Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application [2nd Edition] 9780323568869

Table of contents :
Section 1. Basic Principles of Pharmacology

1. Mechanisms of Drug Action

2. Pharmacokinetics and Pharmacodynamics for Intravenous Anesthetics

3. Pharmacokinetics and Pharmacodynamics of Inhaled Anesthetics

4. Drug Metabolism and Pharmacogenetics

5. Physiology and Pharmacology of Obesity, Prematurity, and Aging

6. Pharmacodynamic Drug Interactions

7. Adverse Drug Reactions

Section 2. Nervous System

8. Central Nervous System Physiology: Neurophysiology

9. Central Nervous System Physiology: Cerebrovascular

10. Pharmacology of Intravenous Anesthetics

11. Pharmacology of Inhaled Anesthetics

12. Neuropharmacology

13. Autonomic Nervous System: Physiology

14. Autonomic Nervous System: Pharmacology

15. Thermoregulation

16. Physiology of Pain

17. Intravenous Opioid Agonists and Antagonists

18. Oral and Non-Intravenous Opioids

19. Non-Opioid Analgesics and Anti-Inflammatory Drugs

20. Local Anesthetics

21. Neuromuscular Physiology and Pharmacology

22. Neuromuscular Blockers and Reversal Drugs

Section 3. Cardiovascular System

23. Cardiovascular Physiology: Cellular and Molecular Regulation

24. Cardiovascular Physiology: Integrative Function

25. Vasopressors and Inotropes

26. Antihypertensive Drugs and Vasodilators

27. Anti-arrhythmic Drugs

28. Cardiopulmonary Resuscitation

Section 4. Pulmonary System

29. Pulmonary Physiology

30. Pulmonary Pharmacology

Section 5. Gastrointestinal and Endocrine Systems

31. Liver and Gastrointestinal Physiology

32. Liver and Gastrointestinal Pharmacology

33. Nutritional and Metabolic Therapy

34. Pharmacology of Postoperative Nausea and Vomiting

35. Endocrine Physiology

36. Endocrine Pharmacology

37. Physiology and Pharmacology of Obstetric Anesthesia

Section 6. Immunity and Infection

38. Chemotherapy, Immunosuppression, and Anesthesia

39. Infection, Antimicrobial Drugs and Anesthesia

Section 7. Fluid, Electrolyte and Hematologic Homeostasis

40. Renal Physiology

41. Intravascular Volume: Regulation and Replacement Therapy

42. Electrolytes and Diuretics

Section 8. Blood and Hemostasis

43. Blood and Coagulation

44. Transfusion and Coagulation Therapy

45. Antiplatelet and Anticoagulant Therapy

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FOR AND

PHARMACOLOGY PHYSIOLOGY ANESTHESIA

FOUNDATIONS AND CLINICAL APPLICATION

Second Edition

FOR AND

PHARMACOLOGY PHYSIOLOGY ANESTHESIA

FOUNDATIONS AND CLINICAL APPLICATION Hugh C. Hemmings, Jr., MD, PhD, FRCA Joseph F. Artusio Jr. Professor and Chair of Anesthesiology Professor of Pharmacology Senior Associate Dean for Research Weill Cornell Medicine Anesthesiologist-in-Chief NewYork-Presbyterian Hospital Adjunct Professor The Rockefeller University New York, New York

Talmage D. Egan, MD Professor and Chair of Anesthesiology Adjunct Professor of Pharmaceutics, Bioengineering, and Neurosurgery K.C. Wong Presidential Endowed Chair Holder University of Utah School of Medicine Salt Lake City, Utah

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

PHARMACOLOGY AND PHYSIOLOGY FOR ANESTHESIA: FOUNDATIONS AND CLINICAL APPLICATION, Second Edition

ISBN 978-0-323-48110-6

Copyright © 2019 by Elsevier, Inc. All rights reserved. Previous edition copyrighted 2013 by Saunders, an affiliate of Elsevier, Inc. 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).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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. Library of Congress Cataloging-in-Publication Data Names: Hemmings, Hugh C., Jr., editor. | Egan, Talmage D., editor. Title: Pharmacology and physiology for anesthesia : foundations and clinical application / [edited by] Hugh C. Hemmings, Jr., Talmage D. Egan. Description: Second edition. | Philadelphia, PA : Elsevier, Inc., [2019] | Includes bibliographical references and index. Identifiers: LCCN 2017060069 | ISBN 9780323481106 (hardcover : alk. paper) Subjects: | MESH: Anesthesia | Pharmacological Phenomena | Physiological Phenomena Classification: LCC RD82 | NLM WO 200 | DDC 617.9/6—dc23 LC record available at https://lccn.loc.gov/2017060069

Senior Content Strategist: Sarah Barth Senior Content Development Specialist: Joan Ryan Publishing Services Manager: Catherine Jackson Senior Project Manager: Sharon Corell Book Designer: Ryan Cook

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

To my wife, Katherine, and daughter, Emma, whose support and understanding were essential to the completion of this book; and to my mentors and students who have taught me so much and from whom I continue to learn. H.C. Hemmings, Jr. To my wife, Julie, and our children, James, Adam, Ezekiel, Sarajane, and Elizabeth— I am the luckiest; to my mentors Drs. Merritt Egan, Glen Church, K.C. Wong, Mike Cabalan, Don Stanski, and Steve Shafer— you are the wind beneath my wings. T.D. Egan

Contributors

Contributors Associate Editors: Physics Sections

Anatomy and Imaging Sections

Kai Kuck, PhD

Jeffrey D. Swenson, MD

Geoffrey W. Abbott, PhD Professor Department of Pharmacology University of California, Irvine Irvine, California

Edward A. Bittner, MD, PhD Assistant Professor of Anesthesia Harvard Medical School Program Director Critical Care Fellowship Department of Anesthesia, Critical Care, and Pain Medicine Massachusetts General Hospital Boston, Massachusetts

Martin S. Angst, MD Professor of Anesthesiology, Perioperative and Pain Medicine Stanford University School of Medicine Stanford, California Sherif I. Assaad, MD Assistant Professor of Anesthesiology Department of Anesthesiology Yale University, School of Medicine New Haven, Connecticut; Attending Anesthesiologist Department of Anesthesiology Veterans Affairs Healthcare System West Haven, Connecticut Ani Bagdasarjana, PharmD Clinical Pharmacist Department of Pharmacy University of California Los Angeles Medical Center Los Angeles, California Travis Bailey, BS Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Renee Bassaly, DO Morsani College of Medicine University of South Florida Tampa, Florida Jonathan Bilmen, MBChB(Hons), BMedSc(Hons), FRCA, PhD Consultant Anaesthetist Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom

Daniel Bolliger, MD Department for Anesthesia Surgical Intensive Care Prehospital Emergency Medicine and Pain Therapy University Hospital Basel Basel, Switzerland Michelle Braunfeld, MD Professor and Vice Chair Department of Anesthesiology and Perioperative Medicine David Geffen School of Medicine University of California, Los Angeles; Chief Department of Anesthesiology Greater Los Angeles Veterans Hospital Los Angeles, California Shane E. Brogan, MB, BCh Associate Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Kyle Burke, BS Departments of Anesthesiology and Bioengineering University of Utah School of Medicine Salt Lake City, Utah Michael Cahalan, MD Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

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Contributors

June M. Chan, MB BS, FANZCA Assistant Professor Department of Anesthesiology Weill Cornell Medicine Attending Anesthesiologist NewYork-Presbyterian Hospital New York, New York Ben Chortkoff, MD Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah George J. Crystal, PhD Professor Department of Anesthesiology University of Illinois College of Medicine Chicago, Illinois Jennifer A. DeCou, MD Associate Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Rebecca Desso, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah John C. Drummond, MD, FRCPC Professor of Anesthesiology University of California, San Diego Staff Anesthesiologist Veterans Affairs Medical Center San Diego, California

Charles W. Emala, Sr., MS, MD Henrik H. Bendixen Professor of Anesthesiology Vice Chair for Research Department of Anesthesiology Columbia University New York, NY Katherine T. Forkin, MD Assistant Professor of Anesthesiology Department of Anesthesiology University of Virginia Health System Charlottesville, Virginia Tong J. Gan, MD, MHS, FRCA Professor and Chairman Department of Anesthesiology Stony Brook University Stony Brook, New York Paul S. García, MD, PhD Department of Anesthesiology Emory University School of Medicine Atlanta VA Medical Center Atlanta, Georgia Peter Gerner, MD Professor and Chairman Department of Anesthesiology, Perioperative Medicine, and Intensive Care Salzburg General Hospital Paracelsus Medical University Salzburg, Austria Jacqueline A. Hannam, Ph.D., BSc (Hons) Lecturer Department of Pharmacology and Clinical Pharmacology The University of Auckland Auckland, New Zealand

Thomas J. Ebert, MD, PhD Vice Chair for Education Professor of Anesthesiology and Residency Program Director Anesthesiology Medical College of Wisconsin Milwaukee, Wisconsin

Paul M. Heerdt, MD, PhD Professor of Anesthesiology and Pharmacology Weill Cornell Medicine Member, Anesthesiology and Critical Care Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Talmage D. Egan, MD Professor and Chair of Anesthesiology Adjunct Professor of Pharmaceutics, Bioengineering, and Neurosurgery K.C. Wong Presidential Endowed Chair Holder University of Utah School of Medicine Salt Lake City, Utah

Hugh C. Hemmings, Jr., MD, PhD, FRCA Joseph F. Artusio Jr. Professor and Chair of Anesthesiology Professor of Pharmacology Senior Associate Dean for Research Weill Cornell Medicine Anesthesiologist-in-Chief NewYork-Presbyterian Hospital Adjunct Professor The Rockefeller University New York, New York

Matthias Eikermann, MD, PhD Professor of Anesthesia and Vice Chair Department of Anesthesia, Critical Care, and Pain Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

Contributors

Karl F. Herold, MD, PhD Research Associate Department of Anesthesiology Weill Cornell Medicine New York, New York Soeren Hoehne, Dipl.-Ing. Senior Biomedical Research Engineer Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Harriet W. Hopf, MD Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Philip M. Hopkins, MBBS, FRCA, MD Professor of Anaesthesia University of Leeds Honorary Consultant Anaesthetist Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Elizabeth Horncastle, MBChB Specialist Trainee Department of Anaesthesia Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Andrew E. Hudson, MD, PhD Assistant Professor-in-Residence Anesthesiology and Perioperative Medicine University of California, Los Angeles David Geffen School of Medicine Los Angeles, California Julie L. Huffmyer, MD Associate Professor of Anesthesiology Department of Anesthesiology University of Virginia Health System Charlottesville, Virginia Natalia S. Ivascu, MD Associate Professor of Clinical Anesthesiology Weill Cornell Medicine New York, New York Robert H. Jenkinson, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Ken B. Johnson, MD Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

Joel O. Johnson, MD, PhD Professor of Anesthesiology University of Wisconsin Hospital and Clinics Madison, Wisconsin Abhinav Kant, MD, MBBS, FRCA, FHEA Consultant in Anaesthesia and Critical Care Harrogate and District NHS Foundation Trust Harrogate, North Yorkshire, Great Britain Mark T. Keegan, MB, MRCPI, MSc Professor of Anesthesiology Division of Critical Care Mayo Clinic and Mayo Clinic College of Medicine Rochester, Minnesota Patrick Kolbay, BS Departments of Anesthesiology and Bioengineering University of Utah School of Medicine Salt Lake City, Utah Kai Kuck, PhD Professor of Anesthesiology Adjunct Professor of Bioengineering Harry C. Wong Presidential Endowed Chair Director of Bioengineering Research Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Shreyajit R. Kumar, MD Assistant Professor of Clinical Anesthesiology Division of Critical Care Medicine Weill Cornell Medicine New York, New York James P. Lee, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Brian P. Lemkuil, MD Director of Neuroanesthesia and Neurocritical Care University of California, San Diego San Diego, California Roberto Levi, MD, DSc Professor Department of Pharmacology Weill Cornell Medicine New York, New York Jerrold H. Levy, MD, FAHA, FCCM Professor of Anesthesiology Professor of Surgery (Cardiothoracic) Co-Director Cardiothoracic ICU Duke University Hospital Durham, North Carolina

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x

Contributors

Cynthia A. Lien, MD John P. Kampine Professor and Chair Department of Anesthesiology Medical College of Wisconsin Milwaukee, Wisconsin

Jennifer Nguyen-Lee, MD Assistant Clinical Professor David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Philipp Lirk, MD, PhD Attending Anesthesiologist Brigham and Women’s Hospital Associate Professor of Anesthesia Harvard Medical School Boston, Massachusetts

Shinju Obara, MD, PhD Assistant Professor of Anesthesiology Fukushima Medical University, School of Medicine Deputy Director Intensive Care Department Fukushima Medical University Hospital Fukushima, Fukushima Prefecture, Japan

Andrew B. Lumb, MB, BS, FRCA Consultant Anaesthetist Department of Anaesthesia St. James’s University Hospital Leeds, United Kingdom Srinand Mandyam, MD Georgia Pain and Wellness Lawrenceville, Georgia Robert G. Martindale, MD, PhD Professor of Surgery Chief of Gastrointestinal and General Surgery Medical Director Hospital Nutritional Service Professor of Surgery Division of Gastrointestinal and General Surgery School of Medicine OHSU Healthcare Portland, Oregon J.A. Jeevendra Martyn, MD, FRCA, FCCM Professor of Anesthesiology Harvard Medical School Anesthetist-in-Chief Shriners Hospital for Children Boston, Massachusetts Joseph S. Meltzer, MD Associate Clinical Professor of Anesthesiology and Perioperative Medicine University of California, Los Angeles David Geffen School of Medicine Los Angeles, California Edward C. Nemergut, MD Professor of Anesthesiology and Neurosurgery Department of Anesthesiology University of Virginia Health System Charlottesville, Virginia Christine T. Nguyen-Buckley, MD Clinical Instructor David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Daniel W. Odell, MD Assistant Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Takahiro Ogura, MD, PhD Research Fellow Department of Anesthesiology National Defense Medical College Tokorozawa, Saitama, Japan Japan Maritime Self Defense Force Hospital Yokosuka, Kanagawa Prefecture, Japan Shannon M. Page, MD Assistant Professor Department of Anesthesia Duke University Medical Center Durham, North Carolina Hahnnah Park, BS Department of Anesthesiology David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Piyush M. Patel, MD, FRCPC Professor of Anesthesiology University of California, San Diego Staff Anesthesiologist Veterans Affairs Medical Center San Diego, California Misha Perouansky, MD Professor Anesthesiology and Perioperative Care University of Wisconsin SMPH Madison, Wisconsin Nicholas Pierson, MD Assistant Professor Department of Radiology University of Utah School of Medicine Salt Lake City, Utah

Contributors

Alex Proekt, MD, PhD Assistant Professor Department of Anesthesiology University of Pennsylvania Philadelphia, Pennsylvania

John W. Sear, MD, PhD, MBBS Professor Nuffield Department of Anaesthetics University of Oxford Oxford, Great Britain

Kane O. Pryor, MD Assistant Professor in Anesthesiology Assistant Professor of Anesthesiology in Psychiatry Weill Cornell Medicine New York, New York

Peter S. Sebel, MD, PhD, MBA Department of Anesthesiology Emory University School of Medicine Atlanta, Georgia

Daniel Pulsipher, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Aeyal Raz, MD, PhD Department of Anesthesiology University of Wisconsin Madison, Wisconsin; Department of Anesthesiology Rabin Medical Center Petah-Tikva, Israel Paul M. Riegelhaupt, MD, PhD Assistant Professor of Anesthesiology Associate Program Director Anesthesiology Residency Weill Cornell Medicine New York, New York Peter Rodhe, PhD, M.Sc.Eng Senior Consultant Karolinska Institutet Department of Clinical Science and Education Unit of Anesthesiology and Intensive Care Stockholm South General Hospital and ÅF Digital Solutions Stockholm, Sweden

xi

Timothy G. Short, MB, ChB, MD, FANZCA Honorary Associate Professor Department of Anesthesia School of Health Sciences University of Auckland Department of Adult and Trauma Anaesthesia Auckland City Hospital Auckland, New Zealand Jill E. Sindt, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah John Skaggs, MD Assistant Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Roman M. Sniecinski, MD Associate Professor of Anesthesiology Division of Cardiothoracic Anesthesiology Emory University School of Medicine Atlanta, Georgia

Derek K. Rogalsky, MD Oregon Health and Science University Portland, Oregon

Randolph H. Steadman, MD Professor and Vice Chair Department of Anesthesiology David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Mark D. Rollins, MD, PhD Professor and Director of Obstetric Anesthesiology Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

David Stenehjem, PharmD, BCOP Associate Professor Department of Pharmacy Practice and Pharmaceutical Sciences University of Minnesota, College of Pharmacy Duluth, Minnesota

David Royston, FRCA Consultant in Cardiothoracic Anaesthesia, Critical Care, and Pain Royal Brompton and Harefield NHS Foundation Trust Harefield Hospital Harefield, United Kingdom

Sarah E. Stilwill, MD Assistant Professor Department of Radiology University of Utah School of Medicine Salt Lake City, Utah

Elizabeth Ryals, MD Department of Radiology University of Utah School of Medicine Salt Lake City, Utah

Kingsley P. Storer, MD, PhD Assistant Professor of Anesthesiology Weill Cornell Medicine New York, New York

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Contributors

Bradley Stringer, MS Departments of Anesthesiology and Bioengineering University of Utah School of Medicine Salt Lake City, Utah Suzuko Suzuki, MD Anesthesiologist Eastside Anesthesia New York, New York Christer Svensen, MD, PhD, EDA, MBA Professor Director of Doctoral Education Senior Consultant Karolinska Institutet Department of Clinical Science and Education Unite of Anaesthesiology and Intensive Care Stockholm South General Hospital Stockholm, Sweden Jeffrey D. Swenson, MD Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Christopher W. Tam, MD Assistant Professor of Clinical Anesthesiology Department of Anesthesiology Weill Cornell Medicine New York, New York Kenichi A. Tanaka, MD, MSc Department of Anesthesiology University of Maryland Baltimore, Maryland

Elizabeth Thackeray, MD Associate Professor Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah Ian Welsby, MBBS Associate Professor of Anesthesiology Department of Anesthesiology and Critical Care Duke University School of Medicine Durham, North Carolina Matthew K. Whalin, MD, PhD Department of Anesthesiology Emory University School of Medicine Atlanta, Georgia Eric S. Zabirowicz, MD Assistant Professor Department of Anesthesiology Stony Brook University Stony Brook, New York Khaled J. Zaza, MD College of Medicine Alfaisal University Riyadh, Saudi Arabia Josh Zimmerman, MD, FASE Associate Professor Director, Perioperative Echocardiography Director, Preoperative Clinic Department of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

Preface to the Second Edition

Preface to the Second Edition

We are delighted to present the updated and revised Second Edition of Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application. Like its predecessor, this new edition’s primary aim is to bridge the gap between introductory texts and comprehensive reference books by providing an in-depth overview of pharmacology and physiology for anesthesiology, intensive care, and pain medicine specialists, whether in training or practicing. The topics are chosen to cover fundamentals included in training and recertification examinations by bridging scientific principles and clinical practice. The Second Edition has been thoroughly updated. Each revised chapter includes the latest advances in clinical science along with relevant, novel basic science discoveries. Hundreds of new segments, figures, and references have been added to provide essential information for trainees and practicing anesthetists alike. This thoroughly revised edition includes extensive new content. New chapters on special populations (e.g., anesthetic pharmacology in obesity, geriatrics, and pediatrics), oral and non-intravenous opioids, thermoregulation, physiology and pharmacology of obstetric anesthesia, chemotherapeutic and immunosuppressive drugs, and surgical infection and antimicrobial drugs were commissioned and written by recognized experts in these fields. Two entirely new features have been incorporated into the Second Edition to provide essential basic information in relevant areas of physics, anatomy, and imaging. The Physics sections, edited

by Dr. Kai Kuck, review essential physics and engineering concepts important in anesthesia practice. The Anatomy and Imaging sections, edited by Dr. Jeffrey D. Swenson, outline practical anatomic and imaging concepts that are now indispensable in modern anesthesia. Interspersed throughout the book, these new sections are beautifully and copiously illustrated. The Second Edition also benefits from all the enhancements that are part of the “Expert Consult” platform at Elsevier, including the “eBook” feature that enables portability and searchability on most common electronic devices; the book’s full text and all the other assets are available anywhere on your mobile device. Shareable social media features also augment the Second Edition’s utility. We are grateful to the authors for their contributions to the Second Edition; their high-level knowledge and expertise are evident throughout. We also express our appreciation to the dedicated professionals at Elsevier; special thanks are due to Sarah Barth, William Schmitt, Joan Ryan, and Sharon Corell for their collective experience and hard work. We are confident that the newly updated and expanded Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application will build your understanding of the fundamental concepts underpinning anesthesia practice and thereby improve your ability to deliver outstanding care to your patients. Hugh C. Hemmings, Jr. Talmage D. Egan

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Excerpts from the Preface to the First Edition

Excerpts from the Preface to the First Edition

The successful practice of the art of anesthesia, critical care, and pain medicine demands a sound understanding of core scientific concepts founded in physiology and pharmacology. The importance of physiology and pharmacology to anesthesiology is recognized in postgraduate anesthesia training programs and certification examinations worldwide because a thorough understanding of these disciplines is essential for graduation, certification, and successful clinical practice. Although this scientific foundation is available from a number of sources, the necessary level of detail is often insufficient in introductory texts and perhaps too esoteric in specialized monographs targeted to academics. The goal of Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application is to bridge this gap between introductory texts and comprehensive reference books by providing a detailed overview of these fundamental subject areas for anesthesiologists, intensivists, and pain practitioners, both in training and in practice. Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application is intended to be a definitive source for in-depth coverage of these core basic and clinical sciences in a single text. Focusing on physiology, pharmacology, and molecular-cellular biology, the text’s approach is integrated and systems oriented, avoiding the artificial boundaries between the basic and clinical sciences. The book is divided into eight sections: Basic Principles of Pharmacology; Nervous System; Cardiovascular System; Pulmonary System; Gastrointestinal and Endocrine Systems; Immunity and Infection; Fluid, Electrolyte, and Hematologic Homeostasis; and Blood and Hemostasis. Recognizing that no single author possesses the necessary breadth and depth of understanding in all the core subject areas, each chapter is authored by an expert representing many of the finest institutions of North America, the United Kingdom, Europe, and Asia. This allows an international presentation of current anesthesia

science presented by recognized experts at the cutting edge of anesthesia research and education. A number of features significantly enhance the use of Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application as a tool for learning, teaching, and review. These include access to the online text via the Expert Consult platform, including a complete, downloadable image bank. Recognizing that graphics are often the most expressive and effective way of conveying concepts, full-color illustrations facilitate use of the book as a learning aid and make it enjoyable to read. The text is copiously illustrated; all figures having been drawn or redrawn by the superb artists at Elsevier. Each chapter stresses the scientific principles necessary for the understanding and management of various situations encountered in anesthesia practice. Detailed explanations of clinical techniques are avoided because this information is available in many comprehensive and subspecialty clinical anesthesia texts and handbooks. This book is not intended to provide a detailed review of specialized research areas for the scientist. Rather, the fundamental information necessary to understand essential concepts and principles is stressed, and basic science concepts are related to relevant clinical anesthesia applications. Chapters are self-contained with minimal repetition and include a short list of key points for review and key references to stimulate further exploration of interesting topics. The expertise and hard work of the contributing authors is evident in the quality of each chapter. We are confident that Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application will help solidify your understanding of core anesthesia topics and thereby improve the safety and effectiveness of the care you render to your patients. Hugh C. Hemmings, Jr. Talmage D. Egan

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Section I Basic Principles of Pharmacology 1

11

Pharmacology of Inhaled Anesthetics, 217 Andrew E. Hudson, Karl F. Herold, and Hugh C. Hemmings, Jr.

Mechanisms of Drug Action, 2 Alex Proekt and Hugh C. Hemmings, Jr.

2

Shinju Obara and Talmage D. Egan

3

12

Drugs for Neuropsychiatric Disorders, 241 Kane 0. Pryor and Kingsley P. Storer

13

Autonomic Nervous System: Physiology, 270 Joel 0. Johnson

14

Autonomic Nervous System Pharmacology, 282

Pharmacokinetic and Pharmacodynamic Principles for Intravenous Anesthetics, 20

Pharmacoklnetlcs of Inhaled Anesthetics, 44 Andrew E. Hudson and Hugh C. Hemmings, Jr. PHYSICS: LIQUIDS, VAPORS, GASES, ANDTHE GASLAWS,60 Kai Kuck

Thomas J. Ebert

15

PHYSICS: MONITORING GAS CONCENTRATIONS, 66 Kyle Burk and Kai Kuck

4

Drug Metabolism and Pharmacogenetics, 70

Khaled J. Zaza and Ha"iet W. Hopf

16

JuneM.Chan

5

Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly, 91

Pharmacodynamlc Drug Interactions, 113

17

Adverse Drug Reactions, 130 Abhinav Kant, Jonathan Bi/men, and Philip M. Hopkins

Intravenous Opioid Agonists and Antagonists, 332 Takahiro Ogura and Talmage D. Egan

18

Timothy G. Short and Jacqueline A. Hannam

7

Nociceptive Physiology, 311 Paul M. Riegelhaupt and Martin S. Angst

Ken B. Johnson, Travis Bailey, and Elizabeth Thackeray

6

Thermoregulation: Normal Physiology, Anesthetic Effects, and Perioperative Considerations, 300

Nonintravenous Opioids, 354 Jill E. Sindt and Robert H. Jenkinson

19

Nonopioid Analgesics, 369 Shane E. Brogan, Srinand Mandyam, and Daniel W. Odell

Section II Nervous System 8

Central Nervous System Physiology: Neurophysiology, 145

20

Suzuko Suzuki, Peter Gerner, and Philipp Lirk PHYSICS: MEDICAL ULTRASOUND, 409 Bradley Stringer and Kai Kuck

Aeyal Raz and Misha Perouansky PHYSICS: BASIC ELECTRONICS AND ELECTRICAL HAZARDS, 170 Kai Kuck

9

Central Nervous System Physiology: Cerebrovascular, 174 Brian P. Lemkuil John C. Drummond, and Piyush M. Patel ANATOMY AND IMAGING: THE NERVOUS SYSTEM, 188 Nicholas Pierson, Sarah E. Stilwill Elizabeth Ryals, and Jeffrey D. Swenson

21

Neuromuscular Physiology and Pharmacology, 412 Edward A. Bittner andJ.A. Jeevendra Martyn

22

Neuromuscular Blockers and Reversal Drugs, 428 Cynthia A. Lien and Matthias Eikermann

Section Ill Cardiovascular System 23

10

Local Anesthetics, 390

Pharmacology of Intravenous Anesthetics, 193

cardiovascular Physiology: Cellular and Molecular Regulation, 456

Paul S. Garcia, Matthew K. Whalin, and Peter S. Sebel

Sherif I. Assaad, Paul M. Heerdt and George J. Crystal

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24

Contents

Cardiovascular Physiology: Integrative Function, 473

33

Nutritional and Metabolic Therapy, 657 Derek K. Rogalsky and Robert G. Martindale

George J. Crystal, Sherif I. Assaad, and Paul M. Heerdt ANATOMY AND IMAGING: THE CARDIOVASCULAR SYSTEM,500 Rebecca Desso andJeffrey D. Swenson PHYSICS: FLUID DYNAMICS, 51 O Patrick Ko/bay and Kai Kuck PHYSICS: INVASIVE AND NONINVASIVE BLOOD PRESSURE MEASUREMENT, 514 Jennifer A. Decou and Kai Kuck

25

Vasopressors and lnotropes, 520

34

Eric S. Zabirowicz and Tong J. Gan

35

Antlhypertenslve Drugs and Vasodilators, 535 John W.Sear

27

Antlarrhythmlc Drugs, 556

36

Cardiopulmonary Resuscitation, 575 Christopher W. Tam, Shreyajit R. Kumar, and Natalia S. lvascu

37

Pulmonary Physiology, 586 Andrew B. Lumb and Elizabeth Horncastle

Section VI Immunity and Infection 38

Chemotherapy, lmmunosuppresslon, and Anesthesia, 753 Ben Chortkaffand David Stenehjem

39

Infection, Antimicrobial Drugs, and Anesthesia, 769 Khaled J. Zaza and Harriet W. Hopf

Section VII Fluid, Electrolyte, and Hematologic Homeostasis

ANATOMY AND IMAGING:THETHORACICWALL, INTERCOSTAL SPACE, AND THORAX, 599 Jeffrey D. Swenson and John Skaggs

40

PHYSICS: BLOOD GAS MEASUREMENT, 603 Kai Kuck

41

PHYSICS: REGULATORS, MEDICAL GAS CYLINDERS, AND PRESSURE MEASUREMENT OF GASES, 606 Daniel Pulsipher and Kai Kuck

42

PHYSICS: PULSE OXIMETRY, 609 Soeren Hoehne and Kai Kuck

Section VIII Blood and Hemostasis

Renal Physiology, 782 Joseph S. Meltzer

lntravascularVolume Replacement Therapy, 795 Christer Svensen and Peter Rodhe

Electrolytes and Diuretics, 814 Christer Svensen

43 30

Physiology and Pharmacology of Obstetric Anesthesia, 732 Shannon M. Page and Mark D. Rollins

Section IV Pulmonary System 29

Endocrine Pharmacology, 708 Mark T. Keegan

Geoffrey W. Abbott and Roberto Levi

28

Endocrine Physiology, 693 Katherine T. Forkin, Julie L. Huffmyer, and Edward C Nemergut

Josh Zimmerman, James P. Lee, and Michael Cahalan

26

Pharmacology of Postoperative Nausea and Vomiting 671

Pulmonary Pharmacology, 613

Blood and Coagulation, 837 Jerrold H. Levy, Roman M. Sniecinski, and Ian Welsby

Charles W. Ema/a, Sr.

44 Transfusion and Coagulation Therapy, 849

Section V Gastrointestinal and Endocrine Systems 31

Liver and Gastrointestinal Physlology, 630 Randolph H. Steadman, Michelle Braunfeld, and Hahnnah Park

32

Liver and Gastrointestinal Pharmacology, 645 Jennifer Nguyen-Lee, Christine T. Nguyen-Buckley, and Ani Bagdasarjana

Kenichi A. Tanaka and Daniel Bolliger

45

Anticoagulant and Antiplatelet Therapy, 870 David Royston

PHARMACOLOGY ~PHYSIOLOGY ~ANESTHESIA FOUNDATIONS AND CLINICAL APPLICATION

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1 CHAPTER OUTLINE The Receptor Concept

Historical Beginnings Modern Development Pharmacodynamics

Drug Binding From Drug Binding to Physiologic Effect Efficacy

Full Agonists, Partial Agonists, and Inverse Agonists Antagonism Allosteric Drug Interactions Multiple Binding Sites on the Same Receptor Protein Allosteric Binding Sites

Pharmacogenetics Drug Discovery

Structure-Activity Relationship Identification of Drug Targets Purification of Receptors Drug Targets

Cell Signaling Emerging Developments Pharmacophore Modeling Phenotype-Based Drug Discovery

Novel Antidotes

U

nderstanding the basic principles of pharmacology is fundamental to the practice of medicine in general, but is perhaps most relevant to the practice of anesthesiology. It is now widely accepted that cells contain a host of specific receptors that mediate the medicinal properties of drugs. Although the use of plant-derived medicinal compounds dates back to antiquity, the mechanisms by which these drugs act to modify disease processes remained mysterious until relatively recently. As late as 1964, de Jong wrote, "To most of the modern pharmacologists the receptor is like a beautiful but remote lady. He has written her many a letter and quite often she has answered the letters. From these answers the pharmacologist has built himself an image of this fair lady. He cannot, however, truly, claim ever to have seen her, although one day he may do so." 1 This chapter briefly reviews the history of the receptor concept from the abstract notion alluded to by de Jong to the modern view of receptors as specific, identifiable cellular macromolecules to which drugs must bind in order to initiate their effects. Also 2

introduced and defined are basic concepts that describe drug-receptor interactions such as affinity, efficacy, specificity, agonism, antagonism, and the dose-response curve. Finally, the evolving discipline of molecular pharmacology is discussed as it relates to modern drug development. Mathematical representations of the concepts are included in the form of equations for the reader seeking quantitative understanding, although the exp anations of key concepts in the text are intended to be understood without reliance on mathematics.

The Receptor Concept Historical Beginnings % e specificiry of drugs for a particular disease has been known since at least the 17th century. The best known example of this is d ie effi oxygen supply). With reduced coronary reserve, increases in heart rate and preload are detrimental in that both these factors reduce oxygen supply (coronary blood flow) while increasing oxygen demand. An increase in aortic pressure augments myocardial oxygen supply by increasing blood flow, but it also increases myocardial oxygen demand by increasing wall tension.

CHAPTER 24  Cardiovascular Physiology: Integrative Function



Key References Bradley AJ, Alpert JS. Coronary flow reserve. Am Heart J. 1991;122(4 Pt 1):1116–1128. Well-written discussion of the concept of coronary flow reserve: its physiologic underpinnings, measurement, and alterations by disease processes. (Ref. 104). Braunwald E. Control of myocardial oxygen consumption: physiologic and clinical considerations. Am J Cardiol. 1971;27:416–432. A classic paper summarizing the findings obtained in animal models describing factors regulating myocardial oxygen consumption. (Ref. 107). Brutsaert DL, Sys SU. Relaxation and diastole of the heart. Physiol Rev. 1989;69:1228–1315. A critical assessment of the literature relating to events during diastole, the relaxation phase of the cardiac cycle in the normal heart, as well in pathophysiologic scenarios. (Ref. 11). Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol. 2005;289:H501–H512. A discussion of the use of pressure-volume analysis to assess the systolic and diastolic properties of the ventricle. The article provides the theoretical basis of pressure-volume analysis plus practical information and simple guidelines for application and interpretation of pressure-volume data in preclinical and clinical studies. (Ref. 31). Dull RO, Cluff M, Kingston J, et al. Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyxmediated mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2012;302:L816–L828. An animal study about the effect of various pulmonary capillary hydrostatic pressure on capillary permeability and the role of glycocalyx in mediating these changes in pulmonary permeability (Ref. 47). Honig CR. Modern Cardiovascular Physiology. Boston: Little, Brown; 1981. A classic textbook covering a broad range of topics in cardiovascular physiology. It is distinguished by its attention to clinical applications of physiologic principles, and by its reliance on two themes: the concept of margin of safety or reserve of function and a systems-oriented approach. (Ref. 76). Mebazaa A, Karpati P, Renaud E, et al. Acute right ventricular failure—from pathophysiology to new treatments. Intensive Care Med. 2004;30:185–196. A succinct and informative summary of right ventricular function under normal and pathophysiologic conditions. (Ref. 3). Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med. 1987;13:223–229. Discusses the determinants of systemic oxygen delivery (DO2) and how increases in oxygen extraction normally compensate for decreases in DO2 to maintain oxygen consumption constant until a critical threshold is reached, the so-called critical oxygen delivery, under normal and various pathologic conditions. (Ref. 91). Summerhill EM, Baram M. Principles of pulmonary artery catheterization in the critically ill. Lung. 2005;183:209–219. Describes the indications, uses, limitations, and pitfalls in the use of the balloon-tipped pulmonary artery catheter to assess cardiac function and to guide fluid and vasoactive drug therapy in the care of critically ill patients. (Ref. 22). Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng. 2007;9:121–167. An excellent review about the structure and function of the glycocalyx and its role in fluid transport across the capillaries (Ref. 54).

References 1. Rothe C. Cardiodynamics. In: EE S, ed. Physiology. Boston: Little, Brown; 1971:321–344. 2. Guarracino F, Cariello C, Danella A, et al. Right ventricular failure: physiology and assessment. Minerva Anestesiol. 2005;71:307–312. 3. Mebazaa A, Karpati P, Renaud E, et al. Acute right ventricular failure–from pathophysiology to new treatments. Intensive Care Med. 2004;30:185–196.

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4. Price LC, Wort SJ, Finney SJ, et al. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14:R169. 5. Braunwald E, Ross J Jr, Sonnenblick E. Mechanisms of Contraction of the Normal and Failing Heart. Boston: Little, Brown; 1968:72–91, 269–291. 6. Shernan SK. A practical approach to the echocardiographic evaluation of ventricular diastolic function. In: Perrino A, Reeves S, eds. A Practical Approach to Transesophageal Echocardiography. Philadelphia: Lippincott Williams & Wilkins; 2013:138–156. 7. Lang RM, Borow KM, Neumann A, et al. Systemic vascular resistance: an unreliable index of left ventricular afterload. Circulation. 1986;74:1114–1123. 8. Sagawa K. Analysis of the ventricular pumping capacity as function of input and output pressure loads. In: Reeve E, Guyton A, eds. Physical Bases of Circulatory Transport: Regulation and Exchange. Philadelphia: WB Saunders; 1967. 9. Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. N Engl J Med. 1977;297:27–31. 10. Wiggers CJ. Studies on the consecutive phases of the cardiac cycle I. The duration of the consecutive phases of the cardiac cycle and the criteria for their precise determination. Am J Physiol. 1921;56: 415–438. 11. Brutsaert DL, Sys SU. Relaxation and diastole of the heart. Physiol Rev. 1989;69:1228–1315. 12. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105:1387– 1393. 13. Gibson DG, Francis DP. Clinical assessment of left ventricular diastolic function. Heart. 2003;89:231–238. 14. Villars PS, Hamlin SK, Shaw AD, et al. Role of diastole in left ventricular function, I: Biochemical and biomechanical events. Am J Crit Care. 2004;13:394–405. 15. Stewart GN. Researches on the circulation time and on the influences which affect it. J Physiol. 1897;22:159–183. 16. Hamilton WF, Moore JW, Kinsman JM, et al. Simultaneous determination of the pulmonary and systemic circulation times in man and of a figure related to the cardiac output. Am J Physiol. 1928;84:338–344. 17. Hamilton WF, Moore JW, Kinsman JM, et al. Studies on the circulation IV. Further analysis of the injection method, and of changes in hemodynamtcs under physiological and pathological conditions. Am J Physiol. 1932;99:534–551. 18. Reuter DA, Huang C, Edrich T, et al. Cardiac output monitoring using indicator-dilution techniques: basics, limits, and perspectives. Anesth Analg. 2010;110:799–811. 19. Scheinman MM, Abbott JA, Rapaport E. Clinical uses of a flowdirected right heart catheter. Arch Intern Med. 1969;124: 19–24. 20. Swan HJ, Ganz W, Forrester J, et al. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med. 1970;283:447–451. 21. Chatterjee K. The Swan-Ganz catheters: past, present, and future. A viewpoint. Circulation. 2009;119:147–152. 22. Summerhill EM, Baram M. Principles of pulmonary artery catheterization in the critically ill. Lung. 2005;183:209–219. 23. Godje O, Peyerl M, Seebauer T, et al. Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients. Eur J Cardiothorac Surg. 1998;13:533–540. 24. Sakka SG, Ruhl CC, Pfeiffer UJ, et al. Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution. Intensive Care Med. 2000;26:180–187. 25. Mason DT. Usefulness and limitations of the rate of rise of intraventricular pressure (dp-dt) in the evaluation of myocardial contractility in man. Am J Cardiol. 1969;23:516–527.

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SE C T I O N III

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26. Punjani S, Garwood S. Left ventricular systolic performance and pathology. In: Perrino A, Reeves S, eds. A Practical Approach to Transesophageal Echocardiography. Philadelphia: Lippincott Williams & Wilkins; 2013:51–81. 27. Gleason WL, Braunwald E. Studies on the first derivative of the ventricular pressure pulse in man. J Clin Invest. 1962;41: 80–91. 28. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685–713, quiz 786–688. 29. Schertel ER. Assessment of left-ventricular function. Thorac Cardiovasc Surg. 1998;46(suppl 2):248–254. 30. Frank O. Zur Dynamic des Herzmuskels. Z Biol. 1895;32:370–447. 31. Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol. 2005;289:H501–H512. 32. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res. 1973;32:314–322. 33. Fortuin NJ, Pawsey CG. The evaluation of left ventricular function by echocardiography. Am J Med. 1977;63:1–9. 34. Dodge HT, Sandler H, Ballew DW, et al. The use of biplane angiocardigraphy for the measurement of left ventricular volume in man. Am Heart J. 1960;60:762–776. 35. Redington AN, Gray HH, Hodson ME, et al. Characterisation of the normal right ventricular pressure-volume relation by biplane angiography and simultaneous micromanometer pressure measurements. Br Heart J. 1988;59:23–30. 36. Folkow B, Neil E. Circulation. New York: Oxford University Press; 1971:6. 37. Salem MR, Crystal GJ. Pulmonary vascular tone and the anesthesiologist. Middle East J Anaesthesiol. 2011;21:147–151. 38. Messmer K. Hemodilution. Surg Clin North Am. 1975;55: 659–678. 39. Messmer K, Sunder-Plassmann L. Hemodilution. Prog Surg. 1974;13:208–245. 40. Feigl E. Physics of the cardiovascular system. In: Ruch T, Patton H, eds. Physiology and Biophysics II: Circulation, Respiration, and Fluid Balance. Philadelphia: WB Saunders; 1974:10–22. 41. Berne R, Levy M. Principles of Physiology. St. Louis: CV Mosby; 1990:195. 42. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol. 1896;19:312–326. 43. Assaad S, Popescu W, Perrino A. Fluid management in thoracic surgery. Curr Opin Anaesthesiol. 2013;26:31–39. 44. Friedman J. Microcirculation. In: Selkurt E, ed. Physiology. Boston: Little, Brown; 1971:269. 45. Tarbell JM. Shear stress and the endothelial transport barrier. Cardiovasc Res. 2010;87:320–330. 46. West J. Respiratory physiology: The Essentials. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008. 47. Dull RO, Cluff M, Kingston J, et al. Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyxmediated mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2012;302:L816–L828. 48. Zarins CK, Rice CL, Peters RM, et al. Lymph and pulmonary response to isobaric reduction in plasma oncotic pressure in baboons. Circ Res. 1978;43:925–930. 49. Miserocchi G, Negrini D, Passi A, et al. Development of lung edema: interstitial fluid dynamics and molecular structure. News Physiol Sci. 2001;16:66–71. 50. Downs CA, Kriener LH, Yu L, et al. Beta-adrenergic agonists differentially regulate highly selective and nonselective epithelial

sodium channels to promote alveolar fluid clearance in vivo. Am J Physiol Lung Cell Mol Physiol. 2012;302:L1167–L1178. 51. Berger MM, Rozendal CS, Schieber C, et al. The effect of endothelin-1 on alveolar fluid clearance and pulmonary edema formation in the rat. Anesth Analg. 2009;108:225–231. 52. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res. 2010;87:198–210. 53. Adamson RH, Lenz JF, Zhang X, et al. Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J Physiol. 2004;557:889–907. 54. Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng. 2007;9:121–167. 55. Crystal GJ, Salem MR. The Bainbridge and the “reverse” Bainbridge reflexes: history, physiology, and clinical relevance. Anesth Analg. 2012;114:520–532. 56. Sagawa K. Baroreflex control of systemic arterial pressure and vascular bed, handbook of physiology. The cardiovascular system. Peripheral circulation and organ blood flow. Am Physiol Soc. 1983;453–496. 57. Dampney RA. Functional organization of central pathways regulating the cardiovascular system. Physiol Rev. 1994;74:323–364. 58. Rushmer R. Cardiovascular Dynamics. 3rd ed. Philadelphia: Saunders; 1970:165. 59. Aviado DM, Guevara Aviado D. The Bezold-Jarisch reflex. A historical perspective of cardiopulmonary reflexes. Ann N Y Acad Sci. 2001;940:48–58. 60. Campagna JA, Carter C. Clinical relevance of the Bezold-Jarisch reflex. Anesthesiology. 2003;98:1250–1260. 61. Bezold A, Hirt L. Uber die physiologischen Wirkungen des essigsauren Veratrine. Unters Physiol Lab Wurzburg. 1867;1:75–156. 62. Jarisch A, Richter H. Die afferenten bahnen des veratrine effektes in den herznerven. Arch Exp Pathol Pharmacol. 1939;193:355–371. 63. Jarisch A, Richter H. Die kreislauf des veratrins. Arch Exp Pathol Pharmacol. 1939;193:347–354. 64. Thoren PN. Characteristics of left ventricular receptors with nonmedullated vagal afferents in cats. Circ Res. 1977;40:415–421. 65. Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol. 1983;1:90–102. 66. Secher NH, Sander Jensen K, Werner C, et al. Bradycardia during severe but reversible hypovolemic shock in man. Circ Shock. 1984;14:267–274. 67. Secher NH, Jacobsen J, Friedman DB, et al. Bradycardia during reversible hypovolaemic shock: associated neural reflex mechanisms and clinical implications. Clin Exp Pharmacol Physiol. 1992;19:733–743. 68. Oberg B, White S. The role of vagal cardiac nerves and arterial baroreceptors in the circulatory adjustments to hemorrhage in the cat. Acta Physiol Scand. 1970;80:395–403. 69. Oberg B, Thoren P. Increased activity in left ventricular receptors during hemorrhage or occlusion of caval veins in the cat. A possible cause of the vaso-vagal reaction. Acta Physiol Scand. 1972;85:164–173. 70. Bainbridge FA. The influence of venous filling upon the rate of the heart. J Physiol. 1915;50:65–84. 71. Goetz KL. Effect of increased pressure within a right heart cul-de-sac on heart rate in dogs. Am J Physiol. 1965;209:507–512. 72. Ledsome JR, Linden RJ. The effect of distending a pouch of the left atrium on the heart rate. J Physiol. 1967;193:121–129. 73. Boettcher DH, Zimpfer M, Vatner SF. Phylogenesis of the Bainbridge reflex. Am J Physiol. 1982;242:R244–R246. 74. Coleridge JC, Linden RJ. The effect of intravenous infusions upon the heart rate of the anaesthetized dog. J Physiol. 1955;128: 310–319. 75. Nunn J. Nunn’s Applied Respiratory Physiology. Oxford: Butterworth Heinemann; 1993:255. 76. Honig C. Modern Cardiovascular Physiology. Boston: Little, Brown; 1981:181–187.



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77. Weibel E. The Pathway for Oxygen. Cambridge, Mass: Harvard University Press; 1984:149. 78. Krogh A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol. 1919;52:409–415. 79. Kety SS. Determinants of tissue oxygen tension. Fed Proc. 1957;16:666–671. 80. Crystal GJ, Weiss HR. V̇ O2 of resting muscle during arterial hypoxia: role of reflex vasoconstriction. Microvasc Res. 1980;20: 30–40. 81. Crystal GJ, Downey HF, Bashour FA. Small vessel and total coronary blood volume during intracoronary adenosine. Am J Physiol. 1981;241:H194–H201. 82. Tenney SM. A theoretical analysis of the relationship between venous blood and mean tissue oxygen pressures. Respir Physiol. 1974;20:283–296. 83. Nunn JF, Makita K, Royston B. Validation of oxygen consumption measurements during artificial ventilation. J Appl Physiol. 1985;67:2129–2134, 1989. 84. Makita K, Nunn JF, Royston B. Evaluation of metabolic measuring instruments for use in critically ill patients. Crit Care Med. 1990;18:638–644. 85. Smithies MN, Royston B, Makita K, et al. Comparison of oxygen consumption measurements: indirect calorimetry versus the reversed Fick method. Crit Care Med. 1991;19:1401–1406. 86. Webster NR, Nunn JF. Molecular structure of free radicals and their importance in biological reactions. Br J Anaesth. 1988;60: 98–108. 87. Astiz ME, Rackow EC, Kaufman B, et al. Relationship of oxygen delivery and mixed venous oxygenation to lactic acidosis in patients with sepsis and acute myocardial infarction. Crit Care Med. 1988;16:655–658. 88. Pinsky MR. Assessment of adequacy of oxygen transport in the critically ill. Appl Cardiopulm Pathophysiol. 1990;3:271–278. 89. Levy PS, Chavez RP, Crystal GJ, et al. Oxygen extraction ratio: a valid indicator of transfusion need in limited coronary vascular reserve? J Trauma. 1992;32:769–773, discussion 773–764. 90. Barcroft J. On anoxaemia. Lancet. 1920;196:485–489. 91. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med. 1987;13:223–229. 92. Cain SM. Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol Respir Environ Exerc Physiol. 1977;42:228–234. 93. Shibutani K, Komatsu T, Kubal K, et al. Critical level of oxygen delivery in anesthetized man. Crit Care Med. 1983;11:640–643. 94. Danek SJ, Lynch JP, Weg JG, et al. The dependence of oxygen uptake on oxygen delivery in the adult respiratory distress syndrome. Am Rev Respir Dis. 1980;122:387–395.

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95. Mohsenifar Z, Goldbach P, Tashkin DP, et al. Relationship between O2 delivery and O2 consumption in the adult respiratory distress syndrome. Chest. 1983;84:267–271. 96. Feigl EO. Coronary physiology. Physiol Rev. 1983;63:1–205. 97. Crystal GJ, Pagel PS. Right ventricular perfusion: Physiology and clinical implications. Anesthesiology. 2018;128:202–218. 98. Deussen A, Ohanyan V, Jannasch A, et al. Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol. 2012;52:794–801. 99. Crystal GJ. Carbon dioxide and the heart: Physiology and clinical implications. Anesth Analg. 2015;121:610–623. 100. Crystal GJ, Salem MR. Myocardial and systemic responses to arterial hypoxemia during cardiac tamponade. Am J Physiol. 1989;257:H726–H733. 101. Crystal GJ, Kim SJ, Salem MR. Right and left ventricular O2 uptake during hemodilution and beta-adrenergic stimulation. Am J Physiol. 1993;265:H1769–H1777. 102. Nimmagadda U, Salem M, Crystal G: Preoxygenation: physiological basis, benefits, and potential risks. Anesth Analg. 2017;124:507–517. 103. Crystal GJ, Zhou X, Alam S, et al. Lack of role for nitric oxide in cholinergic modulation of myocardial contractility in vivo. Am J Physiol Heart Circ Physiol. 2001;281:H198–H206. 104. Bradley AJ, Alpert JS. Coronary flow reserve. Am Heart J. 1991;122:1116–1128. 105. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol. 1974;34:48–55. 106. Marcus M. The Coronary Circulation in Health and Disease. New York: McGraw-Hill; 1983. 107. Braunwald E. Control of myocardial oxygen consumption: physiologic and clinical considerations. Am J Cardiol. 1971;27:416–432. 108. Zong P, Tune JD, Downey HF. Mechanisms of oxygen demand/ supply balance in the right ventricle. Exp Biol Med (Maywood). 2005;230:507–519. 109. Jennings RB, Sommers HM, Smyth GA, et al. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960;70:68–78. 110. Deschamps A, Denault A. Autonomic nervous system and cardiovascular disease. Semin Cardiothorac Vasc Anesth. 2009;13:99–105. 111. Hamburg NM, Benjamin EJ. Assessment of endothelial function using digital pulse amplitude tonometry. Trends Cardiovasc Med. 2009;19:6–11. 112. Funk DJ, Moretti EW, Gan TJ. Minimally invasive cardiac output monitoring in the perioperative setting. Anesth Analg. 2009;108:887–897. 113. Wakeling HG, McFall MR, Jenkins CS, et al. Intraoperative oesophageal Doppler guided fluid management shortens postoperative hospital stay after major bowel surgery. Br J Anaesth. 2005;95:634–642. 114. Krite Svanberg E, Wollmer P, Andersson-Engels S, et al. Physiological influence of basic perturbations assessed by non-invasive optical techniques in humans. Appl Physiol Nutr Metab. 2011;36:946–957.

Anatomy and Imaging: The Cardiovascular System Rebecca Desso and Jeffrey D. Swenson

This special section on Anatomy and Imaging outlines important anatomic structures and imaging techniques for the cardiovascular system, including the heart and major vessels in the neck and groin. Key structures are reviewed in anatomic drawings, anatomic dissections, magnetic resonance imaging (MRI) scans, and ultrasound (US) images. Modern imaging techniques that enable “real-time” visualization of relevant clinical anatomy are emphasized. Much like transesophageal echocardiography (TEE), transthoracic echocardiography (TTE) is emerging as an important technique for anesthesiologists. Although a comprehensive review of TTE is not within the scope of this text, it is appropriate to present an overview of the anatomic basis of this developing area of proficiency for anesthesiologists. Focused Cardiac Ultrasound (FoCUS) is a point-of-care US examination approach aimed at assessing key elements of cardiac anatomy and physiology that can guide treatment or lead to further testing. Any significant abnormalities detected by FoCUS should lead to a full echocardiographic examination (among other techniques). Figs. AI2.1 to AI2.5 give an overview of the basic assessment of cardiovascular function that can be performed using TTE. The necessary probe manipulations are shown in this series of figures.1 The patient is positioned in left lateral decubitus with the left arm above the head (Fig. AI2.1). The right panel shows the transducer positioned with the indicator toward the right shoulder at the third to fourth intercostal interspace. The left panel shows a parasternal long axis image with the right ventricle (RV), left

ventricle (LV), aorta (Ao), aortic valve (AV), mitral valve (MV), and left atrium (LA) labeled. This view allows evaluation of chamber sizes, global function with thickening of the anteroseptal (AS) and inferolateral (IL) walls, the aortic valve, the left ventricular outflow track (LVOT), and mitral valve motion and anatomy. This image is obtained with rotation of the probe clockwise from the parasternal long axis so that the indicator points to the left shoulder, as seen in the right panel (Fig. AI2.2). The left panel shows the parasternal short axis view with the RV and the LV walls labeled: anterior (A), anterolateral (AL), inferolateral (IL), interior (I), inferoseptal (IS), and anteroseptal (AS). From here, the transducer is angled to the floor to scan the LV base and to the right shoulder to scan the apex. This view allows evaluation of global LV function and filling as well as thickening of the walls. With the patient in the left lateral decubitus position at the edge of the examination table, the transducer is placed with the indicator toward the floor, as shown in the right panel (Fig. AI2.3). The transducer is angled to the floor to see the AV or to the right shoulder to see the coronary sinus (CS). The left panel shows the LV, LA, MV, RV, RA, and TV, as labeled. The size of the chambers, thickening of the LV walls, descent of the base of the TV and MV, and structure and function of the MV and TV are examined. The patient is positioned supine, with the abdomen relaxed (Fig. AI2.4). The right panel shows probe placement below the xiphoid, with the indicator to the left. The left panel shows the image with the RV, RA, TV, LA, LV, and MV labeled. The RV size, RV function and thickness, and the pericardium are examined.

• Fig. AI2.1  Cardiac anatomy, as visualized in the parasternal long axis by transthoracic echocardiography. 500

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• Fig. AI2.2

  Cardiac anatomy, as visualized by the parasternal short axis by transthoracic echocardiography.

• Fig. AI2.3  Cardiac anatomy, as visualized by the apical 4-chamber view by transthoracic echocardiography.

• Fig. AI2.4  Cardiac anatomy, as visualized by the subcostal 4-chamber view by transthoracic echocardiography.

Subcostal Inferior Vena Cava Long Axis: The probe is rotated 90 degrees counterclockwise, as shown in the right panel (Fig. AI2.5). The left panel shows the inferior vena cava (IVC) as it enters the RA. An IVC that is small and collapses with the patient sniffing is indicative of low central venous pressure while a large and noncollapsing IVC indicates elevated central venous pressure.

The lower panel is a diagram of coronary artery anatomy (Fig. AI2.6). The left main (LM) and right coronary artery (RCA) are shown with their respective branches. Important branches of the RCA include the marginal branch (MB) and the posterior descending artery (PDA). Left or right vessel dominance of the coronary vasculature is determined by the vessel from which the PDA arises. In approximately 85% of individuals, the PDA arises

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• Fig. AI2.5

  Vena caval and right atrial anatomy, as viewed by the vena cava long axis view by transthoracic echocardiography.

• Fig. AI2.6

 

Coronary artery anatomy, as shown by an idealized anatomic drawing and angiograms.

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from the RCA (right vessel dominant). The left main (LM) coronary artery is typically short in length and gives rise to the left anterior descending (LAD) artery and the left circumflex (LCx) artery. The LAD gives rise to one or more diagonal branches while the LCx gives rise to one or more obtuse marginal (OM) branches. Coronary angiography is an invasive procedure that allows visualization of coronary artery anatomy and is considered the gold standard for diagnosis of coronary artery stenosis. Common images are named according to the relation of the image intensifier (located above the patient) to the patient.2 For example, the left upper and left middle panel show the right anterior oblique (RAO) view of the left main coronary artery (LM), the left anterior descending artery (LAD) with diagonal branch (Diag), and the left circumflex artery (LCx). In the RAO view, the intensifier is over the right shoulder. The right upper panel shows the right coronary artery (RCA) and posterior descending artery (PDA) from the left anterior oblique (LAO) view, in which the intensifier is over the left shoulder. Cardiac magnetic resonance imaging (MRI) can be used to quantify LV and RV function, define cardiac and coronary artery anatomy, evaluate myocardial perfusion, quantify blood flow, and assess myocardial viability (Fig. AI2.7).3 Cardiac MRI allows high temporal and spatial resolution without the need for heart rate control and allows imaging of heavily calcified structures that may not be clearly evaluated via other techniques. The left panel shows the 2-chamber window with the left atrium (LA) and left ventricle (LV). The bottom panel shows the 4-chamber window including the LA, LV, right atrium (RA) and right ventricle (RV). The right panel shows the short axis of the LV and RV. These images correspond to the echocardiogram apical 2-chamber, apical 4-chamber and parasternal short-axis views.

• Fig. AI2.7

 

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Cardiac and coronary computed tomography (CCT) are used to assess coronary atherosclerosis as well as pericardial, valvular, and myocardial heart disease (Fig. AI2.8). CCT is best used for identification of coronary artery disease in patients of low to intermediate risk. CCT is limited, as a heart rate of 60 to 70 is necessary and severe calcification of structures obscures the image. Three-dimensional renderings allow evaluation of cardiac structures.4 An example of a 4-chamber view is shown in the left panel. Three-dimensional renderings of cardiac anatomy are illustrated in the middle panel and in the right panel. This image illustrates lower extremity vascular anatomy at the level of the inguinal ligament (Fig. AI2.9). The top left panel is a fresh cadaver dissection of the right inguinal region. The inguinal ligament, femoral vein (FV), femoral artery (FA), profunda femoris artery (PF), and superficial femoral artery (SFA) are displayed. The forceps indicate the position of the femoral nerve (FN), which is deep to the intact fascia iliaca and not visible. The right upper and lower panels are corresponding ultrasound images; the bottom left panel shows the position of the transducer used to visualize these structures. The top right panel is an ultrasound image of the right inguinal region immediately proximal to the take-off of the PFA (not visible). The FA, FV, and FN are visible. The lower right panel illustrates how easily the femoral vein is compressed using gentle pressure with the transducer. Images such as these are important in vascular access and nerve block techniques in the groin, such as femoral artery cannulation and fascia iliaca nerve block catheters. The right panel of this figure shows the transducer position used to image the right carotid artery (CA) and internal jugular vein (IJ) at the level of the sixth cervical vertebra (Fig. AI2.10). The linear transducer is positioned at the level of the cricoid cartilage

Cardiac anatomy, as assessed by cardiac magnetic resonance imaging.

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• Fig. AI2.8

• Fig. AI2.9

 

 

Cardiac anatomy, as assessed by cardiac and coronary computed tomography.

The vascular anatomy of the groin, as shown by anatomic dissection and ultrasonography.

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• Fig. AI2.10

 

505

The vascular anatomy of the lateral neck, as visualized by ultrasonography.

while the head is rotated away from the transducer. The left panels are ultrasound images showing the CA, IJ, thyroid tissue, and sternocleidomastoid muscle (SCM). Two important features are illustrated. First, there is considerable variability in the size of venous capacitance vessels associated with changes in intrathoracic pressure. In the top left image, the subject is performing a voluntary Valsalva maneuver. The lower left image shows the same subject during spontaneous inhalation. Second, in both images the position of the CA is deep rather than medial to the IJ. Although not typically visualized in ultrasound images, the thoracic duct drains lymph into the circulatory system via the left brachiocephalic vein between the left subclavian and left internal jugular veins. Thus, damage to the thoracic duct that can result in chylothorax is a potential complication of central venous access procedures on the left side of the body but not on the right.

A. The Aortic Arch in an Idealized Anatomic Drawing Major vessels of the head and upper extremities arise from the convex surface of the aortic arch (Fig. AI2.11A). There is asymmetry of these vessels in that right subclavian and right common carotid arteries arise from the brachiocephalic artery. By contrast, the left subclavian and common carotid arteries arise directly from the arch. It is also important to note that the vertebral arteries arise from the subclavian arteries. Occasional anatomic variations can produce unexpected findings on ultrasound and radiographic examinations.

B. Arteries of the Upper Extremity in an Idealized Anatomic Drawing The subclavian artery transitions to the axillary artery at the lateral border of the first rib (Fig. AI2.11B). The axillary artery

then transitions to the brachial artery at the lower border of the teres major muscle. The anterior and posterior circumflex arteries form an anastomosing circle around the surgical neck of the humerus. The profunda artery arises from the brachial artery at the level of the proximal humerus and follows the radial nerve. The superior and inferior ulnar collateral arteries arise from the brachial artery proximally and anastomose distally with the ulnar artery. The superior ulnar collateral artery can be visualized adjacent to the ulnar nerve in the upper arm. The brachial artery terminates at the neck of the radius by dividing into the radial and ulnar arteries. The superficial and deep palmar arches are direct continuations of the ulnar and radial arteries, respectively.

C. Relationships of the Subclavian Vessels, Scalene Muscles, and Brachial Plexus Visualized in an Idealized Anatomic Drawing and by Ultrasonography An important anatomic feature of the subclavian artery is its separation from the subclavian vein by the anterior scalene muscle (Fig. AI2.11C). While the subclavian artery is consistently within the same fascial compartment as the brachial plexus, the same is not true for the subclavian vein. These features are illustrated in the diagram and by an ultrasound image at the level of the first rib.

D. The Profunda Artery as Visualized in an Anatomic Dissection and by Ultrasonogaphy The profunda artery is part of the arterial anastomosis around the elbow joint (Fig. AI2.11D). This image features a fresh cadaver dissection showing the proximity of the radial nerve and profunda artery within the lateral intermuscular septum.

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Right subclavian artery

Left common carotid artery

Left vertebral artery

Left subclavian artery

Right vertebral artery Right common carotid artery Brachiocephalic artery

A Subclavian artery Axillary artery

Anterior circumflex humeral artery Posterior circumflex humeral artery

Profunda artery Brachial artery

Superior ulnar collateral artery Inferior ulnar collateral artery

Radial artery Ulnar artery

Superficial palmar arch Deep palmar arch

B • Fig. AI2.11

 

(A-F) Arteries of the upper extremity with clinically relevant features.

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Middle scalene muscle Brachial plexus Subclavian artery Subclavian Vein

C

Subclavian vein

Brachial Plexus Anterior Subclavian Scalene Muscle Artery

First Rib

Anterior scalene muscle attached to first rib

D • Fig. AI2.11, cont'd Continued

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F • Fig. AI2.11, cont'd



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E. the Brachial Artery as Visualized in an Anatomic Dissection and by Ultrasonography The brachial artery is displayed in these images at a level proximal to the antecubital fossa (Fig., AI2.11E). Note that the brachial artery is in close proximity to the median nerve along its course. The cadaver dissection shows the gradual transition of the nerve from a position superficial to the brachial artery to a more medial position at the level of the elbow.

F. The Ulnar and Radial Arteries as Visualized in an Anatomic Dissection and by Ultrasonography The ulnar and radial arteries in the distal forearm are unique in that the ulnar nerve (see ultrasound image) lies in close proximity

509

on the ulnar side of the ulnar artery (Fig. AI2.11F). By contrast, the radial artery travels in proximity to the superficial branch of the radial nerve in the middle third of the forearm but this branch passes deep to the tendon of the brachioradialis muscle at the distal forearm. Thus, no neural structures are visible on ultrasound in proximity to the radial artery at the level of the wrist.

References 1. Spencer KT, Kimura BJ, Korcarz CE, et al. Focused cardiac ultrasound: recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(6):567–581. 2. Morton. The Cardiac Catheterization Handbook. 6th ed. Philadelphia: Elsevier; 2016 [Ch 3]. 3. Boxt, Abbara. Cardiac Imaging: The Requisites. Philadelphia: Elsevier; 2016 [Ch 3]. 4. Boxt, Abbara. Cardiac Imaging: The Requisites. Philadelphia: Elsevier; 2016 [Ch 4].

Physics: Fluid Dynamics Patrick Kolbay and Kai Kuck

Volumetric Flow OUTLINE Background Fluid Flow Volumetric Flow Mass Flow

Volumetric flow is the rate at which a volume of fluid passes per unit time. Like Ohm’s Law, in which electrical current is proportional to a voltage difference between 2 points and the electrical resistance of the conductor in between, the volumetric flow of a fluid is determined by the difference in pressure between 2 points and the mechanical resistance of the tube in between:

Viscosity Types and Properties of Flow Laminar Flow Turbulent Flow Convection Bernoulli’s Law Flow Meters Differential Pressure Sensors Rotameters Vane Anemometers Hot-Wire Anemometers Ultrasonic Anemometers

volumetric fluid flow =

pressure difference resistance

Volumetric flow is used in anesthesia, for example, when describing the flow of gases. The unit for volumetric flow (according to the International System of Units [SI]) is cubic meters per second (m3/sec); another more commonly used unit in everyday practice is liters per minute (L/min).

Mass Flow Mass flow is the rate at which a mass of fluid passes per unit of time. Mass flow and volumetric flow are related to one another by the density of the fluid, in which density is the mass of a fluid per unit volume as measured in kilograms per cubic meter (kg/m3): mass fluid flow rate = density × volumetric fluid flow rate

Background Ventilation and delivery of inhaled anesthetics involves the flow of gases to and from the patient. Differences in gas properties can have a significant impact on the dynamics of these flows, influencing how anesthetic and ventilation equipment performs. Understanding the basics of fluid dynamics will not only aid in using anesthetic and ventilation equipment efficiently but also help in understanding their limitations. Key concepts that are important to master include fluid flow (e.g., volumetric vs. mass flow), flow properties (e.g., turbulent vs. laminar flow), and common methods to measure gas flows.

Fluid Flow A fluid is a substance that flows freely and takes the shape of its container. Of the 3 phases of matter, gases and liquids are both considered to be fluids. Fluid flow is the motion of a gas or liquid from one location to another. The rate at which fluids flow can be described in 2 ways: volumetric flow and mass flow. 510

In anesthesia, mass flow is used, for example, when describing intravenous delivery of medication, although in this case the mass refers to just 1 component of the fluid. The SI unit for mass flow rate is kilograms per second (kg/sec). More commonly used units are milligrams per minute or micrograms per minute. Gases change volume with changes in pressure and temperature, resulting in changes in their density. Consider, for example, delivery of oxygen to a patient at 2.0 L/min at sea level, where atmospheric pressure is 760 mm Hg. Given that the density of oxygen is 1.35 g/L at sea level, the mass flow rate can be determined as follows: Mass flow rate = 2.0

L g g × 1.35 = 2.70 min L min

If, however, the same volumetric flow rate of 2.0 L/min is delivered at 5000 feet above sea level, where the atmospheric pressure is 630 mm Hg, the mass flow rate changes. Boyle’s Law can be used to determine the change in volume: 760 mm Hg × 2.0 L = 630 mm Hg × volume at altitude

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volume at altitude =

760 mm Hg × 2.0 L 630 mm Hg

= 2.41 L

(Re) is used to predict whether flow will be laminar or turbulent: Reynolds number =

Because the mass of oxygen has not changed (only volume has changed), the density can be recalculated: density =

2.70 g 2.41 L

= 1.12

g L

Using this new density, the new mass flow rate can be determined for an elevation of 5000 feet: mass flow rate = density × volumetric fluid flow rate g g L = 1.12 × 2.0 = 2.24 L min min The important clinical point is that, at higher elevation, the mass of oxygen delivered decreases even when the volume flow rate is the same.

Viscosity Viscosity can be described as the resistance of a fluid to flow. Honey, having a high viscosity, resists being poured and drips slowly from a bottle, while water, having a lower viscosity, readily pours from a bottle (Fig. P5.1). This physical property occurs owing to both the friction between layers of a fluid as well as intermolecular forces within that fluid. The SI unit for viscosity is the pascal second (Pa s) and is often abbreviated as µ (Greek letter mu).

Types and Properties of Flow Flow is classified into 2 types of movement: laminar and turbulent flow. Laminar flow is smooth, uniform flow in 1 direction, whereas turbulent flow is more chaotic and contains swirls of eddies (Fig. P5.2). Popularized in 1883 by Reynolds, the Reynolds number

511

=

density × velocity × tube diameter viscosity 4 × density × volumetric flow viscosity × tube diameter × π

From empirical testing in cylindrical tubes, flows with a Reynolds number below 2000 are likely to be laminar, while those above 2000 tend to be turbulent. Additionally, obstructions, sharp corners, or other irregularities in a tube can also cause turbulent flow. It should be noted that the Reynolds number is not only dependent on the physical properties of the fluid but is also dependent on the properties of the tube within which fluid is flowing.

Laminar Flow The predictable and smooth behavior of laminar flows make them ideal in a variety of ways. Volumetric flow is dependent on both the difference in pressure between two points and the resistance of the tube that it is flowing through. In 1838, French physicist and physiologist Poiseuille was able to describe this relationship for laminar flows as what is now known as Poiseuille’s Law: volumetric flow rate = =

pressure difference resistance pressure difference × tube radius 4 × π 8 × viscosity × length of tube

According to the equation, the radius of the tube dramatically impacts flow rate because flow is proportional to the 4th power of the radius. Similarly, a longer tube generates more friction, causing overall flow to decrease. These principles have important implications in anesthesia, such as the selection of the optimal tracheal tube size.

A

B

• Fig. P5.2 • Fig. P5.1

  Water (left) will pour quickly and easily while honey (right), being more viscous, will flow slowly from its container.

  Fluid flow through a tube. Laminar fluids flow in even layers all in one direction (A), while turbulent fluids swirl and eddy in their flow (B). Determining whether a fluid will be laminar or turbulent is dependent on whether the Reynolds number is below or above 2000.

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Turbulent Flow

Flow Meters

Unlike laminar flow, the resistance of a tube for turbulent flows is not easily calculated. Owing to the chaotic and unpredictable nature of turbulent flow, resistance of a tube is dependent on the volumetric flow itself; thus, it is not possible to calculate the resistance without knowing the flow beforehand. When flow is turbulent, a larger pressure difference between points is required compared to laminar flow. Most fluid flows relevant to anesthesia, such as blood flow and gas flow during normal respiration, exhibit laminar flow. There are a few exceptions, however. Many patients experience momentary turbulence in blood flow in the ascending aorta depending on the compliance of the vascular walls. Additionally, patients suffering from bronchospasm can also exhibit turbulent air flow in the lungs owing to the narrowing of the bronchial lumen. When delivering a mixture of oxygen and helium (known as Heliox), the overall density of the fluid dramatically decreases since helium has 1/8 the density of oxygen. As a result, the Reynolds number also decreases, making the fluid flow more laminar and allowing a higher volumetric flow to the lungs, counteracting the constriction due to bronchospasm.

Many flow meters used in anesthesia measure fluid velocity instead of flow rate. Volumetric flow rate is then determined by multiplying the cross-sectional area of the tube with the measured fluid velocity.

Convection When fluids have a different temperature than their surroundings, they begin to exchange thermal energy (heat) in a process known as convection. Convection can occur naturally or can be forced. Heated fluids are a good example of natural convection. As fluid temperature increases, the fluid begins to expand and decrease in density. This causes the fluid to rise and to be replaced by cooler, denser fluid, generating a current flow, or a convection current. Forced convection occurs when fluids are forced to flow over a surface, thereby adding or removing heat. An example of this is an air conditioning system blowing cold air into a hot room and cooling down the room. Hot-wire flow meters (see later discussion) that are used in many anesthesia machines and ventilators are based on this convection principle. Convection is also the mechanism whereby movement of cold air around an anesthetized patient results in heat loss from the patient. Convection plays an important role in heat loss from anesthetized patients, but the main mechanism of heat loss in these patients is radiation.

Bernoulli’s Law

Differential Pressure Sensors A differential pressure sensor uses the Bernoulli Effect to measure fluid velocity. Two pressure sensors are inserted into a tube with a short constriction in between the sensors (Fig. P5.3). When fluid is not flowing, there is no pressure difference between before and after constriction. However, as fluid begins to flow, there is a decrease in pressure after the constriction due to the Bernoulli Effect that is directly proportional to the fluid velocity. Turbulent flows can cause small sections of higher or lower pressures, making differential pressure sensors not ideal for turbulent flows. Differential pressure sensors are commonly used to measure the flow rates in anesthesia machines and other respiratory devices.

Rotameters Rotameters are simple flow meters used to determine volumetric flow rates of fresh gas flows, often coming from wall sources. The flow meter is a vertical tapered tube that contains a weight inside, also known as a float (Fig. P5.4). As fluid flows up into the tapered tube, a force is generated that pushes the float up and away from the constriction. As the float rises, more fluid passes around the float, until an equilibrium is reached. The position of the float is then compared to the calibrated tick marks on the tube, which correspond to a given flow rate. If the flow rate decreases, so will the generated force against the float, causing the float to sink, reflecting the flow rate of the system. Rotameters are entirely passive and require no electric power. However, what they gain in their simplicity, they lack in accuracy. Small changes in density (which can be affected by pressure, temperature, and gas composition) and generally poor resolution make rotameters less reliable compared to other types of flow meters.

