithelial degeneration, impaired mucociliary clearance, and increased risk of infection.2 A supplemental oxygen source can easily be humidified by bubbling the delivered oxygen through a bottle of sterile saline or water.2 As oxygen is bubbled through the liquid, it becomes humidified and accumulates above the surface of the solution. The gas that collects can then be delivered through a length of oxygen tubing to the patient’s oxygen source, whether it is a mask or tube into some component of the respiratory tract. Commercial bubble humidifiers are readily available and can be a convenient way to provide humidified oxygen; however, they may result in inadequate humidification at high flow rates.3,4 Highflow oxygen delivery systems provide a heat source to air-oxygen

Arterial oxygen content depends on the concentration of hemoglobin and the binding affinity or degree of oxygen saturation (SaO2) of the hemoglobin present. The majority of arterial oxygen is delivered to tissues while bound to hemoglobin. A small fraction is delivered as dissolved (or unbound [0.003 3 PaO2]) in plasma (see Box 15.1). Provision of supplemental oxygen by increasing the fraction of inspired oxygen over 21% is an effective means of increasing both bound and unbound oxygen in arterial blood, provided that a pulmonary parenchymal shunt is not present.1

INDICATIONS FOR OXYGEN THERAPY Oxygen supplementation aims to increase CaO2, which is of particular benefit to the hypoxemic animal but is considered of benefit to all patients at risk of tissue hypoxia. Supplemental oxygen administration is

METHODS OF OXYGEN ADMINISTRATION Humidification

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BOX 15.1  Equation of Oxygen Delivery (DO2) DO2 5 Q 3 CaO2 Where Q 5 cardiac output and CaO2 5 arterial oxygen content and is calculated as: CaO2 5 [1.34(ml O2/g) 3 SaO2 (%) 3 Hemoglobin (g/dl)] 1 [PaO2(mm Hg) 3 0.003 (ml O2/dl/mm Hg)]

admixtures and improve humidification of oxygen delivered to the patient5 without the adverse effects of desiccating the nasal mucosa.

Noninvasive Methods Flow-by Oxygen Flow-by oxygen supplementation is one of the simplest techniques to utilize in an emergent patient. Flow-by oxygen provides an increased concentration of oxygen to the patient when a length of oxygen tubing (ideally connected to a humidified oxygen source although not essential for short-term therapy) is held adjacent to or within 2 cm of a patient’s nostril.6 An oxygen flow rate of 2 to 3 L/min generally provides an FiO2 of 25% to 40%.7 An advantage of this technique is that it is generally well tolerated by most patients and can be used while initial triage and assessment are being performed. Because this technique also delivers a large quantity of oxygen to the surrounding environment, it is thus wasteful and not appropriate or economical for long-term use.

Face Mask Short-term oxygen supplementation can be administered by placing a face mask over a patient’s muzzle, then delivering humidified oxygen or tank oxygen in a circle rebreathing or a nonrebreathing circuit. With a tight-fitting face mask, flow rates of 8 to 12 L/min can provide an FiO2 of up to 50% to 60%.6,7 With loose-fitting face masks, higher flow rates of 2 to 5 L/min are recommended, depending on the size of the patient and degree of hypoxemia. With a tight-fitting face mask, rebreathing of CO2 can occur. The face mask should be vented periodically or changed to a looser face mask or alternate means of oxygen supplementation as soon as possible. Awake and coherent patients often do not tolerate oxygen delivered by face mask for long periods. An attendant must be present to ensure that the mask does not become detached and that the patient does not struggle or damage its eyes with the edge of the mask.6,7 Advantages of this technique are that minimal equipment is required and that the patient can be simultaneously treated and evaluated in emergent situations.

Oxygen Hood Several varieties of oxygen hoods are available from commercial manufacturers or can be easily made in hospital with cling film (e.g., Saran Wrap), tape, and a rigid Elizabethan collar. To create an oxygen hood, the front of a rigid Elizabethan collar is covered with lengths of cling film taped in place. A small portion of the front is left open to room air to allow the hood to vent. The collar is then placed over the patient’s neck and secured snugly. A length of oxygen tubing is placed through the back of the collar and taped to the side of the collar so that it doesn’t become dislodged with patient movement. Once the oxygen hood has been flooded with oxygen (1 to 2 L/min), oxygen flow rates of 0.5 to 1 L/min typically will deliver an FiO2 of 30% to 40%,8,9 depending on the size of the patient and how tightly fitted the collar is around the patient’s neck. With extremely small patients, such as toy breeds or neonates, the entire patient can be placed into the collar for a homemade oxygen tent or mini-cage. Some patients will not tolerate the collar and can become hyperthermic. If left unvented, CO2 and

moisture can accumulate within the hood and contribute to patient distress. Overall, an oxygen hood is an economical and practical means of supplemental oxygen administration and is generally well tolerated by most patients.

Oxygen Cage Supplemental oxygen can be delivered into a Plexiglas box to administer higher FiO2 concentrations than nasal, hood, or flow-by oxygen.8,9 Oxygen cages that control oxygen concentration, humidity, and temperature are available from commercial sources. The cages are also vented to decrease buildup of expired CO2. Oxygen cages can be manufactured from human pediatric incubator units into which humidified oxygen is supplied through a length of oxygen tubing. FiO2 levels can reach up to 60% or higher, depending on the size of cage and patient and oxygen flow rate, but typically are maintained at 40% to 50%.2,8,9 Oxygen cages are very useful, but they are an expensive means of administering supplemental oxygen because oxygen within the cage is let out into the external environment whenever the cage is opened. In some patients, hyperthermia can develop if the temperature within the cage is not maintained at 70°F (22°C).8,9 Ice packs can be placed within an oxygen cage to decrease ambient temperature, but they should not be placed directly on the patient because peripheral vasoconstriction can potentially exacerbate hyperthermia. Although many authors describe lack of direct patient access as a disadvantage of this oxygen supplementation technique, the use of continuous monitoring of pulse oximetry, blood pressure, and electrocardiogram allow patient monitoring through the Plexiglas cage doors.8,9

Invasive Methods Nasal Prongs Human nasal prongs can be used in medium and large dogs. They are easy to place, relatively inexpensive, and well tolerated by most dogs. The disadvantages include the ease with which the animal can dislodge the nasal prongs and the unknown FiO2 they supply. It is likely that nasal prongs would provide an FiO2 similar to or possibly higher than flow-by oxygen but less than that provided with a nasal oxygen catheter.

Nasal and Nasopharyngeal Oxygen If supplemental oxygen is going to be required for more than 24 hours, placement of a nasal or nasopharyngeal oxygen catheter should be considered. Nasal oxygen catheters are fairly simple to place, require minimal equipment, and are generally well tolerated by most patients.9 Oxygen insufflation catheters can be placed into the nasal cavity or directly into the nasopharyngeal region by a similar technique. To place a nasal oxygen catheter, the patient’s nasal passage should be anesthetized first with topical 2% lidocaine or proparacaine. Next, the tip of a 5- to 10-French (depending on patient size) red rubber or polypropylene catheter should be premeasured. To approximate the distance to advance a nasal oxygen catheter, it should be premeasured from the nose to the level of the lateral canthus of the eye and the distance marked on the tube using a permanent marker. The tip of the tube is lubricated, and the tube is gently inserted into the ventral nasal meatus to the level of the mark on the tube. To enter the ventral meatus, it may be necessary to angle the tube ventromedially when inserted. The tube can be secured adjacent to the nostril with suture or staples. The length of tube can then be secured to the lateral maxilla or between the patient’s eyes with suture or staples. To help prevent patient intolerance of the tube, be sure to avoid securing the tube to the patient’s whiskers. Oxygen should be provided from a humidified oxygen source to avoid drying and irritation of the nasal mucosa. A large range of FiO2 can be provided by nasal catheters, depending on the size

CHAPTER 15  Oxygen Therapy of the animal, respiratory rate, and panting or mouth breathing.8-11 Flow rates of 50 to 150 ml/kg/min can provide 30% to 70% FiO22,10,11 (Table 15.1). Higher flow rates can be irritating to the patient and cause sneezing. Total oxygen flow rates provide similar tracheal FiO2 when provided through one catheter or divided between two nasal catheters.8-11 Sneezing and patient intolerance can be alleviated in most cases with reapplication of a topical anesthetic or advancement of the nasal catheter into the nasopharyngeal region. The method to place a nasopharyngeal catheter is almost identical to the placement of a catheter into the nasal meatus, with the exception of the anatomic landmark of where to premeasure the tube. After application of the topical anesthetic, the tip of the catheter is placed at the ramus of the mandible and marked at the tip of the nose (Fig. 15.1). The lubricated tube is then placed ventromedially into the ventral nasal meatus. To facilitate passage of the tube ventrally and medially to the turbinates, the lateral aspect of the nostril should be pushed medially, and the patient’s nasal philtrum pushed dorsally as the tube is passed. Once the tube has been passed to the level of the mark on the tube, it can be secured to the patient’s face in an identical manner as the nasal oxygen catheter. Overzealous pressure as either tube is placed can result in epistaxis. After placement of a nasal or nasopharyngeal catheter, an Elizabethan collar should be placed to help avoid iatrogenic tube dislodgement by the patient. A length of oxygen tubing attached to a humidified oxygen source can be attached to the proximal end of the nasal tube with a cut 1-ml syringe or Christmas tree adapter.

TABLE 15.1  Nasal Oxygen Flow Rates and

Associated Tracheal FiO27

Total Oxygen Flow Rate (ml/kg/min) 50

Tracheal FiO2 (%) 29.8 6 5.6

100

37.3 6 5.7

200*

57.9 6 12.7

400*

77.3 6 13.5

Note: The 400 ml/kg/min flow rate was achieved by bilateral nasal oxygen catheters each at 200 ml/kg/min. *Patient discomfort is often noted with flow rates above 100 ml/kg/ min.

Fig. 15.1  Measurement of a red rubber catheter to the ramus of the mandible in preparation for placement of a nasopharyngeal oxygen catheter.

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High-Flow Nasal Oxygen High-flow oxygen devices12 are available from human medical sources and have been used with success in small animal patients.3,5,13 The high-flow oxygen system mixes medical grade air with an oxygen source and then heats it with a water source to provide humidification. The heated, humidified air-oxygen admixture is then passed through a membrane prior to delivery with various sized nasal prongs and circuit tubing, depending on patient size. Manufacturer recommendations suggest that nasal prong size should be no larger than 50% of the diameter of the patient’s nares, to allow for adequate removal of exhaled gases.3 With high-flow oxygenation methods, FiO2 and flow rates can be adjusted from 21%–100% and 25–60 L/min, respectively.13 The recommended starting flow rate for use in clinical patients is 0.4–2.0 L/kg/min for optimal tolerance.13 High-flow nasal oxygen has the ability to provide a higher FiO2 than other nasal oxygen administration techniques as well as the potential to provide continuous positive airway pressure. See Chapter 31, High Flow Nasal Oxygen for more details on this technique.

Transtracheal Oxygen Placement of a catheter directly into the trachea is an effective means of administering increased FiO2 to patients that are intolerant of nasal or hood oxygen, are panting or displaying open-mouthed breathing, or have an upper airway obstruction. Although this technique is more labor intensive and requires a higher degree of skill than placement of a nasal catheter, higher FiO2 with a degree of continuous airway pressure is provided14 and can be beneficial for patients who require a higher degree of supplemental oxygen than that provided with a nasal catheter but who do not require mechanical ventilation, such as animals with severe bronchopneumonia. The use of these techniques in patients with upper airway obstruction should be performed with caution as the animal may not be able to exhale adequately and pulmonary overdistension can occur. It is generally used as a very short term, lifesaving intervention while a patent airway is secured in these patients. Two methods of tracheal oxygen supplementation have been described. The first method uses a through the needle large-bore catheter placed percutaneously through the skin and underlying tissues directly into the trachea.8,14 The patient’s ventral cervical region should be clipped from just proximal to the larynx to the thoracic inlet and laterally off of midline. To avoid iatrogenic introduction of bacteria and debris into the tracheal lumen, aseptic technique must be followed at all times. The clipped area should be aseptically scrubbed. A small bleb of 2% lidocaine should be placed at the level of the third through fifth tracheal ring, infiltrating the subcutaneous tissues and skin as the needle is backed out. The area is aseptically scrubbed again. Wearing sterile gloves, the patient’s trachea is gently palpated, then grasped in the operator’s fingers for stabilization. A small nick incision can be made through the skin with a #11 scalpel blade to decrease tissue drag as the catheter is inserted. The needle of the catheter is then inserted through the skin (with or without the nick incision), through the subcutaneous tissue and sternohyoideus muscle, and into the trachea. A pop will be felt as the needle enters the trachea. Once in place, the catheter with stylette is inserted through the needle into the tracheal lumen. The needle is then removed from the trachea once the catheter has been inserted to its hub. Depending on the size of the animal, the distal end of the catheter may run to the level of the carina. The catheter can be connected to a humidified oxygen source with a cut 1-ml syringe or Christmas tree adapter and oxygen run at a flow rate of 50 to 150 ml/kg/min.14 The catheter should be secured to the neck with lengths of white tape. Caution must be exercised to monitor the patient carefully because ventral flexion of the neck or excessive skin

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folds can cause kinking of the catheter and catheter occlusion. Excessive skin folds can be pulled dorsally and secured on dorsal cervical midline with several horizontal mattress sutures until the catheter is no longer required. The second method of intratracheal oxygen supplementation is more invasive and requires heavy sedation or the administration of a short-acting anesthetic agent such as propofol or fentanyl/diazepam (see Chapters 132 and 133). The patient’s ventral cervical region should be clipped and aseptically scrubbed in an identical manner as listed earlier. The area should be aseptically draped with sterile field towels and infiltrated with a local anesthetic (2% lidocaine, 1 to 2 mg/kg). A vertical skin incision should be made over the third through fifth tracheal rings. The subcutaneous tissues and sternohyoid muscle should be bluntly dissected with a curved hemostat or tips of a Metzenbaum scissors until the trachea is visible. A small incision is then made in between the fourth and fifth tracheal rings with a #11 scalpel blade, taking care to avoid cutting more than 50% circumference of the trachea. A curved hemostat is used to open the hole between tracheal rings, and a grooved director (from a spay pack) is inserted into the tracheal lumen. A large-bore multifenestrated catheter with a stylette is then inserted into the tracheal lumen along the grooved director. Once the catheter is inserted, the grooved director and catheter stylette can be removed and the catheter secured in place. A 4 3 4 square of sterile gauze with antimicrobial ointment should be placed over the incision and the catheter secured with lengths of white tape. The cranial and caudal edges of large skin incisions should be sutured with nonabsorbable suture. The benefit of this technique is that larger catheters can be inserted and administer continuous airway pressure at higher oxygen flow rates than other methods of oxygen supplementation. Oxygen flow rates of 50 ml/kg/min are required to achieve 40% to 60% FiO2.14 This technique is well tolerated by many patients and is economical but has the inherent risks associated with sedation, general anesthesia, and introduction of bacteria directly into the tracheal lumen. Jet lesions and damage to the trachea with tracheitis can occur with this technique.8

Hyperbaric Oxygen Hyperbaric oxygen administers 100% oxygen under supraatmospheric pressures (.760 mm Hg) to increase the percent of dissolved oxygen in the patient’s bloodstream by 10% to 20%.1,15 Dissolved oxygen can diffuse readily into tissues that are damaged and may not have adequate circulation. Hyperbaric oxygen has been recommended for the treatment of severe soft tissue lesions, including burns, shearing injuries, infection, and osteomyelitis. Ruptured tympanum and pneumothorax have been associated with the use of hyperbaric oxygen therapy. Hyperbaric oxygen is rarely used in veterinary medicine, given the expense of the equipment and space required for a specialized “dive chamber” in which to place the patients during treatment. An additional disadvantage is that once the dive chamber has been pressurized to supraatmospheric levels, the chamber cannot be opened to gain patient access should complications occur.

COMPLICATIONS OF OXYGEN THERAPY The administration of supplemental oxygen is not an innocuous treatment. Hypercapnia is the primary stimulus for respiration in normal patients. In patients with chronic respiratory disease and hypercapnia, however, hypercapnic respiratory drive can be diminished or lost and the patient becomes largely dependent on hypoxia as a respiratory

stimulant. The administration of supplemental oxygen to a chronically hypercapnic patient depresses the hypoxic respiratory drive and can result in severe hypoventilation and respiratory failure. Mechanical ventilation may be necessary to treat the severe hypercapnia and hypoxia that develop.1 This “blue bloater” syndrome is an uncommon occurrence in small animal medicine and is best described in human chronic obstructive pulmonary disease patients.

Oxygen Toxicity Oxygen therapy can be directly toxic to the pulmonary epithelium, and it is important to avoid prolonged exposure to high FiO2 levels. As a general rule, an FiO2 level of more than 50% should not be administered for longer than 24 to 72 hours to avoid pulmonary oxygen toxicity.16,17 See Chapter 8, Oxygen Toxicity for a more detailed discussion of this topic.

REFERENCES 1. Tseng LW, Drobatz KJ: Oxygen supplementation and humidification. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Elsevier, pp 205-213. 2. Camps-Palau MA, Marks SL, Cornick JL: Small animal oxygen therapy, Comp Contin Educ Pract Vet 21(7):587, 2000. 3. Daly JL, Guenther CL, Haggerty JM, et al: Evaluation of oxygen administration with a high-flow nasal cannula to clinically normal dogs, Am J Vet Res 78(5):624, 2017. 4. Darin J, Broadwell J, MacDonnell R: An evaluation of water-vapor output from four brands of unheated, prefilled bubble humidifiers, Respir Care 27(1):41, 1982. 5. Keir I, Daly J, Haggerty J, Guenther C: Retrospective evaluation of the effect of high flow oxygen therapy delivered by nasal cannula on PaO2 in dogs with moderate-to-severe hypoxemia, J Vet Emerg Crit Care 26(4):598, 2016. 6. Wong AM, Uquillas E, Hall E, et al: Comparison of the effect of oxygen supplementation using flow-by or a face mask on the partial pressure of arterial oxygen in sedated dogs, N Z Vet J 67(1):36, 2019. 7. Loukopoulos P, Reynolds WW: Comparative evaluation of oxygen therapy techniques in anaesthetized dogs: face-mask and flow-by techniques, Aust Vet Practit 27(1):34, 1997. 8. Drobatz KJ, Hackner S, Powell S: Oxygen supplementation. In Bonagura JD, Kirk RW, editors: Current veterinary therapy XII: small animal practice, Philadelphia, 1995, WB Saunders, pp 175-179. 9. Loukopoulos P, Reynolds W: Comparative evaluation of oxygen therapy techniques in anaesthetized dogs: intranasal catheter and Elizabethan collar canopy, Aust Vet Practit 26(4):199, 1996. 10. Marks SL: Nasal oxygen insufflation, JAAHA 35(5):366, 1999. 11. Dunphy ED, Mann FA, Dodam JR, et al: Comparison of unilateral versus bilateral catheters for oxygen administration in dogs, J Vet Emerg Crit Care 12(4):245, 2002. 12. Matthay MA: Saving lives with high-flow nasal oxygen, N Engl J Med 372(23):2225, 2015. 13. Jagodich TA, Bersenas AME, Bateman SW, et al: Comparison of high flow nasal cannula oxygen administration to traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29:246, 2019. 14. Mann FA, Wagner-Mann C, Allert JA, Smith J: Comparison of intranasal and intratracheal oxygen administration in healthy awake dogs, Am J Vet Res 53(5):856, 1992. 15. Braswell C, Crowe DT: Hyperbaric oxygen therapy, Compend Contin Educ Vet 34:E1–E5, 2012. 16. Jackson RM: Pulmonary oxygen toxicity, Chest 86(6):900, 1985. 17. Mensack S, Murtaugh R: Oxygen toxicity, Compend Contin Educ Vet 21(4):341, 1999.

16 Hypoxemia Steve C. Haskins, DVM, MS, DACVAA, DACVECC, Deborah C. Silverstein, DVM, DACVECC

†

KEY POINTS • Hypoxemia is defined as a partial pressure of oxygen of less than 80 mm Hg or arterial blood hemoglobin saturation of less than 95%. • When cyanosis is manifested as a sign of hypoxemia, it is always a late sign of severe hypoxemia. • There are three causes of hypoxemia: low inspired oxygen concentration, hypoventilation, and venous admixture. • There are four causes of venous admixture: low ventilationperfusion regions, small airway and alveolar collapse or infiltration

(no ventilation-perfusion regions), diffusion defects, and anatomic right-to-left shunts. • There are several methods to assess the severity of hypoxemia, including the physical examination, alveolar to arterial oxygen gradient, PaO2:FiO2 ratio, SaO2:FiO2 ratio, oxygenation index, and oxygen saturation index.

Hypoxemia is generally defined as an arterial partial pressure of oxygen (PaO2) of less than 80 mm Hg or an arterial blood hemoglobin saturation (SaO2 or SpO2) of less than 95%. Serious, potentially lifethreatening hypoxemia is generally defined as a PaO2 less than 60 mm Hg or an SaO2 or SpO2 of less than 90%. Atmospheric oxygen is normally ventilated into the alveoli; it then diffuses across the respiratory membrane along partial pressure gradients into the plasma. Anything that interferes with one or more of these processes will decrease the plasma PO2. Oxygen diffuses from the plasma into the red blood cell and binds to hemoglobin. Both the PaO2 and SaO2 are affected by the same pulmonary processes, and SaO2 or SpO2 is often used as a surrogate marker of PaO2. Blood oxygen can also be expressed as a concentration or content (milliliters of oxygen per 100 ml of whole blood), but this parameter is primarily determined by hemoglobin concentration and is not considered to be a marker of hypoxemia per se.

RECOGNITION OF HYPOXEMIA

COLLECTION OF BLOOD SAMPLES FOR IN VITRO MEASUREMENT Arterial blood should be used for an assessment of pulmonary function. Venous blood comes from the tissues and is more a reflection of tissue function than lung function. The details of blood sampling and storage before analysis have been detailed elsewhere, and further details can be found in Chapter 202, Blood Gas Sampling).1-3 The blood sample must be taken as anaerobically as possible (exposure to air will change the partial pressures of both O2 and CO2) and analyzed as soon as possible. (In vitro metabolism and diffusion of gases into and through the plastic of the syringe will change the partial pressures of both O2 and CO2.4) Excessive dilution with anticoagulant should be avoided.5

†

Author in memoriam

PaO2 The PaO2 is the partial pressure (the vapor pressure) of oxygen dissolved in solution in the plasma of arterial blood and is measured with a blood gas analyzer, usually with a silver anode/platinum cathode system in an electrolyte solution (polarography) separated from the unknown solution (the blood) by a semipermeable (to oxygen) membrane. The arterial PO2 (PaO2) is a measure of the ability of the lungs to move oxygen from the atmosphere to the blood. The normal PaO2 at sea level ranges between 80 and 110 mm Hg.

SpO2 Hemoglobin saturation with oxygen (SaO2) is the inevitable consequence of the increase in PaO2 during the arterialization of venous blood as it traverses the lung; PaO2 and SaO2 are directionally (though not linearly) related. Hemoglobin saturation with oxygen can be measured with a benchtop oximeter (SaO2) using many wavelengths of red to infrared light. Pulse oximeters use only two wavelengths (660 nm and 940 nm) and are designed to measure only oxygenated hemoglobin (SpO2) (see Chapter 184, Oximetry Monitoring).6,7 SpO2 is directionally, but not linearly, associated with PaO2 (Fig. 16.1) and therefore can be used as a surrogate marker of PaO2 (Table 16.1). The SO2/PO2 relationship is described by a sigmoid curve, the oxygen-hemoglobin dissociation curve (Fig. 16.1 and Table 16.1). There are several important clinical implications of this relationship. Most importantly, the difference between normoxemia and hypoxemia is only a few saturation percentage points (Table 16.1), and severe hypoxemia is only a few saturation percentage points below that. Small changes in SpO2 represent large changes in PaO2 in this region of the oxyhemoglobin dissociation curve. Second, severe hypoxemia is defined at a level when the hemoglobin is still 90% saturated. This may not seem fair, but it is the partial pressure of oxygen in the plasma, not hemoglobin saturation, that drives oxygen diffusion down to the mitochondria. PO2 is the driving force; SO2 (more specifically oxygen

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Hemoglobin saturation (%)

Oxyhemoglobin dissociation curves of different species

content) is the reservoir that prevents the rapid decrease in PO2 that would otherwise occur when oxygen diffuses out of the blood. Third, saturation measurements cannot detect the difference between a PaO2 of 100 and 500. This difference is important when monitoring and tracking the progress of animals breathing an enriched oxygen mixture. With these, and a few additional caveats, pulse oximeters noninvasively, continuously, and automatically monitor very well the parameter they were designed to measure—hypoxemia. Pulse oximeter readings are prone to error, and suspected hypoxemia should be corroborated with other clinical signs and an arterial blood gas analysis if necessary.

Cyanosis

Partial pressure of oxygen (PO2) Horse P5023.8

Dog P5028.7

Man

Cat

P5026.8

P5034.1

Fig. 16.1  Oxyhemoglobin dissociation curves for the horse, human, dog, and cat.8-11

TABLE 16.1  Correlation Between PaO2

and SaO2*

Hyperoxemia Normoxemia Hypoxemia Severe hypoxemia Life-threatening Hypoxemia

Grayish to bluish discoloration of mucous membranes commonly signals the presence of deoxygenated hemoglobin in the observed tissues. The observation of cyanosis is dependent on the visual acuity of the observer (some individuals can see it earlier than others), lighting (it is more readily detected in a well-lit room than in the shadows of a cage), and the type of lighting used (it is more readily detectable with incandescent as opposed to fluorescent lighting).12 In general, it requires an absolute concentration of deoxygenated hemoglobin to manifest sufficient cyanosis that everyone agrees to its existence; 5 gm/dl (arterial blood) is the commonly cited figure.13 This is important for two reasons. First, if a dog had a hemoglobin concentration of 15 gm/dl, cyanosis would manifest when the arterial blood saturation decreased to 67% (equivalent to a PaO2 of about 37 mm Hg (Fig. 16.1). When cyanosis is manifested as a sign of hypoxemia, it is always a late sign of severe hypoxemia. Second, if an animal is anemic—for instance, having a hemoglobin concentration of 5 gm/dl—it would die of hypoxemia and the resultant tissue hypoxia long before manifesting cyanosis.

MECHANISMS OF HYPOXEMIA

PaO2 mm Hg .125 80–125 ,80 ,60

SaO2% 100 95–99 ,95 ,90

,30

,40

*This chart represents rounded approximations of the relationship between PaO2 and SaO2 in people and dogs. Cats have a right-shifted curve with an average P50 of 34, in comparison, and the corresponding SaO2 values are lower (see Fig. 16.1).

There are three causes of hypoxemia: low inspired oxygen concentration, hypoventilation, and venous admixture (Fig. 16.2; Table 16.2 and Table 16.3). A fourth cause of hypoxemia can be a reduced venous oxygen content14-18 secondary to low cardiac output or sluggish peripheral blood flow (shock) or high oxygen extraction by the tissues (e.g., seizures). When venous oxygen content is very low, it takes more oxygen and more time for the capillary blood to be arterialized. This lowers alveolar PO2 (PAO2) and therefore PaO2 will be lowered. In practice, the impact of low venous oxygen and blood flow is often offset by a decrease in shunt fraction, which offsets the decrease in PaO2.14,19 Low venous oxygen is verified by measuring central or mixed venous oxygen.

Hypoxemia

Decreased efficiency of transport of oxygen from the alveoli to the pulmonary capillaries

Low alveolar oxygen due to reduced delivery of oxygen to the alveoli

Low V/Q regions Low inspired oxygen

Zero V/Q regions

Hypoventilation Diffusion impairment

Right-to-left A-V shunt

Fig. 16.2  Categorical causes of hypoxemia.

Low alveolar oxygen due to increased extraction of oxygen from the alveoli (see text)

Low venous oxygen content

CHAPTER 16  Hypoxemia

TABLE 16.2  Primary Physiologic Causes

of Hypoxemia Causes of Hypoxemia

Recognition and Examples

Low inspired oxygen

Inspection of the apparatus Improper functioning apparatus to which the animal is attached Depleted oxygen supply; altitude Global Elevated PaCO2, end-tidal hypoventilation CO2, or PvCO2 Neuromuscular dysfunction; airway obstruction, abdominal distention, chest wall dysfunction, pleural space filling defect Venous See Table 16.3 admixture

Treatment Oxygen supplementation if at altitude Disconnect patient from mechanical apparatus and repair/replace apparatus Oxygen supplementation, positive pressure ventilation, remove/bypass obstruction, decompress abdomen, close or stabilize chest wall, perform thoracocentesis See Table 16.3

CO2, carbon dioxide; PvCO2, venous PCO2.

TABLE 16.3  Venous Admixture Mechanisms of Venous Admixture Low V/Q regions

Atelectasis (no V/Q regions) Diffusion defects

Right-to-left shunts

Causes Moderate to severe diffuse lung disease (edema, pneumonia, hemorrhage) Severe to very severe diffuse lung disease (edema, pneumonia, hemorrhage) Moderate to severe, diffuse lung disease (oxygen toxicity, smoke inhalation, ARDS) Right-to-left PDA and VSD; intrapulmonary A-V anatomic shunts

Notes Common; responsive to oxygen therapy Common; not responsive to oxygen but responsive to PPV Uncommon; partially responsive to oxygen

Uncommon; not responsive to oxygen or PPV; surgery possible

A-V, arterial to venous; ARDS, acute respiratory distress syndrome; low V/Q ratio, low ventilation compared with blood flow because of either low regional ventilation or high regional perfusion; PDA, patent ductus arteriosus; PPV, positive pressure ventilation; Q, perfusion; V, ventilation; VSD, ventricular septal defect.

Low Inspired Oxygen Low inspired oxygen must be considered any time an animal is attached to mechanical apparatus such as a face mask, anesthetic circuit, or ventilator or is in an enclosed environment such as an oxygen cage. Inspired or ambient oxygen concentration can be measured with a variety of commercially available oxygen meters. The problem can often be identified by inspection and verification of the improper operation of the mechanical device and remedied by replacing the device with one that is operating properly. The decrease in inspired oxygen concentration decreases the alveolar oxygen concentration and subsequently arterial blood oxygenation.

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High altitude is another cause of low inspired oxygen. Atmospheric oxygen concentration is 21% at any altitude, but as altitude increases, barometric pressure decreases and the partial pressure of oxygen in the atmosphere (PatmO2) represented by 21% also decreases. Normal individuals living at higher altitudes have lower PaO2 values and compensate to some extent by hyperventilating.

Hypoventilation Hypoventilation is defined by an elevated PaCO 2 (45 mm Hg) or one of its surrogate markers: end-tidal CO 2 (usually about 5 mm Hg lower than PaCO2) or central venous PCO2 (usually about 5 mm Hg higher than PaCO2). See Chapter 17 for further discussion of this topic. Alveolar oxygen is the balance between the amount of oxygen being delivered to the alveoli (inspired oxygen concentration and alveolar minute ventilation) and the amount of oxygen being removed from the alveoli by the arterialization of venous blood (ultimately, tissue metabolism). A decrease in alveolar minute ventilation (hypoventilation) decreases the delivery of oxygen to the alveoli and subsequently to the blood leading to hypoxemia. Increasing the inspired oxygen concentration is very effective in preventing hypoxemia secondary to hypoventilation. There are only four gases of note in alveoli: O2, CO2, water vapor, and nitrogen. The partial pressure of alveolar oxygen (PAO2) can be determined by the alveolar air equation (see below). The normal alveolar composition of gases when breathing room air at sea level is water vapor 50 mm Hg (fixed; alveolar gases are always 100% saturated at body temperature), CO2 ,40 mm Hg (regulated by the brainstem respiratory control center; varies between species), O2 105 mm Hg, and nitrogen 560 mm Hg.19 If an animal were to hypoventilate to a PaCO2 of 80 mm Hg, the water vapor pressure and nitrogen levels would remain unchanged, but the oxygen would fall to about 65 mm Hg and the patient would become hypoxemic. When breathing 100% oxygen for a time to allow the elimination of nitrogen from the readily mobilized stores (alveoli, blood, and vessel-rich tissues), the alveolar water vapor and CO2 levels would not change but nitrogen would decrease to near 0 and oxygen would increase to near 665. If an animal were to severely hypoventilate while breathing 100% oxygen, the alveolar CO2 could theoretically rise to about 550 mm Hg before the alveolar oxygen decreased to a level that would lead to hypoxemia (PaO2 ,80 mm Hg). Hence, hypoventilation is a cause of hypoxemia in patients breathing room air but not in patients breathing enriched oxygen mixtures. Further hypoxemia as a result of hypoventilation is readily resolved with oxygen therapy.

Venous Admixture Venous admixture is all the ways in which venous blood can get from the right side to the left side of the circulation without being properly oxygenated. Blood flowing through some regions of the lung may be suboptimally oxygenated or may not be oxygenated at all. When this “venous” blood admixes with optimally arterialized blood flowing from the more normally functioning regions of the lung, the net oxygen content and PaO2 are reduced. There is typically a small amount of venous admixture in the normal lung (,5%).20 There are four causes of venous admixture (see Table 16.2): (1) low ventilation-perfusion regions of the lung, (2) small airway and alveolar collapse (atelectasis or zero ventilation but perfused lung units), (3) diffusion defects, and (4) anatomic right-to-left shunts. Most diffuse lung disease will have a variable combination of several of these mechanisms; however, one often predominates. These mechanisms have important therapeutic implications. It is also inappropriate to use the term ventilation-perfusion (V/Q) mismatch as a cause of hypoxemia

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without some adjective (i.e., “high” or “low”) because not all types of V/Q mismatch contribute to hypoxemia.

Regions of Low Ventilation-Perfusion (V/Q) Ratio Alveoli with a low ventilation-perfusion (V/Q) ratio occur secondary to small airway narrowing or alveolar fluid accumulation which impairs ventilation, but some gas exchanged is maintained. Because it is a ratio, a low V/Q could also be caused by an increased Q, such as that which occurs in pulmonary thromboembolism. Small airway narrowing may be caused by bronchospasm, fluid accumulation along the walls of the lower airways, or epithelial edema. Like global hypoventilation, regional hypoventilation results in the reduced delivery of oxygen to alveoli (compared with that removed by the circulation) and a reduction in alveolar and arterial PO2. Poorly oxygenated blood from these capillary beds admixes with blood from more normally functioning regions of the lung, diluting and reducing the net oxygen concentration. This is a common mechanism of hypoxemia in moderate pulmonary disease. Like global hypoventilation, regional hypoventilation is very responsive to oxygen therapy.

2 µm BM FB

Ep

RBC

Alv IS

Diffusion Impairment Diffusion impairment as a result of a thickened respiratory membrane is an uncommon cause of hypoxemia. Capillaries meander through the interstitial septae, between alveoli, bulging first into one alveolus and then into the adjacent alveolus (Fig. 16.3). The interstitium between the endothelium and the epithelium on the “bulge side” or “active side” of the capillary (encompassing two-thirds to three-fourths of the circumference of the capillary) is either nonexistent (the endothelial and epithelial basement membranes are one and the same) or is functionally nonexistent, and no fluid accumulates here (Fig. 16.3). This “active side” of the septa constitutes the gas exchange surface. Transcapillary fluid leaks occur on the thick (“service”) side of the capillary but do not accumulate here either. Fluid is forced (by the low compliance of the interstitial tissues and lymphatics) upward toward the loose interstitial tissues surrounding the medium-sized arterioles, venules, and bronchioles toward the hilus of the lung.21 Eventually, these interstitial fluids build up enough pressure that they break into the airways and distribute along the airway surfaces, causing first airway narrowing and increased alveolar surface tension (low V/Q units) and then causes small airway and alveolar collapse (zero V/Q units), as discussed earlier and without a diffusion defect per se. In order for a diffusion defect to occur, the flat type I alveolar pneumocytes have to be damaged by inhalation or inflammatory injury. In the healing process, the thick, cuboidal type

Alv

EN

Regions of Zero V/Q Small airway and alveolar collapse (regions of zero V/Q) occurs in diseases associated with the accumulation of airway fluids (transudate, exudates, or blood). Small airway and alveolar collapse is common in the dependent regions of the lung if animals are recumbent for prolonged periods of time (e.g., general anesthesia or coma) in the absence of an occasional deep (sigh) breath. Blood flowing through these areas will not be arterialized. This condition has been referred to as “physiologic shunt” (blood flowing past nonfunctional alveoli) to differentiate it from a “true or anatomic shunt,” where blood completely bypasses all alveoli (whether they’re functional or not). Hypoxemia due to zero V/Q regions is not responsive to oxygen therapy because oxygen cannot get to the gas exchange surface. Collapsed small airways and alveoli can only be “reactivated” by increasing airway or transpulmonary pressure, by taking a deep spontaneous breath, or by augmentation of airway pressure. This is a common mechanism of hypoxemia in severe pulmonary disease as proven by the fact that positive pressure ventilation and positive end-expiratory pressure can be very effective at improving lung oxygenating efficiency.

End

Fig. 16.3  Electron micrograph of alveolar septum. Details of the interstitial space, the capillary endothelium, and alveolar epithelium. Thickening of the interstitial space is confined to the left of the capillary (the service side), whereas the total alveolar/capillary membrane remains thin on the right (the active side) except where it is thickened by the endothelial nucleus. Alv, alveolus; BM, basement membrane; EN, endothelial nucleus; End, endothelium; Ep, epithelium; FB, fibroblast process; IS, interstitial space; RBC, red blood cell. (From Lumb AB, Thomas CR: Nunn and Lumb’s applied respiratory physiology, ed 9, Oxford, 2021, Elsevier. Fig 1.8.)

II alveolar pneumocytes proliferate across the surface of the gas exchange surface. This can occur with oxygen toxicity or during progression of the acute respiratory distress syndrome.22 Such thickening of the gas exchange membrane represents a substantial diffusion defect until such time as the type II pneumocytes mature to type I pneumocytes. Diffusion defects are partially responsive to oxygen therapy.

Anatomic Shunts Anatomic shunts that cause hypoxemia are vascular abnormalities where the blood flows from the right side to the left side of the circulation, bypassing all alveoli in the process. This is not a common mechanism of hypoxemia and is most commonly found in young animals with congenital defects. This cause of hypoxemia is not responsive to either oxygen therapy or positive pressure ventilation. Some are amenable to surgical intervention.

ESTIMATING THE MAGNITUDE OF THE VENOUS ADMIXTURE In pulmonary parenchymal disease, lungs often fail to effectively oxygenate arterial blood before their ability to get CO2 out fails. This is apparent from the rather common cooccurrence of hypocapnia and hypoxemia and is attributed to the fact that alveolar-capillary units that are working relatively well can easily compensate for those that are working relatively poorly with respect to CO2 elimination but not for oxygen intake. It is for this reason that it is important to evaluate PaCO2 and PaO2 separately. PaCO2 defines alveolar minute ventilation; PaO2 defines blood oxygenation. Given the specifics of the situation,

CHAPTER 16  Hypoxemia any combination of ventilation (normo-, hypo-, or hyperventilation) and oxygenation (normo-, hypo-, or hyperoxygenation) can coexist in a patient at a given time, and different combinations mandate different therapeutic strategies. Although PaO2 defines the status of blood oxygenation, the clinical significance of the measurement (the status of lung function; the magnitude of the venous admixture) can only be fully appreciated when PaO2 is referenced to the PaCO2 and the inspired oxygen at the time of measurement.

Alveolar-Arterial PO2 Gradient The alveolar-arterial PO2 gradient (A-a gradient) is the difference between the calculated PAO2 and the measured arterial PaO2. The A-a gradient is useful in assessing the oxygenation ability of the lungs while removing the effects of changes in minute ventilation (PaCO2). In order to calculate the PAO2, the alveolar air equation is used (Box 16.1). At sea level, breathing 21%, the alveolar air equation can be shortened to: PAO2 5 150 2 PaCO2 At different altitudes and inspired oxygen concentrations, the complete formula must be used. Once PAO2 has been calculated, the A-a gradient is calculated by subtracting the measured PaO2 from the calculated PAO2. When breathing room air, the usual A-a gradient is less than 10 mm Hg; values above 20 mm Hg are considered to represent decreased oxygenating efficiency (venous admixture). Unfortunately, the normal A-a gradient increases at higher inspired oxygen concentrations and may be as high as 100 to 150 mm Hg at an inspired oxygen concentration of 100%. As a result, the A-a gradient is of most value when assessing room air blood gases. The A-a gradient evaluates the magnitude of venous admixture; although hypoventilation will cause hypoxemia when breathing room air, it will not cause an abnormal A-a gradient.

PaCO2 1 PaO2 Added Value (“The 120 Rule”) When breathing 21% oxygen at sea level, the PaCO2 1 PaO2 added value calculation can identify the presence of venous admixture, in a manner similar to the A-a gradient. A normal PaCO2 of 40 mm Hg and a minimum PaO2 value for normoxemia of 80 mm Hg add to 120. An added value of less than 120 mm Hg suggests the presence of venous admixture, and the greater the discrepancy, the worse the lung function. If PaCO2 increases from 40 mm Hg to 60 mm Hg by hypoventilation, the PaO2 should decrease from 80 mm Hg to about 60 mm Hg if the animal does not have lung disease, and the addition of the two values will still equal 120. The conclusion is that the cause of the hypoxemia in this situation was purely hypoventilation. If instead the animal has a PaCO2 of 60 mm Hg and a PaO2 of 40 mm Hg, the added value is 100 (less than 120), and it can be concluded that the animal has lung dysfunction in addition to hypoventilation. This added value rule or “120 rule” can only be used when the patient is breathing 21% oxygen at near-sea level conditions. At altitude, atmospheric and alveolar and arterial PO2 and the “added value rule” need to be proportionately decreased.

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PaO2/FiO2 Ratio Many approaches have been suggested that could be used to compensate for the variation in A-a gradient associated with variation in inspired oxygen. The PaO2/fraction of inspired oxygen (FiO2) (or P/F) ratio is the easiest to calculate. The P/F ratio is calculated by dividing the measured PaO2 by the corresponding FiO2 as a decimal value. A normal P/F ratio is approximately 500 (PaO2 5 100 mm Hg, FiO2 5 0.21). If a patient is on 100% O2, their expected PaO2 would be 500 mm Hg. The P/F ratio can be very misleading when used at 21% inspired oxygen concentrations if PaCO2 values are elevated. PaCO2 values have been ignored in this calculation, but when breathing room air, changes in PaCO2 can have a significant impact on PaO2. It is recommended to use the “120 rule” or A-a gradient when evaluating room air blood gases and to use the P/F ratio if evaluating arterial blood gases from patients on supplemental oxygen.

SpO2/FiO2 Ratio The SpO2/FiO2 ratio (S/F) has been studied in dogs as a surrogate for the P/F ratio since it is faster, less invasive, can be measured continuously, and is associated with fewer complications than obtaining an arterial blood sample. S/F values in dogs recovering from surgery with or without supplemental oxygen or those with mild to moderate hypoxemia were moderately to well-correlated with the P/F ratio.23,24 However, it is important to consider the limitations of pulse oximetry stated above. The S/F ratio has been widely studied in several human patient populations with favorable results. In one large human study, an S/F ,315 corresponds with a P/F ,300 and an S/F ,235 with a P/F ,200.25

Oxygenation Index and Oxygen Saturation Index The oxygenation index (OI) is another means of evaluating oxygenation in ventilated patients. This technique takes into account the mean airway pressure (MAP) as a means of comparing patients with different degrees of ventilatory support by performing the following calculation: OI 5 MAP 3 FiO2 3 100/PaO2 A lower number indicates better lung function, and cutoffs have been developed in human medicine (e.g., OI .40 is an indication for extracorporeal membrane oxygenation).26 The OI may also be used for predicting outcome in human neonates.27 The oxygenation saturation index (OSI) replaces the PaO2 with SpO2 in the OI equation and is therefore less invasive and allows continuous measurement of oxygenation: OSI 5 MAP 3 FiO2 3 100/SpO2. It has been studied primarily in neonates with hypoxemic respiratory failure.28

Venous Admixture (Shunt) Calculation If a mixed venous blood sample (pulmonary artery) can be obtained, then venous admixture can be calculated as: Qs  / QT 5 (CcO2 2 CaO2) / (CcO2 2 C2 v O2)

BOX 16.1  Alveolar Air Equation PAO2 5 (PB-PH2O)*FiO2 – (PaCO2/RQ) PB 5 atmospheric pressure PH2O 5 partial pressure of water FiO2 5 concentration of oxygen in inspired air RQ 5 respiratory quotient (,0.8) n the ratio of CO2 produced to O2 consumed by the body PaCO2 5 measured value from the patient

Where QS is shunt fraction, QT is the cardiac output, QS/QT is the venous admixture expressed as a percent of cardiac output, CcO2 is the oxygen content of end-capillary blood, CaO2 is the oxygen content of arterial blood, and CvO2 is the oxygen content of mixed venous blood. Jugular venous blood is sometimes used as a surrogate for pulmonary arterial blood. Arterial and mixed venous PO2 is measured and oxygen content (ml/dl) is calculated as (1.34 3 Hb 3 SO2) 1 (0.003 3 PO2)

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where SO2 is percent hemoglobin saturation with oxygen. Capillary PO2 is assumed to be equal to calculated PAO2 and is used to calculate capillary oxygen content. PO2 is measured and SO2 is either measured (accuracy mandates a benchtop oximeter) or extrapolated from a standard oxyhemoglobin dissociation curve (which is the value reported on the printout from some blood gas analyzers), or can be derived by hand from an oxyhemoglobin dissociation curve such as in Fig. 16.1. Venous admixture is normally less than 5%.20 Values greater than 10% are considered to be increased and may increase to more than 50% in severe, diffuse lung disease. Although the equation shown earlier seems like a lot of math, it is considered to be the most accurate way to estimate venous admixture.29 If blood samples are taken while the patient is breathing room air, all the previously discussed categorical mechanisms of venous admixture are assessed. If blood samples are taken while the patient is breathing 100% oxygen, the low V/Q mechanism of hypoxemia is eliminated from the assessment and diffusion defects are minimized. In this usage, the formula is referred to as the “shunt” formula because it assesses the magnitude of the remaining two causes of venous admixture: “physiologic” shunts secondary to atelectasis and true “anatomic” shunts. Intermediate inspired oxygen concentrations and particularly changes in inspired oxygen concentration will change the venous admixture calculated by this formula by virtue of the impact of the FiO2 on the low V/Q regions.30-32 Like the P/F ratio, venous admixture will also be impacted by changes in MAP by virtue of its impact on the open/closed status of alveoli. It is usually recommended to determine the venous admixture at the current inspired oxygen and ventilator settings, whatever they might be, depending on the needs of the patient.30

REFERENCES 1. Haskins SC: Sampling and storage of blood for pH and blood gas analysis, J Am Vet Med Assoc 170:429-433, 1977. 2. Gray S, Powell LL: Blood gas analysis. In Burkitt-Creedon JM, Davis H, editors: Advance monitoring and procedures for small animal emergency and critical care, Oxford, UK, 2012, John Wiley & Sons, pp 286-292. 3. Kennedy SA, Constable PD, Sen I, Couetil L: Effects of syringe type and storage conditions on results of equine blood gas and acid-base analysis, Am J Vet Res 73:979-987, 2012. 4. Rezende ML, Haskins SC, Hopper K: The effects of ice-water storage on blood gas and acid-base measurements, J Vet Emerg Crit Care 17:67-71, 2006. 5. Hopper K, Rezende ML, Haskins SC: Assessment of the effect of dilution of blood samples with sodium heparin on blood gas, electrolyte, and lactate measurements in dogs, Am J Vet Res 65:656-660, 2005. 6. Biebuyck JF: Pulse oximetry, Anesthesiology 70:98-108, 1989. 7. Ayres DA: Pulse oximetry and CO-oximetry. In Burkitt-Creedon JM, Davis H, editors: Advanced monitoring and procedures for small animal emergency and critical care, Oxford, UK, 2012, John Wiley & Sons, pp 274-285. 8. Smale K, Anderson LS, Butler PJ: An algorithm to describe the oxygen equilibrium curve for the Thoroughbred racehorse, Equine Vet J 26: 500-502, 1994. 9. Kelman GR: Digital computer subroutine for the conversion of oxygen tension into saturation, J Appl Physiol 21:1375-1376, 1966.