Pressure sensor before the partial obstruction

The total energy of a fluid moving horizontally can be described as a combination of the potential energy caused by pressure differences and the kinetic energy from fluid velocity. In 1738, Daniel Bernoulli determined the precise relation of potential and kinetic energy known as Bernoulli’s Law:

Pressure sensor after the partial obstruction

Partial obstruction

1 energy = pressure difference + × density × velocity 2 2 An interesting phenomenon occurs if a fluid flows through a constriction. Because of conservation of mass, the velocity of the fluid must increase to maintain the same flow rate as it enters the constriction. Based on Bernoulli’s Law, since total energy has not changed, pressure must decrease as the velocity increases. This is known as the Bernoulli Effect and is the basis for differential pressure flow sensors used to measure gas flows in anesthesia (see later discussion).

• Fig. P5.3

  Fluid flow from left to right through a tube with a partial obstruction. The pressure that the fluid exerts on the wall of the tube decreases after the partial obstruction, as indicated by the pressure sensors before and after the partial obstruction. The higher the fluid velocity, the higher the pressure drop. This principle is used in differential pressure flow sensors.

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Vane Anemometers

Fr

Volumetric flow can also be measured using a propeller or turbine. A vane anemometer consists of an embedded propeller within a pipe and rotates as fluid flows past. The faster the fluid flows, the faster the propeller spins. The blades of the propeller can be designed to measure precise volumetric flow regardless of changes in density, fluid composition, or turbulence. These devices, too, are often found in anesthesia machines.

Hot-Wire Anemometers

FG

Hot-wire anemometers use convective heat transfer properties to measure fluid flow. A heated wire or film is placed within the fluid stream. As the fluid flows across the heated surface, the heated material begins to cool. The amount of energy needed to maintain the temperature of the wire or film is proportional to fluid velocity. As in differential pressure sensors, small eddy currents from turbulent flow can momentarily increase or decrease fluid velocity at the sensor location and cause inaccurate or noisy readings. For this reason, hot-wire anemometers are typically used only in situations in which flow is laminar. Many anesthesia machines and critical care ventilators use hot-wire anemometers to measure gas flows.

Ultrasonic Anemometers • Fig. P5.4

  Rotameter for measuring fluid flow rate. The red float will change height based on the amount of force exerted from the flowing fluid (Fr) compared to the force of gravity (FG). As the float rises, Fr decreases due to the increased opening of the tapered column. The float rises until Fr and FG have the same value. The height of the float can then be used to indicate the volumetric fluid flow rate.

Ultrasonic anemometers determine the velocity of a fluid by how long it takes a sound wave to travel through the fluid. An ultrasonic pulse is generated in the direction of fluid flow and a sensor downstream records this pulse. Because sound is a mechanical wave that propagates through a medium (in this case, a fluid), if the medium is moving, it carries sound with it. As a result, an ultrasonic pulse traveling in a flowing fluid reaches the downstream sensor sooner than if the fluid is stationary. Therefore, the time it takes for an ultrasonic pulse to travel is proportional to fluid velocity. Some infusion pumps use ultrasonic anemometers.

Physics: Invasive and Noninvasive Blood Pressure Measurement Jennifer A. Decou and Kai Kuck

OUTLINE Background Noninvasive Blood Pressure Measurement Palpation and Oscillometric Method Korotkoff Sounds Continuous, Invasive Blood Pressure Monitoring Resonant or Natural Frequency Damping Fast-Flush Test Morphology of the Arterial Waveform Leveling and Zeroing

Background Systemic arterial blood pressure monitoring is one of the minimum standards of patient monitoring recommended by the American Society of Anesthesiologists (ASA). Together with other monitors, it will help detect up to 93% of adverse events under anesthesia.1 Arterial blood pressure can be obtained intermittently and noninvasively using oscillometry or continuously and invasively with an arterial catheter. An understanding of the physics underpinning the use of noninvasive and invasive blood pressure monitoring techniques facilitates proper interpretation of blood pressure measurements, improving quality of patient care and patient safety.2,3 Noninvasive blood pressure monitoring carries relatively low risk and historically has been interpreted by palpation or auscultatory methods. Oscillometric methods often replace these techniques, but values can be inaccurate, for example, when using a cuff that is too small or too large.4 Invasive blood pressure monitoring provides continuous beat-to-beat measurements and can be useful when titrating vasoactive drugs or when hemodynamic changes are occurring rapidly. Clinicians should understand the concepts of resonance, damping, wave reflection, and leveling or zeroing to correctly interpret the values and waveform morphologies recorded. Ultimately, blood pressure measurements represent a surrogate for tissue perfusion and are only useful insofar as they accurately reflect information about the adequacy of oxygen and energy substrate delivery and metabolic waste removal. Noninvasive methods of blood pressure monitoring have existed since the early 1800s.5 Scipione Riva-Rocci, an Italian physician, 514

is credited for creating the first easy-to-use sphygmomanometer in 1896, the important element being a cuff that encircled the circumference of the arm (Fig. P6.1). After visiting Riva-Rocci in Pavia in 1901, Harvey Cushing began using the device intraoperatively, reproducing Riva-Rocci’s design with some improvements (such as a wider cuff).

Noninvasive Blood Pressure Measurement Palpation and Oscillometric Method During the early use of sphygmomanometers, the method of determining systolic blood pressure was palpation of the pressure at which a distal pulse appears as the cuff pressure decreases. This gives an accurate systolic pressure but is not useful in determining diastolic or pulse pressure. The oscillometric method (Fig. P6.2) involves inflating the cuff to a pressure well above systolic pressure and then slowly lowering its pressure. A sensor registers small, fluctuating cuff pressure variations. In the upper extremity, the oscillations are caused by the throbbing brachial artery as it is partially compressed. The oscillations increase, reach a maximum at the mean arterial pressure, and then decrease again. Thus, the largest of these oscillations are thought to occur at the mean arterial pressure. Systolic and diastolic pressures are determined by algorithms proprietary to the manufacturer, that is, at fixed thresholds of the oscillations, for example, at 75% and 60% of maximum oscillations, respectively. Using this method, the mean, systolic, and diastolic pressures—as well as the pulse pressure and heart rate—can be determined. It is critical to recognize that only the mean arterial pressure and heart rate are measured; the systolic and diastolic pressures are calculated.6

Korotkoff Sounds After Riva-Rocci invented the sphygmomanometer, Russian surgeon Nikolai Korotkoff discovered and described the auscultatory method of measuring blood pressure that has now been in clinical use for over a century. When a stethoscope is placed over the brachial artery with no restriction of flow, no sound can be heard. Similarly, when a cuff is inflated over the upper arm and the pressure in the cuff exceeds systolic blood pressure, no sound can be auscultated over the brachial artery. This is because the artery is completely collapsed, with no flow distal to the cuff. When the cuff is then deflated, either continuously or in a stepwise fashion (at a rate of 2–3 mm Hg per second), the five “Korotkoff sounds” appear in series. When the pressure in the cuff decreases to systolic pressure, the first

CHAPTER 24  Cardiovascular Physiology: Integrative Function



kPa 15

515

Pressure, mm Hg Cuff pressure Systolic pressure 110 100 90

10

80 70

Arterial pressure pulses Diastolic pressure

60 50 5

40 30

Hand bulb

20 10 0

0

Sphygmomanometer cuff

• Fig. P6.1

Posc (mm Hg)

  Many noninvasive blood pressure approaches involve inflating the cuff to above systolic pressure and then slowly reducing that pressure. Intersections with systolic and diastolic pressures result in characteristic palpations or sounds. A kPa is a unit of pressure. It is approximately equal to the pressure that a 10-g mass exerts on a 1-cm2 area. A mm Hg is a manometric unit of pressure, commonly used in medicine, and is equal to the pressure exerted by a column of mercury 1 mm high at 0°C under standard gravity. (From Nara AR, Burns MP, Downs, WG. Blood Pressure. SpaceLabs [Snoqualmie, WA, USA]; 1989 Vol 218. ISBN 0962744905.)

1.25

0

Posc (mm Hg)

0

7 time (sec)

14

MAA estimate

1.25

Continuous, Invasive Blood Pressure Monitoring

0 50

125

200

Pc (mm Hg)

• Fig. P6.2

Korotkoff sound is heard. As the heart ejects blood, some flow will spurt through the brachial artery during the moments when the peak systolic pressure exceeds the cuff pressure, causing a repetitive tapping sound that can be heard by auscultation. As greater flow is allowed through by further decreasing cuff pressure, phase II and phase III of the Korotkoff sounds can be heard with a softer, swishing quality followed by a return to louder, crisper sounds. These have little clinical significance (i.e., they are not linked to specific physiologic variables). During phase IV, the sounds are softened and muted until they disappear completely in phase V, where there is no restriction in flow caused by the cuff, signaling the diastolic pressure, as Korotkoff described it.

  The oscillometric method involves inflating the cuff to a pressure well above systolic pressure. The oscillations increase, reach a maximum at the mean arterial pressure and then decrease again (top). PC is the cuff pressure measured in mm Hg. The cuff pressure at the maximum of the envelope of these oscillations corresponds to the mean arterial pressure according to the maximum amplitude algorithm. POSC is the oscillatory part of the pressure measured in the cuff expressed here in mm Hg (millimeters mercury). PC is the nonoscillatory part of the pressure measured in the cuff. (From Baker, PD, Westenskow, DR, Kuck, K. Theoretical analysis of non-invasive oscillometric maximum amplitude algorithm for estimating mean blood pressure. Med Biol Eng Comput. 1997 35(3): 271–278.)

Invasive arterial blood pressure measurements are considered the gold standard for pressure measurement and give accurate beatto-beat readings (Fig. P6.3). Even before the noninvasive methods were invented, Stephen Hales recognized the importance of blood pressure and measured it invasively by inserting a brass tube into the artery of a horse and observing the height of the column of blood in the tube. Invasive monitoring is not without risk, as Hales discovered, but affords numerous advantages. Continuous blood pressure measurement is useful when rapid hemodynamic changes are anticipated or with infusion of vasoactive drugs, among other situations. The arterial waveform can be analyzed for additional information contained in the pulse contour. Arterial catheters are also useful when noninvasive blood pressure measurement is not feasible or accurate, such as with obesity, limited access to extremities

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3-way stopcock Pressure gauge

Continuous flush valve Pressure bag Fast flush device

Transducer

To monitor

Heparinized saline

Drip chamber

Valve

Arterial pressure extension tubing

Connection for blood sample withdrawal 3-way stopcock

• Fig. P6.3  The components of an invasive arterial blood pressure monitoring system: Intraarterial cannula, fluid-filled tubing, transducer, infusion/flushing system. Not shown are signal processor, amplifier, and display. (From Nara AR, Burns MP, Downs, WG. Blood Pressure. SpaceLabs (Snoqualmie, WA, USA); 1989 Vol 218. ISBN 0962744905.)

(burn patient), or significant arrhythmias. Arterial cannulation also provides the opportunity for convenient sampling of arterial blood for laboratory testing. During cardiac systole, the left ventricle generates a pulse as blood is ejected. The waveform of that pulse travels to the artery being monitored, through the intraarterial cannula, through the fluid-filled tubing system, and to the pressure transducer. The transducer converts physical displacement of the transducer membrane into an electrical signal, which is transmitted to the monitor, amplified, and displayed as an analog waveform. The complex wave of an arterial pressure waveform can be described by a series of sine waves. The periodicity of the wave shows its fundamental frequency, which is the heart rate. In addition,

there are other sine waves that are multiples, or harmonics, of the fundamental frequency. The summation of these waves yields an accurate reproduction of the true intraarterial pressure waveform.

Resonant or Natural Frequency The monitoring system has its own resonant frequency, the natural frequency at which the system tends to vibrate. It is the nature of a resonant system to respond strongly to other vibrations or influences that are close to its resonant frequency, amplifying those influences. It is important that the resonant frequency of the monitoring system does not overlap with the harmonic frequencies present in the arterial pressure waveform (Fig. P6.4). When this

CHAPTER 24  Cardiovascular Physiology: Integrative Function



517

fres = 91 Hz Output divided by input signal of blood pressure measurement

10 fres = 22 Hz

1.0 No bubble

Bubble

0.1

0.01

6

12

24

36

60

132 240 0.6 Frequency (1/min)

• Fig. P6.4

  Invasive blood pressure measurement system’s frequency characteristics. The purple bar in the figure is the range of frequency and harmonics inherent to the patient’s blood pressure wave. A bubble in the system will decrease the resonant frequency (fRes) in the system, bringing it closer to overlapping with the patient’s blood pressure frequencies and causing resonant artifacts. The resonant frequency indicates the frequency that the system maximally amplifies. Frequencies are measured as number of oscillations per second, expressed in Hertz (Hz). (From Nara AR, Burns MP, Downs, WG. Blood Pressure. SpaceLabs (Snoqualmie, WA, USA); 1989 Vol 218. ISBN 0962744905.)

occurs, the monitoring system will resonate, and the output pressure signal will be distorted and exaggerated.7 To prevent this artifact, the natural frequency of the system should be high, exceeding the frequencies of the impulses generated by the arterial pressure wave and its harmonics. In general, the harmonic frequencies generated by the arterial pressure waveform are up to 6 to 10 times the heart rate; if heart rate increases to 120 beats per minute, then the resonant frequencies of the cardiovascular system can increase to about 20 Hz. Therefore, the natural resonant frequency of the monitoring system must exceed 20 Hz in order to reconstruct an accurate waveform without significant artifact.8 Using lengthy extension tubing or excessively soft tubing can decrease the natural frequency of the monitoring system and potentially increase the amount of resonant artifact. These are usually underdamping artifacts that make the blood pressure appear falsely elevated, particularly the systolic pressure.

Damping All hemodynamic monitoring systems are damped to some degree, a necessary quality to avoid excessive and uninterpretable wave propagation. Damping refers to the decrease in amplitude of the mechanical pressure wave due to friction or resistance in the system. Since mechanical waves propagate differently in fluid and air, even

small air bubbles in the tubing of the monitoring system can overdampen the waveform, making the measured blood pressure appear falsely low. Thus, there is an appropriate level of damping and a damping coefficient that is ideal for the natural frequency of each system (Fig. P6.5).

Fast-Flush Test The dynamic response of an invasive blood pressure monitoring system is defined by both its resonant frequency and damping coefficient. These parameters dictate whether the system is overdamped, underdamped, or acceptable. In the fast-flush test, the oscillations and their return to baseline can be examined (Fig. P6.6). In general, the period of the wave can be measured as the distance between two successive peaks. The smaller the period (which is inversely related to frequency), the better the dynamic response of the system. If the period is less than 48 seconds, then the natural frequency is at least 21 Hz, which is almost always adequate. The system is overdamped if there are sluggish or no oscillations. An underdamped system is seen when excessive oscillations, or “ringing,” occurs. Although mean arterial pressure may be accurate, an underdamped system increases the measured systolic blood pressure and lowers the measured diastolic pressure.

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200 ms

A

Undistorted

B

Underdamped

C

Overdamped

Pressure (mm Hg)

150

100

50

0 Time (seconds)

Time (seconds)

Time (seconds)

Pressure (mm Hg)

• Fig. P6.5  All hemodynamic monitoring systems are damped to some degree, a necessary quality to avoid excessive and uninterpretable wave propagation. Damping refers to the decrease in amplitude of the mechanical pressure wave due to friction or resistance in the system. Pressure is expressed in mm Hg (millimeters of mercury); ms refers to milliseconds. (From Nara AR, Burns MP, Downs, WG. Blood Pressure. SpaceLabs (Snoqualmie, WA, USA); 1989 Vol 218. ISBN 0962744905.)

Time (seconds)

Time (seconds)

Time (seconds)

Optimally damped system

Underdamped system

Overdamped system

• Fig. P6.6

  The fast-flush test is performed to determine the system’s dynamic performance from the oscillations and their return to baseline. (From Nara AR, Burns MP, Downs, WG. Blood Pressure. SpaceLabs (Snoqualmie, WA, USA); 1989 Vol 218. ISBN 0962744905.)

Morphology of the Arterial Waveform The different phases of the cardiac cycle can be appreciated within the arterial waveform (Fig. P6.7). The steep upstroke begins with left ventricular contraction and systolic ejection. The peak and early decline occurs when the systolic wave reaches the monitored artery and is caused by displacement of flowing blood volume. The dicrotic notch represents aortic valve closure and subsequent retrograde flow. The location of the dicrotic notch on the downslope of the wave varies according to the timing of aortic valve closure and can be seen farther down on the wave in a state of hypovolemia or when measured at more distal sites in the arterial system. Arterial blood pressure further declines during diastole, its nadir occurring at end-diastole. Other factors influence the morphology of the

arterial wave, including stiffness and compliance of the arteries, heart failure, valvular heart disease, arrhythmias, and heart rate. Wave reflection also contributes to the appearance of the measured arterial waveform. Wave reflection is related to the changes in impedance of the narrowing arteries. This leads to retrograde reflections of the pressure waves that are reflected backwards along the arteries, becoming more pronounced for more peripheral vessels (Fig. P6.8). Similar to waves on a beach, the forward waves collide with the retrograde waves. The summation of these waves tends to augment systolic pressure, particularly in the radial and dorsalis pedis arteries, where systolic blood pressure can be up to 25 mm Hg higher than central aortic pressure.9 Mean arterial pressure can be estimated as the sum of diastolic pressure plus one-third of the difference between the diastolic and

CHAPTER 24  Cardiovascular Physiology: Integrative Function



519

857.1 ms

Pressure (mm Hg)

120

Systolic blood pressure Dicrotic notch

87

Mean blood pressure

70

Diastolic blood pressure Time (seconds)

Pressure (mm Hg)

Aorta

Pressure (mm Hg)

Brachial artery

Pressure (mm Hg)

Radial artery

Pressure (mm Hg)

• Fig. P6.7  The different parts of the cardiac cycle can be appreciated within the arterial blood pressure waveform. Pressure is expressed in mm Hg (millimeters mercury) and time in ms (milliseconds). The depicted cardiac cycle represents 70 beats per minute.

Femoral artery

Leveling with the height of the right atrium eliminates effects of hydrostatic pressure (the pressure exerted by a column of fluid). For every 1 cm of distance that the transducer is above or below the height of the right atrium, 0.74 mm Hg of hydrostatic pressure is subtracted or added to the blood pressure. For example, if the transducer is located 10 cm below the level of the right atrium, the recorded pressure will be 7.4 mm Hg higher than the actual central blood pressure. Leveling depends on which vascular bed is the most significant for the clinical scenario. For example, to measure cerebral perfusion pressure with the patient in the sitting position, the level of the transducer is placed at the level of the Circle of Willis and the expected measured blood pressure will be lower than when measured at the level of the heart.

Pressure (mm Hg)

References Dorsells pedis

Time (seconds)

• Fig. P6.8

  Wave reflection leads to retrograde reflections of the pressure waves that are reflected backwards along the arteries. As a result, waveforms become more pronounced at the more peripheral vessels.

systolic arterial pressure (i.e., the pulse pressure). It can also be calculated by an algorithm as the area under the pressure curve divided by the width of the base of the pressure curve.10 Although the shape of the arterial waveform changes with different locations of measurement, mean arterial pressure remains relatively constant, decreasing only slightly distally. Mean arterial pressure is also less affected by wave reflection or the dynamic characteristics of the monitoring system.

Leveling and Zeroing To zero the monitoring system, one should open the air–fluid interface to atmospheric pressure. This establishes for the monitor atmospheric pressure as the zero reference point.

1. Webb RK, van der Walt JH, Runciman WB, et al. The Australian Incident Monitoring Study. Which monitor? An analysis of 2000 incident reports. Anaesth Intensive Care. 1993;21:529–542. 2. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142–161. 3. Ward M, Langton J. Blood pressure measurement. Contin Educ Anaesth Crit Care Pain. 2007;7:122–126. 4. Mattoo TK. Arm cuff in the measurement of blood pressure. Am J Hypertens. 2002;15(2 Pt 2):67S–68S. 5. Booth J. A short history of blood pressure measurement. Proc R Soc Med. 1977;70(11):793–799. 6. Babbs CF. Oscillometric measurement of systolic and diastolic blood pressures validated in a physiologic mathematical model. Biomed Eng Online. 2012;11:56. 7. Bocchi L, Romagnoli S. Resonance artefacts in modern pressure monitoring systems. J Clin Monit Comput. 2016;30:707–714. 8. Gardner RM. Direct blood pressure measurement–dynamic response requirements. Anesthesiology. 1981;54:227–236. 9. Henneman EA, Henneman PL. Intricacies of blood pressure measurement: reexamining the rituals. Heart Lung. 1989;18:263–271. 10. Darovic GO. Hemodynamic Monitoring: Invasive and Noninvasive Clinical Application. 2nd ed. Philadelphia, Pa.: WB Saunders Co; 1995.

25 

Vasopressors and Inotropes JOSH ZIMMERMAN, JAMES P. LEE, AND MICHAEL CAHALAN

CHAPTER OUTLINE Structure-Activity Relationships

cardiac failure, the effects of vasopressors and cardiotonic drugs depend on many associated factors, including acid-base status, temperature, blood volume, and concomitant drug administration.1

Mechanisms Metabolism/Pharmacokinetics

Historical Perspective

Pharmacodynamics and Drug Interactions

Vasoactive drugs have an extensive history and have been in clinical use for millennia. The early identification and isolation of vasoactive substances was based on extraction from plants and endocrine glands. For instance, ephedrine has been in clinical use as a diaphoretic and circulatory stimulant for more than 5000 years as the active component of the Chinese drug ma huang. Until the drug was finally isolated in 1887, it was extracted from the plant Ephedra sinica.2 Similarly, foxglove had been in use for hundreds of years; William Withering published his historic book An Account of the Foxglove, and Some of Its Medical Uses in 1785.3 This text detailed Withering’s work with extracts of the plant Digitalis purpurea and described effects and side effects of the drugs now known as digoxin and digitoxin. In the late 17th century, it was recognized that “an extract of the suprarenal glands caused contraction of the arteries and led to an increase in the beat of the auricles and ventricles,” and that an extract of the pituitary gland possessed vasopressor activity. These substances would eventually be named epinephrine and vasopressin.4 While early medicinal chemistry work focused on developing progressively purer isolates of the active substances from natural sources, it eventually shifted to synthesizing drugs chemically. Dopamine was first synthesized in 1910 by Barger and Ewins, who immediately recognized its potency as a vasopressor.5,6 Vasopressin was the first polypeptide hormone successfully synthesized, for which du Vigneaud won the Nobel Prize in Chemistry in 1955. Work by von Euler confirmed that norepinephrine helped mediate the activity of the sympathetic nervous system and contributed to his 1970 Nobel Prize.7 In the modern era, attempts were made to develop drugs with specific characteristics. Dobutamine was synthesized in the early 1970s for the specific purpose of providing a high level of inotropy without the vasodilatory limitations of isoproterenol.8 Similarly, milrinone was developed in the early 1980s as an alternative to amrinone but without the high incidence of fever and thrombocytopenia that limited the use of amrinone. The development of novel vasopressors and inotropes continues to this day. Levosimendan, for instance, entered clinical use in Europe as recently as 2000 and numerous drugs are currently under investigation around the world.

Historical Perspective

Pharmacogenetics Individual Drugs Epinephrine Isoproterenol Norepinephrine Dopamine Dobutamine Milrinone Phenylephrine Vasopressin Ephedrine Digoxin Rational Drug Selection Septic Shock Cardiac Arrest Hypotension in the Parturient Right Heart Failure Postbypass Hypotension Emerging Developments

T

his chapter reviews the pharmacology of vasopressors and inotropes used commonly in acute care settings and comparable new drugs with promising clinical potential. It focuses on the pharmacodynamic properties of the drugs to a greater degree than their pharmacokinetic properties because most of these drugs have short half-lives, are administered by continuous infusion, and are titrated to clinical effect. Relying on landmark studies from the past as well as recent findings, this chapter seeks to build the scientific foundation on which the clinical use of these agents is based. Because their application to human pharmacology is unreliable, data derived exclusively from animal studies are not considered. Even when only human data are considered, the effects of vasopressors and inotropes vary substantially because of patient factors. Clinicians know that when treating patients experiencing severe hypotension or 520

CHAPTER 25  Vasopressors and Inotropes 520.e1



Abstract

Keywords

This chapter reviews the pharmacology of vasopressors and inotropes used commonly in acute care settings. It focuses on the pharmacodynamic properties of the drugs to a greater degree than their pharmacokinetic properties as most have short half-lives, are administered by continuous infusion, and are titrated to clinical effect. Clinicians know that when treating patients experiencing severe hypotension or cardiac failure, the effects of vasopressors and cardiotonic drugs depend on many associated factors, including acid-base status, temperature, blood volume, and concomitant drug administration. These factors are reviewed and recommendations are made for the rational selection and application of relevant vasopressors and inotropes.

vasopressors inotropes vasoactive drugs pharmacology

CHAPTER 25  Vasopressors and Inotropes



Structure-Activity Relationships

the parent compound β-phenylethylamine. Many of these drugs are also referred to as catecholamines due to the presence of hydroxyl substitutions on carbons 3 and 4 of the benzene ring of β-phenylethylamine. The most basic example of a catecholamine is dopamine, which is the 3,4-hydroxyl substituted form of

Many of the drugs in this chapter share structural similarities that affect their pharmacologic actions, although a few are chemically unrelated (Fig. 25.1). Many sympathomimetics are derived from

β-Phenylethylamine:

Catechol:

5

6

3

2

4

β 1

α

CH2 CH2 NH2

HO HO

Generic Catecholamine: (Dopamine)

CH2 CH2 NH2

HO

Hydroxyl substitutions ↑ β and α activity

Epinephrine:

HO HO

Isoproterenol: OH OH

No substitution gives less β activity

CH

CH2 NH

OH

CH

↑ substitutions generally ↑ β activity

Distance ↑ sympathomimetic activity

HO

Norepinephrine: OH

CH3

CH

CH2 NH2

OH

OH

CH2 NH

OH

CH(CH3)2 Large substitution gives β selectivity

Dobutamine:

HO

CH2

CH2 NH CH3 CH

HO

CH2 CH2

Large substitution gives β selectivity

Absence of hydroxyl group does not allow effective interaction with the β receptor

OH

Ephedrine:

CH

CH

NH

Phenylephrine:

OH CH2 CH3 No substitution means ↓ potency, ↑ indirect action, and ↑ CNS activity

521

CH OH

CH2 NH

OH

CH3

Substitution ↑ duration of action

Small substitution does not give β activity Milrinone:

N N N

O

• Fig. 25.1  The chemical structure of selected sympathomimetic agents. Most are chemically related as catecholamines. Milrinone is a notable exception.

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Mechanisms

βphenylethylamine. It is the metabolic precursor to both norepinephrine and epinephrine as the substrate for dopamine β-hydroxylase. The addition of an N-substitution increases the activity at β-adrenergic receptors. Norepinephrine, like epinephrine, is derived from β-phenylethylamine, but the lack of N-substitution decreases its activity at the β receptors. The impact of the degree of amino substitution on β-receptor activity is further reflected in the structures of isoproterenol and dobutamine. Both of these drugs have bulky side chains and as such have a high degree of β specificity. Phenylephrine and ephedrine are not considered catecholamines, in that they are not hydroxylated on both the 3 and 4 carbons of their benzene ring (phenylephrine has a single substitution and ephedrine has none). This lack of hydroxylation prevents phenylephrine from effectively binding the β receptor despite the N-methyl substitution. Ephedrine’s lack of hydroxylation substantially decreases its ability to stimulate directly adrenergic receptors. The presence of a methyl group on the α-carbon of ephedrine blocks oxidation by monoamine oxidase and prolongs its action. Milrinone, vasopressin, and levosimendan neither share structural similarities with the sympathomimetic drugs discussed nor with one another. Milrinone is a bipyridine methyl carbononitrile derivative of amrinone. Vasopressin, as a nonapeptide hormone, consists of a sequence of nine amino acids (Cys-Tyr-Phe-Gln-AsnCys-Pro-Arg-Gly), whereas levosimendan is a pyridazone-dinitrile derivative.9

Although the drugs discussed in this chapter are applied in similar clinical settings, they do not all share a pharmacologic class or mechanism. They are perhaps best classified and considered based on their mechanism for increasing inotropy and vasoconstriction (see Chapter 23). Although the drugs that increase inotropy do so by different mechanisms, the common endpoint is positively influencing the interaction of the calcium ion (Ca 2+ ) with actin and myosin in the cardiac myocyte (Fig. 25.2). Each of the β agonists, phosphodiesterase inhibitors, cardiac glycosides, and calcium sensitizers accomplishes this in a different way. Drugs that act on the β1 receptor (such as epinephrine, dobutamine, dopamine, isoproterenol, and, to a lesser extent, ephedrine and norepinephrine) begin by stimulating the receptor on the cardiac myocyte sarcolemma with subsequent activation of the Gs protein. This protein activates adenylyl cyclase and enhances the formation of cyclic adenosine monophosphate (cAMP), which activates protein kinase A, thereby phosphorylating and increasing the open probability of voltage-gated Ca2+ channels. These channels allow Ca2+ influx to increase cytosolic Ca2+ concentration, which activates the coupling of actin and myosin in the myocyte. Protein kinase A also activates a Ca2+-adenosine triphosphatase (ATPase) on the sarcoplasmic reticulum, leading to increased Ca2+ uptake in diastole and improved lusitropic function.

β-agonist

Digitalis Ca2+ channel

+

BAR

–

Gs

ATP

AC

K+ Na+ Na+ Ca2+ Ca2+

+ cAMP PKA

PDE AMP

– PDE-I

+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

RyR1

Ca2+ sensitizers

SR

• Fig. 25.2  Mechanisms of action of selected positive inotropes indicating where the agents act in a cardiomyocyte. Ultimately cytosolic calcium ion (Ca2+) and its interaction with the actin-myosin complex cause myocyte contraction. The β agonists and phosphodiesterase inhibitors accomplish this by increasing the activity of protein kinase A (PKA). The calcium sensitizers act directly by increasing Ca2+ affinity for troponin C at the actin-myosin complex. Digitalis compounds inhibit sodium-potassium adenosine triphosphatase (Na+,K+-ATPase [Na+ pump]) indirectly increasing intracellular Ca2+. AC, Adenylyl cyclase; AMP, adenosine monophosphate; BAR, β-adrenergic receptor; cAMP, cyclic adenosine monophosphate; Gs, G stimulating α subunit; PDE, phosphodiesterase; PDE-I, phosphodiesterase inhibitor; PKA, protein kinase A; SR, sarcoplasmic reticulum.



The inotropic effects of phosphodiesterase inhibitors (e.g., milrinone), like those of the adrenergic agonists, are mediated by cAMP. Unlike adrenergic agonists that increase cAMP by stimulating adenylyl cyclase, milrinone inhibits the breakdown of cAMP by phosphodiesterase type III (PDE3). Increased cAMP enhances Ca2+ release from the sarcoplasmic reticulum and increases the force generated by actin-myosin. The vasodilatory action of milrinone is also cAMP mediated. In vascular smooth muscle, cAMP inhibits myosin light chain kinase, the enzyme responsible for phosphorylating myosin light chains and causing smooth muscle contraction. Inhibition of PDE3 increases cAMP, thereby promoting vascular smooth muscle relaxation. Digoxin increases cytosolic Ca2+ by inhibiting the action of a sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) on the cell membrane of cardiac myocytes. This leads to an increase in cytosolic sodium ion (Na+), thereby decreasing the activity of Na+-Ca2+ exchange and indirectly resulting in an increase in intracellular Ca2+ available to interact with actin and myosin. Levosimendan, referred to as a calcium sensitizer, has a mechanism that is fundamentally different from the other inotropes discussed herein. Rather than increasing the content of intracellular Ca2+, it acts to modulate the interaction of Ca2+. It first binds the N-terminal lobe of cardiac troponin C (TnC), thereby stabilizing the Ca2+-bound form of the protein. This prolongs the systolic interaction between actin and myosin and increases the force of contraction. Because binding of levosimendan to TnC is dependent on the cytosolic Ca2+ concentration, it occurs almost exclusively during systole, leaving diastolic function relatively unaffected. Importantly, unlike other drugs discussed in this chapter, the increased inotropy is achieved without an increase in myocardial oxygen demand.10 The majority of drugs discussed in this chapter exert their vasoconstrictive actions via α1 receptors in the vasculature; the exception is vasopressin that acts on the V1 receptor. Stimulation of α1 or V1 receptors on vascular smooth muscle act (via separate G proteins) to stimulate phospholipase C (PLC), which hydrolyzes phosphatidylinositol bisphosphate (PIP2) to generate inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 increases Ca2+ release from the sarcoplasmic reticulum, while DAG activates protein kinase C to increase Ca2+ influx via voltage-gated Ca2+ channels. This increase in cytosolic Ca2+ increases vascular smooth muscle tone.11–13

Metabolism/Pharmacokinetics Vasopressors and inotropes generally have short half-lives and are rapidly metabolized, are administered by continuous infusion, and are titrated to clinical effect. This means that for practical purposes these drugs are pharmacokinetic equals; thus pharmacokinetic factors do not typically play an important role in rational drug selection of a specific inotrope or vasopressor. In general, these drugs exert their effects with an ongoing infusion; the effects rapidly decrease once the infusion is terminated. Levosimendan is a notable exception to this general rule. The catecholamine class of drugs, which includes epinephrine, norepinephrine, dopamine, dobutamine, and isoproterenol, are all rapidly inactivated by methylation of a hydroxyl group of the catechol structure by catechol-O-methyltransferase (COMT). In addition, monoamine oxidase (MAO) catalyzes oxidative deamination of this group of compounds (with the exception of dobutamine). Approximately 25% of dopamine is converted to norepinephrine in adrenergic nerve terminals; these nerve terminals also take up

CHAPTER 25  Vasopressors and Inotropes

523

norepinephrine. Even though phenylephrine is not a catecholamine, it is nonetheless metabolized by MAO. Ephedrine and milrinone largely resist metabolism and are excreted in the urine, whereas vasopressin is metabolized by specific vasopressinases in the liver and kidney. Levosimendan is unique in this group of drugs, in that it is metabolized to active compounds that are eliminated slowly. This results in clinical effects for up to a week after discontinuation of an infusion.14

Pharmacodynamics and Drug Interactions The pharmacodynamic profile of specific inotropes and vasopressors is a function of their relative receptor activities and mechanisms; an overview of receptor activities and physiologic effects is presented in Table 25.1. Adrenergic receptors have traditionally been divided into α and β, and have been subdivided into α1, α2, β1, β2, and β3. Further subtyping has been performed, and several genetic variations have been described (see “Pharmacogenetics”). The predominant location of α1 receptors is on peripheral vasculature; stimulation results in vasoconstriction of the skin, muscles, and renal and mesenteric vasculature. There is some contribution of peripheral α2 receptors to vasoconstriction, but agonism of α2 receptors is not a major characteristic of drugs discussed here (for pharmacology of α2 agonists, see Chapter 10). β1 Receptors are primarily located in the heart, where their stimulation results in increased inotropy, chronotropy, and lusitropy. β2 Receptors are widely distributed through the vasculature. Stimulation in peripheral vasculature results in dilation of muscular, splanchnic, and renal vessels. Bronchial smooth muscle has a high concentration of β2 receptors, the activation of which causes bronchodilation. Additional effects include stimulation of glycogenolysis in the liver and a slowing of peristalsis. The β3 receptor has been known for years to exist in adipose tissue, where its stimulation results in lipolysis. Its existence in the heart has been more recently recognized, and its role in normal physiology and disease, as well as the pharmacologic implications, is still being investigated. Current thinking suggests that β3-receptor agonism in the heart causes a decrease in inotropy. There is a potential interaction between monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants (TCAs) and several inotropes and vasopressors (Table 25.2). Because MAO contributes to the metabolism of norepinephrine and TCAs inhibit its reuptake, patients taking either type of drug can have an exaggerated hypertensive response to norepinephrine, drugs that enhance norepinephrine release (ephedrine and dopamine), and drugs that are metabolized by MAO. This adverse pharmacokinetic drug interaction can have important implications in the perioperative and intensive care settings.

Pharmacogenetics Although basic knowledge of the α- and β-adrenergic receptors forms the foundation for understanding the pharmacology of inotropes and vasopressors, recent research has unveiled considerable genetic complexity in the receptors.15 There are at least nine distinct receptor subtypes (three subtypes of each α1, α2, and β) that are expressed in a variety of tissues. Many of these receptor subtypes also have well-described genetic variants. For example, 12 singlenucleotide polymorphisms (SNPs) have been identified in the β1 receptor and 19 in the β2 receptor.16,17 These are simple variations in the genetic code, but it is believed that they translate into

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TABLE 25.1  Receptor Activity and Physiologic Effects of Vasopressors and Inotropes

α Receptor

β1 Receptor

β2 Receptor

Cardiac Output

Heart Rate

SVR

MAP

PVR

Epinephrine

++

++

++

↑

↑

↑

↑

0

Isoproterenol

0

+++

+++

↑

↑

↓

↓

0

Norepinephrine

+++

++

0

0

0

↑

↑

↑

Dopamine

++

++

0

↑

↑

↑

↑

0

Dobutamine

0

+++

+

↑

↑

↓

↓

↓

Milrinone

0

0

0

↑

0

↓

↓

↓

+++

0

0

0

↓

↑

↑

↑

Vasopressin

0

0

0

0

0

↑

↑

0

Ephedrine

+

+

+

↑

↑

↑

↑

0

Levosimendan

0

0

0

↑

0

↓

↓

↓

Drug

Phenylephrine

MAP, Mean arterial pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance. Effects vary significantly with dose and between individuals. Increasing levels of stimulation of adrenergic receptors are represented by +, ++, +++.

TABLE 25.2  Application, Dosing, and Interactions of Vasopressors and Inotropes

Drug

Drug of Choice

Bolus Dose

Infusion Dose

Relevant Drug Interactions

Epinephrine

Anaphylaxis; cardiac arrest

5–10 µg, up to 1 mg for cardiac arrest

0.02–0.3 µg/kg per minute

β-blockers, MAOIs, proarrhythmic medications

Isoproterenol

Refractory bradycardia

No bolus dosing

0.01–0.2 µg/kg/min

No co-infusion with alkaline medications

Norepinephrine

Septic shock

No bolus dosing

0.05–0.5 µ/kg per minute

MAOIs, TCAs

Dopamine

Septic shock with systolic dysfunction

No bolus dosing

1–20 µg/kg per minute

MAOIs, TCAs, butyrophenones, phenothiazines, phenytoin

Dobutamine

Stress echocardiography

No bolus dosing

2–20 µg/kg per minute

Co-administration with alkaline solutions can decrease activity

Milrinone

Weaning from cardiopulmonary bypass

Loading dose: 20–50 µg/kg over 10 min

0.2–0.75 µg/kg per minute

Can precipitate with furosemide

Phenylephrine

Mild hypotension from general or regional anesthesia

50–200 µg

20–200 µg/min

MAOIs, TCAs

Vasopressin

Post–cardiopulmonary bypass vasoplegia

0.5–2 units for mild hypotension, 20 units

0.01–0.04 µ/min

Carbamazepine, TCAs, norepinephrine, lithium, heparin

Ephedrine

Mild hypotension from general or regional anesthesia

5–10 mg

No infusion dosing

MAOIs, TCAs

Levosimendan

Unclear at this time

Loading dose: 12 µg/kg over 10 min

0.05–0.2 µg/kg per minute

None yet identified

MAOIs, Monoamine oxidase inhibitors, TCAs, tricyclic antidepressants.

CHAPTER 25  Vasopressors and Inotropes



clinically significant phenotypes. Polymorphisms have also been identified in the α1 and α2 receptors. There appears to be an association between some of these genotypes and the development of hypertension and heart failure.18 The majority of research on the impact of adrenergic receptor genetic variation has focused on its implications on the development and treatment of cardiovascular disease, as well as on the clinical outcomes after certain cardiac diagnoses (e.g., myocardial infarction). Little work has focused on the effects of vasopressors and inotropes in these different genotypes. It is reasonable to expect, however, that clinically significant differences seen in the response to receptor antagonists (e.g., β blockers) might also be observed for receptor agonists. Indeed, a polymorphism in the β1 receptor affects the response to dobutamine, with a significantly greater heart rate and inotropic response.19 Even though much work remains to be done in this area, it is likely that at least some of the large interindividual variability seen in the response to these drugs is a function of genetic variation.

Individual Drugs Epinephrine Epinephrine is a naturally occurring sympathomimetic with nonselective adrenergic agonist activity. It is synthesized, stored, and released by the chromaffin cells of the adrenal medulla in response to physiologic stress. It binds to α, β1 (the predominant β receptor in the heart), and β2 (the predominant ββ receptor in the lungs and vasculature) receptors. Action at the β3 receptor is not currently a target of clinical application of epinephrine. Epinephrine is the drug of choice in two extreme clinical conditions: anaphylactic shock and cardiac arrest (Fig. 25.3). In anaphylaxis, α-receptor–mediated vasoconstriction of small arterioles

β

α Mydriasis

Bronchodilation

↑ Inotropy ↑ Chronotropy ↑ Automaticity

↑ Glycogenolysis ↓ Insulin secretion Lipolysis

Vasodilation

• Fig. 25.3

Vasoconstriction

  Summary of the effects of epinephrine mediated by α- and β-adrenergic receptor stimulation.

525

and precapillary sphincters increases mean arterial pressure (MAP) and decreases mucosal edema. Its β-receptor–mediated effects cause bronchodilation and stabilization of mast cells. The latter decreases the release of histamine, tryptase, and other inflammatory mediators that perpetuate the pathophysiology of anaphylaxis. In cardiac arrest, epinephrine is given in large doses (1 mg every 3–5 minutes) to increase MAP, thereby increasing cerebral perfusion pressure during chest compressions. The value and safety of its β-receptor– mediated effects during cardiac arrest are controversial because they increase myocardial oxygen consumption. However, studies demonstrate better survival with epinephrine than without it.20 Other indications for epinephrine take advantage of specific subsets of its nonselective adrenergic agonism profile. Epinephrine is used to treat asthma (β2-mediated bronchodilation), severe hypotension associated with bradycardia (β1-mediated chronotropy) and/or low cardiac output (β1-mediated inotropy), and to prolong the effects of local anesthetics (α-mediated vasoconstriction). Low doses of epinephrine (0.02–0.05 µg/kg per minute) are used to increase depressed cardiac output after cardiopulmonary bypass; other catecholamines and inotropes have similar effects, but none has proven superior to epinephrine in terms of patient outcome. Epinephrine has also been studied as an alternative to other vasopressors in the treatment of vasodilatory shock from sepsis, even though the data do not yet support its use as a first-line therapy.21 Epinephrine’s effects are route, time, and dose dependent. At low doses (0.01–0.05 µg/kg per minute), the β-receptor effects of epinephrine predominate, while at higher doses, α effects predominate (see Table 25.1). An intravenous bolus of epinephrine (5–15 µg) causes an initial increase in heart rate, systolic blood pressure, and systemic vascular resistance (SVR, from stimulation of α and β receptors), and a subsequent decrease in systolic and diastolic blood pressure and vascular resistance (from continued stimulation of β receptors with peripheral vasodilation.)22 In healthy subjects, increasing rates of epinephrine infusion (0.01–0.2 µg/kg per minute) progressively increase heart rate and systemic blood pressure. In general, at progressively higher continuous infusion rates, heart rate, blood pressure, SVR, and cardiac output increase while pulmonary artery pressure, central venous pressure, and pulmonary artery occlusion pressure remain unchanged. Mast cell stabilization and bronchodilation via stimulation of β2 receptors are the two most important nonhemodynamic, therapeutic effects of epinephrine. Epinephrine has numerous other nonhemodynamic effects that are potentially adverse. At doses typically administered for vasopressor and/or inotropic effects, these potentially adverse effects include the following: • Hyperglycemia—due to increased liver glycogenolysis, reduced tissue uptake of glucose, and inhibition of pancreatic secretion of insulin • Hypokalemia—due to increased uptake of K+ in skeletal muscle secondary to stimulation of β2 receptors. Infusion of epinephrine at a rate of 0.1 µg/kg per minute reduces plasma K+ concentration by about 0.8 mEq/L.23 • Lactic acidosis—in theory due to inhibition of pyruvate dehydrogenase, causing pyruvate to be shunted to lactate.24 Although the mechanism is not fully elucidated, epinephrine infusion results in lactic acidosis even in the absence of tissue hypoxia and may not necessarily signify a poor prognosis.24,25 • Myocardial ischemia—due to hypertension, tachycardia, and increased inotropy that increase myocardial oxygen demand. Epinephrine is administered by continuous infusion, bolus, infiltration, or inhalation. Usual intravenous infusion doses are

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0.02 to 0.3 µg/kg per minutes. Intravenous bolus doses range from 5 to 10 µg for moderate hypotension (MAP 40–60 mm Hg) unresponsive to other vasopressors up to 1 mg as recommended by the American Heart Association guidelines for cardiac arrest.26 The usual intramuscular dose is 0.3 mg administered into the lateral thigh (vastus lateralis), which produces significantly higher plasma concentrations than administration into the deltoid or subcutaneously. Subcutaneous administration results in delayed absorption and lower peak plasma concentrations than other routes. This is generally reserved for treatment of severe asthma in doses of 0.3 to 0.5 mg for adults or 0.01 mg/kg for children, when inhaled selective β2 agonists cannot be administered.27 In addition, epinephrine can be administered via an endotracheal tube during cardiac arrest if other routes are not available; the recommended dose is double the intravenous dose diluted with 10 mL of normal saline solution. Epinephrine is not effective orally owing to rapid metabolism and does not cross the blood-brain barrier in sufficient amounts to directly affect the central nervous system. Epinephrine should not be used in patients with acute cocaine intoxication because of the potential for exacerbation of myocardial ischemia and stroke. In patients with dynamic obstructions to ventricular outflow (e.g., tetralogy of Fallot and hypertrophic obstructive cardiomyopathy), epinephrine can worsen outflow obstruction and lower cardiac output. Administration of epinephrine with a β blocker can lead to significant α-receptor stimulation without opposing β-receptor–mediated vasodilation, which can result in severe vasoconstriction, hypertension, and heart failure. Care should also be taken when administering epinephrine with medications that predispose the heart to arrhythmia, particularly digitalis and halothane.

Isoproterenol Isoproterenol was approved by the U.S. Food and Drug Administration (FDA) in 1947 and was used initially to treat asthma. Interestingly, it was the first drug for which the FDA required a package insert beginning in 1968. As the isopropyl derivative of norepinephrine, isoproterenol is a synthetic sympathomimetic with nonselective β-adrenergic activity. Stimulation of cardiac β1 receptors by isoproterenol increases heart rate, inotropy, and lusitropy, resulting in an increase in cardiac output and systolic blood pressure. Stimulation of β2 receptors results in vasodilation of the muscle, kidney, skin, and splanchnic circulations, thereby decreasing total peripheral vascular resistance and mean and diastolic blood pressure. The decrease in systemic blood pressure combined with increases in myocardial contractility and heart rate can precipitate myocardial ischemia in patients with significant coronary artery disease. At higher doses, palpitations, headache, and flushing can occur. Isoproterenol was used initially via inhaler to treat asthma and bronchospasm but has been replaced by β2-selective bronchodilators. Currently isoproterenol is indicated in hemodynamically significant bradycardia until cardiac pacing can be established. In prior years, it was used immediately following cardiac transplantation to enhance inotropy and chronotropy without concomitantly increasing systematic vascular resistance. Currently other drugs are used in this setting more commonly (e.g., epinephrine, milrinone, and vasopressin with cardiac pacing as necessary). Isoproterenol is also being used during electrophysiology procedures to stimulate the underlying arrhythmia for better mapping and increases the likelihood of a successful ablation.

Norepinephrine Norepinephrine is a naturally occurring sympathomimetic with both α- and β1-receptor affinity. Its effects are comparable to epinephrine on β1 receptors, but because of its greater affinity for α receptors and its near-total inactivity at β2 receptors, it is an intense vasoconstrictor. As the primary neurotransmitter of the sympathetic nervous system, it is released from postganglionic sympathetic nerve endings and represents 10% to 20% of the catecholamine content of the adrenal medulla. Norepinephrine causes an increase in systolic and diastolic blood pressures owing primarily to an increase in SVR (see Table 25.1). Cardiac output does not increase and can decrease owing to increased resistance to ventricular ejection. Heart rate remains unchanged or decreases from compensatory baroreceptor-mediated vagal activity. Blood flow decreases in renal, mesenteric, splanchnic, and hepatic beds. Norepinephrine increases pulmonary vascular resistance (PVR), probably by α1-mediated vasoconstriction.28 Norepinephrine is the drug of choice for septic shock when MAP is less than 65 mm Hg despite adequate volume resuscitation.29 Compared with dopamine in sepsis, norepinephrine is more likely to improve hypotension with fewer arrhythmias and tachycardia.30–32 Norepinephrine is also used to treat hypotension following cardiopulmonary bypass. However, when used to treat hypotension associated with milrinone administration, norepinephrine is less effective than vasopressin in preserving a beneficial ratio of systemic and PVR.33 Although norepinephrine increases PVR, its ability to substantially increase right ventricular perfusion pressure can make it a useful vasopressor in right heart failure.34 With regard to adverse effects, norepinephrine can cause severe hypertension with increased myocardial workload and cardiac ischemia. Systemic vasoconstriction can impair perfusion of the gut and other organs, resulting in organ dysfunction and metabolic acidosis. Clinical studies, however, have not consistently shown a decrease in splanchnic perfusion or worsening organ function when patients with sepsis are treated with norepinephrine.35 In some cases a decrease in splanchnic perfusion is associated with improved gastrointestinal perfusion, suggesting a redistribution of blood flow in the gut.36,37

Dopamine Dopamine is a naturally occurring catecholamine that stimulates β1-and α1-adrenergic receptors, as well as vascular D1-dopamine receptors (primarily in mesenteric and renal vasculature). It is synthesized in the kidney and has both diuretic and natriuretic effects. In addition to its peripheral actions, it is an important neurotransmitter in the central nervous system (see Chapters 8 and 12). At low plasma concentrations, dopamine acts primarily on the D1 receptor in renal, mesenteric, and coronary vasculature (see Table 25.1) to produce vasodilation of these beds with a resultant increase in glomerular filtration rate, renal blood flow, Na+ excretion, and urine output.38 Low doses can also decrease SVR. Higher doses directly stimulate β1 receptors and enhance release of norepinephrine from sympathetic nerve terminals to increase myocardial contractility, heart rate, systolic blood pressure, and pulse pressure. Diastolic blood pressure is minimally affected but PVR can increase.39 At high doses, stimulation of α1 receptors predominates, resulting in generalized peripheral vasoconstriction. It is commonly stated that doses of 0.5 to 3 µg/kg per minute stimulate primarily DA1 receptors, 3 to 10 µg/kg per minute

CHAPTER 25  Vasopressors and Inotropes



stimulate primarily β1 receptors, and greater than 10 µg/kg per minute primarily stimulate α receptors, but clinically the hemodynamic effects of dopamine are difficult to predict based on these empirical dosing guidelines.40 In healthy male volunteers, weightbased dopamine administration resulted in up to 75-fold intersubject variability in plasma concentrations.41 However, no study has yet compared plasma concentrations of dopamine with its effects. Therefore dosing should be titrated to physiologic effect, rather than being based on rigid concepts of relative receptor activity for a given dosage. Dopamine had previously been recommended as a first-line treatment for septic shock with systolic dysfunction. Recent studies showing worse outcomes with dopamine have resulted in a change in recommendations and it is now suggested only in patients at low risk for arrhythmia or those with bradycardia.29,42 Comparison of dopamine with norepinephrine for treatment of shock showed a higher incidence of arrhythmias in all patients and higher mortality in patients with cardiogenic shock treated with dopamine.32 Compared with dobutamine after cardiac surgery and in patients with chronic heart failure, dopamine resulted in less hemodynamic improvement.43,44 When compared with dopexamine, it resulted in significantly more adverse cardiac events.45 Renal dose dopamine refers to an infusion of dopamine in low doses (usually 1–3 µg/kg per minute) for treatment or prevention of acute renal failure with a goal of selective stimulation of D1 receptors. It is a misleading phrase and outdated concept, as the effects of dopamine even in low doses are not exclusively limited to the kidneys. Even though low doses of dopamine increase renal blood flow, glomerular filtration, and urine output, numerous studies have failed to show a decreased incidence of renal failure with its use.46 Dopamine can cause tachycardia, tachyarrhythmias, and myocardial ischemia, and at high doses causes decreased splanchnic perfusion and gut ischemia.35,47 In addition to its hemodynamic effects, dopamine reduces the ventilatory response to hypoxemia, consistent with its role of as a neurotransmitter in the carotid bodies.48 Dopamine infusions alter endocrine and immune function, including decreased secretion of growth hormone, prolactin, and thyroid stimulating hormone.49 Like other vasoconstrictors, dopamine can cause skin necrosis and sloughing if extravasation occurs. The renal and mesenteric vasodilating properties of low-dose dopamine are suppressed by dopamine receptor antagonists such as butyrophenones and phenothiazines.50,51 There are reports of dopamine causing hypotension and bradycardia in patients taking phenytoin.52

Dobutamine Dobutamine is a direct-acting synthetic catecholamine and is the drug of choice for the noninvasive assessment of coronary disease (dobutamine stress echocardiography). Dobutamine is also used for short-term treatment of congestive heart failure and for low cardiac output after cardiopulmonary bypass. In patients with chronic low output cardiac failure, dobutamine was superior to dopamine in its ability to increase cardiac output without untoward side effects.44 Similarly, it is superior to dopamine in managing hemodynamically unstable patients after cardiac surgery, reducing cardiac filling pressures and PVR with less trachycardia.39,43 Compared with milrinone after cardiac surgery, dobutamine was “comparable,” producing a greater increase in cardiac output, blood pressure, and heart rate but with a higher incidence of arrhythmias.53

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In patients with congestive heart failure, the principal effect of dobutamine is an increase in myocardial contractility and ventricular ejection mediated by its β1 effects. In contrast to epinephrine or dopamine, dobutamine generally reduces SVR by a combination of direct vasodilation and a reflex decrease in sympathetic vascular tone. This might be offset by the increase in cardiac output, leading to no change or a decrease in MAP. Dobutamine generally decreases cardiac filling pressures and PVR. Dobutamine has a variable effect on heart rate, but it can significantly increase heart rate (particularly at the higher concentrations used in stress echocardiography).8,54 After cardiopulmonary bypass the primary mechanism of increased cardiac output by dobutamine is an increase in heart rate (approximately 1.4 beats/min per microgram per kilogram per minute) with an increase in SVR.55 The contrasting results of these studies reflect dobutamine’s complex mechanisms of action, particularly with regard to the balance of α1 stimulation and inhibition by its isomers, as well as patient factors. Dobutamine can produce tachycardia, arrhythmias, and hypertension. Dobutamine can exacerbate myocardial ischemia in susceptible patients by increases in heart rate and contractility.

Milrinone Milrinone is a phosphodiesterase type III inhibitor, and as such is a synthetic noncatecholamine inodilator. Milrinone increases cardiac index with reductions in arterial pressure, left ventricular end-diastolic pressure, and PVR. Heart rate can increase, although this is not a consistent response and bradycardia can also occur. Compared with dobutamine, milrinone produces less tachycardia with more pulmonary and systemic vasodilation.56 Milrinone significantly increases success in the first attempt at weaning from cardiopulmonary bypass with less need for catecholamine support but with a greater requirement for additional vasoconstrictors.57,58 Milrinone might be preferable to adrenergic agonists in patients with chronic heart failure undergoing cardiopulmonary bypass as downregulation of adrenergic receptors in this population can lead to decreased responsiveness to catecholamines. In addition, milrinone improves flow in grafted internal mammary artery and saphenous vein grafts.59,60 Intravenous milrinone has also been used to reverse cerebral vasospasm after subarachnoid hemorrhage, while inhaled milrinone has been used to treat severe pulmonary hypertension and acute lung injury.61–64 Milrinone is attractive for use in right heart failure by increasing ventricular contractility and decreasing PVR. However, milrinoneinduced decreases in SVR and arterial blood pressure might offset these benefits and worsen supply-demand balance in the failing right heart. For this reason, milrinone is often combined with norepinephrine or vasopressin in an attempt to offset peripheral vasodilation. Comparing these two combinations, adding low-dose vasopressin to milrinone might be superior to adding norepinephrine in improving the ratio of systemic to PVRs.33 Inhaled milrinone offers the potential advantage of decreased PVR and increased ventricular contractility while maintaining SVR and MAP. Its use has been shown to improve the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FIO2) as well as decrease the intrapulmonary shunt fraction (Qs/Qt).65 When administered during cardiopulmonary bypass, inhaled milrinone may be superior to intravenous administration in reducing pulmonary reperfusion syndrome by preventing endothelial dysfunction in the pulmonary arterial system.66 The most common adverse effect of milrinone is arterial hypotension, though this is often a desired effect. Milrinone use is an

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independent risk factor for the development of atrial fibrillation after cardiac surgery, but the incidence is less than with dobutamine.53,67 About 12% of patients given milrinone in phase II and III trials developed ventricular arrhythmias (primarily premature ventricular contractions). Milrinone is typically given intravenously, but it can also be nebulized. Intravenous dosing of milrinone is initiated with a loading dose of 20 to 50 µg/kg over 10 minutes, followed by an infusion of 0.2 to 0.75 µg/kg per minute. Owing to the high degree of renal clearance, the dose should be reduced in patients with reduced creatinine clearance. Inhaled milrinone is nebulized in a concentration of 1 mg/mL. The most common administration regimen has been a single dose of 5 mg, though longer infusions have been studied as well.

Phenylephrine Phenylephrine is a synthetic noncatecholamine α1 agonist and produces dose-dependent vasoconstriction of cutaneous, muscular, mesenteric, splanchnic, and renal vasculature (see Table 25.1). Systemic arterial vasoconstriction increases systolic, diastolic, and MAPs, with reflex bradycardia. Phenylephrine can also cause pulmonary vasoconstriction and pulmonary hypertension. Phenylephrine is the drug of choice for initial treatment of mild hypotension with normal or increased heart rate in the setting of general or regional anesthesia. The use of phenylephrine to support blood pressure during spinal anesthesia for cesarean section has long been discouraged because of concerns that vasoconstriction could have a deleterious effect on placental blood flow. Several studies have strongly contradicted this traditional teaching by documenting that phenylephrine does not worsen fetal outcome and might in fact be superior to ephedrine.68,69 The use of phenylephrine in the management of septic shock is generally not recommended. Exceptions to this include cases in which norepinephrine causes significant arrhythmia or when vasodilation is refractory to other thrapy.29 Phenylephrine has been used to increase right ventricular perfusion in pulmonary hypertension and right heart failure, though it can worsen right ventricular function and raise pulmonary artery diastolic pressures; norepinephrine appears to be more effective in this setting.70,71 Phenylephrine is used topically as a nasal decongestant; as a mydriatic; and in ear, nose, and throat surgeries to constrict mucosa or control bleeding. Severe bradycardia or even brief asystole can occur with higher doses of phenylephrine. With left ventricular dysfunction, the combination of bradycardia and increased afterload can significantly reduce cardiac output. Case reports document the risk of pulmonary edema, arrhythmias, cardiac arrest, and death when phenylephrine is used topically in excessive doses during head and neck surgery to control bleeding.72 Topical doses should be limited to no more than 0.5 mg in adults, and blood pressure and heart rate should be monitored. Severe hypertension can require treatment with an α1 antagonist such as phentolamine or with a direct vasodilator such as hydralazine. β Blockers or calcium channel blockers should not be administered in this setting because their cardiac depressant effects can result in acute heart failure.72

Vasopressin Arginine vasopressin (AVP, vasopressin, also known as antidiuretic hormone) is a nonapeptide hormone synthesized in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus (see Chapter 36). It is stored and released

from neurosecretory vesicles in the posterior pituitary gland (neurohypophysis).13 Vasopressin is given typically by continuous intravenous infusion. Previously recommended infusion rates for hypotension were from 0.01 to 0.04 units/min based on a study that suggested increased cardiac complications with doses above 0.04 units/min.73 While some evidence suggests that a dose of 0.067 units/min results in better cardiovascular function with no increase in side effects, the surviving sepsis campaign recommends a maximal dose of 0.03 units/min in patients with sepsis and suggests that any further increase should be done only as salvage therapy.74,75 Further study is required to identify the optimal doses for different clinical settings. Vasopressin can be given as a bolus of 1 to 2 units to treat intraoperative hypotension, though its effects are short-lived. The hemodynamic effects of vasopressin are complex and vary depending on the presence or absence of intact sympathetic and renin-angiotensin systems. Interestingly, the effect of vasopressin infusions in healthy volunteers appears to be minimal even at high plasma concentrations.76 This paradoxical finding can be explained by the action of vasopressin on the area postrema of the central nervous system. The expected vasoconstrictive effect is effectively counterbalanced by an augmented baroreflex inhibition of efferent sympathetic activity.77 In patients with septic shock, low-dose vasopressin increases systemic arterial blood pressure and vascular resistance, but it does not alter pulmonary vascular resistance and pressures, cardiac filling pressures, or cardiac index.78 Heart rate can decrease, though this finding is not consistent. Even though it is not considered a first-line therapy, vasopressin is used as an adjunct to catecholamines in the treatment of septic shock. Patients with septic shock have much lower plasma vasopressin concentrations than those with cardiogenic shock. This has been interpreted as a relative vasopressin deficiency caused by early depletion of hypothalamic stores or inhibition of vasopressin release.79 The Vasopressin and Septic Shock Trial (VASST) compared norepinephrine with low-dose vasopressin to norepinephrine alone. There was no difference in overall mortality or adverse events, but mortality was reduced in patients with less severe sepsis who were given vasopressin.80 Guidelines on the use of vasopressin in cardiopulmonary resuscitation are evolving. Endogenous vasopressin levels are higher in patients who are successfully resuscitated.81 Studies have compared the use of vasopressin and epinephrine in cardiac arrest with variable outcomes.82–85 It does not appear that vasopressin confers a significant benefit compared with epinephrine, and the most recent American Heart Association guidelines have removed vasopressin as a single agent to replace a dose of epinephrine.26 Cardiopulmonary bypass is normally associated with a substantial increase in circulating vasopressin.86 In some cases of postbypass hypotension, plasma vasopressin concentrations are inappropriately low.87 These patients frequently respond to low doses of vasopressin, as do some patients with vasodilatory shock after cardiac transplantation or left ventricular assist device placement. Although not supported by specific studies, vasopressin is also used to treat intraoperative hypotension during general or epidural anesthesia. Clinical experience suggests that it might be useful in treating hypotension refractory to catecholamines in patients receiving long-term treatment with drugs that inhibit the reninangiotensin system (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers).88 In patients with septic shock, vasopressin reduces gastrointestinal mucosal perfusion and increases liver enzymes and total bilirubin concentrations.89,90 In addition, it decreases platelet count (likely



due to increased platelet aggregation) but does not significantly alter coagulation.91 Numerous drugs interact with vasopressin. Potentiation of its antidiuretic effect can be seen with carbamazepine, chlorpropamide, clofibrate, fludrocortisone, and TCAs. Inhibition of the antidiuretic effect can be seen with demeclocycline, norepinephrine, lithium, heparin, and alcohol.

Ephedrine Ephedrine is a synthetic noncatecholamine agonist at α, β1, and β2 receptors with both direct and indirect actions. Ephedrine is given as an intravenous bolus of 5 to 10 mg. It is effective in the same dose range when administered intramuscularly, albeit with slower onset and longer duration. When given in repeated doses, tachyphylaxis occurs, probably because of depleted norepinephrine stores. Ephedrine causes an increase in systolic, diastolic, and MAPs. It increases myocardial contractility, heart rate, and cardiac output (see Table 25.1). In the acute care setting, ephedrine is used primarily to treat mild hypotension and bradycardia associated with general or regional anesthesia. Previously, ephedrine was the first-line therapy for parturients with hypotension secondary to spinal or epidural anesthesia based on studies in pregnant ewes suggesting that ephedrine preserved uterine blood flow compared with other vasopressors.92 These data have been challenged recently; phenylephrine appears to be as good or better in preserving uterine blood flow and does not cause or worsen maternal tachycardia.93,94 At higher doses, ephedrine causes hypertension and tachycardia. Because it crosses the blood-brain barrier, ephedrine can cause agitation and insomnia. In patients with prostatic hypertrophy, ephedrine can produce urinary retention. Because ephedrine causes release of norepinephrine, patients taking MAOIs can have an exaggerated hypertensive effect.

Digoxin Digoxin, a cardiac glycoside, exerts its positive inotropic effects by inhibiting the plasma membrane Na+,K+-ATPase of cardiac myocytes. This leads to an increase in available Ca2+ as described earlier. Although digoxin has been in clinical use for hundreds of years as an inotrope and to control heart rate in atrial fibrillation, it has largely been replaced by more effective medications with fewer side effects. Digoxin is currently indicated (as a second- or third-line therapy) for ventricular rate control in atrial fibrillation and in the treatment of systolic heart failure.95,96 Although it is effective in providing symptomatic relief for heart failure, it does so with a significant increase in mortality and its use should essentially be considered palliative.97 It is likewise associated with increased mortality in patients with atrial fibrillation, and although it is effective in decreasing ventricular rate at rest, it does not prevent exercise induced tachycardia, does not aid in conversion to sinus rhythm, and may be associated with conversion from sinus rhythm back to atrial fibrillation.98 In addition to concerns about increased mortality with the use of digoxin, its use is significantly limited by the high incidence of side effects. The therapeutic index of digoxin is very small and requires plasma concentration monitoring, and its use is frequently associated with a wide variety of cardiac arrhythmias, including sinus bradycardia, sinus arrest, atrioventricular conduction delays, second- or third-degree heart block, and malignant ventricular

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arrhythmias. Digitalis toxicity is generally treated with digitalis binding antibody, as well as lidocaine, magnesium, phenytoin, and correction of hypokalemia.

Rational Drug Selection Rational selection of vasopressors and inotropes in clinical practice is founded on numerous factors, including the targeted therapeutic goals and the adverse effects most critical to avoid. Because in most clinical scenarios there is not a clearly established evidencebased approach supported by outcome data, institutional protocols and physician experience often figure prominently in the formulation of a therapeutic plan. Once formulated, the plan is instituted as a therapeutic trial; the complexity and dynamic nature of circulatory physiology might necessitate a change in the initial regimen if the results are unsatisfactory or if conditions change. In situations in which a variety of different drugs could potentially achieve the hemodynamic goals (and given the lack of class I evidence supporting the use of a particular drug), using a drug with which the practitioner has considerable experience is a reasonable approach. On the other hand, there are some clinical situations for which a particular drug might be preferable (see later text). The overarching principle is that rational drug selection must match the physiologic state of the patient with the anticipated effects of the drugs under consideration; the clinician must periodically reassess both the patient’s physiology and the drug choice to determine whether changes are necessary.

Septic Shock The pharmacologic management of septic shock has been the target of a large amount of research as well as the topic of published guidelines.29 Norepinephrine is considered the drug of choice in the septic shock patient when the MAP is below 65 mm Hg despite volume resuscitation.

Cardiac Arrest The use of large doses of epinephrine (up to 1 mg every 3–5 minutes) is the treatment of choice in the pulseless patient while a definitive diagnosis is being sought. Mild, Intraoperative Hypotension

Anesthesiologists are frequently faced with mild hypotension during the course of routine general and neuraxial anesthetics. As in all cases of hypotension, it is of paramount importance to identify the etiology to institute appropriate therapy. While the cause is being investigated, however, it is reasonable to administer small doses of ephedrine. Phenylephrine can also be used if low afterload is suspected and the patient has an adequate heart rate to tolerate the bradycardia associated with phenylephrine. It should be recognized, though, that the use of a vasoconstrictor can compromise cardiac output and organ perfusion in some cases.

Hypotension in the Parturient Until recently, the conventional wisdom has been that phenylephrine is contraindicated in the hypotensive pregnant patient and that ephedrine is the drug of choice. Recent literature, however, has contradicted that traditional teaching. In most routine circumstances, both ephedrine and phenylephrine are reasonable choices depending on the heart rate.

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Postbypass Hypotension

In addition to identifying and treating reversible causes of elevated PVR, pharmacologic management is crucial in the critically ill patient with right heart failure. Guiding principles are to support myocardial contractility as well as perfusion of the ventricle. The combination of milrinone with vasopressin is an excellent choice in this situation. Milrinone provides inotropy and pulmonary vasodilation, whereas vasopressin supports perfusion of the right ventricle by increasing the SVR. When milrinone proves inadequate to increase contractility adequately, the addition of epinephrine might be successful.

Hypotension in the patient being weaned from cardiopulmonary bypass represents an extremely complex interplay of physiologic factors; no single drug or protocol can reasonably be expected to prove universally efficacious. A comprehensive discussion of this topic is beyond the scope of this chapter, but basic concepts guiding the therapeutic decisions are summarized in Fig. 25.4. Before treatment is initiated, the first step is to reach an underlying diagnosis. In contemporary anesthesia practice, transesophageal echocardiography is unparalleled as a diagnostic tool in this setting.

HYPOTENSION AFTER CARDIOPULMONARY BYPASS Assess adequacy of preload1

Hypovolemia

Euvolemia

Administer judicious fluid bolus2

Assess LV systolic function3

Inadequate

Adequate

Initiate inotrope therapy2

Assess RV systolic function2

1. Epinephrine6 2. Milrinone7

Adequate

Consider cardiac pacing

1. Epinephrine6 2. Milrinone7

Initiate vasopressor therapy2

1. Vasopressin 2. Norepinephrine 3. Phenylephrine

Inadequate4

Assess afterload5 Begin again and reassess

Initiate inotrope therapy2

Adequate Assess heart rate

Adequate

Inadequate

Inadequate

1. Generally utilizing a combination of echocardiography and invasive pressure measurements. 2. After each intervention, the clinical scenario should be reassessed to determine if patient has stabilized. 3. LV and RV systolic functions are best evaluated with transesophageal echocardiography. 4. Causes of pulmonary vasoconstriction should be sought and corrected, and consideration should be given to instituting a pulmonary vasodilator such as nitric oxide or inhaled prostacyclin. 5. Low afterload (SVR) is indicated by adequate ventricular filling, a hyperdynamic ventricle, elevated cardiac output, and a low calculated SVR. 6. Dopamine could be considered in place of epinephrine, although epinephrine is usually considered the first-line drug. 7. The use of milrinone to support ventricular function in these patients will generally result in an increase in cardiac output, but to avoid worsening hypotension, it should be accompanied by the addition of vasopressin.

• Fig. 25.4  An approach to management of post–cardiopulmonary bypass hypotension. LV, Left ventricular; RV, right ventricular; SVR, systemic vascular resistance.



A broad differential diagnosis in this situation often includes left and/or right ventricular systolic dysfunction, inappropriate vasodilation, hypovolemia, and inadequate heart rate, each of which alone and in combination requires a different pharmacologic approach. The only drug that has been shown to improve ability to wean from cardiopulmonary bypass is milrinone. It provides excellent inotropic support, particularly in heart failure patients with downregulated autonomic receptors. Because its use is commonly associated with peripheral vasodilation and worsening hypotension, however, milrinone should generally be combined with vasopressin in this population. Epinephrine is also a common and appropriate choice in the hypotensive patient with decreased contractility of the right and/or left ventricle; its use is associated with an increase in cardiac output and blood pressure. When pure vasodilation is the cause of post–cardiopulmonary bypass hypotension, vasopressin is an excellent choice as it acts independently of the adrenergic receptors and as such can be expected to be additive with catecholamines. However, its use in this setting is a relatively new approach. In contrast, dopamine, epinephrine, and to a somewhat lesser extent, norepinephrine have a long history of successful use in supporting hemodynamics following cardiopulmonary bypass.

Emerging Developments Understanding the pharmacogenetic basis of the variability in response to vasopressors and cardiotonic drugs is a primary

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focus of contemporary research in this area. In the future, it is conceivable that vasopressor and inotropic therapy will be personalized to an individual’s genotype based on pretreatment testing. Combined with functional hemodynamic data allowing goal-directed therapy, it might eventually be possible to predict with accuracy and precision how an individual patient will respond to these drugs (see Chapter 4).99 Work continues as well in the area of drug development. Terlipressin, for example, is a recently developed long-acting synthetic analog of vasopressin with a half-life of 6 hours. In a small subset of patients with catecholamine-resistant septic shock, those receiving a single bolus of terlipressin had significantly less rebound hypotension during the reduction or cessation of norepinephrine.100 The calcium sensitizer subclass of drugs has also recently emerged in clinical practice and is being compared to more conventional therapies. Levosimendan is currently the only clinically available calcium sensitizing inodilator. In patients with heart failure, it has been shown to cause an increase in stroke volume and cardiac output with little change in heart rate (see Table 25.1). Cardiac filling pressures and pulmonary artery pressure decrease as well.14 Levosimendan is used in the treatment of acute decompensated heart failure, pulmonary hypertension, postpartum cardiomyopathy, and ventricular dysfunction after cardiac surgery. Several studies have compared levosimendan with dobutamine in acute decompensated heart failure with mixed results.101–104 Nonetheless, it represents a major advance in the development of new vasoactive drugs and exemplifies the continuing need for further research in the field.

Key Points • Vasoactive drugs have an extensive history and have been used clinically for more than 5000 years. • Many inotropes and vasopressors are derivatives of β phenylethylamine; the nature and extent of the ethylamine side chain substitution determines their receptor specificity. • Although various inotropes and vasopressors exert their effects via different receptors and mechanisms, they generally increase the availability of calcium to interact with actin and myosin in either the cardiac myocyte or vascular smooth muscle. • Catecholamines are primarily metabolized by catechol-O-methyl transferase and monoamine oxidase. • Despite well-established profiles in selected populations, the effects of vasopressors and inotropes are difficult to predict in an individual, and thus these drugs should be titrated to effect rather than administered by empiric dosage schemes. • A bolus of epinephrine can result in a transient increase in blood pressure from α-receptor stimulation, followed by a drop below the previous baseline from unopposed β-receptor stimulation. This serves as an example of the variable physiologic response to a given plasma concentration of a vasoactive agent.

• The use of low-dose dopamine as a means to preserve or improve renal function in critically ill patients is not supported by evidence despite extensive study and cannot be recommended. • Phosphodiesterase inhibitors such as milrinone enhance cardiac function by inotropic and vasodilator actions. Their use can facilitate restoration of acceptable hemodynamic parameters following cardiopulmonary bypass. • Contrary to long-standing dogma, either phenylephrine, an α-adrenergic agonist, or ephedrine, a mixed α- and β-adrenergic agonist, is an acceptable agent to treat hypotension in obstetric patients. • Although once a mainstay inotrope in the treatment of heart failure, because of its low therapeutic index and frequent incidence of serious dysrhythmias, digoxin is no longer a first-line therapy. • Treating an overdose of phenylephrine with β blockers or calcium channel blockers is contraindicated and can result in acute heart failure and death as the result of acute pulmonary edema. • Description of the phenotypes associated with genetic variations in adrenergic receptors and development of calcium sensitizers are among important emerging developments in the field.

Key References

Doolan LA, Jones EF, Kalman J, et al. A placebo-controlled trial verifying the efficacy of milrinone in weaning high-risk patients from cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 1997;11:37–41. Demonstrates the ability of milrinone, even a single dose, to improve the success of weaning high-risk patients from cardiopulmonary bypass. (Ref. 58). Groudine SB, Hollinger I, Jones J, et al. New York State guidelines on the topical use of phenylephrine in the operating room. The

Dellinger R, Levy M, Carlet J, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637. Best care of patients with sepsis as defined by a consensus of international experts. The evidence for use of various vasoactive drugs in addition to other medical and fluid management goals are discussed. (Ref. 29).

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Phenylephrine Advisory Committee. Anesthesiology. 2000;92:859–864. Highlights the severe complications of topical phenylephrine overdose as well as the potentially disastrous outcome when phenylephrine overdose is treated with negative inotropes (β blockers or calcium channel blockers). (Ref. 72). Kellum JA, Decker JM. Use of dopamine in acute renal failure: a metaanalysis. Crit Care Med. 2001;29:1526–1531. Meta-analysis of 58 studies concluding that there is no justification for use of low-dose dopamine for treatment or prevention of acute renal failure. (Ref. 46). Linton NW, Linton RA. Haemodynamic response to a small intravenous bolus injection of epinephrine in cardiac surgical patients. Eur J Anaesthesiol. 2003;20:298–304. Describes the hemodynamic response to small (5-µg) boluses of epinephrine, including an initial increase followed by a subsequent decrease in systemic vascular resistance to less than 50% baseline. An excellent example of the response of adrenergic receptors to different plasma concentrations of agonist. (Ref. 22). MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology. 2000;92:338–346. Shows up to 75-fold interpatient variability in plasma concentration when infusing dopamine. This highlights the importance of titrating to physiologic effect. (Ref. 41). Ngan Kee WD, Khaw KS, Tan PE, et al. Placental transfer and fetal metabolic effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology. 2009;111:506–512. Suggests that the balance of fetal oxygen supply and demand might be better achieved with phenylephrine than ephedrine. (Ref. 69). Russell J, Walley K, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–887. Although vasopressin is not recommended as first-line therapy for patients with septic shock, when compared with norepinephrine in this population the outcomes are at least as good. In fact, patients with less severe sepsis have improved outcome with vasopressin. (Ref. 80). Williams TD, Da Costa D, Mathias CJ, et al. Pressor effect of arginine vasopressin in progressive autonomic failure. Clin Sci. 1986;71:173–178. Demonstrates that vasopressin does not appreciably increase mean arterial pressure in healthy volunteers. This highlights the importance of underlying physiologic state when attempting to predict response to a vasoactive substance. (Ref. 76).

References 1. Levy B, Collin S, Sennoun N, et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 2010;36(12):2019–2029. doi:10.1007/ s00134-010-2045-8. 2. Chen KK, Schmidt GF. The action of ephedrine, the active principle of the Chinese drug Ma Huang. J Pharmacol Exp Ther. 1924;24:339–357. 3. Wilkins MR, Kendall MJ, Wade OL. William Withering and digitalis, 1785 to 1985. Br Med J (Clin Res Ed). 1985;290(6461):7–8. 4. Oliver G, Schäfer EA. On the physiological action of extracts of pituitary body and certain other glandular organs: preliminary communication. J Physiol. 1895;18(3):277–279. 5. Barger G, Ewins AJ. CCXXXVII.?Some phenolic derivatives of ?-phenylethylamine. J Chem Soc, Trans. 1910;97:2253. doi:10.1039/ ct9109702253. 6. Barger G, Dale HH. Chemical structure and sympathomimetic action of amines. J Physiol. 1910;41(1–2):19–59. 7. von Euler U. A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and noradrenaline. Acta Physiol Scand. 1946. 8. Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res. 1975;36(1):185–196. 9. Vigneaud du V, Gish DT, Katsoyannis PG. A synthetic preparation possessing biological properties associated with argininevasopressin. J Am Chem Soc. 1954;76(18):4751–4752.

10. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther. 2000;68(5):522–531. doi:10.1067/mcp.2000.110972. 11. Salvi SS. Alpha1-adrenergic hypothesis for pulmonary hypertension. Chest. 1999;115(6):1708–1719. 12. Minneman KP. Alpha 1-adrenergic receptor subtypes, inositol phosphates, and sources of cell Ca2. Pharmacol Rev. 1988;40(2):87–119. 13. Barrett LK, Singer M, Clapp LH. Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med. 2007;35(1):33–40. doi:10.1097/01.CCM.0000251127.45385.CD. 14. Lilleberg J, Laine M, Palkama T, et al. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail. 2007;9(1):75–82. doi:10.1016/j. ejheart.2006.04.012. 15. Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153(3):586–600. 16. Leineweber K, Heusch G. β 1- and β 2-Adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol. 2009;158(1):61–69. doi:10.1111/j.1476-5381.2009.00187.x. 17. Homeyer Von P, Schwinn DA. Pharmacogenomics of β-adrenergic receptor physiology and response to β-blockade. Anesth Analg. 2011; 113(6):1305–1318. doi:10.1213/ANE.0b013e31822b887e. 18. Sheppard R. Vascular tone and the genomics of hypertension. Heart Fail Clin. 2010;6(1):45–53. doi:10.1016/j.hfc.2009.08.009. 19. Bruck H, Leineweber K, Temme T, et al. The Arg389Gly Beta1adrenoceptor polymorphism and catecholamine effects on plasmarenin activity. J Am Coll Cardiol. 2005;46(11):2111–2115. doi:10.1016/j.jacc.2005.08.041. 20. Neumar RW, Otto CW, Link MS, et al. Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18_suppl_3):S729–S767. doi:10.1161/CIRCULATIONAHA.110.970988. 21. De Backer D, Creteur J, Silva E, et al. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med. 2003;31(6):1659–1667. doi:10.1097/01.CCM.0000063045.77339.B6. 22. Linton NWF, Linton RAF. Haemodynamic response to a small intravenous bolus injection of epinephrine in cardiac surgical patients. Eur J Anaesthesiol. 2003;20(4):298–304. 23. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2receptor stimulation by circulating epinephrine. N Engl J Med. 1983;309(23):1414–1419. doi:10.1056/NEJM198312083092303. 24. Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997;25(10):1693–1699. 25. Cori CF, Cori GT. The mechanism of epinephrine action. IV. The influence of epinephrine on lactic acid production and blood sugar utilization. J Biol Chem. 1929;84:683–698. 26. Link MS, Berkow LC, Kudenchuk PJ, et al Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132:S444-S464. doi:10.1161/CIR.0000000000000261. 27. Camargo CA, Rachelefsky G, Schatz M. Managing asthma exacerbations in the emergency department: Summary of the National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for the management of asthma exacerbations. Proc Am Thorac Soc. 2009;6(4):357–366. doi:10.1513/pats.P09ST2. 28. Rudner XL, Berkowitz DE, Booth JV, et al. Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age. Circulation. 1999;100(23):2336–2343. 29. Dellinger RP, Levy MM, Rhodes A. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. 30. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest. 1993;103(6):1826–1831.



31. Meadows D, Edwards JD, Wilkins RG, et al. Reversal of intractable septic shock with norepinephrine therapy. Crit Care Med. 1988;16(7):663–666. 32. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779–789. doi:10.1056/NEJMoa0907118. 33. Jeon Y, Ryu JH, Lim YJ, et al. Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients. Eur J Cardiothorac Surg. 2006;29(6):952–956. doi:10.1016/j. ejcts.2006.02.032. 34. Schreuder WO. Effect of dopamine vs norepinephrine on hemodynamics in septic shock. Emphasis on right ventricular performance. Chest. 1989;95(6):1282. doi:10.1378/chest.95.6.1282. 35. Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA. 1994;272(17):1354–1357. 36. Nygren A, Thorn A, Ricksten S-E. Norepinephrine and intestinal mucosal perfusion in vasodilatory shock after cardiac surgery. Shock. 2007;PAP. doi:10.1097/shk.0b013e318063e71f. 37. Nygren A, Thorn A, Ricksten S-E. Vasopressors and intestinal mucosal perfusion after cardiac surgery: Norepinephrine vs. phenylephrine. Crit Care Med. 2006;34(3):722–729. doi:10.1097/01. CCM.0000201879.20281.C6. 38. McDonald RH Jr, Goldberg LI, McNay JL, et al. Effects of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow*. J Clin Invest. 1964;43(6):1116–1124. doi:10.1172/JCI104996. 39. Salomon NW, Plachetka JR, Copeland JG. Comparison of dopamine and dobutamine following coronary artery bypass grafting. Ann Thorac Surg. 1982;33(1):48–54. 40. Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation. 1985;72(2):245–248. 41. MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology. 2000;92(2):338–346. 42. Sakr Y, Reinhart K, Vincent J-L, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006;34(3): 589–597. 43. Tarr TJ, Moore NA, Frazer RS, et al. Haemodynamic effects and comparison of enoximone, dobutamine and dopamine following mitral valve surgery. Eur J Anaesthesiol Suppl. 1993;8:15–24. 44. Loeb HS, Bredakis J, Gunner RM. Superiority of dobutamine over dopamine for augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation. 1977;55(2):375. 45. Rosseel PM, Santman FW, Bouter H, et al. Postcardiac surgery low cardiac output syndrome: dopexamine or dopamine? Intensive Care Med. 1997;23(9):962–968. 46. Kellum JA, Decker JM. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001;29(8):1526–1531. 47. Nevière R, Mathieu D, Chagnon JL, et al. The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1684–1688. 48. Ward DS, Bellville JW. Reduction of hypoxic ventilatory drive by dopamine. Anesth Analg. 1982;61(4):333–337. 49. Schenarts PJ, Sagraves SG, Bard MR, et al. Low-dose dopamine: a physiologically based review. Curr Surg. 2006;63(3):219–225. doi:10.1016/j.cursur.2005.08.008. 50. Goldberg LI, Yeh BK. Attenuation of dopamine-induced renal vasodilation in the dog by phenothiazines. Eur J Pharmacol. 1971;15(1):36–40. 51. Yeh BK, McNay JL, Goldberg LI. Attenuation of dopamine renal and mesenteric vasodilation by haloperidol: evidence for a specific dopamine receptor. J Pharmacol Exp Ther. 1969;168(2):303–309. 52. Bivins BA, Rapp RP, Griffen WO, et al. Dopamine-phenytoin interaction. A cause of hypotension in the critically ill. Arch Surg. 1978;113(3):245–249.

CHAPTER 25  Vasopressors and Inotropes

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53. Feneck RO, Sherry KM, Withington PS, et al. Comparison of the hemodynamic effects of milrinone with dobutamine in patients after cardiac surgery. J Cardiothorac Vasc Anesth. 2001;15(3):306–315. doi:10.1053/jcan.2001.23274. 54. Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation. 1977;56(3):468–472. 55. Romson JL, Leung JM, Bellows WH, et al Effects of dobutamine on hemodynamics and left ventricular performance after cardiopulmonary bypass in cardiac surgical patients. Anesthesiology. 1999;91(5):1318-1328. 56. Yamani MH, Haji SA, Starling RC, et al. Comparison of dobutaminebased and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J. 2001;142(6):998–1002. doi:10.1067/mhj.2001.119610. 57. Lobato EB, Florete O, Bingham HL. A single dose of milrinone facilitates separation from cardiopulmonary bypass in patients with pre-existing left ventricular dysfunction. Br J Anaesth. 1998;81(5):782–784. 58. Doolan LA, Jones EF, Kalman J, et al. A placebo-controlled trial verifying the efficacy of milrinone in weaning high-risk patients from cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 1997;11(1):37–41. 59. Lobato EB, Urdaneta F, Martin TD, et al. Effects of milrinone versus epinephrine on grafted internal mammary artery flow after cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2000;14(1):9–11. 60. Arbeus M, Axelsson B, Friberg O, et al. Milrinone increases flow in coronary artery bypass grafts after cardiopulmonary bypass: a prospective, randomized, double-blind, placebo-controlled study. J Cardiothorac Vasc Anesth. 2009;23(1):48–53. doi:10.1053/j. jvca.2008.07.005. 61. Fraticelli AT, Cholley BP, Losser M-R, et al. Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2008;39(3):893–898. doi:10.1161/STROKEAHA.107.492447. 62. Bueltmann M, Kong X, Mertens M, et al. Inhaled milrinone attenuates experimental acute lung injury. Intensive Care Med. 2009;35(1):171–178. doi:10.1007/s00134-008-1344-9. 63. Buckley MS, Feldman JP. Nebulized milrinone use in a pulmonary hypertensive crisis. Pharmacotherapy. 2007;27(12):1763–1766. doi:10.1592/phco.27.12.1763. 64. Lamarche Y, Perrault LP, Maltais S, et al. Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg. 2007;31(6):1081–1087. doi:10.1016/j.ejcts.2007.02.019. 65. Wang H, Gong M, Zhou B, et al. Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery. Adv Ther. 2009;26(4):462–468. doi:10.1007/s12325-009-0019-4. 66. Zhang J, Chen F, Zhao X, et al. Nebulized phosphodiesterase III inhibitor during warm ischemia attenuates pulmonary ischemiareperfusion injury. J Heart Lung Transplant. 2009;28(1):79–84. doi:10.1016/j.healun.2008.10.012. 67. Fleming GA, Murray KT, Yu C, et al. Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery. Circulation. 2008;118(16):1619–1625. doi:10.1161/CIRCULATIONAHA .108.790162. 68. Ngan Kee WD, Khaw KS, Lau TK, et al. Randomised double-blinded comparison of phenylephrine vs ephedrine for maintaining blood pressure during spinal anaesthesia for non-elective Caesarean section*. Anaesthesia. 2008;63(12):1319–1326. doi:10.1111/j.1365-2044.2 008.05635.x. 69. Ngan Kee WD, Khaw KS, Tan PE, et al. Placental transfer and fetal metabolic effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology. 2009;111(3):506–512. doi:10.1097/ALN.0b013e3181b160a3. 70. Rich S, Gubin S, Hart K. The effects of phenylephrine on right ventricular performance in patients with pulmonary hypertension. Chest. 1990;98(5):1102–1106.

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71. Kwak YL, Lee CS, Park YH, et al. The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension. Anaesthesia. 2002;57(1):9–14. 72. Groudine SB, Hollinger I, Jones J, et al. New York State guidelines on the topical use of phenylephrine in the operating room. The Phenylephrine Advisory Committee. Anesthesiology. 2000;92(3): 859–864. 73. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest. 2001;120(3):989. 74. Luckner G, Mayr VD, Jochberger S, et al. Comparison of two dose regimens of arginine vasopressin in advanced vasodilatory shock. Crit Care Med. 2007;35(10):2280. 75. Torgersen C, Dünser MW, Wenzel V, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36(1):57–65. 76. Williams TD, Da Costa D, Mathias CJ, et al. Pressor effect of arginine vasopressin in progressive autonomic failure. Clin Sci. 1986;71(2):173–178. 77. Hasser EM, Cunningham JT, Sullivan MJ, et al. Area postrema and sympathetic nervous system effects of vasopressin and angiotensin II. Clin Exp Pharmacol Physiol. 2000;27(5–6):432–436. 78. Tsuneyoshi I, Yamada H, Kakihana Y, et al. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001;29(3):487. 79. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95(5):1122–1125. 80. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887. doi:10.1056/NEJMoa067373. 81. Lindner KH, Haak T, Keller A, et al. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart. 1996;75(2):145–150. 82. Lindner KH, Dirks B, Strohmenger H-U, et al. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. The Lancet. 1997;349(9051):535–537. doi:10.1016/S0140-6736(97)80087-6. 83. Callaway CW, Hostler D, Doshi AA, et al. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol. 2006;98(10):1316–1321. doi:10.1016/j.amjcard.2006 .06.022. 84. Mukoyama T, Kinoshita K, Nagao K, et al. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation. 2009;80(7):755–761. doi:10.1016/j.resuscitation.2009.04.005. 85. Gueugniaud PY, David JS, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359(1):21–30. doi:10.1056/NEJMoa0706873. 86. Levine FH, Philbin DM, Kono K, et al. Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Ann Thorac Surg. 1981;32(1):63–67. 87. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg. 1998;116(6):973–980. 88. Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology. 2003;98(6):1338–1344.

89. van Haren FMP, Rozendaal FW, van der Hoeven JG. The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest. 2003;124(6):2256–2260. 90. Dünser MW, Mayr AJ, Ulmer H, et al. The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis. Anesth Analg. 2001;93(1):7–13. 91. Dünser MW, Fries DR, Schobersberger W, et al. Does arginine vasopressin influence the coagulation system in advanced vasodilatory shock with severe multiorgan dysfunction syndrome? Anesth Analg. 2004;99(1):201–206. 92. Ralston DH, Shnider SM, DeLorimier AA. Effects of equipotent ephedrine, metaraminol, mephentermine, and methoxamine on uterine blood flow in the pregnant ewe. Anesthesiology. 1974;40(4):354–370. 93. Cooper DW, Carpenter M, Mowbray P, et al. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology. 2002;97(6):1582–1590. 94. Lee A, Kee WDN, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2002;94(4):920–926. 95. Developed with the special contribution of the European Heart Rhythm Association (EHRA), Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS), Authors/Task Force Members, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369–2429. doi:10.1093/eurheartj/ehq278. 96. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. J Am Coll Cardiol. 2009;53(15):1343–1382. doi:10.1016/j.jacc.2008.11.009. 97. Lindsay SJ, Kearney MT, Prescott RJ, et al. Digoxin and mortality in chronic heart failure. UK Heart Investigation. Lancet. 1999;354(9183):1003. 98. Gjesdal K, Feyzi J, Olsson SB. Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data. Heart. 2008;94(2):191–196. doi:10.1136/hrt.2006.108399. 99. Giglio MT, Marucci M, Testini M, et al. Goal-directed haemodynamic therapy and gastrointestinal complications in major surgery: a meta-analysis of randomized controlled trials. Br J Anaesth. 2009;103(5):637–646. doi:10.1093/bja/aep279. 100. O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrineresistant septic shock. The Lancet. 2002;359(9313):1209–1210. 101. Delaney A, Bradford C, Mccaffrey J, et al. Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials. Int J Cardiol. 2010;138(3):281–289. doi:10.1016/j. ijcard.2008.08.020. 102. Follath F, Cleland JGF, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360(9328):196–202. 103. Mebazaa A, Nieminen MS, Filippatos GS, et al. Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail. 2009;11(3):304–311. doi:10.1093/ eurjhf/hfn045. 104. Bergh C-H, Andersson B, Dahlström U, et al. Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta-blockers. Eur J Heart Fail. 2010;12(4):404–410. doi:10.1093/eurjhf/hfq032.

26 

Antihypertensive Drugs and Vasodilators JOHN W. SEAR

CHAPTER OUTLINE Historical Perspective Sites and Mechanisms of Antihypertensive and Vasodilator Drugs Basic Pharmacology and Mechanisms of Action of Individual Drug Classes Calcium Channel Blockers β Blockers Action of β Blockers at the Adrenergic Receptor Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists Diuretics Centrally Acting Agents α2 Adrenoreceptor Agonists α1 Adrenoreceptor Antagonists Nitrovasodilators Other Vasodilators Pharmacokinetics, Pharmacodynamics, and Adverse Effects Calcium Channel Blockers Adverse Drug Interactions New Calcium Channel Blockers β Blockers Antihypertensive Effect of β Blockers New β Blockers Adverse Effects of β Blockers

T

here are probably more than 1 billion people worldwide with raised blood pressure.1 It is one of the most common chronic medical conditions internationally (US National Center for Health Statistics, 2005), and occurs almost twice as often in African-Americans than in whites. The incidence of hypertension increases with age, with a slightly greater incidence in men than in women.2 In the United States, hypertension affects about 25% of all adults older than 40 years of age. More importantly, the prevalence of undiagnosed hypertension is about 1 in 15. In the United Kingdom, there are about 7.5 million patients suffering from raised blood pressure; 80% to 85% of these patients are either not treated or are being inadequately treated. Blood pressure has been classified into four categories in the Joint National Committee on Prevention, Detection, Evaluation

Angiotensin-Converting Enzyme Inhibitors Angiotensin II Receptor Antagonists Adverse Effects and Drug Interactions Diuretics Adverse Effects and Drug Interactions α2 Adrenoreceptor Agonists α1 Adrenoreceptor Antagonists Phentolamine and Phenoxybenzamine Vasodilators Hydralazine Nicorandil Minoxidil Nitrates Phosphodiesterase Inhibitors Pharmacotherapy of Hypertension Hypertension and Anesthesia Pulmonary Vasodilators Phosphodiesterase Inhibitors Novel Pulmonary Vasodilators Emerging Developments New Management Guidelines for Hypertension Direct Renin Inhibitors Natriuretic Peptides Endothelin and Endothelin Blockade

and Treatment of High Blood Pressure, 7th Report (JNC 7 Report) based on systolic (left) and diastolic (right) pressures3: • Normotension less than 120 and less than 80 mm Hg • Prehypertension 120 to 139 or 80 to 89 mm Hg • Stage I hypertension 140 to 159 or 90 to 99 mm Hg • Stage II hypertension greater than 160 or greater than or equal to 100 mm Hg In addition, patients with isolated systolic hypertension (ISH) are classified into ISH 1 (140–159/< 90 mm Hg) and ISH 2 (> 160/< 90 mm Hg). In 2014, JNC 8 recommended treatment of systolic blood pressure over 150 mm Hg or diastolic blood pressure over 90 mm Hg to a goal of less than these values for patents aged > 60 years, and treatment for systolic blood pressure over 140 mm Hg or diastolic blood pressure over 90 mm Hg for patients aged D-enantiomer). Metabolism is extensive by O-demethylation (25%) and N-dealkylation (40%) followed by conjugation. Some of the metabolites are active, especially norverapamil, which has about one-fifth to one-tenth the activity of the parent drug. Verapamil has a half-life of about 5 hours (range, 2–7 hours), which can be prolonged in patients with liver disease. The clearance of L-verapamil is greater than that of the D-enantiomer, although the half-lives of the 2 enantiomers are similar. There is greater free fraction of L-verapamil; hence, it has a greater volume of distribution. Verapamil is excreted in the urine (70%; as metabolites and unchanged drug) and feces. Diltiazem (a benzothiazepine) is well absorbed orally (> 90%), but has a smaller fraction undergoing presystemic metabolism (about 50%). Diltiazem is extensively metabolized, and some of these metabolites are active. All dihydropyridines (nifedipine, amlodipine, felodipine, isradipine, nicardipine, lacidipine, lercanidipine, nisoldipine) are well absorbed by the oral route (> 90%), but because of their significant presystemic metabolism, sublingual dosing is preferable for some (e.g., nifedipine). Presystemic metabolism of nifedipine results in inactive metabolites with half-lives of about 9 hours, while that of the parent drug is about 2 to 6 hours, with plasma protein binding of more than 90% and a small volume of distribution (0.3–1.2 L/ kg). Metabolites are excreted in both the urine (80%) and feces. Chemical substitutions in nifedipine at the R1 position, with introduction of long side chains (as amlodipine), produce drugs with a longer duration of action and a half-life of up to 30 to 40 hours (felodipine 12–36 hours; isradipine 2–8 hours; nicardipine

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NO2 R1 • OOC CH3

COO • CH2 • R2 N

CH3

• Fig. 26.7

Structure of the dihydropyridine calcium entry blockers. R1 and R2 are side chains at the 1 and 4 positions of the pyridine ring.  

3–12 hours; amlodipine 35–60 hours; Fig. 26.7). The dihydropyridines are metabolized by hepatic cytochrome P450 (mainly CYP 3A4). Hence, there are many examples of drug–drug interactions either with CYP 3A4 inhibitors (the -azoles, -avirs, erythromycin, clarithromycin) or with other drugs competing for metabolism by the same isoform (e.g., midazolam, alfentanil, cyclosporin). Nifedipine shows a bimodal polymorphism of metabolism by CYP 3A4/5. The calcium channel blockers all demonstrate age-related kinetics due to reduction in cardiac output (and liver blood flow), leading to increased bioavailability and decreased systemic clearance. Other side effects of dihydropyridine include vasodilation with flushing, headaches, ankle edema, and reflex tachycardia. The use of calcium channel blockers is contraindicated in patients with heart failure owing to their negative inotropic effects (especially the nondihydropyridines) and slowing of sinoatrial and atrioventricular node conduction, leading to bradycardia and heart block. Pronounced antihypertensive effects are mainly observed with the dihydropyridines. The decrease in blood pressure is accompanied by reflex tachycardia and increased myocardial oxygen utilization.

Adverse Drug Interactions Dihydropyridines increase plasma digoxin concentrations by inhibiting their tubular secretion by interaction with P-glycoprotein. Verapamil can worsen cardiac failure in affected patients, causing hypotension due to both vasodilation and negative inotropy. If verapamil is given in combination with a β blocker, patients can develop hypotension, asystole, and an increased incidence of arrhythmias. Diltiazem reduces cardiac output and hepatic clearance of flow-limited drugs, such as propranolol and cyclosporin A. Both nondihydropyridines (diltiazem and verapamil) can cause bradycardia and heart block when administered in conjunction with β blockers. They can also exacerbate congestive heart failure through negative inotropic effects. Newer Calcium Channel Blockers Clevidipine (an intravenous dihydropyridine) is characterized by rapid onset of action, vascular selectivity, and unique pharmacokinetics. Unlike other drugs in this class, it is not metabolized in the liver but rather undergoes breakdown of an ester-linkage in blood and extravascular tissues to produce inactive carboxylic acid metabolites. This leads to a rapid onset of effect (within 60 seconds) and short duration of action. It is highly protein bound (> 99.5%) with a small volume of distribution (0.5–0.6 L/kg) and high clearance (0.105 L/kg/min). The rapid offset relates partly to its short elimination half-life (about 15 minutes). After infusions of up to 12 hours, the context-sensitive half-time of the drug is less than 2 minutes. Drug metabolism does not involve CYP enzymes; hence, its elimination is not affected by hepatic or renal disease and there are no significant drug–drug interactions

documented to date.44 Clevidipine might be useful for emergency control of blood pressure by careful titration of an intravenous infusion.45,46

β Blockers There are two main chemical structural types of β blockers: (1) amino-oxypropanol derivatives (propranolol, timolol, pindolol, metoprolol, atenolol, esmolol, and carvedilol) and hydroxyaminoethyl compounds (sotalol and labetalol). Although described in Table 26.7 as β1 selective blocking drugs, metoprolol, celiprolol, and bisoprolol all show β2 antagonism at high doses. Most β blockers are well absorbed when given orally, although atenolol and sotalol, being more polar, have lower oral absorption (about 50%). Carvedilol, metoprolol, and propranolol all undergo extensive presystemic metabolism; bisoprolol shows no presystemic metabolism and is metabolized by only about 50%. Both atenolol and sotalol are eliminated in urine mostly unchanged. The principal kinetics and dynamics of some commonly used β blocking agents for treatment of hypertension are summarized in Table 26.8. Propranolol is a nonselective β-blocking drug (although β1 activity is greater than β2 activity), with some membrane-stabilizing activity (MSA). It is highly lipid soluble and can therefore cross the bloodbrain barrier, which can result in drug-induced depression. Propranolol undergoes extensive hepatic metabolism with less than 4% of the drug excreted unchanged in the urine and feces. Oxprenolol is a β1-selective blocker with intrinsic sympathomimetic activity (ISA) and MSA. Like propranolol, it is extensively metabolized, with less than 5% excreted unchanged in the urine. Metoprolol is a highly selective β1 drug with no MSA and no ISA. Metoprolol shows polymorphism with regard to its metabolism; some of the metabolites (especially α-OH-metoprolol and O-desmethyl-metoprolol) are active at the β1 receptor. There can also be extrahepatic metabolism. Pindolol is excreted in the urine as both unchanged drug (40%) and metabolites following oxidation and glucuronide conjugation. Atenolol has properties similar to those of metoprolol. It is eliminated by renal excretion (90%) as unchanged drug. Being hydrophilic, there are few CNS side effects due to minimal bloodbrain barrier transfer. Bisoprolol is a β1-selective blocker that is well absorbed orally. Elimination is via the kidney (50% unchanged and 50% as an active metabolite) following hepatic biotransformation. Nadolol is a β1-selective blocker that is eliminated solely by the kidney. Hence, its use is contraindicated in patients with renal impairment. Timolol is a nonselective β blocker that is eliminated by both hepatic metabolism and renal excretion (20% as unchanged drug). Bextalol is a cardioselective blocker that is well absorbed and undergoes minimal presystemic metabolism. It has a half-life of 13 to 24 hours and is metabolized by hepatic hydroxylation with little conjugation. The hydroxyl-metabolite is excreted in the urine, together with 10% to 17% unchanged drug. Acebutolol, carteolol, penbutolol, and pindolol are all nonselective agents with some ISA. Acebutolol is biotransformed by hydrolysis and N-acetylation in the liver to an active metabolite, diacetolol, which has a long half-life of 10 to 14 hours. There can also be some drug metabolism in the gut following oral dosing. Celiprolol is a third-generation selective β1 blocker with no MSA. This agent has some ISA at the β2 receptor, manifest as weak bronchodilation and vasodilation.

CHAPTER 26  Antihypertensive Drugs and Vasodilators



545

TABLE 26.8  Pharmacokinetics and Pharmacodynamics of Common β Blockers

Oral ABSN (%) Acebutolol Atenolol

>50 40–50

Bioavailability (%)

T1/2 (hr)

Plasma Protein (%)

Metabolic Route

β1 selectivity

ISA

MSA

Vasodilation

Other

30–50

3–6

26

100% H

Yes

Yes

Yes

No

Nil

>90

6–7

85

4–6

30

Minimal

Yes

No

No

Yes

Yes2

90% H

Yes

No

No

Yes

Yes3

90% H, gut

Yes

No

No

No

Nil

Bisoprolol

>95

Carvedilol

25

Celiprolol

30–70

Labetalol

>95

15–90

3–4

50

Metoprolol*

50–70

40–50

3–7*

5–10

Nadolol

30–40

>95

17–24

30

Minimal

No

No

No

No

Nil

Nebivolol*

?

12–96

12–19*

?

Extensive H

Yes

No

No

Yes

Yes4

Oxprenolol

90

20–70

1–2

80

Extensive H

No

Yes

Yes

No

Nil

Pindolol

>95

85–90

3–4

40

H

No

Yes

Yes

No

Nil

Propranolol

>95

5–50

3–6

80–95

100% H

No

No

Yes

No

Nil

Timolol*

>95

50

2–5

80

80%H

No

No

No

No

Nil

Esmolol

N/A

N/A

0.14–0.18

55

Rbc–esterase

Yes

No

No

No

Nil

*, Drug showing polymorphism; ABSN, absorption; H, hepatic; ISA, intrinsic sympathomimetic activity; MSA, membrane stabilizing activity; plasma protein (%), plasma protein binding; Yes 1, α1, β2 antagonism; Yes 2, β2 agonism; Yes 3, β1 and β2 antagonism, some ISA at β2; Yes 4, nitric oxide-potentiating vasodilatory effect.

Antihypertensive Effect of β Blockers The exact mechanism by which β blockers reduce blood pressure is unclear. They could act through reduction in cardiac output that is not compensated for by baroreflex mechanisms and where there might be a resetting of the reflex. Some of the drugs (those that are lipophilic) can also have a central effect to reduce sympathetic outflow. Another antihypertensive effect can be through inhibition of renin release from the kidney. Newer β Blockers Carvedilol (α1, β1, β2 blocker) has a unique carbazole moiety. It is a nonselective agent that also blocks the α1 receptor. Carvedilol has some MSA but no ISA. It exerts a greater clinical effect than other β blockers in the management of congestive cardiac failure and postmyocardial infarction. It is also an antioxidant with antiarrhythmic, antiapoptotic, and antiproliferative properties that influence carbohydrate and lipid metabolism.47 Carvedilol is metabolized by CYP 2D6 to an active metabolite (a 4-hydroxyphenol). Drug elimination is via the biliary route and excretion in the feces. Carvedilol has an elimination half-life of 7 to 10 hours. Nebivolol is formulated as a racemic mixture. It is highly lipophilic and rapidly absorbed, with a peak effect of 0.5 to 2 hours. It has vasodilating properties that are mediated by stimulation of the L-arginine-NO pathway. It is available only as an oral preparation and undergoes extensive metabolism by glucuronidation and N-dealkylation and oxidation by CYP P450 2D6 with less than 0.5% excreted unchanged. Because of genetic polymorphism of CYP 2D6, bioavailability varies from about 12% in fast metabolizers to 96% in poor metabolizers, and the terminal half- life varies

from 11 hours to 30+ hours, respectively.19,48,49 Both carvedilol and nebivolol reduce blood pressure through a decrease in systemic vascular resistance rather than the proposed decrease in cardiac output (see later discussion).47,49

Adverse Effects of β Blockers Because of differences in pharmacologic profiles, different β adrenoceptor blockers have varied side-effect profiles, but there are some common features: • All β blockers have negative inotropic effects and can cause acute left ventricular failure when given in large doses to patients with impaired left ventricular function. • All β blockers can exacerbate intermittent claudication and the Raynaud phenomenon in patients with coexisting peripheral vascular disease. • Large doses of β blockers can cause bradycardia, leading to syncope. • Nonselective β blockers that interact with β2 receptors can result in bronchospasm in patients with asthma or chronic obstructive pulmonary disease owing to blockade of β 2 receptors. • β Blockade can cause significant blood lipid effects, leading to increased triglycerides and decreased high-density lipoprotein cholesterol. • Lipophilic β blockers that can cross the blood-brain barrier can cause CNS effects, leading to depression, sleep disturbances, vivid dreams, and hallucinations. • Sudden withdrawal of β blockers results in increased catecholamine sensitivity; this upregulation can produce tachycardia, acute hypertension, and palpitations.

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There are also important drug interactions involving β blockers: • Cimetidine (a CYP inhibitor) decreases hepatic first-pass metabolism of propranolol and metoprolol and decreases the hepatic metabolism of bisoprolol. • Carvedilol increases plasma concentrations of digoxin and the risk of toxicity. • Concurrent administration of β blockers and verapamil increases risk of bradyarrhythmias and heart failure. • Avoid use of sotalol in conjunction with other drugs that prolong the QT interval (e.g., amiodarone, disopyramide, procainamide, quinidine). • All β blockers can potentiate the effects of insulin and other oral hypoglycemic drugs and can block the normal sympathetic responses to hypoglycemia. Some evidence suggests that this effect is more pronounced with nonselective β blockers.

Angiotensin-Converting Enzyme Inhibitors Both captopril and enalapril are well absorbed orally, but absorption is decreased to 50% if taken in the presence of food. Captopril has limited presystemic metabolism (3%–14%), has a half-life of 1 to 2 hours, and has plasma protein binding of 30%. It undergoes both hepatic and renal elimination, with 50% excreted unchanged and 50% transformed to inactive metabolites. Enalapril is the orally administered prodrug of the active compound enalaprilat (available for intravenous use), which is formed when enalapril undergoes extensive presystemic metabolism. Enalapril has a half-life of less than 1 hour, but enalaprilat has a long half-life of 35 hours. Enalaprilat is excreted unchanged in urine. Lisinopril shows slow and poor oral absorption (< 25%) and is eliminated unchanged in the urine. It has a half-life of about 12 hours and low protein binding (3%–10%). Ramipril is modestly well absorbed (about 60%) and undergoes some presystemic metabolism. Like enalapril, it is metabolized to the active form ramiprilat, which, in turn, undergoes partial excretion in the bile. Other ACE inhibitor prodrugs include quinalopril and perindopril. The long half-lives of all the ACE inhibitors relate to their extensive binding to ACE in the plasma.

Angiotensin II Receptor Antagonists Angiotensin II receptor antagonists act as competitive antagonists at the AT-1 receptor: currently, they are formulated only as oral medications. Candesartan is rapidly and completely de-esterified during absorption of candesartan axetil. It is highly protein bound, and undergoes part metabolism and part excretion in the bile. Unchanged drug is excreted in the urine. Candesartan has a half-life of about 10 hours, with a peak concentration at 3 to 4 hours. Irbesartan is also rapidly and completely absorbed after oral dosing and undergoes minimal presystemic metabolism. The drug is 90% bound to plasma proteins. It is metabolized by oxidation (CYP 2C9) and glucuronidation, with a half-life of 12 hours. There are interactions between candesartan and other drugs metabolized by CYP 2CP in vitro, although no significant changes in disposition have been reported in vivo. Losartan is well absorbed after oral administration but undergoes extensive presystemic metabolism by CYP 2C9 and 3A4. The parent drug has a half-life of 2 hours, but there is an active metabolite (with a half-life of about 8 hours). Peak concentrations of drug and metabolite occur at about 1 and 4 hours, respectively. Losartan is inactivated by further metabolism with two inactive

metabolites excreted in the bile. Systemic bioavailability is double in patients with liver disease, but there is no change after oral dosing in patients with renal dysfunction. Valsartan has a low systemic bioavailability (25%), reduced even further (to 15%) if administered with food. The drug is extensively protein bound (95%), mostly excreted in the bile and feces (83%), with 13% eliminated in the urine. There is no effect of renal failure on valsartan disposition. It has a half-life of about 6 hours. Other drugs of this class are mainly longer acting (owing to longer elimination half-lives): eprosartan (5–9 hours), olmesartan (about 13 hours), and telmisartan (16–23 hours).

Adverse Effects and Drug Interactions Hypotension is associated with intravascular volume depletion due to accompanying diuretic therapy. ACE inhibitors can cause renal impairment and hyperkalemia, especially in patients with renal artery stenosis, as perfusion of the affected kidney depends on the local production of angiotensin. Rashes are seen in about 10% of patients and can be accompanied by fever and eosinophilia. Rarely, this is associated with episodes of angioneurotic edema. Coadministration of nonsteroidal antiinflammatory drugs (NSAIDs [cyclooxygenase inhibitors]) can reduce the hypotensive effects of ACE inhibitors. ACE inhibitors can inhibit the excretion of lithium and can result in lithium toxicity. Angiotensin II receptor antagonists can cause hypotension if coadministered with diuretics. They should be used with caution in patients with renal failure, because they rarely lead to hyperkalemia. Because these drugs do not affect the breakdown of kinins (as is seen with the ACE inhibitors), patients do not develop episodes of coughing and rarely develop angioneurotic edema.

Diuretics Diuretics are discussed in more detail in Chapter 42. Thiazides are all absorbed when given orally and are excreted unchanged by the kidney. Half- lives range between 3 and 90 hours. Chlorthalidone is well absorbed (60%–70%), with negligible presystemic metabolism. Unlike some other thiazides, it has a long half-life (50–90 hours), with protein binding of 75%. Loop diuretics act by inhibiting Na+ and K+ reabsorption in the ascending loop of Henle by inhibiting Na+/K+/Cl− co-transport. Furosemide is poorly absorbed (50%–65%), with poorer absorption in the presence of heart failure, is excreted mainly unchanged in the urine, has a plasma half-life of about 1 hour, and high protein binding (96%–98%). Bumetanide drug is well absorbed following oral administration (65%–95%). About 60% is excreted unchanged in the urine, with the rest being metabolized by the liver and excreted in urine and bile. Bumetamide has a half-life of 1.5 hours, volume of distribution of 9.5 to 35 L, and high protein binding (95%). As is seen with furosemide and the thiazides, bumetamide, in the presence of hypokalemia, potentiates the effects of glycosides and other antiarrhythmic drugs, thus increasing the incidence of arrhythmias. Diazoxide is well absorbed orally (85%–95%) and has a long half-life (20–40 hours) and high protein binding (90%). Amiloride shows poor oral absorption, with no presystemic metabolism. It has low protein binding, with a large volume of distribution (5 L/kg). Amiloride is almost completely excreted unchanged in urine and has a plasma half-life of 6 to 9 hours. Spironolactone is an aldosterone antagonist that is well absorbed orally, with a short half-life of 10 minutes. It is metabolized in



CHAPTER 26  Antihypertensive Drugs and Vasodilators

547

the liver to the active compound canrenone, which has a half-life of 16 hours and is excreted by the kidney. Protein binding is high (98%). Because of the long half-life of its metabolite, spironolactone has a long duration of action, with the maximum effect of the drug taking some days to be reached. Triamterene undergoes incomplete (30%–83%), although rapid, absorption from the gut. There is some presystemic metabolism, and it is extensively biotransformed in the liver before urinary excretion and variable biliary excretion. The elimination half-life is about 2 hours, with protein binding of 45% to 70%.

cause decreased sympathetic activity, leading to postural or exertional hypotension. Other side effects include ejaculation failure and an effect on CNS-mediated sedation and drowsiness. Significant side effects of α-methyl DOPA include orthostatic hypotension, dizziness, sedation, dryness of the mouth, nasal congestion, headaches, and impotence. Rebound hypertension can occur on withdrawal but occurs less frequently than after cessation of clonidine. It can also cause a reversible positive Coombs test hemolytic anemia. I1 receptor agonists (monoxidine) can cause dry mouth, nausea, fatigue, dizziness, and headaches.

Adverse Effects and Drug Interactions There are important side effects of all diuretics. Prolonged use of thiazides (especially in older adults) can lead to hyponatremia and hypokalemia and an increased plasma uric acid concentration. Prolonged hypokalemia, in turn, leads to impaired glucose tolerance due to inhibition of insulin release and enhancing digitalis toxicity. Whereas thiazides cause a reduction in Ca2+ excretion, the loop diuretics increase Ca2+ excretion. Both groups of diuretics reduce clearance of lithium by the kidney (which increases the risk of toxicity, as the latter has a narrow therapeutic range). Hypokalemia potentiates the effects of cardiac glycosides and alters the effects of antiarrhythmic drugs, leading to ventricular arrhythmias (torsade de pointes). All potassium-sparing diuretics (amilioride, spironolactone, and triamterene) potentiate additively the potassium-sparing effects of ACE inhibitors; therefore, their coadministration can lead to dangerous hyperkalemia. In addition, the potassium-sparing diuretics can lead to hyperkalemia in patients also receiving potassium supplements or in patients with renal failure. These diuretics can also cause renal failure when coadministered to patients receiving NSAIDs. Spironolactone interferes with the assay of digitalis. Triamterene inhibits the urinary excretion of the antiparkinsonian drug amantadine.

α1 Adrenoreceptor Antagonists

α2 Adrenoreceptor Agonists There are no available data to suggest that α2 agonists are useful for the rapid control of blood pressure in the perioperative period. They are used in special circumstances for treatment of chronic hypertension. Clonidine is the archetypal drug of this group. It is moderately lipid soluble, shows complete absorption after oral dosing, but undergoes limited presystemic metabolism (up to 25%). Clonidine has a peak effect at 1 to 1.5 hours and peak plasma concentration at 1 to 3 hours. Clonidine has a long half-life (12–24 hours), protein binding of 20% to 40%, and a large volume of distribution (2–4 L/kg). It is eliminated by both hepatic metabolism and renal excretion. Dexmedetomidine was introduced into clinical practice principally as a sedative rather than antihypertensive. It is the D-enantiomer of medetomidine. Dexmedetomidine has a volume of distribution of 100 L and clearance of about 40 L/hr. There is high protein binding to albumin and α1 glycoprotein, and it undergoes extensive hepatic biotransformation. Dexmedetomidine also has a weak inhibitory effect on CYP 2D6–mediated metabolism in vitro. α-Methyl DOPA is incompletely absorbed following oral dosing and has variable (10%–60%) bioavailability. It has low protein binding (10%–15%), a half-life of 6 to 12 hours, and is eliminated through both the biliary tract and the kidney. An important issue with these drugs is that all α2 agonists have significant side-effect profiles. Central α2 agonists (e.g., clonidine)

Phentolamine and Phenoxybenzamine Phentolamine is a competitive nonselective antagonist of α1 receptors, with a half-life of 3 to 13 hours and protein binding of 54%. Little more is known about its pharmacokinetics or metabolism, although it is excreted mainly unchanged by the kidney. Phentolamine has equal efficacy at α1 and α2 receptors and is a 5-hydroxytryptamine (serotonin) antagonist. Phenoxybenzamine is a haloalkylamine that acts as a noncompetitive, irreversible antagonist. The half-life is 18 to 24 hours, but the duration of effect depends on the cellular turnover of receptors— with evidence of drug action for 3 to 4 days. It is biotransformed probably in the liver. The slow onset of effect is due to the need for initial conversion of its ring structure to a reactive carbonium ion, which covalently binds to the α1 receptor. There are common adverse effects for both drugs (similar to those of other drugs that decrease sympathetic outflow): vasodilation leading to a reflex tachycardia, orthostatic hypotension secondary to venous pooling, nasal congestion, and ejaculatory failure. Headaches, lethargy, dizziness, nausea, and urinary frequency also occur. Although labetalol is normally classified as a β-receptor antagonist, it also shows nonspecific α-receptor antagonist properties. Prazocin, doxazocin, and terazocin are all absorbed orally (up to 65% for doxazocin), undergo some presystemic hepatic metabolism, and are then mostly broken down in the liver by dealkylation followed by conjugation. All three drugs have high protein binding (90% to 98%). Although the half-lives of the drugs vary (prazocin, 2–4 hours; doxazocin, 9–12 hours; terazocin, 11 hours), their therapeutic effects lasts longer (prazocin about 10 hours; doxazocin about 30 hours). Terazocin is eliminated unchanged in the urine and feces. There is need to reduce dosage of all 3 agents in patients with renal failure. This is not owing to drug or metabolite accumulation but rather to increased drug sensitivity. The exact mechanism is unclear but may be due to increased absorption, decreased first-pass metabolism, altered drug binding, or decreased volume of drug distribution. Indoramin is also well orally absorbed (> 90%) but undergoes almost complete metabolism by presystemic metabolism. Indoramin has variable protein binding (72%–92%), a half-life of 2 to 10 hours, and might have active metabolites. The antihypertensive effects of α1 blocking drugs are enhanced by coadministration with other antihypertensive agents, especially diuretics and β blockers. α1 Blockers should not be given in conjunction with MAOIs.

Vasodilators Hydralazine Hydralazine is well absorbed orally, undergoes presystemic metabolism, and shows extensive metabolism (65%–90%) by acetylation

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(with a bimodal distribution). The half-life of hydralazine is 3 to 7 hours; because acetylation by NAT-2 occurs mainly during presystemic metabolism, the subsequent rate of drug clearance is not directly related to the rate of acetylation. There is a bimodal distribution of clearance; slow acetylators are at risk of developing a lupus-type condition. However, acetylator status does not appear to affect the half-life. Hydralazine has high protein binding (87%) and a large volume of distribution (3.6 L/kg). The ratio of fast : slow acetylators in the population is racially determined. In Europe, the ratio is about 40 : 60, in Japan 85 : 15, and in the Inuit population 95 : 5. The consequences of this bimodal metabolic profile are twofold: first, slow acetylators can have an enhanced response to treatment; second, they can also have an increased risk of drug toxicity. The difference between fast and slow acetylators is not dependent on kinetic properties but rather on the amount of the NAT-2 isoform expressed. A reduced dose of hydralazine is indicated in the presence of renal and hepatic disease, regardless of the metabolic phenotype.

Nicorandil Nicorandil acts as a mixed vasodilator with part nitrate-like action and part K+ channel opening effect.50 After oral twice-daily dosing, steady-state concentrations are reached by 96 to 120 hours, although there is an onset of effect by 30 minutes after dosing. Nicorandil undergoes extensive hepatic metabolism to an inactive denitrated metabolite that is excreted in the urine and has a short half-life (1 hour) and high clearance (about 1.1 L/min). Side effects associated with the use of nicorandil include headache in 25% to 50% of patients on starting the drug and dizziness, nausea, and vomiting. Minoxidil Another arterial vasodilator (like hydralazine), minoxidil is well absorbed orally and has an elimination half-life of 3 to 4 hours. The duration of effect of a single dose is 8 to 12 hours. It is mainly prescribed in patients with resistant hypertension but is often accompanied by significant side effects. These include hirsutism (therefore, the drug is usually prescribed only in males) and peripheral edema due to fluid retention. Because it is a powerful vasodilator, other adverse effects include skin flushing, headache, reflex tachycardia, and associated palpitations. To overcome the edema and tachycardia, the drug is often coadministered with a β blocker and diuretic. Nitrates Glyceryl trinitrate (or nitroglycerin) undergoes extensive hepatic presystemic metabolism when given orally. Therefore, it is usually given by the sublingual route, by which it is well absorbed and rapidly taken up into the circulation. Buccal administration has a similar effect; this route is used for more prolonged action over a few hours. When given intravenously, there is drug breakdown by the cells of the vascular endothelium. Nitroglycerin is broken down (bioactivated) to 1,2 glyceryl nitrate and NO by hepatic mitochondrial aldehyde dehydrogenase. Tolerance develops over time, as the enzyme is depleted by continuous exposure. Isosorbide dinitrate (ISDN) is absorbed in the gut and extensively metabolized to active metabolites, especially the mononitrate ISMN, which also shows good oral absorption but, in contrast to ISDN, has low presystemic metabolism. The half-lives of these nitrates are a few minutes for nitroglycerin, 1 hour for ISDN, and 4 hours for ISMN. Protein binding differs for the three agents (ISMN < 5%, for ISDN 30%, and nitroglycerin 60%). There are also

differences in their volumes of distribution (ISMN 3 L/kg; ISDN 1–8 L/kg; nitroglycerin 0.7 L/kg). Sodium nitroprusside is effective within 30 to 40 seconds of infusion, and offset is similarly rapid. It is broken down in the liver to cyanide and thiocyanate; together with the parent drug, both are excreted in the urine. Dose reduction is indicated for all nitrates in patients with renal or hepatic disease. There may be tolerance to vasodilatory effects of nitrates with prolonged dosing, especially when given transdermally. The safe doses of nitroprusside are less than 1.5 µg/kg/min during hypotensive anesthesia and up to 8 µg/kg/min to treat hypertensive crises.

Phosphodiesterase Inhibitors The peripheral actions of the PDEIs are mediated by PDE3. There are two main chemical classes of inhibitors—the bipyridines (amrinone and milrinone) and the imidazolones (enoximone). These drugs cause vasodilation by increasing the intracellular cAMP in vascular smooth muscle, leading to activated outward Ca2+ transport and, hence, a decrease in intracellular Ca2+ concentration. Amrinone has an elimination half-life of 2 to 4 hours, clearance of 4 to 9 mL/kg/min, and a small volume of distribution (1.3 L/ kg). It has low protein binding (20%) and its elimination is not affected by renal disease. On the other hand, milrinone in healthy patients has an intermediate protein binding of 70%, terminal half-life of 2 hours, clearance of 2 to 3 mL/kg/min, and volume of distribution of 0.4 to 0.5 L/kg; its terminal half-life is increased in patients with renal dysfunction. Enoximone has a higher clearance (10 mL/kg/ min), protein binding (70%–85%), and longer terminal half-life of 6 to 7 hours. The action of enoximone is increased in renal failure owing to the accumulation of the active sulfoxide metabolite.51 Other nonspecific PDEIs include the methylxanthines (e.g., theophylline and aminophylline) and the benzylisoquinoline, papaverine.

Pharmacotherapy of Hypertension Treatment of hypertension is indicated to prevent or reduce end organ damage and subsequent morbidity. Current first-line drugs for the treatment of high blood pressure are diuretics, ACE inhibitors and angiotensin II receptor blockers, and calcium channel blockers; the latter three groups of drugs potentiate the effect of the diuretics. The JNC 7 and 8 guidelines indicate that thiazides are the first choice for treatment of uncomplicated hypertension, while combination therapy has greater efficacy than doubling of single-drug dosage.52 However, calcium channel blockers are an effective treatment in hypertensive patients for the prevention of stroke but have little effect on the incidence of heart failure, major cardiovascular events, and cardiovascular and total mortality.53 β Blockers for the treatment of hypertension should be reserved for patients with associated coronary artery disease or tachycardia/ tachyarrhythmias including secondary prevention after myocardial infarction.54–56 In comparisons with other treatments, β blockers show a greater ability to reduce the incidence of stroke (29% vs. 17%) but no difference in prevention of coronary events and heart failure.57 In patients with associated heart failure, thiazides, ACE inhibitors, aldosterone receptor blockers (spironolactone), and low-dose-titrated β blockers are indicated. In patients with renal impairment, ACE inhibitors and angiotensin II receptor antagonists are the drugs of choice.58 A Cochrane Review of randomized trials of at least 1-year duration compared thiazides, β blockers, calcium channel blockers, ACE inhibitors, α1 blockers, and angiotensin II receptor blockers as first-line



therapies for patients with uncomplicated hypertension. The review concluded, “Low-dose thiazides reduced all cause mortality and morbidity (as stroke, coronary heart disease, cardiovascular events); ACE inhibitors and calcium channel blockers might be similarly effective but the evidence is less robust; and high-dose thiazides and β blockers are inferior to low-dose thiazides.”59

Hypertension and Anesthesia Hypertensive patients exhibit greater intraoperative cardiovascular lability, including hypertension with tracheal intubation and post-induction and intraoperative hypotension that is associated with adverse outcomes.59a Present anesthetic practice dictates that antihypertensive therapies (with the possible exception of highdose ACE inhibitors and angiotensin II receptor antagonists4a) are maintained up to the time of surgery. Not all investigators agree that ACE inhibitors and angiotensin II receptor antagonists should be withheld.60,61 However, preoperative evaluation for patients with hypertension should include the measurement of plasma K+ concentrations, especially in patients receiving diuretics or reninangiotensin system antagonists. One of the present controversies concerns which groups of patients (if any) should not undergo surgery because of raised blood pressure. There are few data on the influence of coexisting hypertension on cardiovascular outcome following noncardiac surgery. Mild to moderate preoperative hypertension is not a major risk factor for complications.61a,61b None of the scoring systems used to categorize patient risk include hypertension as a factor. However, a study of outcome from Switzerland identified an increased incidence of cardiovascular complications: 11.2% vs. 4.6% (adjusted odds ratio [AOR], 1.38; 95% confidence interval [CI], 1.27–1.49) in the hypertensive subgroup.62 These results are in keeping with the meta-analysis of Howell and colleagues63 (AOR, 1.35; 95% CI, 1.17–1.56) for perioperative cardiovascular complications of cardiac mortality, myocardial infarction and heart failure, and arrhythmias. The 2014 American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology/ European Society of Anaesthesiology guidelines offer recommendations for management.61a,61b Observational data agree that stage 1 or 2 hypertension is not an independent risk factor for perioperative cardiovascular complications; hence, there is no scientific evidence to support postponing these patients’ surgery in the absence of target organ damage. However, the case for stage 3 (SAP ≥ 180 and/or DAP ≥ 110 m Hg) hypertension is less clear. The guidelines recommend control of blood pressure before surgery, but this is not supported by a large body of data relating exclusively to patients with these levels of blood pressure. An analysis of a large UK primary care database showed an association between elevated diastolic blood pressure and postoperative mortality.64 Based on clinical studies and practice, there is no evidence to cancel and treat hypertensive patients other than those with documented target organ damage. Blood pressure control should be optimized before surgery in patients in whom hypertension is associated with accompanying significant risk factors such as diabetes mellitus, coronary artery disease, peripheral vascular disease, impaired renal function, smoking, or hypercholesterolemia.65,66 Isolated systolic hypertension (ISH) is frequent in older adults. It is characterized by increased systolic pressure as well as pulse pressure due to increased large artery stiffness secondary to aging. There are also often associations with obesity and reduced physical activity. In nonsurgical patients with ISH, there is a clear association with increased prevalence of silent myocardial ischemia. The

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influence of ISH on perioperative outcomes has not been well studied, although a recent study (PROMISE—Perioperative Myocardial Ischemia in Isolated Systolic Hypertension) showed no increased incidence of myocardial ischemia in ISH patients.67 In patients with “white coat” hypertension, as many repeat blood pressure readings as possible should be obtained to inform clinical decisions. Starting a normally normotensive patient with white coat hypertension on inappropriate therapy can be dangerous. If surgery is to be deferred to allow white coat hypertension to be treated, it is unclear how long treatment should be given before surgery.

Pulmonary Vasodilators The pulmonary circulation is normally a low-pressure, low-resistance circuit (see Chapters 29 and 30). Pulmonary hypertension is defined as mean pulmonary artery pressure greater than 20 mm Hg or systolic pulmonary artery pressure greater than 30 mm Hg. The causes of pulmonary hypertension are idiopathic (50%) with the remaining 50% associated with connective tissue disorders; congenital heart disease; portal hypertension; infection with human immunodeficiency virus; or intake of appetite-suppressant drugs, such as fenfluramine or dexfenfluamine. The hypertension can be aggravated by hypoxic vasoconstriction; hence, these patients should receive supplemental oxygen while avoiding causative drugs. Hypoxic pulmonary vasoconstriction (HPV; see Chapter 29) is mediated by the endothelium. The exact mechanism is not well defined, but the “redox theory” proposes the coordinated action of a redox sensor (within the proximal mitochondrial electron transport chain) that generates a diffusible mediator (probably a reactive oxygen species, such as hydrogen peroxide) that regulates an effector protein (either a voltage-gated K+ or Ca2+ channel). The subsequent inhibition of oxygen-sensitive K+ KV1.5 and KV 2.1 channels depolarizes pulmonary artery smooth muscle and activates voltage-gated Ca2+ channels. This leads to an influx of Ca2+, causing vasoconstriction.68 Hypoxic pulmonary vasoconstriction can be modulated by a number of variables. The reflex activity decreases with increases in pulmonary artery pressure, cardiac output, left atrial pressure, and central blood volume. Drugs also modulate the reflex and interfere with ventilation/perfusion matching (Table 26.9). Other perioperative conditions that impair the response include hypocapnia and hypothermia. When hypoxic pulmonary vasoconstriction is inhibited, there is an increase in alveolar–arterial oxygen gradient. Until recently, the prognosis for patients with pulmonary hypertension was poor (with a survival of 5–6 years) even with treatment, and the only useful treatment was chronic calcium channel blockers. This has changed with the introduction of NO, prostacyclin analogs, PDEIs, and lung transplantation. Other useful therapies include inotropic drugs that can cause some right ventricular adaptation secondary to an increase in systolic function. Conversely, these patients tolerate β adrenoceptor blockade poorly. Diuretics can also help by decreasing pericardial and pleural effusions and by improving right ventricular volumes and left ventricular diastolic function. A classification of pulmonary vasodilators is shown in Table 26.10. There is no vasodilator that acts solely on the pulmonary vasculature. Adenosine, acetylcholine, nitroglycerin, and prostacyclin have the best ratio of pulmonary to systemic effects. Most drugs used to attempt a reduction in pulmonary blood pressure are not without significant side effects: systemic hypotension, pulmonary hypertension (drug-induced decrease in systemic blood pressure can increase pulmonary artery pressure by increasing cardiac output and sympathetic tone), decreased myocardial contractility, and

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TABLE Effect of Vasoactive and Other Drugs on the 26.9  Hypoxic Pulmonary Vasoconstrictor Reflex

6-keto metabolite, with a half-life of about 6 minutes. Animal studies show PGI2 to have a high clearance (90–100 mL/kg/min), a volume of distribution of 357 mL/kg, and a half-life of 2.7 minutes.70 Delivery of PGI2 by aerosol causes minimal systemic effects, but achieves a dramatic and rapid improvement in arterial oxygenation and lowering of pulmonary artery pressure.

Drug

Effect

Hydralazine

None

Nifedipine

Inhibition

Verapamil

Inhibition

Phosphodiesterase Inhibitors

Nitroglycerin

Inhibition

Sodium nitroprusside

Inhibition

Nicardipine

None

Labetalol

None

Inhaled anesthetics

None to slight inhibition

Intravenous anesthetics ketamine and propofol

None

Thoracic epidural

No direct effect; but changes likely attributable to alterations in cardiac function

Both NO and atrial natriuretic peptide (ANP) activate smooth muscle cell guanylyl cyclase to decrease intracellular Ca2+ with muscle relaxation, inhibition of cell proliferation, and activation of apoptosis. There is evidence that phosphodiesterase (PDE) is overexpressed in pulmonary hypertension, leading to an increased degradation of cGMP. There is also decreased expression of NO synthase. Hence, therapy has focused on the efficacy of PDE5 inhibitors, which cause pulmonary vasodilation. PDE5 is located in the corpus cavernosus, vascular smooth muscle, and platelets. Sildenafil reduces pulmonary vascular resistance. It has high oral bioavailability, with onset of effect within 15 minutes and peak hemodynamic effect at 2 hours. Sildenafil has a half-life of about 4 hours and is metabolized by two separate routes involving CYP 3A4 (major) and 2C9 (minor). Both pathways are influenced by CYP inhibitors and inducers. The drug is effective in reducing pulmonary artery pressure in both adults and children. Tadalafil has a longer half-life; hence, it is viewed as a onceper-day drug. For the effective treatment of pulmonary hypertension, combination therapies are often the most efficacious.

TABLE 26.10  Classification of Pulmonary Vasodilators Direct-acting: inhaled nitric oxide, hydralazine, nitroglycerin, sodium nitroprusside (through activation of guanylyl cyclase) α Adrenoceptor antagonists: tolazoline, phentolamine β Adrenoceptor agonists: isoproterenol (isoprenaline; activation of adenylyl cyclase) Calcium channel blockers: nifedipine, diltiazem Prostaglandins: PGE1 and prostacyclin Adenosine Endothelin receptor antagonists Indirect-acting vasodilators: such as acetylcholine, that causes the release of nitric oxide Phosphodiesterase inhibitors

Novel Pulmonary Vasodilators A number of therapies are under evaluation in vitro and in animal models—these include potassium channel openers, antiproliferative drugs, rapamycin, and statins.

Emerging Developments New Management Guidelines for Hypertension

hypoxemia. Because of these side effects, there have been a number of new treatments assessed since the mid-1990s. Inhaled nitric oxide (iNO) readily diffuses from the alveoli to the vascular smooth muscle, where it activates guanylyl cyclase to increase cGMP, causing pulmonary vasodilation. NO has little effect on the systemic circulation. It can be administered in doses ranging from 5 to 80 ppm. About 33% of patients with pulmonary hypertension show little or no response to iNO owing to a nonreactive pulmonary circulation, rapid NO inactivation, abnormalities of the guanylyl cyclase system, or rapid breakdown of cGMP (although this can be inhibited by addition of dipyridamole). The main adverse effects of iNO are inhibition of platelet function and rebound hypoxemia and pulmonary hypertension. Prostanoid pulmonary vasodilators can be administered by a variety of different routes—intravenous (epoprostenol, treprostinil, iloprost), subcutaneous (treprostinil), inhalation (iloprost), and oral (beraprost). Prostacyclin (PGI2) is endogenously synthesized, predominantly by endothelial cells, including the pulmonary vascular endothelium. Prostacyclin produces vasodilation in low-resistance beds, such as the pulmonary circulation.69 It not only stimulates the endothelial release of NO but, in turn, NO enhances PGI2 synthesis in smooth muscle cells of the pulmonary artery. PGI2 is spontaneously broken down by plasma hydrolysis to an inactive

New guidelines for the prevention, diagnosis, and treatment of hypertension were released in 2017 by a task force of professional societies.70a Guidelines for the care of pediatric hypertensive patients have also been revised.70b Experts expect these revamped guidelines to have a major impact on physician behavior and public health as it relates to cardiovascular disease.70c,70d A major motivation to update the existing guidelines was a large, randomized, controlled trial commonly referred to as the SPRINT study (Systolic Blood Pressure Intervention Trial).70e As presented in Figure 26.8, SPRINT confirmed the hypothesis that a lower systolic blood pressure target (i.e., ≥ 120 mm Hg instead of the traditional target of ≥ 140 mm Hg) reduces adverse cardiovascular outcomes such as myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, and cardiovascular death in more than 9000 hypertensive patients randomized to standard and more intensive treatment groups. An adverse consequence of the more intensive treatment was a higher risk of hypotensive episodes, syncope, and acute kidney injury, among others. Key components of the new guidelines include confirming the diagnosis of hypertension with multiple “out-of-office” measurements (avoiding false, “white coat” hypertension diagnoses), instituting non-pharmacologic interventions (e.g., weight loss, exercise, healthy diet), and targeting a systolic blood pressure of

CHAPTER 26  Antihypertensive Drugs and Vasodilators



551

Transmembrane NP receptors 0.10

Hazard ratio with intensive treatment, 0.75 (95% Cl, 0.64–0.89)

0.08

NP-A

NP-B

Vasodilation

Inhibition of renin production

Standard treatment 0.06

Increased GFR

0.04

Intensive treatment

Enhanced Na+ and water excretion

0.02 0.00 0

1

2

3

4

5

• Fig. 26.8

Cumulative hazard ratios for the primary outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes) from the SPRINT study comparing standard antihypertensive therapy with more intensive treatment.5 See text for details.  

≥ 130/80 mm Hg.70a,70f Patients with a high risk of adverse cardiovascular outcomes because of other risk factors warrant special attention. The guidelines recommend thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers as first line antihypertensive agents, noting that combination therapy might be necessary to achieve the lower blood pressure targets. Applying these guidelines into everyday clinical care will be challenging.70g The updated guidelines call for an additional 31 million patients in the USA to be treated (and 55 million more will need more intense treatment). The revamped guidelines will change the typical clinical profile of the treated hypertensive patient presenting for anesthesia and surgery.

Direct Renin Inhibitors Direct renin inhibitors are a new class of drugs that act as non– peptide renin inhibitors by binding competitively to renin and blocking the generation of angiotensin I from angiotensinogen. Direct renin inhibitors act on the juxtaglomerular cells of the kidney, where the hormone is produced. They cause arterial and venous dilatation by blocking formation of angiotensin and cause downregulation of sympathetic adrenergic activity and promotion of Na+ and water excretion by the kidneys. Aliskiren can be used in patients when ACE inhibitors or angiotensin receptor antagonists (ARAs) are not tolerated. It has additive antihypertensive effects when combined with ARAs. Unlike ACE inhibitors and ARAs, they do not appear to cause a compensatory rise in plasma renin and produce a more complete block of the pathway.71,72 They appear to possess fewer side effects than either ACE inhibitors or ARAs and are recommended as a third-line treatment for hypertension (especially where resistant to other therapies).73 There are few kinetic data available for the two currently available direct renin inhibitors, aliskiren and remikiren. Both drugs are formulated for oral use only. Aliskiren is a piperidine derivative that is poorly absorbed, with an oral bioavailability of only 2.5%. Peak concentrations are seen at 1 to 3 hours. Aliskiren has a half-life of 24 to 40 hours, and protein binding of 47% to 51%. It is partly metabolized (about 19%) in the liver by CYP 3A4 to O-demethylated and carboxylic acid derivatives. The remainder of the drug is excreted unchanged in the feces.

• Fig. 26.9  Possible mechanisms of action of natriuretic peptides (NP). Atrial and brain natriuretic peptides interact with NP-A and NP-B receptors to reduce blood pressure by vasodilation and enhanced salt and water excretion. GFR, glomerular filtration rate. Remikiren has a similar low bioavailability (< 6%), a half-life of 1.5 hours, and clearance similar to hepatic blood flow. The effect lasts about 24 hours. It is recommended that the dose of both drugs be reduced in patients with renal impairment.74,75 Ivabradine is a specific sinus node inhibitor that slows heart rate without having negative inotropic effects by inhibition of If (“funny channel”) currents. The effects of ivabradine on heart rate also lead to an increased diastolic time and, hence, increased coronary flow. It is an alternative to a β blocker or heart rate-limiting calcium channel blocker and also has antianginal action when given with a β blocker. It has some antihypertensive effect through its action on heart rate. Use of ivabradine can be accompanied by the development of significant side effects: visual symptoms (including blurring of vision), headache, dizziness, and bradycardia.76

Natriuretic Peptides Natriuretic peptides (atrial and brain natriuretic peptides [ANP and BNP, respectively]) act via transmembrane NP-receptors (NP-A, NP-B). Agonists binding to NP-A receptors cause vasodilation with increased glomerular filtration rate and enhanced Na+ and water excretion, while NP-B receptor stimulation inhibits renin production. These peptides reduce blood pressure through vasodilation of both the arterial and venous systems (Fig. 26.9). A number of new therapeutic approaches are being developed related to these peptides. These include neural endopeptidase (NEP) inhibitors (e.g., candoxatril), vasopeptidase inhibitors (e.g., omapatrilat, which inhibits both ACE and NEP), exogenous ANP and BNP (e.g., nesiritide; recombinant BNP), and exogenous ANP as a coronary vasodilator.

Endothelin and Endothelin Blockade Endothelins are vasoconstrictors found in endothelial cells that were first discovered in 1985 and identified in 1988.77 There are four distinct endothelin peptides (1, 2, 3, and 4). ET-1 and ET-3 are the endothelins present in vascular endothelial cells; ET-2 and ET-4 are found in the kidneys and intestines, and ET-3 is also found in the intestines, brain, lungs, and adrenal glands. ET-1 is synthesized as a 212 residue precursor (prepro-ET) that undergoes cleavage by an atypical endopeptidase of the metalloprotease type to big ET-1 and, subsequently, ET-1. This latter cleavage occurs both intracellularly and on the surface of endothelial and smooth muscle cells. The stimuli to endothelin synthesis include the release of any of a series of noxious vasoconstrictor mediators— including activated platelets, endotoxins, thrombin, various cytokines, cell and tumor growth factors, angiotensin II, antidiuretic

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hormone, and epinephrine, as well as other stimuli such as hypoxia and insulin. Inhibitors to synthesis include NO, natriuretic peptides, prostaglandins PGE2 and PGI2, and heparin. It is probable that ET-1 is stored as a preformed molecule in the endothelial cells, while the release mechanism is poorly understood. It is a 21 amino acid peptide with vasoconstrictor and mitogenic properties, being a growth factor for both vascular smooth muscle and fibroblasts. The release of ET-1 appears to be stimulated by hypoxemia and inhibited by NO. There are two distinct endothelin receptors: ET-A and ET-B. Both are G protein–coupled, with ET-1 preferentially activating ET-A. This receptor is, in turn, coupled to second messengers (including phospholipase C, protein kinase C, and IP3). The mRNA for endothelin ET-A receptors is expressed in many human tissues, including vascular smooth muscle, heart, lungs, and kidney. Stimulation of ET-A receptors brings about vasoconstriction and cell proliferation, while ET-B stimulation causes release of NO and prostacyclin.78 Patients with pulmonary hypertension can have enhanced pulmonary production and increased circulating levels of ET-1.79,80 There are two broad classes of blockers—selective to one or other receptor, and nonselective. All are undergoing evaluation in

patients with pulmonary hypertension. They have beneficial effects in the management of the condition by reducing vascular resistance and altering vascular remodeling.78 Bosentan can be given as either a continuous infusion or as an oral preparation. The orally active preparation of this nonselective endothelin blocker has a half-life of about 7 hours. It is metabolized by CYP and is an inducer of CYP 4AA and 2C9.81 Sitaxentan is an endothelin receptor blocker with a specificity of A : B receptors of 6500 : 1 (this compares with a ratio of 20 : 1 for bosentan; a blocker is said to be selective if the ratio is greater than 100 : 1). Sitaxentan is also orally active and rapidly absorbed, with a Tmax of 1 to 4 hours. Its elimination half-life is about 10 hours, and it is metabolized by CYP 2C9 and 3A4. The compound has also been shown to be a competitive inhibitor of CYP 2C9, 2C19, and 3A4/5. Ambrisentan is another nonselective blocker with an A : B specificity of 77 : 1. It has a high oral bioavailability and a long half-life, making it a once-a-day drug. Darusentan is an endothelin A receptor antagonist that reduces both systolic and diastolic pressures. It might be a useful therapy in patients with refractory hypertension.