10. Cambier C, Wierinckx M, Clerbaux T, et al: Haemoglobin oxygen affinity and regulating factors of the blood oxygen transport in canine and feline blood, Res Vet Sci 77:83-88, 2004. 11. Clerbaux T, Gustin P, Detry B, Cao ML, Frans A: Comparative study of the oxyhaemoglobin dissociation curve of four mammals: man, dog, horse, and cattle, Comp Biochem Physiol 106:687-694, 1993. 12. Kelman GR, Nunn JF: Clinical recognition of hypoxaemia under fluorescent lamps, Lancet 1:1400-1403, 1966. 13. Martin L, Khalil H: How much reduced hemoglobin is necessary to generate central cyanosis? Chest 87:182-185, 1990. 14. Bishop MJ, Cheney FW: Effects of pulmonary blood flow and mixed venous O2 tension on gas exchange in dogs, Anesthesiology 58:130-135, 1983. 15. Giovannini I, Boldrini G, Sganga G, et al: Quantification of the determinants of arterial hypoxemia in critically ill patients, Crit Care Med 11: 644-645, 1983. 16. Huttemeier PC, Ringsted C, Eliasen K, Mogensen T: Ventilation-perfusion inequality during endotoxin-induced pulmonary vasoconstriction in conscious sheep: mechanisms of hypoxia, Clin Physiol 8:351-358, 1988. 17. Santolicandro A, Prediletto R, Formai E, et al: Mechanisms of hypoxemia and hypocapnia in pulmonary embolism, Am J Respir Crit Care Med 152:336-347, 1995. 18. Cooper CB, Celli B: Venous admixture in COPD: pathophysiology and therapeutic approaches, COPD 5:376-381, 2008. 19. Lumb AB: Nunn’s applied respiratory physiology, ed 6, Oxford, 2005, Butterworth Heinemann. 20. Haskins SC, Pascoe PJ, Ilkiw JE, et al: Reference cardiopulmonary values in normal dogs, Comp Med 55:158-163, 2005. 21. Staub NC: The pathogenesis of pulmonary edema, Prog Cardiovasc Dis 23:53-80, 1980. 22. Ware LB, Matthay MA: The acute respiratory distress syndrome, N Engl J Med 342:1334-1349, 2000. 23. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23(3):280-285, 2013. 24. Carver A, Bragg R, Sullivan L: Evaluation of PaO2/FiO2 and SaO2/FiO2 ratios in postoperative dogs recovering on room air or nasal oxygen insufflation, J Vet Emerg Crit Care 26(3):437-445, 2016. 25. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB: Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS, Chest 132(2):410-417, 2007. 26. Fletcher K, Chapman R, Keene S: An overview of medical ECMO for neonates, Semin Perinatol 42(2):68-79, 2018. 27. Kumar D, Super DM, Fajardo RA, Stork EE, Moore JJ, Saker FA: Predicting outcome in neonatal hypoxic respiratory failure with the Score for Neonatal Acute Physiology (SNAP) and Highest Oxygen Index (OI) in the first 24 hours of admission, J Perinatol 24(6):376-381, 2004. 28. Rawat M, Chandrasekharan PK, Williams A, et al: Oxygen saturation index and severity of hypoxic respiratory failure, Neonatology 107(3): 161-166, 2015. 29. Wandrup JH: Quantifying pulmonary oxygen transfer deficits in critically ill patients, Acta Anaesthesiol Scand 107:37-44, 1996. 30. Gowda MS, Klocke RA: Variability of indices of hypoxemia in adult respiratory distress syndrome, Crit Care Med 25:41-45, 1997. 31. Whiteley JP, Gavaghan DJ, Hahn DEW: Variation of venous admixture, SF6 shunt, PaO2, and the PaO2/FIO2 ratio with FIO2, Br J Anaesth 88:771-778, 2002. 32. Oliven A, Abinader E, Bursztein S: Influence of varying inspired oxygen tensions on the pulmonary venous admixture (shunt) of mechanically ventilated patients, Crit Care Med 8:99-101, 1980.

17 Hypoventilation Meredith L. Daly, VMD, DACVECC

KEY POINTS • Minute ventilation (V E) is determined by respiratory rate (RR) and tidal volume (VT) (V E 5 RR 3 VT). • Dead space (VD) is the portion of VT that does not participate in gas exchange. • Hypercapnia results when alveolar ventilation is insufficient at removing carbon dioxide produced in the body by aerobic metabolism. • The gold standard for assessment of arterial carbon dioxide (PaCO2) levels is arterial blood gas analysis. • Hyperventilation is generally defined as a PaCO2 less than 30 to 35 mm Hg. Slight species-specific differences exist.

Carbon dioxide (CO2) is the product of aerobic metabolism. It is produced primarily in the mitochondria and subsequently diffuses via a series of sequential partial pressure gradients into the cytoplasm, the extracellular space the intravascular space, and the pulmonary capillaries. Upon reaching the pulmonary capillaries, CO2 diffuses into the alveoli, where a balance between CO2 production and alveolar ventilation determines its concentration. Therefore, in a patient with relatively constant CO2 production, arterial CO2 concentration serves as a surrogate for alveolar ventilation. Conditions that increase CO2 production (e.g., fever), reduce minute ventilation, and/or increase dead space may result in increased arterial CO2 concentrations. The most common cause of hypercapnia in clinical patients is hypoventilation secondary to decreased minute ventilation.

DEFINITIONS AND MEASUREMENT Minute ventilation (V E) is the total volume of gas exhaled per minute. It is equal to the product of tidal volume (VT) and respiratory rate (RR) (V E 5 VT 3 RR). The volume of inhaled air is slightly greater than the exhaled volume because more oxygen is inhaled than CO2 is exhaled; this difference is usually less than 1% of the VT in health. VT is composed of dead space volume (VD), or the portion of VT that does not actively participate in gas exchange, and the volume of fresh gas entering the alveoli that participates in gas exchange (VA).1 Alveolar ventilation (V A) is the volume of fresh air (non-dead space gas) available for gas exchange that enters the alveoli per minute, equivalent to the total amount of gas exhaled per minute (V E) minus the air contained in the dead space per minute (V D). Alveolar ventilation, like minute ventilation is measured during exhalation; inhaled and exhaled volumes are also similar in health. V A can be derived from the following equations: 

VT  VD  V A

(equation 1)

• Hypoventilation is defined as a PaCO2 greater than 40 to 45 mm Hg. Slight species-specific differences exist. • Clinical signs associated with hypoventilation may be the result of the systemic effects of hypercapnia, uncompensated respiratory acidosis, or the disease process causing the hypoventilation. • Hypoventilation is treated by increasing alveolar ventilation through the treatment of the underlying disease, chemical stimulation of breathing, or manual/mechanical ventilation.

multiplying by respiratory rate,

VE  VD VA

(equation 2)

which can be rearranged as

VA  VE  VD

(equation 3)

where V E is the expired minute ventilation and (V D) is the dead space ventilation.1 Dead space ventilation is the portion of VT per minute that does not actively participate in gas exchange. Dead space can be subdivided into anatomic, alveolar, physiologic, and apparatus dead space. The volume of gas filling the upper airway, trachea, and lower airways to the level of the terminal bronchioles does not participate in gas exchange and therefore is considered anatomic dead space. Alveolar dead space is defined as the portion of inspired gas that passes through the anatomic dead space and mixes with gas in the alveoli but does not participate in gas exchange with the pulmonary capillaries.1 Physiologic dead space is comprised of anatomic and alveolar dead space and is the sum of all portions of the VT that do not participate in gas exchange. Physiologic dead space is approximately the same as anatomic dead space in health. However, in the presence of ventilation– perfusion inequality (i.e., when a portion of VT ventilates alveoli that are not perfused), physiologic dead space is increased due to increased alveolar dead space. Lastly, when patients are connected to a breathing device, the circuit may contribute to dead space if a portion of the VT is rebreathed without fresh gas flow replacement. This is known as apparatus dead space and is most important in patients that are small or have decreased ability to generate an effective VT. Dead space ventilation can be measured in several different ways; two of the most common include Fowler’s method and Bohr’s method. Fowler’s method involves measuring the concentration of an exhaled tracer gas, typically nitrogen, over time following a single breath with

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100% oxygen. Nitrogen concentration in the expired gas rises as dead space gas is washed out by alveolar gas over time. The nitrogen concentration is then displayed graphically against the volume of gas exhaled. The anatomic dead space volume is subsequently derived from this graph; it is a function of the geometry of the airways.2 Bohr’s method is different from Fowler’s method; it measures the volume of lung that does not eliminate CO2. Therefore, this method involves measurement of physiologic dead space rather than simply anatomic dead space. Bohr’s method uses the principle that all of the CO2 in the exhaled gas (FE) originates from the alveolus (FA). The CO2 concentration in the exhaled gas (FE) is composed of alveolar CO2 (FA) that has been diluted by the CO2-free gas in the conducting airways and in the airways that are poorly perfused.2 VT  FE  V A  FA

(equation 4)

which can be rearranged knowing that VA 5 VT – VD to VD  V T  (FA  FE) / FA

(equation 5)

The partial pressure of any gas is proportional to its concentration, therefore (equation 6, VD  VT  (PACO 2  PECO 2) / PACO 2 Bohr equation) Assuming alveolar and arterial oxygen PCO2 are equal, then VD  VT  (PaCO 2  PECO 2) / PaCO 2

(equation 7)

Once the corresponding dead space volume is determined, alveolar ventilation can be calculated by subtracting dead space ventilation from the total ventilation measured via spirometry. Alveolar ventilation is reduced by an increase in dead space ventilation, regardless of whether the dead space is of anatomic, alveolar, or apparatus origin. The corresponding changes in alveolar gas tensions are identical to those produced by a decreased V E due to a different cause, such as a decreased RR. Another way of measuring alveolar ventilation is to use the alveolar ventilation equation. The equation states that alveolar PCO2 (PACO2) is directly proportional to the amount of CO2 produced by metabolism (V CO2) and delivered to the lungs and inversely proportional to the alveolar ventilation (V A).1 PACO2  (VCO 2  VA ) k

(equation 8)

Although the derivation of the equation is for alveolar PCO2, its clinical usefulness stems from the fact that alveolar and arterial PCO2 can be assumed to be equal in patients with normal lungs because of the highly diffusible nature of CO2. Therefore,

VA  (VCO 2  PaCO 2) k

(equation 9)

The constant k 5 0.863 is necessary to equate dissimilar units for V CO2 (ml CO2/min), and (V A) (L/min) to PaCO2 pressure units (mm Hg).1 This means, for example, if the alveolar ventilation is halved, the PaCO2 is doubled as long as CO2 production remains unchanged. Even when alveolar and arterial PCO2 are not equal (as in states of severe ventilation–perfusion mismatch), the relationship expressed by the equation (PCO2 ∝V CO2 /V A) remains valid because of the high solubility of CO2 in the circulation. From the alveolar ventilation equation, it can be concluded that the only physiologic reason for increased PaCO2 is a level of alveolar ventilation that is inadequate for the amount of CO2 produced by aerobic metabolism and subsequently delivered to the lungs.1

Arterial PCO2 is therefore a measure of the ventilatory status of a patient. Normal values vary depending upon the analyzer used but generally fall within the range of 30 to 42 mm Hg in the dog and 25 to 36 mm Hg in the cat.3 A PaCO2 less than 30 to 35 mm Hg generally indicates hyperventilation (lower in felines), and a PaCO2 greater than 40 to 45 mm Hg indicates hypoventilation. Venous CO2 values reflect a combination of arterial PCO2, tissue metabolism, and blood flow. Venous CO2 values are typically 3 to 6 mm Hg higher than the corresponding arterial values during steady state (33 to 42 mm Hg canine, 32 to 44 mm Hg feline) but can diverge significantly in disease states, particularly those associated with decreased tissue perfusion and pulmonary circulation.3

MECHANISMS AND ETIOLOGIES OF HYPERCAPNIA Hypercapnia results when alveolar ventilation is inadequate to restore PaCO2 to the normal range. It is the result of increased inspired CO2, increased CO2 production with a fixed V E, or impaired CO2 excretion. CO2 excretion is decreased when V E is decreased secondary to a decreased RR, decreased tidal volume (VT) decreases in both RR and VT, or increases in the dead space fraction of the tidal volume (VD/VT).

Increased Inspired CO2 Under general anesthesia, faulty breathing circuits, excess apparatus dead space, or inadequate fresh gas flows can lead to an increase in the inspired CO2 as a result of rebreathing.5 Exhausted absorbent agents, faulty unidirectional valves, and increased apparatus dead space in smaller patients are common causes of CO2 rebreathing in veterinary patients.18

Increased CO2 Production with a Fixed Minute Ventilation (VE)

If V E is fixed, increased CO2 production secondary to thyrotoxicosis, fever, sepsis, malignant hyperthermia, overfeeding, or exercise will result in hypercapnia. However, these are uncommon causes of hypercapnia in spontaneously breathing patients because compensatory increases in V E typically restore PaCO2 values to the normal range. Though not technically the result of increased CO2 production, systemic absorption of CO2 gas used for peritoneal cavity insufflation during laparoscopy may also contribute to hypercapnia in the presence of a fixed V E.19

Impaired CO2 Excretion Due to Global Hypoventilation or Increased Dead Space

Total minute ventilation (V E) is determined by RR and VT (VD 1 VA), both of which are controlled by central and peripheral factors (see Chapter 14, Control of Breathing). Hypercapnia can be caused by any process interfering with the ability to initiate or generate a normal tidal breath. General categories include central neurologic disease affecting the respiratory control center, peripheral or central chemoreceptor dysfunction, upper or lower motor neuron disease, spinal cord disease, neuromuscular disease, abnormal respiratory mechanics, or increased airway resistance. Specific disease processes causing hypoventilation within each of these categories are listed in Box 17.1. The pathophysiology of hypoventilation associated with each condition is discussed in greater detail in relevant chapters (see Part II, Respiratory Disorders and Chapter 83, Neurological Evaluation of the ICU Patient) which address these disease processes individually. Select conditions are reviewed below to illustrate, more specifically, the impact of disease on total V E, RR, VT, and dead space ventilation. Reduction in either the central respiratory drive or peripheral muscle, nerve, or thoracic cage function will result in global hypoventilation,

CHAPTER 17  Hypoventilation

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BOX 17.114  Differential Diagnosis of Hypoventilation/Hypercapnia Decreased Minute Ventilation 1. Central neurological disease (medulla, cerebrum, pons) a. Sedative overdose (e.g., narcotics or benzodiazepines, anesthetics) b. Encephalitis c. Trauma d. Neoplasia e. Vascular f. Cerebral edema g. Severe metabolic disturbances h. Severe hypothermia (80°F) 2. Cervical spinal cord disease a. Trauma I. Spinal cord hemorrhage II. Fracture b. Neoplasia c. Infection d. Intervertebral disk disease e. Inflammatory f. Anterior horn cell disease 3. Lower motor neuron disease/neuromuscular disease a. Myasthenia gravis b. Neuromuscular blockade c. Botulism d. Tick paralysis e. Demyelination f. Polyradiculoneuritis g. Infection 4. Chemoreceptor abnormalities a. Drugs/anesthetic agents b. Metabolic alkalosis c. Cerebrospinal fluid acidosis 5. Abnormal respiratory mechanics a. Pulmonary fibrosis b. Respiratory fatigue from increased work of breathing c. Pickwickian syndrome d. Pleural space disease I. Pneumothorax II. Hemothorax III. Chylothorax IV. Hydrothorax V. Malignant effusion VI. Space-occupying mass VII. Diaphragmatic hernia e. Loss of elasticity of chest wall/lungs I. Extrathoracic compression II. Fibrosis

normal minute ventilation (VE) with increased VD/VT, or both. The central respiratory center receives inputs from central and peripheral chemoreceptors and baroreceptors, thermal and mechanical receptors in the upper airway and lungs, and cognitive inputs from the cortex, among others. These signals are integrated into a combined output to the muscles of respiration which determinesV E. Central chemoreceptors, located in multiple areas of the brainstem, are thought to be responsible for more than 50% of the hypercapnic ventilatory response.4,14 Any anatomic, physiologic, or pharmacological process that impacts the central respiratory center can cause diminished respiratory drive and hypercapnia as a result of decreased RR or VT. Common causes in veterinary patients include sedative overdose, traumatic brain injury, and neoplasia.

f. Loss of structural integrity of chest wall I. Flail chest II. Chest wound g. Decreased functional residual capacity I. Anesthetic agents II. Patient positioning (especially dorsal recumbency) 6. Increased airway resistance a. Upper airway obstruction I. Mucus plugs II. Neoplasia III. Foreign body IV. Recurrent laryngeal nerve damage V. Laryngeal edema VI. Inflammatory laryngitis VII. Polyp b. Increased breathing circuit resistance under general anesthesia c. Tracheal or mainstem bronchus collapse d. Brachycephalic obstructive airway syndrome e. Bronchoconstriction I. Feline asthma II. Chronic bronchitis Increased Dead Space Ventilation a. Increased physiologic dead space (High V/Q) I. Low cardiac output II. Shock III. Pulmonary embolus IV. Pulmonary hypotension V. Pulmonary bulla b. Increased apparatus dead space I. Excessive dead space in ventilator/anesthesia breathing circuit II. Excessively long endotracheal tube Increased Carbon Dioxide Production with a Fixed Tidal Volume a. Malignant hyperthermia b. Reperfusion injury c. Excessive nutritional support in a ventilated patient d. Fever e. Iatrogenic hyperthermia f. Thyrotoxicosis Increased Inspired Carbon Dioxide a. Expired or old soda lime b. Faulty unidirectional valves c. Increased apparatus dead space

Patients with neuromuscular disease most commonly develop hypoventilation due to a decrease in VT. In health, the muscles of respiration affect VE by altering respiratory rate and the depth and duration of inspiration (VT). In the presence of muscle weakness, patients may adopt a shallower breathing pattern in which tidal volumes are reduced. Given that anatomical dead space volume remains fairly constant in a given patient, a greater proportion of the tidal breath is allocated to the anatomical dead space in a smaller VT breath than in a breath with a normal VT (increased VD/VT). Minute ventilation (V E) may decrease in these patients due to a decreased VT, or it may remain normal as a result of compensatory increases in RR. However even if V E remains normal as a result of increased RR, alveolar ventilation

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will be decreased in patients with shallower breathing due to greater VD/VT, resulting in hypercapnia. Patients with decreased chest wall compliance or function and pleural space disease may develop a decrease in VT due to decreased lung expansion. Minute ventilation (V E) may initially remain normal secondary to increases in RR; however, hypercapnia secondary to decreased alveolar ventilation may be present as a result of lower tidal volumes and greater VD/VT. Additionally, the RR will decrease in these patients due to respiratory muscle fatigue and increased work of breathing over time if the primary condition is not treated. Occasionally, hypercapnia may be seen in patients exhibiting increased V E with normal or increased tidal volumes, and an increase in the arterial to end-expiratory PCO2 gradient. This is the result of decreased alveolar ventilation secondary to increased alveolar dead space, or ventilation to areas of poorly perfused lung, and increased VD/VT. In clinical patients this may be seen in the presence of significant pulmonary thromboembolic disease, pulmonary capillary compression secondary to pulmonary overinflation, and cardiovascular shock.

CLINICAL SIGNS Clinical signs associated with hypoventilation may be the result of the systemic effects of hypercapnia, uncompensated respiratory acidosis, or the disease process causing hypoventilation. Patients with a decreased V E may present with shallow, rapid breathing or deep, slow breathing; increased respiratory effort may or may not be present, depending upon the underlying condition. For example, patients with impaired central respiratory drive often do not appear to have difficulty breathing. However, in patients with acute mechanical failure of the respiratory system, such as a complete upper airway obstruction, an increased breathing effort is readily apparent. In these situations, hypoxemia, rather than hypercapnia, is most often the immediate threat to life. In patients with more chronic respiratory acidosis, clinical signs may be more subtle. Although less common, patients may be hypercapnic despite an increased V E as a result of hypoperfusion of ventilated alveoli, which leads to increased physiologic dead space. Hypercapnia and the accompanying respiratory acidosis can cause diffuse systemic effects; alterations in autonomic, cardiorespiratory, neurologic, and metabolic functions are common. Acute respiratory acidosis has variable effects on the cardiovascular system. Hypercapnia and acidosis directly decrease myocardial contractility and systemic vascular resistance.4 However, these effects are typically offset by increased sympathetic nervous system activation and catecholamine release which occur secondary to acute hypercapnia, leading to increases in heart rate and systemic blood pressure. Tachyarrhythmias are commonly seen, and prolongation of the QT interval has been reported rarely.6 Hypercapnia causes vasoconstriction in the pulmonary circulation.27 Additionally, high PCO2 levels can lead to bronchodilation and decreased diaphragmatic contractility.26 Neurologic sequelae depend upon the magnitude and the duration of the hypercapnia, as well as the degree of concurrent hypoxemia. In general, cerebral blood flow is increased in response to increases in PCO2 as a result of vasodilation of cerebral vasculature and increased systemic blood pressure. This increase in cerebral blood flow leads to increased intracranial pressure. Clinical manifestations are variable and include deteriorating level of consciousness, altered brainstem reflexes, seizures, and altered postural and motor responses. CO2 narcosis, seen when PCO2 is greater than 90 mm Hg, is likely the result of alterations in intracellular pH and changes in cellular metabolism.4,1 Hypercapnia may also impact metabolic and endocrine function. At high levels of PCO2, constriction of the renal afferent arteriole may

result in acute kidney injury and decreased urine output. Hypercapnia may cause increased sodium and water retention, as well as hyperkalemia.27 The anterior pituitary may be stimulated by increased CO2, leading to increased adrenocorticotropic hormone secretion.4 Hypercapnia produces a respiratory acidosis. This acidosis may result in several clinical effects including cardiovascular instability, altered mentation, and electrolyte abnormalities. In addition, hypercapnia (and acidosis) will cause a rightward shift of the oxyhemoglobin dissociation curve, which increases release of oxygen to the tissues.1,2

DIAGNOSIS The gold standard for assessment of arterial PaCO2 levels is arterial blood gas analysis (see Chapter 202, Blood Gas Sampling). Arterial blood samples can be collected via percutaneous puncture of the femoral, dorsal pedal, coccygeal, sublingual, and dorsal auricular arteries in dogs. Obtaining an arterial sample in cats can be more difficult; the most accessible sites are the femoral and coccygeal arteries. If arterial blood cannot be obtained, a venous blood gas sample can be used. Central venous samples obtained from the jugular vein or vena cava or mixed venous samples obtained from a pulmonary arterial catheter provide the most accurate venous results. If these are not available, peripheral venous samples can be used; however, caution should be exercised when interpreting venous PCO2 values in states of reduced blood flow. In normal animals, the venous partial pressure of CO2 is usually about 3 to 6 mm Hg higher than the arterial PaCO2. This normal venous–arterial gradient occurs because CO2 is removed from tissues and transported in venous blood back to the lungs as dissolved CO2 in plasma (about 10%) and buffered within red blood cells as bicarbonate (about 90%).1,4 However, the venous–arterial PCO2 gradient (Pv-aCO2) can increase significantly in states of decreased tissue perfusion. Venous CO2 (PVCO2) is a reflection of arterial CO2 inflow, de novo local tissue CO2 production, and tissue blood flow. PaCO2, as previously discussed, is most dependent on alveolar ventilation. During tissue hypoxia, tissue CO2 production is increased as a result of increased hydrogen ion production secondary to lactate formation and hydrolysis of ATP.7 These protons are buffered by HCO3–, which subsequently leads to increased CO2 production. In addition, CO2 accumulates in tissues if decreased blood flow is present. The net result is increased PvCO2. The difference between venous and arterial PCO2 (Pv-aCO2) has been used to identify patients suffering from decreased tissue blood flow in a variety of disease states. Increased Pv-aCO2 has been correlated with decreased cardiac output in human and canine models of hemorrhagic and septic shock8,9 and decreased Pv-aCO2 has been correlated with return of spontaneous circulation in animal models of cardiopulmonary arrest.10 Therefore, although useful, venous CO2 values should be interpreted in conjunction with measures of oxygen content and tissue perfusion in clinical patients. Direct measurement of PaCO2 remains the gold standard for patient monitoring; however, blood gas analysis provides only a single measurement of what is often a rapidly changing clinical picture. In addition, arterial samples may be difficult to obtain or painful to the patient; a means of continuously monitoring PaCO2 without the need for repeat blood gas analysis is desirable. Invasive continuous arterial blood gas monitoring systems are available in human medicine; however, they are costly and subject to technical difficulties related to the maintenance of arterial blood flow and motion artifact. These difficulties would likely restrict the use of these monitors in veterinary patients to those under general anesthesia or mechanical ventilation. Methods for the continuous noninvasive monitoring of PaCO2 include end-tidal and transcutaneous devices.

CHAPTER 17  Hypoventilation End-tidal capnography is a readily available, noninvasive surrogate for PaCO2 (see Chapter 190, Capnography). Capnography analyzes the CO2 concentration of the expiratory air stream, plotting CO2 concentration against either time or exhaled volume. After anatomic dead space has been cleared, the CO2 rises progressively to its maximal value at end exhalation, a number that reflects the CO2 tension of mixed alveolar gas. When ventilation and perfusion are distributed evenly, as they are in healthy subjects, end-tidal PCO2 (PETCO2) closely approximates PaCO2. Normally PETCO2 underestimates PaCO2 by 2 to 6 mm Hg; this gradient is a function of dead space ventilation and cardiac output and has been shown to change in pathologic conditions that affect these physiologic variables.4 In portions of the lung that are hypoperfused, either because of decreased cardiac output or pulmonary embolism, less CO2 is delivered to the lungs for elimination; this translates to a low PETCO2 and an increased PaCO2-PETCO2 gradient. The PaCO2-PETCO2 difference is minimized when perfused alveoli are recruited maximally. Transcutaneous CO2 (TC-CO2) monitors provide another means of noninvasively monitoring PaCO2. These monitors use heated electrodes to measure CO2 in capillary beds. TC-CO2 monitoring is accurate in human patients with normal respiratory function and more accurate than PETCO2 in patients with ventilation–perfusion mismatching.11 In addition, TC-CO2 monitoring can be applied in situations that impact the accuracy of end-tidal CO2 values, such as highfrequency oscillatory ventilation and oxygen supplementation. TC-CO2 measurement has been used to monitor acid-base balance in human patients with diabetic ketoacidosis and more recently, to assess the adequacy of tissue perfusion in critical illness and shock.11,26 Transcutaneous CO2 monitors have been evaluated in veterinary patients.12,20 To date, studies have found that TC-CO2 values are not a reliable surrogate for PaCO2 in dogs and cats. In addition to blood gas analysis and noninvasive CO2 measurement, tests should be performed to help identify the underlying cause of hypoventilation. A baseline complete blood count, chemistry panel, and urinalysis are recommended. Additional tests include, but are not limited to, chest radiography, thoracic and abdominal ultrasound, cervical radiography, testing for infectious and neuromuscular disease, computed tomography or magnetic resonance imaging, electromyography, nerve conduction velocity testing, cerebrospinal fluid analysis, endocrine and pulmonary function testing, and nerve and muscle biopsies. Test selection should be dictated by the clinical status of the patient and the suspected disease process(es).

TREATMENT Definitive treatment of hypercapnia is achieved through prompt diagnosis and elimination or the management of the underlying cause. In the emergent setting, airway patency should be confirmed immediately, and supplemental oxygen administered as relief of airway obstruction, tracheostomy tube placement, or endotracheal intubation is performed, if indicated. Once an airway has been secured and manual ventilation has been provided, if indicated, hemodynamic stability should be optimized to ensure hypercapnia secondary to poor pulmonary perfusion is not confounding interpretation. Provision of supplemental oxygen to the hypoventilating patient is controversial. Patients with significant hypoxemia require oxygen therapy to prevent life-threatening complications of hypoxemia (see Chapter 16, Hypoxemia). However, hypercapnia secondary to oxygen therapy may be observed in patients with chronic hypoventilation and acute hypoxemia. Patients with chronically increased CO2 levels have a diminished central and peripheral response to CO2; arterial hypoxemia becomes the principal stimulus for ventilation in these patients. In this

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setting, sudden correction of arterial hypoxemia causes further hypercapnia through a combination of three mechanisms: (1) depression of hypoxia-driven chemoreceptors, (2) relief of hypoxic pulmonary vasoconstriction in poorly ventilated lung regions as local perfusion increases without concomitant increase in ventilation, and (3) significant correction of hypoxemia causes better saturation of hemoglobin so that previously buffered protons on deoxyhemoglobin are released with subsequent generation of new CO2 from stores (Haldane effect).13 In human medicine, slow titration of low-flow oxygen (1–2 L/min increased in increments of 1 L/min) to achieve a target arterial PO2 of 60–70 mm Hg and pulse oximetry values of 90%–93% is recommended.25 Close monitoring of PaO2 and PCO2 is recommended during titration to ensure improvement in oxygenation and to prevent oxygen-induced hypercapnia. Additional therapies should be directed at treatment of the underlying cause of the hypercapnia. For example, patients receiving opioids, sedatives, or neuromuscular blockade should receive reversal medications if indicated. Manual/mechanical ventilation may be needed until the medications have been reversed or metabolized. For patients under general anesthesia, the anesthetic circuit and the anesthetic gas adsorbent should be evaluated and changed, if indicated, to address hypercapnia. Patients with pleural space disease should undergo thoracocentesis as soon as possible. In human medicine, the use of respiratory stimulant medications has fallen out of favor in most conditions due to lack of evidence demonstrating improvement in hypercapnia or clinical outcomes with their use.25 Respiratory stimulant medications include doxapram, aminophylline/theophylline, caffeine, and progesterone, among others. Studies evaluating the impact of these medications on hypercapnia and respiratory function in small animal clinical patients are lacking; therefore, careful evaluation of the risks and benefits of these medications in individual patients is advised prior to use. Doxapram stimulates respiration via activation of peripheral chemoreceptors; at higher doses, the medullary respiratory center is stimulated, causing an increase in VT and RR. Side effects of doxapram result from systemic catecholamine release and central nervous system stimulation. In addition, this drug may increase the work of breathing, which can lead to increased oxygen consumption and CO2 production.14 Methylxanthine drugs, including aminophylline, theophylline, and caffeine, have been shown to improve ventilation in experimental both dogs and cats. Methylxanthines have several beneficial respiratory effects including bronchodilation, central respiratory center stimulation, improved skeletal muscle and diaphragmatic contractility, and enhanced mucociliary clearance, among others.15,16 Use has been shown to prevent diaphragmatic fatigue in adult humans.15,16 Aminophylline has been shown to significantly increase V E, VT, RR, and diaphragmatic and intercostal contractility in dogs.23,24 Specific effects appear to vary to some degree between methylxanthines. For example, caffeine is considered to be more effective in stimulating the central nervous and respiratory systems and appears to penetrate the cerebrospinal fluid more readily than theophylline.17 Theophylline is considered a more potent cardiac stimulant and has greater diuretic and bronchodilator effects but is associated with a higher incidence of tachycardia.17 Caffeine citrate has been used in the management of apnea of prematurity because of its more predictable pharmacokinetics and decreased side effect profile in comparison to theophylline. Use has been associated with a decreased apnea frequency and improvement in both short and long-term clinical outcomes in preterm infants.27 Studies evaluating safety and efficacy of caffeine citrate in clinical veterinary patients or neonates are warranted before this medication can be routinely recommended.

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Sodium bicarbonate administration is not indicated for the correction of acidemia secondary to respiratory acidosis. Hypercapnia may worsen after administration due to increased production of CO2 from bicarbonate. Acetazolamide is a diuretic that induces a metabolic acidosis via bicarbonate ion excretion. This acidosis may stimulate ventilation; however, caution should be exercised when using this drug in patients with a preexisting respiratory acidosis; severe systemic complications of acidemia may result. The most effective treatment for hypoventilation is mechanical ventilation (see Chapters 32 and 33, Mechanical Ventilation Core Concepts and Advanced Concepts, respectively). Many patients with central nervous system disease, neuromuscular disease, or altered respiratory mechanics leading to hypoventilation may require this therapeutic modality. Ventilated patients require referral for 24-hour monitoring in an intensive care facility. Mechanical ventilation is lifesaving for patients with reversible causes of hypoventilation and should be strongly considered in these patients when other therapeutic options are unsuccessful.

REFERENCES 1. Lumb AJ: Distribution of pulmonary ventilation and perfusion. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier. 2. West JB: Ventilation, control of ventilation. In West JB, editor: Respiratory physiology: the essentials, ed 6, Baltimore, 2000, Lippincott Williams & Wilkins. 3. Hopper K, Haskins SC: A case-based review of a simplified quantitative approach to acid-base analysis, J Vet Emerg Crit Care 18(5):467, 2008. 4. Lumb AJ: Control of breathing. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier. 5. Mattson S, Kerr C, Dyson D: Anesthetic equipment fault leading to hypercapnia in a cat, Vet Anaes Analg 31:231, 2004. 6. Johnson RA, Autran de Morais H: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 7. Boller MB: CO2 in Low blood flow states. In Multidisciplinary systems review, 17th International VECC Symposium, 2011. 8. Bakker J, Vincent JL, Gris P, et al: Veno-arterial carbon dioxide gradient in human septic shock, Chest 101(2):509, 1992. 9. Van der Linden P, Rausin I, Deltell A, et al: Detection of tissue hypoxia by arteriovenous gradient for PCO2 and pH in anesthetized dogs during progressive hemorrhage, Anesth Analg 80(2):269, 1995.

10. Grundler W, Weil MH, Rackow EC: Arterio-venous carbon dioxide and pH gradients during cardiac arrest, Circulation 74:1071, 1986. 11. Tobias JD: Transcutaneous carbon dioxide monitoring in infants and children, Paediatr Anaesth 19(5):434, 2009. 12. Vogt R, Rohling R, Kästner S: Evaluation of a combined transcutaneous carbon dioxide pressure and pulse oximetry sensor in adult sheep and dogs, Am J Vet Res 68(3):265, 2007. 13. McConville JF, Soloway J: Disorders of ventilation. In Longo DL, Fauci AS, Kasper DL, et al, editors: Harrison’s principles of internal medicine, ed 18, New York, 2011, McGraw-Hill Professional. 14. Campbell VL, Perkowski S: Hypoventilation. In King LK, editor: Textbook of respiratory diseases in dogs and cats, St Louis, 2004, Elsevier. 15. Bhatia J: Current options in the management of apnea of prematurity, Clin Pediatr 39:327, 2000. 16. Randa JV, Gorman W, Bergsteinsson H, et al: Efficacy of caffeine in treatment of apnea in the low-birth-weight infant, J Pediatr 90:467, 1977. 17. Kriter KE, Blanchard J: Management of apnea in infants, Clin Pharmacy 8:577, 1989. 18. Riou B: Case scenario: increased end tidal carbon dioxide, Anesthesiology 112:440, 2010. 19. Fukushima F, Malm C, Andrade MEJ, et al: Cardiorespiratory and blood gas alterations during laparoscopic surgery for intrauterine artificial insemination in dogs, Can Vet J 52:77, 2011. 20. Holowaychuk M, Fujita H, Bersenas A: Evaluation of a transcutaneous blood gas monitoring system in critically ill dogs, J Vet Emerg Crit Care 24:545, 2014. 21. Bar S, Fischer MO: Regional capnometry to evaluate the adequacy of tissue perfusion, J Thorac Dis 11(Suppl 11):S1568, 2019. 22. Dobson NR, Patel RM: The role of caffeine in noninvasive respiratory support, Clin Perinat 43:773, 2016. 23. Jagers JG, Hawes HG, Easton PA: Aminophylline increases ventilation and diaphragm contractility in awake canines, Respir Physiol Neurobiol 167:273, 2009. 24. Suneby J, Ji M, Rothwell B, et al: Aminophylline increases parasternal muscle action in awake canines, Pulm Pharm Ther 56:1, 2019. 25. Feller Kopman D, Schwartzstein RM: The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure, Available at https://www.uptodate.com/contents/the-evaluation-diagnosisand-treatment-of-the-adult-patient-with-acute-hypercapnic-respiratoryfailure. Accessed 2 Dec, 2019. 26. Domino KB, Emery MJ, Swenson ER, et al: Ventilation heterogeneity is increased in hypocapnic dogs but not pigs, Respir Physiol 111:89, 1998. 27. Lumb AJ: Hypercapnia in clinical practice. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier.

18 Upper Airway Disease Dana L. Clarke, VMD, DACVECC

KEY POINTS • Upper airway obstruction is a common cause of respiratory distress in small animals and requires immediate recognition and treatment. • Common diseases leading to upper airway obstruction in dogs include laryngeal paralysis, tracheal collapse, and brachycephalic obstructive airway syndrome. • Upper airway obstruction is less common in cats, and can be secondary to nasal disease, inflammatory laryngeal disease, and tracheal and laryngeal neoplasia.

• Patient stabilization, including oxygen, sedation, and anxiety control, should be a priority over diagnostics to avoid further patient distress. • Complications of upper airway obstruction are common, including hyperthermia, aspiration pneumonia, and noncardiogenic pulmonary edema.

In veterinary medicine, upper airway disease causing airway obstruction and secondary respiratory distress is a common reason for emergency patient evaluation. Regardless of the cause, patients in distress often have exhausted their physiologic compensatory reserves for ventilation and oxygenation, and even small stresses such as restraint for examination can result in rapid decompensation. Prompt treatment with oxygen, anxiolytics, and for some patients, intubation or tracheostomy, may be necessary before the definitive cause is determined or diagnostics performed.

low-pitched snoring such as inspiratory and/or expiratory noise. Obstructive diseases of the larynx or trachea can result in coughing, gagging (particularly with eating or drinking), and respiratory stridor, which is a highpitched noise associated with inspiration. Laryngeal and pharyngeal disease can lead to changes in vocalization (dysphonia).1-4 Coughing is a common clinical sign in animals with tracheal, mainstem bronchus, and laryngeal disease. Since it also commonly is associated with lower airway, pulmonary parenchymal, and cardiac disease, it is important to rule out other causes for coughing. Coughing that results from upper airway disease tends to be dry and nonproductive, whereas coughing of a lower airway or pulmonary parenchymal origin tends to result in a moist, productive cough.5,6 However, many owners have difficulty appropriately determining the productivity of a cough because patients may quickly swallow sputum, or the cough may be associated with terminal, productive retching of gastrointestinal origin.

HISTORY AND CLINICAL SIGNS Clinical signs noted by owners of patients with upper airway disease depend on the location, severity, chronicity, and species. Since cats breathe predominantly through their noses and only open-mouth breathe or pant with severe respiratory compromise, owners may not immediately recognize changes in respiratory comfort. The more sedentary lifestyle of cats can also delay diagnosis of respiratory disease because exercise intolerance is likely to be noticed only as a late change in cats. Dogs with upper airway disease often pant in response to respiratory difficulty. Because panting in dogs may not be recognized as abnormal, respiratory changes may not be obvious when panting is the only clinical sign. The upper airway consists of the nasal passages and choanae, nasopharynx and oropharynx, larynx, and trachea to the thoracic inlet. Clinical signs associated with disease along the upper respiratory tract can by dynamic or static. Dynamic signs occur during inspiration or expiration, depending on the location of the obstruction, or with stress, anxiety, and activity that alter airflow dynamics and precipitate obstruction. Static signs occur with fixed intraluminal or extraluminal obstruction or compression. Disease in the rostral regions of the upper airway (nasal passages, choanae, and nasopharynx) can result in nasal discharge, sneezing, reverse sneezing, snoring, stertorous breathing, and an inability to breathe comfortably when not panting. Stertorous respiration is characterized by

PATIENT EVALUATION Hospitalized patients can develop upper airway obstruction with stress, excessive panting and anxiety, after intubation and recovery from general anesthesia, and after vomiting and regurgitation. Recognition of patients at risk for developing upper respiratory complications, such as those with brachycephalic airway disease, laryngeal dysfunction, and tracheal collapse, is important in order to plan for controlled anesthetic recovery, prepare for reintubation or tracheostomy, and aggressively manage nausea and choose drugs less likely to induce vomiting and regurgitation. Laryngeal, tracheal, and thoracic auscultation often reveals loud, referred upper airway noise, which often can be localized to the point of maximal intensity with thorough auscultation of the entire respiratory tract. Patients with upper airway disease tend to have loud, noisy breathing and increased inspiratory time. Inspiratory noise and distress result from the collapse or obstruction of the upper airway rostral to the thoracic inlet trachea due to the creation of negative intrathoracic

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TABLE 18.1  Commonly Used Medications

for the Management of Patients with Upper Airway Obstruction in the ICU

Fig. 18.1  Bulldog in respiratory distress, demonstrating excessive panting, hypersalivation and orthopnea secondary to upper airway obstruction from brachycephalic obstructive airway syndrome.

pressure upon inspiration that results in a negative transmural pressure and tendency to collapse. This collapse prolongs the inspiratory phase and creates noise from air and tissue reverberation in the lumen. Increased (positive) intrapleural pressure upon expiration collapses the airway caudal to the thoracic inlet (intrathoracic trachea and mainstem bronchi) and results in prolonged expiration, expiratory dyspnea, and lower airway sounds (e.g., wheezes) on auscultation. In a retrospective evaluation of dogs and cats presenting for emergency evaluation of respiratory distress, inspiratory dyspnea in dogs and inspiratory noise in dogs and cats were significantly associated with disease localization to the upper airway. Too few cats in that study had disease isolated to the upper airway to fully characterize the nature of inspiratory dyspnea seen with upper airway disease.7 The degree of upper airway noise often worsens with the severity of the obstruction.1 Thorough auscultation of the pulmonary parenchyma can be difficult in the face of loud referred upper noise but is imperative because of parenchymal complications of upper airway obstruction such as noncardiogenic pulmonary edema and aspiration pneumonia. Panting and subsequent evaporative cooling are major methods of thermoregulation, especially in dogs. Intolerance of warm and humid conditions is often seen in patients with upper airway disease resulting from a decreased ability to efficiently increase minute ventilation to enhance heat dissipation and is a described risk factor for heat stroke.8-11 Hyperthermia and heat stroke can also result from failure to effectively eliminate heat secondary to upper airway obstruction; these are common findings in patients with laryngeal paralysis and brachycephalic airway syndrome. Prompt recognition and treatment of hyperthermia (see Chapter 10, Hyperthermia and Fever) are essential to prevent secondary consequences such as renal, neurologic, cardiovascular, and coagulation disorders.9-11 Since aspiration pneumonia is also a complication of upper airway obstruction, fever should be considered as a source of increased rectal temperature as well (see Chapter 10, Hyperthermia and Fever). In addition to loud respiratory noise, marked respiratory distress, and hyperthermia, other clinical signs that can be recognized with severe upper airway obstruction include extension of the head and neck (orthopnea), cyanosis of the tongue and mucous membranes, and collapse (Fig. 18.1). In such severe cases, immediate intubation or emergency tracheostomy (see Chapter 197, Endotracheal Intubation and Tracheostomy) may be necessary life-saving interventions.

Medication

Dose

Indication/Considerations

Acepromazine

0.005 to 0.02 mg/ kg IV and 0.01 to 0.05 mg/kg IM

Anxiolytic Takes 15 min to reach full effect (IV)12 Caution in cardiovascularly unstable patients

Butorphanol

0.1 to 0.5 mg/kg IM or IV

Sedative, cough suppressant, analgesic

trazodone

2–5 mg/kg PO q8-12

Anxiolytic Oral formulation only

Dexamethasone sodium phosphate

0.05 to 0.2 mg/kg IM, IV, SC

Antiinflammatory glucocorticoid Caution with poor perfusion and suspected airway neoplasia (may impede diagnosis)

STABILIZATION OF PATIENTS WITH UPPER AIRWAY OBSTRUCTION The work of breathing against an upper airway obstruction can precipitate the cycle of edema and inflammation, patient distress, and progressive obstruction, so supplemental oxygen and techniques to minimize patient stress are universally recommended treatment strategies, regardless of the origin of the obstruction. For some patients, the restraint necessary for intravenous catheter placement, venipuncture, and other diagnostics may exacerbate stress and oxygen demands, leading to further respiratory compromise or respiratory arrest. Therefore IM administration of medications is necessary when catheter placement is not safe or feasible. Oxygen therapy can be provided in several different manners; the method selected depends on availability and patient tolerance (see Chapter 15, Oxygen Therapy). An oxygen cage is one of the best ways to provide high levels of inspired oxygen while minimizing patient stress and handling. However, enclosure within an oxygen cage prevents the clinicians and nurses from hearing upper airway noises that can indicate worsening obstruction, which can be dangerous in patients with upper airway disease. Control of anxiety and discomfort is essential for patients with upper airway obstruction and respiratory distress. Treatment of secondary inflammation may also be needed (see Chapter 132, Sedation of the Critical Patient) (Table 18.1). When sedation and anxiety control do not relieve respiratory distress, or for patients at risk of imminent respiratory arrest, rapid induction for endotracheal intubation or tracheostomy is necessary (see Chapters 133 and 197, Anesthesia of the Critical Patient and Endotracheal Intubation and Tracheostomy, respectively). If a challenging intubation is anticipated, as with laryngeal collapse or paralysis, upper airway foreign bodies, or neoplasia, a Cook Airway Exchange Catheter (Cook Medical LLC, Bloomington, IN) can be very helpful to provide initial oxygen insufflation and serve as rigid stylet to facilitate intubation.

DIAGNOSTICS While signalment and physical examination findings are crucial in the evaluation of the upper airway obstruction patient, diagnostics are needed to confirm the etiology, evaluate severity and secondary consequences, and assist in therapeutic decision making. Blood gas analysis is helpful in patients with upper airway obstruction to assess the

CHAPTER 18  Upper Airway Disease degree of ventilatory dysfunction and/or hypoxemia. Arterial blood gas analysis is the standard for assessing oxygenation and ventilation, though collection of an arterial sample is often not possible in patients with respiratory distress (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively) (Table 18.2). Diagnostics imaging is an important part of the work-up in all patients with respiratory disease but must not be obtained at the risk of patient safety (Table 18.2). Heavy sedation or general anesthesia often is required for computed tomography (CT) and skull radiography, so these diagnostics often are performed as second-tier diagnostics. Dynamic disease processes such as nasopharyngeal, laryngeal, and tracheal collapse may not be seen on sedated or anesthetized CT examinations. Studies evaluating a clear plastic patient positioning device (VetMousetrap) that contains the animal and restricts movement have shown promising

TABLE 18.2  Diagnostics Commonly Utilized

in the Patient with Upper Airway Obstruction

Diagnostic Testing Findings with Upper Airway Obstruction Arterial or venous blood gas

Increased partial pressure of carbon dioxide (PaCO2/PvCO2) 6 metabolic compensation

Arterial blood gas

Alveolar-arterial (A-a) gradient to rule out hypoventilation as a contributor to hypoxemia

Thoracic radiographs

Noncardiogenic pulmonary edema Bronchopneumonia (aspiration or infectious), Intrathoracic tracheal collapse Mainstem bronchial collapse Airway or pulmonary neoplasia

Cervical radiographs

Laryngeal and pharyngeal masses Extrathoracic tracheal collapse Radioopaque foreign bodies

Upper airway fluoroscopy

Dynamic assessment of nasopharyngeal, tracheal, and bronchial collapse Lung lobe herniation

Computed tomography

Nasal passage/nasopharynx imaging Bulla Tracheal neoplasia Pulmonary metastasis Radiation planning

Sedated laryngeal examination

Tonsillar eversion, hyperemia, masses Laryngeal structure and function Laryngeal saccular eversion, edema Inflammatory or proliferative laryngeal changes Epiglottic retroversion Soft palate length, thickness, irregularity

Rigid and flexible endoscopy

Nasal turbinate proliferation, inflammation, plaques associated with fungal diseases and nasal masses Nasopharyngeal stenosis, masses, turbinates, foreign bodies Nasopharyngeal collapse Tracheal and mainstem bronchial collapse Tracheal foreign bodies, granulation tissue Tracheal and bronchial neoplasia

Airway sampling (transtracheal, endotracheal, bronchoalveolar lavage)

Airway cytology Aerobic culture and susceptibility testing Mycoplasma culture and PCR

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results for dynamic CT evaluation of upper airway obstruction secondary to laryngeal, tracheal, and bronchial disease without the need for anesthesia or sedation.13 Awake CT examination for cats with upper airway obstruction also has proven effective for diagnosing disease processes such as intramural airway masses, laryngeal paralysis, and laryngotracheitis.14 Sedated laryngeal examination is indicated in all patients with upper airway disease, even if laryngeal disease or dysfunction is not considered the primary pathology. Sedation protocols proven to have minimal influence on laryngeal exam include intravenous propofol slowly titrated to effect, with or without the use of concurrent doxapram (1.1 to 2.2 mg/kg IV), or premedication with acepromazine (0.2 mg/kg IM) and butorphanol (0.4 mg/kg IM) 20 minutes before mask induction with isoflurane.15-19 High-dose intramuscular acepromazine was recommended based on the results from normal dogs that did not permit mask induction when lower doses were used early in the trial, but caution is advised when using higher doses to avoid adverse effects.17 Critically ill or compromised patients require lower doses of intramuscular acepromazine, and titration to effect starting with lower doses (0.01 to 0.05 mg/kg) should be considered for clinical patients (see Chapter 132, Sedation of the Critical Patient). A standard laryngoscope with blade and light source is used most commonly for direct visualization of the larynx and oropharynx, although rostral pulling of the tongue and pressure of the blade on the epiglottis may distort laryngeal and oropharyngeal examination. To avoid distortion and for image archival, transoral rigid or flexible endoscopy is extremely helpful and is advised, whenever possible.15,20,21During laryngeal function assessment, it is important to have an assistant indicating the phases of respiration during laryngeal exam to confirm appropriate laryngeal motion and rule out paradoxical laryngeal motion, which can be confused as laryngeal function in dogs with laryngeal paralysis. Paradoxical laryngeal motion is defined as inward movement of the arytenoids secondary to negative pressure generated upon inspiration. Epiglottic retroversion, or caudal displacement of the epiglottis into the rima glottis, should also be ruled out as an uncommon cause of upper airway obstruction and respiratory distress22 (Fig. 18.2). The length and appearance of the soft palate should be assessed, as should the epiglottis. The caudal aspect of the soft palate should contact the epiglottis or extend no more than a few millimeters past it.23 Bronchopneumonia, whether secondary to aspiration, mucociliary dysfunction, or underlying chronic lower airway disease, is a common secondary complication to upper airway disease and obstruction (see Chapter 24, Pneumonia). Sampling from the airway for cytology and culture is helpful to guide antimicrobial therapy, especially in patients with repeated episodes of pneumonia. However, in animals with severe respiratory distress, airway sampling may not be safe and a delay in antimicrobial therapy could hinder pulmonary parenchymal recovery. Therefore, empiric antimicrobial therapy may be necessary. For patients stable enough to undergo airway sampling, transtracheal, endotracheal, and bronchoalveolar lavage can be considered for airway cytology and aerobic bacterial and Mycoplasma cultures.