Key Points • Pharmacologic control of blood pressure can occur through central or peripheral actions, primarily effects on the sympathetic autonomic nervous system or on the tone of the peripheral vasculature. • Interactions with four classes of adrenergic receptors—α1, α2, β1, and β2—can modulate blood pressure. Antagonists at the α1 receptor counteract the hypertensive effects of α1 agonists and reduce the vascular hypertrophy seen in hypertension. Antagonists at β1 and β2 receptors reduce heart rate and modulate sympathetic effects. • β-adrenoceptor blockers include two classes—the aminooxypropanols (propranolol, metoprolol, esmolol, carvedilol) and the hydroxyaminoethyls (sotalol and labetalol). Pharmacologically, there are three classes: partial agonists (bucindolol and xamoterol), inverse agonists (metoprolol, bisoprolol, nebivolol, sotalol) that stabilize the receptor in an inactive state, and neutral (competitive) antagonists (carvedilol, propranolol) that bind to the receptor without selectivity for active or inactive state. Further functional classification distinguishes antagonists as β1 selective or nonselective, as having ISA, or as having membrane-stabilizing actions. • Antagonists at β1 receptors reduce myocardial remodeling while preserving β2-mediated cardiac protection. Selective β1 blockers also have negative inotropic and chronotropic effects. • For the treatment of hypertension, β-adrenoceptor blockers with inverse agonist activity, or those with associated α1 adrenoceptor blocking activity (labetalol, carvedilol), might be preferred. • Most peripheral vasodilators act through regulation of intracellular Ca2+ concentration in vascular smooth muscle. Vasodilators increase intracellular cAMP or cGMP and bring about vasodilation by phosphorylation of phospholamban and promotion of increased uptake of Ca2+ into the sarcoplasmic reticulum. • Calcium blockers block Ca2+ entry through L-type voltage-gated Ca2+ channels, leading to vasodilation. The three structural classes

•

• • • •

•

•

•

of blockers—phenylalkylamines (verapamil), benzothiazepines (diltiazem), and dihydropyridines (nifedipine)—have two main actions, vasodilation and negative inotropy. Nitrovasodilators either cause spontaneous release of NO or undergo active reduction prior to NO release. NO activates guanylyl cyclase to produce cGMP that activates protein kinase G and activates myosin light chain phosphatase, which dephosphorylates light chains to produce muscle relaxation. Inhibition of the renin–angiotensin system can occur through direct inhibition of ACE, angiotensin II receptor antagonism, or direct renin inhibition. Endothelins activate ET-A receptors to cause vasoconstriction and smooth muscle proliferation; endothelin antagonists mainly block the ET-A receptor to cause vasodilation. Potassium channel openers act by decreasing membrane potential through the efflux of K+, thus reducing the activity of voltagegated Ca2+ channels. Magnesium is a calcium channel blocker that also acts as an antihypertensive agent by stimulating production of prostaglandin E1 and NO and by altering the vascular smooth muscle response to vasoactive agents. The eicosanoids (prostaglandins E1 and E2; and prostaglandin I2, known as prostacyclin) bind specific prostanoid receptors, leading to increased intracellular cAMP, activation of protein kinase A, and inhibition of smooth muscle contraction. Treatment options for pulmonary hypertension include calcium channel blockers, direct-acting nitrovasodilators (e.g., nitroglycerin rather than nitroprusside), inhaled NO, endothelin blockers, prostanoids (prostacyclin), and phosphodiesterase 5 inhibitors (sildenafil and cogeners). Revamped guidelines for the management of hypertensive patients are among the most important emerging developments in the field. The new guidelines call for a lower therapeutic blood pressure target (< 130/80 mm Hg) that will necessitate two-agent therapy in many patients.



Key References Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure. Hypertension. 2003;42:1206–1252. An updated report on the medical aspects of the prevention and management of hypertension (Ref. 3). Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–e137. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J. 2014;35:2383–2431. A set of guidelines for cardiovascular evaluation and care of the patient undergoing noncardiac surgery. (Ref. 61a and 61b). Howell SJ, Foex P, Sear JW. Hypertension and perioperative cardiac risk. Br J Anaesth. 2004;92:570–583. Evidence for an association between hypertensive disease, elevated arterial pressure, and perioperative cardiac outcome are reviewed using a systematic review and meta-analysis of 30 observational studies (Ref. 63). Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part I. Clin Pharmacokin. 1998;34:457–482. Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokin. 1998;35:9–36. Two review papers defining the mechanism of action and pharmacokinetic properties of vasodilator drugs used in the treatment of hypertension (Ref. 10, Ref. 40).Kroen C. Does elevated blood pressure at the time of surgery increase perioperative cardiac risk? Proceedings of the 2nd Annual Cleveland Clinic Perioperative Medicine Summit. Cleve Clin J Med. 2006;33:s5–s6. Elevated blood pressure by itself has not been shown to increase the incidences of perioperative cardiac events. However, target organ damage caused by chronic hypertension can confer increased cardiac risk. A useful review of some of those issues relating to the assessment and treatment of the patient with hypertension (Ref. 65). Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: metaanalysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Br Med J. 2009;338:b1665. A meta-analysis of 147 randomized trials showing that all classes of blood pressure–lowering drugs have a similar effect in reducing coronary heart disease events and stroke for a given reduction in blood pressure (Ref. 57). Sear JW. Perioperative control of hypertension: when will it adversely affect perioperative outcome? Curr Hypertens Rep. 2008;10:480–487. A review of the effects of increased blood pressure on perioperative outcomes. Only patients with a blood pressure greater than or equal to 180/110 mm Hg (stage II of JNC 7) or greater than or equal to 140/90 mm Hg plus target organ damage (stage I) need their surgery to be canceled for institution of treatment before noncardiac surgery (Ref. 66). Whelton PK, Carey RM, Aronow WS, et al. Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13–e115. This influential practice guideline provides comprehensive recommendations for the management of the hypertensive patient. Perhaps the most fundamental change from prior practice is the goal of a lower therapeutic target for blood pressure (< 130/80 mm Hg). Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev. 2009;8:CD0018419, This review sets out to quantify the benefits and harms of the major first-line antihypertensive drug classes: thiazides, β blockers, calcium channel blockers, ACE inhibitors, α blockers, and angiotensin II receptor blockers. First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE

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inhibitors and calcium channel blockers might be similarly effective, but the evidence is less robust. First-line high-dose thiazides and first-line β blockers are inferior to first-line low-dose thiazides (Ref. 59).

References 1. Danaei G, Finucane MM, Lin JK, et al. National, regional and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants. Lancet. 2011;377:568– 577. 2. Borzecki AM, Wong AT, Hickey EC, et al. Hypertension control: how well are we doing? Arch Intern Med. 2003;163:2705–2711. 3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. 3a.  James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520. 4. Pauli W. Ueber ionenwirkungen und ihre therapeutische verwendung. Much Med Wschr. 1903;50:153. 4a.  Roshanov PS, Rochwerg B, Patel A, et al. Withholding versus continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers before noncardiac surgery: an analysis of the vascular events in noncardiac surgery patients cohort evaluation prospective cohort. Anesthesiology. 2017;126:16–27. 5. Johnson CC. The actions and toxicity of sodium nitroprusside. Arch Int Pharmacodyn. 1929;35:480. 6. Page IH, Corcoran AC, Dustan HP, et al. Cardiovascular actions of sodium nitroprusside in animals and hypertensive patients. Circulation. 1955;11:188–198. 7. Sen G, Bose KC. Rauwolfia serpentina, a new Indian drug for insanity and high blood pressure. Indian Med World. 1931;2:194–201. 8. Vakil EJ. A clinical trial of rauwolfia serpentina in essential hypertension. Br Heart J. 1949;11:350. 9. Wilkinson EL, Beckman H, Hecht HH. Cardiovascular and renal adjustments to a hypotensive agent (1-hydrazinophthalazine: CIBA BA-5968; apresoline). J Clin Invest. 1952;31:872–879. 10. Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part I. Clin Pharmacokin. 1998;34:457–482. 11. Bowman WC, Rand MJ. The cardiovascular system. In: Wiffen P, ed. Textbook of Pharmacology. 2nd ed. Oxford: Blackwell Scientific; 1980:23.26–23.58. 12. Klockner U, Isenberg G. Myocytes isolated from porcine coronary arteries: reduction of currents through L-type Ca-channels by verapamil-type Ca-antagonists. J Physiol Pharmacol. 1991;42:163–179. 13. Kurokawa J, Adachi-Akahane S, Nagao T. 1,5-benzothiazepine binding domain is located on the extracellular side of the cardiac L-type Ca2+ channel. Mol Pharmacol. 1997;51:262–268. 14. Skeberdis VA. Structure and function of beta3- adrenergic receptors. Medicina (Kaunas). 2004;40:407–413. 15. Groenning BA, Nilsson JC, Sondergaard L, et al. Anti-modeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. JACC. 2000;36:2072–2080. 16. Udelson JE. Ventricular remodeling in heart failure and the effect of beta-blockade. Am J Cardiol. 2004;93:43B–48B. 17. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). JAMA. 2000;83:1295–1302. 18. Ahmet I, Krawczyk M, Zhu W, et al. Cardioprotective and survival benefits of long-term combined therapy with beta2 adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction. J Pharmacol Exp Ther. 2008;325:491–499.

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19. Prisant LM. Nebivolol: pharmacologic profile of an ultraselective, vasodilatory beta1-blocker. J Clin Pharmacol. 2008;48:225–239. 20. Milne RJ, Buckley M. Celiprolol—an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs. 1991;41:941–969. 21. Carpenter CL. Actin cytoskeleton and cell signaling. Crit Care Med. 2000;28(suppl 4):N94–N99. 22. Shimizu T, Yoshtomi K, Nakamura M, et al. Site and mechanism of actions of trichlormethiazide in rabbit distal nephron segments perfused in vitro. J Clin Invest. 1988;82:721–730. 23. Rose BD. Diuretics. Kidney Int. 1991;39:336–352. 24. Maze M, Tranquilli W. Alpha2-adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology. 1991;74:581–605. 25. Oliver MF, Goldman L, Julian DG, et al. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European mivazerol trial (EMIT). Anesthesiology. 1999;91:951–961. 26. Furchgott RF, Zawadski JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376. 27. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526. 28. Cohen RA, Adachi T. Nitric-oxide-induced vasodilation: regulation by physiologic s-glutathionation and pathologic oxidation of the sarcoplasmic endoplasmic calcium ATPase. Trends Cardiovasc Med. 2006;16:109–114. 29. Yamamoto T, Bing RJ. Nitric oxide donors. Proc Soc Exp Biol Med. 2000;225:200–206. 30. Friederich JA, Butterworth JFT. Sodium nitroprusside: twenty years and counting. Anesth Analg. 1995;81:152–162. 31. Hein TW, Kuo L. cAMP independent dilation of coronary arterioles to adenosine: role of nitric oxide, G proteins and K(ATP) channels. Circ Res. 1999;85:634–642. 32. Sabouni MH, Hussain T, Cushing DJ, et al. G proteins subserve relaxation mediated by adenosine receptors in human coronary artery. J Cardiovasc Pharmacol. 1991;18:696–702. 33. Leblanc N, Wilde DW, Keef KD, et al. Electrophysiological mechanism of minoxidil sulfate-induced vasodilation of rabbit portal vein. Circ Res. 1989;65:1102–1111. 34. Ellershaw DC, Gurne AM. Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery. Br J Pharmacol. 2001;134:621–623. 35. Simpson D, Wellington K. Nicorandil: a review of its use in the management of stable angina pectoris, including high-risk patients. Drugs. 2004;64:1941–1955. 36. Guerrero-Romero F, Rodriguez-Moran M. The effect of lowering blood pressure by magnesium supplementation in diabetic hypertensive adults with low serum magnesium levels: a randomized, double-blind, placebo controlled clinical trial. J Hum Hypertens. 2009;23: 245–251. 37. Spieker LE, Noll G, Luscher TF. Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. Am J Cardiovasc Drugs. 2001;1:293–303. 38. Barton M, Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol. 2008;86:485–498. 39. Brogden RN, Markham A. Fenoldopam: a review of its pharmacodynamic and pharmacokinetic properties and intravenous potential in the management of hypertensive urgencies and emergencies. Drugs. 1997;54:634–650. 40. Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokin. 1998;35:9–36. 41. Corbin JD, Francis SH. Cyclic GMP phosphdiesterase-5: target of silfenadil. J Biol Chem. 1999;274:13729–13732. 42. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326–1331.

43. Godfraind T, Salomone S, Dessy C, et al. Selectivity scale of calcium antagonists in the human cardiovascular system based on in vitro studies. J Cardiovasc Pharmacol. 1992;20(suppl 5):S34–S41. 44. Peacock WF, Angeles JE, Soto KM, et al. Parenteral clevidipine for the acute control of blood pressure in the critically ill patient: a review. Ther Clin Risk Manag. 2009;5:627–634. 45. Erikson AL, DeGrado JR, Fanikos JR. Clevidipine: a short-acting intravenous dihydropyridine calcium channel blocker for the management of hypertension. Pharmacotherapy. 2010;30:515–528. 46. Deeks ED, Keating GM, Keams J. Clevidipine: a review of its use in the management of acute hypertension. Am J Cardiovasc Drugs. 2009;9:117–134. 47. Stroe AF, Gheorghiaede M. Carvedilol: beta-blockade and beyond. Rev Cardiovasc Med. 2004;5:s18–s27. 48. Moen MD, Wagstaff AJ. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66:1389–1409. 49. Munzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009;54:1491–1499. 50. Andersson KE. Clinical pharmacology of potassium channel openers. Pharmacol Toxicol. 1992;70:244–254. 51. Lehtonen LA, Antila S, Pentikäinen PJ. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet. 2004;43:187–203. 52. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290–300. 53. Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol. 2002;39:315–322. Erratum in: J Am Coll Cardiol. 2002;39:1409-1410. 54. De Caterina AR, Leone AM. The role of beta-blockers in first line therapy in hypertension. Curr Atheroscler Rep. 2011;13:147–153. 55. Ram CV. Beta-blockers in hypertension. Am J Cardiol. 2010;106:1819–1825. 56. Ong HT. Beta-blockers in hypertension and cardiovascular disease. Br Med J. 2007;334:946–949. 57. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Br Med J. 2009;338:b1665. doi:10.1136/ bmj.b1665. 58. Staessen JA, Wang J, Bianchi G, et al. Essential hypertension. Lancet. 2003;361:1629–1641. 59. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev. 2009;8(3):CD0018419. 59a.  Monk TG1, Bronsert MR, Henderson WG, et al. Association between Intraoperative Hypotension and Hypertension and 30-day Postoperative Mortality in Noncardiac Surgery. Anesthesiology. 2015;123: 307–319. 60. Sear JW, Jewkes C, Tellez J-C, et al. Does the choice of antihypertensive therapy influence haemodynamic responses to induction, laryngoscopy and intubation? Br J Anaesth. 1994;73:303–308. 61. Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg. 2001;92:26–30. 61a.  Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–e137. 61b.  Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J. 2014;35:2383–2431.



62. Beyer K, Taffé P, Halfon P, et al. Hypertension and intra-operative incidents: a multicentre study of 125,000 surgical procedures in Swiss hospitals. Anaesthesia. 2009;64(5):494–502. 63. Howell SJ, Foex P, Sear JW. Hypertension and perioperative cardiac risk. Br J Anaesth. 2004;92:570–583. 64. Venkatesan S, Myles P, Manning H, et al. Cohort study evaluating preoperative blood pressure (BP) values and risk of 30-day mortality following elective non-cardiac surgery. Br J Anaesth. 2017;119:65–77. 65. Kroen C. Does elevated blood pressure at the time of surgery increase perioperative cardiac risk? Proceedings of the 2nd Annual Cleveland Clinic Perioperative Medicine Summit. Cleve Clin J Med. 2006;33:s5–s6. 66. Sear JW. Perioperative control of hypertension: when will it adversely affect perioperative outcome? Curr Hypertens Rep. 2008;10:480–487. 67. Fayad AA, Yang HY, Ruddy TD, et al. Perioperative myocardial ischemia and isolated systolic hypertension in non-cardiac surgery. Can J Anaesth. 2011;58:428–435. 68. Archer SL, Wu XC, Thebaud B, et al. O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondriaderived hydrogen peroxide. Biol Chem. 2004;385:205–216. 69. Lowson SM, Doctor A, Walsh BK, et al. Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac surgery. Crit Care Med. 2002;30:2762–2764. 70. Vane JR, Botting RM. Pharmacodynamic profile of prostacyclin. Am J Cardiol. 1995;75:A3–A10. 70a.  Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13–e115. 70b.  Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018. 70c.  Greenland P, Peterson E. The New 2017 ACC/AHA guidelines “up the pressure” on diagnosis and treatment of hypertension. JAMA. 2017;318:2083–2084. 70d.  Bundy JD, Mills KT, Chen J, et al. Estimating the association of the 2017 and 2014 hypertension guidelines with cardiovascular events and deaths in US adults: an analysis of national data. JAMA Cardiol. 2018.

CHAPTER 26  Antihypertensive Drugs and Vasodilators

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70e.  Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–2116. 70f.  Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA. 2017;318:2132– 2134. 70g.  Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA. 2018;319:115–116. 71. Barrios V, Escobar C. Aliskiren in the management of hypertension. Am J Cardiovasc Drugs. 2010;10:349–358. 72. Duggan ST, Chwieduk CM, Curran MP. Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension. Drugs. 2010;70:2011–2049. 73. Oh BH, Mitchell J, Herron JR, et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol. 2007;49:1157–1163. 74. Oparil S, Yarrows SA, Patel S, et al. Dual inhibition of the renin system by aliskiren and valsartan. Lancet. 2007;370:221–229. 75. Reboldi G, Gentile G, Angeli F, et al. Pharmacokinetics, pharmacodynamics and clinical evaluation of aliskiren for hypertension treatment. Exp Opinion Drug Metab Toxicol. 2011;7:115–128. 76. Tardif JC, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective if inhibitor compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529–2536. 77. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular and endothelial cells. Nature. 1988;332:411–415. 78. Rich S, Mclaughlin W. Endothelin receptor blockers in cardiovascular disease. Circulation. 2003;108:2184–2190. 79. Stewart DL, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease. Ann Intern Med. 1991;114:464–469. 80. Giaid A, Yanagisawa M, Langleban D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New Engl J Med. 1993;328:1732–1739. 81. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998;98:1400– 1406.

27 

Antiarrhythmic Drugs GEOFFREY W. ABBOTT AND ROBERTO LEVI

CHAPTER OUTLINE Historical Perspective Basic Pharmacology Singh-Vaughan Williams Classification of Antiarrhythmic Drugs Sodium Channels and Class I Antiarrhythmic Drugs β Receptors and Class II Antiarrhythmics Potassium Channels and Class III Antiarrhythmic Drugs Calcium Channels and Class IV Antiarrhythmics Clinical Pharmacology Categories of Arrhythmogenic Mechanisms Automaticity Triggered Conduction Clinical Application Class I—Sodium Channel Blockers Class Ia Nav Channel Blockers Class Ib Nav Channel Blockers Class Ic Nav Channel Blockers Class II—β Blockers Class III—Potassium Channel Blockers Class IV—Calcium Channel Blockers Emerging Developments Molecular Genetics of Arrhythmias Long QT Syndrome Short QT Syndrome Brugada Syndrome Other Inherited Arrhythmia Syndromes hERG Drug Interactions Gene Therapy Guided by Molecular Genetics of Inherited Arrhythmias

Historical Perspective The heart, and more specifically the heartbeat, has throughout history served as an indicator of well-being and disease, both to the physician and to the patient. Through one’s own heartbeat, one can feel the physiologic manifestations of joy, thrills, fear, and passion; the rigors of a sprint or long-distance run; the instantaneous effects of medications, recreational drugs, or toxins; the adrenaline of a rollercoaster ride or a penalty shootout in a World Cup final. Although the complexities of the heart continue to humble the 556

scientists and physicians who study it, the heart is unique in that, despite the complexity of its physiology and the richness of both visceral and romantic imagery associated with it, its function can be distilled down to that of a simple pump, the function and dysfunction of which we now understand a great deal about (see Chapter 24). The history of development of pharmacologic agents to correct abnormalities in heart rhythm is, however, emblematic of drug development as a whole: major successes combined with paradoxes, damaging side effects, and the often frustrating intransigence of what would seem the most intuitive targets for antiarrhythmics—ion channels.1,2 In ancient Greek, Egyptian, and Chinese cultures, the pulse was recognized as a means to assess health, and for millennia it was the only measure of cardiac physiology and pathophysiology. In second-century Rome, Galen’s work De Pulsibus became the first great treatise on the pulse as a window into human health and established Galen as the father of his discipline.3 It was not for another 1500 years that the great physician, scientist, and naturalist William Harvey, of Folkestone in England, published his landmark (and then controversial) work An Anatomical Exercise Concerning the Motion of the Heart and Blood in Animals. This introduced the theory that blood circulates throughout the body, a hypothesis tested rigorously by Harvey with experiments on animals and the cadavers of executed criminals.4 In the late 19th and early 20th centuries, Waller and Einthoven founded the field of electrocardiography, facilitating quantitative differential diagnoses of cardiac arrhythmias. This paved the way for modern cardiology and advances such as Wolff, Parkinson, and White’s neurocardiac theory, the discovery of atrial fibrillation (AF), and the increasingly sophisticated molecular genotype-phenotype correlations from which we benefit today.5,6 These latter advances also owe much to the work of molecular geneticists in the 1990s whose Herculean efforts (before routine high-throughput sequencing) helped identify the mutant ion channel genes underlying inherited arrhythmias such as long QT syndrome, working hand in hand with cellular electrophysiologists and physicians to exemplify the bedside-to-bench model of modern molecular medicine. Having said this, β blockers, the first antiarrhythmics of the modern era, were developed in the later 1950s to early 1960s not with ion channels in mind, but were a by-product of Sir James W. Black’s desire to create improved therapies for angina and essentially “to stop the effects of adrenaline on the heart” following the death of his father after a myocardial infarction. The resulting class II antiarrhythmic drug, propranolol, ushered in a new era of drug development and proved effective in therapy of disorders including angina, arrhythmia, and hypertension.7



Abstract Disturbances in cardiac rhythm, also termed cardiac arrhythmias, can arise from structural heart disease, adverse drug interactions, or inherited gene variants in ion channels or the proteins that regulate them. Cardiac arrhythmias range from relatively common, chronic arrhythmias such as atrial fibrillation, to the rarer but more acutely dangerous ventricular arrhythmias that can culminate in ventricular fibrillation, which is rapidly lethal unless defibrillation is administered. Because ion channels and their regulators conduct electrical currents in the heart that determine cardiac rhythm, most anti-arrhythmic drugs act, directly or indirectly, on cardiac ion channels. As different types of cells in specific regions of the heart each carry their own signature array of ion channels, antiarrhythmic drugs can be chosen to target the specific regions in which the arrhythmia originates or is most critically manifested. In this chapter, after a brief historical perspective, we review antiarrhythmic drugs, first discussing them in the context of the widely used Singh-Vaughan Williams classification system. Next, after a description of the major arrhythmogenic mechanisms, we discuss in detail clinical application of the various classes of anti-arrhythmics. In the final section, we cover inherited cardiac channelopathies and how they have guided our understanding of cardiac physiology, pathophysiology and its treatment, before discussing pharmacogenetics of adverse drug interactions and ideas about future gene therapy approaches. The chapter is intended to be a guide to the major classes of anti-arrhythmic drugs, their usage and mechanisms of action, and, where appropriate, mechanistic insights into the ion channels that they target.

CHAPTER 27  Antiarrhythmic Drugs 556.e1

CHAPTER 27  Antiarrhythmic Drugs



Despite the vast array of imaging, molecular, and electrocardiographic diagnostic tools available to cardiologists and other physicians, measurement of the pulse will likely be central to routine examination of the cardiac and holistic health of individuals for the foreseeable future. Timely, rhythmic beating of the heart is essential for health. When the heart develops sustained nonrhythmic beating, generally termed arrhythmia, the consequences can range from mild (e.g., syncope) to lethal (sudden cardiac death). Cardiac arrhythmias are treated by surgical ablation, electronic pacemaker, cardioversion, pharmacologic agents, or a combination of these, depending on the location and nature of the causal factor. For example, in the case of ventricular fibrillation—a life-threatening, chaotic tachycardia—electrical defibrillation is required immediately to prevent sudden cardiac death. In contrast, in many cases of AF there is an underlying structural defect in the atria that can be successfully treated using radiofrequency catheter ablation—for example, to prevent the aberrantly conducting area from being an arrhythmogenic focus. This chapter focuses on antiarrhythmic medications as frequently encountered in the perioperative and critical care settings. These are a broad class of drugs, incorporating numerous structural classes and modes of action, that are used based on the suspected or known molecular etiology of the arrhythmia to be treated. Recent advances in the understanding of the molecular basis for generation of electrical currents in the heart, and also the genetic basis of many cardiac arrhythmias, have contributed to the development and use of antiarrhythmic drugs. Furthermore, these advances have demonstrated the basis for the proarrhythmic action of some drugs—paradoxically, even some drugs that are classified and used as antiarrhythmics. To fully understand the mechanism of action of antiarrhythmic drugs, one must understand both the underlying cause of the arrhythmia, and the molecular target of the antiarrhythmic; these may or may not be the same entity. Accordingly, this chapter includes not only a description of the basic and clinical pharmacology of the major classes of cardiac arrhythmias, but also a discussion of the mechanistic underpinnings of these arrhythmias.

Basic Pharmacology Singh-Vaughan Williams Classification of Antiarrhythmic Drugs Antiarrhythmic drugs include a wide range of structural and functional classes. Although not perfect, a highly useful framework for their classification is that proposed by Singh and Vaughan Williams, usually referred to as the Singh-Vaughan Williams (SVW) classification. The SVW classification categorizes antiarrhythmic drugs into four classes (Table 27.1). Class I denotes sodium (Na+) channel blocking activity, with resultant delay in phase 0 depolarization and/or altered action potential duration. Class II agents counteract the effects of endogenous catecholamines (in particular epinephrine and norepinephrine) by antagonism of β adrenergic receptors, and hence are known as β blockers or β antagonists. Class III antiarrhythmics prolong the action potential and refractory period, acting primarily by potassium (K+) channel blockade. Class IV agents reduce heart rate, primarily by L-type calcium (Ca2+) channel blockade, which slows conduction through the sinoatrial (SA) and atrioventricular (AV) nodes.8,9 (For a more detailed discussion of cardiac electrophysiology and myocyte depolarization, see Chapter 23). The primary reason that the SVW classification is to some extent imperfect is that many, if not most, antiarrhythmic drugs

557

TABLE Singh-Vaughan Williams Classification of 27.1  Antiarrhythmic Agents

Class

Mechanism of Action +

Drugs

Ia

Na channel blockade, prolonged repolarization

Procainamide, quinidine, disopyramide

Ib

Na+ channel blockade, shortened repolarization

Lidocaine, mexiletine, phenytoin, tocainide

Ic

Na+ channel blockade, repolarization unchanged

Encainide, flecainide, propafenone

II

β-adrenoceptor antagonist

Esmolol, metoprolol, propranolol

III

Marked prolongation of repolarization

Amiodarone, bretylium, ibutilide, sotalol

IV

Calcium channel blockade

Diltiazem, verapamil

exhibit physiologically significant actions in more than one of the four classes. Typically the classification is based on the action that was first described for each drug, which is generally but not necessarily the most therapeutically significant mechanism of action for all types of arrhythmia for which the drug is prescribed. This discrepancy can occur because of nonspecificity of the drug, or because major metabolites of the drug exhibit different activity than that of the drug itself. Furthermore, some important antiarrhythmic drugs, including digoxin and adenosine, do not fit primarily into any of the four classes. However, the SVW classification is still the most useful framework for describing antiarrhythmic drugs, especially if one considers the net effect of each drug rather than all its specific molecular targets. The clinical pharmacology of the major antiarrhythmic drugs is summarized in Table 27.2.

Sodium Channels and Class I Antiarrhythmic Drugs Voltage-gated Na+ (Nav) channels open in response to cell membrane depolarization to permit influx of Na+, further depolarizing the cell. The predominant Nav channel in human cardiac electrophysiology is Nav1.5, which is encoded by the SCN5A gene. In most cardiac myocytes, Nav1.5 activation mediates the upstroke in phase 0 of the action potential, in which the membrane potential is depolarized from around −70 mV to +20 mV as the result of Na+ influx (Fig. 27.1A). Nav1.5, like other mammalian Nav channels, inactivates rapidly, which together with the transient outward K+ current, Ito, shapes the notch in phase 1 at the beginning of the human cardiac myocyte action potential.10 Class I antiarrhythmics exhibit Nav channel blocking activity. These drugs are often referred to as “membrane stabilizing agents” because by blocking cardiac Nav channels, which mediate myocyte depolarization, they reduce cellular excitability. Nav channels are composed of a 24-transmembrane-segment pore-forming α subunit that consists of four homologous domains (DI-DIV) and also bears four voltage-sensing domains and one or more inactivation gates (Fig. 27.2A). The Nav1.5 α subunits form cardiac ion channel complexes with single-transmembrane segment β subunits, encoded by the SCNxB genes, which modify Na v1.5 function and pharmacology.11 Class I antiarrhythmic drugs are thought to bind in the inner pore vestibule of Nav channels, with drugs from different structural

558

SE C T I O N III

Cardiovascular System

TABLE 27.2  Antiarrhythmic Drugs

Class

Mechanism +

Specific Drugs

Clinical Uses

Adverse Effects

Ia

Na channel block (intermediate kinetics); K+ channel block; repolarization prolonged

Quinidine Procainamide Disopyramide

Ventricular arrhythmias Prevention of paroxysmal recurrent atrial fibrillation Conversion of atrial flutter and fibrillation (quinidine, procainamide) Maintenance of sinus rhythm after conversion of atrial flutter and fibrillation Wolff-Parkinson-White syndrome (procainamide)

QTP/torsades de pointes, nausea, diarrhea, hepatotoxicity, myelosuppression Lethal ventricular arrhythmias, QTP/ torsades de pointes, hypotension Lupus-like syndrome, blood dyscrasias Proarrhythmic, torsades de pointes, negative inotropy Parasympatholytic

Ib

Na+ channel block (fast kinetics); repolarization shortened

Lidocaine Tocainide Mexiletine

Ventricular tachycardia/fibrillation (lidocaine) Atrial fibrillation

Seizure, tremor, confusion/delirium

Ic

Na+ channel block (slow kinetics); no effect on repolarization

Flecainide Propafenone

Prevention of paroxysmal atrial fibrillation Recurrent tachyarrhythmias of abnormal conduction system Contraindicated immediately after myocardial infarction

Proarrhythmic, heart failure Proarrhythmic, nausea

II

β blockade Propranolol also shows class I effect

Nonselective Propranolol Nadolol β1 selective Esmolol Metoprolol Atenolol Bisoprolol Nonselective β/α blockade Carvedilol Labetalol

Reduce myocardial infarction mortality Prevention of recurrence of tachyarrhythmias Rate control

Bradycardia, hypotension, fatigue, depression

III

K+ channel block Sotalol is also a β blocker Amiodarone and dronedarone have class I, II, and III activity

Sotalol Ibutilide Dofetilide Amiodarone Dronedarone Bretylium (no longer available in U.S.)

Wolff-Parkinson-White syndrome Ventricular tachycardia/fibrillation (sotalol bretylium, amiodarone) Conversion of atrial flutter and fibrillation (ibutilide, sotalol, dofetilide, amiodarone) Maintenance of sinus rhythm after conversion of atrial flutter and fibrillation (sotalol, dofetilide, amiodarone, dronedarone)

Proarrhythmic, QTP/torsades de pointes, bradycardia, heart failure Proarrhythmic, QTP/torsades de pointes Proarrhythmic, QTP/torsades de pointes Hypotension, bradycardia Pulmonary, neurologic, hepatic, dermatologic, ophthalmic, thyroid Increased mortality with heart failure Nausea, vomiting, diarrhea Proarrhythmic, hypotension

IV

Ca2+ channel block

Dihydropyridine (selective vasodilators) Nifedipine, nicardipine, amlodipine, isradipine Benzothiapine (less vasodilation; sinoatrial and atrioventricular node block) Diltiazem Phenylalkylamine (sinoatrial and atrioventricular node block) Verapamil

Hypertension

Adenosine receptor activation Sodium pump inhibition

Adenosine Digoxin

Supraventricular arrhythmias Heart failure, atrial fibrillation

Ca2+ channel block and other effects

Magnesium

Torsades de pointes

Other

QTP, QT interval prolongation.

Prevention of recurrent paroxysmal supraventricular tachycardia Reduce ventricular rate in atrial fibrillation Prevention of recurrent paroxysmal supraventricular tachycardia Reduce ventricular rate in atrial fibrillation

Ataxia, tremor

Bradycardia, hypotension, ankle swelling Bradycardia, hypotension, constipation

Bradycardia, nausea, vomiting, visual disturbances Hypotension, weakness

CHAPTER 27  Antiarrhythmic Drugs



Early repolarization (1)

Early Afterdepolarization (EAD) (Effect of potassium channel blockers)

Plateau (2)

Ito ICaL 0 mV

IKs

559

Phase 1 Late repolarization (3)

INa

+10 mV

IKr

Phase 2

Phase 3

Upstroke (0)

IK1

0.2 s

IK1

–80 mV

T ↑ Duration of phase 3 QT lengthens

NCX Resting (4)

0 mV

–90 mV If

SA node

Pacemaker function 5 mV

AV node

Delayed Afterdepolarization (DAD) Phase 1 +10 mV

–50 mV 30 mV

–60 mV Atrium

40 mV

Phase 2 Phase 3

Ventricle

–90 mV

Phase 4

B –70 mV

A

–80 mV 1s

C • Fig. 27.1

  Cardiac action potentials and the electrocardiogram. A, Upper, a generic cardiac action potential illustrating the phases and major currents involved. NCX, sodium/calcium exchanger. Lower, comparison of nodal (SA, sinoatrial; AV, atrioventricular), atrial, and ventricular action potentials. B, Upper, ventricular action potential superimposed on an electrocardiogram (ECG) showing the QT interval–prolonging effects of potassium channel block and resultant early afterdepolarizations. Lower, delayed afterdepolarizations. C, ECG showing torsades de pointes. (Trace from Braunwald E, Zipes DP, Libby P, eds. Heart Disease. 6th ed. Philadelphia: WB Saunders; 2001:868.)

560

SE C T I O N III

I.

Na channel

Cardiovascular System

II.

12345

6

12345

III.

6

IV.

12345

6

12345

6

COOH

NH2

I

IV Top view

A Effects on Action Potential O

OH N

β Receptors and Class II Antiarrhythmics

N Class 1a

Quinidine

H N

N O

Class 1b

Lidocaine

F

O

F F

O N H

H N

F F F

among other animal sources, in the nerves, skin, and gonads of the Japanese puffer fish, Fugu rubripes. F. rubripes is saddled with the dual distinction of having the shortest known genome of any vertebrate organism and being a delicacy in Japan that must be prepared by certified chefs to decrease the chances of ingestion of lethal doses of TTX by adventurous diners. Compared with its effects on Nav1.5, TTX acts with up to 103-fold higher potency on the predominantly neuronal Nav channel subtypes Nav1.1-1.3 (SCN1A-3A) and the skeletal muscle–expressed channel Nav1.4 (SCN4A).13 TTX, nicknamed “zombie powder” because its paralysisand coma-inducing effects have led to its use in voodoo ceremonies (it does not cross the blood-brain barrier; those ingesting sublethal doses are potentially conscious while paralyzed), is therefore not a useful antiarrhythmic (owing to its inefficacy and lethality at low doses). However, TTX prolongs the local anesthetic effect of bupivacaine when the two are coadministered.14 A recent highresolution x-ray crystallographic structure of an Nav channel from Arcobacter butzleri has provided a first look at this class of proteins essential to function of nerve and muscle, and will likely enhance future class I antiarrhythmic development (see Chapter 20).15

O

B Class 1c Flecainide • Fig. 27.2  Sodium channels and the class I antiarrhythmics. A, Topology

and subunit organization of the voltage-gated Na+ (Nav) channel α subunit. The 24-transmembrane segments form four homologous domains (I-IV) that fold to create the ion pore. B, Left, effects of class Ia, Ib, and Ic antiarrhythmics (dotted lines) on cardiac myocyte action potentials (purple lines). Right, exemplar class Ia (Quinidine), Ib (Lidocaine), and Ic (Flecainide) antiarrhythmics.

classes, including lidocaine, flecainide, and quinidine, and the anticonvulsant phenytoin, binding to an overlapping but nonidentical site influenced experimentally by mutations in the S6 transmembrane segment of domain IV. 12 Drugs in class I are subcategorized as Ia, Ib, or Ic depending on their effects on Na+ channel conduction and resultant effects on action potentials in cardiac myocytes expressing the predominant cardiac form of Nav channel, Nav1.5 (Fig. 27.2B). Nav1.5 is relatively insensitive to the canonical and lethal Nav channel antagonist tetrodotoxin (TTX), a nerve toxin present,

Class II antiarrhythmic drugs, also known as β blockers, antagonize the β-adrenergic receptor (β receptor). This β blockade prevents activation of adenylyl cyclase and the consequent increase in intracellular cyclic adenosine monophosphate (cAMP), and thus also activation of its principal downstream target cAMP-dependent protein kinase (PKA), and the promotion of maximal myocardial performance that normally results from the enhancement of sympathetic nervous tone (Fig. 27.3; see Chapters 13 and 14). β Blockers are selective, in that they do not block other receptors, and specific, in that they do not antagonize cardiac stimulation and vasodilatation elicited by agents other than β agonists. All β blockers share the basic structure of a β sympathomimetic side chain, which confers affinity for the receptor, along with an aromatic substituent, which determines potency; most are derivatives of the class-defining agent propranolol (see Fig. 27.3B). β Blockers are effective as antiarrhythmic agents because, by blocking the action of the sympathetic nervous system on the heart, they depress SA and AV node function, decrease conduction and automaticity, and prolong atrial refractory periods. β Blockers also reduce blood pressure, probably arising from a combination of reduced cardiac output, renal renin release, and perhaps even effects within the central nervous system (see Chapter 26). 16,17 Inasmuch as an exaggerated increase in sympathetic tone typifies the deleterious reaction to congestive heart failure, β blockers, particularly the cardioselective ones, are used successfully also in the treatment of this ailment.18 Propranolol is marketed as a D,L-racemic mixture (see Chapter 1 for a discussion of the pharmacologic implications of chirality), the reason being that the L-form is the β blocker while the D-form is a “membrane stabilizer,” which adds antiarrhythmic effect to the β-blocking properties of the L-enantiomer.

Potassium Channels and Class III Antiarrhythmic Drugs Class III antiarrhythmic drugs are defined by their ability to block K+ channels. This activity increases action potential duration in cardiac myocytes and prolongs the refractory period—that is, it extends the period during which the heart is refractory to premature electrical stimuli. Cardiac K+ channels exhibit a much wider variety

CHAPTER 27  Antiarrhythmic Drugs



Sympathetic nerve –

NE

α2

NE

β1

β2

Gs AC

Cardiac myocyte

cAMP

ATP

+

Ca2+

+

SR

Ca2+

PK-A

+

Contraction

Ca2+ +

A

Ca2+

O OH

B

N H

Propranolol

• Fig. 27.3

  β-Adrenergic signaling and the class II antiarrhythmics. A, Schematic showing β-adrenergic signaling and its effects on cardiac function. AC, Adenylyl cyclase; Gs, G-stimulatory protein; NE, norepinephrine; PK-A, cAMP-dependent protein kinase; SR, sarcoplasmic reticulum. B, Structure of the canonical β blocker, propranolol.

than other cardiac ion channels. The two most physiologically and therapeutically important families of K+ channels in the heart, based on current understanding, are the voltage-gated K+ (Kv) channels and inward rectifier potassium (Kir) channels.19,20 Channels in both these families are predominantly involved in the repolarization phases of the cardiac myocyte action potential, because both Kv and Kir channels pass inward K+ currents only when the cell membrane potential is negative to the K+ equilibrium potential, which is around −80 mV under physiologic conditions. Kv channels are each composed of several subunit types. Similar to Nav channels, the pore-forming α subunits of Kv channels are arranged in a 24-transmembrane-segment array forming an aqueous central pore with external voltage-sensing modules (Fig. 27.4A). However, in Kv channels, this is composed of a tetramer of noncovalently linked α subunits (each subunit having six transmembrane segments) rather than one contiguous α subunit with four homologous six-segment domains as in Nav and Cav channels. In Kv channel α subunits, the fourth transmembrane segment (S4) bears the basic residues that confer voltage sensitivity, while S6 lines the pore (Fig. 27.4A). High-resolution x-ray crystallographic

561

structures of bacterial and eukaryotic Kv channels have revolutionized the study of these ubiquitous and essential proteins, including current understanding of drug binding sites.21,22 The most important Kv α subunits in human ventricular repolarization are the ether-à-go-go related gene product (hERG; also named KCNH2) and KCNQ1. Tetramers of each of these coassemble with multiple single-transmembrane-domain ancillary or β subunits from the KCNE gene family. KCNQ1-KCNE1 complexes primarily generate the slowly activating I Ks current; hERG-KCNE2 complexes generate IKr; and each of the five KCNE proteins probably regulates these and other α subunits in the heart too.23–26 IKr and IKs are crucial to phase 3 repolarization (see Fig. 27.1A); therefore blocking these currents delays ventricular repolarization, which can be proarrhythmic or antiarrhythmic depending on the disease state and other genetic and environmental factors.27 hERG is particularly sensitive to drug block by a wide range of drugs, owing to its bearing an unusual array of hydrophobic residues, not conserved among other Kv channels, in an internal pore cavity also predicted to be wider than in other Kv channels (Fig. 27.4B).28 Inhibitors of Kv channels tend to bind in one of three distinct sites: the outer vestibule, the inner vestibule (drugs in these classes would be considered pore blockers), or on the voltage sensor, which is rarer among small molecules but is seen with some toxins from venomous animals, such as hanatoxin and SGTx from tarantula spiders.29 The canonical inhibitors of hERG and KCNQ1 are E-4031 and chromanol 293B, respectively, both of which bind in the inner vestibule and show relatively high specificity for their targets. Additionally, both drugs are sensitive to the presence of KCNE subunits in complex with the α subunits.30 E-4031 will not be used in the future for antiarrhythmic therapy because pure hERG antagonists such as this cause dangerous repolarization delays. IKs inhibitors are still being considered because it might be therapeutically useful to counteract the upregulation of IKs during periods of high sympathetic activity associated with arrhythmia triggering. Other important Kv channel targets of class III antiarrhythmic drugs include the Kv4 α subunits that generate human ventricular Ito (particularly active during phase 1 of the ventricular action potential), and Kv1.5, which generates the ultrarapidly activating K+ current, IKur, important in atrial myocyte repolarization. Kv4 and Kv1.5 α subunits are also regulated by the KCNE subunits.31,32 In addition, all the Kv channels discussed herein are regulated by a host of cytoplasmic β subunits and other regulatory proteins (Fig. 27.4C), each of which can affect channel pharmacology either directly or indirectly, because changes in gating alter drug binding kinetics.30,33 Kir channels do not possess a voltage sensor but exhibit inward rectification because they are inhibited at more positive membrane potentials by intracellular constituents, including magnesium (Mg2+) and polyamines such as spermine. These channels are composed of a tetramer of α subunits, each with only two transmembrane segments, around a central, aqueous, K+-selective pore (Fig. 27.4D). The ventricular inward rectifier current IK1 is generated by Kir2 family α subunits and contributes to stabilizing the cardiac potential, passing current at either end but less so when the myocyte is strongly depolarized (see Fig. 27.1A). The KATP channel, which also probably contributes to cardiac excitability, is an octamer of four Kir6 α subunits and four membrane-spanning sulfonylurea receptor subunits that render it sensitive to adenosine triphosphate (ATP).19 A host of class III drugs, including amiodarone and dofetilide, inhibit Kir channels by direct pore block within the inner vestibule.34,35

562

Cardiovascular System

SE C T I O N III

6 12345 + + P +

Kv α

Val625 Thr623 Gly648 Tyr652 KCNE

A

B

KCNE1 N

N

KCNE2 N

N

N

α

Kv4.3 c

c

Yotiao

C

KCNE N

KCNQ1

c

Phe656

c KChAP

KChIP

O

c

c β

PSD

ATP-Sensitive K Channel I

O

N

O I Amiodarone

S O

Sulfonylurea receptor

H N

N

N NBF1

O

O

Kir

O E4031

O O

N

NH O

D

S

O Dronedarone

• Fig. 27.4

  Potassium channels and the class III antiarrhythmics. A, Topology of a Kv α subunit and a KCNE β subunit. B, Left, drug binding site within the ether-à-go-go related gene product (hERG) Kv α subunit. Residues in red are crucial for binding of a variety of drugs, such as cisapride and terfenadine, and undergo π-bonding with the aromatic rings of methanesulfonanilides. Green and blue residues are less impactful on cisapride and terfenadine binding but important for methanesulfonanilide binding.104 Right, structures of some class III antiarrhythmic drugs. C, Cartoons of some heteromeric Kv channels containing α subunits, and both transmembrane and cytoplasmic β subunits. D, Topology of a Kir α subunit and an SUR subunit. ATP, Adenosine triphosphate; K, potassium; KChAP, kt channel associated protein; KChIP, Kv channel–interacting protein; Kir, inward rectifier potassium; NBF, nucleotide-binding fold; SUR, sulfonylurea receptor.

NBF2

CHAPTER 27  Antiarrhythmic Drugs



Calcium Channels and Class IV Antiarrhythmics Class IV agents slow AV nodal conduction, primarily by L-type Ca2+ channel (LTCC) antagonism. LTCCs mediate the upstroke of nodal cell action potentials, unlike true atrial and ventricular myocyte action potentials in which the upstroke is mediated primarily by the faster activating and inactivating Nav channel, Nav1.5. Hence, nodal action potentials exhibit a much slower upstroke than that of typical atrial and ventricular myocytes (see Chapter 23). The transmembrane topology of voltage-gated Ca2+ channel (Cav) α subunits mirrors that of the Nav channel α subunits: 24 transmembrane segments around an aqueous pore. LTCCs also

incorporate a requisite array of ancillary subunits: the cytoplasmic β subunit, transmembrane δ and γ subunits, and extracellular α2 subunit (Fig. 27.5A). In cardiac muscle, the LTCC Cav1.2 α subunit is located in the T-tubules and is activated by cellular depolarization, via its voltage-sensing apparatus, which moves upon membrane depolarization and opens the discrete but connected pore. Ca2+ influx through Cav1.2, down the Ca2+ concentration gradient, helps depolarize the cell and increase cytosolic [Ca 2+] directly, but it also works indirectly by activating the sarcoplasmic reticulum– located ryanodine receptor (RyR2 in cardiac muscle) through Ca2+-activated Ca2+ release. In skeletal muscle, the mechanism is somewhat different: Cav1.1 is mechanically linked to RyR1

α3 I

II

123 5

III

IV

6 P loop C Ca2+

N ∆V N α2 SS SS

Stimulation

Ca2+ Extracellular

Intracellular BID AID

α1

C

N

β

C

A

γ

C N

III– IV

I–II

δ

II III IV

I

II–III

C Anchoring and

N

regulation

B

N

O S

N O

O O

O

C

O

N N

O Diltiazem

O

Verapamil

• Fig. 27.5

Calcium channels and the class IV antiarrhythmics. A, Upper, topology of a voltage-gated Ca2+ channel α subunit (Cav). Note similar structure to Nav shown in Fig. 27.2. Lower, heteromeric voltage-gated Ca2+ channel complex with α2δ accessory subunits. B, Juxtaposition of voltage-gated Ca2+ channel at the cell surface membrane (blue) and the sarcoplasmic reticulum–located ryanodine receptor in skeletal muscle (left) and cardiac muscle (right). C, Structures of verapamil and diltiazem, key class IV antiarrhythmic drugs. BID, B-interacting domain; AID, α-interacting domain; Ca2+, calcium ion; SS, disulfide bond.  

563

564

SE C T I O N III

Cardiovascular System

and acts as the latter’s voltage sensor. Thus in skeletal muscle, RyR1 is activated primarily by membrane depolarization, with the Cav1.1 S4 domains acting as the RyR1 voltage sensors (see Fig. 27.5B).36,37 Most clinically relevant Cav channel blockers are in one of three chemical classes: the dihydropyridines, which are not generally indicated for arrhythmias; the phenylalkylamines, exemplified by verapamil; and the benzothiazepines, exemplified by diltiazem.38 Diltiazem and verapamil (see Fig. 27.5C) are thought to bind overlapping but distinct sites within the S6 segments of repeats III and IV, and the Ca2+ selectivity filter of the α1 subunit of the cardiac LTCC Cav1.2.39–41

Clinical Pharmacology Categories of Arrhythmogenic Mechanisms The mechanistic bases for most, if not all, arrhythmias can be placed in one of three categories. These are discussed with the most common modes of treatment.42–47

Automaticity Arrhythmias in this category arise from changes to the normal process of automaticity essential for cardiac rhythm (see Fig. 27.1). They can be further separated into two subcategories: Normal automaticity arrhythmias are those that elicit speeding or slowing of the heartbeat, initially at least maintaining regular beating, although this is lost at some point—for example, at extremely high heart rates, owing to an intrinsic inability of ion channels to function rapidly enough in concert. Arrhythmias in this category include sinus tachycardia and ventricular tachycardia (both being an increased heart rate). The most common pharmacologic treatment of sinus tachycardia and ventricular tachycardia is with β blockers (class II antiarrhythmics). Abnormal automaticity arrhythmias are those in which regular activity is lost immediately and involve spontaneous impulse formation in partially depolarized cells (membrane potentials in the range of −40 to −60 mV). Examples of arrhythmias that can fall into this category include ventricular tachycardias and ectopic atrial tachycardias in the subacute phase (within 48 hours) following myocardial infarction, exercise-induced idiopathic ventricular tachycardias, and catecholamine-sensitive idiopathic ventricular tachycardias. The most common pharmacologic treatment of idiopathic rhythms and ectopic atrial tachycardias is with Ca2+ channel blockers (class IV antiarrhythmics). Sinus rhythm is regulated by pacemaker channels (i.e., hyperpolarization-activated, cyclic nucleotide-gated monovalent cation-nonselective channels known as HCN), and to a greater or lesser extent, Ca2+ oscillations. Hence, human HCN4 mutation is associated with sinus-mediated pathologic slowing of the heart rate (sinus bradycardia). Triggered Triggered arrhythmias are those in which a mistimed beat occurs before the previous beat is complete (see Fig. 27.1B). The ion channels involved in orchestrating each cardiac myocyte action potential must work in concert to generate rhythmic contraction of the heart. Because the various classes of ion channels each have distinct gating kinetics and refractory periods, if one type of ion channel dysfunctions, it can act asynchronously with the others, potentially causing triggered arrhythmias. Triggered arrhythmias can be separated into two main classes:

Early after-depolarizations (EADs) occur when myocardial repolarization is delayed sufficiently that the next action potential in a given cardiac myocyte begins before that myocyte is fully repolarized. A common clinical consequence is the arrhythmia referred to as torsades de pointes (TdP). TdP is so named because it appears on the electrocardiogram (ECG) as a twisted ribbon owing to the variance in magnitude of the voltages associated with each heartbeat (see Fig. 27.1C). TdP most often occurs because of pharmacologic inhibition of specific ventricular myocyte K + channels, which results in a delay in ventricular myocyte repolarization and consequent prolongation of the QT interval on the ECG. A number of drugs inhibit these channels and can lead to TdP, including several drugs commonly used in anesthesia; some of the major QT interval prolonging drugs are summarized in Table 27.3. The QT interval represents the time from the onset of ventricular depolarization to the end of ventricular repolarization; prolongation of this interval can indicate long QT syndrome, of which there are now many well-defined subtypes with distinct molecular etiologies. When sufficiently long delays in repolarization occur, Nav channels can recover from their refractory period and open before repolarization is complete, leading to an EAD in phase 2, 3, or 4 of the ventricular or atrial action potential (see Fig. 27.1B). The most common pharmacologic treatment of TdP is with magnesium sulfate, β blockers (class II antiarrhythmics), and/or Ca2+ channel blockers (class IV antiarrhythmics). Delayed after-depolarizations (DADs) classically occur in digitalis toxicity. Digitalis toxicity can occur through a variety of mechanisms, but all serve to raise intracellular Ca2+ concentration, generating a net depolarizing current that, together with the tendency of digitalis to increase vagal tone, leads to DADs (among other possible classes of arrhythmias). Unlike most EADs, DADs begin after repolarization but before the next appropriately timed depolarization—that is, in phase 4 of the cardiac action potential (see Fig. 27.1B). The most common pharmacologic treatment of DADs arising from digitalis toxicity is with Ca2+ channel blockers (class IV antiarrhythmics).

Conduction Commonly arising from structural damage to the heart, but also from certain drug-ion channel interactions, localized slowed conduction within regions of the heart can cause reentrant arrhythmias that can be categorized into two main types: Reentrant circuits arise when one area of the heart contains a region of slowed ion conduction. When such regions occur, primarily resulting from the refractory period of Nav channels arising from their rapid and extensive inactivation and its recovery, reentrant circuits are formed because normal conduction cannot proceed unidirectionally but can proceed in a circle (Fig. 27.6A). They can be microreentrant (involving a localized region within [e.g., one chamber of the heart]) or macroreentrant, involving more than one chamber (Fig. 27.6B). Such circuits are incompatible with normal cardiac rhythm because they disturb the (essentially) unidirectional wave of depolarization/repolarization required for normal contraction to occur. These types of circuits cause atrial flutter and ventricular and supraventricular tachycardias. Monomorphic ventricular tachycardia is treated with class Ia Nav channel blockers or K+ channel blockers (class III antiarrhythmics). AV node reentrant tachycardias (supraventricular tachycardia or SVT), which arise from reentry in the region of the AV junction, are treated with Ca2+ channel blockers (class IV antiarrhythmics) or adenosine. Fibrillation occurs when many microreentrant circuits span an entire chamber of the heart. This is a different situation from a

CHAPTER 27  Antiarrhythmic Drugs



TABLE 27.3  Drugs Known to Prolong QT Interval

single macroreentrant circuit and is typically classified (according to the chambers in which it is occurring) as AF or ventricular fibrillation. The substrate for AF is probably most commonly structural heart disease, and while it is typically not acutely dangerous, it requires treatment. This is partly because it suggests an underlying defect and partly because a significant risk in AF is the formation of atrial thrombi that can result in launching of systemic emboli when sinus rhythm is reestablished. Approximately 2 to 3 million people in the United States have AF; the majority are in the aging population, and this number is expected to rise as the population ages. Another common cause of AF is major surgery such as open heart surgery or lung resection, with the underlying mechanism not being entirely clear. Hyperthyroidism can also cause AF; return to euthyroidism abrogates the AF in the majority of cases. AF is most commonly treated with Nav channel blockers (class Ia antiarrhythmics) or K + channel blockers (class III antiarrhythmics). Ventricular fibrillation, in contrast, is acutely life-threatening because the heart in ventricular fibrillation cannot pump blood effectively. An estimated 300,000 people in the United States die annually of sudden cardiac death, with ventricular fibrillation among the most common lethal arrhythmias. Ventricular fibrillation must be rapidly treated (within minutes) using direct current shock. Cardiopulmonary resuscitation (CPR) can be used to keep the brain alive until defibrillation is possible, but CPR cannot restore normal cardiac rhythm. Amiodarone is the first-line antiarrhythmic drug clinically demonstrated to increase return of spontaneous circulation in refractory ventricular fibrillation and pulseless ventricular tachycardia unresponsive to CPR, defibrillation, and vasopressor therapy. If amiodarone is unavailable, lidocaine can be considered as a second-line drug with less evidence of efficacy compared with amiodarone. Magnesium sulfate is used for TdP associated with a long QT interval.

Generic Name

Class

Comments

Amiodarone

Antiarrhythmic

Females > males, torsades de pointes risk low

Arsenic trioxide

Anticancer

Astemizole

Antihistamine

No longer available in U.S.

Bepridil

Antianginal

Females > males

Chloroquine

Antimalarial

Chlorpromazine

Antipsychotic; antiemetic

Cisapride

Gastrointestinal stimulant

Citalopram

Antidepressant

Clarithromycin

Antibiotic

Disopyramide

Antiarrhythmic

Dofetilide

Antiarrhythmic

Domperidone

Antiemetic

Droperidol

Sedative; antiemetic

Erythromycin

Antibiotic; gastrointestinal stimulant

Flecainide

Antiarrhythmic

Halofantrine

Antimalarial

Females > males

Haloperidol

Antipsychotic

When given intravenously or at higher-thanrecommended doses

Ibutilide

Antiarrhythmic

Females > males

Clinical Application

Levomethadyl

Opioid agonist

Not available in U.S.

Class I—Sodium Channel Blockers

Mesoridazine

Antipsychotic

Methadone

Opioid agonist

Moxifloxacin

Antibiotic

Ondansetron

Antiemetic

Pentamidine

Anti-infective

Females > males

Pimozide

Antipsychotic

Females > males

Probucol

Antilipemic

No longer available in U.S.

Procainamide

Antiarrhythmic

Quinidine

Antiarrhythmic

Sevoflurane

Volatile anesthetic

Sotalol

Antiarrhythmic

Sparfloxacin

Antibiotic

Terfenadine

Antihistamine

Thioridazine

Antipsychotic

Vandetanib

Anticancer

See www.azcert.org for more information.

No longer available in U.S.; available in Mexico

Females > males

Not available in U.S.

Females > males

Females > males

Females > males Females > males

No longer available in U.S.

565

Class Ia Nav Channel Blockers The class Ia antiarrhythmics block ion conduction through Nav1.5, the principal cardiac Na+ channel; this delays and reduces the magnitude of peak depolarization in cardiomyocytes and thus prolongs the action potential. Refractoriness is also increased in that Nav channels require a greater hyperpolarization and longer time to recover from inactivation in the presence of class Ia agents. These effects can be therapeutic if the heart is beating too rapidly or in an uncoordinated fashion. Therefore class Ia antiarrhythmics can be indicated for symptomatic premature ventricular beats and ventricular and supraventricular tachyarrhythmias. They can also be used to prevent the acutely life-threatening condition ventricular fibrillation. Quinidine exemplifies the advantages and potential drawbacks of class Ia antiarrhythmic drugs, and of the SVW classification itself. Aside from blocking Nav1.5 channels in the activated state, which slows phase 0 depolarization (see Fig. 27.2B), quinidine also blocks certain voltage-gated K+ channels, which in turn delays phase 3 repolarization and can in itself be proarrhythmic, prolonging the QT interval on the ECG (Fig. 27.1C). It also widens the QRS complex through its effects on Nav1.5. Quinidine can also decrease the slope of phase 4 depolarization in Purkinje fibers, thereby reducing automaticity. Because quinidine has anti–muscarinic-based

566

SE C T I O N III

Cardiovascular System

Normal Distal Purkinje System (1) Normal propagation activates the myocardium...

Terminal Purkinje fiber branches

Reentrant (2) Antegrade propagation encounters depressed area and is blocked 2 1 4

...(4) Reactivates the region after a slow propagation 3

A

Myocardium

SA node Right atrium AV node Right ventricle

...(3) Invades the depressed area in a retrograde direction and... SA node

Left atrium

Left ventricle

Right atrium

Right ventricle

SA node Left atrium

Left ventricle

Right atrium

Right ventricle

Left atrium

Left ventricle

B • Fig. 27.6

  Reentrant circuits. A, Anatomy of a reentrant circuit. Depending on the relative speed of conduction and duration of refractory periods in two alternate longitudinal pathways, anterograde propagation can be blocked in one pathway, whereas retrograde propagation progresses, creating a reentrant circuit. B, Examples of microreentrant and macroreentrant circuits in the heart. Left, a microreentrant circuit in the atrioventricular (AV) node; center, a macroreentrant circuit spanning the AV node and left atrium and ventricle; right, a microreentrant circuit in the right atrium. SA, Sinoatrial.

vagolytic properties that work against its direct action on the SA and AV nodes, it can actually increase conduction through these nodes. This presents problems because it can cause 1 : 1 conduction of AF, thereby also increasing ventricular rate. Thus, if used for AF, quinidine (and the related class Ia agent, procainamide) must be accompanied by an AV node blocking agent to prevent this (e.g., class II or IV antiarrhythmics). Quinidine is also a notable antimalarial: it kills the schizont parasite of Plasmodium falciparum and gametocyte parasite stages of Plasmodium spp. Quinidine is associated with a number of contraindications and precautions aside from the AV conduction issues noted earlier: It can increase digoxin levels by decreasing renal and extrarenal clearance and can aggravate myasthenia gravis.48 Procainamide (available only in an intravenous formulation in the United States) is another important class Ia antiarrhythmic that can be used to treat AF in Wolff-Parkinson-White syndrome (WPWS). Other class Ia agents include ajmaline, lorajmaline, prajmaline, disopyramide, and sparteine.

Class Ib Nav Channel Blockers The class Ib antiarrhythmics have relatively little effect on conduction velocities and low proarrhythmic potential. They exhibit rapid Nav channel binding kinetics and their main actions are to decrease the duration of the ventricular myocyte action potential and the refractory period (see Fig. 27.2B). Class Ib drugs have little effect

on atrial myocyte action potentials, and therefore on atrial tissue, since they are, at baseline, relatively short compared with ventricular action potentials. Thus these drugs are primarily used to treat ventricular arrhythmias.49 Lidocaine (see Fig. 27.2B) is the archetypal class Ib antiarrhythmic. Like all class Ib drugs, its rapid binding and unbinding rates (endowing it with use dependency or frequency dependency) greatly diminish its effects at low heart rates and exaggerate its effects at high heart rates. Lidocaine selectively targets the open and inactivated states of Nav1.5, with low affinity for the deactivated (closed or resting) state. For this reason, lidocaine and other class Ib drugs can be efficacious in the therapy of rapid heart rate conditions, including ventricular tachycardia and ventricular fibrillation prevention, and in cases of symptomatic premature ventricular beats. Other notable class Ib drugs include mexiletine (which is metabolized to lidocaine), phenytoin, and tocainide.47

Class Ic Nav Channel Blockers Class Ic antiarrhythmics exhibit relatively slow Nav channel binding kinetics, and can be used to treat both atrial and ventricular arrhythmias. Drugs in this class are indicated for treatment of nonsustained ventricular tachycardias, but they are contraindicated when there is underlying heart disease such as myocardial infarction or left ventricular hypertrophy.50 Class Ic agents typically slow Nav channel conduction, delaying the peak depolarization and somewhat prolonging the QT interval (Fig. 27.2B).



CHAPTER 27  Antiarrhythmic Drugs

567

Flecainide (see Fig. 27.2B), an important class Ic antiarrhythmic, displays little end-organ toxicity but can exhibit significant proarrhythmic effects. Interestingly, flecainide is now thought to also inhibit Ca2+ release from the cardiac sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor 2 (RyR2), endowing it with therapeutic activity in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT).51 The more wellrecognized, class Ic action of flecainide confers its effectiveness in prevention of paroxysmal AF and flutter, paroxysmal supraventricular tachycardias, and sustained ventricular tachycardias.52

properties because it blocks potassium channels including hERG. Sotalol reduces incidence of postoperative AF, although its use is limited because it increases risk of TdP and bradycardia. Overall, β blockers are effective in treating or preventing arrhythmias that share as a common denominator increased sympathetic activity. These include paroxysmal atrial tachycardia resulting from exercise or emotion, exercise-induced ventricular arrhythmias, arrhythmias associated with pheochromocytoma, arrhythmias associated with myocardial infarction, and all the arrhythmias accompanied by angina or hypertension.17,53

Class II—β Blockers

Class III—Potassium Channel Blockers

β-Adrenoceptor antagonists, also known as β blockers, are pharmacologic agents that competitively antagonize the β effects of catecholamines on the heart, blood vessels, bronchi, and so on (see Chapters 13 and 14). Propranolol was introduced in 1965 as the first therapeutically useful β blocker and more than 20 analogs are available today. They are used not only as antiarrhythmics, but also as antianginals and antihypertensives, in that they limit cardiac oxygen consumption and lower plasma renin activity. Depending on their relative β-receptor affinities, β blockers are classified as nonselective (or “blanket” β blockers) when they block both β1- and β2-receptor subtypes such as propranolol, or cardioselective (i.e., β1-selective), such as metoprolol, atenolol, and nebivolol. Thirdgeneration β blockers endowed with vasodilating properties are also available, such as pindolol and carvedilol, which are therapeutically used in congestive heart failure. Duration of action varies among the various analogs; esmolol has the shortest duration (t1/2 ~9 minutes) and nadolol is the longest-acting drug (t1/2 ~24 hours), allowing once-daily dosing. Lipid/water solubility of the various β blockers influences the route of elimination: the more lipid-soluble are eliminated primarily by the liver (e.g., propranolol and metoprolol), and the more watersoluble are eliminated primarily by the kidney (e.g., atenolol and nadolol). Thus hepatic cirrhosis and renal failure can prolong the action of lipid- and water-soluble β blockers, respectively. Adverse effects of β blockers are due mainly to β2-blocking effects. Among these, bronchospasm in patients with bronchial asthma or chronic obstructive pulmonary disease can cause severe dyspnea. Peripheral vasoconstriction can also occur with blockade of vascular β2 receptors, as shown by a relatively rare worsening of symptoms of peripheral vascular disease (e.g., intermittent claudication, Raynaud phenomenon). On the other hand, excessive β1 blockade can cause bradycardia, hypotension, and AV node conduction block. β-Adrenoceptor stimulation enhances ICa-L and ICa-T currents and slows Ca2+ channel inactivation. It also increases sinus rate by increasing the If pacemaker current and increases Ca2+ storage in the SR, leading to DAD (see Fig. 27.1B). By inhibiting all of these effects, β blockers exert an antiarrhythmic action that is particularly effective whenever sympathetic activity is increased, such as in stressful conditions, acute myocardial infarction, and CPR following cardiac arrest. Bradycardia and slowing of AV nodal conduction (prolongation of the PR interval) are typically observed. Therefore β blockers are valuable in terminating reentrant arrhythmias that include the AV node, and in controlling ventricular rate in AF or flutter. β Blockers can also be used to treat postoperative AF, which commonly occurs following cardiac or thoracic surgery. Postoperative AF incidence is twofold to fivefold higher in patients whose β blockers are discontinued postoperatively. Sotalol is a methanesulfonanilide β blocker that also exhibits class III antiarrhythmic

Kv channels are the primary target for class III antiarrhythmics. By blocking Kv channels, class III agents prolong the action potential and therefore increase refractoriness (see Fig. 27.4B). These drugs can thus be highly efficacious in the treatment of a variety of tachyarrhythmias, both ventricular and atrial. One of the great paradoxes of arrhythmia therapy is that action potential prolongation can be either therapeutic or life-threatening depending on the nature of the genetic, electrical, and/or structural defect in the patient. Although Kv channel blockade can help control dangerous tachycardia, it can also precipitate TdP because of its QTprolonging effects; this in turn can lead to lethal ventricular fibrillation. The problem with many class III agents is that they inhibit the hERG Kv channel (which generates IKr as explained earlier) in a reverse use-dependent manner that does not increase block with heart rate, but rather does the opposite. This impairs the crucial IKr repolarization current, delaying phase 3 repolarization, most aggressively in bradycardia and less so in tachycardia, which can lead to a dangerously proarrhythmic tendency. Two significant advances in the field of class III antiarrhythmic development are overcoming these problems. The first advance is exemplified by amiodarone (see Fig. 27.4B), a drug that actually has actions in all four SVW classes, but the major therapeutic effect of which is thought to result from its class III effects.54 The big advantage of amiodarone over earlier agents (although it was first described in 1961, it was only approved for use in the United States in 1985) is that it inhibits both IKr and IKs. IKs is generated by a heteromer of the KCNQ1 Kv α subunit and most commonly the KCNE1 β subunit, and is the primary slow-activating component of the delayed rectifier K+ current acting in phase 3 repolarization. IKs rises to prominence, in terms of its role in repolarization, at higher heart rates because KCNQ1-KCNE1 channels accumulate in the activated state, and conversely at these rates IKr is less effective at ventricular repolarization—hence the reverse use dependence of “pure” IKr blockers. IKs probably acts as a safety factor, or repolarization reserve, to compensate for the relative impotency of IKr at high heart rates. Amiodarone, by blocking both IKr and IKs, exhibits a safer and more efficacious action on phase 3 repolarization. A related drug, dronedarone, lacks the iodine that is associated with some side effects of amiodarone, including skin photosensitivity and ocular abnormalities, and the former is therefore safer (although less efficacious) and still has the dual action of I Kr and IKs antagonism, as does azimilide.55–57 Azimilide, however, and tedisamil (which inhibits IKr, Ito and the ATP-sensitive inwardly rectifier K+ current IKATP) have proven marginally efficacious and also torsadogenic, leading to doubts about their ultimate usefulness in AF therapy.58,59 Their key problem is that they do not present a big enough therapeutic window to reverse atrial tachyarrhythmias without causing an unsafe

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delay in ventricular repolarization—that is, they lack atrial specificity. Most individuals with AF exhibit chronic, sustained atrial arrhythmia, with clinical manifestations ranging from palpitations to heart failure. The majority of chronic AF cases are linked to underlying disorders, including structural heart disease, chronic alcohol use, hyperthyroidism, and pulmonary embolism. In addition, cardiothoracic surgery predisposes to postoperative AF, with an estimated incidence of ~30% following cardiac surgery, for example.60 Prophylactic amiodarone has been shown to decrease the incidence of postoperative AF, although it did not decrease postoperative mortality.61,62 Perhaps as many as a third of AF patients have “lone” AF, in which underlying heart or extracardiac disease is either occult or absent. Of these patients, some harbor ion channel mutations thought to be the substrate for AF. The KCNQ1 Kv channel gene is again involved. A key step in AF is thought to be shortening of the atrial effective refractory period; therefore it is intuitive that, as with short QT syndrome, gain-of-function mutations in KCNQ1 are linked to AF, in that they have the capacity to hasten repolarization. In addition, mutations in several members of the KCNE gene family of β subunits are associated with AF by increasing currents through the respective KCNQ1-KCNE channel complex.63–65 Inherited mutations in KCNA5, which encodes the atrially expressed Kv1.5 potassium channel α subunit, also associate with AF. Nonchannel genes associated with AF include renin-angiotensin system genes, probably in combination with environmental agents that elevate blood pressure.66,67 Therapeutic approaches to AF involve not just lengthening of the atrial effective refractory period (pharmacologically or by electrical cardioversion), but also surgery to prevent recurrence and anticoagulation for stroke prevention. With respect to pharmacologic intervention to control the heart in AF, control of rhythm appears to offer no significant advantage in terms of mortality or stroke risk compared to controlling the rate—that is, returning the heart rate to somewhere between 60 and 100 beats/min. However, rhythm control is desirable in newly diagnosed AF, and in other cases is dictated by patient-specific factors, and remains the strategy of choice. For pharmacologic rate control, β blockers and Ca2+ channel blockers are most often used, whereas for pharmacologic rhythm control, Na+ channel blockers or K+ channel blockers are used. The pharmacologic control of postoperative AF is summarized in Fig. 27.7. This introduces the second potentially promising direction in class III antiarrhythmic development. The dependency of the human heart for hERG-mediated ventricular repolarization is problematic in an increasingly medicated population owing to the predilection of hERG for nonspecific drug block. In addition, hERG protein folding (part of the process that ensures that hERG channels reach the cell surface and pass K+ ions) is highly sensitive to both drugs and inherited single–amino acid substitutions. This incredibly unfortunate combination of circumstances is due in part to the fact that, for the majority of human evolution, drugs have not been an environmental factor and thus have not had an impact on natural selection.68 However, nature has provided a fortuitous solution to the hERG targeting conundrum. Some potassium channels are enriched in human atria compared with ventricles, thus providing possible therapeutic targets for selective lengthening of atrial effective refractory periods. One example of this is that the ultrarapidly activating Kv current, IKur, is generated by the Kv1.5 (gene name KCNA5) Kv channel α subunit in human atrium, but Kv1.5 is not

Postoperative atrial fibrillation

Depressed ventricular function?

No

Yes

Sotalol Ibutilide Amiodarone Dronedarone Disopyramide Procainamide Quinidine

Amiodarone

• Fig. 27.7

  Rhythm control for postoperative atrial fibrillation. Given the side effect profile of amiodarone, it is generally reserved for use when other drugs are ineffective, contraindicated, or not well tolerated. Dronedarone is contraindicated in patients with acutely decompensated heart failure. Sotalol may be used with caution in selected patients with mild to moderate reduction in left ventricular ejection fraction. (Modified from Martinez EA, Bass EB, Zimetbaum P, et al. Control of rhythm: American College of Chest Physicians Guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005;128[Suppl 2]:48S–55S.)

significantly functionally expressed in human ventricles. In theory, pharmacologic inhibition of Kv1.5 could lengthen the atrial refractory period enough to be of therapeutic benefit in human AF. Crucially, because it does not contribute to ventricular repolarization, specific Kv1.5 inhibition does not delay ventricular repolarization and therefore is not torsadogenic. There are some caveats vis-à-vis Kv1.5 blockers. While Kv1.5 is in a different α subunit subfamily, it has been difficult to develop selective Kv1.5 antagonists that do not also inhibit hERG at therapeutic concentrations. This in itself might be tolerated because the concomitant Nav block by drugs in this class can counteract hERG inhibition. More importantly, IKur blockers have not yet proven a clinical success. MK-0448, the first IKur-selective blocker tested in clinical trials, did not alter atrial (or ventricular) refractoriness, possibly because IKur is not as influential in the human atrium as it is in model animals such as dogs.69 In addition, IKur appears to be reduced due to remodeling in persistent AF, potentially further diminishing its usefulness as a target for AF therapy.70 This still leaves a therapeutic window for future IKur blockers in paroxysmal AF, where remodeling has not yet occurred. Other atrially expressed K+ channels with potential as therapeutic targets in AF include KCNJ3 and KCNJ5, which generate IK,ACh, small conductance Ca2+-activated K+ channels, and K2P channels (two-pore, background K+ channels).71

Class IV—Calcium Channel Blockers The class IV antiarrhythmics block voltage-gated Ca2+ channels; the primary target with respect to arrhythmias is the cardiac L-type Ca2+ channel, Cav1.2. Whereas in atrial and ventricular myocytes the primary role of Ca2+ is signaling in muscular excitationcontraction coupling, in nodal cells its primary role is electrical conduction of a depolarizing signal. By lowering ventricular myocyte intracellular [Ca2+], some class IV antiarrhythmics decrease the

CHAPTER 27  Antiarrhythmic Drugs



force of contraction of the heart, an effect referred to as negative inotropy. By slowing conduction through nodal cells, some class IV drugs reduce the heart rate, an effect referred to as negative chronotropy (Chapter 23). The dihydropyridines (e.g., nifedipine) are used to treat increased systemic vascular resistance but are not generally indicated for arrhythmias. The phenylalkylamines, exemplified by verapamil, are relatively myocardial-specific and cause negative inotropy with minimal vasodilation or reflex tachycardia. Verapamil is indicated for angina, with two probable main modes of action: dilatation of the main coronary arteries and arterioles, inhibiting coronary vasospasm, and reduction of oxygen utilization via unloading of the heart achieved by relaxing the peripheral arterioles. As an antiarrhythmic, verapamil is highly effective at slowing ventricular contraction rate in patients with atrial flutter or AF because it slows AV node conduction in a rate-dependent manner. This rate dependence also accounts for the fact that verapamil generally is much less effective at reducing already normal AV conduction rates—a desirable property—although it can occasionally induce AV node block in the absence of preexisting conduction defects. Verapamil is effective in reducing the frequency of episodes of paroxysmal supraventricular tachycardia, but it can also induce ventricular fibrillation in patients with atrial flutter or fibrillation and a coexisting AV accessory pathway.72–74 The benzothiazepines, exemplified by diltiazem, exhibit myocardial specificity intermediate between the dihydropyridines and phenylalkylamines. Diltiazem causes excitation-contraction uncoupling, relaxation of coronary vascular smooth muscle, and dilatation of coronary arteries, but has relatively modest negative inotropic effects. Diltiazem is typically prescribed for angina and hypertension and is quite effective in lowering blood pressure in hypertensive individuals, with little effect on normotensives. It is also reportedly as effective as verapamil in the treatment of supraventricular tachycardias, and is also indicated for atrial flutter and AF. Its negative dromotropic effect (slowing of conduction through the AV node) reduces oxygen consumption by increasing the time required for each heartbeat.75,76 The rational selection of drugs for controlling heart rate is summarized in Fig. 27.8.

Rate-control drug choices

No heart disease Hypertension

Coronary artery disease

Heart failure

β Blocker Diltiazem Verapamil Combination therapy Digitalis†

β Blocker* Diltiazem Verapamil

β Blocker + Digitalis

Dronedarone

*β Blockers preferred in CAD †Digitalis may be considered as monotherapy in sedentary individuals

• Fig. 27.8  Selection of rate-control drug therapy is based on the presence or absence of underlying heart disease and other comorbidities. Combination therapy might be required. CAD, Coronary artery disease. (Modified from Gillis AM, Verma A, Talajic M, et al. Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: rate and rhythm management. Can J Cardiol. 2011;27:47–59.)

569

Emerging Developments Molecular Genetics of Arrhythmias A combination of molecular genetics, recombinant DNA technology, and physiologic techniques is revealing the secrets of many cardiac arrhythmias; intuitively, the majority of the genes linked thus far to abnormal cardiac rhythm are those that express ion channel proteins.27 Many of these same ion channels are targets for clinically important antiarrhythmic and proarrhythmic drugs. An understanding of the precise molecular basis for an individual’s arrhythmia can remove some of the uncertainty about how best to treat the arrhythmia, and facilitates genetic or other forms of testing of family members, permitting early diagnosis and preventive measures to avoid potentially lethal cardiac events.

Long QT Syndrome A delay in ventricular myocyte repolarization can prolong the QT interval on the ECG and lead to TdP and even ventricular fibrillation. The most common inherited causes of this phenomenon are loss-of-function mutations in ventricular, voltage-gated Kv channels, which are primarily responsible for ventricular myocyte repolarization by virtue of K+ efflux to restore a negative membrane potential (see Fig. 27.1A). Around 45% of individuals diagnosed with inherited long QT syndrome (LQTS) whose DNA has been sequenced have loss-of-function mutations in the KCNQ1 gene. KCNQ1 encodes the Kv channel pore-forming (α) subunit of the same name. KCNQ1 mutations underlie long QT syndrome type 1 (LQT1), which is further divided into the autosomal dominant Romano-Ward syndrome and the recessive cardioauditory Jervell and Lange-Nielsen syndrome (JLNS). Individuals with loss-offunction mutations in both KCNQ1 alleles (i.e., JLNS) exhibit both LQTS and profound sensorineural deafness. KCNQ1, in protein complexes with KCNE1, a single-transmembrane segment ancillary (β) subunit, generates the slowly activating ventricular repolarization current, IKs.77 IKs is important for phase 3 repolarization in the ventricular action potential, particularly when the dominant ventricular repolarization K+ current, IKr (see later text) is compromised, or during sustained exercise or other prolonged sympathetic activation. The KCNQ1-KCNE1 potassium channel is also expressed in the inner ear, where it is responsible for K+ secretion into the endolymph (hence the deafness in JLNS). Individuals with KCNE1 mutations (1%–2% of sequenced LQTS cases) are classified as having LQT5; they exhibit Romano-Ward syndrome or JLNS with similar symptoms as LQT1 patients, indicating the KCNE1 β subunit is important for IKs. IKr is generated by hERG, the voltage-gated K+ channel α subunit encoded by the KCNH2 gene, probably in complexes with the KCNE2 β subunit and perhaps others. KCNH2 loss-of-function mutations (LQT2) account for ~40% of known LQTS cases; KCNE2 mutations (LQT6) account for ~1%. The third most commonly linked LQTS gene is SCN5A, which encodes the Nav1.5 cardiac voltage-gated Na+ channel that underlies the upstroke in phase 0 of the cardiac myocyte action potential (see Figs. 27.1A and 27.2). Nav1.5, like all voltage-gated Na+ channels, inactivates rapidly, which together with the transient outward K+ current, Ito, causes the notch at the beginning of the human ventricular myocyte action potential. Gain-of-function mutations in SCN5A, particularly those that increase Na+ influx during phases 2 and 3 when the majority of Nav1.5 channels are normally inactivated, delay repolarization because they produce

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persistent depolarizing force (Na+ influx). SCN5A mutations account for 5% to 10% of LQTS cases and are categorized as LQT3. Nav1.5 is an important antiarrhythmic target, with many drugs known to alter its inactivation kinetics.78,79 The remaining molecularly defined inherited LQTS cases are relatively rarer and are spread among other genes encoding K+ channel subunits, Ca2+ channel subunits, and channel-associated proteins.

Short QT Syndrome Shortening of the QT interval, indicating premature ventricular repolarization, can also be pathogenic, further illustrating the importance of timely electrical activity in the heart. The majority of sequenced short QT syndrome (SQTS) cases are, intuitively, associated with KCNQ1 or KCNH2 gain-of-function mutations. SQT1 is associated with KCNH2 mutation; SQT2 with KCNQ1; and the inward rectifier K+ channel gene KCNJ2 with SQT3. SQTS is characterized by a corrected QT interval (QTc) of less than 300 msec, and manifests as palpitations, syncope, and sudden cardiac death; patients with a QTc of up to 330 msec are also diagnosed with SQTS if they have had an arrhythmic event such as ventricular fibrillation, syncope, or resuscitated sudden cardiac death. Also associated with an increased risk of both atrial and ventricular fibrillation, SQTS has been found to respond to hydroquinidine, whereas class IC and III antiarrhythmics were unable to prolong the QT interval in this context. However, the current therapy of choice is an implantable cardioverter-defibrillator.80–82 Brugada Syndrome In contrast to the long and short QT syndromes, the majority of sequenced Brugada syndrome cases (perhaps representing 30% of all cases) have been linked to loss-of-function mutations in the SCN5A voltage-gated Na+ channel gene that encodes Nav1.5. Brugada syndrome is an autosomal dominant, idiopathic form of ventricular fibrillation that manifests on the ECG as persistent ST-segment elevation in the right precordial leads, together with complete or incomplete right bundle branch block. Patients with Brugada syndrome are strongly predisposed to life-threatening ventricular fibrillation even with a structurally normal heart, and Brugada syndrome was recently found to be clinically and genetically the same disorder as sudden unexplained nocturnal death syndrome described in Southeast Asia, where Brugada syndrome is endemic and is often mistaken for a supernatural curse by poorly educated people. In patients with Brugada syndrome, the transient outward K+ current that forms a notch at the start of the ventricular action potential is inadequately balanced by the voltage-gated Na+ current owing to loss of function in Nav1.5, which is considered a trigger for ventricular tachycardia and fibrillation. Accordingly, gain-offunction mutations in the KCNE3 and KCNE5 β subunits, which can regulate the K+ channel underlying Ito (Kv4.3), have also been associated with Brugada syndrome.83 An implantable cardioverterdefibrillator is again the treatment of choice for patients with Brugada syndrome, but quinidine can be used to inhibit Ito, and isoproterenol and cilostazol can bolster the voltage-gated Ca 2+ current to the same end—that is, reduction of the action potential notch that provides a substrate for potentially catastrophic ventricular microreentry circuits.84,85 Other Inherited Arrhythmia Syndromes Other inherited arrhythmia syndromes include cardiac conduction disease, WPWS, CPVT, and various sinus node disorders.77,86

Lev-Lenègre syndrome, a progressive cardiac conduction disease, has been linked to SCN5A loss-of-function gene variants, and is characterized by slowed conduction, pathologic slowing of cardiac rhythm and conduction system fibrosis. A pacemaker or implantable cardioverter-defibrillator is the most common therapeutic strategy, although pharmacologic intervention can also be indicated. WPWS, in its rare familial form, is linked to mutations in the PRKAG2 gene, which encodes the γ2 regulatory subunit of AMPactivated protein kinase, but in the sporadic form of the disease this gene is rarely implicated. Other genetic associations include mitochondrial DNA mutations and, in association with hypertrophic cardiomyopathy, TNNI3 and MYBPC3 gene variants.87,88 WPWS manifests as supraventricular arrhythmias associated with palpitations, and preexcitation and syncope. WPWS is caused by an abnormal accessory electrical circuit that is present at birth (known as “the bundle of Kent”), and surgical ablation of this pathway is almost always successful in eliminating the cause and symptoms of WPWS. However, the marginally less effective but much less invasive measure of radiofrequency catheter ablation is now typically used in WPWS.89,90 CPVT is observed clinically as exercise- or emotional stress– induced syncope and sudden cardiac death, and on the body surface ECG as bidirectional or polymorphic ventricular tachycardia. Two genes involved in excitation-contraction coupling have been linked to CPVT: RyR2 (which encodes the cardiac ryanodine receptor, a sarcoplasmic reticulum Ca2+ release channel) and CASQ2 (encoding calsequestrin, which stores releasable Ca2+ within the sarcoplasmic reticulum). Increased RyR2 activity or decreased calsequestrin expression generates spontaneous Ca2+ transients and DADs. CPVT is treated with β blockers, implantable cardioverter-defibrillator, and/or other antiarrhythmic medications. Sinus rhythm is dictated by hyperpolarization-activated, cyclicnucleotide–gated monovalent cation channels known as HCN or pacemaker channels (and to a greater or lesser extent, Ca2+ oscillations, a matter of current debate). Hence, HCN4 mutation is associated with sinus-mediated pathologic slowing of the heart rate (sinus bradycardia). SCN5A sodium channel gene mutations have been linked to sick sinus syndrome, and atrial standstill—which is also associated with a loss-of-function sequence variant in the gene encoding connexin 43, a transmembrane protein that forms gap junctions important to intercellular coupling.

hERG Drug Interactions IKr is the dominant phase 3 repolarization current (see Fig. 27.1A), and by an evolutionary quirk, the hERG α subunit has a propensity for inhibition by a wide range of otherwise potentially clinically useful drugs (see Fig. 27.4). This unfortunate situation has led drug regulatory agencies including the U.S. Food and Drug Administration to mandate that all potential new medications, and current medications linked to increased sudden death or QT prolongation, are subjected to time-consuming and expensive testing for potential hERG antagonism and QT prolongation in experimental preparations including canine Purkinje fibers, which are part of the specialized conduction system of the heart that rapidly conducts signals from the AV node to the ventricles. Indeed, hERG safety concerns have spawned an industry in their own right, with companies being formed the major directive of which is to facilitate hERG safety testing via product development or outsourcing of cellular electrophysiology.91 QT prolongation and TdP thought to result from block of cardiac hERG channels has resulted in withdrawal of drugs for a variety of indications. Between 1997



and 2001, 10 prescription drugs were withdrawn from the U.S. market, 4 because of links to increased incidence of TdP: the antihistamines Seldane (terfenadine) and Hismanal (astemizole), the heartburn medication Propulsid (cisapride monohydrate), and the antibiotic grepafloxacin. Interestingly, some medications (e.g., Trisenox [arsenic trioxide], a last-resort treatment for acute promyelocytic leukemia), and the majority of LQTS-linked KCNH2 mutations, are now known to reduce IKr because of hERG misfolding and/or mistrafficking, rather than impaired conduction or gating of channels at the plasma membrane as was first thought. It remains to be seen whether this holds for other cardiac ion channels, but it is clinically relevant because it will influence the therapeutic strategies used to repair IKr in these cases: Small molecules have been identified that fix LQTS-associated mutant hERG channels, probably by creating nucleation points to aid channel folding.92–95 Future antiarrhythmics could even be targeted toward enhancing “normal” hERG trafficking to overcome other repolarization deficiencies.

Gene Therapy Guided by Molecular Genetics of Inherited Arrhythmias An interesting experimental approach to treatment of arrhythmias is to introduce genes that regulate cardiac rhythm based on their ability to regulate specific ion channels. Three examples stand out in the literature; it should be noted that gene therapy is currently only in experimental and trial phases owing to an array of side effects, not specific to the introduced gene but rather to the delivery method, often a virus. In the first example, researchers have exploited the ability of the KCNE3 K+ channel β subunit to accelerate ventricular repolarization by increasing current through the KCNQ1 Kv α subunit. In the heart, KCNQ1-KCNE1 normally generates the slowly activating IKs repolarizing current. However, in the colon, KCNQ1 complexes with KCNE3, a subunit that locks the KCNQ1 voltage sensor (and thus pore) open, producing a constitutively active yet

CHAPTER 27  Antiarrhythmic Drugs

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K+-selective channel that regulates cAMP-stimulated chloride secretion in vivo.96,97 When KCNE3 was introduced into the guinea pig ventricular cavity by injection of adenovirus containing the KCNE3 gene, the result was a shortening of the action potential and a reduction in QT interval, stemming from the resultant increase in KCNQ1 current (which would have been especially marked at negative voltages, where KCNQ1-KCNE1 is typically closed).98 Second, introduction of HCN channel genes into quiescent ventricular myocytes shows promise for converting them into pacemaker cells. HCN expression endows them with automaticity, the ability to fire spontaneously, because HCN channels open in response to hyperpolarization and initiate depolarization.99,100 Third, a natural polymorphism (Q9E) in the KCNE2 ancillary subunit that regulates the hERG Kv α subunit, increases the sensitivity of hERG-KCNE2 channels to block by the macrolide antibiotic clarithromycin. The polymorphism was discovered in an African American woman with ventricular fibrillation precipitated by clarithromycin, and was later found to be present in 3% of African Americans but absent in Caucasian Americans. This finding was exciting because it uncovered a pharmacogenomic mechanism for increased susceptibility to adverse effects for a significant fraction of a specific ethnic group. However, it was also used ingeniously to engineer experimentally chamber specificity to erythromycin susceptibility with therapeutic goals in mind. Thus viral introduction of Q9E-KCNE2 into the porcine atrium rendered hERG channels within the atrium severalfold more susceptible to block by clarithromycin than their ventricular, wild-type hERG-KCNE2 counterparts. Clarithromycin was found to selectively prolong the atrial refractory period in these pigs without significantly affecting ventricular action potentials, exploiting the increased sensitivity of the mutant KCNE2–containing atrial channels.25,101–103 Future work will build on all these discoveries to create benchto-bedside medicine that uses each patient’s own molecular lesion to tailor highly patient- and target-specific, bespoke gene- and stem cell–related therapies.

Key Points • Antiarrhythmic drugs are organized into the Singh-Vaughan Williams classification, which is a useful framework for categorizing by primary mode of action. • Most antiarrhythmics can be classified into more than one of the four categories. Amiodarone, one of the most efficacious, falls into all four classes. • Class I antiarrhythmics block voltage-gated Na+ channels and are subcategorized into Ia, Ib, and Ic depending on their binding kinetics, which dictate their effects on cardiac myocyte action potentials. They are used for ventricular arrhythmias, but are currently less commonly used because of potential proarrhythmic effects. • Class II antiarrhythmics block β-adrenergic signaling and slow heart rate. Sinus tachycardia and ventricular tachycardia are treated with β blockers. • Class III antiarrhythmics block K+ channels, prolonging the cardiac myocyte action potential and refractory period. They

are used for conversion and prevention of atrial fibrillation/ flutter, and in the case of amiodarone in the treatment of ventricular tachycardia/fibrillation. • Class IV antiarrhythmics block Ca2+ channels, slowing nodal conduction and reducing intracellular [Ca2+], without eliminating sympathetic regulation. Ca2+ channel blockers are used for treatment of idiopathic rhythms, ectopic atrial tachycardias, and atrioventricular nodal reentrant supraventricular tachycardias. • Atrial fibrillation is most commonly treated with Na+ channel blockers (class 1a) or K+ channel blockers (class III). • A number of drugs from a variety of drug classes often used in anesthesia, as well as certain channel mutations, can predispose to torsades de pointes by blocking specific K+ channels and prolonging the QT interval. This is usually treated with intravenous magnesium.

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Key References Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97:175–187. Reported the discovery of a secondary molecular component to IKr, and also the first description of an ion channel polymorphism increasing susceptibility to drug-induced arrhythmia. (Ref. 25). Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113:365–373. A groundbreaking article indicating a major shift in our understanding of the mechanism of hERG-linked arrhythmias. (Ref. 94). Baker JG, Hill SJ, Summers RJ. Evolution of beta blockers: from antianginal drugs to ligand-directed signalling. Trends Pharmacol Sci. 2011;32:227–234. An up-to-the-minute summary of the class II antiarrhythmics. (Ref. 7). Catterall WA. Molecular mechanisms of gating and drug block of sodium channels. Novartis Found Symp. 2002;241:206–232. In-depth review and discussion from one of the leaders in the mechanisms of sodium channel function and pharmacology. (Ref. 11). Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569–580. A clear, concise review of cardiac arrhythmia mechanisms. (Ref. 27). Roden DM. Antiarrhythmic drugs: past, present and future. J Cardiovasc Electrophysiol. 2003;14:1389–1396. A summary of antiarrhythmic agents and their mechanisms of action. (Ref. 16). Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: hERG encodes the IKr potassium channel. Cell. 1995;81:299–307. The article that defined the primary molecular basis for IKr and drug-induced arrhythmias. (Ref. 24). Sanguinetti MC, Chen J, Fernandez D, et al. Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs. Novartis Found Symp. 2005;266:159–170. (Ref. 28). Singh BN. Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent. Am J Cardiol. 1996;78:41–53. A useful description of the complex mechanisms of amiodarone mode of action. (Ref. 54). Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw Hill; 2011. Current knowledge of β blockers and their mechanisms of action. (Ref. 53).

References 1. Roden DM, George AL Jr. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med. 1996;47:135–148. 2. Chaudhry GM, Haffajee CI. Antiarrhythmic agents and proarrhythmia. Criti Care Med. 2000;28:N158–N164. 3. Boylan M. Galen: on blood, the pulse, and the arteries. J History Biol. 2007;40:207–230. 4. McMullen ET. Anatomy of a physiological discovery: William Harvey and the circulation of the blood. J R Soc Med. 1995;88: 491–498. 5. Besterman E, Creese R. Waller—pioneer of electrocardiography. Br Heart J. 1979;42:61–64. 6. Snellen HA. Willem Einthoven Memorial Symposium on Developments in Electrocardiography 1927-1977, Leiden, The Netherlands, 28 October 1977. Introduction. Eur J Cardiol. 1978;8:201–203. 7. Baker JG, Hill SJ, Summers RJ. Evolution of beta blockers: from antianginal drugs to ligand-directed signalling. Trend Pharmacol Sci. 2011;32:227–234. 8. Singh BN. Comparative mechanisms of antiarrhythmic agents. Am J Cardiol. 1971;28:240–242. 9. Cobbe SM. Clinical usefulness of the Vaughan Williams classification system. Eur Heart J. 1987;8(supplA):65–69.

10. Catterall WA. Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev. 1992;72:S15–S48. 11. Catterall WA. Molecular mechanisms of gating and drug block of sodium channels. Novartis Found Symp. 2002;241:206–218, discussion 218–232. 12. Ragsdale DS, McPhee JC, Scheuer T, et al. Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc Natl Acad Sci USA. 1996;93:9270–9275. 13. Lee CH, Ruben PC. Interaction between voltage-gated sodium channels and the neurotoxin, tetrodotoxin. Channels (Austin). 2008;2:407–412. 14. Desai SP, Marsh JD, Allen PD. Contractility effects of local anesthetics in the presence of sodium channel blockade. Reg Anesth. 1989;14:58–62. 15. Payandeh J, Scheuer T, Zheng N, et al. The crystal structure of a voltage-gated sodium channel. Nature. 2011;475:353–358. 16. Roden DM. Antiarrhythmic drugs: past, present and future. J Cardiovasc Electrophysiol. 2003;14:1389–1396. 17. Zicha S, Tsuji Y, Shiroshita-Takeshita A, et al. Beta blockers as antiarrhythmic agents. Hndbk Exp Pharmacol. 2006;235–266. 18. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101:558–569. 19. Deal KK, England SK, Tamkun MM. Molecular physiology of cardiac potassium channels. Physiol Rev. 1996;76:49–67. 20. Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Disc. 2009;8:982–1001. 21. Doyle DA, Morais Cabral J, Pfuetzner RA, et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998;280:69–77. 22. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science. 2005;309:897–903. 23. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V) LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384:80–83. 24. Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: hERG encodes the IKr potassium channel. Cell. 1995;81:299–307. 25. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97:175–187. 26. McCrossan ZA, Abbott GW. The MinK-related peptides. Neuropharmacology. 2004;47:787–821. 27. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569–580. 28. Sanguinetti MC, Chen J, Fernandez D, et al. Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs. Novartis Found Symp. 2005;266:159–166, discussion 166–170. 29. Swartz KJ, MacKinnon R. Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels. Neuron. 1997;18:675–682. 30. Abbott GW, Xu X, Roepke TK. Impact of ancillary subunits on ventricular repolarization. J Electrocardiol. 2007;40:S42–S46. 31. Roepke TK, Kontogeorgis A, Ovanez C, et al. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f ). FASEB J. 2008;22:3648–3660. 32. Zhang M, Jiang M, Tseng GN. MinK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as beta subunit of cardiac transient outward channel? Circ Res. 2001;88: 1012–1019. 33. Panaghie G, Abbott GW. The impact of ancillary subunits on small-molecule interactions with voltage-gated potassium channels. Curr Pharmaceut Design. 2006;12:2285–2302. 34. Bosch RF, Li GR, Gaspo R, et al. Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes. J Pharmacol Exp Ther. 1999;289:156–165.



35. Kiehn J, Wible B, Lacerda AE, et al. Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. Mol Pharmacol. 1996;50:380–387. 36. Proenza C, O’Brien J, Nakai J, et al. Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop. J Biol Chem. 2002;277:6530–6535. 37. Catterall WA, Perez-Reyes E, Snutch TP, et al. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev. 2005;57:411–425. 38. Rowland E. Antiarrhythmic drugs—class IV. Eur Heart J. 1987;8(supplA):61–63. 39. Hockerman GH, Dilmac N, Scheuer T, et al. Molecular determinants of diltiazem block in domains IIIS6 and IVS6 of L-type Ca(2+) channels. Mol Pharmacol. 2000;58:1264–1270. 40. Hockerman GH, Johnson BD, Scheuer T, et al. Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels. J Biol Chem. 1995;270:22119–22122. 41. Kraus R, Reichl B, Kimball SD, et al. Identification of benz(othi) azepine-binding regions within L-type calcium channel alpha1 subunits. J Biol Chem. 1996;271:20113–20118. 42. Cabo C, Wit AL. Cellular electrophysiologic mechanisms of cardiac arrhythmias. Cardiol Clin. 1997;15:517–538. 43. Wit AL. Electrophysiological basis for antiarrhythmic drug action. Clin Physiol Biochem. 1985;3:127–134. 44. Lazzara R, Scherlag BJ. Electrophysiologic basis for arrhythmias in ischemic heart disease. Am J Cardiol. 1984;53:1B–7B. 45. Zipes DP, Foster PR, Troup PJ, et al. Atrial induction of ventricular tachycardia: reentry versus triggered automaticity. Am J Cardiol. 1979;44:1–8. 46. Ashley EA, Niebauer J. Cardiology Explained. London: Remedica; 2004. 47. Singh BN. Acute management of ventricular arrhythmias: role of antiarrhythmic agents. Pharmacotherapy. 1997;17:56S–64S, discussion 89S–91S. 48. Trujillo TC, Nolan PE. Antiarrhythmic agents: drug interactions of clinical significance. Drug Saf. 2000;23:509–532. 49. Anderson JL. Clinical implications of new studies in the treatment of benign, potentially malignant and malignant ventricular arrhythmias. Am J Cardiol. 1990;65:36B–42B. 50. Campbell TJ. Subclassification of class I antiarrhythmic drugs: enhanced relevance after CAST. Cardiovasc Drugs Ther. 1992;6:519–528. 51. Watanabe H, et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15:380–383. 52. Boriani G, Diemberger I, Biffi M, et al. Pharmacological cardioversion of atrial fibrillation: current management and treatment options. Drugs. 2004;64:2741–2762. 53. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw Hill; 2011. 54. Singh BN. Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent. Am J Cardiol. 1996;78:41–53. 55. Karam R, Marcello S, Brooks RR, et al. Azimilide dihydrochloride, a novel antiarrhythmic agent. Am J Cardiol. 1998;81: 40D–46D. 56. Nair LA, Grant AO. Emerging class III antiarrhythmic agents: mechanism of action and proarrhythmic potential. Cardiovasc Drugs Ther. 1997;11:149–167. 57. Nattel S. The molecular and ionic specificity of antiarrhythmic drug actions. J Cardiovasc Electrophysiol. 1999;10:272–282. 58. Jost N, et al. Effect of the antifibrillatory compound tedisamil (KC-8857) on transmembrane currents in mammalian ventricular myocytes. Curr Med Chemistry. 2004;11:3219–3228. 59. Barrett TD, et al. Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence. Br J Pharmacol. 2001;32:1493–1500.

CHAPTER 27  Antiarrhythmic Drugs

573

60. McKeown PP, Gutterman D, American College of Chest Physicians. Executive summary: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005;128:1S–5S. 61. Arsenault KA, Yusuf AM, Crystal E, et al. Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. Cochrane Database Syst Rev. 2013;(1):CD003611. 62. Bagshaw SM, Galbraith PD, Mitchell LB, et al. Prophylactic amiodarone for prevention of atrial fibrillation after cardiac surgery: a meta-analysis. Ann Thorac Surg. 2006;82:1927–1937. 63. Chen YH, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–254. 64. Ellinor PT, et al. Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart. 2004;90:1487–1488. 65. Zhang DF, et al. KCNE3 R53H substitution in familial atrial fibrillation. Chin Med J. 2005;118:1735–1738. 66. Yang T, Yang P, Roden DM, et al. Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation. Heart Rhythm. 2010;7:1246–1252. 67. Abraham RL, Yang T, Blair M, et al. Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J Mol Cell Cardiol. 2010;48:181–190. 68. Anantharam A, Markowitz SM, Abbott GW. Pharmacogenetic considerations in diseases of cardiac ion channels. J Pharmacol Exp Ther. 2003;307:831–838. 69. Pavri BB, Greenberg HE, Kraft WK, et al. MK-0448, a specific Kv1.5 inhibitor: safety, pharmacokinetics, and pharmacodynamic electrophysiology in experimental animal models and humans. Circ Arrhythm Electrophysiol. 2012;5:1193–1201. 70. Ravens U, Wettwer E. Ultra-rapid delayed rectifier channels: molecular basis and therapeutic implications. Cardiovasc Res. 2011;89:776–785. 71. Ravens U, Odening KE. Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers. Pharmacol Ther. 2016. 72. Nademanee K, Singh BN. Control of cardiac arrhythmias by calcium antagonism. Ann N Y Acad Sci. 1988;522:536–552. 73. Singh BN, Nademanee K, Feld G. Antiarrhythmic effects of verapamil. Angiology. 1983;34:572–590. 74. Weiner B. Hemodynamic effects of antidysrhythmic drugs. J Cardiovasc Nurs. 1991;5:39–48. 75. Singh BN, Nademanee K. Use of calcium antagonists for cardiac arrhythmias. Am J Cardiol. 1987;59:153B–162B. 76. Fodor JG, et al. The role of diltiazem in treating hypertension and coronary artery disease: new approaches to preventing first events. Can J Cardiol. 1997;13:495–503. 77. Abbott GW. Molecular mechanisms of cardiac voltage-gated potassium channelopathies. Curr Pharmaceut Des. 2006;12:3631–3644. 78. Wang Q, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80:805–811. 79. Wang Q, Bowles NE, Towbin JA. The molecular basis of long QT syndrome and prospects for therapy. Mol Med Today. 1998;4:382–388. 80. Brugada R, et al. Sudden death associated with short-QT syndrome linked to mutations in hERG. Circulation. 2004;109:30–35. 81. Borggrefe M, et al. Short QT syndrome. Genotype-phenotype correlations. J Electrocardiol. 2005;38:75–80. 82. Grunnet M. Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new antiarrhythmic principle? Acta Physiol (Oxf ). 2010;198(suppl 676):1–48. 83. Ohno S, Zankov DP, Ding WG, et al. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011;4:352–361. 84. Benito B, Brugada J, Brugada R, et al. Brugada syndrome. Rev Esp Cardiol. 2009;62:1297–1315. 85. Shimizu W, Horie M. Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels. Circ Res. 2011;109:97–109. 86. Roepke TK, Abbott GW. Pharmacogenetics and cardiac ion channels. Vasc Pharmacol. 2006;44:90–106.

574

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87. Ehtisham J, Watkins H. Is Wolff-Parkinson-White syndrome a genetic disease? J Cardiovasc Electrophysiol. 2005;16:1258–1262. 88. Gollob MH, Green MS, Tang AS, et al. PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy. Curr Opin Cardiol. 2002;17:229–234. 89. Akhtar M, Tchou PJ, Jazayeri M. Mechanisms of clinical tachycardias. Am J Cardiol. 1988;61:9A–19A. 90. Tischenko A, et al. When should we recommend catheter ablation for patients with the Wolff-Parkinson-White syndrome? Curr Opinion Cardiol. 2008;23:32–37. 91. Hanton G, Tilbury L. Cardiac safety strategies. 25-26 October 2005, the Radisson SAS Hotel, Nice, France. Exp Opin Drug Safety. 2006;5:329–333. 92. Delisle BP, et al. Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. J Biol Chem. 2003;278:35749–35754. 93. Delisle BP, et al. Intragenic suppression of trafficking-defective KCNH2 channels associated with long QT syndrome. Mol Pharmacol. 2005;68:233–240. 94. Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113:365–373. 95. Gong Q, Anderson CL, January CT, et al. Pharmacological rescue of trafficking defective hERG channels formed by coassembly of wild-type and long QT mutant N470D subunits. Am J Physiol. 2004;287:H652–H658.

96. Panaghie G, Abbott GW. The role of S4 charges in voltage-dependent and voltage-independent KCNQ1 potassium channel complexes. J Gen Physiol. 2007;129:121–133. 97. Schroeder BC, et al. A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature. 2000;403:196–199. 98. Mazhari R, Nuss HB, Armoundas AA, et al. Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. J Clin Invest. 2002;109:1083–1090. 99. Satin J, et al. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J Physiol. 2004;559:479–496. 100. Siu CW, Lieu DK, Li RA. HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering. J Membrane Biol. 2006;214:115–122. 101. Burton DY, et al. The incorporation of an ion channel gene mutation associated with the long QT syndrome (Q9E-hMiRP1) in a plasmid vector for site-specific arrhythmia gene therapy: in vitro and in vivo feasibility studies. Hum Gene Ther. 2003;14:907–922. 102. Perlstein I, et al. Posttranslational control of a cardiac ion channel transgene in vivo: clarithromycin-hMiRP1-Q9E interactions. Hum Gene Ther. 2005;16:906–910. 103. Tester DJ, Will ML, Haglund CM, et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2:507–517.

28 

Cardiopulmonary Resuscitation CHRISTOPHER W. TAM, SHREYAJIT R. KUMAR, AND NATALIA S. IVASCU

CHAPTER OUTLINE Historical Perspective Oxygen Delivery, Consumption, and the Margin of Error Compensated Hypovolemia and Supply-Dependent Oxygen Consumption Early Goal-Directed Therapy Cardiopulmonary Resuscitation Compression and Decompression Ventilation and Blood Flow During CPR CPR and Intracranial Pressure Optimizing Chest Compression/Decompression Automated Chest Compression Devices Targeted Temperature Management After Resuscitation Emerging Developments Extracorporeal Life Support for Refractory Cardiac Arrest

T

he objective of cardiopulmonary resuscitation CPR) in the critically ill patient is optimization of both oxygen delivery (DO2) and aerobic metabolism. Shock is defined as dysoxia, or an abnormality in tissue oxygenation. The variables altering the clinical state of shock include DO2, tissue uptake of oxygen (V̇ O2), and the tissue metabolic rate of oxygen (MRO2). The various shock states are defined by causes of decreased Do2. Resuscitation maneuvers improve Do2, optimize tissue uptake of oxygen, and preserve metabolic rate of oxygen. This chapter reviews the cardinal tenets of oxygenation, the physiology of CPR, and the scientific basis of practices of resuscitating the critically ill patient.

Historical Perspective Peter Safar is credited with the first published account of expired gas ventilation via mouth-to-mouth or mouth-to-airway techniques using a novel device of two fused oral airways in 1957.1 Closed chest compression in humans was famously first described in the medical literature by Kouwenhoven and colleagues in 1960.2 However, origins of CPR are evident in 18th-century descriptions the management of drowning victims, as well as prior Biblical descriptions of Elisha who “went up and lay on the child and put his mouth on his mouth…and the flesh of the child became warm.”3,4 In the 1960s the combination of chest compressions and mouth-to-mouth ventilation was popularized as “cardiopulmonary resuscitation” or CPR. It was at this time that the American Heart Association (AHA) was formed and took up the task of teaching physicians, and later the general public, to perform CPR. An ad

hoc committee wrote the first guidelines for CPR established by the National Academy of Sciences of the National Research Council in 1966.5 Over the past 50 years, a breadth of research and several revisions to the CPR guidelines were made; however, survival rates for both out-of-hospital and in-hospital survival for in-hospital cardiac arrest and CPR are 15% and 22%, respectively.6 Neurologic deficits occur in 30% to 50% of patients after out-of-hospital cardiac arrest.7

Oxygen Delivery, Consumption, and the Margin of Error Normal homeostatic mechanisms ensure greater Do2 than the total tissue uptake of oxygen (DO2 > V̇ O2; see Chapter 24).8 This “margin of error” maintains aerobic metabolism during extreme situations, when Do2 is diminished, or when tissue oxygen uptake increases. Do2 is the process by which oxygen is transported from the pulmonary system to the systemic capillary beds (expressed as milliliters per minute per meter squared), and is expressed as the product of the cardiac index (CI) and arterial blood oxygen content (CaO2): DO2 = CI * CaO2. The cardiac index is the cardiac output (Q) normalized for body surface area (BSA): CI = Q/BSA. Normal values of cardiac output and cardiac index in an average size adult are 4.0 to 8.0 L/min and 2.5 to 4.0 L/min per meter squared, respectively. The content of CaO2 depends on the volume of oxygen bound to hemoglobin (Hbg) and of free oxygen dissolved in blood (CaO2 = 1.39 * Hgb * SaO2 + 0.003 * PaO2), where PaO2 is the partial pressure of alveolar oxygen. SaO2 represents the oxygen saturation, PaO2 the arterial oxygen tension (in millimeters of mercury), and 0.003 the plasma solubility coefficient of oxygen (Table 28.1). The vast majority of oxygen is bound to hemoglobin such that even at very high oxygen tensions the additional dissolved oxygen contributes little to overall CaO2. The oxygen uptake from systemic capillaries (V̇ O2) represents oxygen consumption, as oxygen is not stored in tissue. The Fick principle derives oxygen consumption from the difference in oxygen content between arterial and venous blood, V̇ O2 = Q * (CaO2 − CvO2). Normal oxygen consumption in a resting adult is 110 to 160 mL/min per meter squared; V̇ O2 less than 100 mL/min meter squared indicates impaired tissue oxygenation. The oxygen extraction ratio (O2ER) is the ratio of oxygen consumption to Do2 (O2ER = V̇ O2/DO2), and reflects tissue avidity for oxygen. Normal, global O2ER is 0.2 to 0.3, so only 20% to 30% of delivered oxygen is used.9 The O2ER varies for different tissues, with renal O2ER less than 0.15 and cardiac O2ER greater than 0.6. Mixed venous oxygen saturation reflects the state of global oxygen utilization. Oxygen that is not extracted returns to the 575



CHAPTER 28  Cardiopulmonary Resuscitation 575.e1

Abstract

Keywords

Resuscitation maneuvers improve oxygen delivery, optimize tissue uptake of oxygen, and preserve the metabolic rate of oxygen. This chapter reviews the cardinal tenets of oxygenation, the evidencebased practices of resuscitating the critically ill patient, and the physiology of cardiopulmonary resuscitation (CPR). Our understanding of CPR physiology continues to grow, but morbidity and mortality after cardiac arrest remain poor. Optimizing circulation during CPR and avoiding common errors encountered are initial steps toward improving outcomes. Advances and experience with new technology, including automated devices and extracorporeal life support, are actively being pursued.

critical oxygen delivery early goal-directed therapy cardiac pump theory thoracic pump theory extracorporeal cardiopulmonary resuscitation

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TABLE Key Equations Relevant to Oxygen Delivery 28.1  and Metabolism

TABLE Advanced Cardiovascular Life Support (ACLS) 28.2  Drug Chart26

Cardiac index (CI)

CI = Q/BSA

Drug

Indication

IV/IO Dosage

Arterial oxygen content (CaO2)

CaO2 = 1.39 * Hgb * SaO2 + 0.003 * PaO2

Adenosine

Tachycardia

6 mg, may administer second dose of 12 mg

Oxygen delivery (DO2)

DO2 = CI * CaO2

Amiodarone

Tachycardia

150 mg over 10 min

Oxygen consumption (V̇ O2; Fick principle)

V̇ O2 = Q*(CaO2 − CvO2)

Amiodarone

VT/VF

300 mg, repeat 150 mg

Mixed venous oxygenation (ScvO2; Fick principle)

ScvO2.= SaO2 − [V̇ O2/(Hgb * 1.36 * Q)]

Atropine

Bradycardia

0.5 mg, repeat 3–5 min up to 3 mg

Oxygen extraction ratio (O2ER)

O2ER = V̇ O2/DO2

Diltiazem

Tachycardia

15–20 mg over 2 mins, then 20– 25 mg after 15 mins

Dopamine infusion

Bradycardia

2–10 µg/kg/min

Epinephrine

VT/VF/asystole/ PEA

1 mg, repeat 3–5 min

Epinephrine infusion

Bradycardia

2–10 µg/kg/min

Lidocaine

VT/VF

1–1.5 mg/kg, then 0.5–0.75 mg/kg every 5 min

Magnesium sulfate

Torsade de pointes

2 g

Metoprolol

Tachycardia

5 mg, repeat 2–5 min up to 20 mg

Procainamide infusion

Tachycardia

20–50 mg/min

Sotalol

Tachycardia

100 mg (1.5 mg/kg) over 5 min

Verapamil

Tachycardia

2.5–5 mg, then 5–10 mg every 15–30 min

mixed venous circulation. Assuming an SaO2 of 100%, normal mixed venous saturation (ScvO2) of 70% implies 30% extraction of the oxygen delivered. Rearrangement of the Fick equation yields ScvO2 = SaO2 − V̇ O2/(Hgb * 1.36 * Q). Normal ScvO2 sampled from the pulmonary artery is 65% to 75%, implying an oxygen extraction of ~25% to 35%. ScvO2 is inversely proportional to oxygen consumption and directly proportional to arterial saturation, hemoglobin concentration, and cardiac output. Therefore maneuvers to improve ScvO2 aim to increase arterial oxygen content and delivery.

Compensated Hypovolemia and Supply-Dependent Oxygen Consumption In shock, Do2 is reduced and in response vital organ beds become more oxygen avid. The O 2ER increases to maintain aerobic metabolism. Extraction can rise from 20% to 30% to a maximal extraction of 80%. A diminished margin of error (normal DO2 > V̇ O2) of Do2 is compensated by a greater O2ER. “Compensated hypovolemia” describes the response to decreased Do2 in which increased O2ER allows maintenance of V̇ O2. When DO2 diminishes to a critical point, maximal extraction has been reached, aerobic metabolism is no longer supported, V̇ O2 is wholly dependent of Do2 and cellular energy production is limited by the supply of oxygen. This threshold of DO2 marks tissue dysoxia and the shock state (Fig. 28.1). The critically ill patient often survives below the critical DO2 and organ perfusion is entirely supply dependent. This can be due to blood flow redistribution or direct tissue injury, which prevents changes in the O2ER. A static O2ER hinders a patient’s ability to maintain aerobic metabolism in the face of decreased delivery. This supply dependence underscores the importance of Do2 during shock and demonstrates the physiologic basis of goal-directed therapy.

Early Goal-Directed Therapy Evidence supports maximizing Do2 in high-risk surgical patients to replenish tissue oxygen and prevent organ dysfunction.10 Resuscitation to supranormal DO2 after severe trauma improves survival and decreases ventilator days, mean organ failures per patient, and total intensive care unit days.11 Similar management

IO, Intraosseous; IV, intravenous; PEA; pulseless electrical activity; VF; ventricular fibrillation, VT; ventricular tachycardia,

200 Critical DO2 Oxygen uptake (mL min–1)

BSA, Body surface area; CvO2, oxygen content of venous blood; Hgb, hemoglobin; PaO2, arterial oxygen tension; Q, cardiac output; SaO2; oxygen saturation.

150

· VO2 supply independent

· VO2 supply dependent

100

50

0

0

200 400 Oxygen delivery (mL min–1)

600

• Fig. 28.1  The biphasic relationship between oxygen delivery (DO2) and oxygen consumption (V̇ O2).9



of septic shock reduces overall hospital mortality; CI and DO2 are augmented by volume expansion, blood transfusion, mechanical ventilation with a high fraction of inspired oxygen (FIO2), and inotropic drugs.12 In this 1990 cohort, these measures reduced septic shock mortality from 70% to 80% to 59%. The dynamic nature of septic shock is described as an ebb and flow, shifting from hyperdynamic physiology to an end-stage hypodynamic state. The mortality benefit from these early studies is attributed to the perpetuation of a hyperdynamic state. The basis of goal-directed therapy is the benefit of maximizing parameters of Do2. The natural history of septic shock involves an imbalance of Do2 and oxygen demand, leading eventually to global dysoxia and death. This progression hinges on the critical “golden hour” during which the pathophysiology transitions to multiorgan failure. In a seminal 2000 trial, Rivers and colleagues recommended expeditious, protocolized intervention during this golden hour.13 Interventions aim to augment Do2 in the first 6 hours after onset of septic shock by increasing central venous pressure with intravascular volume expansion (central venous pressure goal 8–12 mm Hg), increasing mean arterial pressure (MAP) with vasoactive agents (mean arterial pressure goal 65–90 mm Hg), and maximizing ScvO2 with red cell transfusion and inotropic support (Scv O2 > 70%). The Surviving Sepsis Campaign, an international consortium tasked to recommend best practices for sepsis management, endorsed early goal-directed therapy as first-line treatment. This “6-hour bundle” was disseminated internationally as the standard of care for sepsis management14 by the Surviving Sepsis Campaign as well as the U.S. National Quality Forum and Centers for Medicare and Medicaid Services.15 This streamlined approach to sepsis management consists of risk stratification to identify the transition from systemic inflammatory response syndrome to severe disease, source control and antibiotic therapy, and hemodynamic optimization (Fig. 28.2).

Cardiopulmonary Resuscitation The AHA regularly revises the guidelines for Basic Life Support and Advanced Cardiovascular Life Support based on the latest evidence supporting CPR survival. According to the most recent AHA recommendations, closed chest compression should be conducted at a rate of 100 to 120 compressions per minute while allowing full recoil of the chest between compressions, compression depth of 2 to 2.5 inches, minimal interruptions between compressions achieving adequate ventilation with 2 breaths for every 30 compressions, and an emphasis on compressions before ventilation. A thorough understanding of the basic physiology in CPR and the ramifications of high-quality CPR is essential for improving overall survival.

Compression and Decompression Closed chest cardiac resuscitation entails the physical compression and decompression of the chest in a cyclic fashion to promote organ perfusion. Although the exact mechanism is controversial, there are two leading concepts of the mechanism by which CPR generates perfusion—the cardiac pump concept and the thoracic pump mechanisms (Fig. 28.3).16,17 The cardiac pump mechanism describes squeezing the heart between the sternum and spine with concurrent increase in intrathoracic pressure. With each compression, a pressure gradient is created between the right atrium and left ventricle, which propels blood forward. The closure of the atrioventricular valves prevents

CHAPTER 28  Cardiopulmonary Resuscitation

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reflux of blood.18 The concomitant rise in pressure in the right atrium and aorta forces blood forward in the circulation. The thoracic pump mechanism proposes that the heart, with an open mitral valve, acts as an open conduit during compression. With each cycle, a pressure gradient is formed between intrathoracic and extrathoracic arteries, and this drives blood out of the heart; the valves in the venous system prevent reflux of blood.19 Paradis and colleagues supported this thoracic pump concept with direct measurement of pressure changes in the venous and arterial systems during CPR. The jugular venous bulb to right atrium pressure (JVB-RA) gradient, and the aortic arch to right atrium pressure (Ao-RA) gradient represented cerebral perfusion and coronary artery perfusion pressures during CPR. During chest compressions, the JVB-RA gradient was positive during chest wall relaxation. The Ao-RA gradient was positive during chest compression. They concluded that forward flow was preserved to the brain and heart, and blood did not flow retrograde owing to the presence of one-way valves.19 Transesophageal echocardiography during cardiac arrest helps to elucidate whether the cardiac pump or thoracic pump concept is the physiologic basis for blood flow during CPR.18,20 It is generally accepted that if the mitral valve is closed during cardiac compression, the cardiac pump mechanism predominates, and if the mitral valve is open the thoracic pump mechanism is predominant. Transesophageal echocardiography during CPR has shown the mitral valve to be closed during CPR, which supports the cardiac pump mechanism. Early initiation of CPR led to a blood flow pattern consistent with the cardiac pump mechanism, and patients were more likely to have a return of spontaneous circulation.20 With later onset of CPR or more prolonged CPR, circulation tended to reflect a thoracic pump mechanism, and patients had a lower incidence of return of spontaneous circulation.20,21 Although compression propels blood forward, decompression decreases intrathoracic and intracardiac pressures and promotes passive venous return to the heart. In closed chest CPR, allowing full chest recoil between compressions is crucial for creating this gradient.

Ventilation and Blood Flow During CPR West and colleagues described three zones of lung perfusion (Fig. 28.4; see Chapter 29).22 In zone 1 alveolar pressure is greater than arteriolar and venous capillary pressure (Palveolar > Parteriolar > Pvenous), and dead space ventilation is present. In zone 2, arteriolar pressure is greater than alveolar pressure and venous capillary pressure (Parteriolar > Palveolar > Pvenous),22 and dead space ventilation persists. Gas exchange occurs primarily in zone 3, where arteriolar pressure is greater than both venous capillary pressure and alveolar pressure (Parteriolar > Pvenous > Palveolar). During CPR, positive-pressure ventilation allows pulmonary gas exchange. Hypoxic pulmonary vasoconstriction occurs when PaO2 < 50 mm Hg, potentially impeding blood flow during CPR.23 Oxygenation is a critical part of CPR to prevent this compensatory vasoconstriction to optimize blood flow across the pulmonary bed and maintain CaO2. A balance between the ventilation rate and tidal volume is also necessary to maximize both ventilation and perfusion. Positive-pressure ventilation is deleterious because increased intrathoracic pressure impedes venous return and compresses the pulmonary vasculature. This vascular compression recruits a larger portion of the lung into West zone 1, with substantial expansion of dead space. The balance between compression and ventilation is crucial; hypoventilation results in hypercarbia,

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Suspected infection and document potential source

Risk stratification: Systolic blood pressure 4 mm/L shock index > 0.9

Antibiotics and source control

Hemodynamic optimization and treatment of overt and cryptic shock

Central venous pressure (CVP) >8–12 mm Hg

Decrease oxygen consumption: sedation and mechanical verification

65–90 mm Hg

Central venous oxygen saturation (ScvO2)

93% and Hct > 30%

70% Inotrope(s)

No

Goals achieved in 6 hours and repeat lactate

• Fig. 28.2  The 6-hour bundle for treating sepsis.15 Hct, Hematocrit; SaO2, oxygen saturation; ScvO2, mixed venous saturation.

and hyperventilation impedes cardiac output. The AHA now recommends a compression:ventilation ratio of 30 : 2, which is reduced compared with earlier guidelines, in the presence of an advanced airway. A target tidal volume of 8 mL/kg is recommended to prevent ventilation-perfusion mismatch.

CPR and Intracranial Pressure Neurologic injury after cardiac arrest is devastating; therefore maintenance of adequate cerebral perfusion during CPR is paramount. Increased intrathoracic pressure from both positive-pressure ventilation and chest compression restricts cranial venous drainage,

CHAPTER 28  Cardiopulmonary Resuscitation



Cardiac pump theory (sternal compressions)

Heart Lung

Lung

Lung

 

Lung

Heart Lung

• Fig. 28.3

Heart

Thoracic pump theory (circumferential compressions)

Heart Lung

579

Lung

Lung

Cardiac pump and thoracic pump mechanisms of cardiopulmonary resuscitation.

Zone 1 PA > Pa > PV

Zone 2 Pa > PA > PV

PA Alveolar PV Venous

Distance

Pa Arterial

Zone 3 Pa > PV > PA Blood flow

• Fig. 28.4  The West zones of lung ventilation and perfusion.22 Pa, Arterial pressure; PA, alveolar pressure; Pv, venous pressure. decreases cerebral perfusion, and elevates intracranial pressure (ICP). The paravertebral venous, epidural plexus, and spinal fluid systems all fail to drain adequately, resulting in increased ICP.16,24 Cerebral perfusion during CPR has been studied in a porcine model comparing three positions: supine, 30-degree Trendelenburg, and 30-degree reverse Trendelenburg (Fig. 28.5). In reverse Trendelenburg position, cerebral perfusion pressure was highest and ICP was lowest. In the Trendelenburg position, ICP was highest and central perfusion pressure was lowest. This study also demonstrated the importance of allowing full recoil of the chest during

the decompression phase of CPR to augment passive cerebral venous drainage and subsequently decrease ICP.25

Optimizing Chest Compression/Decompression Providing high-quality CPR is pivotal to survival after cardiac arrest. The 2015 AHA guidelines recommend chest compressions at a rate of 100 to 120 compressions per minute, with a depth of 5 to 6 cm (2 to 2.5 inches), allowing full chest recoil between compressions, a 30 : 2 compression-to-breath ratio with an advanced

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airway, and limiting interruptions of chest compression to less than 10 seconds.26 High-quality CPR and adherence to the AHA guidelines maximize coronary perfusion and increase effectiveness of defibrillation.27 A compression rate of 100 to 120 compressions minute is ideal; lower rates provide insufficient cardiac output and forward flow, and higher rates are inadequate for diastolic filling. With compression rates outside the recommended range, morbidity and mortality increase.16 In the North American Randomized Multicenter Resuscitation Outcomes Consortium PRIMED trial in 2015, half of the study subjects had compression rates outside the recommended range, which was associated with higher mortality.28 This study supports compression rates of 100 to 120 compressions per minute, which are associated with the greatest survival to hospital discharge (Fig. 28.6).28 Chest compression rate and depth are inversely related: rates above 120 compressions per minute lead to shallow compression depth (70%) metabolized in the liver by N-demethylation by CYP 1A2 primarily to 3-methylxanthine. Theophylline is also 8-hydroxylated to 1,3-dimethyluric acid, which is subsequently N-demethylated to 1-methyluric acid. In neonates it is directly 7-methylated to caffeine. About 10% is excreted in the urine unchanged. Many drug classes affect its metabolism and thus serum concentrations (see later text). Roflumilast is metabolized in the liver by CYP 3A4 and 1A2 to roflumilast N-oxide (also a potent PDE4 inhibitor) and then O-deacylated and glucuronidated for urinary excretion.

Clinical Pharmacology Pharmacokinetics, Pharmacodynamics, and Therapeutic Effects Theophylline is 40% protein bound with a volume of distribution of 0.5 L/kg. Oral theophylline is well absorbed from the gastrointestinal tract, resulting in 90% to 100% bioavailability with peak serum levels occurring within 1 to 2 hours of ingestion. Sustained-release formulations are available owing to the relatively short half-life of 8 hours in healthy adults. The elimination half-life varies widely—from 30 hours in premature neonates to 3.5 hours in children, 8 hours in nonsmoking adults, 5 hours in smoking adults, and 24 hours in those with New York Heart Association class III-IV congestive heart failure. The intravenous dose required to achieve a therapeutic concentration of 10 to 20 µg/mL varies fourfold in an otherwise healthy adult population. For rapid treatment of acute bronchospasm a loading dose followed by maintenance infusion is frequently used. In children the rate of clearance of theophylline is 40% greater than adults. Following oral administration of roflumilast, the time to peak plasma concentration is 1 hour, with nearly 99% protein bound. With daily dosing, steady-state levels are achieved in 4 days with a mean plasma half-life of 17 hours. The role of methylxanthines as antiinflammatory and bronchodilator drugs in asthma and COPD is well established. However, methylxanthines are also respiratory stimulants and have been evaluated in central apnea, obstructive sleep apnea, and periodic breathing (Cheyne-Stokes respiration).61 Clinical trials show a benefit in central sleep apnea but not obstructive sleep apnea.62 In animal studies roflumilast did not protect against LTD4– or serotonin-induced bronchoconstriction, and there is no evidence that roflumilast is bronchodilatory in humans with COPD. This suggests that its primary therapeutic benefit is due to its antiinflammatory effects via PDE4 inhibition in airway inflammatory cells. Adverse Effects Adverse reactions are uncommon at serum theophylline levels below 20 µg/mL. Adverse reactions at serum concentrations between 20 and 25 µg/mL include nausea, vomiting, diarrhea, headache, and insomnia. Symptoms of overdosage at concentrations more than 30 µg/mL include seizures, tachyarrythmias, congestive heart failure, tachypnea, hematemesis, and reflex hyperexcitability. Methylxanthine use during anesthesia was also problematic owing to the release of catecholamines in combination with volatile anesthetics that sensitized the myocardium to their arrythmogenic effects (e.g., halothane).63 Morever, aminophylline does not add additional bronchodilatory effect to the bronchodilation achieved by maintenance levels of volatile anesthetics.64

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Drug Interactions Many medications can increase the serum concentrations of theophylline, thereby enhancing their potential for toxicity; these medications include cimetidine, mexiletine, ticlopidine, propranolol, ciprofloxacin, alcohol, allopurinol, disulfiram, erythromycin, and estrogens. Cigarette and marijuana smoking and medications that induce liver metabolic enzymes (e.g., carbamazepine, phenytoin, thiabenzadole) reduce theophylline serum concentrations.

Special Populations Theophylline should be used with caution in patients with active peptic ulcer disease, seizure disorders, cardiac arrhythmias, compromised cardiac function, angina, hypertension, hyperthyroidism, or liver disease.

Clinical Application Common Applications Theophylline is among the most widely prescribed medication for the treatment of asthma worldwide, but it is recommended as second- or third-line therapy behind inhaled corticosteroids and inhaled β agonists because of its potential for systemic toxicity. By the 1980s several studies reported that inhaled β2 agonists were superior to aminophylline or theophylline in acute asthmatic exacerbations.65 Aminophylline and theophylline formulations are less commonly used as maintenance therapy in the United States because of their low therapeutic index.

Leukotriene Receptor Inhibitors and 5-Lipoxygenase Inhibitors Structure-Activity LTs are synthesized from arachidonic acid by 5-lipoxygnase. They are so named owing to their source from leukocytes and the presence of three conjugated double bonds in their structure. The discovery that the slow-reacting substance of anaphylaxis was a mixture of LTs released from mast cells and basophils sparked the search for antagonists of LT receptors. Independent medicinal chemistry strategies were used to identify both of the antagonists in current clinical use (Table 30.3). Montelukast was discovered by modifying a quinoline with LT structural elements. Zafirlukast was based on a compound incorporating components from both FPL 55712 and the natural LTs.66

Mechanism The cysteinyl LTs—LTC4, LTD4, LTE4, and LTB4—are products of plasma membrane phospholipids that increase smooth muscle contraction, microvascular permeablility, and airway mucus secretion. These LTs mediate their airway effects primarily through the cysteinyl LT receptor 1 (CysLT1) receptor subtype that is widely expressed on mast cells, monocytes, macrophages, eosinophils, basophils, neutrophils, T and B lymphocytes, airway smooth muscle cells, microvascular endothelial cells, bronchial fibroblasts, and pluripotent hematopoietic stem cells.67,68 The enzyme 5-lipoxygenase converts arachidonic acid to LTA4, an upstream precursor to the active cysteinyl LTs. This enzyme is inhibited by the only 5-lipoxygenase inhibitor approved for asthma, zileuton. Montelukast

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TABLE Targeted Antiinflammatory Therapies for 30.3  Bronchospasm

Leukotriene

Generic or Trade Name

Mode of Action

Leukotriene Receptor Antagonists Zafirlukast

Accolate

Montelukast

Singulair

Leukotriene D4 and E4 receptor antagonist Cysteinyl leukotriene receptor antagonist

5-Lipoxygenase Inhibitor Zileuton

Zyflo

Inhibits leukotriene synthesis

Intal

Stabilizes mast cell membrane

Xolair Nucala Cinqair

Antibody to IgE Antibody against IL-5 Antibody against IL-5

Biologics (Antibodies)  Omalizumab  Mepolizumab  Reslizumab

Emerging Biologics (Antibodies)  Benralizumab  Dupilumab  Tralokinumab  Lebrikizumab  Pitrakinra  Anrukinzumab  Secukinumab

Common Applications LT receptor antagonists and 5-lipoxygenase inhibitors69,70 are commonly used as adjuvant therapy in asthma.71 The potential toxicity of this therapy appears less than that of inhaled steroids, and LT receptor antagonists can allow reduced steroid use. They are effective as additional therapy for acute asthma. An investigational intravenous formulation of montelukast has an onset within 10 minutes and improves bronchoconstriction for at least 2 hours.72

Monoclonal Antibodies Structure-Activity

Cell Release Inhibitors  Cromolyn

Clinical Application

Dupixent Aerovant Cosentyx

Antibody to IL-5 receptor Antibody IL-4/IL-13 Antibody to IL-13 Antibody to IL-13 Antagonist to IL-4 receptor Antibody to IL-13 Antibody to IL-17

IgE, Immunoglobulin E; IL, interleukin.

and zafirlukast are antagonists of the CysLT1 receptor; they directly block the effect of LTC4, LTD4, and LTE4 on this receptor.

Clinical Pharmacology Pharmacokinetics, Pharmacodynamics, and Metabolism Montelukast and zafirlukast are rapidly absorbed after oral administration and are more than 99% bound to albumin. They achieve peak plasma concentrations within 3 to 5 hours and undergo extensive metabolism by cytochrome P450 subtypes in the liver. Zileuton causes an increase in liver enzymes in 2% of patients and so should be avoided in patients with active liver disease or persistent elevation of liver enzymes.

Drug Interactions Certain anticonvulsants (phenytoin, carbamazepine, oxycarbazepine, phenobarbital) and rifamycin can decrease plasma concentrations of montelukast. Coadministration of zafirlukast with warfarin increases prothrombin time by 35%. Coadministration of zafirlukast with oral theophylline or aspirin reduces zafirlukast plasma concentrations. Zileuton is a weak inhibitor of CYP 1A2 and has been shown to increase theophylline and propranolol concentrations, and it can increase prothrombin times in patients coadministered warfarin.

Asthma is a heterogeneous collection of clinical syndromes that share the characteristic of reversible small airways obstruction. Asthma occurs in 8% to 10% of the U.S. population, and 10% of this group have severe asthma defined as requiring high-dose inhaled or systemic steroids (≥880 µg of inhaled fluticasone propionate or equivalent) in combination with a second long-term inhaled therapy. Patients with severe asthma are further characterized by those with a Th2 phenotype (eosinophilia, high IL-4, IL-5, IL-13), but nearly 40% of those with severe asthma have a non-Th2 phenotype that involves Th17 cells and neutrophils. Emerging biologic therapies target specific cytokines, particularly those of the Th2 subtype. Approved therapies include antibodies against immunoglobulin (Ig) E (IgE; omalizumab) and IL-5 (mepolizumab and reslizumab). These biologics are reserved for patients with severe asthma, but a significant clinical challenge remains in identifying the molecular asthmatic endotype of a given patient who could potentially benefit from these therapies.73 An additional challenge with these therapies is the need to administer them parenterally (typically monthly) in a monitored clinical setting. Omalizumab was the first clinically available biologic in this class and is a recombinant human IgG1κ monoclonal antibody (150 kDa) that selectively binds to human IgE. It is effective as an adjuvant therapy in adults with moderate to severe asthma. This antibody binds to the constant region of circulating IgE molecules, preventing their binding to the high-affinity (FceRI) and low-affinity (FceRII) IgE receptors on mast cells, basophils, B lymphocytes, dendritic cells, and macrophages, thereby impairing mediator release from these cells. One IgE molecule has two antigenic binding sites for omalizumab, and omalizumab in turn has two antigen binding sites; thus IgE/anti-IgE complexes are formed with molecular masses of 500 to 1000 kDa. Mepolizumab and reslizumab are clinically approved biologics that are monoclonal antibodies directed against the cytokine IL-5, a key orchestrator of inflammation in Th2- dominant asthma and an activator of eosinophils (Fig. 30.5).

Mechanism and Metabolism As an anti-IgE antibody, omalizumab binds to circulating IgE molecules, interrupting the allergic cascade. It is effective in treating patients with allergic asthma that exhibit a high concentration of IgE molecules. Neutralizing IgE molecules prevents activation of degranulation in many IgE-presenting cells, including mast cells and basophils, and thus prevents release of histamine, LTs, and cytokines involved in the inflammatory component of reactive airway disease.

CHAPTER 30  Pulmonary Pharmacology



623

• Fig. 30.5  Immunosignaling mechanisms in asthma. Th2-mediated asthma is primarily mediated by IL-4, IL-5, IL-13, and IgE targeted by monoclonal antibodies omalizumab (anti-IgE) or mepolizumab and reslizumab (anti-IL-5). Non–Th2-mediated asthma is modulated by Th1 and TH17 lymphocytes, which in turn activate neutrophils and macrophages. Monoclonal antibodies indicated by italics are in development for clinical use. GSF, Granulocyte-stimulating factor; IgE, immunoglobulin E; IL, interleukin; INF, interferon; TGF, transforming growth factor-β; Th, T helper (lymphocyte); TNF, tumor necrosis factor; TSKP, thymic stromal lymphopoietin.

The IgE/anti-IgE small immune complexes do not precipitate in the kidney and are easily cleared by the liver reticuloendothelial system and endothelial cells. Intact IgG is also excreted in the bile with serum elimination half-life of 26 days. Mepolizumab monoclonal antibody (IgG1κ) and the reslizumab monoclonal antibody (IgG4κ) bind circulating IL-5, which is a key mediator of eosinophilic production, maturation, recruitment, survival, and activation.

Clinical Pharmacology Pharmacokinetics, Pharmacodynamics, and Therapeutic Effects Omalizumab is administered subcutaneously every 2 to 4 weeks based on serum IgE levels and body weight. Absorption is slow after subcutaneous injection with peak serum concentrations achieved at 7 to 8 days with 62% bioavailability. Serum free IgE levels are reduced within 1 hour of the initial dose of omalizumab. In addition to a reduction in serum free IgE levels, omalizumab reduces expression of high-affinity IgE receptors on inflammatory cells and reduces circulating numbers of eosinophils. The beneficial effects of omalizumab in patients with severe persistent asthma include improvements in the respiratory system and quality of

life,74 a reduction in emergency room visits,75 and reduction in steroid use76 and rescue asthma medications. Mepolizumab is administered as a subcutaneous injection (100 mg) every 4 weeks in a monitored clinical setting because of uncommon but potentially serious adverse effects. Reslizumab (3 mg/kg) is administered as an intravenous infusion every 4 weeks over a period of 20 to 50 minutes.

Adverse Effects A concern across this class of therapeutics is the need for parenteral administration and an incidence of anaphylaxis that requires their administration in a monitored health care setting. Anaphylaxis has been reported in 0.2% of patients receiving omalizumab occurring as early as the first dose and as late as 1 year after the initiation of therapy. Although concerns were raised about a small increase in malignant neoplasms and a case of lymphoma in early studies with omalizumab, subsequent review by independent oncologists reported no causal relationship between omalizumab and cancer development.76 Fever, arthralgia, and rash sometimes accompanied by lymphadenopathy occur in some patients 1 to 5 days after omalizumab injections. Parasitic infections are more common in patients receiving omalizumab compared with controls.77

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Hypersensitivity reactions have been reported with mepolizumab, presenting as anaphylaxis, angioedema, bronchospasm, hypotension, urticarial, or rash. Although these reactions typically occur within hours of administration, some reactions have occurred days after administration. More common reactions include headache and soreness at the site of injection. Anaphylaxis has been reported in 0.3% of patients receiving reslizumab, sometimes occurring as soon as the second injection.

TABLE Mucolytics, Surfactants, and α1-Proteinase 30.4  Inhibitors

Mucolytics

Formulation

Mode of Action

 Acetylcysteine

 Mucomyst

Reduced viscosity of mucus by cleavage of disulfide bonds

  Dornase alfa

 Pulmozyme

Reduced viscosity of mucus by cleavage of leukocyte DNA

Clinical Application

Surfactant Substitutes

Common Applications Omalizumab is used as adjuvant therapy in patients older than 6 years with severe persistent asthma who have elevated serum IgE levels and positive skin tests or in vitro reactivity to a seasonal aeroallergen when symptoms are not adequately controlled with an inhaled corticosteroid. Antibodies against IL-5 (mepolizumab and reslizumab) are indicated in patients with severe asthma using high-dose inhaled corticosteroids (defined as >880 µg fluticasone proprionate or equivalent) along with an additional therapies, and who have had two or more exacerbations in the past year and blood eosinophil counts higher than 150 cells/µL.

  Poractant alfa

 Curosurf

 Calfactant

 Infasurf

 Beractant

 Survanta

α1-Proteinase Inhibitors

 Aralast  Glassia  Prolastin-C  Zemaira

Reduced surface tension in alveolus Reduced surface tension in alveolus Reduced surface tension in alveolus Inhibit neutrophil elastase in α1-proteinase inhibitor genetic deficiency, protecting protein components of alveolar wall

Anesthetic Agents as Bronchodilators Most volatile anesthetics are potent bronchodilators,78 yet the mechanism by which this occurs is unknown. With the exception of desflurane, 79,80 volatile anesthetics dose-dependently dilate bronchial airways and protect against reflex-induced bronchoconstriction during intubation in both patients with asthma and those with COPD.81 The mechanism of direct airway smooth muscle relaxation by inhaled anesthetics includes reduction in Ca2+ sensitivity of contractile proteins82 and interruption of G-protein coupling of procontractile receptor agonists (e.g., acetylcholine).83 The intravenous anesthetics vary in their ability to blunt bronchoconstriction induced by tracheal intubation. Historically ketamine was the induction drug of choice for patients with asthma due to its release of catecholamines with their effect on airway smooth muscle β2 adrenoceptors. In the mid-1990s it was recognized that propofol is very protective against bronchoconstriction during intubation in both patients with asthma84 and those with COPD85 compared with thiobarbiturates or etomidate. A direct clinical comparison between propofol and ketamine for bronchoprotective effects has not been done. The mechanism of bronchoprotection afforded by intravenous anesthetics is incompletely understood but might include direct interaction of anesthetics with GABAA receptors expressed on airway smooth muscle.86 Intravenous,87 epidural,88 and inhaled89 local anesthetics have all been shown to inhibit histamine-induced bronchoconstriction.

Mucolytic Therapies Structure-Activity Inhaled mucolytics allow direct deposition of drugs to reduce mucus viscosity in pulmonary diseases, primarily cystic fibrosis (Table 30.4). Acetylcysteine by inhalation serves as a sulfhydryl donor to cleave disulfide bounds in mucus, reducing its viscosity. Acetylcysteine is also used orally as an antidote for acetaminophen overdose. Dornase alfa is recombinant human deoxyribonuclease I produced in cultured Chinese hamster ovary cells. The 37-kDa

native human enzyme cleaves DNA from dead leukocytes, reducing the overall viscosity of pulmonary secretions.

Mechanism and Metabolism Respiratory mucins contain disulfide bonds that contribute to the structure of mature mucins and are the target of sulfhydryl donors such as acetylcysteine. Tenacious airway secretions of cystic fibrosis arise in part from dying and dead leukocytes responding to airway infection and inflammation. The DNA of these dying cells contributes to the viscosity of secretions and is the substrate for degradation by dornase alfa. Acetylcysteine is rapidly deactylated or oxidized in vivo to form cysteine or diacetylcysteine, respectively.

Clinical Pharmacology Pharmacokinetics, Pharmacodynamics, and Therapeutic and Adverse Effects Inhalation of dornase alfa in patients with cystic fibrosis results in measurable DNAse activity in sputum within 15 minutes. Inhalation of 10 mg of dornase alfa 3 times a day for 6 days does not raise serum DNAse levels above endogenous levels.90 Inhaled acetylcysteine has been associated with stomatitis, bronchoconstriction, nausea, vomiting, fever, rhinorrhea, and drowsiness. Bronchoconstriction responds to bronchodilators,91 but gas exchange can initially worsen owing to thin secretions traveling to more distal airways.92 Acetylcysteine delivery through a bronchoscope or endotracheal tube should be followed by suctioning to prevent deterioration in gas exchange.93

Clinical Application Common Clinical Applications Inhaled acetylcysteine (by nebulization or direct tracheal instillation) is indicated for viscous, increased or inspissated secretions in patients with chronic COPD, tuberculosis, primary amyloidosis of the lung, or cystic fibrosis. Dornase alfa is effective in lowering the



viscosity of pulmonary secretions with high DNA content such as in cystic fibrosis. Twice-daily use of dornase alfa reduces the incidence of pulmonary infections requiring parenteral antibiotics by 29%.

Emerging Developments Inhaler Propellants The propellants in most inhalers were chlorofluorocarbons until an international agreement entitled The Montreal Protocol on Substances that Deplete the Ozone Layer led to a ban on this propellant and its replacement with HFAs. Substantial new technology was involved to make HFAs suitable for MDIs.94 This provided the opportunity to improve the performance of inhaled β2-agonist formulations and enhanced the ability of inhaled steroids to reach smaller peripheral airways.95 Ultralong-acting β2-adrenoceptor agonists (olodaterol96 and sibenadet97) that achieve effective bronchodilation for 24 hours are in development. Clinical trials continue to determine whether the risks of LABAs are mitigated by the concurrent use of inhaled corticosteroids.6

Smoking Cessation Although the topic is not traditionally a part of pulmonary pharmacology, perioperative smoking cessation therapy is an emerging part of anesthesia practice.98 As part of a multidisciplinary team, anesthesiologists are increasingly participating in individualized efforts to promote smoking cessation in perioperative patients.99 Often regarded as the single most preventable cause of premature death in industrialized societies, smoking is also a major underlying factor in excess postoperative morbidity and mortality.100 Studies suggest that a coordinated smoking cessation program instituted perioperatively when patients are motivated about personal health can be effective in helping smokers to quit the habit.101,102

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Some advocate that anesthesiologists should play a lead role in this process.103,104 This mandates that anesthesiologists must be conversant with drug and nondrug therapies applied to assist patients in smoking cessation. The anesthesiologist, as a perioperative physician, has the opportunity to participate in interventions that have long-term impacts on patients’ pulmonary health. The stress of the perioperative period has been recognized as a “teachable moment,” a time in the patient’s life where they may be most receptive to advice regarding smoking cessation.105

Novel Therapies It has long been recognized that clinical asthma is a mixture of disease phenotypes such that a variety of mechanisms may lead to airway hyperresponsiveness.106 Future pharmacologic therapy will undoubtedly make use of better phenotypic and genotypic characterization in individual patients. This may allow more directed therapy, particularly in the area of antiinflammatory therapies where nonspecific steroid approaches may be replaced by targeting specific immunomodulatory mediators such as elevated IgE (e.g., omalizumab) or specific interleukins (e.g., IL-13).107,108 A nonpharmacologic therapy directed at airway smooth muscle hyperresponsiveness is bronchial thermoplasty. The belief is that eliminating airway smooth muscle from mid-sized airways by heat destruction will improve asthma symptoms. This invasive procedure requires repeated bronchoscopies and has resulted in some short-term pulmonary complications, but long-term improvements in the use of rescue medications, prebronchodilator FEV1, and quality-of-life measurements.109 A blinded randomized trial reported an improvement in scores on an asthma quality-of-life questionnaire, but no statistical change in several secondary effectiveness endpoints, including FEV1 (before or after bronchodilator), symptom-free days, or rescue medication use.110 A randomized controlled trial demonstrated an improvement in asthma-specific quality of life with a reduction in severe exacerbations and emergency room visits.111,112

Key Points • Inhaled corticosteroids are the preferred initial therapy for the management of asthma. • Use of long-acting β2-adrenoceptor agonists has been associated with increased risk of asthma-related death. • Anticholinergics block acetylcholine released from parasympathetic nerves acting on muscarinic receptors on airway smooth muscle. Anticholinergics are more efficacious in chronic obstructive lung disease than in asthma. • Tracheal intubation or suctioning can induce reflex-induced bronchoconstriction via a reflex arc that can be blocked at

different levels by local anesthetics, intravenous anesthetics, or volatile anesthetics. • Propofol is the preferred intravenous anesthetic for induction in patients with asthma or chronic obstructive lung disease. • Volatile anesthetics, with the exception of desflurane, are potent bronchodilators. • Personalized therapy for asthma is evolving with the introduction of monoclonal antibodies directed against IgE or interleukin 5.