DISEASES OF THE UPPER AIRWAY Brachycephalic Airway Syndrome Brachycephalic airway syndrome (BAS), brachycephalic syndrome, and brachycephalic obstructive airway syndrome are synonymous terms used to describe the cluster of anatomic abnormalities seen in brachycephalic breeds, such as English Bulldogs, Pugs, French Bulldogs, and Boston Terriers, that contribute to dysfunction of the upper airway. The classic primary anatomic components of BAS include stenotic nares and an elongated soft palate, although other commonly

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A

B Fig. 18.2  Rigid endoscopic examination from a Yorkshire Terrier demonstrating epiglottic retroversion where the tip of the epiglottis becomes entrapped over the caudal edge of the soft palate.

recognized components include tracheal hypoplasia and nasopharyngeal turbinates. Secondary complications from chronic increased resistance to airflow on inspiration include everted laryngeal saccules, tonsillar eversion, laryngeal collapse, tracheal collapse, chronic gastrointestinal signs, and even syncope.24-30 Approximately 80% of the resistance to airflow during inspiration is from the nose in normal dogs.1,25,27,31,32 This is exaggerated in brachycephalic animals with stenotic nares, excessive pharyngeal tissues, elongated soft palate, and/or tracheal hypoplasia, which lead to turbulent airflow, edema, and increased inspiratory noise.1,2,25,27 In addition to increased respiratory noise, other clinical signs seen in BAS patients include snoring, stertor, stridor, heat and exercise intolerance, hypersalivation, vomiting, and regurgitation.24,25,28,29 It is most common in young adult dogs (2 to 3 years), although English Bulldogs have been reported to present at younger ages (i.e., 1 year).33-35 Diagnosis of BAS is made based on signalment, clinical signs, and examination of the nares, oropharynx, and larynx during a sedated oral examination using a laryngoscope or endoscope (flexible or rigid). Oral examination should include assessment of the soft palate length, size and shape of the rima glottis, and the presence or absence of laryngeal saccule eversion and laryngeal collapse. Thoracic radiographs can be helpful to evaluate for tracheal hypoplasia, tracheal collapse, hiatal hernia, and pneumonia, although caution must be exercised when diagnosing tracheal hypoplasia when bronchopneumonia is present because inflammation and

edema of the trachea during an active airway infection may be deceiving.36,37 Fluoroscopy can be helpful to evaluate for dynamic nasopharyngeal collapse, which has been described in brachycephalic dogs.38 Blood gas analysis may show signs of hypoxemia and/or hypoventilation, and brachycephalic breeds often have higher carbon dioxide levels and lower oxygen pressures than mesocephalic or dolichocephalic dogs.39 Retroflexed endoscopy of the nasopharynx may show nasopharyngeal inflammation, collapse, or the presence of nasal turbinates protruding in the nasopharynx, which has been documented in approximately 20% of dogs symptomatic for BAS, with 80% of affected dogs being Pugs in one study.26 Bronchoscopic evaluation of dogs with BAS presenting for surgery showed that 87% of dogs had some degree of bronchoscopically detectable collapse or stenosis and that a worsened degree of bronchial collapse was associated with laryngeal collapse.40 Upper gastrointestinal flexible endoscopy is helpful to evaluate for esophagitis, gastritis, reflux, hiatal hernia, and pyloric stenosis, which have been found in up to 80% of BAS patients, with worsened gastrointestinal signs correlated with worsened respiratory clinical signs.29,30 Biomarker evaluation may show increased cardiac troponin I (cTnI), which may be secondary to myocardial injury from chronic hypoxemia. However, C-reactive protein and haptoglobin levels have not been shown to be increased in dogs with upper airway obstruction secondary to BAS, indicating that there may be minimal systemic inflammation.41 First-line management of BAS includes weight loss, control of excitement and activity triggers, medical treatment for gastrointestinal signs, and treatment of underlying pulmonary parenchymal disease. However, surgical correction of BAS anatomic abnormalities often is required for successful management of most animals with clinical signs of upper airway obstruction due to the structural nature of the disease pathology. Since the nasal passage creates the most resistance to airflow, widening the nares is considered the most important aspect of surgery for BAS, especially because many of the other airway changes are considered secondary to stenotic nares. Widening of the nares at a young age is recommended and shown to provide significant improvement in dogs postoperatively, regardless of the multiple techniques available.* Correction of other components of BAS, including soft palate resection, resection of everted laryngeal saccules, and tonsillectomy also may be needed and can be helpful even in advanced BAS cases with laryngeal collapse.33,40,46 Tracheal hypoplasia and bronchial collapse has not been associated with outcome in dogs undergoing surgical intervention for BAS.34,40 Cricoarytenoid lateralization combined with thyroarytenoid caudolateralization (arytenoid laryngoplasty) has been described in patients with advanced laryngeal collapse, a disease for which permanent tracheostomy was previously considered the only viable surgical intervention.47

Nasopharyngeal Polyps Nasopharyngeal polyps are a common cause of upper airway obstruction in cats, accounting for 28% of cats with nasopharyngeal disease.48 They also have been implicated in moderate to life-threatening upper airway obstruction in three dogs.49-51 Nasopharyngeal polyps are benign inflammatory lesions that arise from the mucosa of the auditory tube or middle ear and grow into the nasopharynx or external ear canal. The exact cause is not known, and attempts to isolate and amplify feline herpes virus, feline calicivirus, Mycoplasma species, Bartonella species, and Chlamydophila felis DNA or RNA from feline aural and nasopharyngeal polyps has been unsuccessful.48,52-58 Clinical signs commonly seen in cats with nasopharyngeal polyps include respiratory noise or stertor, sneezing, nasal discharge, and dysphagia, which may contribute to weight loss.52,53,55,57 Progression of the polyp can * References 27, 30, 34, 40, 42-46.

CHAPTER 18  Upper Airway Disease lead to apparent dyspnea and signs consistent with upper airway obstruction. Diagnosis is usually made based on historical information, oropharyngeal examination with palpation of the soft palate, otoscopy, retroflexed rhinoscopy, radiographs, CT, and/or magnetic resonance imaging52,53,56,59 (Fig. 18.3A). Medical management is generally unrewarding; therefore, surgical intervention is recommended. Tractionavulsion is the simplest method of removal but can be associated with a 40% to 50% chance of recurrence, especially if removed from the auditory canal53,56,60,61 (Fig. 18.3B). For this reason, ventral bulla osteotomy (VBO) is recommended, especially for those patients with polyps in the auditory tube or evidence of middle ear disease.53,57,61 VBO is associated with a higher incidence of postoperative Horner syndrome (43% of cats treated with traction and 57% of cats treated with VBO), vestibular dysfunction, and facial and hypoglossal nerve paralysis.53,57,61 In most cats, Horner syndrome resolves postoperatively, although it can take up to 4 weeks.60-62 Preoperative hearing deficits were not reversed in cats with polyps that had VBO performed.63 Prolonged antimicrobial therapy is indicated for bacterial otitis media or interna; however, the role of postoperative steroids for treatment of nasopharyngeal polyps is unclear. However, one study showed decreased incidence of recurrence when prednisolone was administered postoperatively.61 In general, the prognosis for cats treated surgically for inflammatory nasopharyngeal polyps is good.

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Nasopharyngeal Stenosis Nasopharyngeal stenosis (NPS) is reported uncommonly in dogs and cats.64-68 Nasopharyngeal stenosis occurs when there is partial or complete narrowing of the nasopharynx by a membrane caudal to the choanae and rostral to the caudal aspect of the soft palate. It can overlie the hard or soft palate and may cover both if the membrane is thick enough. NPS can be a congenital lesion, or secondary to chronic inflammatory diseases such as rhinitis (infectious or aspiration), trauma, and neoplastic obstructions. Clinical signs, which often persist for months before diagnosis, include chronic nasal discharge, stertor, stridor, exercise intolerance, gagging, and in severe cases, dyspnea.67-72 Diagnosis is generally made through CT and retroflexed rhinoscopy, although barium contrast rhinography also has been described.69 Surgical correction of the stenosis via surgical access through a midline incision in the soft palate has been described in cats.73,74 When retroflexed flexible endoscopy is used to confirm or diagnose NPS, balloon dilation can be performed simultaneously to open the obstruction using minimally invasive techniques. An angioplasty balloon can be passed normograde through the ventral meatus of the nasal passage, or advanced retrograde through the oral cavity over a wire within a cut red rubber catheter that has been passed retrograde through the nose.67,69-71 Balloon dilation is performed under constant retroflexed visualization, with or without concurrent fluoroscopy, once the balloon is positioned across the stenosis and confirming the balloon is not within the choanae. Restenosis over time is common, and repeated balloon dilations may be necessary depending on how clinically affected the patient is and the extent of restenosis.67,68,70,71 In patients in whom balloon dilation has failed to resolve the NPS sufficiently, stent placement may be considered via surgical placement or using combined fluoroscopy and retroflexed rhinoscopy.68,72 All animals had improvement in their respiratory signs poststent placement. Complications include dysphagia and hair entrapment, tissue in-growth, and prolonged nasal discharge.68 Stent erosion through the soft palate in two dogs (4 and 20 months after placement of covered nasopharyngeal stents) has been described. It is a serious complication that should be considered before placement of nasopharyngeal stents, particularly over the soft palate.75

Congenital Choanal Atresia Congenital choanal atresia also has been reported rarely in cats and in one dog and can cause similar clinical signs to NPS, including nasal discharge, stertor, exercise intolerance, and open-mouth breathing.66,76-78 It results from abnormal bone or soft tissue obstructing the caudal nasal passage just rostral to the common nasopharynx and can be unilateral or bilateral. CT and retroflexed rhinoscopy can be used to make a diagnosis of choanal atresia. Treatment options include transnasal puncture with temporary stenting and surgical approach to the nasopharynx.66,76-78

Nasopharyngeal Foreign Bodies and Infection

B Fig. 18.3  A, Retroflexed rhinoscopy of the caudal nasopharynx in an 11-year-old Shih Tzu showing the presence of a dorsal soft tissue mass. B, Appearance of the nasopharynx of the same dog after endoscopic electrocautery snare mass removal. Histopathology confirmed the mass was a benign inflammatory polyp.

Nasopharyngeal foreign bodies and infections occur infrequently in dogs and cats but can result in upper airway obstructive signs. Nasopharyngeal cryptococcosis, blastomycosis, and extensive bacterial infection and bony proliferation of the bulla are documented to result in nasopharyngeal obstruction.79-81 Nasopharyngeal foreign bodies tend to cause acute-onset upper respiratory signs and also may result in sneezing. With chronicity, nasal discharge and halitosis can develop. Foreign bodies are presumed to become lodged in the nasopharynx secondary to inhalation, reflux during vomiting or regurgitation, or ingestion and secondary penetration through the soft palate. Foreign bodies can be removed via transoral removal via traction on the soft palate, retroflexed rhinoscopic basket retrieval, nasal flushing,

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and surgical excision via access through the soft palate. Nasopharyngeal foreign bodies found in dogs and cats include bones, foam, a premolar, a trichobezoar, plant material, a stone, sewing needles, and a pet fish.82-88

Laryngeal Paralysis Laryngeal paralysis is the result of recurrent laryngeal nerve dysfunction that impairs arytenoid cartilage abduction during inspiration, leading to respiratory stridor and distress.15,89-91 It is a common form of upper airway obstruction generally recognized in middle-age to older large and giant breed dogs.91,92 Some studies suggest that Labrador Retrievers are overrepresented.91-94 Congenital and acquired laryngeal paralysis have been described in dogs. The disease process also is recognized in cats, although not nearly as commonly. In normal dogs, the larynx accounts for only 6% of resistance to airflow during nasal breathing because contraction of the dorsal cricoarytenoideus muscle, which is innervated by the recurrent laryngeal nerve, abducts the arytenoid cartilages and widens the glottis.89 In cases of dysfunction of the recurrent laryngeal nerve, atrophy of one or both of the paired dorsal cricoarytenoideus muscles results, impairing abduction of the arytenoid cartilages and vocal folds. The net effect is narrowing of the glottis upon inspiration, causing increased velocity and turbulence of airflow, increased muscular effort for inspiration, dynamic collapse of the larynx, and ultimately, upper airway obstruction.89 The cause of recurrent laryngeal nerve dysfunction can be congenital denervation, traumatic, iatrogenic, idiopathic, neoplastic, and associated with diffuse neuromuscular disease.15,89,90 Congenital laryngeal paralysis has been described in Bouvier des Flandres, Rottweilers, Dalmatians, Siberian Huskies, and Husky mixed breeds, Bull Terriers, Pyrenean Mountain Dogs, and Leonbergers. Affected dogs were less than 1 year of age in all breeds except the Leonbergers.95-101 Injury to the recurrent laryngeal nerve secondary to accidental cervical trauma, cervical, mediastinal or thoracic neoplasia, and iatrogenic injury during thyroidectomy and extraluminal tracheal ring prosthesis placement can result in acquired laryngeal paralysis.15,89-91,102,103 Myasthenia gravis and hypothyroidism have also been implicated in cases of laryngeal paralysis, although the exact relationship is not understood completely.91,102,103,105 However, an underlying cause is not confirmed for most cases of acquired laryngeal paralysis, resulting in many cases being labeled idiopathic, although evidence is growing that laryngeal paralysis is one component of generalized peripheral polyneuropathy.91-94,103,106 Clinical signs recognized in dogs with laryngeal paralysis depend on the severity of airway obstruction and can include inspiratory stridor, change in bark, exercise intolerance, coughing, and gagging. Most dogs do not develop significant clinical signs until bilateral laryngeal paralysis has developed.91 Hypersalivation and vomiting or regurgitation may be seen in patients with laryngeal paralysis; however, the absence of gastrointestinal signs does not exclude the possibility of esophageal dysmotility.91 In more severely affected animals, respiratory distress, cyanosis, and collapse can result. Clinical signs can be exacerbated by exercise, stress, anxiety, and increased ambient temperature or humidity. Animals with profound airway obstruction and laryngeal edema may require emergency intubation or tracheostomy. Before anesthesia for laryngeal examination or definitive surgery, thoracic radiographs are imperative to assess for evidence of pneumonia because resolving or subclinical aspiration pneumonia is common.91,102 Other pulmonary pathology, such as noncardiogenic pulmonary edema, cardiomegaly, and intrathoracic or mediastinal neoplasia affecting the recurrent laryngeal nerve, hiatal hernia, and metastatic neoplasia should also be ruled out prior to anesthesia if feasible. Assessment of esophageal motility may be considered because

dogs with esophageal dysmotility are at higher risk of aspiration pneumonia. Liquid-phase esophagram may better predict postoperative aspiration pneumonia compared with neurologic status.92 Laryngeal paralysis usually is confirmed via sedated, direct laryngeal examination or laryngoscopy. Care must be taken not to distort the oropharynx or larynx if a laryngoscope is used and to ensure paradoxical movement of the arytenoids during examination is not confused with proper, active arytenoid abduction.15,21,22 Transoral flexible video endoscopy can be useful because it provides magnification and allows laryngeal examination without the need for manipulation of the tongue or epiglottis.22 Transnasal flexible endoscopy for evaluation of the larynx also has been described in dogs weighing more than 20 kg and can be performed with lower doses of premedication and induction agents, especially if intranasal lidocaine is applied before the procedure.107 Laryngeal ultrasound (echolaryngography) and CT have also been used successfully for diagnosing unilateral and bilateral laryngeal paralysis.13,108 In dogs that are mildly affected by laryngeal paralysis, symptomatic medical care, including weight loss, avoidance of stressors, heat, and humidity, anxiolytic therapy, and medications for gastrointestinal supportive care (antacid therapy, promotility agents, antiemetic drugs) may ameliorate some clinical signs. Treatment of underlying disorders such as hypothyroidism and myasthenia gravis also may be beneficial. However, in more clinically affected dogs, especially those with upper airway obstruction, surgical intervention is needed to improve or resolve upper airway signs. Multiple surgical techniques are described, and the decision to perform unilateral or bilateral repair is debated in dogs that have bilateral laryngeal paralysis. The goal of surgical intervention is to widen the glottis to relieve the airway obstruction without deforming the laryngeal anatomy to preserve the airway protective function of the larynx.15,89 Surgical techniques are characterized into three main procedural outcome goal categories: widen the dorsal glottis (unilateral and bilateral arytenoid lateralization), widen the ventral glottis (vocal fold resection, partial laryngectomy, modified castellated laryngofissure), and widen the dorsal and ventral glottis (castellated laryngofissure combined with bilateral arytenoid lateralization).89 Unilateral arytenoid lateralization (tie-back) is performed more commonly than bilateral lateralization, even in patients with bilateral laryngeal paralysis.15,91,92,109,110 Bilateral arytenoid lateralization is associated with increased mortality and postoperative complications, including aspiration pneumonia and acute respiratory distress compared with unilateral lateralization and partial laryngectomy.91 The most common postoperative complication is aspiration pneumonia, which is seen in 8% to 33% of patients.91,109,111 Other reported complications include coughing and gagging, return of clinical signs, seroma formation, respiratory distress, and sudden death.15,91,109,111 Despite complications, most animals (90%) experience improvement in their respiratory status and stridor postoperativ­ ely.91,92,109 Arytenoid lateralization also has been described for small breed, nonbrachycephalic dogs with combined laryngeal paralysis and laryngeal collapse as a viable technique to improve upper airway obstructive symptoms.111 Laryngeal paralysis is uncommon in cats, but the clinical signs are often similar to dogs.113-115 Affected cats tend to be older, with median or mean ages reported from 8 to 16 years depending on the study.113-115 Suspected congenital laryngeal paralysis also has been reported sporadically in young cats less than 2 years of age.113,115 No clear guidelines exist regarding whether surgical intervention should be performed in cats with unilateral disease. Postoperative complications include transient Horner syndrome, dyspnea, pulmonary edema, laryngeal edema, and obstructive laryngeal stenosis.113-115 Immediate postoperative aspiration pneumonia has been described in only two cats.113

CHAPTER 18  Upper Airway Disease Laryngeal Collapse While laryngeal collapse is most commonly seen as a secondary complication of BAS, it can also occur with other forms of airway obstruction, such as laryngeal paralysis, tracheal collapse, and as a component of Norwich Terrier upper airway syndrome.116-120 In obstructive diseases, chronically increased negative intraluminal airway pressures lead to weakening of the cartilages, loss of rima glottic diameter, increased work of breathing, inflammation, and airway obstruction. When laryngeal collapse is diagnosed in dogs with tracheal collapse, it is possible that the pathologic chondromalacia affecting the tracheal cartilages could also be affecting the laryngeal cartilages, predisposing them to collapse and exacerbated by the increased respiratory effort associated with tracheal collapse. Additional investigation into these two concurrent disease processes is needed to prove this association. In Norwich Terriers, a unique disease syndrome characterized by narrowed infraglottic lumen, varying degrees of laryngeal collapse, partially or fully obliterated piriform recess, redundant laryngeal mucosa, and redundant dorsal pharyngeal wall has been described through extensive work evaluating the airways of dogs with varying degrees of clinical airway signs and pedigrees.118-120 Work evaluating the genetic basis of the disease and detailed grading system for all laryngeal abnormalities seen in Norwich Terriers is underway.120 Laryngeal collapse is graded on a scale of 1–3, with grade 1 defined by eversion of the laryngeal saccules, grade 2 is medial positioning of the cuneiform processes and aryepiglottic collapse, and grade 3 is collapse of the corniculate cartilages. Clinical signs of laryngeal collapse are similar to those observed with other forms of laryngeal disease, including noisy respiration, gagging, intolerance of heat, stress, or excitement, stridor, and respiratory distress. Initial management strategies with weight loss, stress and anxiety control, and antiinflammatory medications (corticosteroids or nonsteroidal antiinflammatory drugs) may improve respiratory comfort in some patients, especially those that are less severely affected. For more severely affected patients, or those that fail to respond to medical therapy, surgical intervention may be indicated. A variety of techniques have been described to address specific aspects of the complex disease, include sacculectomy, unilateral arytenoid lateralization, unilateral arytenoid laryngoplasty, and ventral laryngotomy.118-120 For advanced cases, or those that fail other surgical attempts, permanent tracheostomy is often performed.121

Inflammatory Laryngeal Disease Upper airway obstruction resulting from inflammatory or granulomatous laryngeal disease is uncommon in veterinary medicine and has been reported only sporadically in cats and dogs.55,122-128 Little is known about the underlying cause, but potential causes include feline respiratory viruses, secondary bacterial infection, endotracheal intubation, previous foreign body, and secondary to laryngeal surgery.122-124,127,128 Cervical radiography may show increased soft tissue opacity or laryngeal narrowing.122,124-128 Sedated laryngeal examination reveals thickening and erythema of the larynx and vocal folds.122,125 Nodules or mass-like lesions may also be seen on the arytenoid cartilages or within the rima glottis.122,124-126 Since the gross appearance cannot differentiate inflammatory or granulomatous laryngitis from neoplasia, fine-needle aspirate, or preferably, biopsy and histopathology must be performed. Depending on the severity of clinical signs, temporary tracheostomy may be necessary, especially if significant inflammation develops secondary to manipulation or biopsy.122,1123 Clinical outcome depends on response to treatment with corticosteroids, antibiotics, and surgical intervention, such as debulking of polypoid or mass-like inflammatory lesions.55,122-125,127,128 Permanent tracheostomy may be necessary for refractory or nonresponsive cases.122,124

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Tracheal Stenosis/Stricture Tracheal injury secondary to intraluminal trauma, as with endotracheal intubation, and extraluminal trauma, which is seen with bite wounds and vehicular trauma, is not commonly reported in dogs and cats.129-133 Injury and tearing of the dorsal tracheal membrane generally result from overinflation of the endotracheal tube cuff or repositioning of the head and neck during anesthesia without disconnecting the endotracheal tube from the anesthetic circuit. Acute injury generally results in pneumomediastinum, pneumothorax, subcutaneous emphysema, and respiratory distress.131 Less severe, full-thickness tracheal tears can result in circumferential tracheal stricture and ultimately tracheal narrowing, which, if severe enough, can result in upper airway obstruction. Tracheal stenosis also can be the result of scarring from prior surgery or tracheal avulsion.129,130,134 Thoracic radiographs, CT, and tracheoscopy can be used to confirm a diagnosis of tracheal stricture. Treatment options include surgical tracheal resection and anastomosis, bronchoscopic debridement of necrotic tissue, and intraluminal tracheal stenting (see Chapter 19, Tracheal Stents: Indications and Management).129,130,132,134,135 Tracheal narrowing leading to upper airway obstruction also has been reported secondary to intraluminal tracheal hemorrhage resulting from anticoagulant rodenticide toxicity and a tracheal hematoma in dogs136-138 (Fig. 18.4).

Tracheal Foreign Bodies Aspiration of foreign material into the trachea can cause coughing, gagging, head and neck extension, and respiratory distress. The duration of clinical signs can vary depending on the type and extent of airway obstruction and the degree of associated inflammation. Retrieved tracheal materials in dogs and cats include grass awns, plant material, plastic material, stones and gravel, an owl tooth, and Cuterebra spp. in cats.139-143 Cervical and thoracic radiographs can be helpful in the diagnosis of tracheal foreign material. Tracheoscopy allows for direct visualization and can be used for the removal of the foreign body using grasping forceps or an endoscopic snare passed through the working channel of the bronchoscope (Fig. 18.5).139,141,142 One study reports an 86% success rate for bronchoscope-assisted foreign body retrieval in dogs and 40% success in cats.139 When bronchoscopic removal is not feasible or fails, surgical excision can be considered.139,142,143 Retrieval using grasping forceps and fluoroscopic guidance has been described as a successful technique for tracheal foreign body removal in cats.141 Novel retrieval techniques using the inflated balloon from a Foley catheter or fluoroscopic guided over-the-wire balloon angioplasty catheters have also been described.140,144

Fig. 18.4  Lateral radiograph showing diffuse tracheal narrowing secondary to hemorrhage into the dorsal tracheal membrane secondary to anticoagulant rodenticide intoxication.

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Fig. 18.5  Endoscopic retrieval of a cherry pit from the trachea of a French Bulldog.

Upper Airway Neoplasia Nasal and nasopharyngeal neoplasia are uncommon causes of upper airway obstructive signs, unless there is complete obstruction to nasal airflow, which can cause nasal discharge, inspiratory dyspnea, openmouth breathing (cats), and inability to sleep (dogs). Canine nasal neoplasias are generally carcinomas (adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma) or sarcomas (fibrosarcoma, osteosarcoma, and chondrosarcoma).145 In cats, nasal lymphoma is most common, but sarcomas (fibrosarcoma, osteosarcoma, chondrosarcoma, and hemangiosarcoma), carcinomas (adenocarcinoma, undifferentiated carcinoma), and olfactory neuroblastomas are also reported.145-147 Since achieving surgical margins is extremely difficult in the nasal passage, treatment usually involves systemic chemotherapy and radiation therapy. Intraarterial chemotherapy delivery has also been described as an adjunct treatment modality for nasal neoplasia. Nasopharyngeal neoplasias reported in dogs include lymphoma, mast cell tumor, squamous cell carcinoma, undifferentiated carcinoma, adenocarcinoma, fibrosarcoma, osteosarcoma, and spindle cell tumor.82 Nasopharyngeal neoplasias are less commonly reported in cats and include lymphoma and adenocarcinoma.14,48,82,147 Surgical treatment may be possible for small or well-circumscribed nasopharyngeal neoplasias, although chemotherapy and radiation are more likely to be beneficial. Primary laryngeal neoplasia is uncommon in dogs and cats and requires histopathology to differentiate from inflammatory/granulomatous laryngitis and benign lesions because they can have similar appearance on direct visual examination.55,122,125 In general, animals with laryngeal tumors are older (median age of 8 years) and tend to have a history of coughing, choking, dyspnea, and voice change.148 Most patients have significant disease progression by the time of presentation. In cats, laryngeal neoplasias include lymphoma, squamous cell carcinoma, poorly differentiated round cell tumor, carcinoma, and adenocarcinoma.55,125,126,148,149 In dogs, confirmed laryngeal neoplasias include chondrosarcoma, extramedullary plasmacytoma, rhabdomyoma, carcinoma, mast cell tumor, squamous cell carcinoma, lymphoma, adenocarcinoma, melanoma, granular cell tumor, and chondroma.148,150-153 Benign laryngeal lipomas and rhabdomyomas also are rarely seen in dogs.148,149,154,155 Surgical resection is difficult and may require total laryngectomy and permanent tracheostomy for

long-term management but can be successful for small or benign lesi­ ons.148,154,155 Overall, prognosis for laryngeal tumors is guarded and depends on type, invasiveness, metastatic spread, resectability, and response to chemotherapy or radiation.149 Primary tracheal neoplasia is also uncommon in dogs and cats, and one study suggests it is less common than primary laryngeal neoplasia.148 The most common tracheal tumor reported in dogs is osteochondroma; however, other reported types include chondrosarcoma, chondroma, adenocarcinoma, carcinoma, mast cell tumor, leiomyoma, extramedullary plasmacytoma, and osteosarcoma.148,156 Lymphoma is the most common feline tracheal tumor; however, carcinoma, adenocarcinoma, adenoma, squamous cell carcinoma, neuroendocrine carcinoma, and basal cell carcinoma also have been reported.126,149,153,156-159 The median age of dogs and cats with tracheal tumors is 9 years except for dogs with osteochondroma and enchondroma, which tend to be less than 2 years of age.148,156 Coughing, wheezing, dyspnea, and stridor are common clinical signs in patients with tracheal tumors.148,156 Cervical and thoracic radiographs can be helpful in the diagnosis of an intraluminal tracheal mass, which can be located at any point in the trachea from caudal to the larynx to the level of the carina. CT, which can be performed in the awake, nonintubated patient, is helpful to more precisely determine the extent of the mass and degree of luminal occlusion.14 Tracheoscopy is valuable for direct visualization of the mass as well as obtaining biopsy or brush cytology samples but often requires extubation in small patients, which can be dangerous with obstructive lesions. Options for the management of tracheal masses include surgical resection, endoscopic snaring, cryotherapy, radiation, chemotherapy, and palliative intraluminal stenting.125,156,157,134 The prognosis varies and depends on the extent of disease, mass type, and treatment response.

Complications of Upper Airway Obstruction In addition to the respiratory distress, hypoxemia, and hypercarbia that can be associated with upper airway obstruction, there are numerous potential secondary complications that can result from obstructive upper airway disease, including hyperthermia (see Chapter 10, Hyperthermia and Fever), noncardiogenic pulmonary edema (see Chapter 23, Pulmonary Edema), and aspiration pneumonia (see Chapter 24, Pneumonia). Temperature should be monitored closely in all patients with upper airway disease, especially if there is concern for obstruction and failure to appropriately dissipate heat. Failure to actively cool a severely hyperthermic patient can result in respiratory, cardiovascular, neurologic, renal, and coagulation derangements that can progress to multiorgan dysfunction syndrome, multiorgan failure, and disseminated intravascular coagulation (see Chapter 7, SIRS, MODS and Sepsis). Identification of pulmonary pathology consistent with noncardiogenic edema (caudodorsal interstitial to alveolar infiltrates) and aspiration pneumonia (cranioventral interstitial to alveolar infiltrates) is important before any anesthetic procedure, and in the case of aspiration pneumonia, warrants consideration for airway sampling for cytology, culture and susceptibility testing at anesthetic induction, and institution of appropriate antimicrobial therapy. Treatment for noncardiogenic pulmonary edema is supportive and should include oxygen therapy and judicious crystalloid and colloid fluid therapy (see Chapter 23, Pulmonary Edema). The use of diuretics and b-agonists in noncardiogenic pulmonary edema is controversial because increased clearance of alveolar fluid has not been proven.160-162

Additional Upper Airway Management Strategies In addition to the specific treatment strategies to manage the underlying cause of upper airway obstruction, additional patient support

CHAPTER 18  Upper Airway Disease strategies may be necessary to provide relief of respiratory distress and improve oxygenation, ventilation and patient comfort. High-flow nasal canula (HFNC) oxygen therapy not only provides high-flow oxygen therapy and continuous positive airway pressure (CPAP), but it also warms and humidifies the air, and is generally well tolerated compared with traditional nasal prongs (see Chapter 31, High Flow Nasal Oxygen). HFNC has proven useful in acutely hypoxic dogs that failed to respond to traditional oxygen supplementation as a method to avoid mechanical ventilation.163 HFNC has also been shown to support hypoxic brachycephalic dogs and improve their dyspnea scores upon recovery from general anesthesia, though impairment in ventilation and aerophagia were noted.164 Another device to deliver CPAP that has been shown to be helpful in acutely hypoxic dogs is a pediatric CPAP helmet or hood.165 In this group of hypoxic dogs with primary pulmonary dysfunction, PaO2, A-a gradient, SpO2, and PaO2:FiO2 were improved and the helmet was well tolerated in 15/17 dogs within an hour of CPAP therapy.165 The V-gel supraglottic airway device was originally designed for blind intubation in pediatric patients anticipated to be difficult to intubate and has documented utility for pediatric intubation by less experienced physicians.166 In healthy cats, the device was found to be useful for mechanical ventilation pressure maintenance up to 16 cm H2O and had less leaking than endotracheal intubation. The device can be placed blindly and with direct visualization in veterinary patients and may help avoid the laryngeal and tracheal irritation associated with endotracheal intubation.167 In another study of healthy cats, less postintubation stridor was associated with V-gel use.168

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40. De Lorenzi D, Bertoncello D, Drigo M: Bronchial abnormalities found in a consecutive series of 40 brachycephalic dogs, J Am Vet Med Assoc 235(7):835-840, 2009. 41. Planellas M, Cuenca R, Tabar MD, et al: Evaluation of C-reactive protein, haptoglobin and cardiac troponin 1 levels in brachycephalic dogs with upper airway obstructive syndrome, BMC Vet Res 8:152-159, 2012. 43. Harvey CE: Stenotic nares surgery in brachycephalic dogs, J Am Anim Hosp Assoc 18:535-537, 1982. 43. Ellison GW: Alapexy: an alternative technique for repair of stenotic nares in dogs, J Am Anim Hosp Assoc 40:484-489, 2004. 44. Huck JL, Stanley BJ, Hauptman JG: Technique and outcome of nares amputation (Trader’s technique) in immature shih tzus, J Am Anim Hosp Assoc 44(2):82-85, 2008. 45. Lodato DL, Hedlund CS: Brachycephalic airway syndrome: management, Compendium 34(8):E4-E7, 2012. 46. Pink JJ, Doyle RS, Hughes JML, et al: Laryngeal collapse in seven brachycephalic puppies, J Small Anim Pract 47(3):131-135, 2006. 47. White RN: Surgical management of laryngeal collapse associated with brachycephalic airway obstruction syndrome in dogs, J Small Anim Pract 28;53(1):44-50, 2011. 48. Allen HS, Broussard J, Noone K: Nasopharyngeal diseases in cats: a retrospective study of 53 cases (1991-1998), J Am Anim Hosp Assoc 35(6): 457-461, 1999. 49. Smart L, Jandrey KE: Upper airway obstruction caused by a nasopharyngeal polyp and brachycephalic airway syndrome in a Chinese Shar-Pei puppy, J Vet Emer Crit 18(4):393-398, 2008. 50. Fingland RB, Gratzek A, Vorhies MW, et al: Nasopharyngeal polyp in a dog, J Am Anim Hosp Assoc 29:311-314, 1993. 51. Pollock S: Nasopharyngeal polyp in a dog, a case study, Vet Med Small Anim Clin 66(7):705-706, 1971. 52. Holt DE: Nasopharyngeal polyps. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 328-332. 53. Reed N, Gunn-Moore D: Nasopharyngeal disease in cats: 1. Diagnostic investigation, J Feline Med Surg 14(5):306-315, 2012. 54. Kudnig ST: Nasopharyngeal polyps in cats, Clin Tech Small Anim Pract 17(4):174-177, 2002. 55. Griffon DJ: Upper airway obstruction in cats: diagnosis and treatment, Compendium 22(10):897-909, 2000. 56. Muilenburg RK, Fry TR: Feline nasopharyngeal polyps, Vet Clin Small Anim Pract 32(4):839-849, 2002. 57. Tillson DM, Donnelly KE: Feline inflammatory polyps and ventral bulla osteotomy, Compendium 26(6):1-5, 2004. 58. Klose TC, MacPhail CM, Schultheiss PC, et al: Prevalence of select infectious agents in inflammatory aural and nasopharyngeal polyps from client-owned cats, J Feline Med Surg 12(10):769-774, 2010. 59. Oliveira CR, O’Brien RT, Matheson JS, et al: Computed tomographic features of feline nasopharyngeal polyps, Vet Radiol Ultrasound 53(4): 406-411, 2012. 60. Kapatin AS, Mattheisen DT, Noone KE, et al: Results of surgery and long term follow up in 31 cats with nasopharyngeal polyps, J Am Anim Hosp Assoc 26:387-392, 1990. 61. Anderson DM, Robinson RK, White RA: Management of inflammatory polyps in 37 cats, Vet Rec 147(24):684-687, 2000. 62. Trevor PB, Martin RA: Tympanic bulla osteotomy for treatment of middle-ear disease in cats: 19 cases (1984-1991), J Am Vet Med Assoc 202(1):123-128, 1993. 63. Anders BB, Hoelzler MG, Scavelli TD, et al: Analysis of auditory and neurologic effects associated with ventral bulla osteotomy for removal of inflammatory polyps or nasopharyngeal masses in cats, J Am Vet Med Assoc 233(4):580-585, 2008. 64. Billen F, Day MJ, Clercx C: Diagnosis of pharyngeal disorders in dogs: a retrospective study of 67 cases, J Small Anim Pract 47(3):122-129, 2006. 65. Henderson SM, Bradley K, Day MJ, et al: Investigation of nasal disease in the cat—a retrospective study of 77 cases, J Feline Med Surg 6(4):245-257, 2004. 66. Coolman BR, Marretta SM, McKiernan BC, et al: Choanal atresia and secondary nasopharyngeal stenosis in a dog, J Am Anim Hosp Assoc 34(6):497-501, 1998.

67. Berent AC, Kinns J, Weisse C: Balloon dilatation of nasopharyngeal stenosis in a dog, J Am Vet Med Assoc 229(3):385-388, 2006. 68. Berent AC, Weisse C, Todd K, et al: Use of a balloon-expandable metallic stent for treatment of nasopharyngeal stenosis in dogs and cats: six cases (2005-2007), J Am Vet Med Assoc 233(9):1432-1440, 2008. 69. Boswood A, Lamb CR, Brockman DJ, et al: Balloon dilatation of nasopharyngeal stenosis in a cat, Vet Radiol Ultrasound 44(1):53-55, 2003. 70. Glaus TM, Tomsa K, Reusch CE: Balloon dilation for the treatment of chronic recurrent nasopharyngeal stenosis in a cat, J Small Anim Pract 43(2):88-90, 2002. 71. Glaus TM, Gerber B, Tomsa K, et al: Reproducible and long-lasting success of balloon dilation of nasopharyngeal stenosis in cats, Vet Rec 157(9):257-259, 2005. 72. Novo RE, Kramek B: Surgical repair of nasopharyngeal stenosis in a cat using a stent, J Am Anim Hosp Assoc 35(3):251-256, 1999. 73. Mitten RW: Nasopharyngeal stenosis in four cats, J Small Anim Pract 29(6):341-345, 1988. 74. Griffon DJ, Tasker S: Use of a mucosal advancement flap for the treatment of nasopharyngeal stenosis in a cat, J Small Anim Pract 41(2):71-73, 2000. 75. Cook AK, Mankin KT, Saunders AB, et al: Palatal erosion and oronasal fistulation following covered nasopharyngeal stent placement in two dogs, Ir Vet J 66(1):8-14, 2013. 76. Khoo A, Marchevsky A, Barrs V, et al: Choanal atresia in a Himalayan cat—first reported case and successful treatment, J Feline Med Surg 9(4):346-349, 2007. 77. Azarpeykan S, Stickney A, Hill KE, et al: Choanal atresia in a cat, N Z Vet J 61(4):237-241, 2013. 78. Schafgans KE, Armstrong PJ, Kramek B, et al: Bilateral choanal atresia in a cat, J Feline Med Surg 14(10):759-763, 2012. 79. Wehner A, Crochik S, Howerth EW, et al: Diagnosis and treatment of blastomycosis affecting the nose and nasopharynx of a dog, J Am Vet Med Assoc 233(7):1112-1116, 2008. 80. Malik R, Martin P, Wigney DI, et al: Nasopharyngeal cryptococcosis, Aust Vet J 75(7):483-488, 1997. 81. Forster-van Hijfte MA, Groth AM, Emmerson TD: Expansile, inflammatory middle ear disease causing nasopharyngeal obstruction in a cat, J Feline Med Surg 13(6):451-453, 2011. 82. Hunt GB, Perkins MC, Foster SF, et al: Nasopharyngeal disorders of dogs and cats: a review and retrospective study, Compendium 24(3):184-203, 2002. 83. Kang MH, Lim CY, Park HM: Nasopharyngeal tooth foreign body in a dog, J Vet Dent 28(1):26-29, 2011. 84. Haynes KJ, Anderson SE, Laszlo MP: Nasopharyngeal trichobezoar foreign body in a cat, J Feline Med Surg 12(11):878-881, 2010. 85. Riley P: Nasopharyngeal grass foreign body in eight cats, J Am Vet Med Assoc 202(2):299-300, 1993. 86. Ober CP, Barber D, Troy GC: What is your diagnosis? J Am Vet Med Assoc 231(8):1207-1208, 2007. 87. Papazoglau LG, Patsikas MN: What is your diagnosis? A radiopaque foreign body located in the nasopharynx, J Small Anim Prac 36(10):425, 434, 1995. 88. Simpson AM, Harkin KR, Hoskinson JJ: Radiographic diagnosis: nasopharyngeal foreign body in a dog, Vet Radiol Ultrasound 41(4):326-328, 2000. 89. Holt DE, Brockman DJ: Laryngeal paralysis. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 319-328. 90. Griffin J: Laryngeal paralysis: pathophysiology, diagnosis, and surgical repair, Compendium 7:1-13, 2005. 91. MacPhail CM, Monnet E: Outcome of and postoperative complications in dogs undergoing surgical treatment of laryngeal paralysis: 140 cases (1985-1998), J Am Vet Med Assoc 218(12):1949-1956, 2001. 92. Stanley BJ, Hauptman JG, Fritz MC, et al: Esophageal dysfunction in dogs with idiopathic laryngeal paralysis: a controlled cohort study, Vet Surg 39(2):139-149, 2010. 93. Thieman KM, Krahwinkel DJ, Shelton D, et al: Laryngeal paralysis: part of a generalized polyneuropathy syndrome in older dogs, Vet Surg 36:E26, 2007.

CHAPTER 18  Upper Airway Disease 94. Thieman KM, Krahwinkel DJ, Sims MH, et al: Histopathological confirmation of polyneuropathy in 11 dogs with laryngeal paralysis, J Am Anim Hosp Assoc 46(3):161-167, 2010. 95. Venker-van Haagen AJ, Bouw J, Hartman W: Hereditary transmission of laryngeal paralysis in Bouviers, J Am Anim Hosp Assoc 17:75-76, 1981. 96. Mahony OM, Knowles KE, Braund KG, et al: Laryngeal paralysis-polyneuropathy complex in young rottweilers, J Vet Intern Med 12:330-337, 1998. 97. Braund KG, Shores A, Cochrane S, et al: Laryngeal paralysis-polyneuropathy complex in young dalmatians, Am J Vet Res 55:534-542, 1994. 98. Polizopoulou ZS, Koutinas AF, Papadopoulos GC, et al: Juvenile laryngeal paralysis in three Siberian husky x Alaskan malamute puppies, Vet Rec 153:624-627, 2003. 99. O’Brien JA, Hendriks JC: Inherited laryngeal paralysis: analysis in the husky cross, Vet Q 8:301-302, 1986. 100. Gabriel A, Poncelet L, Van Ham L, et al: Laryngeal paralysis-polyneuropathy complex in young related Pyrenean mountain dogs, J Small Anim Pract 47(3):144-149, 2006. 101. Shelton GD, Podell M, Poncelet L, et al: Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease? Muscle Nerve 27:471-477, 2003. 102. Klein MK, Powers BE, Withrow SJ, et al: Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989), J Am Vet Med Assoc 206:1007-1009, 1995. 103. White R, Williams JM: Tracheal collapse in the dog-is there really a role for surgery? A survey of 100 cases, J Small Anim Pract 35(4):191-196, 1994. 104. Jaggy A, Oliver JE, Ferguson DC, et al: Neurological manifestations of hypothyroidism: a retrospective study of 29 dogs, J Vet Intern Med 8:328-336, 1994. 105. Dewey CW, Bailey CS, Shelton GD, et al: Clinical forms of acquired myasthenia gravis in dogs: 25 cases (1988-1995), J Vet Intern Med 11:50-57, 1997. 106. Jeffery ND, Talbot CE, Smith PM, et al: Acquired idiopathic laryngeal paralysis as a prominent feature of generalised neuromuscular disease in 39 dogs, Vet Rec 158:17, 2006. 107. Radlinsky MG, Williams J, Frank PM, et al: Comparison of three clinical techniques for the diagnosis of laryngeal paralysis in dogs, Vet Surg 38(4):434-438, 2009. 108. Rudorf H, Barr FJ, Lane JG: The role of ultrasound in the assessment of laryngeal paralysis in the dog, Vet Radiol Ultrasound 42(4):338-343, 2001. 109. Hammel SP, Hottinger HA, Novo RE: Postoperative results of unilateral arytenoid lateralization for treatment of idiopathic laryngeal paralysis in dogs: 39 cases (1996-2002), J Am Vet Med Assoc 228(8):1215-1220, 2006. 110. Snelling SR, Edwards GA: A retrospective study of unilateral arytenoid lateralisation in the treatment of laryngeal paralysis in 100 dogs (19922000), Aust Vet J 81(8):464-468, 2003. 111. Greenberg MJ, Reems MR, Monnet E: Use of perioperative metoclopramide in dogs undergoing surgical treatment of laryngeal paralysis: 43 cases, Vet Surg 36:E11, 2007. 112. Nelissen P, White RAS: Arytenoid lateralization for management of combined laryngeal paralysis and laryngeal collapse in small dogs, Vet Surg 21:261-265, 2011. 113. Hardie RJ, Gunby J, Bjorling DE: Arytenoid lateralization for treatment of laryngeal paralysis in 10 cats, Vet Surgery 38(4):445-451, 2009. 114. Thunberg B, Lantz GC: Evaluation of unilateral arytenoid lateralization for the treatment of laryngeal paralysis in 14 cats, J Am Anim Hosp Assoc 46(6):418-424, 2010. 115. Schachter S, Norris CR: Laryngeal paralysis in cats: 16 cases (1990-1999), J Am Vet Med Assoc 216(7):1100-1103, 2005. 116. Nelissen P, White RA: Arytenoid lateralization for management of combined laryngeal paralysis and laryngeal collapse in small dogs, Vet Surg 41(2):261-265, 2012. 117. MacPhail CM: Laryngeal disease in dogs and cats: an update, Vet Clin North Am Small Anim Pract 50(2):295-310, 2020. 118. Johnson LR, Mayhew PD, Steffey MA, Hunt GB, Carr AH, McKiernan BC: Upper airway obstruction in Norwich Terriers: 16 cases, J Vet Intern Med 27(6):1409-1415, 2013.