Key References

Castro M, Musani AI, Mayse ML, et al. Bronchial thermoplasty: a novel technique in the treatment of severe asthma. Ther Adv Respir Dis. 2010;4:101–116. This was the first randomized and blinded clinical trial of bronchial thermoplasty for control of asthma. (Ref. 110). Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med. 2011;364:2473–2475. This editorial summarizes the ongoing

Brown RH, Mitzner W, Zerhouni E, et al. Direct in vivo visualization of bronchodilation induced by inhalational anesthesia using highresolution computed tomography. Anesthesiology. 1993;78:295–300. This publication demonstrates direct visualization and quantification of airway bronchodilation during volatile anesthetics. (Ref. 78).

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controversy and planned clinical trials to assess the safety of using long-acting β2-adrenoceptor agonists as combined therapy with inhaled corticosteroids. (Ref. 6). Chu EK, Drazen JM. Asthma: one hundred years of treatment and onward. Am J Respir Crit Care Med. 2005;171:1202–1208. This historical review summarizes the origins of pharmacologic therapy for hyperreactive airway disease. (Ref. 32). Haxhiu MA, Kc P, Moore CT, et al. Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses. J Appl Physiol. 2005;98:1961–1982. This publication defines the neural signaling pathways that mediate reflex-induced bronchoconstriction induced by airway irritation by foreign bodies such as endotracheal tubes or suction catheters. It also defines the central nervous sytem neurotransmitters (i.e., glutamate and GABA) transmitting this signal. (Ref. 34). Lazarus SC. Clinical practice. Emergency treatment of asthma. N Engl J Med. 2010;363:755–764. This publication describes the current recommended therapy for treating acute bronchospasm in the emergency room, which is applicable to other acute care settings such as the operating room and intensive care unit. (Ref. 27). Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction of general anesthesia in patients with and without asthma: a randomized blinded trial. Anesthesiology. 1995;82:1111–1116. This publication established propofol as the preferred intravenous anesthetic for anesthetic induction in asthmatics. (Ref. 84).

References 1. Salter H Asthma, Its Pathology and Treatment. London: John Churchill, 1860. 2. Osler W, McCrae T. Bronchial Asthma. The Principles and Practice of Medicine. 8th ed. New York and London: D. Appleton and Co; 1914:627–631. 3. Melland B. The treatment of spasmodic asthma by the hypodermic injection of adrenalin. Lancet. 1910;i:1407–1411. 4. Fraser PM, Speizer FE, Waters SD, et al. The circumstances preceding death from asthma in young people in 1968 to 1969. Br J Dis Chest. 1971;65:71–84. 5. Inman WH, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet. 1969;2:279–285. 6. Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med. 2011;364:2473–2475. 6a.  Busse WE, Bateman ED, Caplan AL, et al. Combined analysis of asthma safety trials of long-acting β-agonists. N Engl J Med. 2018; 378:2497–2505. 7. Stempel DA, Raphiou IH, Kral KM, et al. Serious asthma events with fluticasone plus salmeterol verus fluticasone alone. N Engl J Med. 2016;374:1822–1830. 8. Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016;375:840–849. 9. Ray A, Oriss TB, Wenzel SE. Emerging molecular phenotypes in asthma. AJP Lung. 2015;308:L130–L140. 10. Cazzola M, Testi R, Matera MG. Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet. 2002;41:19–30. 11. Anderson GP, Linden A, Rabe KF. Why are long-acting betaadrenoceptor agonists long-acting? Eur Respir J. 1994;7:569–578. 12. Hochhaus G, Schmidt EW, Rominger KL, et al. Pharmacokinetic/ dynamic correlation of pulmonary and cardiac effects of fenoterol in asthmatic patients after different routes of administration. Pharm Res. 1992;9:291–297. 13. Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma treatment. Clin Pharmacokinet. 1994;26:396–418. 14. Bleecker ER, Tinkelman DG, Ramsdell J, et al. Proventil HFA provides bronchodilation comparable to ventolin over 12 weeks of regular use in asthmatics. Chest. 1998;113:283–289.

15. Gumbhir-Shah K, Kellerman DJ, DeGraw S, et al. Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers. J Clin Pharmacol. 1998;38:1096–1106. 16. Brogden RN, Faulds D. Salmeterol xinafoate. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs. 1991;42:895–912. 17. Barnhart ER. Salmeterol Xinafoate. Physician’s Desk Reference. Oradell NJ: Medical Economics Co; 1998:108–111. 18. Bennett JA, Tattersfield AE. Time course and relative dose potency of systemic effects from salmeterol and salbutamol in healthy subjects. Thorax. 1997;52:458–464. 19. Castle W, Fuller R, Hall J, et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ. 1993;306:1034–1037. 20. Salpeter SR, Buckley NS, Ormiston TM, et al. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006;144:904–912. 21. Chowdhury BA, Dal Pan G. The FDA and safe use of longacting beta-agonists in the treatment of asthma. N Engl J Med. 2010;362:1169–1171. 22. Global Initiative for Asthma (GINA). www.ginasthma.org 8-17-2018. 23. Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. 2007. 8-17-2018. 24. Manthous CA, Hall JB, Schmidt GA, et al. Metered-dose inhaler versus nebulized albuterol in mechanically ventilated patients. Am Rev Respir Dis. 1993;148:1567–1570. 25. Ari A, Areabi H, Fink JB. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 2010;55:837–844. 26. Fink JB, Dhand R, Duarte AG, et al. Aerosol delivery from a metered-dose inhaler during mechanical ventilation. An in vitro model. Am J Respir Crit Care Med. 1996;154:382–387. 27. Lazarus SC. Clinical practice. Emergency treatment of asthma. N Engl J Med. 2010;363:755–764. 28. Anzueto A, Miravitlles M. Efficacy of tiotropium in the prevention of exacerbations of COPD. Ther Adv Respir Dis. 2009;3: 103–111. 29. Anthonisen NR, Connett JE, Enright PL, et al. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002;166:333–339. 30. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:1439–1450. 31. Wood-Baker R, Cochrane B, Naughton MT. Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatment. Intern Med J. 2010;40:94–101. 32. Chu EK, Drazen JM. Asthma: one hundred years of treatment and onward. Am J Respir Crit Care Med. 2005;171:1202–1208. 33. Scullion JE. The development of anticholinergics in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2007;2:33–40. 34. Haxhiu MA, Kc P, Moore CT, et al. Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses. J Appl Physiol. 2005;98:1961–1982. 35. Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. Respir Care. 2011;56:477–487. 36. Joos GF, Schelfhout VJ, Pauwels RA, et al. Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients. Respir Med. 2010;104:865–872. 37. Alagha K, Bourdin A, Tummino C, et al. An update on the efficacy and safety of aclidinium bromide in patients with COPD. Ther Adv Respir Dis. 2011;5:19–28. 38. Gavalda A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331:740–751.



39. Ficker JH, Rabe KF, Welte T. Role of dual bronchodilators in COPD: A review of the current evidence for indacaterol/ glycopyrronium. Pulm Pharm Ther. 2017;45:19–33. 40. Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination long beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev. 2016;(1):Art. No.: CD011721, doi:10.1002/14651858. CD011721.pub2. 2016. 41. Schacke H, Schottelius A, Docke WD, et al. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc Natl Acad Sci USA. 2004;101:227–232. 42. Winkler J, Hochhaus G, Derendorf H. How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc. 2004;1:356–363. 43. Fitzgerald JM, Shragge D, Haddon J, et al. A randomized, controlled trial of high dose, inhaled budesonide versus oral prednisone in patients discharged from the emergency department following an acute asthma exacerbation. Can Respir J. 2000;7:61–67. 44. Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365:1173–1183. 45. Li JT, Ford LB, Chervinsky P, et al. Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitaryadrenal axis and bone mineral density over 2 years in adults with mild asthma. J Allergy Clin Immunol. 1999;103:1062–1068. 46. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med. 1999;159:941–955. 47. Medici TC, Grebski E, Hacki M, et al. Effect of one year treatment with inhaled fluticasone propionate or beclomethasone dipropionate on bone density and bone metabolism: a randomised parallel group study in adult asthmatic subjects. Thorax. 2000;55:375–382. 48. Ljustina-Pribic R, Stojanovic V, Petrovic S. The influence of inhaled fluticasone on bone metabolism and calciuria in asthmatic children. J Aerosol Med Pulm Drug Deliv. 2011;24:201–204. 49. De Wachter E, Malfroot A, De Schutter I, et al. Inhaled budesonide induced Cushing’s syndrome in cystic fibrosis patients, due to drug inhibition of cytochrome. J Cyst Fibros. 2003;2(72–75):P450. 50. Juniper EF, Kline PA, Vanzielghem MA, et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis. 1990;142:832–836. 51. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054–1063. 52. Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med. 2000;343:332–336. 53. Frois C, Wu EQ, Ray S, et al. Inhaled corticosteroids or long-acting beta-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/ salmeterol. Clin Ther. 2009;31:2779–2803. 54. Yawn BP, Raphiou I, Hurley JS, et al. The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD. Int J Chron Obstruct Pulmon Dis. 2010;5:165–178. 55. Sharafkhaneh A, Mattewal AS, Abraham VM, et al. Budesonide/ formoterol combination in COPD: a US perspective. Int J Chron Obstruct Pulmon Dis. 2010;5:357–366. 56. Card GL, England BP, Suzuki Y, et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004;12:2233–2247. 57. Polson JB, Krzanowski JJ, Fitzpatrick DF, et al. Studies on the inhibition of phosphodiesterase-catalyzed cyclic AMP and cyclic GMP breakdown and relaxation of canine tracheal smooth muscle. Biochem Pharmacol. 1978;27:254–256. 58. Peach MJ. Stimulation of release of adrenal catecholamine by adenosine 3’:5’-cyclic monophosphate and theophylline in the absence of extracellular Ca 2. Proc Natl Acad Sci USA. 1972;69:834–836.

CHAPTER 30  Pulmonary Pharmacology

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59. Fredholm BB, Brodin K, Strandberg K. On the mechanism of relaxation of tracheal muscle by theophylline and other cyclic nucleotide phosphodiesterase inhibitors. Acta Pharmacol Toxicol (Copenh). 1979;45:336–344. 60. Kong H, Jones PP, Koop A, et al. Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J. 2008;414:441–452. 61. Tilley SL. Methylxanthines in asthma. Handb Exp Pharmacol. 2011;439–456. 62. Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. 1996;335:562–567. 63. Roizen MF, Stevens WC. Multiform ventricular tachycardia due to the interaction of aminophylline and halothane. Anesth Analg. 1978;57:738–741. 64. Tobias JD, Kubos KL, Hirshman CA. Aminophylline does not attenuate histamine-induced airway constriction during halothane anesthesia. Anesthesiology. 1989;71:723–729. 65. Siegel D, Sheppard D, Gelb A, et al. Aminophylline increases the toxicity but not the efficacy of an inhaled beta-adrenergic agonist in the treatment of acute exacerbations of asthma. Am Rev Respir Dis. 1985;132:283–286. 66. Bernstein PR. Chemistry and structure-activity relationships of leukotriene receptor antagonists. Am J Respir Crit Care Med. 1998;157:S220–S226. 67. Austen KF. The mast cell and the cysteinyl leukotrienes. Novartis Found Symp. 2005;271:166–175. 68. Singh RK, Gupta S, Dastidar S, et al. Cysteinyl leukotrienes and their receptors: molecular and functional characteristics. Pharmacology. 2010;85:336–349. 69. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol. 1996;98:859–871. 70. Berger W, De Chandt MT, Cairns CB. Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract. 2007;61:663–676. 71. Amlani S, Nadarajah T, McIvor RA. Montelukast for the treatment of asthma in the adult population. Expert Opin Pharmacother. 2011;12:2119–2128. 72. Camargo CA Jr, Gurner DM, Smithline HA, et al. A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. J Allergy Clin Immunol. 2010;125:374–380. 73. Ray A, Raundhal M, Oriss TB, et al. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394–2403. 74. Busse WW, Massanari M, Kianifard F, et al. Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis. Curr Med Res Opin. 2007;23:2379–2386. 75. Corren J, Casale T, Deniz Y, et al. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allergy Clin Immunol. 2003;111:87–90. 76. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2011; 139:28–35. 77. Cruz AA, Lima F, Sarinho E, et al. Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy. 2007;37:197–207. 78. Brown RH, Mitzner W, Zerhouni E, et al. Direct in vivo visualization of bronchodilation induced by inhalational anesthesia using highresolution computed tomography. Anesthesiology. 1993;78:295–300. 79. Goff MJ, Arain SR, Ficke DJ, et al. Absence of bronchodilation during desflurane anesthesia: a comparison to sevoflurane and thiopental. Anesthesiology. 2000;93:404–408. 80. Klock PA Jr, Czeslick EG, Klafta JM, et al. The effect of sevoflurane and desflurane on upper airway reactivity. Anesthesiology. 2001;94:963–967.

628

SE C T I O N IV

Pulmonary System

81. Rooke GA, Choi JH, Bishop MJ. The effect of isoflurane, halothane, sevoflurane, and thiopental/nitrous oxide on respiratory system resistance after tracheal intubation. Anesthesiology. 1997;86:1294–1299. 82. Jones KA, Wong GY, Lorenz RR, et al. Effects of halothane on the relationship between cytosolic calcium and force in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 1994;266: L199–L204. 83. Nakayama T, Penheiter AR, Penheiter SG, et al. Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein. Anesthesiology. 2006;105: 313–324. 84. Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction of general anesthesia in patients with and without asthma: a randomized blinded trial. Anesthesiology. 1995;82:1111–1116. 85. Eames WO, Rooke GA, Wu RS, et al. Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance after tracheal intubation. Anesthesiology. 1996;84:1307–1311. 86. Gallos G, Gleason NR, Virag L, et al. Endogenous gammaaminobutyric acid modulates tonic guinea pig airway tone and propofol-induced airway smooth muscle relaxation. Anesthesiology. 2009;110:748–758. 87. Groeben H, Foster WM, Brown RH. Intravenous lidocaine and oral mexiletine block reflex bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med. 1996;154:885–888. 88. Groeben H, Schwalen A, Irsfeld S, et al. High thoracic epidural anesthesia does not alter airway resistance and attenuates the response to an inhalational provocation test in patients with bronchial hyperreactivity. Anesthesiology. 1994;81:868–874. 89. Groeben H, Irsfeld S, Stieglitz S, et al. Lidocaine and bupivacaine, both dose dependently attenuate the response to inhalational challenge in awake volunteers with bronchial hyperreactivity. Anesthesiology. 1994;81:A1470. 90. Aitken ML, Burke W, McDonald G, et al. Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study. JAMA. 1992;267:1947–1951. 91. Kory RC, Hirsch SR, Giraldo J. Nebulization of N-acetylcysteine combined with a bronchodilator in patients with chronic bronchitis. A controlled study. Dis Chest. 1968;54:504–509. 92. Lourenco RV, Cotromanes E. Clinical aerosols II. Therapeutic aerosols. Arch Intern Med. 1982;142:2299–2308. 93. Lieberman J. The appropriate use of mucolytic agents. Am J Med. 1970;49:1–4. 94. Leach CL. The CFC to HFA transition and its impact on pulmonary drug development. Respir Care. 2005;50:1201–1208.

95. Gentile DA, Skoner DP. New asthma drugs: small molecule inhaled corticosteroids. Curr Opin Pharmacol. 2010;10:260–265. 96. Casarosa P, Kollak I, Kiechle T, et al. Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol. J Pharmacol Exp Ther. 2011;337:600–609. 97. Connolly S, Alcaraz L, Bailey A, et al. Design-driven LO: The discovery of new ultra long acting dibasic beta(2)-adrenoceptor agonists. Bioorg Med Chem Lett. 2011;21:4612–4616. 98. Quraishi SA, Orkin FK, Roizen MF. The anesthesia preoperative assessment: an opportunity for smoking cessation intervention. J Clin Anesth. 2006;18:635–640. 99. Warner DO. Helping surgical patients quit smoking: why, when, and how. Anesth Analg. 2005;101:481–487, table. 100. Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology. 2011;114:837–846. 101. Sadr AO, Lindstrom D, Adami J, et al. The efficacy of a smoking cessation programme in patients undergoing elective surgery: a randomised clinical trial. Anaesthesia. 2009;64:259–265. 102. Moller A, Villebro N, Pedersen T. Interventions for preoperative smoking cessation. Cochrane Database Syst Rev. 2001;CD002294. 103. Warner DO. Feasibility of tobacco interventions in anesthesiology practices: a pilot study. Anesthesiology. 2009;110:1223–1228. 104. Warner DO. Surgery as a teachable moment: lost opportunities to improve public health. Arch Surg. 2009;144:1106–1107. 105. Shi Y, Warner DO. Surgery as a teachable moment for smoking cessation. Anesthesiology. 2010;112:102–107. 106. Handoyo S, Rosenwasser LJ. Asthma phenotypes. Curr Allergy Asthma Rep. 2009;9:439–445. 107. Kraft M. Asthma phenotypes and interleukin-13–moving closer to personalized medicine. N Engl J Med. 2011;365:1141–1144. 108. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–1098. 109. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185–1191. 110. Castro M, Musani AI, Mayse ML, et al. Bronchial thermoplasty: a novel technique in the treatment of severe asthma. Ther Adv Respir Dis. 2010;4:101–116. 111. Shifren A, Chen A, Castro M. Point: efficacy of bronchial thermoplasty for patients with severe asthma. Is there sufficient evidence? Yes. Chest. 2011;140:573–575. 112. Michaud G, Ernst A. Counterpoint: efficacy of bronchial thermoplasty for patients with severe asthma. Is there sufficient evidence? Not yet. Chest. 2011;140:576–577.

31 

Liver and Gastrointestinal Physiology RANDOLPH H. STEADMAN, MICHELLE BRAUNFELD, AND HAHNNAH PARK

CHAPTER OUTLINE Liver Anatomy Blood Supply Liver Function Storage Filtering and Cleansing Metabolism of Nutrients Synthesis of Coagulation Factors Bile Secretion Bilirubin and Jaundice Liver Regeneration Portal Hypertension Hepatic Drug Metabolism and Excretion Anesthetic Pharmacology and the Liver Liver Disease: Etiologies and Severity Cirrhosis and Perioperative Risk: Nonhepatic Surgery Hepatic Surgery Gastrointestinal Tract Anatomy Properties of the Gastrointestinal Tract Respiration and Pharyngeal Swallowing Lower Esophageal Sphincter Neural Control Enteric Nervous System Parasympathetic Stimulation Sympathetic Stimulation Hormonal Control Splanchnic Circulation Stomach Emptying Enterogastric Nervous Reflex Secretory Functions Autonomic Stimulation Gastric Secretions Pancreatic Digestive Enzymes Bicarbonate Absorption of Nutrients Glucose Fats Gastrointestinal Disorders Anesthetic Pharmacology and the Gastrointestinal Tract Emerging Developments Tissue Engineering

630

I

n perioperative management, the hepatic and gastrointestinal (GI) systems usually receive consideration after the cardiovascular and respiratory systems. However, potential perioperative problems such as aspiration, ileus, and nausea and vomiting are common and significant. Additionally, end-stage liver disease—often associated with multisystem organ failure—can be life threatening. It is incumbent in anesthesiology to understand the physiologic basis of these conditions to minimize associated complications and optimize patient outcomes.

Liver The liver weighs approximately 1.5 kg, or about 2% of total body weight in an adult. Functionally, the liver metabolizes carbohydrates, proteins, fats, hormones, and foreign substances. In addition, it filters and stores blood; stores vitamins, glycogen, and iron; and produces bile and blood coagulation factors.

Anatomy The functional unit of the liver is the lobule, or liver acinus, a structure roughly 1 × 2 mm that consists of plates of hepatocytes located in a radial distribution about a central vein (Fig. 31.1). Bile canaliculi are located between the plates and collect bile formed in the hepatocytes. The canaliculi drain into bile ducts located at the periphery of the lobule next to portal venules and hepatic arterioles. The bile ducts join to form the common hepatic duct. The cystic duct from the gallbladder and the pancreatic duct join the common hepatic duct before entering the duodenum. The sphincter of Oddi controls the flow of bile into the small intestine.1,2 Portal venules empty blood from the GI tract into the hepatic sinusoids, the space between the plates of hepatocytes that serve as the capillaries of the liver. Hepatic arterioles supply welloxygenated blood to the septa located between the plates of hepatocytes and the sinusoids. The liver typically contains between 50,000 and 100,000 lobules. The large pores of endothelium lining the sinusoids allow plasma and its proteins to move readily into the tissue spaces surrounding hepatocytes, an area known as the space of Disse, or perisinusoidal spaces. This fluid drains into the lymphatic system. The liver is responsible for generating about half of the lymph. Macroscopically the liver is divided unequally into right and left lobes by the falciform ligament (Fig. 31.2A). More recently a segmental, or surgical, anatomy has been described, known as the

CHAPTER 31  Liver and Gastrointestinal Physiology



Diaphragm (pulled up)

Sinusoids Space of Disse Terminal lymphatics

Central vein

Liver cell plate

631

Left triangular ligament

Coronary ligament

Right triangular ligament Left lobe

Kupffer cell Bile canaliculi

Right lobe

Portal vein Gallbladder (fundus)

Hepatic artery Lymphatic duct Bile duct

Round ligament (ligamentum teres)

A

Falciform ligament

Extended right hepatectomy (right trisegmentectomy) Right hepatectomy

• Fig. 31.1

  The structure of the liver lobule, or acinus. Hepatocytes radiate outward from the central vein. Blood enters the lobule from the periphery via the portal vein and hepatic artery and then flows by the plates of hepatocytes before entering the central vein. Bile flows in the opposite direction.

Left lateral Left medial section section Middle hepatic vein Left hepatic vein

Right posterior Right anterior section section Right hepatic vein

II

VII

Couinaud classification. The liver is divided into eight segments based on the anatomy of the portal and hepatic veins (Fig. 31.2B).

VIII

IVa

I

III

Blood Supply The liver receives almost 25% of cardiac output via a dual supply. The portal venules conduct blood from the portal vein that drains the GI tract. The portal vein supplies 75% of liver blood flow, about 1 L/min. The hepatic arterioles supply 25% of blood flow. Each system contributes about 50% of hepatic oxygen supply (Fig. 31.3). The high hepatic blood flow is due to low vascular resistance in the portal vein. The average portal vein pressure is 9 mm Hg, whereas hepatic venous pressure averages 0 mm Hg for a 9-mm Hg perfusion pressure gradient. However, when hepatocytes are injured and replaced by fibrous tissues, blood flow is impeded, resulting in portal hypertension, the hallmark of cirrhosis. Sinusoidal pressures greater than 5 mm Hg are abnormal and define portal hypertension (see later text).3 Sympathetic innervation from T3 to T11 controls resistance in the hepatic venules. Changes in compliance in the hepatic venous system help regulate cardiac output and blood volume. In the presence of reduced portal venous flow, the hepatic artery can increase flow by as much as 100% to maintain hepatic oxygen delivery. The reciprocal relationship between flow in the two afferent vessels is termed the hepatic arterial buffer response.4 The microcirculation of the liver lobule is divided into three zones that receive varying oxygen content.5 Zone 1 receives oxygenrich blood from the adjacent portal vein and hepatic artery. As blood moves through the sinusoid, it passes from the intermediate zone 2 into zone 3, which surrounds the central vein. Zone 3 receives blood that has passed through zones 1 and 2, reducing the oxygen content. Pericentral hepatocytes have a greater quantity of cytochrome P450 (CYP) enzymes and are the site of anaerobic metabolism. Hypoxia and reactive metabolic intermediates from biotransformation affect this zone more prominently than other zones.

IVb VI

Umbilical vein (remnant)

V

Hepatic duct Inferior vena cava Hepatic artery Portal vein Gallbladder Cystic Bile duct duct Left hepatectomy

B

Extended left hepatectomy (left trisegmentectomy)

• Fig. 31.2  Liver anatomy. A, Surface anatomy of the liver depicting the right and left lobes, separated by the falciform ligament. B, The Couinaud segments of the liver and the accompanying vascular structures. The segments resected during various partial hepatectomies are illustrated. Volatile anesthetics decrease hepatic blood flow; however, newer agents (isoflurane, desflurane, and sevoflurane) reduce flow less than older agents such as halothane.6,7

Liver Function Storage Owing to its ability to distend, the liver is capable of storing up to 1 L of blood. Thus the liver serves as a reservoir capable of accepting blood, as in the presence of heart failure, or releasing blood at times of low blood volume. The liver also stores vitamins, particularly vitamins B12 (1-year supply), D (3-month supply), and A (10-month supply). Excess body iron is transported via

632

Gastrointestinal and Endocrine Systems

SE C T I O N V

Hepatic sinuses

Hepatic vein

Inferior vena Hepatic cava artery

Aorta

Portal vein

Splenic vein Superior mesenteric vein

Intestinal vein

Intestinal artery

Spleen

Capillary

• Fig. 31.3

 

The splanchnic circulation.

apoferritin to the liver for storage as ferritin, which is released when circulating iron levels are low. Thus the liver apoferritin system serves for iron storage and as a blood iron buffer.

Filtering and Cleansing Kupffer cells, a type of reticuloendothelial cell, line the venous sinusoids. Kupffer cells are macrophages that phagocytize bacteria that enter the sinusoids from the intestines. Less than 1% of bacteria that enter the liver pass through to the systemic circulation. Metabolism of Nutrients The liver is involved in energy production and storage from nutrients absorbed from the intestines. The liver helps regulate blood glucose concentrations through its glucose buffer function. This is accomplished by storing glucose as glycogen, converting other carbohydrates (principally fructose and galactose) to glucose, and synthesizing glucose from glucogenic amino acids and from glycerol derived from triglycerides (gluconeogenesis).8 In patients with altered liver function, glucose loads are poorly tolerated, and blood glucose concentration can rise severalfold higher than postprandial levels found in patients with normal hepatic function. The liver synthesizes fat, cholesterol, phospholipids, and lipoproteins. It also metabolizes fat efficiently, converting fatty acids to acetyl coenzyme A (CoA), an excellent energy source. Some of the acetyl-CoA enters the citric acid cycle to liberate energy for the liver. The liver generates more acetyl-CoA than it consumes, so it packages the excess as acetoacetic acid for use by the rest of the body via the citric acid cycle. The majority of cholesterol synthesized in the liver is converted to bile salts and secreted in the bile. The remainder is distributed to the rest of the body where it is used to form cellular membranes. Fat synthesis from protein and carbohydrates occurs almost exclusively in the liver, and the liver is responsible for most fat metabolism. The liver also plays a key role in protein metabolism. The liver synthesizes all of the plasma proteins with the exception of gamma globulins, which are formed in plasma cells. The liver is capable of forming 15 to 50 g of protein per day, an amount sufficient to

replace the body’s entire supply of proteins in several weeks. Albumin is the major protein synthesized by the liver and is the primary determinant of plasma oncotic pressure. The liver also synthesizes the nonessential amino acids from ketoacids, which it also synthesizes. The liver can deaminate amino acids, a process required before their use for energy production or conversion to carbohydrates or fats. Deamination results in the formation of ammonia, which is toxic. Intestinal bacteria are an additional source of ammonia. The liver is responsible for the removal of ammonia through the formation of urea.

Synthesis of Coagulation Factors Blood clotting factors, except factors III (tissue thromboplastin), IV (calcium), and VIII (von Willebrand factor), are synthesized in the liver. Vitamin K is required for the synthesis of the calcium ion (Ca2+)-binding proteins prothrombin (factor II) and factors VII, IX, and X (see Chapter 43). Bile Secretion Hepatocytes produce roughly 500 mL of bile daily. Between meals the high pressure in the sphincter of Oddi diverts bile to the gallbladder for storage (Fig. 31.4). The gallbladder holds 35 to 50 mL of bile in concentrated form. The presence of fat in the duodenum causes release of the hormone cholecystokinin from duodenal mucosa, which reaches the gallbladder via the circulation and stimulates gallbladder contraction. Bile contains bile salts, bilirubin, and cholesterol. Bile salts serve as a detergent, solubilizing fat into complexes called micelles, which are absorbed. Bile salts are returned to the liver via the portal vein, completing the enterohepatic circulation. Bile salts are needed for fat absorption, and cholestasis can result in steatorrhea and vitamin K deficiency.

Bilirubin and Jaundice Bilirubin is the major end product of hemoglobin breakdown, which occurs when red blood cells reach the end of their 120-day life span. After phagocytosis by reticuloendothelial cells, hemoglobin is split into globin and heme. The heme releases iron and a fourpyrrole nucleus that forms biliverdin, which is converted to free, or unconjugated, bilirubin. Unconjugated bilirubin is conjugated in the liver, primarily with glucuronic acid, before it is secreted into bile for transport to the intestines. In the intestines, a portion of conjugated bilirubin is converted to urobilinogen by bacteria. Some urobilinogen is reabsorbed from the intestines into the blood, but most is excreted back into the intestines. A small amount is excreted into urine as urobilin. Urobilinogen that remains in the intestines is oxidized to stercobilin and excreted in feces. Jaundice is the yellow-green tint of body tissues that results from bilirubin accumulation in extracellular fluid. Skin discoloration is usually visible when plasma bilirubin reaches three times normal values. Bilirubin accumulation can occur as the result of increased breakdown of hemoglobin (hemolysis) or obstruction of bile ducts. Hemolytic jaundice is associated with an increase in unconjugated (indirect) bilirubin, whereas obstructive jaundice is associated with increases in conjugated (direct) bilirubin.9

Liver Regeneration The liver has the unique ability to restore itself after injury or partial hepatectomy. As much as two-thirds of the liver can be removed with regeneration of the remaining liver in a matter of

CHAPTER 31  Liver and Gastrointestinal Physiology



633

Bile acids via blood stimulate parenchymal secretion of bile Secretin via blood stimulates liver ductal secretion

Vagal stimulation causes weak contraction of gallbladder

Stomach

• Fig. 31.4

 

Neural and hormonal factors that regulate bile

secretion.

Liver

Pancreas Bile stored and concentrated up to 15 times in gallbladder

Sphincter of Oddi

Duodenum

Cholecystokinin via bloodstream causes 1. Gallbladder contraction 2. Relaxation of sphincter of Oddi

Fatty food in duodenum stimulates cholecystokinin release into the bloodstream

weeks.10 Control over this process is not completely understood, but hepatocyte growth factor, produced by mesenchymal cells in the liver, is involved. Other growth factors, such as epidermal growth factor and cytokines, tumor necrosis factor, and interleukin (IL)-6 can also stimulate regeneration. The mechanism responsible for returning the liver to a quiescent state might involve transforming growth factor β, a known inhibitor of hepatocyte proliferation. The signal for cessation of regeneration appears to be related to the ratio of liver to body weight.10,11 In the presence of inflammation, as with viral hepatitis, regeneration is significantly impaired.

Portal Hypertension Ongoing inflammation results in fibrosis that constricts blood flow in the sinusoids, creating increased portal pressures. Portal hypertension is formally diagnosed by measurement of the hepatic venous gradient (HVG), defined as the difference between hepatic venous and portal venous pressures. Because direct measurement of portal venous pressures is not easily accomplished, it is estimated by the wedge pressure of the hepatic veins as measured by a balloon catheter introduced into (typically) the right hepatic vein. The difference between that wedge pressure and the free pressure in the hepatic vein is the HVG, normally 1 to 5 mm Hg. Subclinical portal hypertension appears when the HVG rises to 6 to 9 mm Hg. When HVG reaches 10 to 12 mm Hg, portal hypertension becomes a systemic condition affecting hemodynamics, fluid balance, renal function, and cognition.12 Resistance to portal blood flow causes collateral vessels to develop between portal and systemic veins. With increased pressure in the splenic vein, collateral vessels to esophageal veins develop. These

enlarge and protrude into the esophageal lumen, producing esophageal varices. Variceal size and HVG predict both the likelihood of rupture and ability to control variceal bleeding and rebleeding.13 Within 2 years of diagnosis of portal hypertension, approximately 30% of patients have a variceal hemorrhage.14 The 6-week mortality after variceal hemorrhage is 30%, which increases to 50% with a second episode of bleeding. Prophylaxis to prevent bleeding includes nonselective β blockers, long-acting nitrates, endoscopic obliteration, and endoscopic ligation.15 Portal hypertension results in portosystemic shunting. Shunted blood circumvents the filtering system of the liver. This results in the entry of drugs, ammonia, and other toxins normally handled by the liver into the systemic circulation; hepatic encephalopathy often ensues.16 Splanchnic vasodilatation reduces renal perfusion, resulting in renal failure (hepatorenal syndrome). During the early stages of acute renal injury the kidneys can be functionally normal and the changes reversible. In the absence of improvement in liver function, renal injury can become permanent.17 Systemic vasodilatation leads to hyperdynamic circulation characterized by low normal blood pressure, low systemic vascular resistance, and high cardiac output. Response to vasoconstrictors is often attenuated owing to endogenous vasodilators, an ineffective splanchnic reservoir, and increased sympathetic tone.18

Hepatic Drug Metabolism and Excretion The liver metabolizes and excretes many drugs into the bile. The liver is also responsible for metabolism of a number of hormones, including thyroxine and the steroids estrogen, cortisol, and aldosterone.

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Intrinsic hepatic clearance of a compound divided by the hepatic blood flow determines the extraction ratio. The extraction ratio indicates the efficiency with which various drugs are cleared. Efficiently extracted drugs include many opioids, β blockers (except atenolol), calcium channel blockers, and tricyclic antidepressants. Poorly extracted drugs include warfarin, aspirin, ethanol, and phenobarbital. Elimination of poorly extracted drugs is limited by intrinsic clearance and/or protein binding rather than hepatic blood flow, whereas elimination of highly extracted drugs is dependent on blood flow (see Chapter 4).

Anesthetic Pharmacology and the Liver Volatile anesthetic agents decrease hepatic blood flow. Agents currently in use—isoflurane, sevoflurane, and desflurane—affect hepatic blood flow less than older agents. Despite reductions in hepatic blood flow, liver function testing fails to show alterations of hepatic function after administration of current inhaled anesthetics.19,20 Fewer data exist on the effects of inhaled anesthetics on patients with chronic liver disease. Central neuraxial blockade decreases hepatic blood flow proportionally to the decrease in systemic blood pressure. Hepatic blood flow can be restored by administration of vasopressors. Hepatic dysfunction affects the pharmacokinetics of intravenous anesthetics through alterations in protein binding (as the result of reduced plasma proteins), increases in the volume of distribution, and reductions in hepatic metabolism.21,22 The pharmacodynamic effects of opioids and sedatives can be enhanced in patients with end-stage liver failure who have encephalopathy. Although opioids have been used successfully to treat biliary colic, they can also produce spasm of the sphincter of Oddi.23 Glucagon, opioid antagonists, nitroglycerin, and atropine reverse this effect. Intermediate-duration neuromuscular blocking agents that undergo hepatic elimination have a prolonged duration of action in the presence of liver disease. Atracurium and cisatracurium are not dependent on hepatic elimination, so dosing alterations are not required in patients with hepatic disease (see Chapter 22).

Liver Disease: Etiologies and Severity The most common causes of hepatic cirrhosis are hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. Other causes include biliary cirrhosis, autoimmune disease, hemochromatosis, drug-induced liver disease, metabolic disorders, and hepatocellular cancer.24 Biliary cirrhosis is associated with several forms of cholestatic disease, including primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. Nonalcoholic fatty liver disease (also called steatohepatitis), an increasingly recognized cause, is associated with obesity, type 2 diabetes mellitus, and the constellation of risk factors known as the metabolic syndrome.25 The severity of cirrhosis can be graded using the Child-Turcotte-Pugh (CTP) scoring system (Table 31.1).26 Patients with the most severe disease have a CTP score of 10 points or more (class C). These patients have exceedingly high perioperative mortality (up to 75%).27 Class B (7–9 points) patients also have significant perioperative mortality (30%). Preoperative risk modification, through treatment of encephalopathy and ascites, appears to reduce risk.28 An alternative mortality risk stratification for patients with liver disease undergoing nonhepatic surgery is the Model for End-Stage Liver Disease (MELD) score. The MELD score was developed to predict 90-day mortality in patients undergoing transjugular intrahepatic portosystemic shunt procedures.29 It has since been

TABLE a 31.1  Modified Child-Turcotte-Pugh Scoring System

Parameters

1 Point

2 Points

3 Points

Albumin (g/dL)

>3.5

2.8–3.5

6) lasting for almost 24 hours. Other benefits over PPIs include its stability in acidic environments, improved solubility in the stomach, and stronger inhibition of H+,K+-ATPase activity overall, leading to more effective lowering

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of gastric acid secretion.86 Additional clinical trials are underway, but vonoprazan has not been approved for use in the United States. If approved, vonoprazan could replace PPI use for treatment of gastroesophageal reflux disease, erosive esophagitis, peptic ulcer disease, prevention of nonsteroidal antiinflammatory drug–associated gastrointestinal events, and, used in combination with antibiotics, for treatment of Helicobacter pylori infection.87

Direct-Acting Antivirals for Hepatitis C Treatment Prior treatment of hepatitis C virus (HCV) was based on pegylated IFN-α plus ribavirin therapy, which was associated with a multitude of negative side effects, including anemia, fatigue, and malaise. Since 2011 a new generation of HCV treatments classified as oral direct-acting antivirals has been released, including boceprevir, telaprevir, and simeprevir. The most commonly used is a combination of ledipasvir 90 mg and sofosbuvir 400 mg approved by the FDA in 2014 for genotype 1 HCV infection.88 In a phase III clinical trial, this combination showed a 97% to 99% sustained virologic response (defined as undetectable HCV ribonucleic acid [RNA] at 12 weeks after treatment) in patients receiving once-daily treatment in combination or without concurrent ribavirin treatment with treatment for either 12 or 24 weeks.89 Direct-acting antivirals target the life cycle of the HCV RNA virus to inhibit replication. Ledipasvir targets one of the nonstructural HCV proteins called nonstructural protein 5A (NS5A) used in viral replication and absent in human cells.90 Common side effects include fatigue, headache, nausea, and diarrhea.91 Ledipasvir is used in combination with sofosbuvir, an NS5B polymerase inhibitor owing to its high rate of resistance.90 The ledipasvirsofosbuvir combination is indicated for use in adults with HCV genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis. In combination with ribavirin, it can be used in patients with HCV genotype 1 with decompensated cirrhosis or liver transplant recipients without cirrhosis. It is also FDA approved in children older than 12 years or weighing more than 35 kg. The usual course of treatment is 12 weeks but can be extended to 24 weeks in patients who have received previous treatment with compensated cirrhosis.92

PCSK9 Inhibitors for Dyslipidemia Previous standard treatments for hypercholesterolemia relied on diet modification and use of statins. A novel class of medications— monoclonal antibodies that inhibit proprotein convertase subtilisinkexin type 9 (PCSK9)—includes evolocumab and alirocumab; similar to statins, these agents increase LDL receptor activity in the liver (see Fig. 32.4).93 In phase II and III clinical trials (Open Label Study of Long Term Evaluation Against LDL-C [OSLER-1 and OSLER-2], respectively) common adverse reactions to

evolocumab include injection site reactions, arthralgias, headache, and muscle pain leading to discontinuation of the medication in 2.4% of study patients. When compared with standard therapy, evolocumab decreased LDL cholesterol by 52%, decreased total cholesterol by 36%, and raised high-density lipoprotein cholesterol by 7%.94 Although evolocumab was successful at lowering LDL cholesterol, a follow-up study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk [FOURIER]) was performed to evaluate effects on reducing cardiovascular endpoints, such as myocardial infarction, stroke, unstable angina, or need for coronary revascularization. The combination of evolocumab plus standard statin therapy significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke by 20%, which correlated with decreases in LDL levels.95 Evolocumab is currently FDA approved for treatment of hypercholesterolemia in combination with other lipid-lowering medications (e.g., statins, ezetimibe), and is only recommended as single-agent therapy in patients diagnosed with primary hyperlipidemia, which is typically an inherited disease. It is given as a 140-mg subcutaneous injection once every 2 weeks or 420 mg monthly.96

Obeticholic Acid Nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, and insulin resistance. Behind hepatitis and alcoholic cirrhosis, is the third most common indication for liver transplantation in the United States. In 2009, 9.7% of liver transplant recipients were performed for NASH cirrhosis.97 An emerging treatment for NASH is obeticholic acid, a variant of the naturally produced bile acid chenode oxycholic acid, which activates the farnesoid X nuclear receptor, activation of which promotes insulin sensitivity and decreases hepatic lipid synthesis.98 In the FLINT (Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis) trial of patients with biopsy-proven NASH, 45% of patients treated with obeticholic acid had histologic improvement (decreased fibrosis, hepatocellular ballooning, and steatosis) on liver biopsy compared with 21% in the placebo group. The obeticholic treatment group also showed elevations in total serum cholesterol and LDL cholesterol, particularly within the first 12 weeks of initiating treatment.99 Obeticholic acid was also studied as treatment for primary biliary cholangitis in a randomized phase III clinical trial comparing obeticholic acid in combination with standard of care ursodiol. In the obeticholic acid group, 77% of patients had a reduction of at least 15% in alkaline phosphatase compared with placebo (29%). Other markers, including total bilirubin, conjugated bilirubin, gamma-glutamyl transferase; alanine aminotransferase, and aspartate aminotransferase, also showed decreases in the treatment group. Despite improvement in laboratory values, patient symptoms showed no change on questionnaire.100

Key Points • Hepatic drug metabolism takes place primarily by cytochrome P450 enzymes, where genetic variability in metabolism can affect drug plasma concentrations. • Volatile anesthetics undergo oxidative metabolism in the liver and have variable effects on hepatic blood flow.

• Individual differences in drug metabolism in the intestine and liver are common and are major contributors to differences in drug response, including adverse effects. • Proton pump inhibitors and H2-histamine receptor antagonists are effective in decreasing gastric acid secretion but have

CHAPTER 32  Liver and Gastrointestinal Pharmacology



long-term side effects, including vitamin and electrolyte malabsorption, and possible predisposition toward infections, such as C. difficile and pneumonia. • New treatments for opioid-induced constipation include methylnaltrexone and almivopan. • Statins lower plasma low-density lipoprotein cholesterol and contribute to stabilization of atherosclerotic plaque. Adverse reactions include myopathy, transient transaminase elevations, and rare hepatoxicity, rhabdomyolysis, and renal failure.

Key References Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med. 2018;44:1–11. Large metaanalysis of 57 trials with 7293 patients comparing proton pump inhibitors, H2-histamine receptor antagonists, and sucralfate for stress ulcer prophylaxis. (Ref. 61). American Society of Anesthesiologists Committee. 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 Society of Anesthesiologists Committee on Standards and Practice Parameters. Anesthesiology. 2011;114:495–511. Most recent practice guidelines by the American Society of Anesthesiologists with recommended fasting times and concurrent use of medications to prevent aspiration. (Ref. 62). Beard TL, Leslie JB, Nemeth J. The opioid component of delayed gastrointestinal recovery after bowel resection. J Gastrointest Surg. 2011;15:1259–1268. Elucidates the role of opiates and postoperative ileus, and describes current recommendations for prevention and treatment. (Ref. 66). Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–715. Current recommendations from the American Gastroenterological Association regarding best practice for long-term proton pump inhibitor use. (Ref. 55). Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362:823–832. Primary prophylaxis, treatment, and secondary prophylaxis of variceal bleeding in cirrhotic patients. (Ref. 63). Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–1888. Phase III open-label study dividing 647 patients into 3 treatment groups: ledipasvir-sofosbuvir for 8 weeks, ledipasvirsofosbuvir plus ribavirin for 8 weeks, and ledipasvir-sofosbuvir for 12 weeks, evaluating for sustained virologic response in the treatment of hepatitis C. (Ref. 91). Li H-C, Lo S-Y. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol. 2015;7:1377–1389. Explains the life cycle of the hepatitis C virus and how new direct-activing antivirals target certain parts of the virus. (Ref. 88). Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. Randomized, double-blind, placebo-controlled trial with 27,564 patients showing the efficacy of evolocumab in reducing LDL cholesterol levels and reducing risk of cardiovascular events. (Ref. 95). Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol. 2017;176:527–538. A recent review of acute porphyrias including clinical presentation, triggers and late complications. (Ref. 36)

References 1. Remmer H. The role of the liver in drug metabolism. Am J Med. 1970;49(5):61–629. doi:10.1016/S0002-934380129-2.

653

• Oral direct-acting antivirals are a new generation of hepatitis C treatments, including ledipasvir-sofosbuvir, boceprevir, telaprevir, and simeprevir. • Other novel gastrointestinal medications include vonoprazan fumarate, a reversible potassium-competitive gastric acid blocker, PCSK9 inhibitors, which increase low-density lipoprotein receptor activity in the liver, and obeticholic acid, a novel treatment for nonalcoholic steatohepatitis. 2. Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med. 2001;7:201–204. doi:10.1016/ S1471-4914(01)01986-4. 3. Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 1993;12(1):1–51. doi:10.1089/dna.1993.12.1. 4. Peterson JA, Graham SE. A close family resemblance: the importance of structure in understanding cytochromes P450. Structure. 1998;6(9): 1079–1085. http://www.ncbi.nlm.nih.gov/pubmed/9753700. Accessed March 13, 2017. 5. Smith G, Stubbins MJ, Harries LW, et al. Molecular genetics of the human cytochrome P450 monooxygenase superfamily. Xenobiotica. 1998;28(12):1129–1165. doi:10.1080/004982598238868. 6. Werck-Reichhart D, Feyereisen R. Cytochromes P450: a success story. Genome Biol. 2000;1(6):REVIEWS3003. doi:10.1186/ gb-2000-1-6-reviews3003. 7. Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther. 1995;68(3):385–424. doi:10.1016/0163-7258(95) 02013-6. 8. Murray M. Mechanisms and significance of inhibitory drug interactions involving cytochrome P450 enzymes (review). Int J Mol Med. 1999;3(3):227–238. http://www.ncbi.nlm.nih.gov/pubmed/10028046. Accessed March 13, 2017. 9. Rendic S, Di.Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29:413. 10. Lakhan R, Kumari R, Singh K, et al. Possible role of CYP2C9 & CYP2C19 single nucleotide polymorphisms in drug refractory epilepsy. Indian J Med Res. 2011;134(9):295–301. 11. Wilkinson GR. Drug Metabolism and Variability among patients in drug response. N Engl J Med. 2005;352(21):2211–2221. doi:10.1056/NEJMra032424. 12. Otton S V, Schadel M, Cheung SW, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther. 1993;54(5):463–472. http://www .ncbi.nlm.nih.gov/pubmed/7693389. Accessed March 13, 2017. 13. Hedaya MA. Extravascular routes of drug administration. In: Basic Pharmacokinetics. 2nd ed. Boca Raton, FL: CRC Press, 2012. 14. Wilkinson GR, Shand DG. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975;18(4): 377–390. 15. Peter SDS, Imber CJ, Friend PJ. Liver and kidney preservation by perfusion. Lancet. 2002;359(9306):604–613. doi:10.1016/ S0140-6736(02)07749-8. 16. Bϋdingen FV, Gonzalez D, Tucker AN, et al. Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments. Ther Adv Infect Dis. 2014;2(1):17–42. doi:10.1177/2049936113519089. 17. Grundmann U, Ziehmer M, Raahimi H, et al. Einfluß der volatilen Anästhetika Halothan, Enfluran und Isofluran auf die Leberdurchblutung beim Menschen. Anasthesiol Intensivmed Notfallmed Schmerzther. 1992;27(7):406–413. doi:10.1055/s-2007-1000324. 18. Frink EJ, Morgan SE, Coetzee A, et al. The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiol-

654

SE C T I O N V

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ogy. 1992;76(1):85–90. http://www.ncbi.nlm.nih.gov/pubmed/ 1729941. Accessed January 27, 2017. 19. Gatecel C, Losser M-R, Payen D. The postoperative effects of halothane versus isoflurane on hepatic artery and portal vein blood flow in humans. Anesth Analg. 2003;96(3):740–745. http://www .ncbi.nlm.nih.gov/pubmed/12598255. Accessed January 27, 2017. 20. Thomson IA, Hughes RL, Fitch W, et al. Effects of nitrous oxide on liver haemodynamics and oxygen consumption in the greyhound. Anaesthesia. 1982;37(5):548–553. 21. Armbruster K, Nöldge-Schomburg GF, Dressler IM, et al. The effects of desflurane on splanchnic hemodynamics and oxygenation in the anesthetized pig. Anesth Analg. 1997;84(2):271–277. http:// www.ncbi.nlm.nih.gov/pubmed/9024014. Accessed January 27, 2017. 22. O’Riordan J, O’Beirne HA, Young Y, et al. Effects of desflurane and isoflurane on splanchnic microcirculation during major surgery. Br J Anaesth. 1997;78(1):95–96. http://www.ncbi.nlm.nih.gov/ pubmed/9059215. Accessed January 27, 2017. 23. Leaman DM, Levenson L, Zelis R, et al. Effect of morphine on splanchnic blood flow. Br Heart J. 1978;40(5):569–571. http:// www.ncbi.nlm.nih.gov/pubmed/656226. Accessed March 13, 2017. 24. Dhasmana KM, Prakash O, Saxena PR. Effects of fentanyl, and the antagonism by naloxone, on regional blood flow and biochemical variables in conscious rabbits. Arch Int Pharmacodyn Ther. 1982;260(1):115–129. http://www.ncbi.nlm.nih.gov/pubmed/ 7165416. Accessed March 13, 2017. 25. Meierhenrich R, Gauss A, Mühling B, et al. The effect of propofol and desflurane anaesthesia on human hepatic blood flow: a pilot study. Anaesthesia. 2010;65(11):1085–1093. doi:10.1111/j.13652044.2010.06504.x. 26. Zhu T, Pang Q, McCluskey SA, et al. Effect of propofol on hepatic blood flow and oxygen balance in rabbits. Can J Anaesth. 2008;55(6):364–370. doi:10.1007/BF03021492. 27. Thomson IA, Fitch W, Hughes RL, et al. Effects of certain i.v. anaesthetics on liver blood flow and hepatic oxygen consumption in the greyhound. Br J Anaesth. 1986;58(1):69–80. http:// www.ncbi.nlm.nih.gov/pubmed/3942674. Accessed March 13, 2017. 28. Lawrence CJ, Prinzen FW, de Lange S. The effect of dexmedetomidine on nutrient organ blood flow. Anesth Analg. 1996;83(6):1160–1165. http://www.ncbi.nlm.nih.gov/pubmed/8942579. Accessed March 13, 2017. 29. Gelman S, Reves JG, Harris D. Circulatory responses to midazolam anesthesia: emphasis on canine splanchnic circulation. Anesth Analg. 1983;62(2):135–139. http://www.ncbi.nlm.nih.gov/pubmed/ 6829913. Accessed March 13, 2017. 30. Vagts DA, Iber T, Puccini M, et al. The effects of thoracic epidural anesthesia on hepatic perfusion and oxygenation in healthy pigs during general anesthesia and surgical stress. Anesth Analg. 2003;97(6):1824–1832. http://www.ncbi.nlm.nih.gov/pubmed/ 14633568. Accessed March 13, 2017. 31. Meierhenrich R, Wagner F, Schütz W, et al. The effects of thoracic epidural anesthesia on hepatic blood flow in patients under general anesthesia. Anesth Analg. 2009;108(4):1331–1337. doi:10.1213/ ane.0b013e3181966e6f. 32. Kharasch ED. Metabolism and toxicity of the new anesthetic agents. Acta Anaesthesiol Belg. 1996;47(1):7–14. http://www.ncbi.nlm.nih.gov/ pubmed/8651050. Accessed January 26, 2017. 33. Kharasch ED. Adverse drug reactions with halogenated anesthetics. Clin Pharmacol Ther. 2008;84(1):158–162. doi:10.1038/clpt.2008. 97. 34. Chandok N, Watt KDS. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc. 2010;85(5):451–458. doi:10.4065/mcp.2009.0534. 35. Miller RD, Eriksson LI, Fleisher LA, et al., eds. Miller’s Anesthesia. 8th ed. Philadelphia: Elsevier/Saunders; 2014. 36. Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol. 2017;176(4):527–538. doi:10.1111/ bjh.14459.

37. Gommers D, Bakker J. Medications for analgesia and sedation in the intensive care unit: an overview. Crit Care. 2008;12(suppl 3):S4. doi:10.1186/cc6150. 38. Craig RG, Hunter JM. Neuromuscular blocking drugs and their antagonists in patients with organ disease. Anaesthesia. 2009;64(s1):55–65. doi:10.1111/j.1365-2044.2008.05871.x. 39. Lee LA, Athanassoglou V, Pandit JJ. Neuromuscular blockade in the elderly patient. J Pain Res. 2016;9:437–444. doi:10.2147/JPR. S85183. 40. Appiah-Ankam J, Hunter JM. Pharmacology of neuromuscular blocking drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2004;4(1):2–7. doi:10.1093/bjaceaccp/mkh002. 41. Fujita A, Ishibe N, Yoshihara T, et al. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Acta Anaesthesiol Taiwan. 2014;52(2):54–58. doi:10.1016/j.aat.2014 .04.007. 42. Burks TF. Gastrointestinal pharmacology. Annu Rev Pharmacol Toxicol. 1976;16:15–32. https://www.dropbox.com/home/ PharmacologyGI?preview=Gastrointestinal+Pharmacology+1976. pdf. Accessed March 9, 2017. 43. Shen DD, Kunze KL, Thummel KE. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev. 1997;27(2–3):99–127. http://www.ncbi.nlm.nih.gov/ pubmed/10837554. Accessed March 13, 2017. 44. Cho H-J, Kim J-E, Kim D-D, et al. In vitro-in vivo extrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications. Drug Dev Ind Pharm. 2014;40(8):989–998. doi:10.3109/03639045.2013.83143 9. 45. Riley SA, Sutcliffe F, Kim M, et al. The influence of gastrointestinal transit on drug absorption in healthy-volunteers. Br J Clin Pharmacol. 1992;34(1):32–39. 46. Bailey DG, Spence JD, Munoz C, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet (London, England). 1991;337(8736):268–269. http://www.ncbi.nlm.nih.gov/ pubmed/1671113. Accessed March 13, 2017. 47. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000;75(9):933–942. doi:10.4065/75.9.933. 48. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol. 1998;38(1):389–430. doi:10.1146/annurev.pharmtox.38.1.389. 49. Greenblatt DJ, Harmatz JS. Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. Br J Clin Pharmacol. 2015;80(3): 342–350. doi:10.1111/bcp.12668. 50. Rodrigues RM, De Kock J, Doktorova TY, et al. Measurement of cytochrome P450 enzyme induction and inhibition in human hepatoma cells. Methods Mol Biol. 2015;1250:279–285. doi:10.1007/978-1-4939-2074-7_20. 51. Greenblatt DJ, Zhao Y, Venkatakrishnan K, et al. Mechanism of cytochrome P450-3A inhibition by ketoconazole. J Pharm Pharmacol. 2011;63(2):214–221. doi:10.1111/j.2042-7158.2010.01202.x. 52. DeVault KR, Talley NJ. Insights into the future of gastric acid suppression. Nat Rev Gastroenterol Hepatol. 2009;6(9):524–532. doi:10.1038/nrgastro.2009.125. 53. Pisegna JR, Karlstadt RG, Norton JA, et al. Effect of preoperative intravenous pantoprazole in elective-surgery patients: a pilot study. Dig Dis Sci. 2009;54(5):1041–1049. doi:10.1007/s10620-0080445-1. 54. Metz DC, Pratha V, Martin P, et al. Oral and intravenous dosage forms of pantoprazole are equivalent in their ability to suppress gastric acid secretion in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2000;95(3):626–633. doi:10.1111/j.1572-0241. 2000.01834.x. 55. Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association.



CHAPTER 32  Liver and Gastrointestinal Pharmacology

Gastroenterology. 2017;152(4):706–715. doi:10.1053/j.gastro.2017 .01.031. 56. Eusebi LH, Rabitti S, Artesiani ML, et al. Proton pump inhibitors: risks of long-term use. J Gastroenterol Hepatol. 2017;32(7):1295–1302. doi:10.1111/jgh.13737. 57. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–1917. doi:10.1056/NEJMoa1007964. 58. Howard JM, Chremos AN, Collen MJ, et al. Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology. 1985;88(4):1026–1033. doi:10.1016/ S0016-5085(85)80024-X. 59. Oates JA, Wood AJJ, Feldman M, et al. Histamine2-receptor antagonists. N Engl J Med. 1990;323(25):1749–1755. doi:10.1056/ NEJM199012203232507. 60. Memiş D, Turan A, Karamanlioglu B, et al. The effect of intravenous pantoprazole and ranitidine for improving preoperative gastric fluid properties in adults undergoing elective surgery. Anesth Analg. 2003;97(5):1360–1363. http://www.ncbi.nlm.nih.gov/pubmed/ 14570652. Accessed December 5, 2017. 61. Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med. 2018;44:1–11. doi:10.1007/s00134-017-5005-8. 62. American Society of Anesthesiologists Committee. 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. Anesthesiology. 2011;114(3):495–511. doi:10.1097/ALN.0b013e3181fcbfd9. 63. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362(9):823–832. doi:10.1056/ NEJMra0901512. 64. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20(3):157–198. doi:10.1006/frne.1999.0183. 65. Byram SW, Gupta RA, Ander M, et al. Effects of continuous octreotide infusion on intraoperative transfusion requirements during orthotopic liver transplantation. Transplant Proc. 2015;47(9):2712–2714. doi:10.1016/j.transproceed.2015.07.036. 66. Beard TL, Leslie JB, Nemeth J. The opioid component of delayed gastrointestinal recovery after bowel resection. J Gastrointest Surg. 2011;15(7):1259–1268. doi:10.1007/s11605-011-1500-3. 67. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332–2343. doi:10.1056/NEJMoa0707377. 68. Kraft M, Maclaren R, Du W, et al. Alvimopan (entereg) for the management of postoperative ileus in patients undergoing bowel resection. P T. 2010;35(1):44–49. http://www.ncbi.nlm.nih.gov/ pubmed/20182561. Accessed March 17, 2017. 69. Din SA, Naimi I, Beg M, et al. A perplexing presentation. Case Rep Gastroenterol. 2016;10(3):714–719. doi:10.1159/000452736. 70. Toyoyama H, Kariya N, Hase I, et al. The use of intravenous nitroglycerin in a case of spasm of the sphincter of Oddi during laparoscopic cholecystectomy. Anesthesiology. 2001;94(4):708–709. http://www .ncbi.nlm.nih.gov/pubmed/11379694. Accessed March 31, 2017. 71. Afghani E, Lo SK, Covington PS, et al. Sphincter of Oddi function and risk factors for dysfunction. Front Nutr. 2017;4:1. doi:10.3389/ fnut.2017.00001. 72. Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J. 2006;6(6):360–374. doi:10.1038/sj.tpj.6500384. 73. Schartl M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation. 2001;104(4):387–392. http:// www.ncbi.nlm.nih.gov/pubmed/11468198. Accessed January 8, 2018.

74. Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther. 2007;25(10):1135–1151. doi:10.1111/j.13652036.2007.03307.x. 75. Lee C. Succinylcholine should be avoided in patients on statin therapy. Anesthesiology. 2011;115(1):6–7. doi:10.1097/ALN .0b013e3182207a16. 76. Turan A, Mendoza ML, Gupta S, et al. Consequences of succinylcholine administration to patients using statins. Anesthesiology. 2011;115(1):28–35. doi:10.1097/ALN.0b013e31822079fa. 77. Di Padova C, Tritapepe R, Rovagnati P, et al. Double-blind placebocontrolled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids. Methods Find Exp Clin Pharmacol. 1984;6(12):773–776. http://www.ncbi.nlm.nih.gov/pubmed/ 6397677. Accessed January 8, 2018. 78. De Marzio DHNV. Hepatotoxicity of cardiovascular and antidiabetic medications. Lipid lowering agents. In: Kaplowitz NDL, ed. Drug-Induced Liver Disease. 3rd ed. Amsterdam: Elsevier; 2013: 519–540. 79. Zimmerman HJ. Drugs used in the treatment of hypercholesterolemia and hyperlipidemia. In: Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Philadelphia: Lippincott; 1999:660–662. 80. Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800–1808. doi:10.1056/NEJMoa1205409. 81. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon Alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med. 1998;339(21):1493–1499. doi:10.1056/NEJM199811193392102. 82. Poynard T, Regimbeau C, Myers RP, et al. Interferon for acute hepatitis C. Myers RP. ed. Cochrane Database Syst Rev. 2002;(1):CD000369, doi:10.1002/14651858.CD000369. 83. Bonkovsky HL. Therapy of hepatitis C: other options. Hepatology. 1997;26(S3):143S–151S. doi:10.1002/hep.510260725. 84. Kountouras J, Zavos C, Chatzopoulos D. Apoptosis in hepatitis C. J Viral Hepat. 2003;10(5):335–342. doi:10.1046/j.1365-2893.20 03.00452.x. 85. Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2016;55(4):409–418. doi:10.1007/ s40262-015-0326-7. 86. Otake K, Sakurai Y, Nishida H, et al. Characteristics of the novel potassium-competitive acid blocker vonoprazan fumarate (TAK-438). Adv Ther. 2016;33(7):1140–1157. doi:10.1007/s12325-016-0345-2. 87. Martinucci I, Blandizzi C, Bodini G, et al. Vonoprazan fumarate for the management of acid-related diseases. Expert Opin Pharmacother. 2017;18(11):1145–1152. doi:10.1080/14656566.2017.1346087. 88. Li H-C, Lo S-Y. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol. 2015;7(10):1377. doi:10.4254/wjh.v7.i10.1377. 89. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889–1898. doi:10.1056/NEJMoa1402454. 90. Gentile I, Buonomo AR, Borgia F, et al. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs. 2014;23(4):561–571. doi:10.1517/13543784.2014 .892581. 91. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879–1888. doi:10.1056/NEJMoa1402355. 92. Gilead. Harvoni (ledipasvir and sofosbuvir) tablets, for oral use: US prescribing information. 2017. http://www.gilead.com/~/media/Files/ pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed 28 December 2017. 93. Cicero A, Colletti A, Derosa G. Retargeting the management of hypercholesterolemia – focus on evolocumab. Ther Clin Risk Manag. 2016;12:1365–1376. doi:10.2147/TCRM.S116679.

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SE C T I O N V

Gastrointestinal and Endocrine Systems

94. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–1509. doi:10.1056/NEJMoa1500858. 95. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722. doi:10.1056/NEJMoa1615664. 96. Amgen. Repatha (evolocumab) injection, for subcutanous use: US prescribing information. 2017. http://pi.amgen.com/~/media/amgen/ repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf. Accessed January 4, 2018. 97. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249–1253. doi:10.1053/j. gastro.2011.06.061. 98. Arrese M, Cabrera D, Barrera F. Obeticholic acid: expanding the therapeutic landscape of NASH. Ann Hepatol. 2015;14(3):430–432. http://www.ncbi.nlm.nih.gov/pubmed/25864227. Accessed January 4, 2018. 99. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, randomised,

placebo-controlled trial. Lancet. 2015;385(9972):956–965. doi:10.1016/S0140-6736(14)61933-4. 100. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–643. doi:10.1056/NEJMoa1509840. 101. Isoherranen N, Lutz JD, Chung SP, et al. Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol. 2012;25(11):2285–2300. doi:10.1021/tx300192g. 102. Rane A, Wilkinson GR, Shand DG. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J Pharmacol Exp Ther. 1977;200(2):420–424. http://www.ncbi.nlm.nih.gov/ pubmed/839445. Accessed May 4, 2017. 103. Huet PM, Villeneuve JP. Determinants of drug disposition in patients with cirrhosis. Hepatology. 1983;3(6):913–918. http:// www.ncbi.nlm.nih.gov/pubmed/6629320. Accessed May 4, 2017. 104. Le Couter DJ, McLean AJ. The aging liver. Clin Pharmacokinet. 1998;34(5):359–373. 105. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–1161. doi:10.1007/s00228-008-0553-z.

33 

Nutritional and Metabolic Therapy DEREK K. ROGALSKY AND ROBERT G. MARTINDALE

CHAPTER OUTLINE Fasting in the Perioperative Period Benefits of Early Enteral Feeding Timing of Nutrient Delivery Pharmaconutrition-Immunonutrition Specific Nutrients Glutamine Clinical Outcome Studies Using Glutamine Arginine Clinical Outcome Studies Using Arginine Recommendations Regarding Delivery of Arginine Omega-3 Fatty Acids Clinical Outcome Studies Using 20 and 22 Carbon Omega-3 Fatty Acids Recommendations Regarding Delivery of Omega-3 Fatty Acids Timing of Delivery of Nutrients as Pharmacologic Agents Use of Protocols Enhance Safe Delivery of Nutrients Emerging Developments New Malnutrition Definitions and Other Nutrients Probiotics Conclusion

M

acronutrients have traditionally been regarded as a means to satisfy basic energy needs for cellular homeostasis, while amino acids are considered necessary for anabolism and protein synthetic machinery of the cell. Surgical, traumatically injured, and critically ill patients, however, are in a dynamic state between systemic inflammation, immune suppression, and persistent chronic inflammatory states.1 It often takes weeks or months for the inflammatory states resulting from major surgical intervention or intensive care unit (ICU) admission to resolve. Nutrition plays an integral and ever-changing role in both sustaining life and modifying critical illness. Many factors will influence the duration and severity of the hyperdynamic inflammatory state, including preoperative nutritional optimization of the patients, timing of surgery or injury, the anesthesia and sedation provided, and the provision of appropriate postoperative nutrition to both support a patient’s macronutrient needs and modify the inflammatory status. As a result of a recent elucidation of metabolic pathways from tracer technology, gene regulation, proteomics, and genomics, the

basic science and clinical research supporting the benefits of supplemental specific nutrients have increased exponentially.2–6 Although it has long been realized that preoperative malnutrition is a risk factor for poor wound healing,7 perioperative complications,8 and even mortality,9 the most common anesthetic consideration is fasting status. While gastric volume and pH at the time of induction of anesthesia affect the risk of aspiration of stomach contents, other aspects of a patient’s nutritional state will significantly influence the patient’s outcome and that patient’s ability to tolerate the procedure. Indeed, the paradigm of many hours of preoperative fasting has been challenged in multiple ways, with an aggressive trend to minimize periods of “fasting.”

Fasting in the Perioperative Period Time elapsed from last oral intake is perhaps the most immediate and relevant issue regarding how nutrition affects the delivery of anesthesia to patients. The risk of aspiration on induction presents a severe, potentially modifiable risk to patients, such that the American Society of Anesthesiology promulgates fasting guidelines for patients undergoing elective procedures requiring anesthesia. The most recent 2017 guidelines recommend fasting times for clear liquids of 2 or more hours, 4 or more hours for breast milk, 6 or more hours for a light meal, and eight or more hours for a fatty meal, prior to undergoing general anesthesia, regional anesthesia, or sedation.10,11 With the emergence of Enhanced Recovery After Surgery (ERAS) pathways, there has been renewed interest in nutritional optimization in the immediate perioperative period. The thought that major elective surgery is stressful and strenuous has led investigators to question whether preoperative carbohydrate loading might improve outcomes. In a recent meta-analysis, Amer et al. showed that a carbohydrate load of at least 10 g of glucose within 4 hours of surgery conferred a small, but real benefit in hospital length of stay (LOS) when compared to fasting.12 It appears that “carbo loading” may yield attenuation of the insulin resistance associated with the surgical insult.13 If not for the risk of aspiration, might it be optimal to continue nutrition through the surgical period? While it is standard care to continue parenteral nutrition (PN) through surgery, as there is no increased risk for aspiration, best practices for enteral nutrition (EN) are still the subject of debate and research. It is clear that there are certain populations of patients who benefit from EN up to and during surgical interventions. In critically injured burn patients, it has become common practice at many centers to feed through operations with significant improvement in total calories delivered.14 Feeding up to and through surgery has also been reported in orthopedic procedures and has recently been extended to other 657



CHAPTER 33  Nutritional and Metabolic Therapy 657.e1

Abstract

Keywords

The field of surgical and critical care nutrition has evolved beyond the basic provision of macronutrients to sustain metabolism into a discipline that treats and modifies disease states with immunonutrients and timely provision of macronutrients to modulate deranged physiology. Evidence-based, multidisciplinary, and protocol-driven nutritional interventions have proven effective in improving outcomes in surgical and critically ill patients. A mastery or at least understanding of the principles of nutrition therapy are in integral part of the practice of anesthesia, surgery, and critical care medicine.

perioperative fasting enteral feeding nutrient delivery immunonutrients nutrition protocols

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surgical groups.15 There are also data to suggest that continuing postpyloric tube feeding in the critically ill intubated patient presenting for nonabdominal surgery does not increase the incidence of aspiration, suggesting that EN can be safely continued in the perioperative period.16

Benefits of Early Enteral Feeding Early EN in the ICU has myriad reports explaining the diverse mechanisms to support the observed benefits (Table 33.1). The gastrointestinal tract comprises the largest immune organ in the body and is responsible for the production of over 80% of the immunoglobulin transported to extraintestinal sites. The ability of the gut to function appropriately as an immune organ is dependent on the maintenance of both structural and functional integrity. The integrity of the gut, in turn, is greatly dependent on continued exposure to luminal nutrient substrates. Both adaptive and innate immune defenses are active in this process. Innate mechanisms are dependent on epithelial tight junctions and secretory capabilities of the mucosa. Secretory immunoglobulin A (IgA) is an important component of the adaptive immune system, as antigens are tagged and presented to dendritic cells within Peyer patches, which are in highest concentration in the distal small bowel. Gut disuse over a period of as little as 5 days has been shown to dramatically decrease the mass of gut-associated lymphoid tissue (GALT) and the production of secretory intestinal IgA.4,5,17 These changes are completely reversed with reinstitution of EN therapy.6 Increases in intestinal permeability have been shown to correlate with the development and severity of multi-organ failure (MOF) syndrome.3,18 Using EN to modify the severity of the systemic inflammatory responses by attenuating metabolic and oxidative stress is a primary goal of nutritional therapy in the surgical or critically ill patient.19,20

Timing of Nutrient Delivery The optimal time to start nutrition support is influenced by a host of factors, including age, premorbid conditions, route of nutrient delivery, metabolic state, and organ perfusion and function.21,22 As previously noted, literature evaluating nutritional support for critically ill patients has analyzed heterogeneous populations. Nevertheless, these diverse studies provide a foundation to guide nutritional therapy in a wide range of ICU patient types (e.g., burn, trauma, abdominal surgery, oncologic surgery, and so on).23,24

The reported physiologic benefits of early EN are, among others, prevention of adverse structural and functional alterations in the mucosal barrier, augmentation of visceral blood flow, and enhancement of local and systemic immune response.25,26 The clinical benefits of early EN, defined as within 24 to 48 hours of ICU admission, include reduced infectious morbidity, LOS, and, in some reports, reduced mortality, all with minimal risk of harm to the patient.27–31 Despite these acknowledged benefits, nutrition delivery remains suboptimal in a significant percentage of critically ill patients.32,33 Acknowledging that the early initiation of nutrition support constitutes best practice, a multidisciplinary approach to determining appropriate timing in the individual patient cannot be overemphasized. Enteral feeding should not proceed until appropriate resuscitation has been undertaken (Table 33.2). Early resuscitation remains a cornerstone of ICU therapy. Early and aggressive resuscitation, or “early goal-directed therapy,” involves the placement of invasive lines for monitoring, drug delivery, and volume resuscitation, with vasopressors if the patient fails to respond appropriately to volume expansion.34 While there is no one laboratory or hemodynamic parameter signaling the successful resuscitation of the critically ill patient, trends in hemodynamic parameters—including mean arterial pressures, central venous pressures, and pressor requirements in conjunction with urine output, arterial base deficit, serum lactate, and venous oxygen saturations—are utilized in order to determine the relative success of resuscitation. Splanchnic circulation can increase by as much as 40% to 60% in the setting of enteral feeding. The specific actions of digestion and absorption increase the metabolic demand and oxygen utilization by the gastrointestinal tract.35 If supply falls short of demand, rare but devastating complications, such as nonocclusive mesenteric ischemia (NMI), can ensue (Fig. 33.1). Fortunately, nonocclusive mesenteric ischemia is a very rare complication, but since its effects can be devastating, with mortality rates reported as high as 80%,36 enteral feeding in the hemodynamically unstable patient should be undertaken with extreme caution.24 Following adequate resuscitation and assuming that no other absolute contraindication to enteral feeding exists (e.g., bowel obstruction), enteral support should be initiated as soon as possible,

TABLE Considerations Before Any Nutritional 33.2  Intervention, Either Enteral or Parenteral, in

Intensive Care Unit Settings

TABLE 33.1  Metabolic Benefits of Early Enteral Feeding Attenuates inflammatory response to stress/critical illness Prevents mucosal atrophy, loss of gut barrier Luminal delivery maintains GALT and MALT Supports systemic immune response Helps maintain normal gut bacterial flora (microbiome) Decreases insulin resistance, better glycemic control Maintains vagal-mediated antiinflammatory reflex Luminal (portal) nutrient delivery allows for hepatic first-pass metabolic effects More balanced nutrient delivery possible when compared to parenteral nutrition GALT, Gut-associated lymphoid tissue; MALT, mucosal-associated lymphoid tissue.

Optimize Timing and Intensity of Resuscitation Correct volume deficits, electrolytes, acid–base disorders. Obtain infection source control if it is in question.

Institute Antibiotic Therapy as Indicated Early, aggressive broad-spectrum antibiotics, then deescalate as cultures become available.

Attempt to Maximize Visceral Perfusion Prevents loss of gut mucosal integrity.

Consider Specific Organ Support as Indicated Examples: pulmonary, renal, cardiac, hepatic

Maintain Glycemic Control Intravenous insulin drips (protocols) to maintain glycemic control in range of 140–80 mg/dL

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Severe metabolic stress

659

Impaired esophageal peristalsis Lower GES pressure

Increased catecholamines

Increased vasoconstriction

Reduced mucosal blood flow

↓ Cardiac output

Splanchnic hypoperfusion

Barrier disruption

Altered GI motility

Hypovolemia

Proinflammatory cytokine release

Changes in bacterial flora and virulence

Barrier dysfunction, MODS, worsening sepsis

• Fig. 33.1  Pathophysiology of splanchnic hypoperfusion often associated with critical illness. GI, Gastrointestinal; MODS, multiple organ dysfunction syndrome. (Modified from Schmidt H, Martindale R. The gastrointestinal tract in critical illness: nutritional implications. Curr Opin Clin Nutr Metab Care. 2003;6:587–591; and Mutlu GM, et al. GI complications in patients receiving mechanical ventilation. Chest. 2001;119:1222–1241.)

regardless of the status of traditional markers of bowel function (bowel sounds, flatus, passage of stool). Numerous reports support the concept that the initiation of EN should not be delayed while waiting for evidence of bowel function, though the absence of the clinical markers of bowel function may be predictive of worse patient clinical outcomes and higher rates of EN intolerance.37 The approach of waiting for these signs leads to unnecessary delays in feeding. In a randomized trial, oral feeding initiated within 48 hours of gastrectomy, without waiting for traditional predictors of feeding tolerance (e.g., passing flatus) demonstrated the safety of the approach.38 There was no increase in morbidity, and there was a reduction in LOS. A recent meta-analysis, examining 15 studies and 1240 patients with gastrointestinal anastomoses, demonstrated reduced postoperative complications when feeding was initiated within 24 hours of operation.31 Other meta-analyses, specifically in ICU and trauma patients, report a significant decrease in mortality and infectious complications.18,39 Recent approaches to maximize gut function in the postoperative and critical care settings include maintenance of visceral perfusion; glycemic control; electrolyte correction; early EN; and minimization of medications that alter gastrointestinal function, such as anticholinergic agents, opioids, and high-dose vasopressors.37 Gastrointestinal intolerance should be continually reassessed, as it can manifest clinically in a variety of forms, including acidosis, abdominal distension, increased gastric residual volumes or nasogastric output, abdominal pain, or diarrhea. The segmental contractility of the gastrointestinal tract should be considered, as dysmotility can be focal (affecting predominantly either the proximal or distal bowel) or diffuse. Impaired gastric and proximal gastrointestinal motility (Fig. 33.2) can be overcome rather efficiently through the placement of postpyloric feeding tubes. Postpyloric tubes can be successfully placed at the bedside in greater than 80% of patients.40

Increased pyloric tone Increased PPW

Gastric stasis Multiple etiologies

Antral hypomotility

• Fig. 33.2  Mechanisms involved in gastric dysmotility in the intensive care unit population. GES, Gastroesophageal sphincter; PPW, pyloric pressure wave. (Modified from Caddell KA, Martindale R, McClave SA, et al. Can the intestinal dysmotility of critical illness be differentiated from postoperative ileus? Curr Gastroenterol Rep. 2011;13:358–367.)

Prokinetic agents can be used early and are helpful in some patients. Erythromycin acts on motilin receptors, resulting in increased motility, and can be used on a short-term basis but is limited due to tachyphylaxis. Metoclopramide, a 5-hydroxytryptamine (5HT4) receptor agonist, works via cholinergic stimulation and is primarily efficacious in the proximal gut. When using metoclopramide (see Chapter 32), one must also consider the potential for extrapyramidal side effects, especially in patients with altered mental status from traumatic head injury or cerebral vascular events. Alvimopam (see Chapters 17 and 18), a peripherally acting µ-antagonist, has demonstrated some success in the setting of dysmotility associated with opioid administration in the postoperative setting.41 No single prokinetic agent will have uniform success in the ICU, and the factors contributing to gastrointestinal dysmotility in each patient must be considered. Caution should be taken when using prokinetic agents on patients at high risk for bowel necrosis or obstruction. Early EN is best accomplished in the ICU and postoperative settings, using standardized protocols.25,42 Protocolizing early enteral feedings in appropriately selected patients can reduce duration of mechanical ventilation, infectious complications, hospital LOS, and mortality.43

Pharmaconutrition-Immunonutrition In 1794, John Hunter described in his book, A Treatise on Blood, Inflammation and Gunshot Wounds, A Mechanism of Inflammation, an observation that “many types of injury produce a similar inflammation.”44 Similarly, in 1904, Sir William Osler stated, “except on few occasions the patient appears to die from the body’s response to infection rather than from it.” These two extremely insightful and prophetic comments were both made over 100 years ago. The current strategy in the ICU of using nutrition therapy to modulate inflammation and immune response in the surgical, traumatically

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Muscle unloading in the ICU

Protein degradation

↓ Specific force

Apoptosis

Synthesis

↓ Muscle mass

Generalized weakness

• Fig. 33.3  Explanation for muscle loss during unloading of muscle in the intensive care unit. These effects culminate in prolonged, generalized muscle weakness. Weakness lasts for weeks to months; up to 50% of survivors do not return to pre-ICU function at 1 year.

injured, and critically ill populations is now widely accepted. This strategy of nutrition therapy, sometimes called pharmaconutrition or immunonutrition, uses specific nutrients to attenuate or control the body’s metabolic response to stress and trauma rather than allowing systemic inflammatory response syndrome (SIRS) to progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The metabolic response to stress that can ultimately lead to PICS has been well described,45 which includes a hyperdynamic cardiac and pulmonary state, insulin resistance, hyperglycemia, accelerated protein catabolism from muscle, poor adaptation to starvation, and increased oxidative stress. Unabated, the metabolic response to stress can culminate in immune suppression.46 During this hyperdynamic phase of critical illness, surgery, or trauma, the loss of lean body mass continues, despite delivery of seemingly adequate enteral or parenteral protein and calories. In effect, administration of standard “calories and protein” to the hyperdynamic patient will not reverse the adverse effects of ongoing loss of lean body tissue. The hyperdynamic induced loss of lean body tissue is made worse by “muscle unloading” (Fig. 33.3). Several reports have now shown that using specific nutrients— such as fish oils, selected amino acids (e.g., arginine, glutamine, leucine), antioxidants, and nucleic acids—in quantities greater than necessary for “normal” metabolism has resulted in multiple outcome benefits, including shortened length of ICU and hospital stays, decreased incidence of infections, and reduced mortality in some cases.24,47,48 A wide range of select specific nutrients have been reported to benefit the critically ill patient when delivered at pharmacologic quantities. Many of these compounds are now considered to be therapeutic agents in the management of complex, catabolically stressed patients (Table 33.3). A collaboration between the Society of Critical Care Medicine (SCCM) and the American Society of Parenteral and Enteral Nutrition (ASPEN) resulted in Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient, which has been recently updated. These guidelines summarize the available evidence, and recommend that postoperative surgical ICU patients and patients with traumatic brain injury benefit from EN with immunomodulating formulas. Several immune and/or metabolic modulating enteral formulas are now available globally. These products contain a variable quantity of nutrients identified and reported as beneficial during critical illness. Well over 100 prospective randomized human trials have

TABLE Nutrients/Compounds Reported to Have 33.3  Immune and/or Metabolic Activity Arginine* Boswellia Caffeine Capsaicin Carnitine Chamomile Creatine Curry paste Cysteine Echinacea Garlic

Ginger Glucosamine Glutamine* Glutathione Leucine* Licorice Probiotics Omega-3 FA (EPA/DHA)* Resveratrol Saffron

Selenium* Shark cartilage Taurine Threonine Tumeric Vitamin C* Vitamin E* Willow bark Zinc*

DHA, Docosahexaenoic acid; EPA, eicosapentaenoic acid; FA, fatty acid. These compounds have all been reported to alter metabolic or immune function in human models. The majority of data is with vitamins E and C, trace mineral zinc and selenium, the amino acids, glutamine, arginine, and leucine, in addition to the fish oils (indicated with asterisk).

been conducted with different combinations of these immune and metabolic modulating nutrients in various ICU, surgical, and medical populations. A wide range of methodologic quality is observed in these studies from relatively small, poorly designed studies to large prospective randomized clinical trials with intentionto-treat analysis. Most of the larger studies have been extensively analyzed and methodologically scrutinized by numerous reviewers. Despite the heterogeneity of the study designs, the majority of these studies report a clear benefit of reduced intensive care and hospital LOS, decreased antibiotic use, and reduced rates of infection.24,49 In particular, evidence cited in ASPEN/SCCM Guidelines suggests clinical effects of specific pharmaconutrients. These nutrients—including glutamine, fish oils, and arginine—have been credited with a reduction in infections and LOS in surgical patients. They produce a similar favorable impact on these outcomes in other ICU populations, although less dramatic benefit is noted.

Specific Nutrients For decades, amino acids were believed to modulate intermediary metabolism, but the clinical outcome benefits of specific amino acids have only been reported over the last 15 years. Dietary supplementation with the amino acids glutamine, arginine, and leucine has been the focus of the majority of clinical trials, but other amino acids—specifically, glycine, taurine, citrulline, and glutamate—have received interest recently. 50 This chapter will present only a brief summary of amino acid and Omega-3 fatty acid supplementation.

Glutamine Since the early 1980s, glutamine has gained popularity in the critical care and surgical arena, following reports of its wide range of metabolic and outcome benefits, from decreasing mortality in critical care and trauma to enhancing mood in psychiatry.51 Although little controversy exists over the potential benefits of glutamine in the surgical setting, there is still some doubt about the need for routine supplementation in all ICU populations.52 Glutamine is a nonessential amino acid that can be synthesized in most tissues of the body.53 Skeletal muscle, by virtue of its mass,



produces the majority of endogenous glutamine. During major catabolic insults, demand for glutamine outstrips the endogenous supply, resulting in its designation as a conditionally essential amino acid. Glutamine serves as the primary oxidative fuel for rapidly dividing tissues, such as the small bowel mucosa, proliferating lymphocytes, and macrophages.54 Glutamine has numerous roles in intermediary metabolism, including maintenance of acid–base status, as a precursor of urinary ammonia, and in interorgan nitrogen transfer for the biosynthesis of nucleotides, amino sugars, arginine, glutathione, and glucosamine.55,56 During periods of stress, glutamine can provide the carbon skeleton for gluconeogenesis and is the primary substrate for renal gluconeogenesis.55 In addition to the proposed benefits described earlier, glutamine supplementation has recently been shown to be effective in decreasing peripheral insulin resistance in stressed human and other mammalian models.57–59 In addition, glutamine supports optimal gut growth and repair and decreases sepsis and other infectious conditions. Further, glutamine enhances nitrogen balance and supports endogenous antioxidant functions via nuclear factor kappa B (NFkB) and glutathione.60 There is a rapidly growing volume of human data regarding the use of parenteral and enteral glutamine supplementation.61 There is little dispute that administration by the parenteral route as a dipeptide currently yields a better clinical outcome than the enteral route in the ICU population.62 The majority of enterally delivered glutamine, estimated at 70% to 80%, is metabolized in the viscera, with only a fraction reaching the systemic circulation. Despite this, outcome benefits have been reported with the delivery of enteral glutamine.61,63 As a result of the constraints by the US Food and Drug Administration, parenteral glutamine is not readily available in the United States. Intravenous glutamine is widely used by much of the world in the form of glutamine dipeptide.64 In animal models and limited human experience, supplemental glutamine has been shown to enhance intestinal adaptation after massive small bowel resection65 and to attenuate intestinal and pancreatic atrophy.56 Glutamine appears to maintain gastrointestinal tract mucosal thickness, stabilize DNA and protein content, and reduce bacteremia and mortality after chemotherapy and following sepsis or endotoxemia.58,61 Glutamine has also been reported to enhance glutathione synthesis, the primary endogenously produced antioxidant in mammalian species.59 One additional mechanism grounded in basic science literature explaining some of the benefits observed with glutamine supplementation is the induction of heat shock proteins (HSPs; HSP-70, HSP-32, HSP-27), which are critical to the cell’s ability to survive injury and attenuate SIRS during critical illness.66–69 HSPs are a family of highly conserved cellular cytosolic chaperone proteins involved in cell protection during various metabolic stressors.70 They assist in cellular recovery following injury and partially protect the cell and involved organ from subsequent failure.68

Clinical Outcome Studies Using Glutamine In humans undergoing surgical stress, glutamine-supplemented PN appears to help maintain nitrogen balance and the intracellular glutamine pool in skeletal muscle tissue.71 In trauma patients, a reduction in pneumonia by over 50% has been demonstrated with glutamine supplementation when compared to an isonitrogenous, isocaloric control.63 In critically ill patients, glutamine supplementation has been shown to attenuate villous atrophy and the increased intestinal mucosal permeability associated with parenteral nutrition.72,73 In a randomized blinded trial of 84 critically ill patients, of which 71% were septic on admission, parenteral glutamine

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supplementation showed significant improvement in mortality at 6 months.74 PN supplemented with glutamine has also resulted in fewer infections, improved nitrogen balance, and significantly shorter mean hospital LOSs in bone marrow transplantation patients.75 Oral glutamine supplementation reduced the severity and decreased the duration of stomatitis that occurred during chemotherapy in bone marrow transplant patients.76 Glutamine supplementation at the level of 30 g/d in esophageal cancer patients undergoing radiation was associated with preserved lymphocyte response and decreased gut permeability.77 In a multicenter, prospective, blinded trial involving 114 ICU patients with multiple trauma, complicated surgery, or pancreatitis, total PN supplemented with the dipeptide L-alanyl-L-glutamine was compared to L-alanine + L-proline control. The glutamine supplemented group had significantly fewer infections, decreased incidence of pneumonia, and better glycemic control.64 In 2002, a meta-analysis evaluating the use of glutamine in the ICU population concluded that in surgical patients, glutamine supplementation may be associated with a reduction in infectious complication rates and shorter LOS.78 Large multicenter trials using glutamine have recently been published with mixed results, depending on dosing concentrations, patient heterogeneity, and route of delivery.62,79 A large multicenter trial in the United Kingdom in which patients received 20 g/d resulted in no benefit in reducing infections, LOS, and modified Sequential Organ Failure Assessment (SOFA) score.79 In the Scandinavian glutamine trial, in which glutamine dipeptide was delivered at a dose of approximately 0.3 g/kg/d, there was a reduced mortality benefit in those patients who received glutamine for greater than 3 days.62 Trials in enteral glutamine continue, notably the RE-ENERGIZE Study (RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury), which is ongoing.80

Arginine Arginine is considered a nonessential amino acid under normal physiologic conditions of cell growth and development. Arginine becomes conditionally essential in the stressed mammalian host and plays a significant role in the intermediary metabolism of the critically ill patient.81 Key contributions of arginine include it being a secretagogue for the release of growth hormone, prolactin, and insulin, as well as stimulation of proliferation and activation of T cells.82,83 L-Arginine is available to the host from endogenous synthesis as part of the urea cycle (via citrulline conversion in the kidney), from endogenous protein breakdown, and from dietary protein sources (Fig. 33.4). A typical western diet only contributes about 20% to 25% of total arginine. Arginine is a prominent intermediate in polyamine synthesis (one of the primary regulators of cell growth and proliferation), proline synthesis (wound healing and collagen synthesis), and is the only biosynthetic substrate for nitric oxide (NO) production from the three isoforms of nitric oxide synthase (eNOS, iNOS, nNOS). NO is a potent intracellular signaling molecule influencing virtually every mammalian cell type. Arginine also serves as a potent modulator of immune function via its effects on lymphocyte proliferation and differentiation,53,82 as well as its benefits in improved bactericidal action via the arginine NO pathway. The de novo synthesis and dietary intake is reduced in acute surgical and major metabolic insults. Following these insults, immature cells of myeloid origin are present in the circulation and lymph tissue; these cells express high levels of arginase-1,

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Metabolic Routes of Arginine

Food Breakdown of body protein

L-Arginine

Fumarate

Urea

iNOS Arginase

ASL Arginino succinate

Nω-hydroxy-L-Arginine

ASS

Aspartate

L-Ornithine

OTC

L-Citrulline

Carbamyl phosphate

+ NO LUNG AIR

NO

NO ↓ BLOOD NO2–/NO3–

KIDNEY NO3–

URINE

• Fig. 33.4  Metabolic pathways for arginine. In critical illness, the exogenous supply of L-arginine is reduced and endogenous demand is increased by increases in arginase and iNOS activity. Reduced levels of L-arginine lead to T-cell dysfunction and impaired immune responses, resulting in infection. ASL, Arginosuccinate lyase; ASS, arginosuccinate synthase; NO, nitric oxide; NO2−, nitrate; NO3−, nitrate; iNOS, inducible nitric oxide synthase; OTC, ornithine transcarbamylase. an enzyme that degrades arginine to ornithine. While exogenous and endogenous supply of arginine is decreased, the host’s cellular demand for arginine is increased. This accelerated demand for arginine in the settings of trauma, surgery, sepsis, and critical illness is driven mainly by the upregulation of arginase in several tissue beds (arginase I and arginase II) yielding urea and ornithine and of iNOS yielding NO and citrulline.53,84 This state of relative arginine deficiency is manifested in the suppression of T-lymphocyte function and proliferation. Other signs of T-cell dysfunction after surgery or trauma include a decrease in the number of circulating CD4 cells, increased production of interleukin-2 and interferon gamma, and the loss of the zeta chain peptide, which is essential in the T-cell receptor complex. These changes in arginase activity result in impaired immune function at multiple levels of the immune response.85 This defect in immunocompetence can contribute to an increased risk of infection for critically ill patients. Making generalized statements about amino acid metabolism in critical care is extremely difficult because the ICU population is such a heterogeneous group. Without strong scientific evidence validating the toxicity or benefits of today’s most popular dietary supplements, let alone an amino acid with the metabolic complexity of arginine, making global recommendations is naïve. Both animal and human data are available to support arguments for and against the use of supplemental arginine in the ICU populations. These results will strongly depend on dose given, model chosen to study, and duration of therapy. Trends are beginning to show the majority

of the literature supporting use of arginine supplementation in both medical and surgical populations.28,86

Clinical Outcome Studies Using Arginine Of all the pharmaconutrients, arginine has prompted the most controversy. The theoretical concept that arginine may pose a threat to the surgical or critically ill patient is mainly based on the perception that postoperative or septic surgical patients are often hemodynamically unstable, with upregulated iNOS enzyme activity. Consequently, by delivering supplemental arginine in metabolic states of upregulated iNOS, an increase in NO will result in vasodilation and hypotension, leading to even greater hemodynamic instability and organ dysfunction.87 This hypothesis has not held up in clinical practice; a nonselective NOS inhibitor was administered in high doses to counteract vasodilation and hypotension in patients with severe sepsis in septic shock. The 28-day mortality rate was significantly increased when compared to patients receiving placebo (5% dextrose), 59% versus 49%, respectively (P < 0.001).83 In fact, in this study, the highest mortality occurred within 72 hours in the treatment group. An alternate, equally valid hypothesis would be that controlled vasodilation would be beneficial in critical illness and sepsis. Shock, by definition, is inadequate delivery of oxygen and nutrients to maintain normal tissue and cellular function.87 It is logical to think that the vasodilation resulting from supplemental arginine is a cellular adaptive mechanism attempting to increase delivery of oxygen to the cell. This concept was illustrated



in a study in which investigators attempted to modulate asymmetricdimethylarginine (ADMA) in septic patients by tight glycemic control but was unsuccessful in altering the course of sepsis. As with other studies, the investigators were left to question whether the effect of an endogenous inhibitor of NOS synthases is preferable to potentially beneficial effects of arginine.88,89 ADMA has been shown to increase in states of inflammation in acute infections and other stress models and has been well described.89 It has been suggested that an imbalance of arginine and ADMA is associated with altered endothelial cell function and cardiac dysfunction. Some investigators reported that elevated arginine and lower ADMA resulted in improved mortality in septic patients.90 A lower ratio of arginine to ADMA resulted in poor organ perfusion and decreased cardiac output. Until recently, few studies had evaluated supplemental arginine as a single agent in the critically ill and septic patient population. An elaborate series of tracer studies in a clinical trial dealing with citrulline and arginine metabolism in septic patients has shed light on this controversy.91 The complex metabolic alterations noted in sepsis that contribute to reduced citrulline and arginine availability suggest that supplemental arginine may, in fact, be beneficial in the septic population. In another study using tracer technology, investigators evaluated arginine in sepsis and also concluded that arginine may be deficient in sepsis because of inadequate de novo synthesis.92 Arginine is perhaps the most controversial of the immunomodulating nutrients, but it is important to reiterate that investigations examining the physiologic impact of arginine and its related enzymes, the NOSs, have been conducted in different critically ill populations (medical vs. surgical, severely septic vs. nonseptic, and so on) using variable dosing, making generalizations to all ICU populations difficult. Current expert opinion suggests that there may be subgroups of patients whose vascular function is improved by L-arginine supplementation and there may be other subgroups of patients who simply do not benefit from L-arginine dietary supplementation. At this time, the ASPEN/SCCM 2016 guidelines do not recommend routine arginine supplementation for medical ICU patients, but do recommend its routine use in surgical and trauma patients, including those with traumatic brain injury. Arginine dose and patient selection are likely important factors affecting any study outcome.93 Arginine is available to the host from numerous sources. “Normal” arginine intake for a western diet is between 5 and 7 g/d, while endogenous production of arginine is estimated at 15 to 20 g. Studies using different doses of arginine, from 5 to 30 g/d in the normal host, have shown varying results. It appears that orally delivered arginine supplementation up to 30 g/d is safe, with few gastrointestinal side effects.50,83 The current routinely used critical care enteral formulas deliver between 0 to 18.7 g of supplemental arginine per liter of formula. It is estimated that, on average, an ICU patient receiving arginine supplemented enteral feeding at prescribed rates would receive between 15 to 30 g/d of supplemental arginine. Several factors must be considered when deciding if arginine fits into the therapeutic plan of the critically ill patient. One must evaluate organ systems involved, timing of nutrient delivery, and location and route of delivery and, interestingly, coadministration without other “immune” or “metabolically” active agents (e.g., fish oils or nucleic acids). In very different models, several studies have both shown that delivery of an omega-3 fatty acid (FA) with arginine will significantly alter the arginine metabolism via arginase and iNOS, possibly yielding more available arginine.94,95 Ornithine alpha-ketoglutarate (OKG) and citrulline are other nutrients that have been reported to have potential

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interaction with arginine. Citrulline is poorly metabolized by the liver, essentially bypassing the first-pass hepatic nutrient metabolism, making it highly bioavailable via oral route. Citrulline is then converted to arginine in the kidney, making citrulline a key component in arginine homeostasis, especially in the critically ill population.84 Ultimately, it can be difficult to tease out the separate effects, as immunonutrients are often given together with overall good clinical outcomes in both critically ill patients and those who are not critically ill.27,96 The appropriate arginine level and supplemental dose of arginine in the critically ill or hypermetabolic patient in which a proinflammatory state exists is difficult to determine and remains to be defined. Arginine is very tightly regulated within the cell by multiple mechanisms—including regulation of arginine membrane transporters, as well as arginase and NOS enzymatic activity—and the colocalization of enzymes in the membrane leads to variable concentration within the intracellular space.84 Arginine appears safe and beneficial in the levels delivered by commercially available formulations containing supplemental arginine. It is clear that additional research is needed on the influence of arginine in specific populations, specific disease conditions, and the gene–nutrient interactions.

Recommendations Regarding Delivery of Arginine It appears from review of human data that arginine is safe and beneficial at doses delivered in immune and metabolic modulating formulas for most all hemodynamically stable ICU populations able to tolerate enteral feeding. This would include medical and surgical ICU patients, trauma patients, major surgical patients, and those post-myocardial infarction or with pulmonary hypertension. Elective major surgical patients across multiple surgical specialties can be expected to benefit from a reduction of surgical infections when arginine-containing formulations are applied in the perioperative setting.49

Omega-3 Fatty Acids Although lipids are a mainstay in nutritional therapy for the critically ill and surgical populations and numerous choices exist (Table 33.4). Controversy still exists regarding lipid digestion, absorption, and utilization in hyperdynamic surgical settings.97,98 The heterogeneous nature of the ICU population makes lipid administration in these groups somewhat challenging. Although uncertainty exists on which lipid formulation to deliver, there is no debate regarding the need to meet the essential FA and cellular oxidation requirements. The use of lipids in this manner replaces malabsorbed lipid nutrients and serves as a daily source of calories shown to be equally nitrogen sparing with glucose when administered continuously for 4 days.99 The beneficial antiinflammatory effects of n-3 FAs, primarily eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA, respectively), have been well documented in several chronic inflammatory diseases, including rheumatoid arthritis, Crohn disease, ulcerative colitis, lupus, multiple sclerosis, and asthma (see Table 33.4).59,100–102 In addition to the use of antiinflammatory lipids in the setting of chronic illness, the use of specific antiinflammatory lipid substrates in the acute hyperdynamic setting to maintain vital organ function and to modulate key processes—such as immunity, inflammation, and antioxidant defenses—has now become routine in many surgical and ICU settings.103 It has been reported in numerous human randomized clinical trials that appropriate use of omega-3 FAs (EPA/DHA) can partially attenuate the metabolic response,

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TABLE Lipid Choices in Intensive Care Unit 33.4  Stress States Lipid absorption and utilization is very dependent on source, route, and metabolic state of the patient.

Enhance diaphragm function ↓ ICAM1 and E-selectin

EPA/DHA

Enteral vs. Parenteral Lipids Enteral superior to parenteral: significantly more lipid options enterally

Lipid Substrate SCFA (requires colonic fermentation of soluble fibers) Acetate, butyrate, propionate Increase utilization in stress models MCFA 6–12 carbons Dual absorption via portal and lymphatics No carnitine required to enter inner mitochondria membrane for β oxidation Increase utilization LCFA Omega-6 Omega-3 Utilization variable depending on carnitine, oxygenation, for example LCFA, Long-chain fatty acids; MCFA, medium-chain fatty acids; SCFA, short-chain fatty acids.

reverse or minimize the loss of lean body tissue, prevent oxidative injury in a variety of tissues, and improve outcome by modulating synthesis of proinflammatory and antiinflammatory mediators.97,103–105 The mechanisms of these effects are multiple, which include changes in cell membrane phospholipids, alterations in gene expression, and modifications to endothelial expression of intracellular adhesion molecule 1 (ICAM)-1, E-selectin, and other endothelial receptors regulating vascular integrity and function. Additionally, EPA and DHA derivatives—including resolvins, docosatrienes, and neuroprotectins—now commonly called specialized proresolving molecules (SPMs) have been shown to be potent active effectors of the resolution of inflammation.97,106 SPMs regulate polymorphonuclear neutrophil (PMN) transmigration and decrease neutrophil infiltration, proinflammatory gene signaling, and NFκB binding. These protective mediators are found to be highly conserved among species, from primitive fish to mammals.107 In fact, some data suggest that EPA can help prevent loss of diaphragm function in sepsis108 and promote resistance to gram-negative pathogens, such as pseudomonas.109 Recent evidence supports the concept that EPA and DHA can be thought of as not just passively modulating the inflammatory process but as actively involved in the resolution of inflammation via these SPM compounds.110,111 The use of enteral and parenteral formulations containing antiinflammatory lipids, primarily EPA and DHA, can be used as pharmacologic agents to modulate the hyperdynamic response and outcomes in surgical and critically ill patients.

Clinical Outcome Studies Using 20 and 22 Carbon Omega-3 Fatty Acids When evaluating the literature regarding the use of omega-3 FAs, it is important to take into account the species evaluated and the experimental model, along with the total quantity of macronutrient delivered, carbon structure, and lipid ratios involved. Variable and occasionally even contradictory results can be obtained in cell cultures, animal models, or in human clinical trials depending on

↓ TLR4 receptor binding

Alters membrane fluidity

Receptors

Membrane phospholipids

Eicosanoids

Decrease (↓) inflammation in muscularis via vagal mechanism ↑ Resolvins ↑ Protectins ↓ Signal transduction pathways (NFκB)

↓ Proinflammatory cytokines

Enzymes ↓ Inflammation and ↑ immunity

• Fig. 33.5

  Multiple beneficial effects of eicosapentanoic acid and docosa hexaenoic acid in the critical care setting. DHA, Docosahexaenoic acid; EPA, eicosapentaenoic acid; ICAM-1, intracellular adhesion molecule-1; NFκB, nuclear factor kappa B; TLR-4, toll-like receptor-4.

these factors. Other significant factors to evaluate are the route of delivery, timing of delivery in relation to the specified event, and the percent of lipid calories delivered. If the omega-3 fat is delivered in the 18 carbon α-linolenic acid form (canola oil or flaxseed oil), it often has little effect in humans.112 If it is given as EPA or DHA, however, rapid and dramatic effects have been reported.113 Other issues to evaluate include the amount of antioxidant vitamins and micronutrients being delivered simultaneously. This is especially important for vitamin E, as the amount of polyunsaturated fatty acid (PUFA) delivered can alter vitamin E requirements.114

Recommendations Regarding Delivery of Omega-3 Fatty Acids Similar to the pharmaconutrients previously discussed, the optimal dose, timing, and formulation of omega-3 FAs is unknown. A prominent meta-analysis that aggregated the results of 3 randomized clinical trials (RCTs) conducted in patients with adult respiratory distress syndrome (ARDS) found that an enteral formula enriched with fish oils appears to significantly reduce ICU LOS, ventilator days, and mortality.115 More recent prospective, randomized trials of fish oils and borage oil in ARDS, however, have shown no benefit.116,117 Several issues should be resolved before abandoning the use of fish oils in ARDS, such as the method of feeding, background nutrition, and the patient’s absorptive capacity with bolus delivery of the pharmacologic agents. Previous studies supplied adequate additional macronutrients as background when giving the antiinflammatory lipid compounds, while the two most recent studies delivered the bolus irrespective of background nutrition. While there is variability in outcome benefit seen in results from clinical trials using omega-3 antiinflammatory therapy in critically ill patients, doses greater than 5 g/d have consistently shown significant benefit in this population, specifically those with acute lung injury (ALI)/ARDS or sepsis/septic shock.118 Numerous other studies in ICU populations continue to support the use of fish oils Fig. 33.5.119

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Timing of Delivery of Nutrients as Pharmacologic Agents The timing for optimal delivery of pharmaconutrients appears to be before the stressful or traumatic event. A now classic study demonstrated that when the nutrients arginine, fish oils, and nucleic acids were given as oral supplements 5 to 7 days before major gastrointestinal surgery, there was a lower infection rate and a lower overall complication rate.120 Most recently, a meta-analysis of 35 studies concluded that when arginine is given preoperatively, benefits include a significant decrease in infectious complications.49 This effect was consistent over a wide range of surgical specialties. To date, we have inadequate supportive literature to yield the optimal time to deliver immune and metabolically active nutrients once a planned metabolic stress has taken place as opposed to that found in the surgical setting. Timing will depend on several factors, such as the route of delivery, dosing, and method of delivery (e.g., bolus as a single agent versus infusion with other nutrients). The conventional wisdom is that early institution of therapy is likely to be optimal. Growing evidence from mammalian models of sepsis and shock suggest that once oxidative stress has damaged cells, changes in energy production potential may be irreversible.121,122 It would be safe to say that once the patient has been adequately resuscitated and able to receive enteral feeding, these agents would be safe. One study specifically evaluated delivery of glutamine during shock resuscitation in the emergency department and found it to be safe and associated with enhanced intestinal tolerance to subsequent enteral feeding.123 No prospective randomized trials have evaluated or compared the enteral versus parenteral route with regard to delivery of

metabolically active nutrients. The optimal route of delivery for the majority of active nutrients remains uncertain, although it appears that the parenteral route may be favorable for glutamine.24 Parenteral EPA and DHA are reported to have beneficial influences within 1 to 24 hours, while enteral delivery may need 12 to 72 hours to demonstrate the beneficial and antiinflammatory effects.119,124

Use of Protocols Enhance Safe Delivery of Nutrients Protocols to deliver early nutrition effectively and safely either parenterally or enterally have been widely published.30,42,43,125–128 These protocols have reported advantages in decreasing ventilator days, length of ICU stay, and even mortality.25,128 The “CAN WE FEED” protocol links resuscitation with clinical assessment and nutrient delivery.42 This protocol has rapidly gained widespread acceptance in ICUs across the globe, and a protocol-driven approach to initiating EN or PN in critically ill patients is recommended by the ASPEN/SCCM guidelines.

Emerging Developments New Malnutrition Definitions and Other Nutrients New definitions for malnutrition have recently been developed129 (Fig. 33.6). This will aid in the ability to better define the various populations and assess outcomes of interventions.

New Definition of Malnutrition Three Distinct Forms of Malnutrition

Starvation-related

Chronic disease-related

Acute disease or injury-related

No inflammation Example: Anorexia nervosa

Mild-mod inflammation Example: COPD, pancreatic cancer, sarcopenic obesity

Severe inflammation Example: Burn, trauma, major infection, surgery

• Fig. 33.6

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  Refined definitions for malnutrition. COPD, Chronic obstructive pulmonary disease. (Modified from Jensen GL, Mirtallo J, Compher C, et al. Adult starvation and disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the international consensus guideline committee. J Parenter Enteral Nutr. 2010;34:156–159.)

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Several other specific nutrients have been reported to be beneficial in the surgical population. Antioxidants, such as vitamin C and E, and trace minerals, such as selenium and zinc, which function as cofactors for several potent endogenous antioxidants (superoxide dismutase and glutathione peroxidase) have received attention for their ability to improve outcomes in surgical and trauma patients.130 Other amino acids—including citrulline, taurine, leucine, and creatine—have also had variable success in improving metabolic outcomes or surrogate markers following major surgery or major trauma.50 As with glutamine and arginine, these amino acids have been shown to alter gene expression, intracellular protein turnover, and regulate metabolic pathways.105,131

Probiotics The use of probiotics has recently been brought to the forefront, with several studies showing that these “functional foods” can decrease the inflammatory response, stabilize and support the mucosal surface, improve immune function, and decrease infectious complications, including ventilator-associated pneumonia (VAP) and Clostridium difficile diarrhea.132–135 Probiotics are defined as “live microbial organisms which beneficially affect human health through the prevention of specific disease states.”136 Studies suggest that probiotics may help reduce the incidence of VAP locally by promoting selective colonization and perhaps systematically by immunomodulation.137 In a well-executed, prospective, randomized, double-blinded, placebo-controlled trial of 138 mechanically ventilated patients at high risk of developing VAP examined the influence of probiotic therapy.46 Patients in the treatment arm received 109 colony-forming units of Lactobacillus rhamnosus GG twice daily, delivered to the gastrointestinal tract via a nasogastric tube. The probiotic group not only decreased VAP infections by about 50% compared to placebo but also reduced the amount of total antibiotics needed when compared to placebo-treated patients. Other groups have used different bacterial species and protocols, including swabbing the mouths of intubated patients with probiotics, and have also found benefit.138 The clinical science for using probiotics to prevent Clostridium difficile diarrhea is even more robust.134 General use of probiotics in critically ill patients does not yet have sufficient evidence to be recommended as routine. The majority of studies, however, report trends suggesting a treatment effect of probiotics in terms of reducing the incidence of VAP, Clostridium difficile, and antibiotic-associated diarrhea, but controversy remains as to which probiotic to use, optimal timing, duration of therapy, route, and method of delivery.

Conclusion It is a dynamic and exciting time for the field of nutrition therapy. Of course there are still numerous questions and controversies in the field (Table 33.5). The use of protocols to enhance the safe, early delivery of enteral nutrients is now well established. A large number of new or ongoing randomized controlled trials continue to advance our understanding of the mechanisms that drive the benefits, harms, toxicities, or null effects of pharmaconutrients. Future studies must focus on evidence-based therapies that impact clinically relevant surgical endpoints, such as LOS, infectious morbidity, and mortality, as well as more subtle clues of successful modulation of the stress response, wound healing, time to tracheal

TABLE Current Issues and Problems With Intensive 33.5  Care Unit Nutrition Failure to predict who will need support Lack of adequate assessment markers Surrogate markers albumin, prealbumin, CRP, IGF-1 not currently useful Controversy regarding what is the best formula to feed Lack of understanding of “neutraceutical” approach Glutamine, arginine, fish oils (DHA, EPA), carnitine Overreliance and inappropriate use of parenteral nutrition (PN) Starting PN for “1 or 2” days Nonphysiologic lipid and amino acid solutions (in United States) The morbidly obese critically ill patient How many calories, IBW, ABW, BMI remain in question Failure to maximize use of early enteral feeding Failure to get adequate safe early enteral access Unfounded indications for stopping and holding enteral feeding Diagnostic tests, NPO for OR, “road trips,” bathing ABW, Actual body weight; BMI, body mass index (formula: weight (kg)/[height(m)]2; CRP, C-reactive protein; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IBW, ideal body weight; IGF-1, insulin-like growth factor-1; NPO, nothing by mouth; OR, operating room.

TABLE 33.6  Critical Care Guidelines Areas of common agreement: ADA, ASPEN, CPG, ESPEN, SCCM Early enteral feeding Enteral superior to parenteral nutrition Fish oils beneficial (except ADA) Postpyloric feeding preferable if possible Supplemental antioxidants Use of glutamine (except ADA) Use of arginine in surgery patients Preop in addition to postop when possible ADA, American Dietetic Association; ASPEN, American Society of Parenteral and Enteral Nutrition; CPG, Canadian Clinical Practice Guidelines; ESPEN, European Society of Parenteral and Enteral Nutrition; SCCM, Society of Critical Care Medicine.

extubation, hemodynamic stability, and early mobility. The translation from human trials, mammalian models, and basic science cellular studies has resulted in better understanding of immune and metabolic nutrients. Focused nutrition therapy has now reached a point at which early aggressive enteral feeding via protocols and the use of pharmaconutrients should be incorporated into standard surgical and ICU practice. Novel therapies—such as probiotics and specific amino acid therapy combined with exercise in the ICU setting (even with ongoing mechanical ventilation)—will undoubtedly change practice in the future. The questions of optimal doses, timing, and routes of these nutrients remain to be determined. Despite the variety of controversy in critical care nutrition, most major nutrition societies agree on the majority of issues (see Table 33.6).

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Key Points • Preoperative malnutrition is a risk factor for poor wound healing, perioperative complications, and mortality. • The metabolic response to stress includes a hyperdynamic cardiac and pulmonary state, insulin resistance, hyperglycemia, and accelerated protein catabolism from muscle; unabated, this can culminate in PICS, MOF, and death. • Early enteral feeding in critically ill patients is associated with numerous benefits, including attenuation of the inflammatory response to stress, prevention of loss of gut barrier function, maintenance of GALT, maintenance of normal gut bacteria, and support of the systemic immune response, among others. • Enteral feeding should not begin until relative hemodynamic stability and other acute resuscitation issues have been accomplished. Institution of premature enteral feeding can result in

Key References Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491–1501. This is an important paper clarifying the evolving epidemiologic terms and concepts relating to persistent inflammation and immunosuppression in the ICU (e.g.., SIRS, compensatory anti-inflammatory response syndrome [CARS], MOF, PICS). (Ref. 1). Moncure M, Samaha E, Moncure K, et al. Jejunostomy tube feedings should not be stopped in the perioperative patient. JPEN J Parenter Enteral Nutr. 1999;23(6):356–359. This is a prospective study suggesting that postpylorus tube feedings need not be stopped in the perioperative period. (Ref. 16). Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition reduces mortality in trauma patients requiring intensive care: A meta-analysis of randomised controlled trials. Injury. 2011;42(1):50–56. This is an important meta-analysis suggesting that early enteral nutrition improves survival. The study acknowledges the need for larger, confirmatory clinical trials. (Ref. 18). Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: executive summary. Crit Care Med. 2009;37(5):1757–1761. This is a summary of current evidence-based practice guidelines for the provision of nutritional support in critically ill patients put forward by a group of experts representing respected professional societies. (Ref. 24).

References 1. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491–1501. 2. Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011;62:1–8. 3. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348(2):138–150. 4. Kochanek KD, Xu J, Murphy SL, et al. Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59(4):1–51. 5. Manship L, McMillin RD, Brown JJ. The influence of sepsis and multisystem and organ failure on mortality in the surgical intensive care unit. Am Surg. 1984;50(2):94–101. 6. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997;278(3):234–240.

nonocclusive mesenteric ischemia (NMI), a devastating complication with a high mortality rate. • Pharmaconutrition or immunonutrition is defined as the provision of key nutrients that may modulate the inflammatory and/or catabolic response associated with critical illness. Pharmaconutrition is distinct from the delivery of balanced macronutrient energy supply to support normal cell metabolism and division. • Glutamine, arginine, and fish oils are the most prominent pharmaconutrients in contemporary nutritional therapy. The exact dosage and timing of delivery of these pharmaconutrients are not yet well established. • Nutritional therapy in the ICU is best accomplished on a multidisciplinary basis according to evidence-based protocols and multifaceted assessments (e.g., CAN WE FEED). 7. Cruse PJ, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg. 1973;107(2):206–210. 8. Studley HO. Percentage of weight loss: a basic indicator of surgical risk in patients with chronic peptic ulcer. 1936. Nutr Hosp. 2001;16(4):141–143, discussion 140–141. 9. Reinhardt GF, Myscofski JW, Wilkens DB, et al. Incidence and mortality of hypoalbuminemic patients in hospitalized veterans. JPEN J Parenter Enteral Nutr. 1980;4(4):357–359. 10. 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: a report by the American Society of Anesthesiologist Task Force on preoperative fasting. Anesthesiology. 1999;90(3):896–905. 11. Apfelbaum JL, et al. Practice guidelines for preopeative fasting and the use of pharmacologic agents to reduce risk of pulmonary aspiration: application to healthy patients undergoing elective procedures. Anesthesiology. 2017;126(3):376–393. 12. Amer MA, Smith MD, Herbison GP, et al. Network meta-analysis of the effect of preoperative carbohydrate loading on recovery after elective surgery. Br J Surg. 2017;104(3):187–197. 13. Wang ZG, Wang Q, Wang WJ, et al. Randomized clinical trial to compare the effects of preoperative oral carbohydrate versus placebo on insulin resistance after colorectal surgery. Br J Surg. 2010;97(3):317–327. 14. Varon DEFG, Goel N, Wall J, et al. Intraoperative feeding improves calorie and protein delivery in acute burn patients. J Burn Care Res. 2017;38(5):299–303. 15. Schricker T, Wykes L, Meterissian S, et al. The anabolic effect of perioperative nutrition depends on the patient’s catabolic state before surgery. Ann Surg. 2013;257(1):155–159. 16. Moncure M, Samaha E, Moncure K, et al. Jejunostomy tube feedings should not be stopped in the perioperative patient. JPEN J Parenter Enteral Nutr. 1999;23(6):356–359. 17. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. JPEN J Parenter Enteral Nutr. 1995;19(6):453–460. 18. Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition reduces mortality in trauma patients requiring intensive care: a meta-analysis of randomised controlled trials. Injury. 2011;42(1):50–56. 19. McClave SA, Lowen CC, Martindale RG. The 2016 ESPEN Arvid Wretlind Lecture: the gut in stress. Clin Nutr. 2018 Feb;37(1):19–36. doi: 10.1016/j.clnu.2017.07.015. Epub 2017 Jul 29. 20. Petrov MS, Loveday BP, Pylypchuk RD, et al. Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis. Br J Surg. 2009;96(11):1243–1252. 21. Lewis SJ, Egger M, Sylvester PA, et al. Early enteral feeding versus “nil by mouth” after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ. 2001;323(7316):773–776.

668

SE C T I O N V

Gastrointestinal and Endocrine Systems

22. Mutlu GM, Mutlu EA, Factor P. Prevention and treatment of gastrointestinal complications in patients on mechanical ventilation. Am J Respir Med. 2003;2(5):395–411. 23. Martindale RGSS, Nishikawa R, Siepler JK. The metabolic response to stress and alterations in nutirent metabolism. In: Shikora SAMR, Schartzberg SD, eds. Nutritional Considerations in the Intensive Care Unit: Science, Rationale, and Practice. Dubuque, IA: Kendall-Hunt; 2002:11–20. 24. Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: executive summary. Crit Care Med. 2009;37(5):1757–1761. 25. Heyland DK, Cahill NE, Dhaliwal R, et al. Impact of enteral feeding protocols on enteral nutrition delivery: results of a multicenter observational study. JPEN J Parenter Enteral Nutr. 2010;34(6):675–684. 26. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med. 2001;29(12):2264–2270. 27. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159–211. 28. Marik PE. Arginine: too much of a good thing may be bad! Crit Care Med. 2006;34(11):2844–2847. 29. Zaloga GP, Roberts PR, Marik P. Feeding the hemodynamically unstable patient: a critical evaluation of the evidence. Nutr Clin Pract. 2003;18(4):285–293. 30. Heyland DK, Dhaliwal R. Early enteral nutrition vs. early parenteral nutrition: an irrelevant question for the critically ill? Crit Care Med. 2005;33(1):260–261. 31. Osland E, Yunus RM, Khan S, et al. Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a meta-analysis. JPEN J Parenter Enteral Nutr. 2011;35(4):473–487. 32. Martins JR, Shiroma GM, Horie LM, et al. Factors leading to discrepancies between prescription and intake of enteral nutrition therapy in hospitalized patients. Nutrition. 2012;28(9):864–867. 33. McClave SA, Sexton LK, Spain DA, et al. Enteral tube feeding in the intensive care unit: factors impeding adequate delivery. Crit Care Med. 1999;27(7):1252–1256. 34. 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. 2001;345(19):1368–1377. 35. Revelly JP, Tappy L, Berger MM, et al. Early metabolic and splanchnic responses to enteral nutrition in postoperative cardiac surgery patients with circulatory compromise. Intensive Care Med. 2001;27(3):540–547. 36. Park WM, Gloviczki P, Cherry KJ Jr, et al. Contemporary management of acute mesenteric ischemia: factors associated with survival. J Vasc Surg. 2002;35(3):445–452. 37. Caddell KA, Martindale R, McClave SA, et al. Can the intestinal dysmotility of critical illness be differentiated from postoperative ileus? Curr Gastroenterol Rep. 2011;13(4):358–367. 38. Suehiro T, Matsumata T, Shikada Y, et al. Accelerated rehabilitation with early postoperative oral feeding following gastrectomy. Hepatogastroenterology. 2004;51(60):1852–1855. 39. Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med. 2009;35(12):2018–2027. 40. Gatt M, MacFie J. Bedside postpyloric feeding tube placement: a pilot series to validate this novel technique. Crit Care Med. 2009;37(2):523–527. 41. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240(4):728–734, discussion 734–725.

42. Miller KR, Kiraly LN, Lowen CC, et al. “CAN WE FEED?” A mnemonic to merge nutrition and intensive care assessment of the critically ill patient. JPEN J Parenter Enteral Nutr. 2011;35(5):643–659. 43. Kozar RA, McQuiggan MM, Moore EE, et al. Postinjury enteral tolerance is reliably achieved by a standardized protocol. J Surg Res. 2002;104(1):70–75. 44. Hunter J. A treatise on the blood, inflammation, and gun-shot wounds. 1794. Clin Orthop Relat Res. 2007;458:27–34. 45. Cuthbertson D, Tilstone WJ. Metabolism during the postinjury period. Adv Clin Chem. 1969;12:1–55. 46. Alfaleh K, Anabrees J, Bassler D, et al. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011;(3):Cd005496. 47. Cerantola Y, Hubner M, Grass F, et al. Immunonutrition in gastrointestinal surgery. Br J Surg. 2011;98(1):37–48. 48. Hardy G, Manzanares W. Pharmaconutrition: how has this concept evolved in the last two decades? Nutrition. 2011;27(10):1090–1092. 49. Drover JW, Dhaliwal R, Weitzel L, et al. Perioperative use of arginine-supplemented diets: a systematic review of the evidence. J Am Coll Surg. 2011;212(3):385–399, 399.e381. 50. Wu G. Amino acids: metabolism, functions, and nutrition. Amino Acids. 2009;37(1):1–17. 51. Wischmeyer PE. Glutamine: role in gut protection in critical illness. Curr Opin Clin Nutr Metab Care. 2006;9(5):607–612. 52. Alpers DH. Glutamine: do the data support the cause for glutamine supplementation in humans? Gastroenterology. 2006;130(2 suppl 1):S106–S116. 53. Santora R, Kozar RA. Molecular mechanisms of pharmaconutrients. J Surg Res. 2010;161(2):288–294. 54. Curi R, Newsholme P, Procopio J, et al. Glutamine, gene expression, and cell function. Front Biosci. 2007;12:344–357. 55. Griffiths RD. Glutamine: establishing clinical indications. Curr Opin Clin Nutr Metab Care. 1999;2(2):177–182. 56. Ziegler TR, Bazargan N, Leader LM, et al. Glutamine and the gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2000;3(5):355–362. 57. Roth E. Nonnutritive effects of glutamine. J Nutr. 2008;138(10): 2025S–2031S. 58. Grau T, Bonet A, Minambres E, et al. The effect of L-alanyl-Lglutamine dipeptide supplemented total parenteral nutrition on infectious morbidity and insulin sensitivity in critically ill patients. Crit Care Med. 2011;39(6):1263–1268. 59. Weitzel LR, Wischmeyer PE. Glutamine in critical illness: the time has come, the time is now. Crit Care Clin. 2010;26(3):515–525, ix–x. 60. Rodas PC, Rooyackers O, Hebert C, et al. Glutamine and glutathione at ICU admission in relation to outcome. Clin Sci. 2012;122(12):591–597. 61. Wernerman J. Glutamine supplementation. Ann Intensive Care. 2011;1(1):25. 62. Wernerman J, Kirketeig T, Andersson B, et al. Scandinavian glutamine trial: a pragmatic multi-centre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand. 2011;55(7):812–818. 63. Houdijk AP, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet. 1998;352(9130):772–776. 64. Dechelotte P, Hasselmann M, Cynober L, et al. L-alanyl-L-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind, multicenter study. Crit Care Med. 2006;34(3):598–604. 65. Byrne TA, Wilmore DW, Iyer K, et al. Growth hormone, glutamine, and an optimal diet reduces parenteral nutrition in patients with short bowel syndrome: a prospective, randomized, placebo-controlled, double-blind clinical trial. Ann Surg. 2005;242(5):655–661. 66. Hamiel CR, Pinto S, Hau A, et al. Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity. Am J Physiol Cell Physiol. 2009;297(6):C1509–C1519. 67. Singleton KD, Serkova N, Beckey VE, et al. Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression. Crit Care Med. 2005;33(6):1206–1213.



68. Wischmeyer PE, Heyland DK. The future of critical care nutrition therapy. Crit Care Clin. 2010;26(3):433–441, vii. 69. Ziegler TR, Ogden LG, Singleton KD, et al. Parenteral glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med. 2005;31(8):1079–1086. 70. Macario AJ, Conway de Macario E. Sick chaperones, cellular stress, and disease. N Engl J Med. 2005;353(14):1489–1501. 71. Wischmeyer PE. Glutamine: role in critical illness and ongoing clinical trials. Curr Opin Gastroenterol. 2008;24(2):190–197. 72. Nose K, Yang H, Sun X, et al. Glutamine prevents total parenteral nutrition-associated changes to intraepithelial lymphocyte phenotype and function: a potential mechanism for the preservation of epithelial barrier function. J Interferon Cytokine Res. 2010;30(2):67–80. 73. Ren ZG, Liu H, Jiang JW, et al. Protective effect of probiotics on intestinal barrier function in malnourished rats after liver transplantation. HBPD INT. 2011;10(5):489–496. 74. Griffiths RD. Outcome of critically ill patients after supplementation with glutamine. Nutrition. 1997;13(7–8):752–754. 75. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med. 1992;116(10):821–828. 76. Anderson PM, Schroeder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer. 1998;83(7):1433–1439. 77. Yoshida S, Matsui M, Shirouzu Y, et al. Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg. 1998;227(4):485–491. 78. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002;30(9):2022–2029. 79. Andrews PJ, Avenell A, Noble DW, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011;342:d1542. 80. Heyland DK. The RE-ENERGIZE Study: RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury (RE-ENERGIZE); 2009. https://clinicaltrials.gov/ct2/show/NCT00985205. Accessed November 14, 2017. 81. Zhu X, Herrera G, Ochoa JB. Immunosupression and infection after major surgery: a nutritional deficiency. Crit Care Clin. 2010;26(3):491–500, ix. 82. Popovic PJ, Zeh HJ 3rd, Ochoa JB. Arginine and immunity. J Nutr. 2007;137(6 suppl 2):1681s–1686s. 83. Zhou M, Martindale RG. Arginine in the critical care setting. J Nutr. 2007;137(6 suppl 2):1687s–1692s. 84. Morris SM Jr. Arginine: master and commander in innate immune responses. Sci Signal. 2010;3(135):pe27. 85. Bansal V, Ochoa JB. Arginine availability, arginase, and the immune response. Curr Opin Clin Nutr Metab Care. 2003;6(2):223–228. 86. Luiking YC, Poeze M, Dejong CH, et al. Sepsis: an arginine deficiency state? Crit Care Med. 2004;32(10):2135–2145. 87. Martindale RG, McCarthy MS, McClave SA. Guidelines for nutrition therapy in critical illness: are not they all the same? Minerva Anestesiol. 2011;77(4):463–467. 88. Iapichino G, Albicini M, Umbrello M, et al. Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients. Intensive Care Med. 2008;34(10):1843–1850. 89. Zoccali C, Maas R, Cutrupi S, et al. Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections. Nephrol Dial Transplant. 2007;22(3):801–806. 90. Visser M, Vermeulen MA, Richir MC, et al. Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr. 2012;107(10):1458–1465. 91. Luiking YC, Poeze M, Ramsay G, et al. Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr. 2009;89(1):142–152.

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92. Kao CC, Bandi V, Guntupalli KK, et al. Arginine, citrulline and nitric oxide metabolism in sepsis. Clin Sci. 2009;117(1):23–30. 93. Boger RH. The pharmacodynamics of L-arginine. J Nutr. 2007;137(6 suppl 2):1650s–1655s. 94. Alexander JW, Metze TJ, McIntosh MJ, et al. The influence of immunomodulatory diets on transplant success and complications. Transplantation. 2005;79(4):460–465. 95. Bansal V, Syres KM, Makarenkova V, et al. Interactions between fatty acids and arginine metabolism: implications for the design of immune-enhancing diets. JPEN J Parenter Enteral Nutr. 2005;29(1 suppl):S75–S80. 96. Cereda E, Klersy C, Serioli M, et al. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015;162(3):167–174. 97. Calder PC. Rationale and use of n-3 fatty acids in artificial nutrition. Proc Nutr Soc. 2010;69(4):565–573. 98. Calder PC, Yaqoob P. Understanding omega-3 polyunsaturated fatty acids. Postgrad Med. 2009;121(6):148–157. 99. Jeejee hoy KN, Anderson GH, Nakhooda AF, et al. Metabolic studies in total parenteral nutrition with lipid in man. Comparison with glucose. J Clin Invest. 1976;57(1):125–136. 100. Bhangle S, Kolasinski SL. Fish oil in rheumatic diseases. Rheum Dis Clin North Am. 2011;37(1):77–84. 101. Turner D, Shah PS, Steinhart AH, et al. Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses. Inflamm Bowel Dis. 2011;17(1):336– 345. 102. Wilczynska-Kwiatek A, Bargiel-Matusiewicz K, Lapinski L. Asthma, allergy, mood disorders, and nutrition. Eur J Med Res. 2009;14(suppl 4):248–254. 103. Singer P, Shapiro H, Theilla M, et al. Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med. 2008;34(9):1580– 1592. 104. Pittet YK, Berger MM, Pluess TT, et al. Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil. Intensive Care Med. 2010;36(2):289–295. 105. Wischmeyer P. Nutritional pharmacology in surgery and critical care: ‘you must unlearn what you have learned’. Curr Opin Anaesthesiol. 2011;24(4):381–388. 106. Massaro M, Scoditti E, Carluccio MA, et al. Omega-3 fatty acids, inflammation and angiogenesis: basic mechanisms behind the cardioprotective effects of fish and fish oils. Cell Mol Biol (NoisyLe-Grand). 2010;56(1):59–82. 107. Serhan CN, Krishnamoorthy S, Recchiuti A, et al. Novel antiinflammatory–pro-resolving mediators and their receptors. Curr Top Med Chem. 2011;11(6):629–647. 108. Supinski GS, Vanags J, Callahan LA. Eicosapentaenoic acid preserves diaphragm force generation following endotoxin administration. Crit Care. 2010;14(2):R35. 109. Tiesset H, Bernard H, Bartke N, et al. (N-3) Long-chain PUFA differentially affect resistance to pseudomonas aeruginosa infection of male and female cftr-/- mice. J Nutr. 2011;141(6):1101–1107. 110. Bannenberg G, Serhan CN. Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim Biophys Acta. 2010;1801(12):1260–1273. 111. Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol. 2008;3:279–312. 112. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013;75(3):645–662. 113. Pluess TT, Hayoz D, Berger MM, et al. Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects. Intensive Care Med. 2007;33(5):789–797. 114. Atkinson J, Harroun T, Wassall SR, et al. The location and behavior of alpha-tocopherol in membranes. Mol Nutr Food Res. 2010;54(5):641–651. 115. Jones NE, Heyland DK. Pharmaconutrition: a new emerging paradigm. Curr Opin Gastroenterol. 2008;24(2):215–222.

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116. Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574–1581. 117. Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med. 2011;39(7):1655–1662. 118. Todd SR, Gonzalez EA, Turner K, et al. Update on postinjury nutrition. Curr Opin Crit Care. 2008;14(6):690–695. 119. van der Meij BS, van Bokhorst-de van der Schueren MA, Langius JA, et al. N-3 PUFAs in cancer, surgery, and critical care: a systematic review on clinical effects, incorporation, and washout of oral or enteral compared with parenteral supplementation. Am J Clin Nutr. 2011;94(5):1248–1265. 120. Braga M, Gianotti L, Nespoli L, et al. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg. 2002;137(2):174–180. 121. Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth. 2011;107(1):57–64. 122. Garrabou G, Moren C, Lopez S, et al. The effects of sepsis on mitochondria. J Infect Dis. 2012;205(3):392–400. 123. McQuiggan M, Kozar R, Sailors RM, et al. Enteral glutamine during active shock resuscitation is safe and enhances tolerance of enteral feeding. JPEN J Parenter Enteral Nutr. 2008;32(1):28–35. 124. Calder PC. Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol. 2011;668(suppl 1):S50–S58. 125. Davies AR, Morrison SS, Bailey MJ, et al. A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med. 2012;40(8):2342–2348. 126. Marr AB, McQuiggan MM, Kozar R, et al. Gastric feeding as an extension of an established enteral nutrition protocol. Nutr Clin Pract. 2004;19(5):504–510. 127. Marshall AP, Cahill NE, Gramlich L, et al. Optimizing nutrition in intensive care units: empowering critical care nurses to be effective agents of change. Am J Crit Care. 2012;21(3):186–194.

128. Martin CM, Doig GS, Heyland DK, et al. Multicentre, clusterrandomized clinical trial of algorithms for critical-care enteral and parenteral therapy (ACCEPT). CMAJ. 2004;170(2):197–204. 129. Jensen GL, Mirtallo J, Compher C, et al. Adult starvation and disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the international consensus guideline committee. JPEN J Parenter Enteral Nutr. 2010;34(2):156–159. 130. Heyland DK, Dhaliwal R, Suchner U, et al. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med. 2005;31(3):327–337. 131. Jayarajan S, Daly JM. The relationships of nutrients, routes of delivery, and immunocompetence. Surg Clin North Am. 2011;91(4): 737–753, vii. 132. Jeppsson B, Mangell P, Thorlacius H. Use of probiotics as prophylaxis for postoperative infections. Nutrients. 2011;3(5):604–612. 133. Lundell L. Use of probiotics in abdominal surgery. Dig Dis. 2011;29(6):570–573. 134. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;(5):CD006095. 135. Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med. 2010;182(8):1058–1064. 136. Fuller R. Probiotics in human medicine. Gut. 1991;32(4): 439–442. 137. Loprinzi CL, Levitt R, Barton DL, et al. Evaluation of shark cartilage in patients with advanced cancer: a north central cancer treatment group trial. Cancer. 2005;104(1):176–182. 138. Randomized controlled study of probiotics containing lactobacillus casei (shirota strain) for prevention of ventilator-associated pneumonia. J Med Assoc Thai. 2015;98(3):253–259.

34 

Pharmacology of Postoperative Nausea and Vomiting ERIC S. ZABIROWICZ AND TONG J. GAN

CHAPTER OUTLINE Historical Perspective Mechanisms of Nausea and Vomiting Serotonin Receptor Antagonists Ondansetron Granisetron and Dolasetron Palonosetron Dopamine Receptor Antagonists Droperidol Haloperidol Metoclopramide Corticosteroids NK1 Receptor Antagonists Aprepitant Scopolamine H1-Receptor Antagonists Dimenhydrinate and Diphenhydramine Promethazine GABA Receptor Agonists Propofol Benzodiazepines Opioid Receptor Antagonists Naloxone Alvimopan Cannabinoids Risk-Based Prophylaxis Enhanced Recovery After Surgery Multimodal Therapy Emerging Developments Novel Antiemetic Drugs Postdischarge Nausea and Vomiting

Historical Perspective In the first half of the 20th century, one of the most feared complications of general anesthesia was postoperative vomiting (POV), primarily because aspiration of gastric contents into the lungs

could lead to death. Early prophylaxis sometimes consisted of advising patients to consume olive oil before general anesthesia to shield the intestinal wall from emetogenic gases. Prevention of POV was one of the primary motivations for developing local/ regional anesthesia blocks, first with cocaine and procaine, then with lidocaine. Postoperative nausea, on the other hand, was considered too minor a complication to measure—until the development in the 1950s and 1960s of anesthetic drugs that could be cleared more rapidly (e.g., halothane, barbiturates, and novel opioids), which meant that patients spent more of the immediate postoperative period awake.1 While the antiemetic effect of some drugs, such as anticholinergics, were first described more than a century ago, modern understanding of the specific receptor pathways and intracellular processes involved in postoperative nausea and vomiting (PONV) is relatively recent. It was not until the 1950s that interest in antiemetic drugs took off, with the identification of histamine and dopamine receptors in the nausea and vomiting pathway, and hence the clinical utility of H1- and D2-receptor antagonists like cyclizine, chlorpromazine, and promethazine. This surge in research on antiemetics was largely driven by advances in chemotherapy and a focus on chemotherapy-related outcomes. For example, neuro-oncologists first noticed the antiemetic effect of corticosteroids before the same observation was made for PONV in the 1990s.1 The development of 5-hydroxytryptamine type 3 (5-HT3)receptor antagonists marks the greatest advance in antiemetic drug research. Early 5-HT3-receptor antagonists were not more effective than other available antiemetics, but they were the first to be specifically designed by the pharmaceutical industry to target chemotherapy-induced nausea and vomiting (CINV) and PONV. This led to an increase in large, well-designed PONV studies, marketing of antiemetic agents, and a focus on PONV as a significant postoperative outcome.1 The first-generation 5-HT3receptor antagonists are associated with QTc prolongation, but the newest 5-HT3-receptor antagonists, palonosetron, appears to have improved efficacy, duration of action, and side effect profile compared with its predecessors. Neurokinin-1 (NK1)-receptor antagonists, such as aprepitant and rolapitant, are the newest class of antiemetic drugs, and they too benefit from a long duration of action and favorable side effect profile. As the current understanding of the nausea and vomiting pathway, pharmacokinetics and pharmacodynamics, and genetics continues to improve, antiemetic drugs are likely to become safer and easier to tailor to individual patients. 671



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting 671.e1

Abstract

Keywords

Postoperative nausea and vomiting (PONV) are common problems following surgery. This chapter is designed to educate the readers on the spectrum of antiemetic therapy available, and to which populations the modalities may prove most useful. The pharmacology of both traditional and novel drugs is discussed as well as synergies gained from multi-modal combination drug therapy. The use of routine antiemetic prophylaxis is essential for a successful enhanced recovery pathway.

Multimodal drug therapy Risk-based prophylaxis Antiemetic prophylaxis vs. rescue therapy Enhanced Recovery after Surgery

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Mechanisms of Nausea and Vomiting Despite thousands of studies, new insights into target receptor function, and the successful development of novel antiemetic agents, the actual mechanisms of nausea and vomiting remain unclear. Most antiemetic drugs act on one of several putative neurotransmitter pathways. 5-HT3- receptor antagonists are the most commonly used antiemetic class of drugs (Table 34.1). Other classes include dopamine (D2), histamine (H1), NK1, gamma-aminobutyric acid (GABA) A , opioid, and muscarinic cholinergic receptor antagonists. The receptors on which antiemetics act certainly play a role in nausea and vomiting. However, given that only 20% to 30% of patients respond to any one agent, nausea and vomiting cannot be solely attributed to activity of one—or several—of these receptor classes. It is also likely that individual variability plays a larger role than previously acknowledged. Although it is essential to understand and investigate the drug-receptor relationship, the therapeutic potential of targeting specific receptor classes is limited.

Nausea and vomiting can be triggered by a variety of stimuli, including toxins, anxiety, adverse drug reactions, pregnancy, radiation, chemotherapy, and motion. These stimuli are integrated by the vomiting center in the nucleus tractus solitarius (NTS), located primarily in the medulla as well as in the lower pons. The vomiting center receives input from the adjacent chemoreceptor trigger zone (CTZ), the GI tract, the vestibular system, and the cerebral cortex (Fig. 34.1). The CTZ is located at the caudal end of the fourth ventricle in the area postrema, a highly vascularized structure that lacks a true blood-brain barrier. Therefore chemosensitive receptors in the CTZ can be directly stimulated by toxins, metabolites, and drugs that circulate in the blood and cerebrospinal fluid. The CTZ communicates with the vomiting center primarily via D2 receptors as well as 5-HT3 receptors. Enterochromaffin cells in the GI tract release serotonin, which stimulates vagal afferents that terminate in the CTZ and communicate information regarding intestinal luminal compounds and gastric tone. The vestibular system, located in the bony labyrinth of the temporal lobe, detects changes in Higher Central Nervous System Centers

5-HT 5-HT3, receptor Amygdala

• Fig. 34.1

Vagus nerve

Schematic of pathways involved in postoperative nausea and vomiting. 5-HT, 5-hydroxytryptamine; 5-HT3, 5-hydroxytryptamine type 3 receptor; AP, area postrema; NTS, nucleus tractus solitarius.  

Dorsal vagal complex

MEDULLA

AP and NTS Central pattern generator

Chemotherapy Enterochromaffin cells

SMALL INTESTINE

Vagal afferents

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

equilibrium, which can cause motion sickness. Histamine (H1 receptor) and acetylcholine (muscarinic acetylcholine receptors) are the neurotransmitters that communicate between the vestibular system and the vomiting center. Anticipatory or anxiety-induced nausea and vomiting probably originates in the cerebral cortex. The cortex has direct input to the vomiting center via several types of neuroreceptors.

Serotonin Receptor Antagonists Serotonin (5-HT3) receptors are ligand-gated sodium ion (Na+) and potassium ion (K+) channels found throughout the central and peripheral nervous systems, notably in the CTZ and afferent fibers of the vagus nerve in both the gut and central nervous system (CNS; see Fig. 34.1). Serotonin activation of the CTZ and vagal afferents can both trigger the vomiting reflex. Serotonin plays an important role in anesthesia-, chemotherapy-, and radiation-induced nausea and vomiting. Serotonin receptor antagonists can be used as antiemetic treatment because they inhibit both central and peripheral stimulation of 5-HT3 receptors, and they are effective, nonsedative, and generally well tolerated. Thus 5-HT3-receptor antagonists are currently the most commonly used antiemetic agents for PONV, CINV, and rescue treatment.

Ondansetron Ondansetron was the first 5-HT3-receptor antagonist approved by the U.S. Food and Drug Administration (FDA), and at the time of its development, was the safest and most effective treatment for early CINV.2 Its reputation for superior CINV prophylaxis carried over to PONV, but a factorial trial in more than 5000 patients showed that 4 mg ondansetron was only as effective as 4 mg dexamethasone and 1.25 mg droperidol for PONV.3 Contrary to the common clinical impression that ondansetron is less effective against nausea than against vomiting, the relative risk reduction (RRR, risk ratio) of ondansetron is the same for nausea and for vomiting.4 However, ondansetron’s plasma half-life is only about 4 hours, which is probably why several studies found it to be more efficacious when administered toward the end rather than at the beginning of anesthesia.5 Like other 5-HT3-receptor antagonists, ondansetron’s side effects are generally mild to moderate and include constipation and headache, the latter of which is increased by about 3%.6 First-generation 5-HT3-receptor antagonists like ondansetron have also been associated with QTc prolongation, which potentially increases the risk of cardiac arrhythmia and cardiac arrest.7 The QTc prolongation associated with ondansetron use is similar to that caused by droperidol.8 Even though 5-HT3-receptor antagonists are among the most effective antiemetic treatments for CINV, 20% to 30% of patients do not respond to 5-HT3-receptor antagonism in the early phase of CINV.9 Furthermore, 50% to 60% of high-risk patients do not respond to these drugs in the late phase of CINV.10,11 Several studies have shown that responsiveness to ondansetron appears to be modulated by variations in cytochrome P450 enzyme 2D6 (CYP 2D6) activity and the ABCB1 gene. The ability to predict patient responsiveness to 5-HT3-receptor antagonists based on genetic testing for known polymorphisms could prove to be an important breakthrough in individualizing antiemetic therapy. Ondansetron is partially metabolized by hepatic CYP 2D6. There are numerous CYP 2D6 polymorphisms, each associated with one of four metabolic phenotypes: poor (no functional alleles), intermediate (less activity than one functional allele), extensive

673

90 80 Incidence of POV (%)



70 60 50 40 30 20 10 0

Poor

Intermediate Extensive

Ultrarapid

Metabolizer status

• Fig. 34.2

  Patients with a genotype associated with ultrarapid metabolism (i.e., three functional copies of CYP 2D6) are at increased risk for postoperative vomiting (POV) after prophylaxis with ondansetron in the first 24 postoperative hours. (Adapted from Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549.)