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119. Koch DA, Rosaspina M, Wiestner T, Arnold S, Montavon PM: Comparative investigations on the upper respiratory tract in Norwich terriers, brachycephalic and mesaticephalic dogs, Schweiz Arch Tierheilkd 156(3):119-124, 2014. 120. Lai G, Stanley B, Nelson N, et al: Clinical and laryngoscopic characterization of Norwich Terrier Upper Airway Syndrome (NTUAS): preliminary results, Athens, Greece, July 4-6, 2018, European College of Veterinary Surgeons (ECVS). 121. Gobbetti M, Romussi S, Buracco P, Bronzo V, Gatti S, Cantatore M: Long-term outcome of permanent tracheostomy in 15 dogs with severe laryngeal collapse secondary to brachycephalic airway obstructive syndrome, Vet Surg 47(5):648-653, 2018. 122. Costello MF, Keith D, Hendrick M, et al: Acute upper airway obstruction due to inflammatory laryngeal disease in 5 cats, J Vet Emerg Crit Care 11(3):205-210, 2001. 123. Costello MF: Upper airway disease. In Silverstein DC, Hopper KA, editors: Small animal critical care medicine, St Louis, 2009, Elsevier, pp 67-71. 124. Tasker S, Foster DJ, Corcoran BM, et al: Obstructive inflammatory laryngeal disease in three cats, J Feline Med Surg 1(1):53-59, 1999. 125. Taylor SS, Harvey AM, Barr FJ, et al: Laryngeal disease in cats: a retrospective study of 35 cases, J Feline Med Surg 11(12):954-962, 2009. 126. Jakubiak MJ, Siedlecki CT, Zenger E, et al: Laryngeal, laryngotracheal, and tracheal masses in cats: 27 cases (1998-2003), J Am Anim Hosp Assoc 41(5):310-316, 2005. 127. Oakes MG, McCarthy RJ: What is your diagnosis? [granulomatous laryngitis], J Am Vet Med Assoc 204:1891, 1994. 128. Harvey CE, O’Brien JA: Surgical treatment of miscellaneous laryngeal conditions in dogs and cats, J Am Anim Hosp Assoc 18:557-562, 1982. 129. Roach W, Krahwinkel DJ: Obstructive lesions and traumatic injuries of the canine and feline tracheas, Compendium 31(2):86-93, 2009. 130. Holt DE: Tracheal trauma. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 359-363. 131. Mitchell SL, McCarthy R, Rudloff E, et al: Tracheal rupture associated with intubation in cats: 20 cases (1996-1998), J Am Vet Med Assoc 216(10):1592-1595, 2000. 132. Alderson B, Senior JM, Dugdale AHA: Tracheal necrosis following tracheal intubation in a dog, J Small Anim Pract 47(12):754-756, 2006. 133. Jordan CJ, Halfacree ZJ, Tivers MS: Airway injury associated with cervical bite wounds in dogs and cats: 56 cases, Vet Comp Orthop Traumatol 26(2):89-93, 2013. 134. Culp WTN, Weisse C, Cole SG, et al: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007. 135. White RN, Milner HR: Intrathoracic tracheal avulsion in three cats, J Amall Anim Pract 36(8):343-347, 1995. 136. Blocker TL, Roberts BK: Acute tracheal obstruction associated with anticoagulant rodenticide intoxication in a dog, J Small Anim Pract 40(12):577-580, 1999. 137. Berry CR, Gallaway A, Thrall DE, et al: Thoracic radiographic features of anticoagulant rodenticide toxicity in fourteen dogs, Vet Radiol Ultrasound 34:391-396, 1993. 138. Pink JJ: Intramural tracheal haematoma causing acute respiratory obstruction in a dog, J Small Anim Pract 47(3):161-164, 2006. 139. Tenwolde AC, Johnson LR, Hunt GB, et al: The role of bronchoscopy in foreign body removal in dogs and cats: 37 cases (2000-2008), J Vet Intern Med 24(5):1063-1068, 2010. 140. Goodnight ME, Scansen BA, Kidder AC, et al: Use of a unique method for removal of a foreign body from the trachea of a cat, J Am Vet Med Assoc 237(6):689-694, 2010. 141. Tivers MS, Moore AH: Tracheal foreign bodies in the cat and the use of fluoroscopy for removal: 12 cases, J Small Anim Pract 47(3):155-159, 2006. 142. Dvorak LD, Bay JD, Crouch DT, et al: Successful treatment of intratracheal cuterebrosis in two cats, J Am Anim Hosp Assoc 36(4):304-308, 2000. 143. Bordelon JT, Newcomb BT, Rochat MC: Surgical removal of a Cuterebra larva from the cervical trachea of a cat, J Am Anim Hosp Assoc 45(1): 52-54, 2009.

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144. Pratschke KM, Hughes JML, Guerin SR, et al: Foley catheter technique for removal of a tracheal foreign body in a cat, Vet Rec 144(7):181-182, 1999. 145. Malinowski C: Canine and feline nasal neoplasia, Clin Tech Small Anim Pract 21(2):89-94, 2006. 146. McEntee MC: Neoplasms of the nasal cavity. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 293-301. 147. Little L, Patel R, Goldschmidt M: Nasal and nasopharyngeal lymphoma in cats: 50 cases (1989-2005), Vet Pathol 44(6):885-892, 2007. 148. Carlisle CH, Biery DN, Thrall DE: Tracheal and laryngeal tumors in the dog and cat: literature review and 13 additional patients, Vet Radiol Ultrasound 32(5):229-235, 1991. 149. Saik JE, Toll SL, Diters RW, et al: Canine and feline laryngeal neoplasia: a 10-year survey, J Am Anim Hosp Assoc 22:359-365, 1986. 150. Muraro L, Aprea F, White RAS: Successful management of an arytenoid chondrosarcoma in a dog, J Small Anim Pract 54:33-35, 2013. 151. Witham AI, French AF, Hill KE: Extramedullary laryngeal plasmacytoma in a dog, N Z Vet J 60(1):61-64, 2012. 152. Hayes AM, Gregory SP, Murphy S, et al: Solitary extramedullary plasmacytoma of the canine larynx, J Small Anim Pract 48(5):288-291, 2007. 153. Rossi G, Magi GE, Tarantino C, et al: Tracheobronchial neuroendocrine carcinoma in a cat, J Comp Pathol 137(2-3):165-168, 2007. 154. O’Hara AJ, McConnell M, Wyatt K, et al: Laryngeal rhabdomyoma in a dog, Aust Vet J 79(12):817-821, 2001. 155. Brunnberg M, Cinquoncie S, Burger M, et al: Infiltrative laryngeal lipoma in a Yorkshire Terrier as cause of severe dyspnoea, Tierarztl Prax Ausg K Kleintiere Heimtiere 41(1):53-56, 2013. 156. Brown MR, Rogers KS: Primary tracheal tumors in dogs and cats, Compendium 25(11):854-860, 2003. 157. Drynan EA, Moles AD, Raisis AL: Anaesthetic and surgical management of an intra-tracheal mass in a cat, J Feline Med Surg 13(6):460-462, 2011. 158. Jelinek F, Vozkova D: Carcinoma of the trachea in a cat, J Comp Pathol 147(2-3):177-180, 2012.

159. Green ML, Smith J, Fineman L, et al: Diagnosis and treatment of tracheal basal cell carcinoma in a Maine Coon and long-term outcome, J Am Anim Hosp Assoc 48(4):273-277, 2012. 160. Bachmann M, Waldrop JE: Noncardiogenic pulmonary edema, Compendium 34(11):E1-E9, 2012. 161. Hughes D: Pulmonary edema. In Silverstein DC, Hopper KA, editors: Small animal critical care medicine, St. Louis, 2009, Elsevier, pp 86-90. 162. Boothe DM: Drugs affecting the respiratory system. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 229-252. 163. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL: High-flow nasal cannula oxygen therapy in acute hypoxemic respiratory failure in 22 dogs requiring oxygen support escalation, J Vet Emerg Crit Care (San Antonio) 30(4):364-375, 2020. 164. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL: Preliminary evaluation of the use of high-flow nasal cannula oxygen therapy during recovery from general anesthesia in dogs with obstructive upper airway breathing, J Vet Emerg Crit Care (San Antonio) 30(4):487-492, 2020. 165. Ceccherini G, Lippi I, Citi S, et al: Continuous positive airway pressure (CPAP) provision with a pediatric helmet for treatment of hypoxemic acute respiratory failure in dogs, J Vet Emerg Crit Care (San Antonio) 30(1):41-49, 2020. 166. Bielski A, Smereka J, Madziala M, Golik D, Szarpak L: Comparison of blind intubation with different supraglottic airway devices by inexperienced physicians in several airway scenarios: a manikin study, Eur J Pediatr 178(6):871-882, 2019. doi:10.1007/s00431-019-03345-4. 167. Prasse SA, Schrack J, Wenger S, Mosing M: Clinical evaluation of the vgel supraglottic airway device in comparison with a classical laryngeal mask and endotracheal intubation in cats during spontaneous and controlled mechanical ventilation, Vet Anaesth Analg 43(1):55-62, 2016. 168. van Oostrom H, Krauss MW, Sap R: A comparison between the v-gel supraglottic airway device and the cuffed endotracheal tube for airway management in spontaneously breathing cats during isoflurane anaesthesia, Vet Anaesth Analg 40(3):265-271, 2013.

19 Tracheal Collapse: Management & Indications for Tracheal Stents Dana L. Clarke, VMD, DACVECC

KEY POINTS • Tracheal collapse is a progressive, degenerative disease of the tracheal cartilages commonly seen in older toy and small breed dogs. • Signalment, history, and physical examination are used to determine if the patient is clinical for obstructive tracheal collapse, with diagnostic imaging used to support this tentative diagnosis. • Tracheal stenting is a minimally invasive intervention to restore airway patency in both acute and chronic cases of airway obstruction.

• Tracheal stents can effectively palliate dogs and cats with obstructive tracheal neoplasia. • Complications associated with tracheal stenting include stent fracture, migration, chronic infections, and granulation tissue formation. Case selection and precise sizing are imperative to reduce the risk of short- and long-term complications.

ETIOLOGY

into the histopathologic and clinical presentation differences is needed to definitively redefine the grading scheme for tracheal collapse, as well as determine if this is a congenital condition or a different form of acquired progressive airway obstruction.

Tracheal collapse is a progressive, degenerative disease of the tracheal cartilages commonly seen in older toy and small breed dogs, particularly Yorkshire Terriers.1 The disease has been reported in dogs of all ages, although the majority are middle aged. It is rarely reported in cats and miniature horses. The exact cause of tracheal collapse is unknown; however, dorsal trachealis flaccidity and loss of rigidity of the tracheal cartilages resulting from decreased glycosaminoglycan, chondroitin, and calcium content are suspected.2-6 The result is airway narrowing and collapse and an inability to withstand changing intraluminal airway pressures during respiration. The repeated mucosal contact from cyclic collapse results in chronic irritation, inflammation, and the loss of the ciliated columnar epithelial component of the mucociliary escalator. The tracheal mucosa undergoes squamous metaplasia, and coughing becomes the major mechanism of tracheobronchial clearance in the absence of a functional mucociliary escalator. Bronchomalacia is the result of similar pathology to cartilage of the bronchi and bronchioles, which can occur as an isolated disease process or in conjunction with tracheal collapse.5-9 Tracheal collapse has historically been graded as I–IV, with each grade an approximately 25% progressive reduction in tracheal diameter lumen and flattening of the tracheal cartilages and dorsal tracheal membrane. Grade IV also has the feature of inversion of the ventral tracheal cartilages.10 More recent investigation has suggested that there are two forms of tracheal collapse: traditional chondromalacia with dynamic collapse and a static form of airway obstruction.11 Dogs with the static form of airway obstruction have ventral cartilage inversion into the tracheal lumen (grade IV/“W” shape to the ventral margin of the trachea). This inversion varies from rigid and noncompressible to soft and easily displaced ventrally out of the airway lumen. This is a new concept in tracheal collapse classification, with the developing thought that what was previously called grade IV tracheal collapse is a separate disease process from traditional chondromalacia changes (grades I–III), though dogs may have both static rigid cartilage malformation and dynamic motion from the redundant tracheal membrane.11 Research

CLINICAL SIGNS Tracheal collapse can affect the trachea along its length, and the location of collapse often determines clinical signs. Patients with cervical (extrathoracic) tracheal collapse tend to have inspiratory dyspnea resulting from the inability of the tracheal cartilages to withstand the negative airway pressure created by chest wall expansion, diaphragmatic contraction, and progressively negative airway pressures. Conversely, on expiration, increased intrapleural pressure tends to collapse the diseased intrathoracic trachea. Animals with collapse of the thoracic inlet trachea can have both inspiratory and expiratory signs. Tracheal malformations tend to occur at the thoracic inlet, and depending on the rigidity of the malformation, as well as the presence or absence of concurrent chondromalacia in other regions of the trachea, they can result in static or dynamic respiratory dyspnea.11 Clinical signs vary depending on the location and severity of collapse and whether or not there is concurrent nasopharyngeal, laryngeal, bronchial, or pulmonary parenchymal disease. Classifying clinical signs and physical examination findings into two broad categories, obstructive “honkers” and nonobstructive coughers, can be very helpful to guide differentials, diagnostics, and management strategies (Table 19.1).12 This is a general classification; there are cases with signs from both categories. For these patients, it is important to determine what percentage of their clinical signs are attributable to each classification in order to best understand how much medical management and airway intervention will alleviate their symptoms and improve their quality of life. The honking sound heard during respiration and panting is characteristic of obstructive airway disease, generally with collapse of the cervical or thoracic inlet trachea. Heat, stress, activity, and excitement can worsen the severity of honking. Exercise and stress intolerance are common. Other clinical signs

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TABLE 19.1  Clinical Characteristics of

Honkers with Airway Obstruction Versus Coughers with Lower Airway Disease Honkers

Coughers

Abducted elbows

Increased respiratory effort on expiration

Prolonged inspiratory phase of respiration

Expiratory abdominal “push”

Increased respiratory effort on inspiration

Harsh expiratory lung sounds

Pectus excavatum

Herniation of cranial lung lobes

Sinus arrhythmia

Crackles on pulmonary auscultation

External rotation of the costochondral junctions creating pointed ventral ribs

Overdeveloped abdominal musculature creating a “heave line”

Extended head/neck/orthopnea

Perineal hernia

Increased or decreased sounds on cervical/thoracic inlet tracheal auscultation

Fecal incontinence from increased abdominal pressure on coughing expiration

From Clarke DL: Interventional radiology management of tracheal and bronchial collapse, Vet Clin North America 48(5):765-779, 2018.

include excessive panting, stridor, gagging after eating or drinking, and respiratory distress.1,3,10 Coughers tend to have a dry, hacking cough, which can also be high pitched, productive, and associated with a terminal retch. Coughing tends to be the result of bronchial collapse, chronic bronchitis, pulmonary parenchymal disease, and/or intrathoracic tracheal collapse.6 These dogs do not tend to have exercise intolerance or respiratory distress when mildly to moderately affected. However, with more advanced lower airway collapse or concurrent pulmonary parenchymal disease that impedes oxygenation, exercise intolerance may be present. Extensive literature and consensus are lacking regarding reclassification of tracheal collapse into traditional chondromalacia and tracheal malformations, but preliminary literature suggests that dogs with malformations tend to be younger when diagnosed with tracheal collapse.11 Clinical experience supports this finding; these dogs also often have more static respiratory signs and physical examination changes such as elbow abduction, sinus arrythmia, pectus excavatum, and palpable changes to the costochondral junctions. If there is concurrent chondromalacia, dynamic respiratory signs may also be present in addition to the static respiratory compromise. Nasopharyngeal collapse has been documented in dogs with tracheal collapse and is believed to contribute to upper airway noise, snoring, and possibly sleep apnea.13 The exact etiology and cause for this disease process are not known, nor is the timing for the development of nasopharyngeal collapse development in relation to onset of signs of tracheal collapse. It is suspected that nasopharyngeal collapse may occur secondary to chronic inspiratory airway obstruction and work of breathing; however, more research into nasopharyngeal collapse and its association with airway disease is needed.

DIAGNOSTIC EVALUATION Thoracic radiographs alone are of modest benefit for diagnosing tracheal collapse because they rely on static images to document a dynamic process.10 Paired inspiratory and expiratory thoracic radiographs improve their utility but can still underestimate severity and extent of disease.14 Radiographs misdiagnosed the location of tracheal

Fig. 19.1  Lateral radiograph of a dog with a thoracic inlet tracheal malformation/grade 4 collapse showing an intraluminal soft tissue opacity arising from the ventral border of the trachea.

collapse in 44% of dogs and failed to diagnose tracheal collapse in 8% of dogs when compared with fluoroscopy.14 However, thoracic radiographs are essential to assess for chest wall conformation changes, cardiomegaly, lower airway disease, bronchiectasis, interstitial lung disease, and pulmonary parenchymal infiltrates such as pneumonia or pulmonary edema.1,10,15 Radiographs are also very important for tracheal malformation assessment. Malformations tend to occur at the thoracic inlet and appear as a soft tissue opacity or irregular tracheal margin arising from the ventral aspect of the tracheal border (Fig. 19.1). Fluoroscopy provides dynamic assessment of the tracheal diameter changes along the length during the entire breath cycle and when coughing and allows for evaluation of lung lobe herniation.16 Assessment of nasopharyngeal and mainstem bronchial collapse also can be performed during fluoroscopy, which is important since both disease processes have been documented to occur concurrently with tracheal collapse.13 Tracheal ultrasound and computed tomography (CT) have been shown to have adjunctive diagnostic benefit in tracheal collapse patients, improve tracheal diameter measurements under positive pressure ventilation, and further characterize severity and extent of tracheal malformations.17-20 When a patient positioning device (VetMousetrap[TM] Universal Medical Systems, Solon, Ohio) is used to reduce patient movement, CT can also be used for dynamic airway assessment in awake or lightly sedated patients.17 Primary pulmonary hypertension can exacerbate coughing and secondary pulmonary hypertension can be seen with chronic lower airway and pulmonary parenchymal disease. Echocardiography is warranted in dogs with coughing as their primary clinical sign, as treatment for pulmonary hypertension may improve coughing and respiratory effort. Tracheobronchoscopy is the gold standard for grading the severity of tracheal collapse, though endoscopic collapse grade does not necessarily correspond with clinical signs.6,10,19,21 It is also helpful to rule out tracheal masses, evaluate for bronchial collapse, and assess for the presence of a tracheal malformation (Fig. 19.2).11 Concurrent bronchial collapse has been documented in 83% of dogs with cervical tracheal collapse.6,10 Since general anesthesia is required for tracheobronchoscopy, recovery from this procedure can be challenging in patients with tracheal collapse and upper airway obstruction without intervention. Therefore, it is often delayed until definitive treatment for airway obstruction is planned. If anesthesia is performed in patients with tracheal collapse, a systematic laryngeal examination is imperative, as laryngeal dysfunction has been documented in up to 30% of patients with tracheal collapse.10,22 Laryngeal collapse has also been documented in dogs undergoing tracheal stenting (Fig. 19.3).

CHAPTER 19  Tracheal Collapse: Management & Indications for Tracheal Stents

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determination of oxygenation, especially if underlying lung disease is present. Dogs with severe tracheal obstruction can have impaired ventilation and respiratory acidosis, characterized by increased PaCO2/ PvCO2, which should be reevaluated upon resolution of the upper airway obstruction.

MEDICAL MANAGEMENT

Fig. 19.2  Endoscopic image obtained during tracheobronchoscopy demonstrating the ventral tracheal cartilage inversion noted in grade 4 tracheal collapse/tracheal malformations.

Fig. 19.3  Endoscopic image of grade 2/3 laryngeal collapse in a dog undergoing tracheal stenting.

Airway sampling via endotracheal wash or bronchoalveolar lavage for cytology and aerobic culture and susceptibility testing also should be performed in all dogs with tracheal collapse to rule out active tracheal infection prior to placement of a permanent implant and the postoperative use of antiinflammatory doses of steroids and cough suppression. In normal dogs, the trachea is not sterile, therefore cytologic evidence of infection or inflammation is important to correlate with concurrent positive culture results. In dogs with tracheobronchial collapse diagnosed via endoscopy, as well as those undergoing tracheal stent placement, commonly reported bacterial isolates cultured include Pseudomonas, Pasteurella, Escherichia coli, Staphylococci and Enterobacter aerogenes.23-26 Mycoplasma culture and PCR should also be considered, though the exact role of this pathogen in tracheobronchial collapse is not fully understood. Complete blood count and serum chemistry evaluation should be performed in patients with tracheal collapse to look for inflammatory leukogram changes consistent with infection and evidence of liver injury and dysfunction (elevated alanine aminotransferase and bile acids), which has been documented in dogs with tracheal collapse and is suspected to be secondary to hypoxemia.27 If possible, pulse oximetry and arterial blood gas analysis should be performed for objective

Medical management is the mainstay of tracheobronchial collapse management. However, medications can only control the clinical signs of coughing and inflammation; they do not directly address the physiology of airway collapse or obstruction. If possible, efforts should be made to institute medical therapies before surgical or interventional options are pursued, since up to 71% of dogs can be effectively managed with medications for more than 12 months.1 Oftentimes, breaking the cycle of dyspnea, distress, and anxiety with sedation (see Chapter 132, Sedation of the Critically Ill Patient), anxiolytics, oxygen supplementation (see Chapter 15, Oxygen Therapy), cough suppression (0.25–0.5 mg/kg hydrocodone PO q4-8, 0.1–0.3 mg/kg butorphanol PO q6-12), and tapering antiinflammatory doses of corticosteroids (if indicated) can relieve the airway obstruction crisis well enough to facilitate discharge with continued medical management. The benefit of inhaled over systemic steroids in dogs with tracheal collapse has not yet been determined. The role of bronchodilators in tracheal collapse alone is controversial, though they may be indicated in patients with bronchial collapse and/or chronic bronchitis, for whom coughing is their primary concern. In one study evaluating theophylline as a first-line therapy for dogs with tracheal collapse, coughing did improve with the use of theophylline, though the final dose was associated with degree of intrathoracic tracheal collapse. Less than five dogs in the retrospective study had signs of dyspnea, and instead their primary clinical sign was coughing, with many dogs having evidence of collapse of the carina. These findings likely support that the dogs in this study were more clinically affected by coughing, and not honking and airway obstruction, supporting the possibility that theophylline may provide more of a benefit with coughing than airway obstruction.28 Use of a harness (rather than a collar around the neck), weight loss, and control of exacerbating factors, such as heat, stress, and excitement, are also essential elements of medical management. When medical management fails to control clinical signs, the patient’s quality of life is declining, or respiratory distress and compromise cannot be relieved with medical therapies, surgical or interventional options to address tracheal collapse should be considered.

TRACHEAL RINGS In dogs with cervical tracheal and/or proximal thoracic inlet collapse that have failed medical therapy or are in too severe of respiratory distress to allow time for medical therapy to be effective, prosthetic extraluminal tracheal rings can be considered. Commercially made rings are available in four sizes from New Generation Devices (http:// ngdvet.com). Extraluminal rings can also be made from sterilized polypropylene syringes or syringe cases. Caution must be exercised during tracheal dissection and ring placement to avoid damaging the segmental tracheal blood supply and the recurrent laryngeal nerve. The success rate for prosthetic rings is reported to be 75% to 85%.10,29 Postoperative complications include infection, laryngeal paralysis (10% to 21%), tracheal necrosis, and progressive tracheal collapse.1,4,10,29,30 Patients typically are hospitalized for several days of intensive monitoring after ring placement. In dogs with cervical tracheal collapse treated with prosthetic ring placement, no survival difference was found between dogs with cervical collapse alone and those with concurrent intrathoracic tracheal collapse, indicating that even dogs with intrathoracic

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disease may benefit from ring placement if inspiratory dyspnea is severe enough to warrant intervention.30

TRACHEAL STENTING In dogs with tracheal collapse at any point along the trachea, including diffuse collapse, or those deemed to be poor surgical candidates for ring placement (laryngeal dysfunction, impaired healing concerns, concerns for prolonged anesthesia), endoluminal tracheal stenting can be considered.1,29,31-38 Tracheal stents have also been beneficial in dogs with tracheal collapse that present in respiratory crisis that are nonresponsive to medical stabilization and animals with airway obstruction secondary to nonresectable tracheal masses or strictures.34,35,39 Management of expectations and an understanding of what can and cannot be accomplished with tracheal stenting is important prior to proceeding with stent placement. For dogs with airway obstruction and respiratory distress secondary to tracheal collapse, tracheal stenting is a life-saving procedure to alleviate the obstruction and improve respiratory comfort. For dogs in whom the majority of their clinical signs are associated with coughing and not airway obstruction, tracheal stenting is unlikely to provide significant relief. Most dogs for whom tracheal stents are placed will require lifelong cough suppression, even those that did not cough prior to stent placement. It is imperative that clients understand ongoing medical therapy will likely be needed. Initial experience with tracheal stenting using biliary wall stents or balloon expandable stents was met with significant complications, such as foreshortening, migration, fracture, and excessive airway irritation.31-33,36,40-43 Negative experience and outcomes led to tracheal stenting being considered a salvage procedure, which was likely a function of stent type(s) placed, lack of experience, and patient selection. Tracheal stents made for dogs (http://infinitimedical.com) have gone through multiple design iterations and engineering adjustments, including the development of a tapered stent to optimally fit the nonuniform tracheal diameter. These design enhancements have improved their sizing and placement predictability, patient tolerance, and risk for fracture.11,37,44,45 Measurements to determine tracheal stent size are made under general anesthesia, with stent placement immediately following ideal size determination. The use of radiographs, fluoroscopy, and CT have been described to measure anesthetized maximal tracheal diameters, which are used to select stent size.20,46 Currently, there is no method to predict the appropriate stent size in the awake patient. Therefore, a variety of stent lengths and diameters need to be readily available prior to anesthesia, especially in critical patients for whom recovery without definitive intervention for their airway obstruction would not be possible. In addition, since most tracheal stent complications result from sizing issues, every effort to size the stent as ideally as possible is imperative for good patient outcomes.11,46 Once under anesthesia, the patient is placed in right lateral recumbency, and a marker catheter is positioned in the esophagus to calibrate the digital radiography or fluoroscopy unit used for precise tracheal diameter measurements (Fig. 19.4). The boundaries of the trachea, the caudal aspect of the cricoid cartilage and cranial aspect of the carina, must be visualized to prevent malposition of the stent into the larynx or bronchi. Maximal tracheal diameter measurements are made along the length of the trachea, using positive pressure breath holds at 20 cm H2O and the inflated endotracheal tube cuff to maintain airway pressure. Using the maximal tracheal diameter determined, a stent diameter 10%–20% larger than this value is chosen so that there is constant outward force of the stent on the tracheal mucosa to maintain positioning. Once the diameter determination has been made, the length is

Fig. 19.4  Fluoroscopic image of an esophageal marker catheter used for measurement calibration during tracheal stent sizing.

chosen to span the entire length of the trachea aside from 1 cm caudal to the cricoid cartilage and 1 cm cranial to the carina. 19-Fluoroscopy is used traditionally for stent placement, but bronchoscopic guidance has also been described.38 Tracheal stents are placed through an endotracheal tube with a bronchoscope adapter attached so that oxygen can be provided during stent positioning and deployment. Constant fluoroscopic visualization during deployment is preferred to ensure appropriate positioning and adequate expansion and to avoid inadvertent deployment within the endotracheal tube, carina, or larynx. Most tracheal stents are reconstrainable and can be recaptured into the delivery sheath until approximately 75% of the stent is deployed. Once the stent position is confirmed to be appropriate, it is fully deployed, and the delivery system removed from the endotracheal tube. Immediately after stent placement, tracheoscopy is repeated to confirm positioning and apposition of the stent with the tracheal mucosa. Gaps in contact between the stent and mucosa contribute to poor mucosalization, which may precipitate mucous accumulation, recurrent chronic tracheal infections, and granulation tissue formation (Fig. 19.5). Since these areas of poor contact/gapping, mucus accumulation, and chronic infection do not become clinically apparent for several months, the time delay to diagnosis precludes stent removal. For this reason, repeat tracheoscopy immediately after stent placement has become an invaluable aspect of successful case management. Areas of poor contact are of particular concern when stenting cases of tracheal malformations since the circular stent may not conform the W shape of the tracheal lumen. If the stent fails to expand in the region

Fig. 19.5  Endoscopic image of a tracheal stent with focal areas of poor stent contact with the tracheal mucosa, creating a “gutter” for mucus accumulation and chronic infection.

CHAPTER 19  Tracheal Collapse: Management & Indications for Tracheal Stents of the malformation or has poor contact with the tracheal mucosa because of the malformation, balloon dilation of the stent with the endotracheal tube cuff balloon under fluoroscopy may help expand the stent and engage the mucosa. If this is ineffective at resolving regions of poor contact (“gutters”), stent removal and placement of a larger diameter stent or placement of a second stent within the first may be indicated. However, tracheal stents are strongest when fully expanded to their nominal diameter, and weaker with progressive constraint to a smaller diameter. Therefore, placing a larger diameter stent into an area that physically cannot be expanded by the rigid nature of the malformation may result in a weaker stent that is more predisposed to fracture. If there is imperfect contact that has not improved with focal balloon dilation, but the sizing of the stent diameter based on the rest of the tracheal measurements is appropriate, placement of second stent may be the best method to achieve increased outward forces to displace the malformation.

POST-STENTING MANAGEMENT CONSIDERATIONS Most patients are discharged the day after stent placement, unless concurrent diseases such as pneumonia necessitate ongoing hospital care. Patients are discharged with antibiotics pending airway culture results, a 2–3 week tapering course of steroids, and regular (q6-8h) cough suppression. A short, dry, self-limiting cough is to be expected for 6–8 weeks post-stent placement while the stent is becoming incorporated into the tracheal mucosa. It is important that clients are advised of this expected postoperative clinical sign, as many clients are very nervous and stressed about coughing being an indication of possible stent complication while adjusting to the new normal life with their stented dogs. Long-term, thoracic radiographs are monitored every 3–4 months for the first year after placement, then every 6 months thereafter. If at any point post-stent placement the patient develops a change in their cough or respiratory comfort, thoracic radiographs should be taken to evaluate for stent complications such as fracture, migration, granulation tissue, and pneumonia. Since granulation tissue can be challenging to diagnose radiographically, tracheoscopy and endotracheal wash may be needed to determine the etiology of the change in the nature of the cough.

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stent/mucosal contact, long-term diligent monitoring for changes to the nature or frequency of coughing is essential. When tracheal infections are documented early, they can often be managed with cultureguided antibiotic therapy and steroids after confirming infection via endotracheal wash, culture, and tracheoscopy. These dogs may require intermittent (1–2 times per year) treatment for chronic infections, which can be expensive and intensive, but they may mitigate the need for placement of a second stent if obstructive granulation tissue development can be prevented through effective infection management.

STENTING FOR TRACHEAL NEOPLASIA Tracheal stents can be considered for palliation nonresectable obstructive tracheal neoplasia, after regrowth of previously resected tracheal masses, and restoration of luminal patency secondary to tracheal strictures.47 They can also be used to improve patient stability in preparation for palliative radiation therapy when surgery is not possible or desired (Fig. 19.6). Preoperative imaging, including thoracic radiographs, CT, and tracheoscopy are valuable for assessing for mass extent and proximity to the larynx or carina, checking for metastasis, radiation planning, and endoscopic biopsy collection. Stent sizing and the placement procedure are similar to stenting for tracheal collapse. Case reports and clinical experience for tracheal stenting for neoplasia describe the use of uncovered tracheal stents, though covered stents may also be considered in cases of tracheal strictures to prevent ingrowth of the stricture into the stent.47

TRACHEAL STENT COMPLICATIONS Historically, tracheal stent fractures were thought to be a catastrophic complication of tracheal stents. However, with improved patient selection, sizing technique, stent design, including tapered stents that avoid oversizing of the intrathoracic trachea, and experience with placement of a second stent within the fractured stent, this complication is infrequent and readily manageable.11,40-42,45 Tracheal stent migration is uncommon when appropriately (10%–20%) oversized stents are selected based on anesthetized maximal tracheal diameter measurements. Since migration tends to be an early complication, if promptly recognized, these stents can be removed and a larger diameter stent placed. Inflammatory (granulation) tissue formation in dogs with tracheal stents is thought to occur in patients with areas of poor mucosal ingrowth into the stent, resulting in mucus accumulation in the tracheal gutters and chronic infection. Management of nonobstructive granulation tissue has anecdotally shown promising response to immunosuppressive steroid therapy and airway culture-guided antibiotic therapy. For cases in which granulation tissue progresses to airway obstruction, early experience with repeated tracheal stenting, steroids, and antimicrobials has shown success. In dogs with areas of imperfect

A

B Fig. 19.6  Radiographic image of an obstructive, nonresectable tracheal mass in a dog (A) and use of tracheal stent to restore luminal patency and palliate the obstruction in preparation for radiation therapy (B).

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REFERENCES 1. White R, Williams JM: Tracheal collapse in the dog-is there really a role for surgery? A survey of 100 cases, J Small Anim Pract 35(4):191-196, 1994. 2. Dallman MJ, McClure RC, Brown EM: Histochemical study of normal and collapsed tracheas in dogs, Am J Vet Res 49(12):2117-2125, 1988. 3. Mason RA, Johnson LR: Tracheal collapse. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 346-355. 4. Payne JD, Mehler SJ, Weisse C: Tracheal collapse, Compendium 28(5): 373-383, 2006. 5. Done SH, Drew RA: Observations on the pathology of tracheal collapse in dogs, J Small Anim Pract 17(12):783-791, 1976. 6. Johnson LR, Pollard RE: Tracheal collapse and bronchomalacia in dogs: 58 cases (7/2001-1/2008), J Vet Intern Med 24(2):298-305, 2010. 7. Adamama-Moraitou KK, Pardali D, Dai MJ, et al: Canine bronchomalacia: a clinicopathological study of 18 cases diagnosed by endoscopy, Vet J 191(2):261-266, 2012. 8. Bottero E, Bellino C, De Lorenzi D, et al: Clinical evaluation and endoscopic classification of bronchomalacia in dogs, J Vet Intern Med 27(4):840-846, 2013. 9. Maggiore AD: Tracheal and airway collapse in dogs, Vet Clin North Am Small Anim Pract 14(1):117-127, 2014. 10. Tanger CH, Hobson H: A retrospective study of 20 surgically managed cases of collapsed trachea, Vet Surg 11(4):146-149, 1982. 11. Weisse C, Berent A, Violette N, et al: Short-, intermediate-, and long-term results for endoluminal stent placement in dogs with tracheal collapse, J Am Vet Med Assoc 254(3):380-391, 2019. 12. Clarke DL: Interventional radiology management of tracheal and bronchial collapse, Vet Clin North Am Small Anim Pract 48(5):765-779, 2018. 13. Rubin JA, Holt DE, Reetz JA, Clarke DL: Signalment, clinical presentation, concurrent diseases, and diagnostic findings in 28 dogs with dynamic pharyngeal collapse, J Vet Intern Med 29(3):815-821, 2015. 14. Macready DM, Johnson LR, Pollard RE: Fluoroscopic and radiographic evaluation of tracheal collapse in dogs: 62 cases (2001–2006), J Am Vet Med Assoc 230(12):1870-1876, 2007. 15. Marolf A, Blaik M, Specht A: A retrospective study of the relationship between tracheal collapse and bronchiectasis in dogs, Vet Radiol Ultrasound 48(3):199-203, 2007. 16. Nafe LA, Robertson ID, Hawkins EC: Cervical lung lobe herniation in dogs identified by fluoroscopy, Can Vet J 54(10):955-959, 2013. 17. Stadler K, Hartman S, Matheson J, et al: Computed tomography imaging of dogs with primary laryngeal or tracheal airway obstruction, Vet Radiol Ultrasound 52(4):377-384, 2011. 18. Eom K, Moon K, Seong Y, et al: Ultrasonographic evaluation of tracheal collapse in dogs, J Vet Sci 9(4):401-405, 2008. 19. Heyer CM, Nuesslein TG, Jung D, et al: Tracheobronchial anomalies and stenoses: detection with low-dose multidetector CT with virtual tracheobronchoscopy-comparison with flexible tracheobronchoscopy, Radiology 242(2):542-549, 2007. 20. Scansen BA: Tracheal diameter and area: computed tomography versus fluoroscopy for stent sizing in 12 dogs with tracheal collapse, J Vet Intern Med 28(4):1364, 2014. 21. Bottero E, Bellino C, De Lorenzi D, et al: Clinical evaluation and endoscopic classification of bronchomalacia in dogs, J Vet Intern Med 27(4):840-846, 2013. 22. Johnson LR: Laryngeal structure and function in dogs with cough, J Am Vet Med Assoc 249(2):195-201, 2016. 23. McKiernan BC, Smith AR, Kissil M: Bacterial isolates from the lower trachea of clinically healthy dogs, J Am Anim Hosp Assoc 20:139-142, 1984. 24. Johnson LR, Fales WH: Clinical and microbiologic findings in dogs with bronchoscopically diagnosed tracheal collapse: 37 cases (1990-1995), J Am Vet Med Assoc 219(9):1247-1250, 2001.

25. Clarke DL, Luskin A, Brown D: Endotracheal wash cytology and microbiologic results in dogs undergoing tracheal stenting: 34 cases (2011-2014), J Vet Emerg Crit Care 25(S1):S1-S34, 2015. 26. Lesnikowski S, Weisse C, Berent A, et al: Bacterial infection before and after stent placement in dogs with tracheal collapse syndrome, J Vet Intern Med 34:725-733, 2020. 27. Bauer NB, Schneider MA, Neiger R, et al: Liver disease in dogs with tracheal collapse, J Vet Intern Med 20(4):845-849, 2006. 28. Jeung SY, Sohn SJ, An JH, et al: A retrospective study of theophyllinebased therapy with tracheal collapse in small-breed dogs: 47 cases (20132017) [published correction appears in J Vet Sci. 2019 Nov;20(6):e66], J Vet Sci 20(5):e57, 2019. doi:10.4142/jvs.2019.20.e57. 29. Buback JL, Boothe HW, Hobson HP: Surgical treatment of tracheal collapse in dogs: 90 cases, J Am Vet Med Assoc 208:380-384, 1996. 30. Becker WM, Beal M, Stanley BJ, et al: Survival after surgery for tracheal collapse and the effect of intrathoracic collapse on survival, Vet Surg 41(4):501-506, 2012. 31. Sura PA, Krahwinkel DJ: Self-expanding nitinol stents for the treatment of tracheal collapse in dogs: 12 cases (2001-2004), J Am Vet Med Assoc 232(2):228-236, 2008. 32. Moritz A, Schneider M, Bauer N: Management of advanced tracheal collapse in dogs using intraluminal self-expanding biliary wallstents, J Vet Intern Med 18(1):31-42, 2004. 33. Sun F, Usón J, Ezquerra J, et al: Endotracheal stenting therapy in dogs with tracheal collapse, Vet J 175(2):186-193, 2008. 34. McGuire L, Winters C, Beal MW: Emergency tracheal stent placement for the relief of life-threatening airway obstruction in dogs with tracheal collapse, J Vet Emerg Crit Care 23(S1):S9, 2013. 35. Beal MW: Tracheal stent placement for the emergency management of tracheal collapse in dogs, Top Comp Anim Med 28(3):106-111, 2013. 36. Gellasch KL, Gomez TDC, McAnulty JF, et al: Use of intraluminal nitinol stents in the treatment of tracheal collapse in a dog, J Am Vet Med Assoc 221(12):1719-1723, 2002. 37. Kim JY, Han HJ, Yun HY, et al: The safety and efficacy of a new self-expandable intratracheal nitinol stent for the tracheal collapse in dogs, J Vet Sci 9(1):91-93, 2008. 38. Durant AM, Sura P, Rohrbach B, et al: Use of nitinol stents for end-stage tracheal collapse in dogs, Vet Surg 41(7):807-817, 2012. 39. Culp WT, Weisse C, Cole SG, et al: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007. 40. Radlinsky MG, Fossum TW, Walker MA, et al: Evaluation of the Palmaz stent in the trachea and mainstem bronchi of normal dogs, Vet Surg 26(2):99-107, 1997. 41. Mittleman E, Weisse C, Mehler SJ, Lee JA: Fracture of an endoluminal nitinol stent used in the treatment of tracheal collapse in a dog, J Am Vet Med Assoc 225(8):1217-1221, 2004. 42. Ouellet M, Dunn ME, Lussier B, Chailleux N, Hélie P: Noninvasive correction of a fractured endoluminal nitinol tracheal stent in a dog, J Am Anim Hosp Assoc 42(6):467-471, 2006. 43. Woo HM, Kim MJ, Lee SG, et al: Intraluminal tracheal stent fracture in a Yorkshire terrier, Can Vet J 48:1063-1066, 2007. 44. Clarke DL, Tappin S, de Madron E, et al: Evaluation of a novel tracheal stent for the treatment of tracheal collapse in dogs, J Vet Intern Med (4):1364, 2014. 45. Violette NP, Weisse CW, Berent AC, et al: Correlations among tracheal dimensions, tracheal stent dimensions, and major complications after endoluminal stenting of tracheal collapse syndrome in dogs, J Vet Intern Med 33:2209-2216, 2019. 46. Weisse CW: Intraluminal tracheal stenting. In Weisse CW, Berent AC, editors: Veterinary image guided interventions, Ames, Iowa, 2015, Wiley Blackwell, pp 73-82. 47. Culp WT, Weisse C, Cole SG, Solomon JA: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007.

20 Feline Bronchopulmonary Disease Elizabeth Rozanski, DVM, DACVIM (SA-IM), DACVECC, Gareth J. Buckley, MA, VetMB, MRCVS, DACVECC, DECVECC KEY POINTS • Airway disease typically affects young to middle-aged cats. • Bronchopulmonary disease is a spectrum of diseases, ranging from true asthma to bronchiectasis. • Expiratory distress is a common clinical sign, with historical cough frequently mistaken for hairballs.

• Glucocorticoids, either inhaled or orally administered, are the mainstay of treatment. • Parasitic infections and hypersensitivity disorders should be excluded.

Respiratory distress in cats is a true emergency. It is commonly caused by airway disease, but other frequent etiologies include congestive heart failure, pleural space disease, and neoplasia. It is essential to attempt to accurately determine the cause of the distress in order to have the best chance of a successful outcome. Feline bronchopulmonary disease is an umbrella term encompassing a spectrum of airway disease in cats and may be referred to as feline asthma.1 Airway diseases in cats may include upper airway disease as well, and the concept of the “unified airway” has been applied to allergic airway diseases affecting people and should likely be considered in cats as well.2 While the focus of this chapter is bronchopulmonary disease, other diseases should be excluded, if possible, before treatment for bronchopulmonary disease is initiated. Mammalian airways can respond to stimuli in a limited number of ways, including airway smooth muscle hypertrophy, excessive mucus production, and bronchoconstriction. These changes result in the clinical signs of difficulty breathing and cough.1 Airway disease or bronchopulmonary disease in cats may be divided into asthma and chronic bronchitis. Feline asthma is defined as hyperreactive airways with reversible bronchoconstriction, while chronic bronchitis is characterized by thickening of the airways and excessive mucus production. Feline asthma is considered to be a type I hypersensitivity reaction following sensitization to aeroallergens. The actual allergen is uncommonly identified. Some cats may have signs of both chronic cough and episodic bronchoconstriction leading to increased end-expiratory lung volume, increased work of breathing, and ultimately respiratory fatigue.3 The stimulus for the development of airway disease remains unknown in most cats. A similar syndrome can be mimicked in the laboratory by sensitizing cats to an aeroallergen, such as Bermuda grass.2,5 It is assumed but not proven that cats with airway disease have an allergy to some environmental trigger. A recent study documented increased serum IgE levels in some cats with eosinophilic airway disease.6 It is also possible to have intrinsic asthma, where a specific trigger is not detected. In children, viral infections early in life predispose them to asthma; viral upper respiratory infections are very common in cats, but the relationship to the subsequent development of asthma in cats is also unknown. Parasitic infection may produce similar respiratory signs.

HISTORY AND PHYSICAL EXAMINATION Most cats are young adult to middle-aged at the first development of clinical signs of airway disease. Siamese cats were overrepresented in one report, but overall the vast majority of cats are of mixed heritage. Young cats (,1 year) typically have infectious causes of respiratory distress (viral or parasitic) or occasionally, nasopharyngeal polyps. Older cats more commonly have neoplastic processes, including laryngeal masses, which may cause audible wheezes. Bronchopulmonary disease is typically lifelong, so older cats may be affected, but clinical signs usually appear at an earlier age. While uncommonly used in cats, potassium bromide has been associated with cough and respiratory disease, and its use should be discontinued in any cat with respiratory disease. Physical examination typically shows a well-conditioned cat with respiratory distress and/or cough. Weight loss, unkempt coats, or muscle wasting are rare to nonexistent. Cats may present only with intermittent cough, which may be mistaken for hairballs, or may present with respiratory distress. Cats with airway disease severe enough to require admission to the ICU will have expiratory distress due to airtrapping and bronchoconstriction; however, this can be occasionally hard to detect due to tachypnea with resulting short inspiratory and expiratory time. Cats may also have crackles and wheezes, which represent fluid/mucus in the airways causing them to collapse and reopen with each breath. A murmur may also be present due to concurrent heart disease or simply a flow murmur. In contrast to cats with active congestive heart failure, cats with bronchopulmonary disease will have normal rectal temperatures. Imaging The classical imaging modality used for identification of airway disease is thoracic radiographs. Bronchial or bronchointerstitial patterns are the most frequently observed, with occasional collapse of the right middle lung lobe due to mucus plug formation (Fig. 20.1). Hyperinflation caused by air-trapping is also common due to expiratory flow limitation. Bronchiectasis may also be present. Completely normal thoracic radiographs should prompt consideration for another disease process, such as a laryngeal mass or paralysis, particularly in a geriatric cat that has no prior history of cough or wheeze.

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Fig. 20.1  A lateral thoracic radiograph from a cat with airway disease demonstrating right middle lung lobe collapse. Also note the hyperinflation and bronchial pattern.

Fig. 20.2  A computed tomography scan showing severe bronchiectasis in a cat with chronic bronchopulmonary disease. Note the dilated, mucus-filled airway in the left caudal lung field.

Point-of-care ultrasound (POCUS) may be used to demonstrate the lack of B-lines (see Chapter 189, Point-of-Care Ultrasound in the ICU), but despite widespread use in the diagnosis of pulmonary parenchymal diseases, POCUS has not been evaluated in cats with airway disease. In children with asthma, POCUS is useful for excluding other conditions such as pneumonia.6 Echocardiography or N-terminal pro-brain natriuretic peptide (NT-pro-BNP) testing is useful to exclude clinically significant heart disease. Pulmonary hypertension due to airway disease has not been reported in cats to the authors’ knowledge, although it has been described in horses with experimental asthma.8 Other imaging modalities, such as computed tomography (CT) scanning, are rarely used in cats with airway disease, unless the diagnosis is unclear or if there is concern for other comorbidities (see Fig. 20.2 demonstrating severe bronchiectasis; this CT was performed due to poor response to steroids and recognition of an abnormality on thoracic radiographs).

PFT determinations with airway sampling.8 Arterial blood gases might document hypercarbia or hypoxemia but are practically very challenging to perform in cats with respiratory distress. A venous blood gas can document severe hypercarbia if present. Awake pulse oximetry and end-tidal CO2 analysis are unreliable in cats. The 6-minute walk test has not been attempted in cats.

LABORATORY TESTING Complete blood count and chemistry profile are typically within references ranges. Some cats have circulating eosinophilia, although absence of this does not rule out airway disease. Cats should be tested for heartworm disease if they live within endemic areas and a Baermann fecal sedimentation should be performed for diagnosis of potential lung worm infection. Serum allergy testing may be pursed in cats with severe signs; hyposensitization was found to be useful in research cats, but testing in naturally affected cats has not been evaluated.5

LUNG FUNCTION TESTING While pulmonary function testing (PFT) is widely used in people, due to challenges in cooperation, PFT is far less widely used in cats. However, in an intubated patient hooked up to a critical care ventilator, static and dynamic compliance, as well as airway resistance, may be easily calculated.9,10 In the authors’ practice, it is simple to combine

AIRWAY SAMPLING An endotracheal wash or bronchoalveolar lavage may be performed for confirmation of the diagnosis or when looking for evidence of infectious or parasite disease. Cytological changes consistent with allergic airway disease most commonly include the presence of eosinophilia, although in cases of chronic bronchitis, a neutrophilic infiltrate may be detected. Larva may be detected with lungworms, and bacteria may be observed with infection. The degree of normal airway eosinophilia in cats has been debated with some studies suggesting as much as 17%.9,10 A more recent study concluded that greater than 5% eosinophil percentage was abnormal.11 An upper airway examination prior to intubation may be indicated. Pretreatment with albuterol or terbutaline is suggested prior to sampling to minimize reflex bronchoconstriction which can be severe. Most cats (.95%) tolerate airway wash with only transient desaturation, but this technique should be performed with caution in cats with moderate or severe respiratory distress.12 Airway sampling may be combined with tracheobronchoscopy if desired.

TREATMENT The mainstay therapy for cats with bronchopulmonary disease is to remove any potential allergens (e.g., air fresheners, cigarette smoke, dust exposure) and treat the airway inflammation. The two most common mistakes that clinicians make in treating bronchopulmonary disease in cats are trying to stop steroids and prescribing daily bronchodilators. Unless a specific underlying cause can be identified and eliminated, glucocorticoids are the mainstay of

CHAPTER 20  Feline Bronchopulmonary Disease therapy. Glucocorticoids may be administered as an oral tablet/ liquid, most commonly as prednisolone. A typical dose would be 5 mg per cat twice daily until remission occurs, then once daily and then tapered but not stopped to 2.5 mg twice a week. Glucocorticoids may also be administered via a metered dose inhaler, most commonly as fluticasone. Inhalant medication requires the use of a chamber and face mask. Using inhalant medications over orally administered glucocorticoids have been shown to be effective in treatment of feline bronchopulmonary disease; they reduce but do not entirely eliminate systemic glucocorticoid effects in cats.9 Fluticasone is dosed at 110–220 mcg twice daily, with rare cats requiring a lower dose. Almost all cats can be trained to accept the mask. In rare cases where oral or inhaled medication administration is not possible or practical, glucocorticoids may be administered via a reposital preparation, such as methylprednisolone (DepoMedrol) at a dose of 10–20 mg/cat every 2–6 weeks. Bronchodilators should only be administered if there are signs of bronchoconstriction; daily use may lead to tachyphylaxis as well as signs of restlessness or anxiety. In an acute crisis, albuterol by aerosol (1–2 puffs/cat) or terbutaline (0.01 mg/kg IV, SQ or IM) are useful for promoting bronchodilation. Theophylline, which has been historically used, is hard to find outside of compounding pharmacies, and more importantly, appears to have limited efficacy in cats and has tricky pharmacokinetics.13 Other therapies that may be considered include antimicrobials if there is evidence of neutrophilic inflammation or a septic process, or potentially a secondary infection (e.g., Mycoplasma or Bordetella bronchiseptica). Cats should be dewormed if there is evidence of parasitic infection or potential for lung worms such as Aelurostrongylus abstrusus (fenbendazole, 50 mg/kg PO 3 14 days).

PROGNOSIS The prognosis for most cats with bronchopulmonary disease is excellent, although in a small subgroup of cats, severe recurrent airway obstruction associated with bronchoconstriction or mucus plugging can be fatal. In an ICU setting, cats should be “better by morning” if typical feline bronchopulmonary disease is present. However, owners should understand that bronchopulmonary disease is not cured, but rather chronic environmental and medical management are typically

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necessary. Failure to improve with emergent treatment should cause the clinician to reassess the diagnosis. Disclosures: One of the authors (ER) has received research support from Trudell Medical, the makers of the Aerokat chamber.

REFERENCES 1. Trzil JE, Reinero CR: Update on feline asthma, Vet Clin North Am Small Anim Pract 44(1):91-105, 2014. 2. Stachler RJ: Comorbidities of asthma and the unified airway, Int Forum Allergy Rhinol 5(Suppl 1):S17-S22, 2015. 3. O’Donnell DE, Laveneziana P: Physiology and consequences of lung hyperinflation in COPD, Eur Respir Rev 15(100):61-67, 2006. 4. Reinero CR, Byerly JR, Berghaus RD, et al: Rush immunotherapy in an experimental model of feline allergic asthma, Vet Immunol Immunopathol 110(1-2):141-153, 2006. 5. Buller MC, Johnson LR, Outerbridge CA, et al: Serum immunoglobulin E responses to aeroallergens in cats with naturally occurring airway eosinophilia compared to unaffected control cats, J Vet Intern Med 34(6):26712676, 2020. 6. Dankoff S, Li P, Shapiro AJ, Varshney T, Dubrovsky AS: Point of care lung ultrasound of children with acute asthma exacerbations in the pediatric ED, Am J Emerg Med 35(4):615-622, 2017. 7. Decloedt A, Borowicz H, Slowikowska M, Chiers K, van Loon G, Niedzwiedz A: Right ventricular function during acute exacerbation of severe equine asthma, Equine Vet J 49(5):603-608, 2017. 8. Vershoor-Kirss M, Rozanski EA, Sharp CR, et al: Treatment of naturally occurring asthma with inhaled fluticasone or oral prednisolone: a randomized pilot trial, Can J Vet Res 85(1):61-67, 2021. 9. Bernhard C, Masseau I, Dodam J, et al: Effects of positive end-expiratory pressure and 30% inspired oxygen on pulmonary mechanics and atelectasis in cats undergoing non-bronchoscopic bronchoalveolar lavage, J Feline Med Surg 19(6):665-671, 2017. 10. Shibly S, Klang A, Galler A, et al: Architecture and inflammatory cell composition of the feline lung with special consideration of eosinophil counts, J Comp Pathol 150:408-415, 2014. 11. Johnson LR, Drazenovich TL: Flexible bronchoscopy and bronchoalveolar lavage in 68 cats (2001-2006), J Vet Intern Med 21(2):219-225, 2007. 12. Guenther-Yenke CL, McKiernan BC, Papich MG, et al: Pharmacokinetics of an extended-release theophylline product in cats, J Am Vet Med Assoc 15;231(6):900-906, 2007.

21 Lower Airway Disease in Dogs Lynelle R. Johnson, DVM, MS, PhD, Dipl ACVIM (SAIM)

KEY POINTS • Most airway diseases (bronchitis, bronchomalacia, eosinophilic lung disease, and bronchiectasis) are common in both small and large dogs, but tracheal collapse is almost exclusively a disease of small breed dogs. • Identification of complicating conditions that exacerbate airway collapse such as infection, inflammation, obesity, aspiration injury, and cardiac disease can provide avenues for interventions that will improve quality of life.

• Treatment of airway collapse relies on conservative measures to reduce the stressors that trigger cough and airway irritation. • Anxiety or overexcitement can be limited by judicious use of anxiolytics (e.g., trazodone) in conjunction with avoidance measures. • Narcotic cough suppressants are often required for management of cough associated with airway collapse after infection and inflammation have been resolved.

INTRODUCTION

crackles. Both conditions can also be associated with an abnormal pattern of breathing; an expiratory push or exaggerated abdominal effort is common and appears to be more severe in dogs with bronchomalacia. Definitive diagnosis of respiratory conditions requires a combination of laboratory testing, diagnostic imaging, laryngeal examination, and airway sampling. Documentation of airway collapse is particularly challenging. The presence of bronchiectasis suggests more substantial inflammation, and established bronchiectasis that can be visualized on radiographs is typically irreversible. Computed tomography has proven useful in early detection of the more subtle changes and is characterized by a pulmonary arterial to bronchial lumen ratio that exceeds 2.0.4 Dynamic changes in airway diameter can be visualized better when multiple views are obtained (e.g., right and left lateral images along with cervical radiographs). Where available, fluoroscopy is valuable for real-time assessment of dynamic airway collapse (Fig. 21.1). It can also document tracheal kinking and cranial lung herniation, the latter of which occurs in up to 70% of dogs with airway collapse.5 In some practices, bronchoscopy will have been utilized to detect tracheobronchomalacia (Fig. 21.2). Bronchomalacia is characterized by .50% collapse of airway luminal diameter. It can be static or dynamic and affect a single bronchus or multiple airways. Bronchiectasis can also be visualized during bronchoscopy by thinning of airway bifurcations and increased luminal space, with or without accumulation of secretions. While this procedure requires anesthesia, it also allows for a comprehensive laryngeal examination, as well as collection of airway samples to determine the type of inflammation present and to perform culture and susceptibility testing. Bronchoalveolar lavage fluid normally comprises 70%–75% macrophages and 5%–8% neutrophils, eosinophils, and lymphocytes. Alterations in cell percentages are used to characterize inflammatory airway disease, and neutrophils are scrutinized for intracellular bacteria to document infection, bearing in mind that up to 25% of dogs with infection might lack evidence of airway sepsis.6 Aerobic and Mycoplasma cultures are warranted in dogs that have airway samples collected for evaluation of cough, and anaerobic cultures are also recommended in dogs with bronchiectasis or suppurative pneumonia.

The most common disorders affecting the lower airways of dogs are related to structural disease (tracheal and bronchial collapse or bronchiectasis), airway infection, and airway inflammation, including eosinophilic lung disease, lymphocytic inflammation, or chronic bronchitis characterized by nonseptic suppurative inflammation. Many dogs will suffer from multiple disorders concurrently1-3 requiring extensive work-up beyond that performed in the ICU setting.

DIAGNOSIS OF UNDERLYING CONDITIONS Dogs with airway disease are typically presented for evaluation of a cough that has finally exceeded the tolerance of the owner. Signalment can be helpful in prioritizing the type of airway disease present because younger animals are more likely to have infectious disease (canine infectious respiratory disease complex) and cervical tracheal collapse while older dogs tend to be affected by bronchomalacia, with or without tracheal collapse, and chronic bronchitis. Bronchiectasis can be found in a young dog with ciliary dyskinesia or eosinophilic lung disease but is more commonly encountered in older dogs with chronic inflammatory or infectious disease or in older dogs with chronic aspiration injury. Tracheal collapse is almost exclusively a disease of small breed dogs; however, all other airway diseases (bronchitis, bronchomalacia, eosinophilic lung disease, and bronchiectasis) are common in both small and large dogs. Physical examination reveals tracheal sensitivity in most dogs with cough, regardless of etiology because irritant receptors between epithelial cells can be activated by infection, inflammation, or airway compression. Detection of abnormal lung sounds is variable, and increased breath sounds (rather than adventitious sounds) might be the only abnormality detected. Bronchomalacia can result in inspiratory and/or expiratory crackles when airways dynamically open and close during the respiratory cycle. Bronchitis is occasionally associated with an expiratory wheeze as air flows from the alveolar region to the glottis through narrowed airways, but this can also result in expiratory

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CHAPTER 21  Lower Airway Disease in Dogs

A

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B

Fig. 21.1  An inspiratory lateral image captured from a fluoroscopic study (A) reveals attenuation of the luminal diameter of the trachea as it traverses the thoracic inlet, consistent with cervical tracheal collapse. During expiration (B), the intrathoracic trachea is almost completely collapsed, as are the cranial and caudal lobar bronchi.

and while uncommon, secondary infection can develop from immunosuppression in some dogs, necessitating repeated diagnostic testing.

DISEASE EXACERBATION Cranial Caudal

Exacerbations of disease can be reflected by worsening cough, acute onset of respiratory distress, or by the development of systemic signs of illness such as anorexia, exercise intolerance, or collapse. Any of these features can result in presentation to the emergency room and hospitalization in the ICU, with varying degrees of urgency in reaching a diagnosis and establishing a treatment plan.

Infection

Fig. 21.2  Bronchoscopic view of the left cranial and caudal lobar bronchi of a dog with severe bronchial collapse.

STANDARD TREATMENT Treatment of airway collapse relies on conservative measures to reduce the stressors that trigger cough and airway irritation. Anxiety or overexcitement can be limited by judicious use of anxiolytics (e.g., trazodone) in conjunction with avoidance measures. Exercise should be discouraged in hot or humid environments, and a harness should be used in place of a collar. While controversial, extended-release theophylline appears to be clinically beneficial in reducing cough and respiratory effort by improving expiratory airflow.7 Caution is warranted when using this drug because vomiting and agitation are recognized side effects, which could trigger exacerbation of disease. Currently, extended-release theophylline is available only from compounding pharmacies, and little data are available on these medications, although one formulation has been demonstrated to have good bioavailability.8 Steroids are typically indicated for management of bronchitis and eosinophilic lung disease; however, in the absence of airway sampling, it is important to recognize that not all cases of bronchomalacia have inflammation, and steroids can actually aggravate clinical signs in some dogs by induction of panting, weight gain, and worsening of preexisting infections. Disease can worsen as drug dosages are tapered downward,

The most common sources of infection in client-owned dogs are exposure to organisms in the canine infectious respiratory disease complex (viruses and bacteria) or via aspiration (see below). Dogs receiving corticosteroids should be considered particularly at risk for infection at any time, and a quick history should be obtained to assess exposure history to a potentially infected dog while triaging the patient. Also, dogs with airway collapse that come into contact with infected dogs seem to be more likely to trap certain organisms in the lower airways and display worsening or refractory disease. Pronounced coughing is likely the most common presenting complaint in affected dogs. When an infectious organism is considered likely to contribute to disease exacerbation, infection is typically local and complete blood count changes are not seen. Similarly, radiographic changes are not expected, although they are typically performed at an emergency visit to rule out other conditions. When the dog appears healthy and physical examination is relatively unremarkable apart from tracheal sensitivity, treatment is predicated on the knowledge of the characteristics of organisms involved. The decision to collect a lower airway sample is clinically based. Oropharyngeal swab cultures should not be considered suitable substitutes for a bronchial sample in most cases.9 Current guidelines for the management of acute respiratory infection presumed related to Mycoplasma, Bordetella, and other respiratory pathogens recommend the use of doxycycline (3–5 mg/kg PO BID).10 Owners should be advised to deliver water or food after administration of the drug to reduce the risk of esophageal stricture formation. Follow-up clinical assessment should be obtained if the condition worsens or cough does not resolve within 7–10 days.

Intubation A dog with tracheal or airway collapse can present to the ICU for worsened cough after anesthesia and intubation for diagnostic testing or completion of an elective procedure. Airway irritation from the endotracheal tube can initiate an unrelenting cough in an affected dog typically results within 1–2 days of the procedure. This seems to occur most commonly in small breed dogs, which are frequently affected by

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lower airway disease and also dental disease that requires treatment under general anesthesia. Any animal suspected of having purely tracheal irritation from intubation should be screened for possible aspiration of gastric contents or dental material with a complete blood count and thoracic radiographs. It is rare that cases of intubation injury require tracheoscopy to assess the severity of injury, especially given the potential risk of pneumothorax. Even when subcutaneous edema or pneumomediastinum raise concern for tracheal rupture, it is uncommon to be able to visualize the area of tracheal injury and therefore the potential benefit may not be worth the risk. Dogs with intubation irritation alone are typically managed with sedation (e.g., gabapentin, trazodone or acepromazine) and cough suppression (e.g., butorphanol or hydrocodone). Home treatment with neuroleptanalgesia is advised along with continued monitoring over the course of 10–14 days for worsened or persistent cough, as well as for development of signs consistent with a tracheal tear.

Cardiac Enlargement or Congestive Heart Failure Controversy exists over the role of left atrial enlargement or cardiomegaly in the generation or exacerbation of cough, and this is particularly challenging to define in dogs with airway collapse. Due to the positioning of the heart within the thorax in relation to several of the large lobar bronchi (left cranial, right middle, and accessory), enlargement of the heart could theoretically lead to compression of the airways between other thoracic structures. However, the commonality of left mainstem bronchial compression in brachycephalic breeds11 might argue for a more complex role of anatomical considerations other than simple cardiomegaly. Many small breed dogs are affected by combinations of mitral valve disease, bronchomalacia, and chronic bronchitis, making it difficult to assess the contribution of various diseases to the generation of cough (Fig. 21.3). One study failed to find a difference in the location or severity of airway collapse between a group of dogs with left atrial enlargement due to myxomatous mitral valve disease and a control group of dogs lacking cardiomegaly.12 In dogs evaluated in that study, most had evidence of inflammatory airway disease in conjunction with airway collapse, suggesting that airway disease was the primary cause of cough.

Fig. 21.3  Right lateral radiograph showing marked left atrial enlargement but no evidence of congestive heart failure. The pulmonary veins are equal in size to the pulmonary arteries, and no pulmonary infiltrates are present. The cardiac silhouette appears enlarged although this is likely related to pulmonary hypoinflation. The diagnosis in this dog was diffuse bronchomalacia.

Findings of tachypnea and tachycardia in a dog with heart murmur would support the likelihood of congestive failure because pulmonary edema initially fills the interstitium and induces tachypnea (see Chapter 41, Mechanisms of Heart Failure).13 Cardiomegaly is virtually always present when left-sided congestive heart failure develops, with left atrial and left ventricular enlargement, pulmonary venous enlargement, and interstitial to alveolar infiltrates in the hilar or caudal lung region (Fig. 21.4). In such a case, a trial on furosemide (1–4 mg/kg IV) would be advised. Follow-up thoracic radiographs obtained 24–48 hours after a furosemide trial that confirm clearing of infiltrates would support a diagnosis of congestive heart failure (see Part IV, Cardiovascular Disorders).

Pulmonary Hypertension (see Chapter 22, Pulmonary Hypertension) Virtually any chronic pulmonary disease can result in the complication of increased pulmonary vascular pressure, likely due to increased pulmonary vascular resistance associated with obstructive or obliterative diseases of the vasculature or from chronic and global hypoxic vasoconstriction. Pulmonary hypertension has been described in association with a variety of congenital and acquired cardiopulmonary conditions, including pneumonia in young dogs, brachycephalic syndrome, chronic tracheobronchial disease (bronchitis or airway collapse), embolic disease, and suspected interstitial lung disease.14 Syncope appears to be a relatively common finding, and recent onset of collapse in a respiratory patient should prompt consideration of pulmonary hypertension. Stabilization in oxygen should be performed with subsequent referral to a cardiologist.

Obesity Although not typically considered a cause for ICU admission, weight gain can have disastrous consequences for the dog with respiratory disease, and owners might be unaware of how the situation has progressed until the dog develops acute worsening of cough or respiratory difficulty. Excessive fat on the thoracic cage compromises respiration by reducing chest wall compliance, decreasing diaphragmatic excursion through fat deposition in the abdomen, and enhancing airway compression.15 These features are most deleterious for animals with lower respiratory tract disease including airway collapse and inflammatory airway disease, but they are also important for brachycephalic dogs and dogs with laryngeal paralysis.

Fig. 21.4  Right lateral radiographs displaying moderate to severe interstitial to alveolar infiltrates in conjunction with left atrial enlargement, consistent with heart failure.

CHAPTER 21  Lower Airway Disease in Dogs Although somewhat uncommon, dogs with lower airway disease can become tolerant of gradual carbon dioxide retention, causing chemoreceptors to lose the ventilatory response to hypercapnia. When placed into an oxygen-enriched environment, these dogs can decompensate, as evidenced by increased work of breathing and worsened respiratory distress. This rare occurrence usually responds to withdrawal of exogenous oxygen supplementation. Dogs should subsequently be referred to their local veterinarian for a comprehensive work-up of medical conditions that can contribute to weight gain and the development of a weight-loss plan that relies on calculation of calories based on body condition scoring.

Aspiration Injury (see Chapter 24, Pneumonia) Risk factors for aspiration pneumonia include swallowing disorders (megaesophagus or esophagitis), vomiting, decreased level of consciousness (postanesthesia, postictus, head trauma), and laryngeal dysfunction or surgery. Acid injury is primarily responsible for the ventilatory abnormalities seen in animals with aspiration pneumonia, although some dogs have a substantial bacterial component to their disease. Physical examination in dogs with acute and moderate to severe aspiration injury is characteristic of pneumonia, with a rapid shallow breathing pattern and cough. Special attention should be paid to identifying any physical examination factors that relate to risk factors for aspiration, with careful auscultation over the larynx to detect stridor on inspiration, suggesting laryngeal paralysis as a predisposing feature. Laboratory testing is beneficial for assessing the severity of inflammation and for following the response to therapy. A complete blood count often reveals leukocytosis, although the severity and the presence of a band response are variable. A biochemical panel can provide early detection of systemic changes that might accompany multiorgan failure. Pulse oximetry is a worthwhile screening tool to determine whether an arterial blood gas analysis should be obtained, when available. An oxygen saturation (SpO2) below 95% correlates with a partial pressure of oxygen (PaO2) ,80 mm Hg and indicates that a blood gas analysis should be considered. Although the pulse oximeter provides only a crude estimate of arterial oxygenation, it can be useful in conjunction with a physical examination and lung auscultation for quantifying trends in clinical improvement or worsening of pneumonia. Thoracic radiographs in patients with aspiration pneumonia typically show cranioventral alveolar infiltrates or middle lung lobe disease; however, the position of the animal at the time of aspiration will affect the radiographic distribution. Also, the time that has elapsed since aspiration will determine whether an interstitial or alveolar infiltrate is identified. Conflicting results have been obtained in studies that compared the severity of radiographic changes with outcome;16,17 therefore, caution is warranted in offering prognosis based on radiographs alone. If the aspiration event has been witnessed or if an inert substance such as mineral oil has been aspirated, immediate bronchoscopic suction of the material can be beneficial; however, this is rarely clinically possible. If bronchoscopy is performed, excessive fluid lavage should be avoided because this can force particulate matter deeper into the parenchyma and result in airway obstruction or deep-seated inflammation or infection. General treatment of pneumonia is implemented in the animal that has aspirated, including antimicrobial therapy directed at gastrointestinal and oropharyngeal bacteria, anaerobes, and Mycoplasma (see Chapter 172, Antimicrobial Use in the Intensive Care Patient). In hospitalized patients, parenteral administration of a penicillin and fluoroquinolone is typically advised.10 Intravenous fluid support is usually indicated for supportive care, and airway nebulization can be performed to liquefy secretions. Coupage should not be performed if

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the animal is vomiting or regurgitating. Terbutaline administration (0.01 mg/kg SQ, IM, or IV BID to TID) can be considered in the first 24–48 hours to combat acid-induced bronchoconstriction. If hypoxemia is severe, the animal displays clinical evidence of poor tissue oxygenation, or if exaggerated work of breathing is noted, exogenous oxygen supplementation should be provided. High inspiratory oxygen and long periods of oxygen supplementation should be avoided to limit oxygen-induced lung injury through generation of free radicals and toxic oxygen species (see Chapter 8, Oxygen Toxicity).18 Aspiration pneumonia can progress to acute respiratory distress syndrome, and ventilatory support is required in animals that display severe derangements in gas exchange and/or excessive work of breathing. Importantly, the underlying condition that resulted in aspiration must be identified and aggressively managed in order to avoid further episodes of aspiration and recurrent lung damage. Fortunately, overall survival can approach 75% despite the presence of multiple risk factors for aspiration.19

CONCLUSION Chronic respiratory conditions can be worsened by a variety of events, some easily recognized and others that are more challenging to define. Immediate stabilization of the patient with oxygen and sedation is often the best strategy, followed by investigation of the underlying inciting event with laboratory testing and thoracic radiographs.

REFERENCES 1. Johnson LR, Pollard RE: Tracheal collapse and bronchomalacia in dogs: 58 cases (2001-2008), J Vet Intern Med 24:298-305, 2010. 2. Johnson LR, Vernau W: Bronchoalveolar lavage lymphocytosis in 104 dogs (2006-2016), J Vet Intern Med 33(3):1315-1321, 2019. 3. Johnson LR, Johnson EG, Hulsebosch SE, Dear JD, Vernau W: Eosinophilic lung disease in 76 dogs (2006-2016), J Vet Intern Med 33:2217-2226, 2019. 4. Cannon MS, Johnson LR, Pesavento PA, Kass PH, Wisner ER: Quantitative and qualitative computed tomographic characteristics of bronchiectasis in 12 dogs, Vet Radiol Ultrasound 54:351-357, 2013. 5. Nafe L, Robertson ID, Hawkins EC: Cervical lung lobe herniation in dogs identified by fluoroscopy, Can Vet J 54:955-959, 2013. 6. Johnson LR, Queen EV, Vernau W, Sykes JE, Byrne BA: Microbiologic and cytologic assessment of bronchoalveolar lavage fluid in dogs with lower respiratory tract infection, J Vet Intern Med 27:259-267, 2013. 7. Jeung SY, Sohn SJ, An JH, et al: A retrospective study of theophyllinebased therapy with tracheal collapse in small-breed dogs: 47 cases (2013-2017), J Vet Sci 20(5):e57, 2019. doi:10.4142/jvs.2019.20.e57. 8. Cavett CL, Li Z, McKiernan BC, Reinhart JM: Pharmacokinetics of a modified, compounded theophylline product in dogs, J Vet Pharmacol Ther 42:593-601, 2019. doi:10.1111/jvp.12813. 9. Sumner CM, Rozanski EA, Sharp CR, Shaw SP: The use of deep oral swabs as a surrogate for transoral tracheal wash to obtain bacterial cultures in dogs with pneumonia, J Vet Emerg Crit Care 21:515-520, 2011. 10. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats: antimicrobial guidelines working group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31(2):279-295, 2017. 11. De Lorenzi D, Bertoncello D, Drigo M: Bronchial abnormalities found in a consecutive series of 40 brachycephalic dogs, J Am Vet Med Assoc 235:835-840, 2009. https://doi.org/10.2460/javma.235.7.835. 12. Singh MK, Johnson LR, Kittleson MD, Pollard RE: Bronchomalacia in dogs with myxomatous mitral valve degeneration, J Vet Intern Med 26:312-319, 2012. 13. Ferasin L, Crews L, Biller DS, Lamb KE, Borgarelli M: Risk factors for coughing in dogs with naturally acquired myxomatous mitral valve disease, J Vet Intern Med 27:286-292, 2013.

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14. Johnson LR, Stern JA: Clinical features and outcome in 25 dogs with respiratory-associated pulmonary hypertension treated with sildenafil, J Vet Intern Med 34:65-73, 2020. 15. Bach JF, Rozanski EA, Bedenice D, et al: Association of expiratory airway dysfunction with marked obesity in healthy adult dogs, Am J Vet Res 68:670-675, 2007. 16. Kogan DA, Johnson LR, Jandrey KE, Pollard RE: Clinicopathologic and radiographic findings in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1642-1747, 2008. 17. Tart KM, Babski DM, Lee JA: Potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in dogs with

presumptive aspiration pneumonia: 125 cases (2005-2008), J Vet Emerg Crit Care 20:319-329, 2010. 18. Knight PR, Kurek C, Davidson BA, et al: Acid aspiration increases sensitivity to increased ambient oxygen concentrations, Am J Physiol Lung Cell Mol Physiol 278:L1240-L1247, 2000. 19. Kogan DA, Johnson LR, Sturges BK, Jandrey KE, Pollard RE: Etiology and clinical outcome in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1748-1755, 2008.

22 Pulmonary Hypertension Lance C. Visser, DVM, MS, DACVIM (Cardiology), Yu Ueda, DVM, PhD, DACVECC

KEY POINTS • Pulmonary hypertension (PH) is caused by increased pulmonary blood flow, increased pulmonary vascular resistance, increased pulmonary venous pressure, or a combination thereof. It represents an abnormal hemodynamic condition and not a disease in and of itself. • PH can exacerbate clinical signs and worsen the prognosis of certain diseases, ultimately leading to right heart failure. • Echocardiography performed by a skilled and knowledgeable operator represents a key clinical tool to diagnose PH. • PH is classified into groups of similar diseases/conditions, which includes PH secondary to 1) pulmonary arterial hypertension,

2) left-sided heart disease, 3) respiratory disease/hypoxia, 4) pulmonary thrombi/thromboemboli, 5) parasitic diseases (heartworm or Angiostrongylus infection), or 6) multifactorial or unclear mechanisms. • Optimal management of clinically significant PH is best accomplished by determining and treating the underlying disease, and, in most cases, a PH-specific treatment such as a phosphodiesterase5 inhibitor (sildenafil or tadalafil). • Phosphodiesterase-5 inhibitors are not first-line therapy for dogs with PH secondary to left heart disease/failure (e.g., myxomatous mitral valve disease).

DEFINITIONS AND TERMINOLOGY

vascular disease, or both. In several diseases this is the primary cause of (precapillary) PH. However, increased pulmonary blood flow (e.g., from a left-to-right cardiac shunt) or, as previously described, chronically increased pulmonary venous pressure (from left-sided heart disease) can also lead to increases in PVR. This is thought to occur secondary to reactive vasoconstriction, pulmonary vascular disease (wall stiffening, endothelial dysfunction, vascular inflammation & thrombosis, and fibrosis), or both.2-4 Increased PVR results in increased RV afterload. This triggers RV hypertrophy, which is typically a mixed hypertrophy (wall thickening and chamber dilation). Over time, sustained increases in PAP can cause RV dysfunction/failure largely because the RV is not well suited to sustained pressure overloads. Clinically, this manifests as right-sided heart failure, i.e., increased systemic venous pressures and subsequent pleural and/or abdominal effusions.

Pulmonary hypertension (PH) is not a defining characteristic of a specific disease. It represents a hemodynamic and pathophysiologic state that might be present in and contribute to the morbidity and mortality in a broad spectrum of diseases. It is defined by abnormally increased pressure within the pulmonary vasculature. In humans, PH has been defined by a mean pulmonary arterial pressure (PAP) $25 mm Hg at rest measured invasively by right heart catheterization.1 PH can be caused by 1) increased pulmonary blood flow (cardiac output), 2) increased pulmonary vascular resistance (PVR), 3) increased pulmonary venous pressure or some combination thereof (Table 22.1). PH caused by increased PVR in the absence of increased pulmonary venous pressure is called precapillary PH. This is typically the result of vasoconstriction, structural pulmonary arterial changes due to pulmonary vascular disease, or both. PH associated with increased pulmonary venous pressure is called postcapillary PH (also called pulmonary venous hypertension). Postcapillary PH occurs secondary to left-sided heart disease and increased left atrial (LA) pressure. Increased LA pressure and subsequently increased pulmonary venous pressure ultimately increases the load the right ventricle (RV) has to pump through the pulmonary circulation. Chronic postcapillary PH (typically from severe left heart disease or failure) can lead to pulmonary arterial vasoconstriction and pulmonary vascular disease, which increases PVR. Therefore, postcapillary PH can occur in isolation (isolated postcapillary PH, also called “passive PH”) or can be paired with increased PVR (combined postcapillary and precapillary PH, also called “reactive PH”) as a result of chronic, severe left-sided heart disease.

PATHOPHYSIOLOGY Sustained increases in PAP result from increases in PVR due to pulmonary artery (arteriolar) vasoconstriction, pulmonary arterial remodeling/

ASSESSMENT OF PH The gold standard method for the assessment of PH is right heart catheterization with direct assessment of PAP and pulmonary artery wedge pressure (surrogate of LA pressure), where cardiac output can be measured and PVR can be calculated. This is rarely performed in clinical patients. Thus, veterinarians rely heavily on echocardiography and other supportive clinical findings for the noninvasive assessment of PH. Because echocardiography does not provide a definitive diagnosis, it should be viewed as a clinical tool to help assess the probability that a patient has PH (versus a definitive diagnosis of PH).5-7 The American College of Veterinary Internal Medicine (ACVIM) consensus guidelines on PH provide criteria to help assess the probability (low, intermediate, or high) that a patient has clinically significant PH using echocardiography.7 Details of echocardiographic assessment of PH are beyond the scope of this chapter but the criteria involve two key components:

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TABLE 22.1  Mechanisms for the

Development of Pulmonary Hypertension (PH) Mechanisms of PH*

Examples of Causes

Increased pulmonary blood flow

Left-to-right shunt due to intra- or extracardiac defects (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect) Pulmonary arterial (arteriolar) vasoconstriction Pulmonary arterial thrombosis Pulmonary endothelial dysfunction Pulmonary vascular remodeling Perivascular inflammation Pulmonary vascular luminal obstruction Increased blood viscosity Pulmonary arterial wall stiffening Pulmonary parenchymal destruction Left heart disease (e.g., myxomatous mitral valve disease) Compression or stenosis of a large pulmonary vein(s)

Increased pulmonary vascular resistance

Increased pulmonary venous pressure

*Combinations of the mechanisms of PH are possible. Dogs with chronic and progressive left heart disease and increased pulmonary venous pressure can develop increased pulmonary vascular resistance (combined postcapillary and precapillary PH). Dogs with leftto-right shunts can also develop increased pulmonary vascular resistance.

1) characteristic cardiac changes that occur secondary to PH (so-called echocardiographic signs of PH) and 2) estimates of systolic PAP using Doppler echocardiography. Echocardiographic changes commonly seen with PH include structural or functional changes of the ventricles (e.g., RV hypertrophy and systolic dysfunction, left ventricular underfilling, flattening of the interventricular septum), pulmonary artery (e.g., dilation and altered blood flow profile), and right atrium (RA)/caudal vena cava (i.e., enlargement). In the absence of a RV outflow tract obstruction, estimating systolic PAP using echocardiography largely involves quantifying peak tricuspid regurgitation velocity (TRV). This can be converted to a pressure gradient (between the RA and RV in systole) using the simplified Bernoulli equation: pressure gradient 5 4 3 velocity [m/s]2 This pressure gradient has been conventionally used to quantify the degree of PH as mild (30–50 mm Hg), moderate (50–75 mm Hg), and severe (.75 mm Hg). However, the ACVIM consensus guidelines point out these cutoffs are arbitrary and potentially inaccurate and misleading.7 Severity of clinical signs, degree of structural and functional changes identified by echocardiography, and the TRV are likely more accurate to determine the severity of PH. Clinically significant PH is unlikely unless clinical signs are apparent (Table 22.2) and at least an intermediate probability of PH is present as determined by echocardiographic examination by a skilled sonographer.7 This involves a TRV cutoff of .3.4 m/s (pressure gradient .46 mm Hg). The proposed criteria set forth by the ACVIM consensus guidelines are intended to avoid a misdiagnosis and inappropriate treatment of PH that might have a lasting impact or, in some cases, cause harm. It should also be recognized that echocardiography represents one, albeit important, aspect of the assessment of PH. Echocardiographic findings should always be interpreted within the clinical context and in light of other diagnostic tests.

TABLE 22.2  Clinical Signs/Findings

that Might be Associated with Clinically Significant Pulmonary Hypertension (PH)* Strongly Suggestive of PH

Possibly Suggestive of PH

Syncope (especially with exertion or excitement) Respiratory distress at rest Activity/exercise terminating in respiratory distress Right heart failure (cardiogenic ascites)

Tachypnea at rest Increased respiratory effort at rest Prolonged postexercise/activity tachypnea

*None of these clinical signs/findings are specific to PH and should be interpreted within the clinical context. Adapted from the American College of Veterinary Internal Medicine consensus guidelines.7

CLASSIFICATION OF PH In addition to the hemodynamic classification (i.e., precapillary PH, postcapillary PH), the ACVIM consensus guidelines have proposed a clinical classification scheme for PH in dogs that consists of six groups: PH secondary to 1) pulmonary arterial hypertension (PAH), 2) leftsided heart disease (LHD), 3) respiratory disease/hypoxia, 4) pulmonary thrombotic or thromboembolic disease (PT/PTE), 5) parasitic disease (heartworm or Angiostrongylus), and 6) multifactorial or unclear mechanisms (Table 22.3). These groups are modeled after the classification scheme used in humans8 and are grouped based on similarities in the causes of PH, including clinical presentation, hemodynamic characteristics, pathophysiology, and treatment. A summary of the terminology, hemodynamic definitions, and echocardiographic findings with the corresponding clinical classification is presented in Table 22.4. Due to the high prevalence of subclinical myxomatous mitral valve disease (MMVD) in middle-aged to older dogs, one specific classification warrants brief discussion. For PH to be considered secondary to LHD (e.g., MMVD), two criteria must be met via echocardiography: 1) documentation of LHD, and, importantly, 2) documentation of unequivocal LA enlargement.7 Documentation of LA enlargement serves as a surrogate, albeit crude, marker for chronically increased LA pressure (postcapillary PH). In other words, it should be considered very unlikely for PH to be secondary to LHD/MMVD unless unequivocal LA enlargement is identified. In the authors’ experience, PH secondary to PAH (group 1) or respiratory disease/hypoxia (group 3) are frequently encountered in dogs with incidentally detected subclinical MMVD without LA enlargement. These dogs should be considered to have PH secondary to PAH (group 1) and respiratory disease/hypoxia (group 3), respectively, and not LHD (group 2).

CLINICAL FINDINGS Clinical findings of animals affected with PH are variable and largely reflect the underlying cause of PH. The severity of clinical signs generally relates to the severity of PH. Clinical findings commonly seen in animals with PH are presented in Table 22.2. Syncope (especially following exertion), respiratory difficulty, and exercise intolerance are among the most common clinical signs reported that are suggestive of PH in dogs.9-11 Physical examination might reveal abnormal respiratory sounds, tachypnea, apparent dyspnea, cyanotic or pale mucous

CHAPTER 22  Pulmonary Hypertension

TABLE 22.3  Classification of Pulmonary

Hypertension (PH) in Dogs Proposed by the American College of Veterinary Internal Medicine Consensus Guidelines7 Classification and examples of diseases/conditions in each group Group 1. Pulmonary arterial hypertension (PAH) 1a. Idiopathic (IPAH) 1b. Heritable 1c. Drugs and toxins induced 1d. Associated with (APAH) 1d1. Congenital cardiac shunts 1d2. Pulmonary vasculitis 1d3. Pulmonary vascular amyloid deposition 1e. Pulmonary vasoocclusive disease or pulmonary capillary hemangiomatosis Group 2. PH secondary to left heart disease 2a. Left ventricular dysfunction 2a1. Canine dilated cardiomyopathy 2a2. Myocarditis 2b. Valvular disease 2b1. Acquired 2b1a. Myxomatous mitral valve disease 2b1b. Valvular endocarditis 2c. Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 2c1. Mitral valve dysplasia 2c2. Mitral valve stenosis 2c3. Aortic stenosis Group 3. PH secondary to respiratory disease, hypoxia or both 3a. Chronic obstructive airway disorders 3a1. Tracheal or mainstem bronchial collapse 3a2. Bronchomalacia 3b. Primary pulmonary parenchymal disease 3b1. Interstitial lung disease 3b1a. Fibrotic lung disease 3b1b. Cryptogenic organizing pneumonia/secondary organizing pneumonia 3b1c. Pulmonary alveolar proteinosis 3b1d. Unclassified interstitial lung disease 3b1e. Eosinophilic pneumonia/eosinophilic bronchopneumopathy 3b2. Infectious pneumonia, pneumocystis 3b3. Diffuse pulmonary neoplasia 3c. Obstructive sleep apnea/sleep disordered breathing, brachycephalic obstructive airway syndrome 3d. Chronic exposure to high altitude 3e. Developmental lung disease 3f. Miscellaneous: bronchiolar disorders, bronchiectasis, emphysema, postpneumonectomy Group 4. PH secondary to pulmonary thrombus/thromboembolism (PT/PTE) 4a. Acute PT/PTE 4b. Chronic PT/PTE Group 5. PH secondary to parasitic disease (Dirofilaria, Angiostrongylus infection) Group 6. PH with multifactorial or unclear etiologies 6a. Disorders having clear evidence of two or more underlying Groups 1–5 pathologies contributing to PH 6b. Masses compressing the pulmonary arteries (e.g., neoplasia, fungal granuloma) 6c. Other disorders with unclear mechanisms

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membranes, jugular venous distension or pulsation, and/or ascites from right heart failure. Cardiac auscultation might yield a loud or split second heart sound. Systolic heart murmurs over the mitral (secondary to concurrent MMVD) and/or tricuspid valve are common. Loud murmurs over the tricuspid valve region are highly suggestive of PH in dogs with MMVD.12

DIAGNOSTIC EVALUATION From a critical care perspective, veterinarians should know when to request an echocardiographic examination for assessment of PH, i.e., when the aforementioned clinical findings (Table 22.2), physical examination, baseline bloodwork, and thoracic imaging are present without another clear etiology. A common clinical scenario when assessment for PH may be warranted is a dog that has experienced syncope that is not associated with a brady- or tachyarrhythmia, severe heart disease/failure, neurologic disease, or severe metabolic/hematologic derangements. Unexplained abdominal effusion (modified transudates) coupled with a dilated caudal vena cava should also warrant an echocardiographic examination to assess the probability of PH. Right heart failure secondary to PH is a more likely explanation in this scenario. The ACVIM consensus guidelines provide other clinical scenarios and should be reviewed for additional guidance.7 These guidelines also provide suggested diagnostic evaluations for dogs with an intermediate or high probability of PH. Determining the underlying cause of PH is highly recommended because it is of key importance for optimal clinical management of PH.

CLINICAL MANAGEMENT Clinical management of PH centers around treatment of the underlying disease(s)/factors contributing to the PH in addition to PHspecific treatment. General recommendations such as oxygen supplementation (as indicated and at least in the short term), heartworm prevention, exercise restriction, and avoiding air travel and high altitude (without oxygen supplementation) also seem prudent. A discussion of specific treatments of the underlying disease(s) contributing to PH are beyond the scope of this chapter; some recommendations are provided elsewhere7 and in other chapters. A consultation with a specialist may be beneficial. The most common PH-specific treatment used in dogs is phosphodiesterase-5 inhibitors (PDE5i), which cause accumulation of cyclic guanosine monophosphate (cGMP) in pulmonary vascular smooth muscle cells by inhibiting cGMP catabolism. Accumulation of cGMP results in relaxation of vascular smooth muscle and inhibition of pulmonary arterial smooth muscle cell hypertrophy. PDE5i drugs are generally effective at lowering PVR and potentially delaying adverse remodeling of pulmonary arteries, both of which represent the primary therapeutic target for patients with precapillary PH. PDE5i’s are also thought to increase the cGMP concentration in the myocardium and augment myocardial function and limit cardiac hypertrophy.13 Sildenafil (1–3 mg/kg PO q8h) is a highly selective PDE5i, and several studies have suggested a clinical benefit (improved clinical signs, quality of life, and exercise capacity) in dogs with PH.10,14-16 However, a PDE5A gene polymorphism has been identified,17 and one study has suggested that the polymorphism can blunt the effectiveness of sildenafil in dogs with PH.14 Sildenafil is ideally administered every 8 hours given its short half-life.18 Another PDE5i medication with a longer half-life, tadalafil, appears to be a reasonable alternative. Tadalafil can be administered every 24 hours (2 mg/kg PO q24h). In a randomized double-blinded pilot study comparing sildenafil and tadalafil, tadalafil

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did not cause any significant differences in improvements in clinical signs, quality of life, or outcome.19 Additional PH-specific therapies have been proposed for use in dogs and include phosphodiesterase 3 inhibitors (pimobendan, milrinone), tyrosine kinase inhibitors (toceranib, imatinib), and L-arginine. These therapies are not routinely recommended. The reader is referred elsewhere for further discussion of these therapies.7 The decision to start PDE5i therapy should be made based on an echocardiographic examination performed by a skilled and knowledgeable sonographer (cardiology specialist in most cases). In general, a PDE5i is only recommended in dogs with clinical signs/findings suggestive of PH and an intermediate or high echocardiographic probability of PH (precapillary PH), i.e., when significant right heart remodeling has been demonstrated (in the absence of other causes), TRV is .3.4 m/s, or both.7 Provided these conditions are met, treatment with a PDE5i can be considered for dogs with PH classified in groups 1 and 3–5. Use of PDE5i in dogs in group 2 are discussed below. PH-specific treatment in dogs in group 6 are made on a caseby-case basis. Empirical use of PDE5i therapy is discouraged and PDE5i treatment should be used with caution in dogs with PH secondary to LHD since treatment could induce pulmonary edema in these patients. In dogs with PH secondary to LHD, increased PVR may (combined postcapillary and precapillary PH) or may not (isolated postcapillary PH) be present (Table 22.4). Thus, first-line therapy is centered around decreasing LA pressure (e.g., furosemide and pimobendan in dogs with MMVD) and management of heart failure, if present. First-line therapy should not include a PDE5i because administering a PDE5i to a dog without increased PVR or with increased PVR but with especially responsive pulmonary arterioles will likely acutely increase right heart cardiac output and venous return to the LA. This will increase LA, pulmonary venous, and pulmonary capillary pressure, potentially culminating in iatrogenic pulmonary edema. As previously described, some dogs with PH secondary to LHD develop combined postcapillary and precapillary PH and predicting vascular responsiveness to a PDE5i in this situation is difficult. Thus, PDE5i should only be considered (typically starting with conservative doses e.g., sildenafil 0.5 mg/kg PO q8h) if dogs remain symptomatic following strategies to lower LA pressure and if left heart failure is well controlled (if initially present) or if right heart failure is present.7 Close monitoring of breathing rate and effort is advised.

Critical Care Management of PH Animals with PH may require critical care management due to acute decompensation of hemodynamic and oxygenation status as a result of PH progression or because of triggering factors (e.g., PTE, arrhythmia, sepsis, and fluid overload). These animals may present with right heart failure and systemic hypotension with low cardiac output and/or respiratory distress and hypoxemia. The initial management should focus on addressing any potential triggering factors and reducing the RV afterload by administering PDE5i.20,21 In addition, respiratory and hemodynamic resuscitation should be attempted as soon as possible. Providing oxygen therapy and meticulous fluid volume management to optimize the preload are important, as hypervolemia can have detrimental effects. In some cases, diuretics are often indicated to optimize blood volume and RV preload. In cases of severe decompensation (impaired cardiac output due to severe RV systolic dysfunction) positive inotropic therapy should be considered. In humans, low-dose dobutamine is often utilized as a first-line inotrope; however, dobutamine might worsen systemic hypotension because of its vasodilatory effect. In case of persistent systemic hypotension, norepinephrine could also be considered because it increases systemic vascular resistance and RV contractility (see Chapter 147, Catecholamines).21

PROGNOSIS AND MONITORING The prognosis for dogs with PH is variable and linked to the cause and severity of the underlying disease(s) causing the PH. PH might be reversible in some cases but is likely to worsen survival in most diseases when compared with dogs affected with the same disease that do not suffer from PH. Studies have shown that PH worsens the prognosis of dogs affected with MMVD22 and respiratory disease/hypoxia.23,24 Clinical experience suggests that dogs with right heart failure secondary to PH have a worse prognosis. Monitoring response to PH-specific therapy is advised. This should largely be tailored to the individual patient. Clinical response to therapy is the most important and typically involves reassessment of clinical signs or adverse clinical findings. The utility of performing repeat echocardiographic examinations for all cases of PH is debatable but unlikely to be necessary. Improvement in echocardiographic variables (e.g., TRV and estimated PAP) is not always documented following administration of PDE5i. However, this should not dissuade the use of PH-specific therapy or trigger dose adjustments if clinical response is otherwise positive.

TABLE 22.4  Summary of the Terminology, Hemodynamic Classification, Key Echocardiographic

Findings, and Clinical Classification Groups Related to Pulmonary Hypertension (PH) Hemodynamic Classification

Key Echocardiographic Findings

Clinical Classification Group

Precapillary PH • Increased PVR • LA pressure not increased

• No LA enlargement • Structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava are expected

Postcapillary PH • Isolated postcapillary PH • Increased LA pressure • PVR not increased • Combined postcapillary and precapillary PH • Increased LA pressure • Increased PVR

• Unequivocal LA enlargement • No/minimal structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava

Group 1. Pulmonary arterial hypertension* Group 3. Respiratory disease/hypoxia Group 4. Thrombi/thromboemboli Group 5. Parasitic disease Group 6. Multifactorial/unclear mechanisms Group 2. Left heart disease

• Unequivocal LA enlargement • Structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava are expected

Group 2. Left heart disease Group 6. Multifactorial/unclear mechanisms

LA, left atrial; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrial; RV, right ventricle. *With shunting lesions, the primary abnormality might be increased right heart cardiac output and not solely increased pulmonary vascular resistance. Adapted from the American College of Veterinary Internal Medicine consensus guidelines.7

CHAPTER 22  Pulmonary Hypertension

REFERENCES 1. Hoeper MM, Bogaard HJ, Condliffe R, et al: Definitions and diagnosis of pulmonary hypertension, J Am Coll Cardiol 62(Suppl 25):D42-D50, 2013. 2. Thenappan T, Ormiston ML, Ryan JJ, Archer SL: Pulmonary arterial hypertension: pathogenesis and clinical management, BMJ 360:j5492, 2018. 3. Guazzi M, Arena R: Pulmonary hypertension with left-sided heart disease, Nat Rev Cardiol 7(11):648-659, 2010. 4. Guazzi M, Naeije R: Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives, J Am Coll Cardiol 69(13):1718-1734, 2017. 5. Augustine DX, Coates-Bradshaw LD, Willis J, et al: Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography, Echo Res Pract 5(3):G11-G24, 2018. 6. Galiè N, Humbert M, Vachiery JL, et al: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT), Eur Heart J 37(1):67-119, 2016. 7. Reinero C, Visser LC, Kellihan HB, et al: ACVIM consensus statement guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension in dogs, J Vet Intern Med 34(2):549-573, 2020. 8. Simonneau G, Gatzoulis MA, Adatia I, et al: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 62(Suppl 25):D34-D41, 2013. 9. Campbell FE: Cardiac effects of pulmonary disease, Vet Clin North Am Small Anim Pract 37(5):949-962, vii, 2007. 10. Kellum HB, Stepien RL: Sildenafil citrate therapy in 22 dogs with pulmonary hypertension, J Vet Intern Med 21(6):1258-1264, 2007. 11. Kellihan HB, Stepien RL: Pulmonary hypertension in dogs: diagnosis and therapy, Vet Clin North Am Small Anim Pract 40(4):623-641, 2010. 12. Ohad DG, Lenchner I, Bdolah-Abram T, Segev G: A loud right-apical systolic murmur is associated with the diagnosis of secondary pulmonary arterial hypertension: retrospective analysis of data from 201 consecutive client-owned dogs (2006-2007), Vet J 198(3):690-695, 2013. 13. Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA: Cardiac uses of phosphodiesterase-5 inhibitors, J Am Coll Cardiol 59(1):9-15, 2012.

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14. Ueda Y, Johnson LR, Ontiveros ES, Visser LC, Gunther-Harrington CT, Stern JA: Effect of a phosphodiesterase-5A (PDE5A) gene polymorphism on response to sildenafil therapy in canine pulmonary hypertension, Sci Rep 9(1):6899, 2019. 15. Brown AJ, Davison E, Sleeper MM: Clinical efficacy of sildenafil in treatment of pulmonary arterial hypertension in dogs, J Vet Intern Med 24(4):850-854, 2010. 16. Bach JF, Rozanski EA, MacGregor J, Betkowski JM, Rush JE: Retrospective evaluation of sildenafil citrate as a therapy for pulmonary hypertension in dogs, J Vet Intern Med 20(5):1132-1135, 2006. 17. Stern JA, Reina-Doreste Y, Chdid L, Meurs KM: Identification of PDE5A:E90K: a polymorphism in the canine phosphodiesterase 5A gene affecting basal cGMP concentrations of healthy dogs, J Vet Intern Med 28(1):78-83, 2014. 18. Akabane R, Sato T, Sakatani A, Miyagawa Y, Tazaki H, Takemura N: Pharmacokinetics of single-dose sildenafil administered orally in clinically healthy dogs: effect of feeding and dose proportionality, J Vet Pharmacol Ther 41(3):457-462, 2018. 19. Jaffey JA, Leach SB, Kong LR, Wiggen KE, Bender SB, Reinero CR: Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study, J Vet Cardiol 24: 7-19, 2019. 20. Savale L, Weatherald J, Jaïs X, et al: Acute decompensated pulmonary hypertension, Eur Respir Rev 26(146), 2017. 21. Hoeper MM, Granton J: Intensive care unit management of patients with severe pulmonary hypertension and right heart failure, Am J Respir Crit Care Med 184(10):1114-1124, 2011. 22. Borgarelli M, Abbott J, Braz-Ruivo L, et al: Prevalence and prognostic importance of pulmonary hypertension in dogs with myxomatous mitral valve disease, J Vet Intern Med 29(2):569-574, 2015. 23. Johnson LR, Stern JA: Clinical features and outcome in 25 dogs with respiratory-associated pulmonary hypertension treated with sildenafil, J Vet Intern Med 34(1):65-73, 2020. 24. Jaffey JA, Wiggen K, Leach SB, Masseau I, Girens RE, Reinero CR: Pulmonary hypertension secondary to respiratory disease and/or hypoxia in dogs: clinical features, diagnostic testing and survival, Vet J 251:105347, 2019.

23 Pulmonary Edema Sophie Adamantos, BVSc, CertVA, DACVECC, DECVECC, MRCVS, FHEA, Dez Hughes, BVSc (Hons), DACVECC

KEY POINTS • Pulmonary edema is a common cause of dyspnea in dogs and cats. • Two main pathophysiologic forms exist: high hydrostatic pressure edema and increased permeability edema. • The most common cause of pulmonary edema in dogs and cats is cardiogenic edema. • The prognosis for animals with pulmonary edema and the response to therapy depends on the underlying cause.

• Cardiogenic pulmonary edema usually responds well to loop diuretic therapy, whereas noncardiogenic pulmonary edema responds less readily to treatment. • Fluid therapy should be administered with caution in all patients with pulmonary edema.

Pulmonary edema is the accumulation of extravascular fluid within the pulmonary parenchyma or alveoli. The two main pathophysiologic forms are high hydrostatic pressure edema (due to increased pulmonary capillary hydrostatic pressure) and increased permeability edema (due to damage of the microvascular barrier and alveolar epithelium in more severe cases). Pulmonary edema is a relatively common disease process in veterinary patients that can quickly become life threatening. The diagnostic approach to pulmonary edema is to rapidly determine whether it is cardiogenic (i.e., caused by left-sided cardiac failure) or noncardiogenic edema (all the causes other than failure of the left side of the heart). Recent advances in knowledge and skill set in point-of-care ultrasound allow rapid identification of pulmonary edema and the presence of cardiac disease.

Pulmonary edema occurs when the rate of interstitial fluid formation overwhelms the protective fluid clearance mechanisms. Hydrostatic pressure is the main determinant of fluid extravasation and edema formation in the lungs,6 providing the rationale for using hydrostatic pressure modulators in the treatment of all forms of pulmonary edema. The pulmonary ultrastructure is designed to protect gaseous diffusion. Most interstitial fluid flow is on the side of the capillary opposite to that where gas exchange occurs (see Fig. 16.3), and the distensibility of the lung interstitium increases toward the peribronchovascular region. This results in initial fluid accumulation in areas not used for gas exchange.7 High hydrostatic pressure edema forms as a result of increasing pulmonary capillary pressure leading to fluid extravasation that eventually overwhelms the lymphatic removal capacity. Fluid initially flows toward the peribronchovascular interstitium, then distends all parts of the pulmonary interstitium and eventually spills into the airspaces at the junction of the alveolar and airway epithelia.6 In many animals with cardiogenic edema, the increase in pressure occurs gradually and overt edema may develop over a period of months; however, if there are acute increases in hydrostatic pressure (e.g., chordae tendineae rupture) then edema will form rapidly. Increased permeability edema occurs secondary to injury to the microvascular barrier and alveolar epithelium, resulting in extravasation of fluid with a high protein content.6 Any protective fall in COP is thereby diminished, so the hydrostatic pressure becomes the main determinant of edema formation. Interstitial fluid accumulation can then occur at even lower hydrostatic pressures and relatively small rises in pressure can result in greater edema formation. In more severe cases in which the alveolar epithelium is also damaged, a direct conduit may form between the intravascular space and the alveoli, and interstitial edema progresses rapidly to alveolar flooding. This explains the greater severity and fulminant course of increased permeability edema compared with hydrostatic edema. Although the lymphatic system plays a major role in limiting interstitial fluid accumulation, it has only a minor role in the clearance of

PATHOPHYSIOLOGY In normal tissues, transvascular fluid fluxes are determined by the capillary hydrostatic pressure, interstitial hydrostatic pressure, capillary colloid osmotic pressure (COP), the COP beneath the endothelial glycocalyx, and the reflection and filtration coefficients for the tissues.1 The filtration coefficient is a measure of fluid efflux from the vasculature of specific tissues and is dependent on the capillary surface area and hydraulic conductivity. The reflection coefficient indicates the relative permeability of the membrane to protein. In tissues with a nondistensible interstitium, such as the lung, increased interstitial hydrostatic pressures and increased driving pressure for lymphatic flow (which can increase up to 10 times normal) protect the lung against edema. The pulmonary capillary microvascular barrier is relatively permeable to protein compared with other tissues,2 so this increased lymphatic flow is largely responsible for protecting the lung against edema.3 The reduced role of the COP gradient also helps explain why hypoproteinemia per se rarely results in pulmonary edema. Some studies have demonstrated that the pulmonary glycocalyx is thicker than in other tissues,4,5 and is lost during endotoxemia,5 but the understanding of the role of the pulmonary glycocalyx in transvascular fluid flux is still in its infancy.

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CHAPTER 23  Pulmonary Edema pulmonary edema. Most fluid is cleared via the bronchial circulation, probably because most fluid tends to accumulate in the peribronchovascular areas.8 The rate of resolution depends on the fluid type, with pure water being reabsorbed much more rapidly than fluid containing macromolecules (including artificial colloids) and cells.

CLINICAL PRESENTATION Pulmonary edema results in reduced oxygenation (usually as a result of ventilation–perfusion mismatching) so most animals have signs of respiratory distress usually with tachypnea. Oxygen should be given to all patients with respiratory distress and the benefits of giving an animal time to recover in a quiet, oxygen-enriched environment cannot be overemphasized. As in all animals presenting with respiratory distress, careful evaluation of the patient is necessary to prioritize problems and identify likely differentials. Historical information that should alert the clinician to possible cardiogenic pulmonary edema includes cardiac disease or a murmur/ gallop sound, or previous congestive heart failure. Noncardiogenic pulmonary edema may be associated with environmental exposure to smoke inhalation, near strangulation, electric shock, head trauma or seizures. In some cases, pulmonary edema is a feature of a disease, with patients presenting with clinical signs referable to the primary condition (e.g., sepsis). Physical examination of animals with pulmonary edema will include tachypnea and/or dyspnea. There is controversy regarding whether cough is a major feature of pulmonary edema specifically, rather than a feature of the primary disease process or coexistent diseases.9 Lung sounds will generally be increased in animals with pulmonary edema and careful auscultation will usually reveal the presence of pulmonary crackles or louder and coarser lung sounds. These may be difficult to hear in dogs and cats with low tidal volumes or high respiratory rates. Careful auscultation may allow the abnormal lung sounds to be localized to one region and this may aid in the diagnosis, such as a cranioventral distribution with aspiration pneumonia and a perihilar distribution with cardiogenic pulmonary edema in the dog.

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congestion, which in its most life-threatening form is pulmonary edema. As a result of chronic increases in blood volume, the capillary pressure at which edema forms is higher than in the normal dog or cat. In severe cases, blood vessel rupture may occur, leading to a serosanguineous appearance of secretions, as evidenced by pink frothy sputum. There are a few common diseases that cause cardiogenic pulmonary edema, and signalment can be extremely useful in narrow diagnoses. Middle-aged, large breed dogs tend to have dilated cardiomyopathy, whereas the smaller breeds tend to have mitral valve disease. Cats are more prone to myocardial disease, with hypertrophic and restrictive cardiomyopathies seen most commonly.11,12

Fluid Therapy Fluid therapy is an uncommon cause of pulmonary edema without preexisting heart or lung disease, due to the effective safety mechanisms within the lung. However, fluid therapy may cause rapid increases in hydrostatic pressure in animals with preexisting (although asymptomatic) heart disease, leading to pulmonary edema. Experimental studies have demonstrated that dogs are able to cope with large volumes: dosages of 360 ml/kg of crystalloid over 1 hour were given before severe fluid overload was seen.13 Clinically, it appears that cats are more likely to develop respiratory signs associated with fluid overload than dogs, although this and the relative incidence of pulmonary edema versus pleural effusion are poorly documented in the literature. One retrospective case series demonstrated that cats with urethral obstruction that developed volume overload developed respiratory signs. Cats were more likely to develop signs of fluid overload if they received a fluid bolus or developed a murmur or gallop during treatment. Most of the cats that were assessed with echocardiogram had evidence of underlying heart disease.14 Other reasons for this might include relative overdosing of fluid therapy as cats have a lower blood volume than dogs and a reduced capacity to cope with extra intravascular volume.15 When there are other risk factors, such as systemic inflammation and pulmonary parenchymal disease, fluid therapy may more easily lead to pulmonary edema.

High Hydrostatic Pressure Edema

Increased Permeability Edema

Cardiogenic Edema

An increase in permeability is caused by direct injury to the microvascular barrier, alveolar epithelium, or both. Increased permeability edema is synonymous with acute respiratory distress syndrome (ARDS). ARDS (see Chapter 25, Acute Respiratory Distress Syndrome) is the most severe form of increased permeability edema and is extremely difficult to manage. Other causes of increased permeability edema include pneumonia, pulmonary thromboembolism, and ventilator-associated lung injury.

Cardiogenic pulmonary edema is probably the most common form of high-pressure edema. It occurs as a result of left-sided congestive heart failure. Cardiac disease is often chronic, and in dogs there is usually a history of clinical signs consistent with heart disease: cough, orthopnea, exercise intolerance, and usually, a heart murmur. An acute onset of signs may be seen, particularly if there has been a precipitating event such as stress. Cardiac disease is the most common cause of dyspnea in cats,10 and approximately half of cats with left-sided congestive heart failure will have pulmonary edema. Owners may not report premonitory clinical signs prior to the onset of dyspnea in cats, although there may be a precipitating stressful event. Over half of cats presenting with heart failure will have reduced appetite, and weight loss is present in about a third. In contrast to dogs, a significant proportion of cats will not have auscultatable cardiac abnormalities detected, with one study reporting about 20% of cats with left-sided heart failure having no auscultatory abnormalities,11 and a more recent study reported murmurs in 23% cats and a gallop in 23% of cats with heart failure. Gallop sounds are more specifically associated with the presence of heart failure than murmurs.10 Due to the chronic progression of heart disease, compensatory mechanisms result in fluid retention to maintain cardiac output and, although beneficial in the short term, this eventually leads to signs of

Mixed Cause Edema There are a number of other causes of pulmonary edema in which the pathophysiology is incompletely understood that are probably due to a combination of hydrostatic and increased permeability edema. Neurogenic pulmonary edema (NPE) and negative pressure pulmonary edema (NPPE) are probably the most common forms and have been discussed and described synonymously in the veterinary literature. However, it is worth separating these conditions to improve clarity and understanding. NPE is seen following an acute neurological event, such as head trauma or seizures. The proposed mechanism is that there is a surge in intracranial pressure that results in a catecholamine surge. This increases systemic vascular resistance and results in alveolar capillary leakage. A number of mechanisms have been proposed to cause the pulmonary edema. These include direct myocardial injury, altered

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ventricular compliance secondary to the increased systemic and pulmonary pressures, acute transient rise in capillary pressure inducing barotrauma and damage to the capillary alveolar membrane (known as Blast theory16,17), and direct damage to the pulmonary vascular bed due to pulmonary venular adrenergic hypersensitivity. The clinical course of NPE is variable. The edema can form up to 24 hours after the initial insult and is believed to resolve within 48 hours. Radiographic features of NPE in dogs and cats have been reported to be less severe than NPPE18 but are highly variable.19 NPPE is seen following upper airway obstruction.18,19 In some cases the obstruction can appear relatively mild (e.g., a sharp pull on a lead). In these cases, negative intrathoracic pressure is thought to cause the pathophysiological cascade resulting in pulmonary edema. The amount of negative intrathoracic pressure generated is particularly high in young people, and this may be why younger animals seem to be more easily affected by NPPE than older animals. In NPPE the negative intrathoracic pressure increases venous return to the right side of the heart, leading to increased pulmonary venous pressures and decreased perivascular interstitial hydrostatic pressure; there is also increased left ventricular afterload due to transmural pressure across the cardiac wall. This results in the movement of fluid from the pulmonary capillaries into the interstitium and alveoli. Hypoxia causes cardiac dysfunction. Sympathetic stimulation increases venous return secondary to venoconstriction and increased systemic vascular resistance. The end result of these cardiovascular changes is that there is formation of pulmonary edema. NPPE has been documented in both dogs and cats and tends to be acute in onset and resolve within 48 hours. Other forms of edema include reexpansion edema, which has been reported in dogs and cats after acute reexpansion of chronically collapsed lung lobes. Suggested mechanisms include trauma, decreased surfactant levels in collapsed lung tissue, negative interstitial pressure, and oxygen free radical formation and reperfusion injury.

DIAGNOSTIC TESTS Conventionally, thoracic radiographs have been the most widely used diagnostic test for the identification of pulmonary edema; however, they can be highly stressful and should be avoided in the most severely dyspneic patient until initial stabilization with empiric therapy has been attempted. Equipment should be made ready in advance and oxygen supplementation should be available before attempting to radiograph these patients. The distribution of the alveolar pattern can be helpful in discriminating between cardiogenic (Fig. 23.1) and noncardiogenic edema, but nearly all causes of edema can cause a diffuse alveolar pattern. Mild cardiogenic edema in dogs is typically seen in the perihilar region. In cats, however, there tends to be an interstitial-alveolar pattern that can be patchy and almost nodular (Fig. 43.1). Pulmonary veins that are more distended than the pulmonary arteries may also be seen in some cases of left-sided heart failure. A brief echocardiogram may reveal an enlarged left atrium, which raises the likelihood of congestive heart failure; however, dyspneic patients should not be stressed excessively to obtain an echocardiogram. A dorsocaudal alveolar pattern suggests noncardiogenic pulmonary edema; however, a recent case series has described highly variable radiographs in this condition.19 In dyspneic patients, positioning to obtain diagnostic quality radiographs maybe challenging and risky. Because of the challenges obtaining diagnostic radiographs in dyspneic dogs and cats, there has been an increase in the use of point- of-care ultrasound. Pulmonary edema can be suspected based on the presence of increased numbers of B-lines within the lung tissue.

A

B Fig. 23.1  A, Lateral thoracic radiograph of a dog (Doberman Pinscher) showing marked perihilar alveolar infiltrates, an enlarged cardiac silhouette, and left atrial enlargement. This dog had severe congestive heart failure secondary to dilated cardiomyopathy. B, Lateral radiograph of the same dog 3 days later after intensive diuretic, positive inotropic, and vasodilator therapy (furosemide, dobutamine, pimobendan, and nitroprusside). There is marked improvement in the alveolar pattern, although mild perihilar infiltrates are still present.

Although other lung conditions may be associated with B-lines (e.g., other interstitial or alveolar diseases), the presence of B-lines in the acutely dyspneic patient should alert the clinician to the presence of pulmonary edema.20 Supportive evidence such as increased left atrial to aortic ratio may increase suspicion of cardiogenic pulmonary edema, particularly in cats. Ultrasonography in experienced hands is likely more sensitive for the identification of pulmonary edema than radiography. Arterial blood gas analysis or pulse oximetry may be used to provide objective evidence of hypoxemia; however, these tests are not essential for stabilization and can cause too much stress to be worthwhile in many animals. Pulse oximeters can be unreliable, especially in conscious patients that are moving or have darkly pigmented skin, although new technology is increasing reliability. Pulse oximeters with plethysmography indexes can allow assessment of the quality of the saturation readings as this is a noninvasive indicator of peripheral perfusion. Blood gas analyzers are becoming increasingly available,

CHAPTER 23  Pulmonary Edema and with practice, arterial blood sampling is a relatively easy technique to master. Arterial blood gas analysis also allows calculation of the alveolar-arterial gradient and the partial pressure of arterial oxygen: fraction of inspired oxygen ratio (PaO2:FiO2), which can be used to potentially assess the efficacy of therapy (see Chapters 16, Hypoxemia and 184, Oximetry Monitoring).

TREATMENT Oxygen Therapy Treatment of pulmonary edema depends on the underlying cause. No therapy is uniformly effective. Oxygen supplementation should be provided by the least stressful means to increase arterial oxygen content and tissue oxygen delivery. Patients should be subjected to minimal stress and movement or struggling should be limited to prevent increases in oxygen demand. Dyspneic animals should never be forcibly restrained. A purpose-built oxygen cage is ideal for cats or small dogs following initial evaluation, but these are expensive and require maintenance and large oxygen supplies. Administration by mask, flowby, or nasal cannula can be considered if a cage is unsuitable or not available, but these techniques are of limited use in cats. High flow oxygen therapy is increasingly available in veterinary hospitals and provides a noninvasive way of providing oxygen supplementation; however, sedation is required to improve tolerance in some patients.21 If noninvasive methods for oxygen supplementation fail, invasive methods may be required. Continuous positive airway pressure (CPAP) ventilation is less invasive than traditional intermittent positive pressure ventilation (PPV). Both require deep sedation or, more commonly, anesthesia and maintenance of an airway either via a laryngeal mask or endotracheal tube. CPAP is sometimes possible via nasal cannulae, but this is limited by equipment design. PPV is indicated in patients that cannot maintain a hemoglobin saturation above 90% or a PaO2 over 60 mm Hg with noninvasive methods of oxygen supplementation or those with evidence of hypoventilation (PaCO2 .55 to 60 mm Hg). If impending respiratory fatigue is a concern, PPV should be considered before there is significant deterioration. There is contradictory evidence in the literature regarding the effects of PPV on the resolution of pulmonary edema; PPV may help to resolve pulmonary edema in some situations, but slow it in others.22,23 There can be significant morbidity associated with PPV, so careful case-by-case consideration should be made before commencing ventilation. PPV is of particular benefit in patients where there are reversible causes of pulmonary edema such as cardiogenic mechanisms. Body position can also be important. Sternal recumbency aids with gas exchange, probably by reducing atelectasis. In animals with unilateral disease, it is preferable initially to place the patient with the affected lung lobe down if the animal will not tolerate sternal recumbency. In some patients placing the more severely affected lung uppermost can precipitate severe hypoxemia and respiratory arrest.

Medical Therapy The key to managing cardiogenic pulmonary edema is the reduction of pulmonary capillary pressures by reducing preload. Promotion of left-sided forward flow is also important in patients with large regurgitant fractions. The drugs used can be split into two groups: diuretics and vasodilators. Furosemide is the most frequently used diuretic and is particularly useful because of its rapid onset of action (Chapter 151, Diuretics). Excessive use and lack of close monitoring could result in hypovolemia as a result of an excessive reduction in preload. For acute congestive heart failure in dogs, furosemide should be administered at 1–2 mg/kg hourly until the respiratory status is stabilized of a maximum dose of 8 mg/kg has been reached and evidence of pulmonary

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congestion is improved. In life-threatening pulmonary edema, constant rate infusion (CRI) administration alongside bolus is recommended.24 The frequency and dosage are subsequently reduced. The dose in cats should be moderate as cats are more sensitive to the effects of furosemide than dogs. There is evidence that furosemide acts as a pulmonary vasodilator and bronchodilator and causes an increase in COP secondary to hemoconcentration. These changes, in combination with the resultant reduction in pulmonary hydrostatic capillary pressure, may assist with alveolar fluid reabsorption.25,26 Concerns have been expressed about reduced mucociliary clearance due to excessive dehydration of secretions, but in life-threatening situations this is not an immediate concern. Bolus injection of furosemide in people has been associated with excessive volume contraction, and as a result, CRIs have been suggested as an alternative with fewer complications. CRIs are more effective in promoting fluid excretion than intermittent boluses in people with congestive heart failure, and experimental studies in healthy greyhounds have shown better diuresis with a CRI than with bolus injection.27 Human studies have shown bolus injection and CRIs to be equally effective for management of heart failure using endpoints other than diuresis, and so there is limited evidence to suggest one over the other.28 CRIs are associated with greater diuresis and should be used in cats with caution. Because hydrostatic pressure influences edema due to increased permeability edema and increased hydrostatic pressure, capillary pressure modification can be considered in all cases of pulmonary edema. Most patients with increased permeability edema do not respond as well as those with cardiogenic edema to medical interventions to decrease hydrostatic pressure. In noncardiogenic pulmonary edema, there is limited clinical evidence for a beneficial effect with furosemide, but most experimental data support therapies that modulate hydrostatic pressure. When there is any concern of hypoperfusion the use of any diuretic may still be logical, but there should be careful risk– benefit analysis. Notably, diuresis is not recommended in any form of noncardiogenic pulmonary edema in people. In the absence of heart disease, therefore, if in risk–benefit analysis, use of a diuretic is considered appropriate, then lower doses of furosemide should be used for diuresis and monitored for effect in order to prevent unwanted hypoperfusion. Care should be taken if this approach is used. Vasodilators are less commonly used but can prove beneficial. A number of drugs are available, but in acute situations the most useful group are the nitric oxide donors, which include nitroprusside, isosorbide dinitrate, and glycerol trinitrate (nitroglycerin). Nitroprusside causes dilation of arteries and veins, whereas nitroglycerine is mainly a venodilator. Nitroprusside may cause hypotension due to arteriolar dilation. It has a short half-life and is therefore administered intravenously as a CRI. Nitroprusside should be used with extreme caution in hypotensive patients because the general goal with therapy is to only reduce the mean arterial pressure (or systolic blood pressure) by 10 to 15 mm Hg from the baseline pressure. In hypotensive patients, nitroprusside should not be used without a positive inotrope; however, there is evidence to suggest that even in patients with severe left ventricular dysfunction, nitroprusside is associated with beneficial cardiopulmonary effects.29 Animals should be monitored carefully for clinical signs of hypotension, ideally with invasive blood pressure monitoring, although this may not be possible in all cases. In addition to its hypotensive effects, nitroprusside may cause a reduction in hypoxic pulmonary vasoconstriction, thereby increasing ventilation– perfusion mismatch. A reflex tachycardia can also be observed. Nitroprusside is difficult to obtain in many countries and can be expensive, but its use is included in the ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs.24

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Nitroglycerin is mainly a venodilator, and minimal hypotension or tachycardia is seen with this drug, making it safe in most cases. Nitroglycerin is available in some countries as a paste, which is applied to hairless areas such as the axilla or ear flap, or as a spray that can be applied to mucous membranes. Empiric doses are recommended. Tachyphylaxis occurs rapidly, and the drug may have reduced efficacy after as little as 24 hours. There is limited evidence of efficacy in dogs and cats, and its use is no longer recommended.30 a-Adrenergic antagonists have been used experimentally and clinically in cases of NPE and have been associated in limited cases with rapid improvement.17,31 There is no evidence of use in veterinary patients, but this therapy may prove useful in some cases. Other drugs that have been of benefit in experimental models of noncardiogenic pulmonary edema include b2-agonists, such as terbutaline.32,33 These act via cyclic adenosine monophosphate (cAMP)32 to increase fluid reabsorption from the alveolar space. Use of intravenous and inhaled salbutamol in people with respiratory failure and ARDS revealed worse outcome including death and ventilator free days, possibly due to increased cardiac output. Because of these unwanted side effects, the use of b-2-agonists cannot be routinely recommended, and they should only be used, if at all, with extreme caution.34,35 Phosphodiesterase inhibitors such as pimobendan increase cAMP levels, and these drugs may also prove useful in the management of pulmonary edema. Intravenous administration of pimobendan in healthy dogs rapidly increases blood pressure and reduces left ventricular end diastolic pressure36, and may be of particular benefit in dogs with forward and congestive failure.

Fluid Therapy Because the hydrostatic pressure gradient is so important in the pathogenesis of pulmonary edema, it seems prudent to restrict fluid administration to these patients. In all cases, the decision to restrict intravenous fluid administration should be balanced against the risks of compromised renal function and multiple organ failure although hypovolemia would have to be severe and persistent to cause such severe effects. The pulmonary, microvascular barrier is relatively permeable to protein,2 and therefore natural or synthetic colloids such as albumin or hetastarch, respectively, may equilibrate rapidly across the endothelial space. If there is increased permeability such that more than half of the number of colloid molecules extravasate, colloid therapy may worsen pulmonary edema. Furthermore, macromolecular clearance from the alveoli is slow compared to isotonic electrolyte solutions and water. Because there is no way yet of clinically determining vascular, interstitial, and epithelial permeability, one has to rely on response to therapy. Given the lack of a supportive evidence base for the use of artificial colloids for many conditions, it could be argued that their use in animals with pulmonary edema fails a risk–benefit analysis and so should be avoided.

PROGNOSIS Because of the diversity of causes of pulmonary edema, general statements about prognosis cannot be made. Usually when there is no serious underlying disease, the prognosis for resolution is relatively good. In contrast, when there is evidence of multisystemic disease and severe increased permeability edema, the prognosis is guarded at best. The prognosis for cardiogenic edema is related to the severity of the underlying disease; some dogs with mitral valve disease may survive for 2 or 3 years after initial diagnosis of left-sided heart failure, with a median of 276 days,37 whereas the prognosis for dogs in forward failure with dilated cardiomyopathy may be poorer.38 In cats, the prognosis with congestive heart failure seems less favorable and few of these animals

live beyond 1 to 1½ years from the time of diagnosis, with a median of 194 days.11 The outcome in animals with pulmonary edema severe enough to warrant PPV is generally poor, although financial concerns are often involved in many of these decisions.39,40

REFERENCES 1. Starling EH: On the absorption of fluid from connective tissue spaces, J Physiol 19:312, 1896. 2. Taylor AE: The lymphatic safety factor: the role of edema-dependent lymphatic factors (EDLF), Lymphology 23:111, 1990. 3. Zarins CK, Rice CL, Smith DE, et al: Role of lymphatics in preventing hypooncotic pulmonary edema, Surg Forum 27:257, 1976. 4. Yang Y, Schmidt EP: The endothelial glycocalyx, Tissue Barriers 1 (1):e23494, 2013. doi:10.4161/tisb.23494. 5. Schmidt EP, Yang Y, Janssen WJ, et al: The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis, Nat Med 18:1217-1223, 2012. http://dx.doi.org/10.1038/ nm.2843. 6. Demling RH, LaLonde C, Ikegami K: Pulmonary edema: pathophysiology, methods of measurement, and clinical importance in acute respiratory failure, New Horiz 1:371, 1993. 7. Conhaim ROL, Lai-Fook SJ, Staub NC: Sequence of perivascular liquid accumulation in liquid-inflated dog lung lobes, J Appl Physiol 60:513, 1986. 8. Fukue M, Serikov VB, Jerome EH: Bronchial vascular reabsorption of low protein interstitial edema liquid perfused in sheep lungs, J Appl Physiol 81:810, 1996. 9. Ferasin L and Linney C: Coughing in dogs: what is the evidence for and against a cardiac cough? J Small Anim Pract 60:139-145, 2019. doi:10.1111/jsap.12976. 10. Dickson D, Little CJL, Harris J, et al: Rapid assessment with physical examination in dyspnoeic cats: the RAPID CAT study, J Small Anim Pract 59:75-84, 2018. doi:10.1111/jsap.12732. 11. Payne J, Luis Fuentes V, Boswood A, et al: Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005), J Small Anim Pract 51:540, 2010. 12. Ferasin L: Feline myocardial disease 1: classification, pathophysiology and clinical presentation, J Feline Med Surg 11:3, 2009. 13. Cornelius LM, Finco DR, Culver DH: Physiologic effects of rapid infusion of Ringers lactate solution into dogs, Am J Vet Res 39:1185, 1978. 14. Ostroski CJ, Drobat, KJ, Reineke EL: Retrospective evaluation of and risk factor analysis for presumed fluid overload in cats with urethral obstruction: 11 cases (2002–2012), J Vet Emerg Crit Care (San Antonio) 27:561-568, 2017. doi:10.1111/vec.12631. 15. Paige CF, Abbott JA, Elvinger F, et al: Prevalence of cardiomyopathy in apparently healthy cats, J Am Vet Med Assoc 234:1398, 2009. 16. Robin TJ: Speculations on neurogenic pulmonary edema (NPE), Am Rev Respir Dis 113:405, 1976. 17. Davison DL, Terek M, Chawla LS: Neurogenic pulmonary edema, Crit Care 16:212, 2012. 18. Drobatz KJ, Saunders HM, Pugh CR, et al: Noncardiogenic pulmonary edema in dogs and cats: 26 cases (1987-1993), J Am Vet Med Assoc 206(11):1732-1736, 1995. 19. Bouyssou S, Specchi S, Desquilbet L, et al: Radiographic appearance of presumed noncardiogenic pulmonary edema and correlation with underlying cause in dogs and cats, Vet Radiol Ultrasound 58:259-265, 2017. doi:10.1111/vru.12468. 20. Ward JL, Lisciandro GR, Keene BW, et al: Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea, J Am Vet Med Assoc 250(6):666-675, 2017. 21. Pouzot-Nevoret C, Hocine L, Nègre J, et al: Prospective pilot study for evaluation of high-flow oxygen therapy in dyspnoeic dogs: the HOT-DOG study, J Small Anim Pract 60:656-662, 2019. doi:10.1111/jsap.13058.

CHAPTER 23  Pulmonary Edema 22. Colmenero-Ruiz M, Fernandez-Mondejar E, Fernandez-Sacristan MA, et al: PEEP and low-tidal volume ventilation reduce lung water in porcine pulmonary edema, Am J Respir Crit Care Med 155:964, 1997. 23. Blomqvist H, Wickerts CJ, Berg B, et al: Does PEEP facilitate the resolution of extravascular lung water after experimental hydrostatic pulmonary oedema? Eur Respir J 4:1053, 1991. 24. Keene BW, Atkins CE, Bonagura JD, et al: ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs, J Vet Intern Med 33:1127-1140, 2019. https://doi.org/10.1111/ jvim.15488. 25. Schuster CJ, Weil MH, Besso J, et al: Blood volume following diuresis induced by furosemide, Am J Med 76:585, 1984. 26. Ali J, Chernicki W, Wood LDH: Effect of furosemide in canine low-pressure edema, J Clin Invest 64:1494, 1979. 27. Adin DB, Taylor AW, Hill RC, et al: Intermittent bolus injection versus continuous infusion of furosemide in normal adult greyhound dogs, J Vet Intern Med 17:632, 2003. 28. Felker GM, Lee KL, Bull DA, et al: Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med 364:797, 2011. 29. Khot UN, Novaro GM, Popovicc ZB, et al: Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis, N Engl J Med 348:1756, 2003. 30. Stillion JR, Boysen SR: Does adding transdermal nitroglycerine to other therapies used for management of left-sided congestive heart failure in dogs speed the resolution of clinical signs? Vet Evid 2(4), 2017. https://doi. org/10.18849/ve.v2i4.115. 31. Wohns RN, Tamas L, Pierce KR, Howe JF: Chlorpromazine treatment for neurogenic pulmonary edema, Crit Care Med 13:210, 1985.

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32. McAuley DF, Frank JA, Fang X, et al: Clinically relevant concentrations of b2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury, Crit Care Med 32:1470, 2004. 33. Sakuma T, Okaniwa G, Nakada T, et al: Alveolar fluid clearance in the resected human lung, Am J Respir Crit Care Med 150:305, 1994. 34. Matthay MA, Brower RG, Carson S, The Acute Respiratory Distress Syndrome Network et al: Randomized, placebo-controlled clinical trial of an aerosolized beta-2 agonist for treatment of acute lung injury, Am J Respir Crit Care Med 342:1301, 2011. 35. Smith FG, Perkins GD, Gates S, et al., for the BALTI-2 study investigators: Effect of intravenous b-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial, Lancet 379:229, 2012. 36. Hori Y, Taira H, Nakajima Y, et al: Inotropic effects of a single intravenous recommended dose of pimobendan in healthy dogs, J Vet Med Sci 81(1):22-25, 2019. doi:10.1292/jvms.18-0185. 37. Häggström J, Boswood A, O’Grady M, et al: Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study, J Vet Intern Med 22:1124, 2008. 38. O’Grady MR, Minors SL, O’Sullivan ML, Horne R: Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy, J Vet Intern Med 22:897, 2008. 39. King LG, Hendricks JC: Use of positive-pressure ventilation in dogs and cats: 41 cases (1990-1992), J Am Vet Med Assoc 204:1045, 1994. 40. Lee JA, Drobatz KJ, Koch MW, King LJ: Indications for and outcome of positive-pressure ventilation in cats: 53 cases (1993-2002), J Am Vet Med Assoc 226:924, 2005.

24 Pneumonia Amanda K. Boag, MA, VetMB, DECVECC, DACVECC, DACVIM, FHEA, FRCVS, Gretchen L. Schoeffler, DVM, DACVECC

KEY POINTS • Pneumonia is an infection of the lung; bacteria are the most common causative agent, although other infectious organisms (viral, parasitic, mycotic) may be involved. • In dogs and cats with pneumonia, an underlying cause is almost always present and must be identified and treated to minimize persistence and recurrence of disease. • Diagnosis is usually based on history, physical examination, and radiography. The severity of respiratory compromise is best assessed and monitored by arterial blood gas analysis. • Antimicrobial drug therapy should be directed by cytologic evaluation, Gram stain, and bacterial culture and susceptibility testing of biologic samples.

• Bacterial culture and susceptibility testing with prompt deescalation to targeted antimicrobial therapy can reduce antibiotic resistance and adverse drug reactions. • The optimal duration of antimicrobial therapy and timing of clinical and radiographic follow-up to assess for treatment failure are not known. Factors to consider include choice of antimicrobials, severity of disease and presence of comorbidities, and the patient’s initial response to treatment.

PATHOLOGY

associated with viral pneumonia typically starts in the interstitium and in severe cases extends into the alveolar spaces.

The pathologic process common to all pneumonias is infection and inflammation of the distal pulmonary parenchyma.1, 2 Infections are primarily caused by bacteria and viruses and less commonly by fungi and parasites. Aspiration pneumonia, an important cause of pneumonia in dogs and cats, results when bacterial infection develops in patients following aspiration and subsequent pneumonitis. Pneumonia is characterized by the infiltration of polymorphonuclear leukocytes, edema fluid, erythrocytes, mononuclear cells, and fibrin into the lung. Individual types of pneumonia may differ by the route of infection and mode of spread. Anatomically, three different distribution patterns can differentiate pneumonias that follow a lobar pattern, from those that behave more like a bronchopneumonia, and those with the pattern of an interstitial pneumonia. These anatomical distributions are reflected in radiographic changes. Lobar pneumonia describes a pattern that characteristically encompasses an entire lung lobe. Spread of lobar pneumonia is believed to occur from alveolus to alveolus and from acinus to acinus through interalveolar pores. Bronchopneumonia is characterized by distal airway inflammation and alveolar disease, and the inflammatory process is thought to spread through airways rather than through adjacent alveoli and acini. Bronchopneumonias have a patchy distribution, whereas lobar pneumonias appear as dense consolidations involving a portion or the entire lobe. With interstitial pneumonia, the inflammatory process initially occurs within the interstitium rather than alveolar spaces. Individual patients with pneumonia may have a mixture of each of the three patterns in varying proportions. For example, the inflammatory process

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PATHOPHYSIOLOGY Infectious pneumonia results when the patient’s protective upper airway mechanisms and humoral and cell-mediated immunity become overwhelmed. The upper and lower airways provide a first line of defense against inhaled pathogens and contaminated particulate matter. They protect the lung through a variety of defenses including anatomical barriers, cough reflex, the mucociliary apparatus with its associated enzymes and secretory immunoglobulin (IgA), and phagocytic dendritic cells within the basal layer of the respiratory mucosa. Particles smaller than 3 µm may bypass the upper respiratory tract defenses and get deposited in the alveoli.1 The bronchoalveolar junction is a major site of small particle (0.5 to 3 µm) deposition and is especially vulnerable to damage. Surfactant and alveolar macrophages are quickly overwhelmed when considerable numbers of organisms or those with high virulence are deposited. Complex interactions between the cell-mediated and humoral immune systems and elevated levels of cytokines and chemokines induce an inflammatory response to clear the offending agents. Infection and inflammation of the distal pulmonary parenchyma may lead to hypoxemia via ventilation–perfusion (V/Q) mismatch, intrapulmonary shunting, and impaired diffusion resulting in an increased alveolar-arterial gradient and, in some cases, limited oxygen responsiveness. Hypercapnia is less common3 and suggests respiratory muscle fatigue, bronchoconstriction, or the presence of severe pulmonary parenchymal disease (see Chapter 17, Hypoventilation).

CHAPTER 24  Pneumonia

SPECIFIC TYPES OF PNEUMONIA Bacterial Pneumonia Other than some specific primary bacterial pathogens (e.g., Bordetella bronchiseptica and Mycoplasma cynos), most dogs and cats with bacterial pneumonia have an underlying predisposition to lung disease that should be investigated as part of their evaluation. Predisposing factors and disorders associated with pneumonia are listed in Table 24.1. Bacteria may gain entry to the pulmonary parenchyma through a variety of routes including inhalation, aspiration, direct extension from the pleural space and other intrathoracic structures, and via hematogenous spread. The most common bacteria isolated from tracheal wash samples collected from dogs with pneumonia include the Gramnegative bacilli Pasteurella spp. (22% to 28% of dogs with bacterial pneumonia) and Enterobacteriaceae such as Escherichia coli (17% to 46%), and Gram-positive cocci such as Staphylococcus spp. (10% to

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16%) and Streptococcus spp. (14% to 21%).3-5 In puppies with pneumonia, Bordetella bronchiseptica is most common (49%).6 Anaerobic bacteria are isolated in 10% to 21% of cases,3,4 and their presence warrants suspicion for pulmonary abscess formation. Mycoplasma spp. are commonly detected, either as sole organisms (8%) or as coinfections with other bacteria in a large proportion of dogs with bacterial pneumonia (62%).5,7 Often, bacterial cultures from small animal patients with pneumonia reveal multiple species of bacteria (e.g., 43%,4 47%,3 and 74% [including Mycoplasma]8 of dogs and 38% of cats).9

Aspiration Pneumonia Aspiration pneumonia can result from bacterial colonization of the lung after aspiration of acid or gastrointestinal material that is contaminated with oropharyngeal bacteria. Studies suggest that the magnitude of lung injury after gastric aspiration depends on the pH, volume, osmolality, and presence of particulate matter in the aspirate.10,11 Severe

TABLE 24.1  Factors Predisposing to or Associated with Pneumonia in Dogs and Cats Factor

Comment

Impaired Patient Mobility Unconsciousness (natural or via general anesthesia)*

Attenuation, loss of reflexes (gag, cough)

Mechanical ventilation

Intubation bypass normal defense mechanisms of the upper airway; normal movement and coughing prevented Regurgitation or aspiration of oropharyngeal bacteria may contribute

Weakness, paresis, paralysis* Upper Airway Disorders Laryngeal mass or foreign body*

— Successful laryngeal examination possible in many/most unsedated dogs using only a bright light source (Finnoff transilluminator), especially in dogs with marked dyspnea from upper airway obstruction

Laryngeal paralysis* Laryngeal or pharyngeal dysfunction or surgery*

Regurgitation Syndromes Esophageal motility disorder*

Aspiration pneumonia (without overt clinical signs)—a common postoperative complication in animals with laryngeal paralysis (see Chapter 18, Upper Airway Disease) Dynamic esophagram (barium swallow) required for diagnosis Important if other tests do not identify an underlying cause for pneumonia

Esophageal obstruction*

Foreign body sometimes visible on thoracic radiographs Caution necessary with barium swallow procedures (barium aspiration risk); endoscopy may be preferable

Megaesophagus*

Often identifiable on plain thoracic radiographs

Other Factors Bronchoesophageal fistula

Usually acquired via trauma (e.g., perforating esophageal foreign body)

Cleft palate

Aspiration of ingesta from nasal cavity

Crowded or unclean housing

Increased concentration and persistence of infectious organisms in the environment

Forceful bottle feeding*

Aspiration possible when care provider squeezes the nursing bottle during suckling or if hole in nipple is too large

Gastric intubation*

—

Immune compromise

Specific conditions: anticancer or immunosuppressive chemotherapy; concurrent illness, including feline leukemia, feline infectious peritonitis, diabetes mellitus, or hyperadrenocorticism; primary ciliary dyskinesia; immunoglobulin or leukocyte defects or deficiencies

Inadequate vaccination

Viral, bacterial, or parasitic infection with secondary opportunistic bacterial pneumonia

Induced vomiting*

—

Seizures*

Must differentiate pneumonia radiographically from noncardiogenic pulmonary edema

Tracheostomy*

—

*Indicates predisposition to aspiration pneumonia.

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histologic damage is caused by aspirates with a pH less than 1.5, but minimal damage is caused by aspirates with pH greater than 2.4 unless they also contain particulate matter.12,13 Inhaled particulate matter may cause small airway obstruction, prolong the inflammatory response, and act as a source of, and nidus for, bacterial infection.14 Combination acid-particulate aspirates induce greater injury than either component alone.15 The development of pneumonia after gastric aspiration is a risk factor for subsequent development of both acute respiratory distress syndrome (ARDS)16 and sepsis,17,18 which substantially increase the risk of mortality. Bacteria that are commonly cultured from companion animals with aspiration pneumonia include enteric bacteria such as Escherichia coli, Klebsiella spp., and Enterococcus spp.; oropharyngeal Mycoplasma spp.; primary respiratory pathogens, including Pasteurella spp., Pseudomonas spp., and Streptococcus spp.; and commensals such as Staphylococcus spp.19,20 Gastrointestinal disorders (.60%) are the most common risk factor, and megaesophagus is the leading cause (26%) of aspiration pneumonia in dogs.17,19 Other important predisposing disorders include neurologic (18%) and laryngeal (13%) dysfunction.17,19 Like people, many dogs have multiple risk factors, including recent anesthesia.21

Pneumonia Associated with Canine Infectious Respiratory Disease Pneumonia can be a serious complication of canine infectious respiratory disease (CIRD) complex. CIRD is an endemic, worldwide syndrome in which multiple viral and bacterial pathogens sequentially or synergistically coinfect dogs. Organisms associated with this complex are ubiquitous in densely populated settings, and development of illness likely depends on a combination of both host and environmental factors. Naive and immunocompromised dogs that are exposed to novel pathogens in new, overcrowded environments are at highest risk.22 Viral pathogens implicated in CIRD include canine adenovirus type-2, canine parainfluenza, canine distemper virus, canine respiratory coronavirus, canine influenza virus, canine pneumovirus, and canine herpesvirus.23-29 Infection with either canine adenovirus type-2 or canine parainfluenza virus typically results in mild, self-limiting respiratory signs but infection with these viruses can be more serious when complicated by coinfection or immunosuppression.29,30 In contrast, infection with canine distemper virus leads to severe systemic disease. The canine distemper virus initially replicates in the lymphoid cells of the respiratory tract before spreading to the epithelial cells of other organ systems, including the central nervous system. Clinical signs may include ocular and nasal discharge, respiratory distress, vomiting, diarrhea, hyperkeratosis of the foot pads, and progressive neurological dysfunction.29-31 Canine respiratory coronavirus infection contributes to decreased mucociliary clearance and facilitates secondary infection.29 Two influenza subtypes, H3N8 and H3N2, are important in dogs. Both strains are unique in that they can be transmitted horizontally between dogs and when complicated by bacterial coinfection, can result in hemorrhagic bronchopneumonia with mortality rates as high as 80%. While infections in canines with other subtypes have been reported (H5N1, H1N1, and H3N1), they have only rarely been associated with clinical disease.29,32 Canine pneumovirus has only recently been isolated from dogs with respiratory disease and little is known about its pathogenesis. Infection with canine herpes virus commonly leads to death in immunologically naive fetuses and puppies less than 2 weeks of age; however, clinical signs in older puppies and adults are uncommon.29 Younger dogs and dogs with a higher number of coinfections are more likely to develop secondary bacterial pneumonia and have more severe clinical signs associated with CIRD.22 It is probable that an initial pathogen alters the patient’s pulmonary defense mechanisms

thereby allowing additional organisms to infect the respiratory tissues. The most common bacterial pathogens identified in CIRD patients are Bordetella bronchiseptica, Streptococcus equi subspecies zooepidemicus, and Mycoplasma cynos.23, 27, 29, 33-35 B. bronchiseptica is a Gram-negative, aerobic coccobacillus that can act as a primary pathogen or cause CIRD concurrently with other bacteria and viruses. Affected animals develop a dry, paroxysmal cough with nasal discharge, and in severe cases, infection with B. bronchiseptica can lead to pneumonia and death.29 In shelters, Streptococcus equi subspecies zooepidemicus, a Gram-positive, beta hemolytic coccus, belonging to the Lancefield group C, has been associated with a syndrome of acute, hemorrhagic, fatal pneumonia in dogs, suggesting that contagion may play an important role.36-38 Mycoplasma spp. lack a cell wall and are fastidious and difficult to grow in culture and as a result may frequently be underdiagnosed. Though Mycoplasma spp. can be normal commensal organisms, Mycoplasma cynos has been implicated as an important, primary pathogen in the lower respiratory tract of dogs and cats.

Foreign Body Pneumonia Grass awns and other foreign materials contaminated with bacteria and fungi can be inhaled, lodge in a bronchus, and may ultimately lead to lobar pneumonia and other complications such as pneumo- and pyothorax. The organisms most frequently cultured from patients with foreign body pneumonia include Pasteurella spp., Streptococcus spp., Nocardia spp., Actinomyces spp., and various anaerobic bacteria.39-41 Many of these patients are young, sporting breed dogs from geographic regions with exposure opportunities for specific types of grass awns and other risky plant materials. These patients frequently have a history of recurrent clinical and radiographic signs as well as cutaneous and visceral foreign body migrations.

Parasitic Pneumonia Parasitic pneumonia may result when nematodes and trematodes migrate through the lung. Dogs and cats may be asymptomatic, or they may have variable, nonspecific clinical signs (e.g., cough). Clinical suspicion is based on the pet’s geographic location, lifestyle, immunocompetency, and radiographic findings. Both dogs and cats can be infected with Eucoleus (Capillaria) aerophilus and Paragonimus kellicotti, and cats can be infected with Aelurostrongylus abstrusus. Dogs can be infected with Filaroides hirthi, Crenosoma vulpis, and Oslerus (Filaroides) osleri. Additionally, canine neonates with severe diarrhea that are seriously infected with Strongyloides stercoralis may develop life-threatening bronchopneumonia and pulmonary hemorrhage. Lastly, while the lifethreatening effects of Angiostrongylus vasorum infection are most often associated with bleeding tendencies, respiratory signs can be severe.

Mycotic Pneumonia Infection with fungal agents is a relatively uncommon and geographically restricted cause of pneumonia in dogs and cats. Some fungal agents such as Blastomyces dermatitidis and Histoplasma capsulatam typically cause insidious onset systemic disease with lower respiratory tract signs as an important, but not the only, symptom. Pneumocystis carinii, which was previously classified as a protozoon, is another fungal agent that can cause severe pneumonia and is seen most in certain small breed dogs (notably Miniature Dachshunds and Cavalier King Charles Spaniels).42 As it is a ubiquitous saprophyte with low virulence, it is thought these breeds’ susceptibility may be due to localized pulmonary immunodeficiency.

Ventilator-Associated Pneumonia Ventilator-associated pneumonia is an iatrogenic cause of pneumonia associated with the use of mechanical ventilation for intensive respiratory

CHAPTER 24  Pneumonia

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support. It will not be covered in this chapter as it is addressed separately and in more detail in Chapter 40, Ventilator-Associated Pneumonia.

CLINICAL FEATURES Patients with pneumonia can present with a wide range of clinical signs. Critically ill animals with pneumonia require rapid identification and treatment because deterioration may occur quickly. Nonspecific signs of inappetence and lethargy, mild tachypnea, increased respiratory effort, and a soft cough may be the earliest signs in some dogs and cats. Additionally, patients with pneumonia may show no respiratory signs (e.g., 36% of cats),9 with the diagnosis being made incidentally on thoracic radiographs. Pneumonia may become a consideration at one of at least three points in the evolution of a case: when clinical signs are noted by the owner, veterinarian, or both; when predisposing causes are identified; or when characteristic findings are apparent on thoracic radiographs.

History A full clinical history from the primary caregiver is important in making a diagnosis of pneumonia. Elements of a patient’s history that should raise the clinician’s index of suspicion are numerous. Broadly, historical clues include recent vomiting, regurgitation or anesthesia, respiratory signs (cough, increased respiratory effort, purulent nasal discharge), systemic signs including lethargy and inappetence, and signs associated with predisposing or underlying causes. Approximately 36% to 57% of dogs with pneumonia are found to have a concurrent predisposing disorder (Table 24.1).4, 6 With aspiration pneumonia, an index of suspicion must be maintained even in the absence of a clear history of aspiration because aspiration episodes are rarely witnessed. Hospitalized patients perceived as “at risk” should have frequent respiratory system assessments and aspiration should be suspected if respiratory distress develops acutely. Vaccination history may raise or lower the likelihood of specific infectious etiologies (e.g., canine distemper in puppies), and geographic location and travel history may reveal important details to consider in patients suspected of having fungal or parasitic disease.

Physical Examination Physical abnormalities in patients with pneumonia are often nonspecific.1,6 Demeanor may be normal, with some patients showing a bright and alert disposition, or abnormal, with lethargy or even obtundation predominating. Fever is a highly variable finding in both dogs and cats, and pneumonia can be neither confirmed nor ruled out based on body temperature. Mucous membrane color is frequently pink, but hyperemic or cyanotic membranes may be observed. Mucopurulent nasal discharge may or may not be present in either species. Respiratory pattern, rate, rhythm, effort, and depth should be noted, though respiratory abnormalities are rarely sensitive or specific. For example, respiratory distress may occur with moderate or severe pneumonia but is usually absent in mild cases; 78% of puppies with pneumonia are tachypneic and 72% have an increased respiratory effort.6 Cats with infectious pneumonia rarely cough (8%)9 in contrast to dogs (47%).8 The cough of a patient with pneumonia may be moist or dry and may be elicited with tracheal pressure in some patients and not in others. Auscultation of adventitious lung sounds are nonspecific and do not allow differentiation from other respiratory diseases (pulmonary edema, pulmonary hemorrhage); however, most dogs with pneumonia (.90%) have abnormally loud breath sounds, crackles, or wheezes on pulmonary auscultation.8 It is particularly important to consider whether the lung sounds are appropriate for the patient’s respiratory rate and effort.43 Rarely, lung sounds may be

Fig. 24.1  The “chessboard” analogy, wherein the lung fields are subdivided into smaller areas to enhance sensitivity of auscultation and to enable more accurate localization of abnormal lung sounds.

significantly decreased if a large bronchus becomes filled with exudates and cellular debris preventing the passage of air. Subdivision of the lung fields for auscultation may aid in lesion localization and improve detection rates (Fig. 24.1). Patients that aspirate typically have an acute change in respiratory pattern accompanied by weakness or collapse, cough, and abnormal lung sounds.19,44 Fine crackles may be heard during inspiration, with the location suggesting the cause (e.g., predominantly cranioventral following aspiration if patient is standing or sternal). In addition, patients that aspirate frequently display additional clinical signs such as nausea, vomiting, and regurgitation. Animals with fungal, viral, parasitic, or protozoal pneumonia may have multisystem involvement (e.g., bone, intestinal tract, lymph nodes). These patients frequently have other associated physical examination findings related to the underlying etiology (ocular involvement, draining tracts, evidence of coagulopathy).

DIAGNOSTIC APPROACH Pneumonia is suspected in an animal when one or more compatible signs are noted in the history and physical examination, especially in a patient with a predisposing condition (see Table 24.1). Evaluation of patients suspected of having pneumonia is centered on diagnostic imaging and sampling of respiratory secretions.

Radiography Thoracic radiography remains the routine imaging test of choice for patients with pneumonia. Three-view thoracic radiography (a dorsoventral or ventrodorsal projection and both lateral projections) is recommended in all pneumonia suspects to minimize the effects of positional atelectasis and false-negative results. When the patient is in left lateral recumbency, the right lung is better aerated and radiographically visualized and when the patient is in right lateral recumbency, the left lung is better aerated and radiographically visualized. Early radiographic evidence of pneumonia may appear as a focal, multifocal, or diffuse interstitial pattern that over time progresses to an alveolar pattern. Patients who have aspirated typically develop an alveolar lung pattern as a result of displacement of air from alveoli by fluid accumulation and cellular infiltration, although an interstitial pattern may also be seen.44 In the dog and cat, aspiration pneumonia typically affects the right middle lung lobe (which may silhouette with the heart in lateral radiograph projections) and ventral parts of the other lobes (Fig. 24.2A–B); however, lesion distribution may be affected by patient position at the time of aspiration.45 Radiographic signs of aspiration pneumonia may lag hours behind the onset of respiratory

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PART II  Respiratory Disorders Viral, bacterial, and fungal pneumonias are more likely to be distributed caudodorsally and diffusely. Inhaled foreign bodies frequently enter the accessory and right and left caudal lung bronchi and are commonly associated with a more caudodorsal, focal or lobar, recurrent alveolar pattern.46 These patients may also have radiographic evidence of pneumo- or pyothorax. Parasitic pneumonia that results from infection with A. vasorum is uniquely associated with a peripheral alveolar pattern radiographically.47 Mycotic pneumonia might show focal airspace disease or a more diffuse, reticulonodular “snowstorm” radiographic pattern.48

Computed Tomography Computed tomography (CT) may be beneficial in animals with complicated pulmonary disease or those suspected of having foreign body–associated pneumonia; the results commonly assist in planning further surgical strategies or diagnostic techniques. Typical CT findings in patients with aspiration pneumonia have been described,45 and there is evidence to suggest CT may provide important additional information in select cases.49 However, thoracic CT has not been widely used for evaluation of veterinary patients with aspiration pneumonia partly because of the accuracy of plain radiography. Animal patients commonly need sedation or general anesthesia and intubation to facilitate control of breathing to optimize the scan. The potential risks associated with sedation and or anesthesia of a patient, combined with the radiation and contrast burden, and the higher costs associated with CT are all factors that should be taken into consideration.

A

Point-of-Care Lung Ultrasound (see also Chapter 189, Point-of-Care Ultrasound in the ICU)

B Fig. 24.2  Thoracic radiographs (A, right lateral projection; B, dorsoventral projection) from a dog taken because of new-onset severe dyspnea, fever, ataxia, and obtundation during anesthetic recovery. There is severe alveolar opacification of most of the left lung, consistent with pneumonia. Infiltrates are especially prominent over the cardiac silhouette in A, a finding that may be missed with a cursory evaluation of the radiographs. The peracute postoperative onset suggests the cause was aspiration of refluxed gastroesophageal contents; atelectasis caused by the patient’s prolonged left-sided recumbency is less likely because the mediastinum has not shifted from midline.

Recently, point-of-care ultrasound techniques have become increasingly used as a noninvasive way of assessing for disease. In early or mild pneumonia, patchy areas of fluid-filled alveoli surrounded by aerated lung result in corresponding areas where numerous B-lines can be visualized. B-lines arise from the pleural line. They are hyperechoic and narrow, spanning across the entire ultrasound image without fading, and they move with lung sliding. B-lines are indicative of “wet lung” and are not specific for pneumonia. As the pneumonia progresses and portions of the lung become consolidated, the echotexture begins to resemble liver; this is referred to as hepatization and can be difficult to distinguish ultrasonographically from atelectasis. Consolidation can be further analyzed by looking for evidence of air bronchograms and the shred sign. Air bronchograms are visualized when air-filled bronchi, surrounded by consolidated tissue, reflect the ultrasound beam, and appear as bright, hyperechoic lines. The shred sign is noted when an irregular (not sharp) interface between an area of consolidated lung and an area of aerated lung is imaged. The visualization of both air bronchograms and the shred sign are suggestive of pneumonia.50

Tracheal Wash distress, change markedly over time, and persist for several days despite clinical improvement. Correlations between radiographic severity and clinical signs, hypoxemia, and prognosis are generally poor, although involvement of multiple lobes has been associated with reduced survival.19 Radiography is also useful for identifying disorders that predispose to aspiration. While megaesophagus is identified readily on plain thoracic radiographs, contrast studies are often needed to identify other pharyngeal and esophageal motility disorders. Contrast studies should be performed with caution since contrast media may be easily aspirated by these patients.

Tracheal wash (TW) is a minimally invasive diagnostic test used in both dogs and cats to obtain airway samples for cytologic analysis, bacterial and fungal culture and susceptibility, and other assays to look for viral and parasitic organisms. TW can be performed via transtracheal wash (TTW) or endotracheal wash (ETW) techniques, depending on the size and stability of the patient. Both techniques are suitable for investigation of suspected pneumonia, with ETW typically being preferred in brachycephalic and smaller patients. In dogs, TTW may be as sensitive as transbronchial biopsy, lung aspirates, and bronchoalveolar lavage (BAL) for diagnosis of pneumonia,51 although it may be less specific than other techniques. The use of TTW to diagnosis bacterial pneumonia has a sensitivity rate of 45% to 70%.19,52,53

CHAPTER 24  Pneumonia

Bronchoscopy and Bronchoalveolar Lavage Bronchoscopy allows visualization of the luminal surface of the respiratory tract (typically to the level of the tertiary bronchi), assessment of airway injury, and collection of lavage samples. BAL retrieves fluid directly from visibly affected areas and may provide greater sensitivity, specificity, and increased diagnostic yield. Guidelines for human adults recommend BAL for obtaining quantitative bacterial cultures and to differentiate pneumonitis from pneumonia.54 In dogs and cats this distinction is less clear, however, and the procedure is not without risk in patients suffering from respiratory compromise. BAL necessitates general anesthesia, is a more invasive diagnostic sampling technique than TW, and may cause bronchospasm and transient, but potentially significant, decreases in lung function. A blind BAL technique is described in which the sampling tube is inserted through the ET tube and advanced until resistance is met before the lavage fluid is injected. The technique is a valuable option in children,55 and clinical experience suggests it is also useful in veterinary patients.

Transcutaneous Fine-Needle Lung Aspirate Transcutaneous fine-needle aspiration of lung in suspected cases of infectious pneumonia may be a low-yield, high-risk procedure, especially in dogs with diffuse pulmonary disease; a lower risk is expected if the patient is kept in lateral recumbency, aspirated side down, for 30 to 60 minutes after the procedure (15 to 20 minutes if anesthetized).7 In cats with unexplained pulmonary parenchymal disease, fine-needle aspiration may provide a better yield than ETW.56

Complete Blood Cell Count and Serum Biochemistry Blood samples for complete blood cell count (CBC) and serum biochemistry values are indicated in all patients suspected of having pneumonia. Although many animals with pneumonia have unremarkable CBC results, abnormalities can include leukocytosis characterized by neutrophilia, left shift, lymphopenia, and monocytosis.8,19,44 Animals that are severely affected may be leukopenic, and dogs with idiopathic eosinophilic pneumonia may have a peripheral eosinophilia. Serum biochemistry changes such as hypoalbuminemia are nonspecific and reflect the degree of inflammatory response. Both CBC and serum biochemistry analysis are useful for identifying and investigating comorbidities.

Ancillary Laboratory Tests A coagulation profile often is helpful in assessing critically ill patients that may have a bleeding disorder or pulmonary hemorrhage. Testing for hypercoagulability (e.g., d-dimer, fibrin degradation products, antithrombin levels, and thromboelastography) may be indicated in some patients, particularly if pulmonary thromboembolism is suspected. Additional diagnostic tests that may also be indicated include fungal titers, serologic titers for heartworm disease and toxoplasmosis, viral testing, and fecal examination (flotation, Baermann sedimentation).

Biomarkers The use of biomarkers in critical illness is an area of active investigation both to help diagnose and track progress of disease, and pneumonia is no exception. Single biomarkers such as procalcitonin, Creactive protein (CRP), and interleukin-6 have all been evaluated in human community-acquired pneumonia.57 None are considered to be ideal markers, although procalcitonin may provide prognostic information.58 CRP is a nonspecific marker of the acute phase response in dogs; in dogs with respiratory disease it may be a useful additional tool in distinguishing between bacterial pneumonia and other causes.59 Cytokine profiles in BAL fluid correlate well with type and duration of injury but are yet to be validated in human studies.60 As

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evaluation of cytokines is becoming more common, developments in this area may improve the clinician’s diagnostic and prognostic accuracy in the future.

THERAPEUTIC APPROACH In veterinary patients, where the distinction between pneumonitis and pneumonia is often unclear, the principle aims of therapy are to (1) support respiratory function through airway management, oxygen supplementation, and mechanical ventilation, if necessary; (2) treat infections with appropriate antimicrobial therapy; and (3) manage underlying and predisposing conditions. In addition to managing the patient’s respiratory dysfunction, the emergency and critical care specialist must also work to prevent the emergence of systemic complications (e.g., multiple organ dysfunction), and the spread of contagion.

Airway Management After a witnessed aspiration event, foreign material obstructing the airway must be removed and airway patency ensured. Though aspirated liquid disperses quickly, suctioning of the pharynx may reduce further aspiration and will facilitate intubation, when necessary. When suctioning the airway, care should be taken to avoid mucosal damage. Therapeutic bronchoscopy is only indicated for atelectasis caused by mucous plugs, which are uncommon in animals after aspiration, and large-volume lavage of the affected areas is not recommended. Experimental work suggests that instillation of exogenous surfactant might be beneficial in canines with aspiration pneumonitis.61 Although recent large-scale trials in human ALI/ARDS were not successful,62 subgroup analyses suggested that patients with aspiration pneumonia might benefit.63 Unfortunately, a large-scale human trial investigating this treatment failed to confirm benefit, and the future of surfactant therapy following aspiration is uncertain.64

Oxygen Therapy Patients with pneumonia may have severe hypoxemia because of V/Q mismatch, intrapulmonary shunting, and hypoventilation. Oxygen therapy is indicated in animals with respiratory distress, hypoxemia, or inadequate hemoglobin saturation. Numerous minimally invasive techniques are described, including nasal flow-by or high flow oxygen, masks, insufflation via nasopharyngeal catheters, oxygen hoods, and oxygen cages (see Chapter 15, Oxygen Therapy). Supplemental oxygen should be humidified and whenever possible, a sensor used to monitor the inspired oxygen concentration. Oxygen administration should be sufficient to ensure adequate arterial partial pressure of oxygen (PaO2) and alleviate respiratory distress. Standard, low-flow intranasal oxygen should be delivered at a flow rate of 50 to 100 ml/kg/min/nare but never at a rate that causes discomfort or triggers the patient to actively close the nasopharynx (see Chapter 15, Oxygen Therapy). There is increasing interest in the use of high flow nasal oxygen delivery systems to provide additional respiratory support without requiring intubation and its associated risks (see Chapter 31, High Flow Nasal Oxygen). There is recent evidence to indicate that it is not only feasible but is also beneficial in some canine patients with respiratory compromise.65-67 Oxygen toxicity has not been reported in the clinical veterinary literature, but experimental studies suggest prolonged, high inspired oxygen concentrations may have detrimental effects, including increased lung permeability, protein extravasation, and impaired compliance.68 Over-supplementation should therefore be avoided.

Mechanical Ventilation Ventilatory support may be required in patients with progressive ventilatory failure (hypercarbia), or failure of pulmonary oxygen delivery

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PART II  Respiratory Disorders

and exchange (hypoxemia), and when less invasive methods of oxygen support are inadequate (see Chapter 32, Mechanical Ventilation: Core Concepts). The decision to mechanically ventilate is most often based on serial arterial blood gas analyses and patient assessment. Patients ventilated for pulmonary parenchymal diseases (hypoxemic failure) generally have a poorer prognosis than those ventilated for neuromuscular disease (ventilatory failure). This is likely because patients with pulmonary parenchymal disease have a much higher risk of complications of ventilation, including alveolar rupture, pneumothorax, capillary endothelial damage, impairment of venous return, and ventilatorassociated pneumonia, compared with patients with hypercapnia and primary ventilatory failure. Use of lung-protective strategies has significantly improved survival rates in human with ARDS (see Chapter 33, Mechanical Ventilation–Advanced Concepts).69 When possible, ventilation of these patients may be worthwhile because up to 30% are successfully discharged from the hospital.70

Antimicrobial Therapy Empiric antimicrobial therapy is often appropriate in the initial stages of managing patients with suspected pneumonia. Collection of appropriate samples (e.g., ETW or TTW fluid, sputum, blood, urine) for bacterial culture and susceptibility testing before initiating treatment (Table 24.2) is preferred; however, results will not be available for a minimum of 2–3 days and sample acquisition will not be possible in

all patients. Pending culture and susceptibility results, antimicrobial choices should be guided by cytologic and Gram stain analysis of airway samples. Empirical antimicrobial therapy should be chosen with consideration of local resistance profiles and should be deescalated or withdrawn if bacterial cultures are negative. Regardless of whether therapy is empirical or based on culture, it must be regularly reevaluated based on clinical response; if patients are worsening, alternative therapy and repeated airway sampling and culture should be considered. In patients with worsening respiratory signs or failure, research suggests that the bacterial isolates may have different resistance profiles from those infecting patients with less severe disease.71 Patients with pneumonia should be reevaluated no later than 10–14 days after instituting antimicrobial therapy and the decision on whether to continue antimicrobial therapy should be based on clinical, hematological, and radiographic findings.72 Long-term oral therapy may be necessary, but the exact duration of treatment must be adjusted to each patient because outcome depends on underlying cause, local immunity, nature of pathogenic organisms, and client factors. The pharmacokinetics of antimicrobial agents should be considered during product selection (see Chapter 172, Antimicrobial Use in the Critical Care Patient). Antimicrobial drugs that penetrate lung tissue and reach therapeutic levels in bronchial secretions are preferable (such as chloramphenicol, doxycycline, enrofloxacin, trimethoprim-sulfamethoxazole, and clindamycin). Polar drugs such as the cephalosporins

TABLE 24.2  Common Medications Used to Treat Pneumonia Drug

Effect or Spectrum

Dosage

Antibacterial Agents: Injectable Amikacin (Amiglyde-V)

G2

15 mg/kg (dog), 10 mg/kg (cat) IV q24h provided renal function and hydration are sufficient

Ampicillin (many names)

G1, some G2 (certain E. coli and Klebsiella strains), some anaerobes (Clostridia)

22 mg/kg IV q6-8h

Azithromycin

G1, G2, Mycoplasma

5–10 mg/kg IV q24h

Cefoxitin (Mefoxin)

Some G1, some anaerobes

30 mg/kg IV q6-8h

Clindamycin

G1, Mycoplasma, Toxoplasma, anaerobes

10 mg/kg IV q8-12h

Enrofloxacin (Baytril)

G2, Mycoplasma

5–10 mg/kg, dilute 1:1 in saline and give IV q12h or 12.5– 20 mg/kg IV q24h (dog) or maximum 5 mg/kg q24h (cat)

Gentamicin (Gentocin)

G2

10 mg/kg (dog), 6 mg/kg (cat) IV q24h provided hydration and renal function are sufficient

Metronidazole (Flagyl)

Anaerobes

10 mg/kg slow IV infusion q12h

Piperacillin-Tazobactam (Zosyn)

G1, G2, anaerobes

40–50 mg/kg slow IV infusion q6h

Trimethoprim-sulfamethoxazole

Some G1, some G2

15–30 mg/kg IV q12h

Antibacterial Agents: Oral Azithromycin (Zithromax)

G1, G2, Mycoplasma

5–10 mg/kg PO q24h

Clindamycin (Antirobe)

G1, Mycoplasma, Toxoplasma, anaerobes

10 mg/kg PO q8-12h

Metronidazole (Flagyl)

Anaerobes

10–15 mg/kg PO q12h

Trimethoprim-sulfamethoxazole (Ditrim, Tribrissen)

Some G1, some G2

15–30 mg/kg PO q12h

Additional Therapeutic Agents Aminophylline

Bronchodilator and respiratory stimulant

5 mg/kg IV q8h (dilute and give over 30 minutes; up to 10 mg/kg in dog)

Caffeine

Bronchodilator, respiratory stimulant

5–10 mg/kg IV q6-8h (dilute and give over 30 minutes)

N-Acetylcysteine

Mucolytic

70 mg/kg IV q6h (dilute and give over 30 minutes)

Terbutaline

Bronchodilator

0.01 mg/kg SC/IM/IV q4-6h

G2, Gram-negative; G1, Gram-positive; IM, intramuscularly; IV, intravenously; PO, per os; SC, subcutaneously.

CHAPTER 24  Pneumonia and penicillins are thought to penetrate poorly, although pulmonary inflammation may allow these antimicrobials to penetrate during disease states. Aminoglycosides such as amikacin and gentamicin have the advantage of rapid onset of action and bactericidal activity. They are favored for treatment of euvolemic, normotensive patients but should be used with caution in rapidly deteriorating patients with fulminant pneumonia and sepsis that are considered likely to be of Gram-negative bacterial origin, as seen in 33 of 65 puppies (51%) with bacterial pneumonia.6 Dogs and cats with moderate to severe pneumonia (based on respiratory signs, extent of pulmonary infiltrates on radiographs, appetite, and demeanor) and patients hospitalized for any reason should receive parenteral therapy.72 If a patient with pneumonia has clinical evidence of sepsis, empiric coverage should address Gram-positive, Gram-negative, and anaerobic bacteria. In many of these patients, initial therapy with either ampicillin or clindamycin combined with enrofloxacin is reasonable.72 Specifically, in patients with suspected aspiration, antimicrobial therapy is not indicated in the early stages of aspiration pneumonitis management. Early use of antimicrobials after aspiration may be more appropriate in patients with additional risk factors for pneumonia such as concurrent antacid use or gastrointestinal obstruction. If the patient is acutely but mildly affected and does not have evidence of systemic sepsis, then administration of a b-lactam antimicrobial such as ampicillin, ampicillin sulbactam, or a first-generation cephalosporin as a single agent may be sufficient. Sicker patients with aspiration pneumonia may require more broad-spectrum antimicrobials or the use of several agents with overlapping spectra, though anaerobic coverage is unlikely to be necessary.19,71 Commonly used antimicrobials include b-lactamases in combination with fluoroquinolones.17,19 Due consideration, for prudent use of antimicrobials, should be given before use of second- or third-line drugs.73 A 7–10 day course of doxycycline is a reasonable first-line antimicrobial for dogs and cats with mild pneumonia and no systemic manifestation of disease, especially those patients that may have had extensive contact with other animals and may be infected with Bordetella bronchiseptica or Mycoplasma spp. Likewise a penicillin, amoxicillin, or ampicillin may be adequate for dogs that are suspected to be infected with a strain of Streptococcus equi subspecies zooepidemicus.72

Bronchodilator Therapy The use of bronchodilators in animals with pneumonia is controversial. There is an argument that this class of drugs may be helpful in select cases by increasing airflow, improving ciliary activity, and increasing the serous nature of respiratory secretions (mucokinetic properties). Conversely, their use may suppress the cough reflex, enhance the spread of exudates within the affected lung to unaffected portions of the lung, and increase perfusion of poorly ventilated lung units thus worsening hypoxemia (V/Q mismatch). Bronchodilators may also have an impact on inflammation based on their mechanism of action. b-Agonists may have a direct antiinflammatory effect by decreasing mucosal edema and downregulating cytokine release. However, two human trials of inhaled albuterol in ALI/ARDS both suggest that this approach is unlikely to be beneficial and may worsen outcomes.74,75 Methylxanthine bronchodilators may increase mucociliary transport speed, inhibit degranulation of mast cells, and decrease microvascular permeability and leak. Additionally, aminophylline is a respiratory stimulant, and it helps increase the strength of diaphragmatic contractility to assist animals with ventilatory fatigue. Intravenous caffeine has been used in place of aminophylline, although its benefit in veterinary medicine remains unproven.

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Bronchodilator drugs such as salbutamol and terbutaline may be of use in patients with acute aspiration pneumonitis if bronchoconstriction is part of the physiologic response to acid injury. Only when bronchospasm can be identified or is strongly suspected is bronchodilator therapy rational.

Cardiovascular Support Fluid therapy should be used judiciously in patients with aspiration pneumonitis or pneumonia because any increase in pulmonary capillary hydrostatic pressure will tend to exacerbate fluid extravasation into the alveoli. The patient’s intravascular volume and hydration status should be assessed frequently, and the patient’s fluid therapy tailored to the individual, with due consideration for the degree of cardiovascular and respiratory compromise (see Chapters 63 and 67, Assessment of Hydration and Daily Intravenous Fluid Therapy, respectively). In patients with sepsis secondary to pneumonia, optimization of hemodynamic parameters through use of goal-directed therapy should be undertaken (see Chapters 7 and 90, SIRS, MODS and Sepsis and Sepsis and Septic Shock, respectively, and the Surviving Sepsis guidelines).76

Glucocorticoids Few therapies in medicine cause more contention than the use of glucocorticoids; the situation is no different in pneumonia, where recent systematic reviews fail to reach consistent and strong evidence-based conclusions.77-78 Glucocorticoids could theoretically be beneficial in suppressing the proinflammatory state that occurs in patients with aspiration pneumonitis; however, these agents suppress the immune system by decreasing levels of T-lymphocytes, inhibiting chemotaxis and phagocytosis, and antagonizing complement. In the absence of developed evidence in veterinary patients, caution is recommended and only in the specific case of vasopressor-dependent septic shock secondary to pneumonia (or patients with previously diagnosed hypoadrenocorticism) should low-dose hydrocortisone be considered.76

Nebulization Nebulizers change liquids into a mist that can be inhaled. The efficacy of nebulization treatment depends largely on the size of the droplets generated. Droplets that are between 0.5 and 5 mm are appropriate for pharmaceutical aerosols and are the size most likely to deposit in the lower airways. Very small droplets (,0.5 mm in diameter) may be exhaled and not deposit in the respiratory tract at all and particles .5–10 mm in diameter are likely to deposit in the nose, mouth, and upper airway. Vaporizers and humidifiers are not effective because the particle size generated with these methods is greater than 3 µm in diameter. Nebulization should be performed every 4 to 6 hours (or continuously) in animals with pneumonia. Nebulization using 0.9% sodium chloride is an effective means of increasing particulate saline droplets in the inhaled airstream and to liquefy thick lower airway secretions to hydrate the mucociliary system and enhance productive clearing. Mucolytic therapy is used commonly in veterinary patients, but scientific proof of its benefit is lacking. Nacetylcysteine (NAC) leads to a breakdown of the disulfide bonds in thick airway mucus and is also a precursor to glutathione, a free radical scavenger. Aerosolized NAC may irritate the airways and cause a reflex bronchoconstriction, however, and is not recommended. Dilute intravenous NAC therapy has been used in small animals, but its effects on the respiratory system via this route are unknown.

Physiotherapy Respiratory physiotherapy may be employed to support recovery in patients with pneumonia. A variety of techniques can be used with

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coupage, often following nebulization, being the most common in veterinary practice. Coupage of the chest refers to a rapid series of sharp percussions of the patient’s chest using cupped hands and closed fingers. The theory is that compression of air between the cupped hand and the chest wall creates vibrational energy that is transmitted to the underlying lungs to loosen deep secretions and consolidated areas of the lung and stimulate the cough reflex. Coupage is unnecessary in animals that are coughing spontaneously and frequently and may be contraindicated in animals that are coagulopathic, frequently regurgitating, showing signs of pain in the chest region, or are fractious. Further, no studies evaluating the impact of respiratory physiotherapy have been performed in veterinary patients. Even in human patients, the evidence base is weak and reliable conclusions about its utility cannot be made.79 Equally for recumbent patients, because atelectasis can exacerbate respiratory insufficiency, hospitalized patients with pneumonia who are recumbent should be turned every 1 to 2 hours (with exceptions made to allow for restful sleep). They should also be supported in an upright position at least every 12 hours and short walks should be encouraged.

PREVENTION Patients with severe pneumonia require intensive treatment and suffer considerable morbidity and mortality. Whenever possible, strategies to mitigate the risk of pneumonia should be implemented. For ventilator-associated pneumonia, good respiratory hygiene measures are crucial and are described in more detail in Chapters 37 and 40, Nursing Care of the Ventilator Patient and Ventilator-Associated Pneumonia, respectively. Proactive intervention can reduce the risk of perianesthetic aspiration. Guidelines on perianesthetic fasting suggest that 6 hours is appropriate to minimize gastric volumes and only 2 hours is necessary after liquid ingestion;80 however, the recommendation for perianesthetic fasting should not impede sedation or anesthesia in emergency situations. Evacuation of the stomach via suction or using a nasogastric or orogastric tube in anesthetized, high-risk patients may be appropriate.81 Enteral feeding, whether it is esophageal, gastric, or post pyloric, predisposes patients to aspiration pneumonia.82,83 Because nutritional support of critical patients is important for recovery, the aspiration risk should be minimized using safe feeding protocols. Care should be taken when recumbent patients are fed enterally, and the residual gastric volume should be ascertained before administration of food when possible. Feeding should be stopped at any sign of patient discomfort or resistance and the tube position checked.

PROGNOSIS AND OUTCOME Response to antimicrobial therapy is observed in most dogs (69% to 88%) when pneumonia is managed appropriately;5,8 acute, fulminant, hemorrhagic pneumonia of shelter dogs is an important exception.36,38 Long-term outcome depends on the ability to resolve the inciting or associated cause, with a cure expected when reversal of the trigger is possible (e.g., foreign body removal).84 In contrast, long-term management and frequent relapses can be expected when the predisposing cause lingers (e.g., idiopathic megaesophagus). Recurrent bouts of bacterial pneumonia should prompt the clinician to rule out laryngeal, pharyngeal, and esophageal disorders, bronchiectasis, the presence of an abscess or foreign body, other structural changes in the respiratory tract (e.g., ciliary dyskinesia), and inappropriate antimicrobial therapy (e.g., discontinuing therapy prematurely or antibiotic resistance).

Surgical treatment (lung lobectomy) has led to resolution of lobar pneumonia in 54% of dogs, with a higher percentage of success when a foreign body, or no bacterial isolates, were identified.84 Anecdotal reports and observations suggest that certain bacteria, specific underlying disorders, and empiric antimicrobial treatment instead of management based on culture and susceptibility are associated with a worse prognosis.5,8 Subjectively, the initial severity of clinical signs and response during treatment also offer prognostic information; however, a comprehensive assessment of specific, evidence-based prognostic parameters is lacking for small animals with bacterial pneumonia. Reported survival rates for aspiration pneumonia managed in academic referral institutions are 77% to 82%,17,19 and outcome does not appear to be dependent on the type or number of underlying disorders. Few prognostic indicators have been identified in dogs, but it should be recognized that lung injury severity after gastric aspiration represents a continuum between subclinical pneumonitis and ARDS with respiratory failure. Disease progression to ARDS and the need for ventilation heralds a lower survival rate. Fungal, viral, parasitic, and protozoal pneumonias vary in their response to management, often depending on pathogenicity of the offending organism, degree of systemic involvement, immunocompetence of the patient, and underlying risk factors.

REFERENCES 1. Brady CA: Bacterial pneumonia in dogs and cats. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 412-421. 2. Cohn L: Pulmonary parenchymal diseases. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St. Louis, 2010, Elsevier, pp 1096-1119. 3. Wingfield WE, Matteson VL, Hackett T, et al: Arterial blood gases in dogs with bacterial pneumonia, J Vet Emerg Crit Care 7:75, 1997. 4. Angus JC, Jang SS, Hirsh DC: Microbiological study of transtracheal aspirates from dogs with suspected lower respiratory tract disease: 264 cases (1989-1995), J Am Vet Med Assoc 210:55, 1997. 5. Jameson PH, King LA, Lappin MR, Jones RL: Comparison of clinical signs, diagnostic findings, organisms isolated, and clinical outcome in dogs with bacterial pneumonia: 93 cases (1986-1991), J Am Vet Med Assoc 206:206, 1995. 6. Radhakrishnan A, Drobatz KJ, Culp WTN, et al: Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002), J Am Vet Med Assoc 230:1493, 2007. 7. Chandler JC, Lappin MR: Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), J Am Anim Hosp Assoc 38:111, 2002. 8. Thayer GW, Robinson SK: Bacterial bronchopneumonia in the dog: a review of 42 cases, J Am Anim Hosp Assoc 20:731, 1984. 9. Macdonald ES, Norris CR, Berghaus RB, Griffey SM: Clinicopathologic and radiographic features and etiologic agents in cats with histologically confirmed infectious pneumonia: 39 cases (1991-2000), J Am Vet Med Assoc 223:1142, 2003. 10. Exarhos ND, Logan WD Jr, Abbott OA, et al: The importance of pH and volume in tracheobronchial aspiration, Dis Chest 47:167, 1965. 11. Kennedy TP, Johnson KJ, Kunkel RG, et al: Acute acid aspiration lung injury in the rat: biphasic pathogenesis, Anesth Analg 69:87, 1989. 12. Schwartz DJ, Wynne JW, Gibbs CP, et al: The pulmonary consequences of aspiration of gastric contents at pH values greater than 2.5, Am Rev Respir Dis 121:119, 1980. 13. Knight PR, Rutter T, Tait AR, et al: Pathogenesis of gastric particulate lung injury: a comparison and interaction with acidic pneumonitis, Anesth Analg 77:754, 1993. 14. Britto J, Demling RH: Aspiration lung injury, New Horiz 1:435, 1993. 15. Knight PR, Davidson BA, Nader ND, et al: Progressive, severe lung injury secondary to the interaction of insults in gastric aspiration, Exp Lung Res 30:535, 2004.

CHAPTER 24  Pneumonia 16. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17:333, 2007. 17. Kogan DA, Johnson LR, Sturges BK, et al: Etiology and clinical outcome in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1748, 2008. 18. Peyton JL, Burkitt JM: Critical illness-related corticosteroid insufficiency in a dog with septic shock, J Vet Emerg Crit Care 19:262, 2009. 19. Tart KM, Babski DM, Lee JA: Potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in dogs with presumptive aspiration pneumonia: 125 cases (2005-2008), J Vet Emerg Crit Care 20:319, 2010. 20. Hoareau GL, Mellema MS, Silverstein DC: Indication, management, and outcome of brachycephalic dogs requiring mechanical ventilation, J Vet Emerg Crit Care 21:226, 2011. 21. Raghavendran K, Nemzek J, Napolitano LM, et al: Aspiration-induced lung injury, Crit Care Med 39:818, 2011. 22. Maboni G, Sequel M, Lorton A, et al: Canine infectious respiratory disease: new insights into the etiology and epidemiology of associated pathogens, PLoS One 14(4):0215817, 2019. 23. Chalker V, Brooks H, Brownlie J: The association of Streptococcus equi subsp. Zooepidemicus with canine infectious respiratory disease, Vet Microbiol 95(1-2):149, 2003. 24. Knesl O, Allan F, Shields S: The seroprevalence of canine respiratory coronavirus and canine influenza virus in dogs in New Zealand, N Z Vet J 57(5):295, 2009. 25. An D, Jeoung H, Jeong W, et al: A serological survey of canine respiratory coronavirus and canine influenza virus in Korean dogs, J Vet Med Sci 72(9):1217, 2010. 26. Kawakami K, Ogawa H, Maeda K, et al: Nosocomial outbreak of serious canine infectious tracheobronchitis (kennel cough) caused by canine herpesvirus infection, J Clin Microbiol 48(4):1176, 2010. 27. Jambhekar A, Robin E, Le Boedec K: A systematic review and meta-analysis of the association between 4 mycoplasma species and lower respiratory tract disease in dogs, J Vet Intern Med 33:1880-1891, 2019. 28. Mitchell J, Brooks H, Szladovits B, et al: Tropism and pathological findings associated with canine respiratory coronavirus (CRCoV), Vet Microbiol 162(2-4):582, 2013. 29. Day MJ, Carey S, Clercx C, et al: Aetiology of canine infectious respiratory disease complex and prevalence of its pathogens in Europe, J Comp Pathol 176:86-108, 2020. 30. Viitanen SJ, Lappalainen A, Rajamaki MM: Co-infections with respiratory viruses in dogs with bacterial pneumonia, JVIM 29(2):544-551, 2015. 31. Elia G, Camero M, Losurdo M, et al: Virological and serological findings in dogs with naturally occurring distemper, J Virol Methods 213:127-130, 2015. 32. Yoon KJ, Cooper VL, Schwartz KJ, et al: Influenza virus infection in racing greyhounds, Emerg Infect Dis 11(12):1974-1976, 2005. 33. Keil D, Fenwick B: Canine respiratory bordetellosis: keeping up with an evolving pathogen. In Carmichael LE, editor. Recent advances in canine infectious disease, Ithaca, NY, 2000, International Veterinary Information Service. Available at: http://www.ivis.org/advances/Infect_Dis_Carmichael/ keil/chapter.asp?LA51. 34. Chalker V, Owen W, Paterson C, et al: Mycoplasmas associated with canine infectious respiratory disease, Microbiology 150(10):3491, 2004. 35. Taha-Abdelaziz K, Bassel L, Harness M, et al: Cilia-associated bacteria in fatal Bordetella bronchiseptica pneumonia of dogs and cats, J Vet Diagn Invest 28(4):369, 2016. 36. Pesavento PA, Hurley KF, Bannasch MJ, et al: A clonal outbreak of acute fatal hemorrhagic pneumonia in intensively housed (shelter) dogs caused by Streptococcus equi subsp. zooepidemicus, Vet Pathol 45:51, 2008. 37. Priestnall S, Erles K: Streptococcus zooepidemicus: an emerging canine pathogen, Vet J 188(2):142, 2011. 38. Gower S, Payne R: Sudden deaths in greyhounds due to canine haemorrhagic pneumonia (letter), Vet Rec 170:630, 2012. 39. Workman H, Bailiff N, Jang S, et al: Capnocytophaga cynodegmi in a Rottweiler dog with severe bronchitis and foreign-body pneumonia, J Clin Microbiol 46(12):4099, 2008.

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40. Schultz R, Zwingenberger A: Radiographic, computed tomographic, and ultrasonographic findings with migrating intrathoracic grass awns in dogs and cats, Vet Radiol Ultrasound 49(3):249, 2008. 41. Tenwolde A, Johnson L, Hunt G, et al: The role of bronchoscopy in foreign body removal in dogs and cats: 37 cases (2000-2008), J Vet Intern Med 24(5):1063, 2010. 42. Danesi P, Ravagnan S, Johnson LR, et al: Molecular diagnosis of Pneumocystis pneumonia in dogs, Med Mycol 55(8):828-842, 2017. 43. Sigrist NE, Adamik KN, Doherr MG, et al: Evaluation of respiratory parameters at presentation as clinical indicators of the respiratory localization in dogs and cats with respiratory distress, J Vet Emerg Crit Care 21:13, 2011. 44. Kogan DA, Johnson LR, Jandrey KE, et al: Clinical, clinicopathologic, and radiographic findings in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1742, 2008. 45. Eom K, Seong Y, Park H, et al: Radiographic and computed tomographic evaluation of experimentally induced lung aspiration sites in dogs, J Vet Sci 7:397, 2006. 46. Dear JD: Bacterial pneumonia in dogs and cats: an update, Vet Clin North Am Small Anim Prac 50(2):447-465, 2020. 47. Boag AK, Lamb CR, Chapman PS, Boswood A: Radiographic findings in 16 dogs infected with Angiostrongylus vasorum, Vet Record 154(14): 426-430, 2004. 48. Crews LJ, Feeney DA, Jessen CR, Newman AB: Radiographic findings in dogs with pulmonary blastomycosis: 125 cases (1989-2006), J Am Vet Med Assoc 232:215-221, 2008. 49. Prather AB, Berry CR, Thrall DE: Use of radiography in combination with computed tomography for the assessment of noncardiac thoracic disease in the dog and cat, Vet Radiol Ultrasound 46:114, 2005. 50. Touw HRW, Tuinman PR, Gelissen HPMM, et al: Lung ultrasound: routine practice for the next generation of internists, Neth J Med 73(3): 100-107, 2015. 51. Moser KM, Maurer J, Jassy L, et al: Sensitivity, specificity, and risk of diagnostic procedures in a canine model of Streptococcus pneumoniae pneumonia, Am Rev Respir Dis 125:436, 1982. 52. Creighton SR, Wilkins RJ: Bacteriologic and cytologic evaluation of animals with lower respiratory tract disease using transtracheal aspiration biopsy, J Am Anim Hosp Assoc 10:227, 1974. 53. Angus JC, Jang SS, Hirsh DC: Microbiological study of transtracheal aspirates from dogs with suspected lower respiratory tract disease: 264 cases (1989-1995), J Am Vet Med Assoc 210:55, 1997. 54. Woodhead M, Blasi F, Ewig S, et al: Guidelines for the management of adult lower respiratory tract infections—full version, Clin Microbiol Infect 17(Suppl 6):E1, 2011. 55. Sachdev A, Chugh K, Sethi M, et al: Diagnosis of ventilator-associated pneumonia in children in resource-limited setting: a comparative study of bronchoscopic and nonbronchoscopic methods, Pediatr Crit Care Med 11:258, 2010. 56. Sauve V, Drobatz KJ, Shokek AB, et al: Clinical course, diagnostic findings, and necropsy diagnosis in dyspneic cats with primary pulmonary parenchymal disease: 15 cats (1996-2002), J Vet Emerg Crit Care 15:38, 2005. 57. Karakioulaki M, Stoltz D: Biomarkers in pneumonia: beyond calcitonin, Int J Mol Sci 20:2004, 2019. 58. Berg P, Lindhardt BO: The role of procalcitonin in adult patients with community-acquired pneumonia—a systematic review, Dan Med J 59:A4357, 2012. 59. Vitaanes SJ, Laurila HP, Lilja-Maura LI, et al: Serum C-reactive protein as a diagnostic biomarker in dogs with bacterial respiratory disease, J Vet Intern Med 28(1):84-91, 2014. 60. Jaoude PA, Knight PR, Ohtake P, et al: Biomarkers in the diagnosis of aspiration syndromes, Expert Rev Mol Diagn 10:309, 2010. 61. Zucker AR, Holm BA, Crawford GP, et al: PEEP is necessary for exogenous surfactant to reduce pulmonary edema in canine aspiration pneumonitis, J Appl Physiol 73:679, 1992. 62. Willson DF, Notter RH: The future of exogenous surfactant therapy, Respir Care 56:1369, 2011. 63. Taut FJ, Rippin G, Schenk P, et al: A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled

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analysis of five studies with recombinant surfactant protein-C surfactant (Venticute), Chest 134:724, 2008. 64. Spragg RG, Taut FJ, Lewis JF, et al: Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury, Am J Respir Crit Care Med 183:1055, 2011. 65. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: Comparison of high flow nasal cannula oxygen administration to traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29(3):246-255, 2019. 66. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: High-flow nasal cannula oxygen therapy in acute hypoxemic respiratory failure in 22 dogs requiring oxygen support escalation, J Vet Emerg Crit Care 30(4):364-375, 2020. 67. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: Preliminary evaluation of the use of high-flow nasal cannula oxygen therapy during recovery from general anesthesia in dogs with obstructive upper airway breathing, J Vet Emerg Crit Care 30(4):487-492, 2020. 68. Nader-Djalal N, Knight PR, Davidson BA, et al: Hyperoxia exacerbates microvascular lung injury following acid aspiration, Chest 112:1607, 1997. 69. Matthay MA, Ware LB, Zimmerman GA: The acute respiratory distress syndrome, J Clin Invest 122:2731, 2012. 70. Hopper K, Haskins SC, Kass PH, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64, 2007. 71. Epstein SE, Mellema MS, Hopper K: Airway microbial culture and susceptibility patterns in dogs and cats with respiratory disease of varying severity, J Vet Emerg Crit Care 20:587, 2010. 72. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats: antimicrobial guidelines working group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31:279, 2017. 73. Morley PS, Apley MD, Besser TE, et al: Antimicrobial drug use in veterinary medicine, J Vet Intern Med 19:617, 2005.

74. Matthay MA, Brower RG, Carson S, et al: Randomized, placebo-controlled clinical trial of an aerosolized beta (2)-agonist for treatment of acute lung injury, Am J Respir Crit Care Med 184:561, 2011. 75. Gao Smith F, Perkins GD, Gates S, et al: Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicenter, randomized controlled trial, Lancet 379:229, 2012. 76. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012, Intensive Care Med 39:165, 2013. 77. Stern A, Skalsky K, Avni T, et al: Corticosteroids for pneumonia, Cochrane Database Syst Rev 12:CD007720, 2017. 78. Povoa P, Coelho L, Salluh J: When should we use corticosteroids in severe community acquired pneumonia? Curr Opin Infect Dis 34(2):169, 2021. 79. Chaves GSS, Freitas DA, Santino TA, et al: Chest physiotherapy for pneumonia in children, Cochrane Database Syst Rev 1:CD010277, 2019. 80. ASA: Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the American Society of Anesthesiologists Committee on Standards and Practice Parameters, Anesthesiology 114:495, 2011 81. Jensen AG, Callesen T, Hagemo JS, et al: Scandinavian clinical practice guidelines on general anaesthesia for emergency situations, Acta Anaesthesiol Scand 54:922, 2010. 82. Kazi N, Mobarhan S: Enteral feeding associated gastroesophageal reflux and aspiration pneumonia: a review, Nutr Rev 54:324, 1996. 83. Marik PE, Zaloga GP: Gastric versus post-pyloric feeding: a systematic review, Crit Care 7:R46, 2003. 84. Murphy ST, Ellison GW, McKiernan BC, Mathews KG, Kubilis PS: Pulmonary lobectomy in the management of pneumonia in dogs: 59 cases (1972-1994), J Am Vet Med Assoc 210:235, 1997.

25 Acute Respiratory Distress Syndrome Laura Osborne, BVSc Hons, DACVECC, Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • Acute respiratory distress syndrome (ARDS) is a syndrome of increasing severity of pulmonary edema resulting from an increase in pulmonary capillary endothelial permeability in response to an underlying local or systemic inflammatory process. • ARDS is a clinical diagnosis, recognized by the development of respiratory failure as evidenced by specific criteria in a patient with a predisposing medical or surgical risk factor.

• ARDS is associated with a high mortality rate. Management strategies involve implementation of lung protective ventilatory support in addition to identification and specific treatment of the predisposing underlying clinical risk factor.

INTRODUCTION

injury (VILI) (see Chapter 39). Many of the changes seen on histopathology can be created by VILI; however, the incidence of adverse effects (e.g., diffuse alveolar damage) has declined with the widespread use of lung protective ventilation.4 This may account for some of the variability in histopathological changes noted between studies.

Acute respiratory distress syndrome (ARDS) is a form of severe hypoxemic respiratory failure with a high mortality rate that results from an inflammatory insult to the lung. It most commonly occurs secondary to an infectious process, with pneumonia, aspiration pneumonia, and sepsis accounting for more than 85% of human cases of ARDS.1 The clinical diagnosis of ARDS lacks a gold standard and relies on meeting a set of nonspecific criteria, which likely results in underdiagnosis of the disease.2 The incidence of ARDS in small animal veterinary medicine is unknown as most animals are not screened with the appropriate diagnostic tests to make a definitive diagnosis. In human medicine, the incidence of ARDS in the ICU patient population is reported to range from 2% to 19%.2 The difference likely reflects variations in diagnostic criteria for ARDS, as well as the nature of the ICU populations in these studies.

PATHOPHYSIOLOGY The major gas exchange surface of the alveolus is composed of type 1 alveolar epithelial cells in close association with the pulmonary capillary endothelium. The type 1 cells perform the crucial role of maintaining the permeability function of the alveolar membrane.3 The inciting cause of ARDS is an inflammatory insult that damages either the alveolar epithelial cells or the pulmonary capillary endothelial cells. This insult impairs the normal barrier function and results in a permeability defect that leads to flooding of the interstitium and alveoli with protein-rich fluid and inflammatory cells. This leads to surfactant dysfunction, which promotes atelectasis and altered pulmonary mechanics, as well as impaired gas exchange through both diffusion impairment and venous admixture from intrapulmonary shunting.1 The inciting inflammatory insult to the lung can be of local origin (primary pulmonary disease) or extrapulmonary origin. The progression of ARDS has been divided into phases that are described here to aid in understanding, but it is recognized that there is substantial variability and overlap between phases in clinical patients. The pathophysiology of ARDS is further confounded by the influence of ventilator-induced lung

Acute Exudative Phase The first 1 to 7 days of ARDS is typified by diffuse alveolar damage with hyaline membrane formation and neutrophil influx. Alveolar flooding with fluid, protein, leukocytes, and red blood cells occurs as a result of injury to the alveolar epithelial cell-capillary endothelial cell barrier. These changes are the result of activation of the innate immune system of the lung, causing stimulation of alveolar macrophages and recruitment of neutrophils and circulating macrophages to the lung. Immune cell activation results in widespread release of inflammatory mediators including cytokines, reactive oxygen species, and eicosanoids. These have many deleterious actions such as alveolar epithelial cell damage, protein degradation, surfactant dysfunction, increased permeability of the endothelialepithelial barrier of the alveolus, and development of local microthrombi. Neutrophils are considered to play a central role in this response, accumulating in the lung and releasing numerous injurious substances.5

Fibroproliferative Phase In the weeks following the exudative phase, there is proliferation of type II alveolar epithelial cells, interstitial fibrosis, and organization of the exudate. In human patients this phase can last for more than 3 weeks. As fibrosis progresses, there is further derangement of the architecture of the lung, resulting in significant reductions in lung compliance. Proliferation of type II alveolar epithelial cells, interstitial thickening, and obliteration of alveoli and capillary networks contribute to ongoing hypoxemia during this period. There is evidence that fibrosis can begin as early as 48 hours after onset of ARDS.6

Outcome The resolution of ARDS requires apoptosis of neutrophils, differentiation of type II alveolar epithelial cells into type I, termination of the

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fibroproliferative response, and reabsorption of alveolar edema and the provisional matrix.1 Pulmonary fibrosis following ARDS may or may not fully resolve; however, most surviving human patients recover near-normal pulmonary function within 6–12 months. Despite this, many have long-term disability and compromised quality of life.7

Ventilator-Induced Lung Injury It is now well recognized that the ventilatory strategy utilized in the management of ARDS patients may augment lung injury or impair healing. Experimental studies using animals with healthy lungs have demonstrated that ventilatory strategies using large tidal volumes or high peak airway pressures elicit clinical, physiologic, and histologic abnormalities analogous to those observed in patients with ARDS. The alveolar overdistention (volutrauma) created by these ventilatory modes is criticized as the crucial insult in the production and propagation of lung injury. Other mechanisms potentially contributing to VILI include repetitive recruitment and collapse of the distal airways and alveoli (atelectrauma), which in turn stimulates the release of proinflammatory mediators (biotrauma), as well as disruption of alveoli due to excessive pressure (barotrauma) and oxygen toxicity.8

TABLE 25.1  Reported Causes of Acute

Respiratory Distress Syndrome in Veterinary Patients12,13 COMMONLY REPORTED CAUSES ON DOGS AND CATS Direct Pulmonary Causes Aspiration pneumonia14 Pneumonia Pulmonary contusions Chest trauma Mechanical ventilation

Indirect Extrapulmonary Causes Sepsis SIRS Shock Pancreatitis15 Trauma16,17 Acute kidney injury Multiple transfusions18

Additional Causes Reported in Veterinary Medicine Bee envenomation21 Smoke inhalation19 20 Lung lobe torsion Adverse drug reactions22-24 Tracheal collapse Paraquat intoxication25

ARDS Phenotypes Two phenotypes of ARDS have been identified on the basis of clinical indices and biomarkers: hypoinflammatory and hyperinflammatory. The hyperinflammatory phenotype, which constitutes approximately 30% of patients, is associated with an increased prevalence of shock and metabolic acidosis, as well as a higher mortality rate than the hypoinflammatory phenotype.9 The two phenotypes have also been shown to have different responses to positive end expiratory pressure (PEEP) and fluid management interventions in the ALVEOLI and FACCT trials respectively, and therefore may require different management strategies. Increased awareness of the heterogeneity of ARDS and enhanced understanding of the underlying pathophysiology may improve prognostication and enable specific biological therapies in the future.10

CAUSES/RISK FACTORS ARDS represents the manifestation of an inflammatory insult to the lung from a variety of inciting causes. The inciting cause of ARDS is commonly categorized as either primary pulmonary disease (direct cause) or extrapulmonary disease (indirect cause). Direct lung injury results in local damage to the lung epithelium, whereas indirect lung injury is due to systemic inflammatory disorders that diffusely damage the vascular endothelium.11 The two retrospective studies evaluating risk factors for ARDS in veterinary medicine have noted aspiration pneumonia as a common direct inciting cause in dogs, and SIRS and sepsis as common indirect causes in both dogs and cats (Table 25.1).12,13

DIAGNOSTIC CRITERIA Diffuse alveolar damage is the pathological hallmark of ARDS. To date, there is no specific diagnostic laboratory test for the diagnosis of ARDS, and in small animals it is based on clinical criteria that have been adapted from human medicine.26 In 1994, the American European Consensus Conference (AECC) established the original diagnostic criteria for ARDS, which were clinically based and included (1) acute onset of respiratory distress, (2) bilateral infiltrates on chest radiographs, (3) hypoxemia, and (4) pulmonary artery wedge pressure ,18 mm Hg or the absence of clinical evidence of left atrial hypertension.27 The definition regarded acute lung injury (ALI) as a continuum, identifying ARDS in patients with more severe oxygenation abnormalities. The AECC definition was subsequently challenged due

to issues regarding its reliability and validity between the clinical diagnosis of ARDS and autopsy findings.28 The human medical definition was revised in 2012 to address limitations regarding the lack of standardized ventilator settings at the time of blood gas analysis, resulting in the modified Berlin definition. This removed the term ALI and categorizes ARDS as mild, moderate, or severe in patients receiving mechanical ventilation with a PEEP of 5 mm Hg (Table 25.2).29 In 2007, the Dorothy Russell Havemeyer Working Group developed diagnostic criteria for ARDS in small animals, which mirrored the original AECC definition (Table 25.2). Similarly, four criteria were required for the diagnosis of ARDS: (1) acute onset of respiratory distress (,72 hours), (2) presence of known risk factors, (3) evidence of pulmonary capillary leak without increased pulmonary capillary pressure, and (4) evidence of inefficient gas exchange. Evidence of diffuse pulmonary inflammation was included as an optional fifth criterion due to the logistical and financial constraints of performing airway sampling in critically ill animals. Using this definition, animals with mild hypoxemia (PaO2/FiO2 ratio 300) are categorized as having ALI.26 Similar to the first iteration of the human definition, the VetARDS definition has limitations and does not account for animals receiving mechanical ventilation. Thoracic imaging is a crucial diagnostic criterion and CT imaging, while not commonly performed in the veterinary respiratory distress patient, is considered the gold standard imaging modality. One human study concluded that thoracic radiographs may underestimate the occurrence of ARDS.30,31 It has also been demonstrated that even amongst trained experts there is often disagreement regarding the interpretation of the thoracic radiograph.32 In addition, none of the tests within the VetARDS criteria for evidence of pulmonary capillary leak without increased pulmonary capillary pressure are ideal methods for evaluation of left atrial pressure, as highlighted in a retrospective cohort study in which a necropsy diagnosis of CHF was made in two dogs with a clinical diagnosis of ARDS.12 Furthermore, arterial blood gas analysis is not always achievable in dogs and is generally unfeasible in cats with respiratory distress. Studies in human medicine have validated the use of the oxygen saturation/fraction of inspired oxygen (SpO2/FiO2 [S/F]) ratio for the diagnosis of ARDS.33,34 Studies in dogs have found a good correlation between the P/F and S/F ratios,35,36 and the use of the S/F ratio as a surrogate marker of hypoxemia may be an attractive alternative to aid in the diagnosis of ARDS in small animals.

CHAPTER 25  Acute Respiratory Distress Syndrome

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TABLE 25.2  Comparison of the Berlin Definition26 with the Veterinary Definition of Acute Lung

Injury and Acute Respiratory Distress Syndrome26 Criteria Timing Origin of Edema/ Diagnostics

Oxygenation*

The Berlin Definition of Acute Respiratory Distress Syndrome

Definition of Veterinary Acute Lung Injury and Acute Respiratory Distress Syndrome

Within 1 week of a known clinical insult or new or worsening respiratory symptoms • Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present • Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules (chest radiograph or computed tomography) Mild: 200 mm Hg ,PaO2/FiO2 #300 mm Hg with PEEP or CPAP $5 cm H2O Moderate: 100 mm Hg ,PaO2/FiO2 #200 mm Hg with PEEP $5 cm H2O Severe: PaO2/FiO2 #100 mm Hg with PEEP $5 cm H2O

• Acute onset (,72 hours) of tachypnea and labored breathing at rest • Known risk factors Evidence of pulmonary capillary leak without increased pulmonary capillary pressurea (any one of the following): a. Bilateral/diffuse infiltrates on thoracic radiographs (more than 1 quadrant/lobe) b. Bilateral dependent density on computed tomography c. Proteinaceous fluid within the conducting airways d. Increased extravascular lung water Evidence of inefficient gas exchange (any one or more of the following): a. Hypoxemia without PEEP or CPAP and known FiO2 i. PaO2/FiO2 ratio 1. #300 mm Hg for VetALI 2. #200 mm Hg for VetARDS ii. Increased alveolar–arterial oxygen gradient iii. Venous admixture (noncardiac shunt) b. Increased dead space ventilation Evidence of diffuse pulmonary inflammation a. Transtracheal wash/bronchoalveolar lavage sample neutrophilia b. Transtracheal wash/bronchoalveolar lavage biomarkers of inflammation c. Molecular imaging (PET)

Additional Criteria

*If at altitude higher than 1000 m, then a correction factor should be calculated as follows: [PaO2/FiO2 3 (barometric pressure/760)] a No evidence of cardiogenic edema (one or more of the following): PAOP ,18 mm Hg; no clinical or diagnostic evidence supporting left sided heart failure, including echocardiography. CPAP, continuous positive airway pressure; PEEP, positive end expiratory pressure; PET, positron emission tomography.

MANAGEMENT A hallmark of ARDS is refractory hypoxemia that is primarily due to venous admixture from intrapulmonary shunting.6 Severely affected patients are not responsive to oxygen therapy but may be responsive to positive pressure ventilation, which recruits alveoli and reduces the shunt fraction. Basic management strategies for patients with ARDS include provision of lung protective ventilatory support in addition to the identification and specific treatment of the predisposing underlying clinical risk factor. In one retrospective study, VetALI and VetARDS necessitated mechanical ventilation in 50% of dogs and 80% of cats,13 while a second retrospective study reported that mechanical ventilation was recommended in 86% of animals with a clinical diagnosis of ARDS.12 See Chapter 33 for more information regarding advanced mechanical ventilation of small animals; management strategies specific to ARDS patients are detailed below.

The Baby Lung Concept The baby lung concept originated from observations of CT images of ARDS patients that demonstrated two distinct lung regions: the nondependent nearly normal lung with dimensions similar to a healthy baby that was subject to harm from mechanical ventilation, and the second dependent region of consolidated and collapsed lung that was primarily responsible for the impairment in oxygenation.37 This concept is now understood to be a functional rather than anatomical division of the lung and provides physiologic reasoning to help understand VILI and the rationale for lung protective ventilation.38

The Open Lung Strategy and Lung Protective Ventilation The open lung strategy, originally proposed by Lachmann, aims to reduce atelectrauma and shear stress in heterogeneously ventilated lungs by using recruitment maneuvers to open up collapsed lung and higher PEEP to maintain alveolar stability.4 The use of recruitment maneuvers is currently controversial, with the ART trial reporting that its application was associated with increased mortality in patients with moderate to severe ARDS.39 The PHARLAP trial was subsequently abandoned due to loss of clinical equipoise following the ART trial; however, it did reveal that the intervention was associated with harmful cardiovascular consequences.40 Two recent systematic reviews of recruitment maneuvers found no improvement in mortality rate and increased rates of hemodynamic compromise despite improvement in oxygenation and reduced use of rescue therapies for hypoxemia.14,41 The open lung concept, combined with low tidal volume ventilation in line with the baby lung concept, form the foundation of lung protective ventilation. It is well established that mechanical ventilation with lower tidal volumes (4–6 ml/kg predicted body weight) and end-inspiratory plateau pressures (,30 cm H2O) reduce mortality in human patients with ARDS.42 By preventing alveolar overdistention and the associated VILI, this lung protective strategy preserves the epithelial–endothelial barrier and improves outcomes.43 PEEP is a major component of the protective ventilatory strategy; by recruiting atelectatic lung units and preventing cyclic atelectasis, it increases the functional residual capacity, decreases the shunt fraction, and allows for a reduction to a less toxic FiO2. While conventional mechanical ventilation is most commonly utilized in veterinary medicine, airway pressure release ventilation is an inverse ratio, pressure controlled,

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intermittent mandatory ventilation with unrestricted spontaneous breathing based on the open lung approach, and its use has been reported in the successful management of a canine patient with refractory hypoxemia.44

Conservative Fluid Management Due to increased endothelial permeability, fluid therapy may exacerbate alveolar edema in ARDS patients. Conservative fluid management has been shown to reduce ventilator days in people with ARDS.45

Pharmacologic Therapy Reported benefits of corticosteroids in ARDS include attenuation of proinflammatory cytokine production and prevention of progression to the fibroproliferative stage through inhibition of fibroblast proliferation and collagen deposition.46 There is currently controversy and low certainty evidence regarding the use of corticosteroids in ARDS, with studies demonstrating both increased and decreased mortality rates and no conclusive large scale trial in the period of lung protective ventilation.47 Current human guidelines suggest the use of corticosteroids in patients with early moderate to severe ARDS.48 Many other pharmacologic agents have been trialed for the treatment of ARDS with limited success, including inhaled pulmonary vasodilators, inhaled surfactants, N-acetylcysteine, statins, and beta- agonists. Inhaled nitric oxide and prostacyclins act as selective pulmonary vasodilators, resulting in improved ventilation–perfusion matching and arterial oxygenation; however, they have not shown a mortality benefit. Injury to type II alveolar epithelial cells in ARDS patients reduces the amount and function of surfactant produced, increasing alveolar surface tension and promoting atelectasis. Treatment of ARDS patients with surfactant nevertheless has not been demonstrated to alter mortality or reduce the duration of mechanical ventilation. Similarly, a benefit of antioxidant therapy with N-acetylcysteine has not been demonstrated. It has also been concluded that the antiinflammatory and immunomodulatory effects of statins probably make no difference to early mortality or duration of mechanical ventilation. Both aerosolized and intravenous beta-agonists have been trialed in ARDS to improve alveolar fluid clearance; however, they have been unsuccessful and their use is possibly associated with increased early mortality.47,48

PROGNOSIS The clinical risk factors associated with the development of ARDS appear to greatly influence the expected outcome, with the nature of the inciting insult (direct pulmonary insult vs extrapulmonary) affecting the response to ventilatory support. Recent studies evaluating lung protective ventilation strategies have demonstrated a significant reduction in mortality rate; however, current mortality rates for human ARDS patients are still higher than 40%.1,42,49 A retrospective study on long-term mechanical ventilation in dogs and cats found that ARDS was associated with a mortality rate of 92%.50 There are numerous case reports describing ARDS in dogs, with only one dog surviving without mechanical ventilation.51 There are two case reports describing ARDS in cats, with one dying and the other being euthanatized.16,52 In one retrospective cohort study, the overall case fatality rate in animals diagnosed clinically with ARDS was 84% in dogs and 100% in cats, with the majority being euthanatized within the 24 hour period following diagnosis of ARDS.12 In another retrospective evaluation of 29 cases in dogs and cats, only 10% of patients survived.13 Given the costs associated with long-term mechanical ventilation, a true understanding of the natural mortality rate of this disease in veterinary patients is clouded by elective euthanasia.

REFERENCES 1. Thompson BT, Chambers RC, Liu KD: Acute respiratory distress syndrome, N Engl J Med 377:562-572, 2017. 2. Bellani G, Laffey JG, Pham T, et al: Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries, JAMA 315:788-800, 2016. 3. Lumb A, ed: Functional anatomy of the respiratory tract. In Nunn’s applied respiratory physiology, ed 8, New York, 2017, Elsevier, pp 3-16. 4. van der Zee P, Gommers D: Recruitment maneuvers and higher PEEP, the so-called open lung concept, in patients with ARDS, Crit Care 23:73, 2019. 5. Matthay MA, Zemans RL: The acute respiratory distress syndrome: pathogenesis and treatment. In Abbas AK, Galli SJ, Howley PM, editors: Annual review of pathology: mechanisms of disease, vol 6, Palo Alto, 2011, Annual Reviews, pp 147-163. 6. Bellingan GJ: The pulmonary physician in critical care * 6: The pathogenesis of ALI/ARDS, Thorax 57:540-546, 2002. 7. Matthay MA, Zemans RL, Zimmerman GA, et al: Acute respiratory distress syndrome, Nat Rev Dis Primers 5:22, 2019. 8. Beitler JR, Malhotra A, Thompson BT: Ventilator-induced lung injury, Clin Chest Med 37:633, 2016. 9. Spadaro S, Park M, Turrini C, et al: Biomarkers for acute respiratory distress syndrome and prospects for personalised medicine, J Inflamm (London) 16:1, 2019. 10. Sinha P, Calfee CS: Phenotypes in acute respiratory distress syndrome: moving towards precision medicine, Curr Opin Crit Care 25:12-20, 2019. 11. Shaver CM, Bastarache JA: Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury, Clin Chest Med 35:639-653, 2014. 12. Boiron L, Hopper K, Borchers A: Risk factors, characteristics, and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29:173-179, 2019. 13. Balakrishnan A, Drobatz KJ, Silverstein DC: Retrospective evaluation of the prevalence, risk factors, management, outcome, and necropsy findings of acute lung injury and acute respiratory distress syndrome in dogs and cats: 29 cases (2011-2013), J Vet Emerg Crit Care 27:662-673, 2017. 14. Pensier J, de Jong A, Hajjej Z, et al: Effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis, Intensive Care Med 45(12):1691-1702, 2019. 15. López A, Lane IF, Hanna P: Adult respiratory distress syndrome in a dog with necrotizing pancreatitis, Can Vet J 36:240-241, 1995. 16. Katayama M, Okamura Y, Katayama R, et al: Presumptive acute lung injury following multiple surgeries in a cat, Can Vet J 54:381, 2013. 17. Kelmer E, Love LC, Declue AE, et al: Successful treatment of acute respiratory distress syndrome in 2 dogs, Can Vet J 53:167-173, 2012. 18. Thomovsky EJ, Bach J: Incidence of acute lung injury in dogs receiving transfusions, J Am Vet Med Assoc 244:170-174, 2014. 19. Guillaumin J, Hopper K: Successful outcome in a dog with neurological and respiratory signs following smoke inhalation, J Vet Emerg Crit Care 23:328-334, 2013. 20. Neath P, Brockman D, King L: Lung lobe torsion in dogs: 22 cases (1981-1999), J Am Vet Med Assoc 217:1041-1044, 2000. 21. Annane MD, Pastores AS, Rochwerg SB, et al: Guidelines for the diagnosis and management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017, Crit Care Med 45:2078-2088, 2017. 22. Hart SK, Waddell L: Suspected drug-induced infiltrative lung disease culminating in acute respiratory failure in a dog treated with cytarabine and prednisone, J Vet Emerg Crit Care 26:844-850, 2016. 23. Greensmith TD, Cortellini S: Successful treatment of canine acute respiratory distress syndrome secondary to inhalant toxin exposure, J Vet Emerg Crit Care 28:469-475, 2018. 24. Botha H, Jennings SH, Press SA, et al: Suspected acute respiratory distress syndrome associated with the use of intravenous lipid emulsion therapy in a dog: a case report, Front Vet Sci 6:225, 2019.

CHAPTER 25  Acute Respiratory Distress Syndrome 25. Kelly DF, Morgan DG, Darke PGG, et al: Pathology of acute respiratory distress in the dog associated with paraquat poisoning, J Comp Pathol 88:275-294, 1978. 26. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17:333-339, 2007. 27. Bernard GR, Artigas A, Brigham KL, et al: The American-European consensus conference on ARDS - definitions, mechanisms, relevant outcomes, and clinical-trial coordination, Am J Respir Crit Care Med 149:818-824, 1994. 28. Esteban A, Fernández-Segoviano P, Frutos-Vivar F, et al: Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings, Ann Intern Med 141:440-445, 2004. 29. Ranieri VM, Rubenfeld GD, Thompson BT, et al: Acute respiratory distress syndrome: the Berlin Definition, JAMA 307:2526-2533, 2012. 30. Zompatori M, Ciccarese F, Fasano L: Overview of current lung imaging in acute respiratory distress syndrome, Eur Respir Rev 23:519-530, 2014. 31. Figueroa-Casas JB, Brunner N, Dwivedi AK, et al: Accuracy of the chest radiograph to identify bilateral pulmonary infiltrates consistent with the diagnosis of acute respiratory distress syndrome using computed tomography as reference standard, J Crit Care 28:352-357, 2013. 32. Peng JM, Qian CY, Yu XY, et al: Does training improve diagnostic accuracy and inter-rater agreement in applying the Berlin radiographic definition of acute respiratory distress syndrome? A multicenter prospective study, Crit Care (London, England) 21:12, 2017. 33. Bilan N, Dastranji A, Ghalehgolab Behbahani A: Comparison of the Spo2/ Fio2 ratio and the Pao2/Fio2 ratio in patients with acute lung injury or acute respiratory distress syndrome, J Cardiovasc Thorac Res 7:28-31, 2015. 34. Rice TW, Wheeler AP, Bernard GR, et al: Comparison of the SpO(2)/ FIO2 ratio and the Pao(2)/FIO2 ratio in patients with acute lung injury or ARDS, Chest 132:410-417, 2007. 35. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23:280, 2013. 36. Carver A, Bragg R, Sullivan L: Evaluation of PaO2/FiO2 and SaO2/FiO2 ratios in postoperative dogs recovering on room air or nasal oxygen insufflation, J Vet Emerg Crit Care 26:437-445, 2016. 37. Gattinoni L, Pesenti A: The concept of “baby lung”, Intensive Care Med 31:776-784, 2005. 38. Gattinoni L, Marini J, Pesenti A, et al: The “baby lung” became an adult, Intensive Care Med 42:663-673, 2016. 39. ART Investigators Writing Group: Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in

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patients with acute respiratory distress syndrome: a randomized clinical trial, JAMA 318(14):1335-1345, 2017. 40. Hodgson CL, Cooper DJ, Arabi Y, et al: Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A phase II, multicenter randomized controlled clinical trial, Am J Respir Crit Care Med 200(11):1363-1372, 2019. 41. Cui Y, Cao R, Wang Y, Li G: Lung recruitment maneuvers for ARDS patients: a systematic review and meta-analysis, Respiration 99(3): 264-276, 2020. 42. Brower R, Matthay M, Morris A, et al: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, N Engl J Med 342:1301-1308, 2000. 43. Parsons EP, Eisner DM, Thompson TB, et al: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury, Crit Care Med 33:1-6, 2005. 44. Sabino CV, Holowaychuk M, Bateman S: Management of acute respiratory distress syndrome in a French Bulldog using airway pressure release ventilation, J Vet Emerg Crit Care 23:447-454, 2013. 45. Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluidmanagement strategies in acute lung injury. (Disease/Disorder overview), N Engl J Med 354:2564, 2006. 46. Aharon MA, Prittie JE, Buriko K: A review of associated controversies surrounding glucocorticoid use in veterinary emergency and critical care, J Vet Emerg Crit Care 27:267-277, 2017. 47. Lewis SR, Pritchard MW, Thomas CM, et al: Pharmacological agents for adults with acute respiratory distress syndrome, Cochrane Database Syst Rev 7:CD004477, 2019. 48. Buckley MS, Dzierba AL, Muir J, et al: Moderate to severe acute respiratory distress syndrome management strategies: a narrative review, J Pharm Pract 32:347-360, 2019. 49. Villar J, Blanco J, Añón J, et al: The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation, Intensive Care Med 37:1932-1941, 2011. 50. Hopper K, Haskins SC, Kass PH, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64-75, 2007. 51. Walker T, Tidwell AS, Rozanski EA, et al: Imaging diagnosis: acute lung injury following massive bee envenomation in a dog, Vet Radiol Ultrasound 46:300-303, 2005. 52. Evans NA, Walker JM, Manchester AC, et al: Acute respiratory distress syndrome and septic shock in a cat with disseminated toxoplasmosis, J Vet Emerg Crit Care (San Antonio, Tex: 2001) 27:472-478, 2017.

26 Pulmonary Contusions and Hemorrhage Sergi Serrano, LV, DVM, DACVECC

KEY POINTS • Pulmonary commonly occur in patients after blunt chest trauma. The contusions consist of interstitial and alveolar hemorrhage, accompanied by parenchymal destruction that starts immediately after the impact and can worsen for 24 to 48 hours after injury. • The lesions typically resolve within 3 to 10 days unless complications such as pneumonia or acute respiratory distress syndrome ensue. • Clinical signs may be acute and severe or may develop progressively over several hours after trauma. • The diagnosis of pulmonary contusions is based on a history of trauma and the presence of respiratory changes, ranging from tachypnea to severe respiratory distress, in conjunction with compatible blood gas abnormalities and characteristic changes seen on

thoracic radiographs. Thoracic ultrasound and computed tomography scanning are becoming more widely used and may have diagnostic advantages compared with radiographs. • Treatment of patients with pulmonary contusions is supportive and consists of oxygen therapy, judicious fluid administration, and analgesia for concurrent injuries. Ventilatory support may be necessary in severe cases. • Less common causes of pulmonary hemorrhage include coagulopathies, thromboembolic disease, infectious disease (viral, bacterial, and parasitic), exercise-induced hemorrhage, and neoplasia. • Treatment of atraumatic pulmonary hemorrhage is directed toward the underlying disease while providing respiratory and ventilatory support when needed.

Pulmonary contusions consist of pulmonary interstitial and alveolar hemorrhage and edema associated with blunt chest trauma, usually after a compression-decompression injury of the thoracic cage. Such injury in small animals is most commonly associated with motor vehicle trauma1 and high-rise falls2 in cats in urban areas. Thoracic bite trauma may also lead to severe contusions,3 as may other animal interactions (e.g., horse kicks), human abuse, and shock waves from explosions. Thoracic trauma has been reported in 34%,4 38.9%,5 and 57%6 of dogs and 17% of cats5 that sustain limb fractures in road traffic accidents. Pulmonary contusions may also be present in traumatized animals without limb injuries; in one study, only 32% of dogs had concurrent fractures or luxations.7 In general, pulmonary contusions are the most prevalent thoracic lesion after trauma and occur in roughly 50% of animals with thoracic injuries. They may occur as an isolated abnormality or in combination with other thoracic injuries, including pneumothorax, pleural effusion, rib fractures, diaphragmatic rupture, cardiac arrhythmias, and pericardial effusion.5,8 The clinical manifestations of pulmonary contusions can be acute and lead to immediate, severe respiratory distress or may develop progressively over several hours after the injury. Patients may display few clinical signs associated with the contusions initially; in one study, 79% of dogs with abnormal thoracic radiographic findings or low arterial partial pressure of oxygen (PaO2) had no physical examination findings that were suggestive of thoracic injury on initial examination.5 Another study found that the American Society of Anesthesiologists grade was significantly increased with the information provided by thoracic radiography.9 However, radiographic changes may also be delayed. Because aggressive fluid therapy and general anesthesia have

the potential to worsen contusions, the emergency clinician must not discount the possibility of their presence when evaluating more severe injuries, even if clinical signs of thoracic injury or respiratory distress are not apparent initially.

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PATHOPHYSIOLOGY AND PATHOLOGY Pulmonary contusions result from the release of direct or indirect energy within the lung. High-velocity missiles and blasts also lead to pulmonary contusions as shock waves pass through the parenchymal tissue and lead to bleeding into the alveolar spaces and disruption of normal lung structure and function. Several mechanisms have been postulated as potential etiologies of pulmonary contusion.10 Because of the compressible nature of the thoracic cage, acute compression and subsequent expansion lead to the transmission of mechanical forces and energy to the pulmonary parenchyma. As a result, the lung is directly injured by the increased pressure due to the spalling effect, a shearing or bursting phenomenon that occurs at gas–liquid interfaces and may disrupt the alveolus at the point of initial contact with shock waves. The inertial effect that occurs when low-density alveolar tissue is stripped from heavier hilar structures as they accelerate at different rates results in both mechanical tearing and laceration of the lungs. Finally, an implosion effect resulting from rebound or overexpansion of gas bubbles after a pressure wave passes can lead to tearing of the pulmonary parenchyma from excess distention.11,12 The parenchyma may also be injured by the displacement of fractured ribs. Subsequent hemorrhage results in bronchospasm, increased mucus production, and alveolar collapse as a result of decreased production of surfactant. In addition to hemorrhage, traumatic damage to the

CHAPTER 26  Pulmonary Contusions and Hemorrhage lung parenchyma results in the inflammatory response with increased capillary permeability and extravasation of protein-rich fluid.13 Damage to the lung leads to complex changes in respiratory function. The parenchymal damage causes ventilation-perfusion (V/Q) mismatch as the alveoli are flooded with blood and are poorly ventilated. In addition, the increase in lung water resulting from the accumulation of protein-rich edema subsequently decreases lung compliance.14 Recent experimental studies in pigs show that both true shunt and areas of low V/Q mismatch exist at both 2 and 6 hours after injury; true shunt appears to be the major cause of hypoxemia.15,16 At the expense of blood flow to areas with normal V/Q quotient, the shunt fraction and dead space ventilation increase. Both the shunt (Q) and volume of poorly aerated and nonaerated lung tissue correlate independently with PaO2.15 There is also a variable vascular reaction in response to local hypoxia (hypoxic pulmonary vasoconstriction), which may be followed by a further decrease in local perfusion secondary to vascular congestion and thrombosis. In some patients, this leads to reduced perfusion to the unventilated lung, thus minimizing an increase in the shunt fraction.17 Regardless, the patient subsequently displays apparent dyspnea from hypoxemia. Either hypocarbia or hypercarbia may be present, depending on the severity of the contusions and the effects of concurrent injuries on ventilation. In animals that survive the initial hours following injury, the respiratory derangements associated with pulmonary contusions usually resolve in 3 to 7 days, but delayed deterioration may occur; this may be secondary to complications such as bacterial pneumonia or acute respiratory distress syndrome (ARDS) due to the local or systemic inflammatory response.11 The frequency of these complications has not been well described in dogs and cats. In humans, pulmonary contusions cause severe immunodysfunction both locally and systemically, and this immunosuppression is associated with a decreased survival rate if a septic complication occurs.18 Histologic progression of pulmonary contusions has been demonstrated in a canine experimental model.19 Immediate interstitial hemorrhage is followed by interstitial edema and infiltration of monocytes and neutrophils during the first few hours. Twenty-four hours after injury, the alveoli and smaller airways are full of protein, red blood cells, and inflammatory cells. At this stage the normal architecture has been lost and edema is severe. Alveoli adjacent to the affected region remain normally perfused, but they are less compliant because of the edema and disruption of the surfactant layer. Thus they are poorly ventilated, which leads to an increase in V/Q mismatch.14,17,20,21 Furthermore, experimental studies in pigs have demonstrated that local pulmonary contusions may lead to generalized pulmonary dysfunction secondary to impaired surfactant activity and a subsequent decrease in alveolar diameter.22 Forty-eight hours after injury, healing has started and the lymphatic vessels are dilated and filled with protein. The parenchyma and affected airways contain fibrin, cellular debris, granules from type II alveolar cells, neutrophils, and macrophages.14 Another study found that within 7 to 10 days after trauma, canine lungs were almost completely healed with little scarring.20 Clinically, there is not always a clear correlation between the apparent extent of the affected lung and the clinical signs. At a mechanistic level, more recent studies on the pathophysiology of pulmonary contusions are focusing on the role of the acute inflammatory response and its impact on severity. Experimental studies highlight the potential importance of neutrophil activation, Toll-like receptors, and type II pneumocyte apoptosis in the progression of lung contusions.23 Type II pneumocyte injury leading to generalized surfactant dysfunction may also play an important role and could be a therapeutic target.24 Finally, the interactions of lung contusions with other pulmonary injuries, such as silent aspiration of gastric contents, may exacerbate permeability

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changes and the inflammatory response, potentially contributing to the more severe forms of pulmonary contusions and their progression to acute lung injury/ARDS and pneumonia.24

DIAGNOSIS Physical Examination Findings Clinically, patients usually have tachypnea or apparent dyspnea, depending on the severity of the contusions and the time between injury and arrival at the veterinary hospital. Auscultation findings may be normal, or increased breath sounds, crackles, and/or wheezes can be present and may worsen over the initial 24-hour period. These abnormalities are often asymmetric and may be truly unilateral. Lung auscultation findings can be more difficult to interpret when concurrent conditions, such as pneumothorax, are present, and frequent monitoring of respiratory rate, effort, and pulmonary auscultation is warranted. Hemoptysis (the expectoration of blood from distal to the larynx) is present in a high proportion of human patients. It appears to be an uncommon finding in small animals but is usually associated with severe pulmonary lesions. Because there is a high incidence of thoracic trauma associated with skeletal injuries and respiratory symptoms may be absent or masked initially, the clinician should maintain a high index of suspicion for contusions in any traumatized patient.

Imaging: Radiology, Computed Tomography, and Ultrasound Animals that sustain thoracic trauma may have multiple thoracic injuries, making a precise diagnosis based on the physical examination alone challenging. Imaging studies may be helpful in identifying and defining all injuries; however, as with all dyspneic patients, the riskbenefit ratio of the imaging procedure should be considered carefully, and patients should be stabilized before imaging is attempted. Thoracic ultrasound has rapidly gained acceptance as a bedside test in people and similarly in veterinary medicine because it requires minimal handling and restraining resulting in a safer option for unstable patients. Although both the presence of alveolar interstitial syndrome and peripheral parenchymal syndrome have high sensitivity and specificity for the detection of contusions,25 recent studies favor using alveolar interstitial syndrome with a cutoff of six B-lines per intercostal space.26 Lung ultrasound on admission identifies patients at risk of developing ARDS after blunt trauma in people.27 Ultrasonography has been found to be a better screening tool in the detection of pulmonary contusion than thoracic radiographs28 and is a better diagnostic test than physical examination and thoracic radiographs when evaluating patients for pulmonary contusions or pneumothorax after chest trauma.29 In veterinary medicine, point-of-care thoracic ultrasound has become widespread, and although studies are still small, findings are similar to those in people and suggest high value in the diagnosis of lesions associated to blunt chest trauma, including but not limited to pulmonary contusions.30 The accuracy of lung ultrasound, however, is more operator- and equipment-dependent than other diagnostic techniques (see Chapter 189, Point of Care Ultrasound in the ICU). Radiographic changes in patients with pulmonary contusions consist of areas of patchy or diffuse interstitial or alveolar lung infiltrates that can be either localized or generalized (Fig. 26.1). Radiographic changes may lag behind clinical signs by 12 to 24 hours, and therefore normal radiographic findings may be seen in animals with pulmonary contusions. Patients with more severe radiographic changes initially may require a longer duration of oxygen supplementation and longer hospitalization times. However, the relationship between the severity

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A

B

Fig. 26.1  Lateral (A) and dorsoventral (B) radiographs showing the characteristic appearance of pulmonary contusions. Note the diffuse alveolar pattern. It is common to see additional radiographic abnormalities such as multiple rib fractures, subcutaneous emphysema, pneumomediastinum, and pneumothorax, as seen in this case.

of the contusion based on radiographic changes and survival has not been established.7 Although computed tomography (CT) has been shown experimentally to be more sensitive for detecting initial lesions and accurately reflecting the extent of the lesion than standard radiographic techniques, lack of availability in veterinary hospitals and the need for sedation or anesthesia in a traumatized patient have so far limited its widespread use. An experimental canine model of pulmonary contusions found that a CT scan enabled detection of 100% of the pulmonary lesions, but initial thoracic radiographs only allowed identification in 37%. In addition, 21% of lesions still not visible radiographically after 6 hours. In this study, CT imaging underestimated the extent of the lesions in only 8% of the animals, whereas thoracic radiography underestimated the extent in 58% of the animals.31 In people, CT is considered the gold standard for the diagnosis of pulmonary contusions and may be predictive of progression and treatment needs. A contused volume of 20% or more is highly predictive of the need for mechanical ventilation (8% of patients with contused volume #20% compared with 40% of those patients with volumes .20%).32 The percentage of contused volume is also an independent predictive factor for the development of ARDS, with 21.5% being the best cutoff for severe pulmonary contusions.33 Furthermore, in people with blunt pulmonary contusions, the absence of a blunt pulmonary contusion volume of 20% or more, more than four fractured ribs, or a Glasgow Coma Scale score higher than 14 precluded mechanical ventilation in 100% of the cases, while the presence of all three findings together predicted the need for mechanical ventilation in 100% of the cases.34 Overall, the superior sensitivity of CT allows for the identification of injuries that would otherwise go unrecognized (occult injuries). In people, patients with occult injury and those with no injury have similar ventilator needs and requirements, while those with occult injuries remain hospitalized longer, leading to the argument that occult injuries have little to no clinical significance yet utilize increased hospital resources and cost.35

Blood Gas Analysis and Pulse Oximetry Arterial blood gas analysis is the most objective method for assessing and monitoring the physiologic effects of thoracic trauma (see Chapter 184, Oximetry Monitoring). Clinical data in dogs with pulmonary contusions reveal a high incidence of hypoxemia; however, it is usually

mild to moderate.6,7 This may be because many of the most severe cases will die before arriving at the veterinary clinic. Either hypocarbia or hypercarbia may be seen, depending on the severity of the parenchymal injury, the nature of concurrent thoracic injuries, and other factors such as pain, distress, and the effect of concurrent metabolic acid-base derangements. In humans, the arterial oxygen tension/fractional concentration of inspired oxygen ratio (PaO2/FiO2) is directly correlated with the volume of contused lung for the first 24 hours after injury, although this correlation is not consistent beyond 1 week.27 Whether this association exists in small animal patients is unknown. Although pulse oximetry has some limitations, it may be a useful quantitative assessment of oxygenation in cases in which an arterial blood gas analysis is not possible (e.g., cats). It is a less accurate indicator of impaired oxygen and does not provide a measure of ventilation, and reliable measurements can be difficult to obtain in patients that are in shock. A pulse oximeter reading of less than 95% indicates hypoxemia, and values less than 90% are consistent with severe hypoxemia (see Chapter 16, Hypoxemia).

MANAGEMENT Initial Approach Management of pulmonary contusions is supportive. Initial triage and major body system assessment should be done in any traumatized patient, and injuries should be ranked and managed based on their threat to patient life (see Chapter 1, Evaluation and Triage of the Critically Ill Patient). Prehospital management rarely occurs. However, the animal should be transported to the clinic lying in its preferred posture or kept in sternal recumbency if possible.36 Oxygen therapy, judicious fluid therapy, and adequate analgesia are essential components of patient management.

Oxygen Therapy and Ventilation Oxygen should be administered to all dyspneic patients (see Chapter 15, Oxygen Therapy). Noninvasive methods such as flow-by, nasal oxygen delivery, or oxygen cages and hoods are commonly used. More recently, high-flow nasal oxygen is being used and can prevent mechanical ventilation in some severely dyspneic patients (see Chapter 31, High Flow Nasal Oxygen). In severely affected cases, intubation and

CHAPTER 26  Pulmonary Contusions and Hemorrhage mechanical ventilation may be necessary (see Chapters 32 and 33, Mechanical Ventilation-Core and Advanced Concepts, respectively). In people, pressure-controlled ventilation with positive end-expiratory pressure is the preferred method of mechanical ventilation.37 Recent studies have shown that, contrary to previous beliefs, the presence of contusions neither increases mortality, length of stay, or pneumonia rates in severely injured human trauma patients that undergo mechanical ventilation,38 suggesting the effect of ventilation on contusions may not be as deleterious as previously thought, and ventilation should not be withheld for fear of worsening the contusions. One canine study examined 10 dogs with pulmonary contusions that required positive pressure ventilation and found that 50% of the dogs benefited from this intervention, and animals that weighed more than 25 kg were more likely to survive.39 The lack of available neonatal or pediatric ventilators may have resulted in more complications in smaller patients. Alveolar recruitment strategies and the use of low tidal volumes have been shown to increase both oxygenation and lung aeration in humans with severe chest trauma,40 although similar studies in dogs and cats are lacking. Improved ventilator strategies are being continuously evaluated. Recently the early use of high-frequency oscillatory ventilation has been deemed safe and efficacious,41 and airway pressure release ventilation is associated with a reduced risk for ventilator-associated pneumonia without changing either the need for ventilation days or the mortality rate.42 Extracorporeal membrane oxygenation has been used in people with severe pulmonary contusions and yielded good results43,44; however, this and other advanced ventilatory techniques that may prove useful such as jet ventilation, selective bronchial intubation, and dual-lung ventilation are not used routinely in the clinical setting for the management of pulmonary contusions in people or the veterinary field.

Fluid Therapy Many patients with thoracic trauma will have some degree of concurrent hypovolemic shock. The debate regarding the optimal fluid therapy strategy for use in trauma and shock patients has yet to be resolved; however, it seems that optimizing fluid therapy to maintain adequate perfusion while avoiding overzealous administration is likely to give the best results (see Chapter 68, Shock Fluid Therapy). In any patient with multiple traumatic injuries, the clinician must prioritize treatment decisions based on which major body system is most severely affected. Several fluid options are available, and the fluid type and administration strategy chosen must take into account both the cardiovascular and pulmonary changes present. Regardless of the type of fluid chosen, increases in pulmonary capillary hydrostatic pressure may lead to increased fluid extravasation into the alveoli and worsening of pulmonary function. The clinician should aim to optimize tissue perfusion while avoiding excessive fluid administration that could worsen the pulmonary edema and hemorrhage. Careful monitoring and tailoring of the fluid protocol to the patient are preferable to administering preset volumes and rates. Isotonic crystalloids are the most economical fluids and are at least as effective as colloids for resuscitation of the shock patient.45,46 Evidence for the treatment of patients with pulmonary contusions is scarce, and papers yield conflicting results. Some have shown no benefits when using hypertonic saline over isotonic solutions in experimental porcine models of pulmonary contusions,47 whereas others show less lung water retention and higher PaO2 values with the use of hypertonic saline dextran versus Ringer acetate or saline.48 Blood products and synthetic colloids may contribute to worsening pulmonary edema if they leak into the airways or interstitium.49

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Although clinical evidence is lacking, common sense dictates that although strict fluid restriction is not indicated, caution should be exercised when administering intravenous fluids to shock patients with suspected pulmonary contusions. Patients should be monitored carefully to detect any worsening of pulmonary function during fluid administration and fluid rates adjusted accordingly (see Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively).

Analgesia Hypoventilation caused by pain from concurrent injuries can be severe and should be managed proactively with analgesics (see Chapter 134, Analgesia and Constant Rate Infusions). Ideally, drugs that cause minimal impairment of cardiac and respiratory functions should be used. Intercostal, intrapleural, and epidural analgesic administration can be used in conjunction with or as an alternative to systemic opioid administration. Thoracic epidural analgesia, while not widely used in veterinary medicine, has been associated with reduced mortality in people with rib fractures.50 Gabapentin has not been shown to be superior to placebo in people with rib fractures, but studies in dogs and cats are indicated.51

Antimicrobial Therapy Based on the reported low incidence of pneumonia after pulmonary contusions (1%),7 indiscriminate use of antimicrobial agents should be avoided to limit bacterial resistance. In the small number of patients that do develop bacterial pneumonia, antibiotic therapy should be based on culture and susceptibility testing results of airway cytology (see Chapter 24, Pneumonia).

Glucocorticoids There are little supportive data for glucocorticoid use in the treatment of pulmonary contusions. Although some animal studies have shown a reduction in hypoxemia and lesion size after steroid administration,52 others have shown no benefit.53 Because of their potential deleterious effects, including increased susceptibility to infection and gastrointestinal ulceration, and the lack of positive effects on outcome, these agents are not recommended for the routine management of pulmonary contusions.

Other Therapies Pulmonary contusion continues to be a significant cause of morbidity and mortality despite the standard management strategies described earlier. Ongoing research continues to identify improved treatment options. Clinically, the combined administration of vitamins C and E has been associated with improved arterial blood gas parameters and a reduction in ICU stay for people with lung contusions,54 and the use of surfactant has been proven to improve both oxygenation and compliance in patients with severe pulmonary contusions.55 Experimental studies suggest that dexmedetomidine improves hemodynamics, reduces the presence of inflammatory cells in the alveolar spaces, and modifies the inflammatory response by interfering with cytokine release.56 Melatonin has been found to cause improved histopathology from pulmonary contusions and distant organs by diminishing oxidative stress,57 and salbutamol may reduce edema, hemorrhage, leukocyte infiltration, and total lung injury score.58 The utility of these therapies in veterinary clinical patients is unknown.

PROGNOSIS AND OUTCOME Outcome is related to the severity of pulmonary contusions as well as any coexisting thoracic and extrathoracic lesions. Survival rates of 82%

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have been described,7 although the true survival rate may be lower because some of the most severely affected animals die before reaching a veterinary facility or before a diagnosis is made. Patients may require hospitalization for periods ranging from a few hours to several days, and oxygen supplementation can be required for several days to weeks. In more severely affected patients, two retrospective studies have shown that approximately 30% of dogs requiring mechanical ventilation for contusions survived to discharge.7,37 It is possible that newer lung-protective ventilatory strategies could improve outcomes. Although the long-term prognosis for animals with pulmonary contusions has not been investigated, most animals that survive to discharge do not have residual long-term sequelae. In people, even patients with severe injuries requiring ventilation show a substantial recovery, with postexercise oxygen saturations returning to normal values.59

TABLE 26.1  Etiologies of Atraumatic

ATRAUMATIC PULMONARY HEMORRHAGE

Coagulation abnormalities

Atraumatic pulmonary hemorrhage may occur secondary to a diverse range of disease conditions (Table 26.1). Although hemoptysis may occur in animals with pulmonary hemorrhage, it is an uncommon initial finding in small animals,60 and pulmonary hemorrhage cannot be ruled out based on the absence of this symptom. In a population of cats undergoing airway cytologic analysis for a variety of disease conditions, pulmonary hemorrhage was identified in 63% of cases; the incidence of hemoptysis was not reported.61

DIAGNOSTIC EVALUATION Pulmonary hemorrhage is identified by hemoptysis or hemorrhage on cytologic samples from tracheal, bronchial, or bronchoalveolar washes. The emergency clinician must be careful to distinguish true hemoptysis from hematemesis or bleeding from a source cranial to the larynx (nasal cavity, oropharynx). When using cytology specimens, acute hemorrhage is defined by the presence of red blood cells and white blood cells in proportions similar to those in peripheral blood. Platelets may be present but tend to disappear within minutes after the hemorrhagic event. Within minutes to hours, erythrophagocytosis is present within the macrophages. Considering the diverse range of differential diagnoses, a thorough and careful diagnostic evaluation, including full history, diligent physical examination, and clinicopathologic testing and imaging, may be required to reach the correct diagnosis. Historical information suggests certain diagnoses may include exposure to toxins such as rodenticides or animals living in or having traveled to areas with a high incidence of certain infectious diseases (e.g., heartworms, lungworms, leptospirosis). Location may also support exposure to envenomation (such as the eastern brown snake in Australia). The influence of any concurrent drug therapy should be considered, such as high doses of glucocorticoids, especially in patients that are at risk for pulmonary thromboembolism. Historical information may also be suggestive of chronic medical conditions and may guide and inform further testing. The patient’s signalment may suggest an increased possibility of certain coagulopathies, such as von Willebrand disease in Doberman Pinschers. The physical examination of animals with pulmonary hemorrhage may reveal clinical signs limited to the respiratory system, including hemoptysis, dyspnea, tachypnea, cough, and abnormal auscultation findings. Adventitious lung sounds are variable but may include focal or generalized harsh lung sounds progressing to crackles, focal muffled lung sounds corresponding to areas with consolidation or complete filling of the small airways, or wheezes. Heart murmurs or cardiac

Pulmonary Hemorrhage and Examples of Each Infectious

Bacterial

Leptospirosis53 Escherichia coli61 Streptococcus equi subsp. Zooepidemicus62

Fungal

—

Mycoplasmal

—

Parasitic

Heartworms (Dirofilaria spp.) Lungworms (Angiostrongylus vasorum)

Viral

—

Defects of primary hemostasis

Thrombocytopathia

Defects of secondary hemostasis

Anticoagulant rodenticide toxicity

Severe thrombocytopenia Uremia Hepatic failure

von Willebrand disease Hemophilia Thromboembolism

Cushing disease Diabetes mellitus Nephrotic syndrome Glucocorticoid therapy

Cardiac

Heart failure Pulmonary hypertension

—

Neoplasia

Primary Metastatic

—

Anatomic

Lung lobe torsion

—

Environmental

Aspiration pneumonia Foreign body

—

Miscellaneous

Exercise-induced pulmonary hemorrhage in racing Greyhounds Pulmonary-renal syndrome Postseizure67

Glomerulonephritis68

Iatrogenic

Fine-needle aspiration Percutaneous biopsy

—

Toxic

Envenomations

Eastern brown snake69

arrhythmias may also be noted a