(two functional alleles, and the most common phenotype), and ultrarapid (three functional alleles). Ultrarapid metabolizers can degrade ondansetron more quickly and are therefore less likely to benefit from prophylaxis with the drug. In fact, several studies have shown that patients with three CYP 2D6 alleles, especially those with three functional alleles, are significantly more likely to experience PONV after prophylaxis with ondansetron than patients with fewer alleles (Fig. 34.2).9,12 Ultrarapid metabolism by CYP 2D6 is believed to be partially responsible for prophylactic ondansetron failures in individuals with an ultrarapid metabolic genotype, whereas other enzymes that metabolize ondansetron—namely, CYP 3A4, CYP 2E1, and CYP 1A2—are thought to play a larger role in drug clearance in individuals with poor, intermediate, and extensive metabolism genotypes.12 Ondansetron pharmacokinetics also appear to be modulated by polymorphisms of the gene that codes for the drug efflux transporter adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1). The ABCB1 pump transports at least three 5-HT3-receptor antagonists, including ondansetron, across the blood-brain barrier, thereby limiting accumulation of these drugs in the CNS.13 Polymorphisms of ABCB1 that reduce its activity increase the concentration of 5-HT3-receptor antagonists in the brain, which enhances efficacy. Indeed, cancer patients with a 3435C>T genetic polymorphism were less likely to experience chemotherapy-induced vomiting (CIV) in the first 24 hours after prophylaxis with ondansetron. 13 Similarly, 3435C>T and/or 2677G>T/A polymorphisms are associated with a lower incidence of PONV in surgery patients, but only within the first 2 postoperative hours.14

Granisetron and Dolasetron Other first-generation 5-HT3-receptor antagonists include granisetron and dolasetron. Both drugs have a plasma half-life about

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TABLE 34.1  Properties of Individual Antiemetic Drugs

Empirical Formula

Administration

Daily Dosage (mg) PONV CINV

1,2,3,9-tetrahydro-9-methyl-3-[(2methyl-1H-imidazol-1-yl)methyl]-4Hcarbazol-4-one, monohydrochloride, dihydrate

C18H19N3O

IV

4

endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3carboxamide hydrochloride (2α,6α,8α,9αβ)-octahydro-3-oxo-2,6methano-2H-quinolizin-8-yl-lHindole-3-carboxylate monomethanesulfonate, monohydrate 1αH,5αH-Tropan-3α-yl indole-3carboxylate (3aS)-2-[(S)-1-Azabicyclo [2.2.2] oct-3-yl]-2,3,3α,4,5,6-hexahydro-1oxo-1H benz[de]isoquinoline hydrochloride

C18H24N4O

IM Oral Sup IV Oral TD IV Oral

4 16 16 1 1 3.1 12.5 100

IV Oral IV Oral

2 5 0.075 0.075

5 5 0.25 0.5

15.1 3.46 5.6

25

3.2

Chemical Name

Cmax (ng/mL)

5-HT3 Receptor Antagonists Ondansetron (Zofran)

Granisetron (Kytril) Dolasetron (Anzemet) Tropisetron (Navoban) Palonosetron (Aloxi)

C19H20N2O3

C17H20N2O2 C19H24N2O

32 (0.15 mg/kg × 3) 8 8×2 16 10 µg/kg 2 3.1

64

100

D2 Receptor Antagonists Droperidol Haloperidol (Haldol) Metoclopramide (Reglan)

1-[1-[3-(p-Fluorobenzoyl) propyl]1,2,3,6-tetrahydro-4-pyridyl]-2benzimidazolinone 4-[4-(p-chloro-phenyl)-4hydroxypiperidino]-4′— fluorobutyrophenone 4-amino-5-chloro-N-[2-(diethylamino) ethyl]-2-methoxybenzamide monohydrochloride monohydrate

C22H22FN3O2

IV IM

0.625–1.25 × 6–8 0.625–1.25 × 6–8

C21H23ClFNO2

IV IM Oral IV

1–2

IM Oral

25–50

9-fluoro-11β, 17,21-trihydroxy-16αmethylpregna-1,4-diene-3,20-dione

C22H29FO5

IV IM SC Oral

4

C14H22ClN3O2

25–50

100 (1–2 mg/kg) × 8–12

Corticosteroids Dexamethasone

4×4 4×4 4×4

NK1 Receptor Antagonists Aprepitant (Emend)

5-([(2R,3S)-2-((R)-1-[3,5bis(trifluoromethyl)phenyl]ethoxy)-3(4-fluorophenyl)morpholino] methyl)-1H-1,2,4-triazol-3(2H)-one

C23H21F7N4O3

Oral

40

α-(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo [3.3.1.02,4] non-7-yl ester

C17H21NO4

TD

0.5

Anticholinergics Transdermal scopolamine (Transderm Scop)

125 D1/80 D2-3

0.7 (40 mg); 1.6 (125 mg); 1.4 (80 mg)

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



AUC (ng•hr/mL)

Tmax (hr)

0.4

Bioavailability (%)

Vd (L/kg)

56

Protein Bound (%)

Metabolism

70–76

CYP 3A4, CYP 1A2, CYP 2D6

Plasma Half-Life (hr)

Adverse Effects

Other

Constipation, headache, QTc prolongation

No sedation

675

4

0.7 1.5–2.2

527

20.7 32.9 35.8

48 0.6 1

60

3

65

CYP 3A

75

5.8

69–77

CYP 2D6, CYP 3A, flavin monooxygenase

8

71

CYP 3A4, CYP 1A2, CYP 2D6 CYP 2D6, CYP 3A, CYP 1A2

6–8

60–80 2.6 97

8.3

62

3–14 HPB black box warning (Canada)

40

No QTc prolongation

EPS, QTc prolongation 69

1.5

>90

2–3

50–60

18

92

12–36

80

3.5

30

5–6

17.8

0.2–0.3 3–6 1–2

80–90

70

CYP 3A4

36–54a

FDA black box warning

Cumulative CINV doses associated with significant EPS

10 mg PONV dose insufficient EPS 90

0.5

Vd (L/kg)

9–16

97

CYP 3A4

2–6

61

78

CYP 2D6

2–9

25

93

2–3 16–19

CH3

O

N

HO

NH2 N H Serotonin

NN CH3

Tropisetron

Granisetron

N N CH3

N

N

O

O HO

Ondansetron

• Fig. 34.3

N N H

O N H

CH3

O

N N

O N H

O

H Palonosetron

Dolasetron

  Palonosetron and other 5-hydroxytryptamine type 3 receptor antagonists. The structure of the serotonin is shown on the left.

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100 75

No 5-HT3 Receptor Antagonist

50 25 0

Ca2+ internal release

SE C T I O N V

Ca2+ internal release

678

125

75 50 25 0

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

Ondansetron

100

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

SP concentration (M, log scale) SP

125

SP + 5-HT

Granisetron

100 75 50 25 0

C

B

Ca2+ internal release

Ca2+ internal release

A

SP concentration SP SP + 5-HT SP + 5-HT + Ondansetron 100

Palonosetron

75 50 25 0

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

SP concentration

SP concentration

SP SP + 5-HT SP + 5-HT + Granisetron

D

SP SP + 5-HT SP + 5-HT + Palonosetron

• Fig. 34.4

  The effect of 5-hydroxytryptamine type 3 receptor antagonists on serotonin enhancement of substance P (SP)-induced intracellular calcium ion (Ca2+) release. NG108-15 neuroblastoma cells were incubated with SP and subsequently exposed to serotonin. A, Serotonin (5-HT) enhancement of the SP response. Ondansetron (B), granisetron (C), and palonosetron (D) were preincubated with NG108-15 cells for 2 hours, then removed, after which serotonin was added and the SP response was measured. Unlike ondansetron and granisetron, palonosetron can partially reduce serotonin enhancement of SP activity. (From Rojas C, Li Y, Zhang J, et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther. 2010;335:362–368.)

shown that prophylaxis with palonosetron decreases CIV in a significant proportion of patients in the 5 days following chemotherapy treatment.19 Another mechanism that contributes to palonosetron’s high efficacy is its inhibition of cross talk between 5-HT3 and NK1 receptor signaling pathways.20 Palonosetron and the NK1 agonist substance P (SP) cannot bind to each other’s respective target receptors. However, serotonin and SP enhance each other’s potency, and 5-HT3-receptor antagonists and NK1-receptor antagonists block activation of vagal afferents by the other agonist.20 Palonosetron is associated with a sixfold reduction in serotonin enhancement of SP potency in vitro (Fig. 34.4). Granisetron and ondansetron, on the other hand, had no effect on SP potency in vitro. In an in vivo study in rat nodose ganglia, palonosetron reduced cisplatin-induced SP activation for hours after cisplatin administration.20 Palonosetron thus appears to have a prolonged downstream effect on SP function in vitro and in vivo that might be due to palonosetron’s ability to cause 5-HT3 receptor internalization and reduce receptor density at the cell surface. Studies have shown that 0.25 mg and 0.075 mg palonosetron are effective doses for preventing CINV and PONV, respectively, and with a half-life of 40 hours, palonosetron provides therapeutic effect for a 72-hour period.19,21 Unlike other 5-HT3-receptor

antagonists, palonosetron is not associated with QTc prolongation. Palonosetron’s long half-life makes it a potentially important treatment for postdischarge nausea and vomiting (PDNV), although its relative efficacy in this setting has yet to be demonstrated.

Dopamine Receptor Antagonists Droperidol Low-dose (0.625–1.25 mg intravenously [IV]) droperidol is an effective antiemetic for treatment of PONV and opioid-induced nausea and vomiting (OINV), with similar efficacy against nausea (RR [relative risk] = 0.65) and vomiting (RR = 0.65).3,22 Droperidol has a short half-life of 3 hours and, if used for the prevention of PONV, should be administered toward the end of anesthesia. At low doses, droperidol is an α-adrenergic receptor blocker that causes increased sedation (RR = 1.32).23 Therefore for PONV prophylaxis, droperidol should be administered at the minimum effective dose of 0.625 mg IV to reduce the risk of adverse effects. For OINV prophylaxis, although 50 µg of droperidol is the most effective dose to add to a morphine or piritramide patient-controlled analgesia (PCA) infusion pump, 25 µg of droperidol is the safer, recommended dose.24



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

In 2001, reports of arrhythmia and death associated with use of droperidol led the FDA to attach a black box warning to the drug’s label, after which droperidol use decreased 10-fold in the United States. According to the new label, droperidol is contraindicated in patients with known or suspected QT prolongation. Therefore absence of QT prolongation must be confirmed by electrocardiogram before droperidol administration, and electrocardiogram monitoring must be continued for 2 to 3 hours after drug administration. Many hospitals have removed droperidol from their formularies or placed restrictions on its use, in addition to drug shortages, so that droperidol usage is less than 2% of cases in the United States, even though more than 90% of anesthesiologists believe that the FDA black box warning is unwarranted.25 Those who argue against the black box warning question the clinical relevance of droperidol-induced QT prolongation, particularly because QT prolongation is associated with general anesthesia itself, as well as other drugs commonly administered during surgery (e.g., antibiotics). QTc prolongation after placebo, 0.625 mg droperidol, and 1.25 mg droperidol were 12, 15, and 22 msec, respectively.26 Similarly, 0.75 mg droperidol and 4 mg ondansetron were associated with 17- and 20-msec QT prolongation, respectively.8 It is possible, however, that these studies were inadequately powered to include patients with a rare but clinically significant predisposition to QT prolongation.8,26 Of note, there are polymorphisms in the ether-à-go-go related gene (hERG) receptor that occur in about 0.5% to 2% of the population, and it is possible that these are the patients who are at high risk when exposed to droperidol. Thus it is not possible to exclude the possibility that adding droperidol to other QT-prolonging interventions, including general anesthesia, can trigger QT prolongations that lead to cardiac arrhythmia.27

Haloperidol As a result of the black box warning for droperidol, there is a renewed interest in haloperidol, an older butyrophenone. Haloperidol is an effective treatment for psychiatric disorders at high doses and is an effective antiemetic at low doses. Haloperidol has a longer plasma half-life of 10 to 20 hours after intravenous administration. Like other D2-receptor antagonists, haloperidol is associated with extrapyramidal effects, including acute dystonia, pseudoparkinsonism, and akathisia.28 Haloperidol is metabolized in the liver, where 23% of haloperidol is reduced by a carbonyl reductase into a functional metabolite with high binding affinity to σ-opioid and D2 and D3 receptors.28 However, there is significant interindividual variation in haloperidol pharmacokinetics.28 Plasma concentrations of haloperidol correlate with dosage, drug efficacy, and incidence of adverse effects.28 Although CYP 3A4 is the primary enzyme responsible for haloperidol metabolism, with CYP 2D6 appearing to play only a minor role, several studies have shown that certain CYP 2D6 genotypes are associated with poor metabolism and are correlated with higher haloperidol plasma concentrations and lower drug clearance than genotypes associated with extensive metabolism (Fig. 34.5A and B). Specifically, individuals with 0, 1, 2, and more than 2 active CYP 2D6 alleles are considered poor, intermediate, extensive (most common), and ultrafast metabolizers, respectively. Thus poor metabolizers are at higher risk for adverse effects than are intermediate and extensive metabolizers.28 Reports of QT prolongation, torsades de pointes, and sudden death associated with use of haloperidol similar to those associated with droperidol led the FDA to issue an FDA alert for haloperidol

679

in 2007. It has not received a black box label because these severe adverse effects occurred in patients who had received off-label intravenous administration of haloperidol at doses greater than 35 mg/day, whereas only intramuscular administration has been approved by the FDA.

Metoclopramide Metoclopramide, a procainamide derivative and a benzamide prokinetic agent, is the most commonly used D2-receptor antagonist for antiemetic prophylaxis, primarily for PONV and chemotherapy associated with low emetogenic risk. It is assumed that both the central D2-receptor antagonist activity at the CTZ and vomiting center and peripheral activity in the GI tract contribute to the antiemetic effect. Metoclopramide acts on peripheral D2, muscarinic, and 5-HT4 receptors to induce prokinetic activity. Opioids can cause delayed gastric emptying, but metoclopramide enhances gastric motility and increases intestinal peristalsis, which reduces reflux of stomach contents and the urge to vomit. Because of its short half-life of 5 to 6 hours, metoclopramide is likely to have greatest efficacy if administered at the end of surgery. Metoclopramide was first prescribed for CINV in high doses (e.g., 200 mg every 4–6 hours), which cause extrapyramidal symptoms in more than 10% of patients.29 To reduce the incidence of adverse effects, metoclopramide is available in vials of just 10 mg. However, extensive studies and a meta-analysis have demonstrated that 10 mg metoclopramide has no clinically relevant antiemetic effect.30 In fact, a large and well-designed dose-response study in more than 3000 patients demonstrated that doses of 25 and 50 mg metoclopramide are effective in reducing PONV by about 37% (RR = 0.63, a similar efficacy as other commonly used antiemetics), whereas the rate for extrapyramidal symptoms was less than 1% (see Fig. 34.5C).31 Like haloperidol, metoclopramide is metabolized primarily by CYP 2D6. Although several studies have shown CYP 2D6 polymorphisms that result in reduced CYP 2D6 activity are associated with a higher incidence of metoclopramide adverse effects, no studies have investigated yet whether CYP 2D6 polymorphisms influence the antiemetic efficacy of the drug. Given that nearly 25% of metoclopramide is excreted unchanged, however, the effect of CYP 2D6 polymorphisms might be relatively small, at least in patients with normal renal function. Like other D2-receptor antagonists, metoclopramide is associated with severe cardiac adverse effects.32 High doses are associated with a high incidence of extrapyramidal symptoms, but lower doses (25–50 mg) are associated with a less than 1% incidence of dyskinetic and/or extrapyramidal symptoms.31 It is important to note that the FDA issued a black box warning for metoclopramide, given the high risk of developing tardive dyskinesia if metoclopramide use extends beyond 12 weeks. However, this concern likely does not apply to a short-term course of metoclopramide in the perioperative setting. Other D2-receptor antagonists such as alizapride, perphenazine, and prochlorperazine might be as effective as other commonly used antiemetics, but they are rarely used, and their side effect profiles are unclear compared with that of other antiemetics.22

Corticosteroids Dexamethasone is a synthetic glucocorticoid with antiinflammatory and immunosuppressant properties. With 20 to 30 times the binding affinity for glucocorticoid receptors of endogenous cortisol,

Gastrointestinal and Endocrine Systems

SE C T I O N V

Reduced haloperidol/dose [10–3/L]

680

n=3

n = 53

n = 99

n=4

0

1

2

3

• Fig. 34.5  Dependence of reduced haloperidol serum trough levels (A) and extrapyramidal symptoms (EPS) (B) on CYP 2D6 genotype after haloperidol doses of 2 to 24 mg. On the x-axis, 0 = no active alleles; 1 = 1 active allele; 2 = 2 active alleles; and 3 = 1 active and 1 or 2 duplication alleles. Black lines show medians, blue boxes show interquartile ranges, and error bars show the ranges of measured data. C, Cumulative incidence of postoperative nausea and vomiting (PONV) in treatment groups receiving placebo or 10, 25, and 50 mg metoclopramide. (A and B, From Brockmoller J, Kirchheiner J, Schmider J, et  al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther. 2002;72:438–552; C, From Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ. 2006;333:324.)

2.00

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Number of active CYP2D6 genes n=5

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n = 102

n=5

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Metoclopramide None 10 mg 25 mg 50 mg

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dexamethasone is a potent treatment for PONV and CINV. Even though dexamethasone is one of the most commonly used antiemetics, its mechanism of action remains unclear. Studies in animal models suggest that dexamethasone acts on the glucocorticoid receptor–rich bilateral NTS (i.e., the vomiting center), but not the area postrema.33 Although 8 mg is the most commonly used dose for prevention of PONV, dose-response studies suggest that 5 mg is the minimum effective dose for PONV prophylaxis (Fig. 34.6).34 Furthermore, a large factorial trial in more than 5000 patients found that 4 mg dexamethasone has similar efficacy to 4 mg ondansetron or 1.25 mg droperidol.35 Thus ambulatory surgery guidelines recommend 4 to 5 mg dexamethasone.36 Dexamethasone is more effective when given at the beginning rather at the end of surgery, which suggests that there is a delay in onset of action by about 2 hours.37 Furthermore, a single intraoperative dose of dexamethasone has not been associated with adverse effects.36 However, like other intravenous drugs containing phosphate esters, dexamethasone has been associated with perineal burning and itching when injected in awake patients.38 In addition, doses of 12 to 20 mg can be given for CINV.39 Dexamethasone is an effective and well-tolerated component of antiemetic combination therapy.35 Adding aprepitant to the typical treatment regimen for CINV—a 5-HT3-receptor antagonist (ondansetron) and a corticosteroid (dexamethasone)—further reduces the incidence of CINV. The doses of aprepitant recommended for CINV (125 mg on day 1, 80 mg on days 2 and 3) moderately inhibits CYP 3A4, the enzyme responsible for dexamethasone metabolism. In fact, aprepitant’s inhibition of CYP 3A4 activity approximately doubles the plasma concentration of dexamethasone (Fig. 34.7). Given that dexamethasone has high (80%) oral bioavailability, and that aprepitant also increases the peak plasma concentration and half-life of dexamethasone, aprepitant’s inhibition of CYP 3A4 activity probably plays a larger role in systemic rather than first-pass clearance of dexamethasone.40 Therefore doses of dexamethasone that are coadministered with aprepitant should be reduced by half to maintain dexamethasone plasma concentrations that are similar to regimens without aprepitant. The pharmacokinetics of ondansetron, which is partially metabolized by CYP 3A4, are not affected by aprepitant.40

NK1 Receptor Antagonists NK1 receptors are G-protein–coupled receptors found in both the central and peripheral nervous systems. NK1 receptors are

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



Striatal NK1 receptor occupancy (%)

0.6

Incidence (%)

0.5 0.4 0.3 0.2 0.1 Nausea

Vomiting

Placebo 5 mg* dexamethasone

>4 vomiting Use of rescue episodes antiemetics

1.25 mg dexamethasone 10 mg* dexamethasone

2.5 mg dexamethasone

• Fig. 34.6

  Incidence of nausea, vomiting, severe vomiting, and need for rescue antiemetics 0 to 24 hours after dexamethasone prophylaxis in a dose-ranging study. *P < 0.05 compared to placebo. (From Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg. 2000;91:1404–1407.)

350 Dexamethasone concentration (ng/mL)

100 90 80 70 60 50 40 30 20 10 0 0

0

300

681

1

10

100

1000

10000

Aprepitant plasma concentration (ng/mL)

• Fig. 34.8

  High correlation between aprepitant plasma concentration and NK1 receptor occupancy (0.97 [P < 0.001; 95% confidence interval = 0.94-1.00]). (From Bergstrom M, Hargreaves RJ, Burns HD, et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004;55:1007–1012.)

reduce emesis associated with a range of stimuli, including cisplatin, cyclophosphamide, irradiation, ipecacuanha, copper sulfate, opioids, and motion.41 NK1 receptor antagonists competitively inhibit SP binding to central NK1 receptors, effectively preventing neurotransmission within the central pattern generator for vomiting.42 Because cisplatin increases plasma levels of SP, NK1 receptor antagonists are particularly important for the prevention and treatment of CINV.43

250

Aprepitant

200 150 100 50 0

0

6

12

18

24

Time (hr) 20 mg oral dexamethasone + 32 mg ondansetron IV 125 mg oral aprepitant + 20 mg oral dexamethasone + 32 mg ondansetron IV 125 mg oral aprepitant + 12 mg oral dexamethasone + 32 mg ondansetron IV

• Fig. 34.7

  Mean plasma concentration profiles of dexamethasone when combined with other antiemetics. Aprepitant markedly increased the plasma concentration of dexamethasone. IV, Intravenous. (From McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the NK1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17–24.)

found in the GI tract and in high concentrations in regions responsible for regulating the vomiting reflex, including the brainstem nuclei, the NTS, and the area postrema. SP, a member of the tachykinin family of neuropeptides, is the dominant ligand of NK1 receptors. In animal models, SP activation of NK1 receptors in the area postrema induces retching, and NK1 receptor antagonists

Currently aprepitant is the only FDA-approved NK1 receptor antagonist. Aprepitant has greater efficacy for preventing vomiting than any other single intervention, with RR reductions of more than 50%.41,44 Furthermore, aprepitant has greater efficacy against both acute and delayed POV and CIV.43,45,46 Aprepitant is available as an oral capsule that is easy to coadminister with other surgical premedication for PONV prophylaxis. Whereas aprepitant is highly effective on its own, it reaches its optimal efficacy against early emesis when combined with other antiemetics, such as 5-HT3receptor antagonists and/or dexamethasone.43,45,46 Its efficacy against nausea, however, appears to be comparable to other treatment options.41 Like 5-HT3-receptor antagonists, aprepitant is nonsedative; it has a long half-life of 9 to 13 hours. Furthermore, aprepitant is not associated with QTc prolongation.41 Aprepitant is primarily metabolized by CYP 3A4; CYP 1A2 and CYP 2C19 also contribute to its metabolism. Positron emission tomography studies have shown that aprepitant can penetrate the blood-brain barrier to bind to NK1 receptors in the area postrema.47 The FDA-approved dose of aprepitant for PONV prophylaxis is 40 mg, which is associated with only 75% receptor occupancy (Fig. 34.8). Doses of 100 mg or more, such as the FDA-approved 125 mg for CINV prophylaxis, are sufficient to achieve greater than 90% NK1 receptor occupancy. Patients with cancer typically receive 125 mg aprepitant the day of chemotherapy, followed by 2 days of 80 mg aprepitant.48 Aprepitant doses as high as 375 mg are associated with the same level of receptor occupancy as 125 mg and thus have no clinical advantage.

Gastrointestinal and Endocrine Systems

Scopolamine Scopolamine is a competitive antagonist of acetylcholine at muscarinic receptors, and the most effective single agent for preventing motion sickness.49 Scopolamine is available in oral, parenteral, and transdermal formulations. The 0.3- to 0.6-mg oral and 0.2-mg parenteral doses are associated with a short duration of action of 5 to 6 hours and some adverse effects, most commonly dry mouth, drowsiness, and blurred vision.50 Redosing with oral or parenteral doses can result in variable drug plasma concentrations, which if too high are associated with severe autonomic and CNS effects and if too low are associated with inadequate antiemetic efficacy. A transdermal formulation of scopolamine was developed to overcome the limited half-life and clinical efficacy of the oral and parenteral formulations. A transdermal delivery system is also an advantage when oral doses are intolerable. Transdermal scopolamine (TDS) is available in a thin (0.2-mm) patch made up of four layers: an outer membrane, a drug reservoir mixed with mineral oil and polyisobutylene, a rate-limiting microporous membrane, and an adhesive layer closest to the skin. In vitro studies using human cadavers show wide variation in skin permeability between both application sites and individuals. Therefore the patch is recommended for use at the postauricular site, a highly permeable area, and the rate-limiting microporous membrane has been designed to deliver scopolamine at a slower rate than that achieved in the least porous postauricular skin sample tested.49 In addition, the adhesive layer contains a 140-µg priming dose of scopolamine to overcome the skin as the primary compartment before a more constant scopolamine delivery leads to steady-state plasma concentrations. The drug reservoir contains 1.5 mg scopolamine that is released at a constant rate of about 5 µg/hr for 3 days. The controlled drug delivery decreases the incidence of adverse side effects compared with oral and parenteral formulations. 51,52 This delivery rate maintains therapeutic plasma concentrations, estimated to be greater than 50 pg/mL. Plasma concentrations greater than 50 pg/mL and antiemetic efficacy are both observed 6 hours after patch application (Fig. 34.9A).53,54 Drug efficacy peaks at plasma concentrations greater than 100 pg/mL, observed 8 to 12 hours after application. Therefore TDS should be administered ideally 4 to 6 hours before an antiemetic effect is required. However, supplementing TDS with 0.3 to 0.6 mg oral scopolamine results in therapeutic plasma concentrations after only 1 hour (see Fig. 34.9B and C).55

500 Total quantity of scopolamine permeated (µg/cm2)

The neurotransmitter acetylcholine acts on cholinergic receptors in the CTZ, vestibular system, and cerebellum. According to the current model of motion sickness, an orientation disparity comparator in the cerebellum compares expected sensory input from memory with actual sensory input, and any significant discrepancy between the two triggers symptoms of motion sickness. Acetylcholine might be involved in integrating sensory stimuli in the vestibular nuclei, as well as transmitting information regarding expected sensory input to the cerebellum. Therefore anticholinergic agents like scopolamine might facilitate habituation to motion by preventing acetylcholine from relaying signals to the comparator and instead allowing a new sensory pattern to develop that reflects the actual environment.49 Acetylcholine released from the gut wall also appears to increase gut motility and secretion. Anticholinergic agents thus play an important role in the prevention of motion sickness and PONV.

400 300 200 100 0

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SE C T I O N V

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6 12 18 24 30 36 42 48 54 60 66 72

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682

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C • Fig. 34.9

TDS + 0.6 mg oral scopolamine

TDS + 0.3 mg oral scopolamine

TDS

  A, In vitro permeation of scopolamine at 30°C from various patch locations. B, Transdermal scopolamine (TDS) effects on plasma concentrations. Plasma concentrations of scopolamine persist up to 72 hours after TDS application (n = 15). C, Percentage of subjects with plasma scopolamine concentration greater than 50 pg/mL, 0 to 22 hours after treatment in three experimental groups. *P < 0.05 (Fisher’s exact test) when TDS + 0.6 mg and TDS + 0.3 mg are compared with TDS only group. (From Nachum Z, Shupak A, Gordon CR. Transdermal scopolamine for prevention of motion sickness: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2006;45:543–566.)

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



TDS is an effective antiemetic intervention, associated with a risk reduction of 0.56 and 0.54 for PON and POV, respectively, if applied the night before surgery, and with a risk reduction of 0.61 and 0.74 for PON and POV, respectively, if applied the day of surgery.56 Interestingly, despite wide variation between individual plasma concentrations, correlation of plasma concentrations 8 hours after TDS application in the same individual on different occasions is still 0.52 (P < 0.05).57 TDS is generally well tolerated; adverse effects are similar to those associated with oral and parenteral scopolamine. The most common adverse effects are dry mouth, allergic contact dermatitis, and drowsiness. The drowsiness appears to be associated with PONV more than motion sickness.49 Scopolamine is not recommended for pediatric patients and should be used with caution in older patients because of the sedative effects and the risk of delirium.

H1-Receptor Antagonists H1-receptor antagonists can be used for management of motion sickness, PONV, and OINV. Agents like diphenhydramine, promethazine, and cyclizine are reversible competitive H1-receptor antagonists with moderate anticholinergic (antimuscarinic) and weak antidopaminergic activity. Although the mechanism of their antiemetic efficacy is not fully understood, H1-receptor antagonists likely act on receptors in the vestibular system and vomiting center.23 Side effects include drowsiness, dry mouth, blurred vision, urinary retention, and extrapyramidal symptoms.22,58 Although H1-receptor antagonists are generally well tolerated, cost-effective, and have been used in clinical practice for several decades, they have not been as well studied as other more recently developed antiemetics.59 Dose-response relationships, side effect profiles, and the benefit of repeat dosing remain unclear.58,60 Their efficacy against motion

sickness might give H1-receptor antagonists an important role in antiemetic prophylaxis for ambulatory patients.61

Dimenhydrinate and Diphenhydramine Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chlorotheophylline, a chlorinated theophylline derivative, in a 1 : 1 ratio. Dimenhydrinate must be metabolized into its active ingredient diphenhydramine to attain antiemetic efficacy. Therefore dimenhydrinate has a slower onset of action and is administered as a 60-mg dose to match the potency of 30 mg diphenhydramine.59 Diphenhydramine itself undergoes N-demethylation to its principal metabolite monodesmethyldiphenhydramine (DMDP) in the liver.62 Oral diphenhydramine bioavailability ranges from 43% to 72%, probably owing to first-pass metabolism, with peak plasma concentrations of approximately 64 ng/mL after approximately 2.5 hours. 62,63 Plasma concentration of diphenhydramine covaries with that of DMDP (Fig. 34.10A). The observed plasma half-life of oral dimenhydrinate is 3 to 9.3 hours, and the elimination half-lives after intravenous and oral administration are 8.4 and 9.2 hours, respectively, for diphenhydramine and 9.3 and 7.3 hours, respectively, for DMDP (see Fig. 34.10B).64 The observed metabolite area under the curve (AUC) after oral administration (218 hr.ng/mL) is significantly larger than after intravenous administration (145 hr-ng/mL).64 Sedative and performance-impairing side effects are typically associated with diphenhydramine doses greater than or equal to 50 mg and differ from placebo only within the first 3 hours.62,65 Although there is a positive correlation between plasma concentration and sedative effects, there is also wide variation among individuals in the severity and persistence of these effects.65

300

r = 0.79 (P < 0.05) Intravenous

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• Fig. 34.10  A, Plasma concentrations of diphenhydramine and its metabolite desmethyl diphenhydramine following intravenous and oral administration of diphenhydramine. B, Relation of clearance of intravenous diphenhydramine to total area under the plasma concentration-time curve (AUC) for the metabolite desmethyl diphenhydramine, as determined by linear regression analysis. Appearance of the metabolite thus mirrors the disappearance of diphenhydramine. (From Blyden GT, Greenblatt DJ, Scavone JM, et al. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol. 1986;26:529–533.)

9

Gastrointestinal and Endocrine Systems

A systematic review incorporating 18 clinical trials and 3045 patients demonstrated that diphenhydramine is associated with decreased POV and PONV, although its impact on PON was not significant.58 In addition, 50 mg IV dimenhydrinate is similarly effective as 4 mg IV ondansetron for the prevention of PONV in patients undergoing elective laparoscopic cholecystectomy.66 For management of motion sickness, 100 mg oral dimenhydrinate is superior to TDS, whereas 50 mg is similarly effective as TDS.49 For OINV management, diphenhydramine can be safely and effectively coadministered with morphine via a PCA pump, especially given the similar pharmacokinetic profiles of the two drugs. Administering 30 mg diphenhydramine at induction, followed by a 4.8 : 1 diphenhydramine-morphine solution via a PCA pump, reduced emesis without morphine-sparing or sedative effects.59 The initial intraoperative dose serves to establish a therapeutic plasma concentration before the infusion, thereby minimizing the risk of sedative side effects associated with larger diphenhydramine doses during the postoperative period.

Promethazine Promethazine is a phenothiazine derivative and a potent antihistamine with moderate antimuscarinic activity. Although more than 80% is absorbed, promethazine undergoes extensive first-pass hepatic glucuronidation and sulfoxidation, resulting in low absolute bioavailability of approximately 25%.67 Peak plasma concentrations of promethazine (2.4–18.0 ng/mL) are observed between 1.5 and 3 hours after administration (Fig. 34.11A). Like other drugs that undergo extensive hepatic first-pass metabolism, plasma concentrations of its metabolite, promethazine sulfoxide (PMZSO), peak earlier and higher following oral administration compared with intravenous administration (see Fig. 34.11B).67 Overall, however, PMZSO plasma AUCs are not significantly different following oral or intravenous administration. Time to effect after intravenous and intramuscular injection is 5 and 20 minutes, respectively.68 With a plasma half-life after intravenous and intramuscular injection of 9 to 16 hours and 6 to 13 hours, respectively, promethazine’s duration of effect is typically 4 to 6 hours, up to 12 hours.68 Promethazine is also effective for rescue treatment of established PONV and has been combined with 5-HT3-receptor antagonists and TDS to reduce both the frequency and severity of PONV.69–72 For PONV management, 12.5 to 25 mg is administered toward the end of surgery and every 4 hours, as needed, with doses of coadministered analgesics and/or barbiturates reduced accordingly.68 Studies investigating a 6.25-mg promethazine dose to reduce the incidence of sedative side effects have produced conflicting results on antiemetic efficacy.71 Because H1 receptors are involved in the development of inflammatory pain and hyperalgesia, administering antihistamines like promethazine can also reduce pain levels in addition to the incidence of emesis. In one study, preoperative administration of 0.1 mg/kg IV promethazine reduced postoperative morphine consumption by approximately 30% in the first 24 postoperative hours.73 Promethazine received a black box warning from the FDA in 2004 indicating that the drug should not be used in children younger than 2 years of age because of potential fatal respiratory depression. The warning label also recommends that promethazine should be administered with caution and at the lowest effective dose in children 2 years of age and older. The promethazine hydrochloride injection also received a black box warning from the FDA in 2009 indicating that severe tissue injuries, including gangrene, can rarely be associated with intravenous administration

Blood concentration of promethazine (ng/mL)

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• Fig. 34.11

  Blood concentration-time profiles of promethazine (A) and promethazine sulfoxide (B) in a human volunteer following administration of 12.5 mg intravenous (IV, purple) or 25 mg oral (blue) promethazine. (From Taylor G, Houston JB, Shaffer J, et al. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol. 1983;15:287–293.)

of promethazine. In anesthesia practice it is important to inject promethazine only through a well-established and secure IV line or infuse the drug diluted in saline solution.

GABA Receptor Agonists Propofol Propofol has several mechanisms of action, including potentiation of GABAA receptors. Administration of propofol-based total intravenous anesthesia (TIVA) instead of volatile anesthetics can reduce the incidence of PONV by about 20%.35 That propofol



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

has antiemetic effects is supported by the finding that repeat doses of 20 mg propofol via a patient-controlled delivery device in the postanesthesia care unit (PACU) significantly reduced PONV.74 However, this effect could not be reproduced in a similar study, and another study found that both propofol and midazolam had antiemetic properties only under clinical sedation.75,76 Therefore it is likely that the reduced incidence of PONV after TIVA with propofol compared with general anesthesia with inhaled gas is at least in part a result of not administering volatile anesthetics rather than the potential antiemetic effects of propofol. Some patients experience anticipatory nausea and vomiting before chemotherapy begins or earlier in the treatment regimen than expected. As a learned response to chemotherapy, anticipatory nausea and vomiting can affect up to 25% of patients by the fourth treatment cycle.77,78 However, much about its pathogenesis and management remains unclear.

Benzodiazepines Benzodiazepines are currently the most commonly used anxiolytics. These agents act as positive modulators of GABAA receptors. Increased GABAA receptor activity results in varying levels of CNS depression, including sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic effects. In addition to decreased anxiety, the mechanism of action of benzodiazepines is believed to involve GABAA receptor-mediated reduction of dopamine and 5-HT3 receptor activity in the CTZ.79 Another specific pathway that has been suggested is that benzodiazepines decrease adenosine reuptake, thereby leading to decreased synthesis, release, and postsynaptic activity of dopamine in the CTZ.80,81 GABAA-receptor activation is also associated with reduced opioid analgesia.82 Opioids are believed to produce an analgesic effect by inhibiting GABA-receptor pain modulation in the periaqueductal gray matter and the rostral ventral medulla. In one study, 0.75 mg IV flumazenil, a benzodiazepine antagonist, enhanced postoperative morphine analgesia in patients who received intravenous diazepam preoperatively compared with patients who did not receive flumazenil.82 Therefore opioid analgesia can be improved by using benzodiazepines of short duration of action and/or by coadministering flumazenil with morphine in the immediate postoperative period. Diazepam is typically administered as a 5- to 10-mg dose 2 hours before surgery. The agent appears to be effective against both nausea (RR = 0.50, 95% confidence interval [CI] 0.25–0.99) and vomiting (RR = 0.85, 95% CI 0.58–1.24).22 Because of a long half-life of more than 24 hours, other benzodiazepines with shorter durations of action, such as lorazepam and midazolam, can be used instead. Lorazepam is the preferred agent for anticipatory nausea and vomiting. It can also be used for the prophylaxis and treatment of PONV and CINV.83 Like diazepam, lorazepam appears to have a greater effect on nausea (RR = 0.55, 95% CI 0.33–0.93) than vomiting (RR = 0.61, 95% CI 0.33–1.13) compared with placebo.22 For PONV prophylaxis, patients receive 0.05 mg/kg (up to 4 mg maximum) 1 to 2 hours before surgery. For anticipatory nausea and vomiting, guidelines recommend 0.5 to 2 mg lorazepam on the night before and morning of surgery, and for CINV management, 0.5 to 2 mg every 4 to 6 hours on days 1 to 4 posttreatment.84 Lorazepam might be insufficient as an antiemetic on its own, but it can be safely combined with other antiemetic agents to manage CINV.85 A randomized controlled trial found lorazepam effective in managing anticipatory, acute, and delayed CINV, especially

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when coadministered with 2 mg/kg metoclopramide IV.86 Mild sedation (lethargy but arousable without any disorientation) and amnesia (no memory of chemotherapy treatment) were more common in patients treated with lorazepam. Lorazepam is readily absorbed into the bloodstream with an absolute bioavailability of 90%. Peak plasma concentrations of 20 ng/mL after a 2-mg dose are reached approximately 2 hours after administration. The plasma half-life of lorazepam is approximately 12 hours and 18 hours for its primary metabolite, lorazepam glucuronide. Intravenous midazolam is the most commonly used premedication in ambulatory surgery for induction of general anesthesia and preoperative sedation owing to its rapid onset of action, relatively short half-life, low cost, and low incidence of side effects.87 For PONV prophylaxis, a 2-mg dose of midazolam can be given before or after induction or postoperatively as a continuous infusion. Ahn and colleagues examined previous randomized controlled trials of midazolam and PONV via a database search. The investigation revealed a reduction in PONV (RR 0.45, number needed to treat 3) with similar findings for PON and POV in isolation.88 Midazolam is rapidly metabolized to 1′-hydroxymidazolam by both hepatic and intestinal CYP 3A4. Therefore drugs like aprepitant that inhibit CYP 3A4 activity could lead to prolonged sedation owing to increased exposure to midazolam. In a study in which healthy volunteers received a 2-mg dose of oral midazolam during the week preceding the study, a second dose on day 1, and a third on day 5, participants were randomly assigned to receive an aprepitant dosing regimen similar to CINV (125 mg on day 1 and 80 mg on days 2–5) or PONV prophylaxis (40 mg on day 1 and 25 mg on days 2–5).89 CINV doses of aprepitant led to a 2.3-fold increase in midazolam plasma AUC on day 1 and a 3.3-fold increase on day 5 (Fig. 34.12A, upper panel), as well as increased maximum observed plasma concentrations and half-life of midazolam. The latter can be explained by inhibition of both first-pass metabolism and systemic clearance of midazolam by aprepitant. PONV doses of aprepitant had no significant effect on oral midazolam metabolism (see Fig. 34.12A, lower panel). Because aprepitant cannot inhibit first-pass metabolism of CYP 3A4 substrates when they are given intravenously, it is not surprising that both CINV and PONV doses of aprepitant have no significant effect on intravenous midazolam metabolism (see Fig. 34.12B).90–92

Opioid Receptor Antagonists Although the FDA has not specifically approved the use of 5-HT3and D2-receptor antagonists for OINV, these agents significantly reduce the incidence of nausea and vomiting after opioid administration.93–97 Antiemetic agents that specifically target opioid receptors might also have efficacy against OINV, which has the advantage of simultaneously targeting multiple other opioid-induced adverse effects, such as postoperative ileus.98

Naloxone Other techniques to reduce PONV can come from novel uses of preexisting medications. One such technique is using a low-dose naloxone infusion to reduce the side effects of opioid administration. In one study the authors randomly assigned 60 patients receiving morphine PCA to a continuous infusion of naloxone 0.25 µg/kg per hour, 1 µg/kg per hours, or placebo. They found a reduced rate of adverse side effects, including nausea and vomiting, in both naloxone groups compared with the placebo group. Interestingly,

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  Interaction between midazolam and aprepitant. A, Plasma concentration-time profiles of 2 mg oral midazolam before the study, on day 1, and on day 5 when coadministered with 125 mg aprepitant on day 1 and 80 mg on days 2 to 5 in 8 healthy male subjects (upper panel). Plasma concentrationtime profiles of 2 mg oral midazolam before the study, on day 1, and on day 5 when coadministered with 40 mg aprepitant day 1 and 25 mg days 2 to 5 (lower panel). B, Plasma concentrations of midazolam when administered intravenously, alone, and with 125 mg oral aprepitant in 12 healthy subjects. C, Incidence of opioid-induced nausea and vomiting after prophylaxis with 6 and 12 mg alvimopan. CINV, Chemotherapy-induced nausea and vomiting; PONV, postoperative nausea and vomiting. (A, From Majumdar AK, McCrea JB, Panebianco DL, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther. 2003;74:150–156; B, From Majumdar AK, Yan KX, Selverian DV, et al. Effect of aprepitant on the pharmacokinetics of intravenous midazolam. J Clin Pharmacol. 2007;47:744–750; C, From Adolor Corporation. Advisory Panel briefing document. Entereg (alvimopan) Capsules for postoperative ileus. 2007. Available at: http://www.fda.gov/ohrms/dockets/ ac/08/briefing/2008-4336b1-02-Adolor.pdf.)

there appeared to be an opioid-sparing effect in the low-dose naloxone group as this cohort used less morphine in the study period compared with placebo.99

Alvimopan Alvimopan, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, is approved by the FDA to reverse postoperative ileus after colectomy. Although opioids do have some peripherally mediated analgesic effects, opioid analgesia primarily involves central µ, κ, and δ receptors in the rostral anterior cingulate cortex, the brainstem, and the dorsal horn of the spinal cord.100 Opioid agonist activity

at peripheral receptors in the gut, on the other hand, inhibits the release of acetylcholine from the mesenteric plexus and stimulates µ receptors, thereby reducing muscle tone and peristaltic activity. The resulting delayed gastric emptying and gastric distention stimulate visceral mechanoreceptors and chemoreceptors, which trigger nausea and vomiting via a serotonergic signaling pathway. Alvimopan’s high polarity and large zwitterionic structure prevent penetration of the blood-brain barrier, such that potency at binding peripheral µ receptors is 200 times that of central µ receptors.98,101 By selectively targeting peripheral µ receptors, alvimopan prevents peripheral opioid emetogenic effects without affecting their central analgesic effects.102,103

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

Cannabinoids Cannabinoids have demonstrated some success in the prevention of CINV but have never been shown to prevent PONV. KleineBrueggeney et al. administered 0.125 mg/kg IV tetrahydrocannabinol or placebo to 40 patients at high risk for PONV. The endpoints examined included PONV during the first 24 hours and side effects including sedation and psychotropic alterations. They found the tetrahydrocannabinol group had a 12% reduction in overall PONV compared with placebo. The authors postulated that this is a less significant effect than standard therapies, which produce a 25% reduction in PONV; this combined with an unacceptable side effect profile provoked the investigators to terminate the study before completion. Thus with the current evidence, cannabinoids cannot be recommended for prevention of PONV in high-risk patients.105

Risk-Based Prophylaxis Although all FDA-approved antiemetics have been proven to be safe in multiple clinical trials, no agent is without side effects. Therefore only patients at moderate to high risk for PONV should receive prophylaxis. A simplified risk score, such as the Apfel score (Fig. 34.13), can be useful for predicting PONV in adult patients undergoing inhalational anesthesia and thus for identifying which patients should be targeted for prophylaxis. The positive predictors included in the Apfel score are female gender, history of motion sickness or PONV, nonsmoking, and use of postoperative opioids.106 The incidence of PONV associated with 1, 2, 3, and 4 risk factors is 10%, 21%, 39%, 61%, and 79%, respectively (Fig. 34.14). An easy-to-remember guideline is that one antiemetic intervention is recommended for each risk factor present. It is also important to note that multimodal therapy should include drugs of different receptor classes, because repeat dosing of drugs of the same receptor class do not improve protection against PONV.107

Enhanced Recovery After Surgery A risk-based assessment of PONV and antiemetic prophylaxis should be part of an enhanced recovery pathway. Patients can be stratified based on established risk factor scoring systems. With increasing risk of PONV, multimodal prophylactic antiemetics should be implemented. Patients with 1 or 2 risk factors should be supplied with 2 prophylactic agents, whereas those with 3 or 4 risk factors should receive 3 prophylactic agents with consideration

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Because of its high binding affinity (Ki = 0.4 nM) and low dissociation rate (half-life = 30-44 min), alvimopan has low bioavailability (6%).104 Alvimopan is quickly absorbed, with a time to maximum plasma concentration of 2 hours after administration. Alvimopan also has a long half-life of 10 to 17 hours.104 Plasma clearance averages at 400 mL/min and is primarily mediated by biliary secretion. Alvimopan is metabolized by intestinal flora, with an active but clinically irrelevant amide hydrolysis metabolite (ADL 08-0011) that has lower binding affinity than alvimopan itself. Alvimopan is only available as a 12-mg oral capsule. Patients can be given 12 mg 30 minutes to 5 hours before surgery, followed by 12 mg twice a day for up to 7 days after surgery (maximum of 15 doses).104 Furthermore, 12-mg alvimopan has been shown to reduce OINV and to be well tolerated by ambulatory patients in the postdischarge period (Fig. 34.12C).103

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  Results of the IMPACT trial showing the effect of multimodal prophylactic antiemetic therapy on postoperative nausea and vomiting (PONV). N = 5161 patients. Blue dots show the average value for each number of prophylactic antiemetics. Orange dots show the incidence for each antiemetic or combination of antiemetics. Ond, Ondansetron; Dex, dexamethasone; Dro, droperidol. (From Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–2451.)

of adding TIVA. In addition to prophylactic antiemetics, the choice of anesthetics, reduction in preoperative fasting, and adequate hydration may all contribute to the reduction of PONV in this patient population. An overall strategy of minimizing opioids in favor of regional anesthesia and adjuvant nonopioid medications also reduces the likelihood the patient will experience bowel dysfunction, nausea, and vomiting postoperatively.108

Multimodal Therapy No antiemetic agent can completely eliminate the incidence of PONV. A Cochrane review found the overall RR for antiemetics

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to be 0.60 to 0.80, that is, an RRR of 20% to 40%.22 However, the treatment effect might be slightly optimistic given that there is evidence of publication bias toward small studies with more positive results. The International Multicenter Protocol to quantify the relative impact of single and combined Antiemetics in a randomized Controlled Trial of factorial design (IMPACT) found that the RRs for 4 mg ondansetron, 4 mg dexamethasone, and 1.25 mg droperidol all equal approximately 0.75 (i.e., an RRR of 25% for each intervention; see Fig. 34.14).35 The study also demonstrated that each antiemetic intervention acted independently, which means that the efficacy of combination therapy can be estimated by multiplying the RR associated with each intervention. This independence of action implies that each additional antiemetic intervention is associated with less effectiveness than the previous one owing to an already decreased baseline risk of PONV. Using new classes of antiemetics synergy with mainstay drugs has reduced the incidence of PONV compared with conventional treatment. Numerous studies have demonstrated improved outcomes when multiple classes of antiemetics are used together as prophylaxis. One example is a study of chemotherapy-naive patients who were pretreated with antiemetic therapy comprising palonosetron (0.75 mg IV), dexamethasone (9.9 mg IV), and aprepitant (125 mg orally) The primary endpoint was the proportion of patients who did not experience vomiting and did not require rescue medication. Prevalence of the primary endpoint during the acute phase, delayed phase, and overall was 100%, 91.9%, and 91.9%.109 A prospective, double-blinded, randomized study compared aprepitant 40 mg orally with dexamethasone versus ondansetron 4 mg IV with dexamethasone in patients undergoing elective craniotomy. The aprepitant dexamethasone group significantly decreased POV up to 48 hours postoperatively (16% vs. 38%). There was no difference in the incidence of nausea or need for rescue medication between the study groups.110 A new combination drug available is NEPA, an oral fixed-dose combination of 300 mg netupitant and 0.5 mg palonosetron. In a study of 1455 chemotherapy patients who received dexamethasone plus either single-dose NEPA or palonosetron alone were evaluated for no emesis and no rescue therapy for 25 to 120 hours. Complete response was significantly higher in the NEPA versus the palonosetron group (76.9% vs. 69.5%, P = 0.001). The side effect profiles for both drugs were similar. This fixed-dose antiemetic combination offers improved prophylaxis from single-dose treatment.111 Acupuncture has been extensively studied as a nonpharmacologic method for the prevention of PONV. Although there are more than 300 acupuncture points, one point that has been shown to be efficacious is the P6 point (the sixth point along the pericardial meridian). It can be located at 2 inches proximal to the palmar aspect of the wrist, between the flexor carpi radialis and palmaris longus tendons. Stimulation of the P6 acupuncture point has shown efficacy for prevention and treatment of nausea and vomiting in the perioperative period. A Cochrane review summarizing 59 trials with 7667 participants drew the following conclusions. P6 acupoint stimulation significantly reduced postoperative nausea (RR = 0.60), vomiting (RR = 0.68), and the need for rescue antiemetics (RR = 0.64) compared with placebo or sham. There is no difference between P6 acupoint stimulation and established antiemetic pharmacotherapy for prevention of PONV. Lastly, there is insufficient evidence to suggest combination therapy is beneficial over acupressure or drug prophylaxis as a sole treatment.112 However, some studies have demonstrated mixed results. A study of 94 patients undergoing cesarean section with spinal

anesthesia were randomly assigned to receive transcutaneous accupoint electrical stimulation at the P6 point versus a sham location in hope of relieving both intraoperative and postoperative nausea and vomiting. No difference was found between the groups for either endpoint. The authors mentioned the study might have been underpowered.113 In general, direct acupuncture needle stimulation and electroacupuncture are associated with greater efficacy compared with acupressure. However, the optimal duration of stimulation and the amount of current is not known.

Emerging Developments Novel Antiemetic Drugs With the success of novel antiemetics like aprepitant and palonosetron, there is great promise for other new agents currently under investigation. These include newer NK1 receptor antagonists like the intravenous prodrug of aprepitant known as fosaprepitant, as well as the phase III–ready rolapitant (rolapitant hydrochloride, Schering-Plough SCH619734), both developed for CINV prevention. Upon injection, fosaprepitant is rapidly converted to aprepitant and therefore has the same mechanism of action as aprepitant. For CINV prevention, patients can receive fosaprepitant 150 mg as an IV infusion over 20 to 30 minutes before chemotherapy on the day of chemotherapy, followed by 2 to 3 days of treatment with other antiemetic agents like dexamethasone and ondansetron. Rolapitant appears to have several advantages over aprepitant, including a long half-life of 180 hours. It is more rapidly absorbed and does not inhibit CYP 2C9, 2C19, 2D6, and 3A4 or P-glycoprotein in vitro, suggesting that rolapitant has a low risk of interacting with concomitant medications.114 Oral doses of rolapitant appear to be rapidly absorbed and well tolerated without significant side effects. A dose-response study reported that rolapitant reduced POV up to 120 hours after surgery in high-risk patients, and that 70 mg and 200 mg were the most effective doses in terms of complete response.114 However, the optimal rolapitant dose has yet to be determined. In addition, rolapitant is currently available only in an oral formulation and therefore must be administered preoperatively. Amisulpride, a dopamine D2/D3 antagonist, is currently in phase III trials. It is being examined for its efficacy in the prevention of PONV in the adult surgical population. A multicenter study of adult inpatients undergoing elective surgery with general anesthesia randomly assigned participants to amisulpride 5 mg IV on induction or placebo. The primary endpoint was no retching or vomiting in the 24-hr postoperative period and no use of rescue antiemetics. The incidence of nausea was a secondary endpoint. In the U.S. component of the study, 46.9% of patients achieved the primary endpoint in the amisulpride group while 33.8% achieved in the placebo group (P = 0.026). Nausea occurred less in the study group. There was no clinically significant difference in the safety profile of the study drug compared with the placebo. Specific concerns examined were QT prolongation, extrapyramidal side effects, and sedation that were problematic for this group of antiemetics in the past.115

Postdischarge Nausea and Vomiting As the number of surgeries performed on an outpatient basis continues to grow, there is increasing interest in using antiemetic agents to prevent and treat postdischarge nausea and vomiting



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

(PDNV). Because outpatient procedures are typically less invasive and shorter in duration than inpatient procedures, the relatively lower exposure to emetogenic inhalational anesthetics and opioids predicts a relatively lower incidence of PONV in the postanesthesia care unit. However, a study in 2170 ambulatory patients in the United States found that the incidence of nausea and vomiting after discharge from the hospital was 37%, even after intraoperative prophylaxis with ondansetron or dexamethasone.116 PDNV is

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particularly a concern because it occurs when patients no longer have access to fast-acting intravenous rescue treatment, and PDNV limits their ability to tolerate oral antiemetics. Ideal antiemetics for PDNV should have a long duration of action with a safe side effect profile, such as dexamethasone, palonosetron, TDS, and aprepitant. However, further studies are required to investigate the absolute and relative value of these and other antiemetics in the postdischarge setting.

Key Points • Despite new insights into relevant target receptor function and the successful development of novel antiemetic agents, the actual mechanisms of PONV remain unknown. • Ondansetron is the most commonly used serotonin type 3 (5-HT3)-receptor antagonist for prevention and treatment of PONV and CINV, probably because it is not associated with sedation that might slow recovery from anesthesia. • Low-dose droperidol (0.625–1.25 mg), a dopamine type 2 (D2) receptor antagonist, used to be the most commonly used antiemetic for the prevention of PONV; however, potential for torsades de pointes and cardiac arrest led to an FDA black box warning that has significantly reduced its usage in the United States. • Metoclopramide is an alternative D2 receptor blocker; 25 mg is the minimally effective dose for preventing PONV. Extrapyramidal symptoms associated with the 25-mg dose affect less than 1% of patients, but like other D2 antagonists, arrhythmias have been described. • The antiemetic effect of glucocorticoids such as dexamethasone is well established although poorly understood. Most doseresponse studies suggest that 4 mg is the minimally effective dose with equal efficacy as 4 mg ondansetron and 1.25 mg droperidol.

• Aprepitant is the first FDA-approved NK1 receptor antagonist. An oral dose of 40 mg aprepitant reduces nausea by about 30% and vomiting by more than 50%. It is thus particularly useful for surgeries in which postoperative vomiting might affect the success of the surgery. • TDS is the only approved anticholinergic for prevention of PONV. RRR is comparable to other antiemetics; its long duration of action makes TDS a suitable antiemetic for preventing PDNV in ambulatory patients. • H1 antagonists such as dimenhydrinate, cyclizine, and promethazine are less popular, mainly because of their sedative and psychotropic side effects and the potential for vein irritation and tissue damage. • Alvimopan is a peripheral opioid receptor antagonist indicated for the prevention of ileus after colectomies. Secondary data analyses suggest that it might reduce OINV. • The effectiveness of antiemetics when given prophylactically is critically dependent on the patient’s risk for PONV. This can be easily assessed using a simplified risk score for PONV consisting of four risk factors: female sex, history of motion sickness and/or PONV, nonsmoking status, and anticipated use of postoperative opioids.

Key References

Carlisle J, Stevenson C. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2006;(3):CD004125, A systematic review of more than 730 trials that assessed the efficacy of all antiemetic agents as well as their associated side effects. The individual relative risk versus placebo for all effective antiemetics ranged between 0.60 and 0.80. (Ref. 22). Cubeddu LX, Hoffmann IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med. 1990;322:810–816. One of the first papers to show that ondansetron safely and effectively reduced the incidence of CINV in cancer patients undergoing chemotherapy. The results also suggested that cisplatin treatment triggered enterochromaffin cells to release serotonin and that ondansetron worked by blocking 5-HT3 receptors. (Ref. 2). Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118:85–113. Hvarfner A, Hammas B, Thörn SE, et al. The influence of propofol on vomiting induced by apomorphine. Anesth Anal. 1995;80:967–969. This study reported that propofol did not protect against nausea and vomiting at nonsedative doses, but that at sedative doses, propofol did have an antiemetic effect similar to that of midazolam. Therefore the antiemetic effect often attributed to propofol is more likely an effect of sedation. (Ref. 76). Kovac AL, O’Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth. 1999;11:453–459. Patients who received 4 mg IV

Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–2451. A large multicenter trial of more than 5000 patients demonstrating that the relative risk reduction for three commonly used antiemetic interventions are all in the range of 25%, that efficacy is independent of patient risk, and that antiemetic drugs of different classes act independently of each other. (Ref. 35). Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from crossvalidations between two centers. Anesthesiology. 1999;91:693–700. According to the simplified PONV risk score reported in this study, patients are likely to benefit from receiving antiemetic prophylaxis if they have at least two of the following four risk factors: female gender, history of PONV and/or motion sickness, nonsmoking status, and use of postoperative opioids. (Ref. 106). Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549. The CYP2D6 gene is responsible for metabolism of several antiemetic drugs, including ondansetron. Patients with three functional copies of the CYP2D6 gene were more likely to require rescue treatment for vomiting after prophylaxis with ondansetron. Some interindividual differences in response to prophylaxis might therefore be due to genetic variations among patients. (Ref. 12).

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ondansetron for prophylaxis against PONV did not benefit from additional doses of ondansetron in the postanesthesia care unit. This study highlights the importance of administering antiemetics of different receptor classes for prophylaxis and/or rescue treatment to increase protection against PONV. (Ref. 107). Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107:469–478. The first molecular-level study to differentiate between palonosetron and first generation 5-HT3-receptor antagonists. Only palonosetron binds allosterically and cooperatively to the 5-HT3 receptor, and its effect on receptor function persists longer than its binding to the receptor at the cell surface, suggesting that palonosetron induces receptor internalization. These unique mechanisms might account for palonosetron’s superior efficacy against delayed PONV. (Ref. 16). Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ. 2006;333:324. A dose-response trial in 3140 patients that determined that 25 mg was the minimum effective dose of metoclopramide for PONV prophylaxis, and that the commonly used dose of 10 mg was insufficient. Extrapyramidal symptoms associated with the 25-mg dose affected less than 1% of patients. (Ref. 31).

References 1. Raeder J. History of postoperative nausea and vomiting. Int Anesth Clin. 2003;41:1–12. 2. Cubeddu LX, Hoffmann IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatininduced nausea and vomiting. N Engl J Med. 1990;322:810–816. 3. Apfel CC, Korttila K, Abdalla M, et al. An international multicenter protocol to assess the single and combined benefits of antiemetic interventions in a controlled clinical trial of a 2x2x2x2x2x2 factorial design (IMPACT). Control Clin Trials. 2003;24:736–751. 4. Jokela RM, Cakmakkaya OS, Danzeisen O, et al. Ondansetron has similar clinical efficacy against both nausea and vomiting. Anaesthesia. 2009;64:147–151. 5. Tang J, Wang B, White PF, et al. The effect of timing of ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in the ambulatory setting. Anesth Analg. 1998;86:274–282. 6. Tramer MR, Reynolds DJ, Moore RA, et al. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology. 1997;87:1277–1289. 7. Benedict CR, Arbogast R, Martin L, et al. Single-blind study of the effects of intravenous dolasetron mesylate versus ondansetron on electrocardiographic parameters in normal volunteers. J Cardiovasc Pharmacol. 1996;28:53–59. 8. Charbit B, Albaladejo P, Funck-Brentano C, et al. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology. 2005;102:1094–1100. 9. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol. 2002;20:2805–2811. 10. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998;55:173–189. 11. Hickok JT, Roscoe JA, Morrow GR, et al. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer. 2003;97:2880–2886. 12. Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do

CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549. 13. Babaoglu MO, Bayar B, Aynacioglu AS, et al. Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists. Clin Pharmacol Ther. 2005;78:619–626. 14. Choi EM, Lee MG, Lee SH, et al. Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting. Anaesthesia. 2010;65:996–1000. 15. Philip BK, McLeskey CH, Chelly JE, et al. Pooled analysis of three large clinical trials to determine the optimal dose of dolasetron mesylate needed to prevent postoperative nausea and vomiting. The Dolasetron Prophylaxis Study Group. J Clin Anesth. 2000;12:1–8. 16. Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107:469–478. 17. Rojas C, Thomas AG, Alt J, et al. Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol. 2010;626:193–199. 18. Wong EH, Clark R, Leung E, et al. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol. 1995;114:851–859. 19. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570–1577. 20. Rojas C, Li Y, Zhang J, et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther. 2010;335:362–368. 21. Kovac AL, Eberhart L, Kotarski J, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008;107:439–444. 22. Carlisle J, Stevenson C. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2006;(3):CD004125. 23. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs. 2000;59:213–243. 24. Culebras X, Corpataux J-B, Gaggero G, et al. The antiemetic efficacy of droperidol added to morphine patient-controlled analgesia: a randomized, controlled, multicenter dose-finding study. Anesth Analg. 2003;97:816–821. 25. Habib AS, Gan TJ. The use of droperidol before and after the Food and Drug Administration black box warning: a survey of the members of the Society of Ambulatory Anesthesia. J Clin Anesth. 2008;20:35–39. 26. White PF, Song D, Abrao J, et al. Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebocontrolled study. Anesthesiology. 2005;102:1101–1105. 27. Scuderi PE. You (still) can’t disprove the existence of dragons. Anesthesiology. 2005;102:1081–1082. 28. Brockmoller J, Kirchheiner J, Schmider J, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther. 2002;72:438–452. 29. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med. 2007;14:715–721. 30. Henzi I, Walder B, Tramer MR. Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth. 1999;83:761–771. 31. Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. Br Med J. 2006;333:324. 32. Bentsen G, Stubhaug A. Cardiac arrest after intravenous metoclopramide—a case of five repeated injections of metoclopramide causing five episodes of cardiac arrest. Acta Anaesthesiol Scand. 2002;46:908–910.



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

33. Ho CM, Ho ST, Wang JJ, et al. Dexamethasone has a central antiemetic mechanism in decerebrated cats. Anesth Analg. 2004;99:734–739. 34. Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg. 2000;91:1404–1407. 35. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–2451. 36. Gan TJ, Meyer TA, Apfel CC, et al. Society for ambulatory anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2007;105:1615–1628. 37. Wang JJ, Ho ST, Tzeng JI, et al. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg. 2000;91:136–139. 38. Perron G, Dolbec P, Germain J, et al. Perineal pruritus after I.V. dexamethasone administration. Can J Anaesth. 2003;50:749–750. 39. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. Oncologist. 2007;12:1143–1150. 40. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17–24. 41. Apfel CC, Malhotra A, Leslie JB. The role of neurokinin-1 receptor antagonists for the management of postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2008;21:427–432. 42. Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci. 2003;91:87–94. 43. Van Belle S, Lichinitser MR, Navari RM, et al. Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869. Cancer. 2002;94:3032–3041. 44. Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg. 2007;104:1082–1089. 45. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatininduced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group. N Engl J Med. 1999;340:190–195. 46. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4112–4119. 47. Bergstrom M, Hargreaves RJ, Burns HD, et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004;55:1007–1012. 48. Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapyinduced nausea and vomiting. Cancer. 2003;97:2290–2300. 49. Nachum Z, Shupak A, Gordon CR. Transdermal scopolamine for prevention of motion sickness: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2006;45:543–566. 50. Parrott AC. The effects of transdermal scopolamine and four dose levels of oral scopolamine (0.15, 0.3, 0.6, and 1.2 mg) upon psychological performance. Psychopharmacology (Berl). 1986;89:347–354. 51. Price NM, Schmitt LG, McGuire J, et al. Transdermal scopolamine in the prevention of motion sickness at sea. Clin Pharmacol Ther. 1981;29:414–419. 52. Graybiel A, Knepton J, Shaw J. Prevention of experimental motion sickness by scopolamine absorbed through the skin. Aviat Space Environ Med. 1976;47:1096–1100. 53. Parrott AC. Transdermal scopolamine: a review of its effects upon motion sickness, psychological performance, and physiological functioning. Aviat Space Environ Med. 1989;60:1–9.

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54. Clissold SP, Heel RC. Transdermal hyoscine (Scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1985;29:189–207. 55. Nachum Z, Shahal B, Shupak A, et al. Scopolamine bioavailability in combined oral and transdermal delivery. J Pharmacol Exp Ther. 2001;296:121–123. 56. Apfel CC, Zhang K, George E, et al. Transdermal scopolamine for the prevention of postoperative nausea and vomiting: a systematic review and meta-analysis. Clin Ther. 2010;32:1987–2002. 57. Gil A, Nachum Z, Dachir S, et al. Scopolamine patch to prevent seasickness: clinical response vs. plasma concentration in sailors. Aviat Space Environ Med. 2005;76:766–770. 58. Kranke P, Morin AM, Roewer N, et al. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: a meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand. 2002;46:238–244. 59. Lin TF, Yeh YC, Yen YH, et al. Antiemetic and analgesic-sparing effects of diphenhydramine added to morphine intravenous patientcontrolled analgesia. Br J Anaesth. 2005;94:835–839. 60. Eberhart LHJ, Seeling W, Ulrich B, et al. Dimenhydrinate and metoclopramide alone or in combination for prophylaxis of PONV. Can J Anaesth. 2000;47:780–785. 61. Turner KE, Parlow JL, Avery ND, et al. Prophylaxis of postoperative nausea and vomiting with oral, long-acting dimenhydrinate in gynecologic outpatient laparoscopy. Anesth Analg. 2004;1660–1664. 62. Scavone JM, Greenblatt DJ, Harmatz JS, et al. Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers. J Clin Pharmacol. 1998;38:603–609. 63. Luna BG, Scavone JM, Greenblatt DJ. Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives. J Clin Pharmacol. 1989;29:257–260. 64. Blyden GT, Greenblatt DJ, Scavone JM, et al. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol. 1986;26:529–533. 65. Carruthers SG, Shoeman DW, Hignite CE, et al. Correlation between plasma diphenhydramine level and sedative and antihistamine effects. Clinical Pharmacol Ther. 1978;23:375–382. 66. Kothari SN, Boyd WC, Bottcher ML, et al. Antiemetic efficacy of prophylactic dimenhydrinate (Dramamine) vs ondansetron (Zofran): a randomized, prospective trial inpatients undergoing laparoscopic cholecystectomy. Surg Endosc. 2000;14:926–929. 67. Taylor G, Houston JB, Shaffer J, et al. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol. 1983;15:287–293. 68. Phenergan (Promethazine Hydrochloride) Injection, Solution [Package Insert]. Deerfield, IL: Baxter Healthcare Corporation; 1997. 69. Kreisler NS, Spiekermann BF, Ascari CM, et al. Small-dose droperidol effectively reduces nausea in a general surgical adult patient population. Anesth Analg. 2000;91:1256–1261. 70. Khalil S, Philbrook L, Rabb M, et al. Ondansetron/promethazine combination or promethazine alone reduces nausea and vomiting after middle ear surgery. J Clin Anesth. 1999;11:596–600. 71. Gan TJ, Candiotti KA, Klein SM, et al. Double-blind comparison of granisetron, promethazine, or a combination of both for the prevention of postoperative nausea and vomiting in females undergoing outpatient laparoscopies. Can J Anaesth. 2009;56:829–836. 72. Tarkkila P, Torn K, Tuominen M, et al. Premedication with promethazine and transdermal scopolamine reduces the incidence of nausea and vomiting after intrathecal morphine. Acta Anaesthesiol Scand. 1995;39:983–986. 73. Chia YY, Lo Y, Liu K, et al. The effect of promethazine on postoperative pain: a comparison of preoperative, postoperative, and placebo administration in patients following total abdominal hysterectomy. Acta Anaesthesiol Scand. 2004;48:625–630. 74. Gan TJ, El-Molem H, Ray J, et al. Patient-controlled antiemesis: a randomized, double-blind comparison of two doses of propofol versus placebo. Anesthesiol. 1999;90:1564–1570.

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75. Scuderi PE, D’Angelo R, Harris L, et al. Small-dose propofol by continuous infusion does not prevent postoperative vomiting in females undergoing outpatient laparoscopy. Anesth Analg. 1997;84:71–75. 76. Hvarfner A, Hammas B, Thorn SE, et al. The influence of propofol on vomiting induced by apomorphine. Anesth Analg. 1995;80:967–969. 77. Morrow GR, Rosenthal SN. Models, mechanisms and management of anticipatory nausea and emesis. Oncology. 1996;53(suppl 1):4–7. 78. Morrow GR, Roscoe JA, Kirshner JJ, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer. 1998;6:244–247. 79. Takada K, Murai T, Kanayama T, et al. Effects of midazolam and flunitrazepam on the release of dopamine from rat striatum measured by in vivo microdialysis. Br J Anaesthesia. 1993;70:181–185. 80. Phillis JW, Bender AS, Wu PH. Benzodiazepines inhibit adenosine uptake into rat brain synaptosomes. Brain Res. 1980;195:494–498. 81. Di Florio T. The use of midazolam for persistent postoperative nausea and vomiting. Anaesth Intens Care. 1992;20:383–386. 82. Gear RW, Miaskowski C, Heller PH, et al. Benzodiazepine mediated antagonism of opioid analgesia. Pain. 1997;71:25–29. 83. Jordan K, Kasper C, Schmoll HJ. Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. Eur J Cancer. 2005;41:199–205. 84. Effective interventions for CINV: NCCN Antiemesis Clinical Practice Guidelines in Oncology. ONS News. 2004;19:17–18. 85. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24:2932–2947. 86. Malik IA, Khan WA, Qazilbash M, et al. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol. 1995;18:170–175. 87. Bauer KP, Dom PM, Ramirez AM, et al. Preoperative intravenous midazolam: benefits beyond anxiolysis. J Clin Anesth. 2004;16:177–183. 88. Ahn EJ, Kang H, Choi GJ, et al. The effectiveness of midazolam for preventing postoperative nausea and vomiting: a systematic review and meta-analysis. Anesth Analg. 2016;122(3):664–676. 89. Majumdar AK, McCrea JB, Panebianco DL, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther. 2003;74:150–156. 90. Lee Y, Wang JJ, Yang YL, et al. Midazolam vs ondansetron for preventing postoperative nausea and vomiting: a randomised controlled trial. Anaesthesia. 2007;62:18–22. 91. Emend (Aprepitant) [Package Insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2006. http://www.emend.com/emend/shared/documents/ pi.pdf. 92. Majumdar AK, Yan KX, Selverian DV, et al. Effect of aprepitant on the pharmacokinetics of intravenous midazolam. J Clin Pharmacol. 2007;47:744–750. 93. Rung GW, Claybon L, Hord A, et al. Intravenous ondansetron for postsurgical opioid-induced nausea and vomiting. Anesth Analg. 1997;84:832–838. 94. Chung F, Lane R, Spraggs C, et al. Ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis in post-surgical adult patients. Eur J Anaesthesiol. 1999;16:669–677. 95. Sussman G, Shurman J, Creed MR, et al. Intravenous ondansetron for the control of opioid-induced nausea and vomiting. International S3AA3013 Study Group. Clin Ther. 1999;21:1216–1227. 96. Herndon CM, Jackson KC 2nd, Hallin PA. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy. 2002;22:240–250. 97. Aldrete JA. Reduction of nausea and vomiting from epidural opioids by adding droperidol to the infusate in home-bound patients. J Pain Symptom Manage. 1995;10:544–547. 98. Bates JJ, Foss JF, Murphy DB. Are peripheral opioid antagonists the solution to opioid side effects? Anesth Aanalgesia. 2004;98:116–122.

99. Gan TJ, Ginsberg B, Glass PS, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology. 1997;87(5):1075–1081. 100. Machelska H, Stein C. Immune mechanisms in pain control. Anesth Analg. 2002;95:1002–1008. 101. Schmidt W. Alvimopan*(ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001;182:S27–S38. 102. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—-a 21-day treatmentrandomized clinical trial. J Pain. 2005;6:184–192. 103. Herzog T, Coleman R, Guerrieri J. A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006;195:445–453. 104. Adolor Corporation. Entereg (alvimopan) capsules for postoperative ileus FDA Advisory Panel briefing document. http://www.fda.gov/ ohrms/dockets/ac/08/briefing/2008-4336b1-02-Adolor.pdf. 105. Kleine-Brueggeney M, Greif R, Brenneisen R, et al. Intravenous delta-9-tetrahydrocannabinol to prevent postoperative nausea and vomiting: a randomized controlled trial. Anesth Analg. 2015;121(5): 1157–1164. 106. Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999;91: 693–700. 107. Kovac AL, O’Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth. 1999;11:453–459. 108. Feldheiser A, Aziz O, Baldini G, et al. Enhanced Recovery After Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice. Acta Anaesthesiol Scand. 2016;60(3):289–334. 109. Miya T, Kobayashi K, Hino M, et al. East Japan Chesters Group. Efficacy of triple antiemetic therapy (palonosetron, dexamethasone, aprepitant) for chemotherapy-induced nausea and vomiting in patients receiving carboplatin-based, moderately emetogenic chemotherapy. Springerplus. 2016;5(1):2080. 110. Habib AS, Keifer JC, Borel CO, et al. A comparison of the combination of aprepitant and dexamethasone versus the combination of ondansetron and dexamethasone for the prevention of postoperative nausea and vomiting in patients undergoing craniotomy. Anesth Analg. 2011;112:813–818. 111. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapyinduced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014;25(7):1328–1333. 112. Lee A, Chan SK, Fan LT. Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2015;(11):CD003281. 113. Habib AS, Itchon-Ramos N, Phillips-Bute BG, et al. Duke Women’s Anesthesia (DWA) Research Group. Transcutaneous accupoint electrical stimulation with the ReliefBand for the prevention of nausea and vomiting during and after cesarean delivery under spinal anesthesia. Anesth Analg. 2006;102(2):581–584. 114. Gan TJ, Gu J, Singla N, et al. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg. 2011;112:804–812. 115. Gan TJ, Kranke P, Minkowitz HS, et al. Intravenous amisulpride for the prevention of postoperative nausea and vomiting: two concurrent, randomized, double-blind, placebo-controlled trials. Anesthesiology. 2017;126(2):268–275. 116. Apfel CC, Philip BK, Cakmakkaya OS, et al. Who is at risk for post-discharge nausea and vomiting after ambulatory surgery? Anesthesiology. 2012;117(3):475–486.

35 

Endocrine Physiology KATHERINE T. FORKIN, JULIE L. HUFFMYER, AND EDWARD C. NEMERGUT

CHAPTER OUTLINE Pituitary Physiology Anterior Pituitary Hyperpituitarism and Anterior Lobe Tumors Posterior Pituitary Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone Parathyroid Physiology Primary Hyperparathyroidism Multiple Endocrine Neoplasia Secondary Hyperparathyroidism Hypoparathyroidism Thyroid Physiology Hypothyroidism Hyperthyroidism Thyroiditis Adrenal Gland Physiology Adrenal Cortex Physiology Cushing Syndrome Glucocorticoid Deficiency Hyperaldosteronism Hypoaldosteronism Adrenal Medulla Physiology Pheochromocytoma Pancreas Physiology Diabetes Mellitus Emerging Developments

E

ndocrine physiology encompasses processes that range from master regulation by the pituitary gland to the much larger pancreas, which controls energy utilization processes of the body. This chapter reviews normal endocrine physiology and pathophysiology, as well as the basic anesthetic implications associated with the 5 major endocrine organs relevant to anesthesiologists: the pituitary gland, parathyroid glands, thyroid gland, adrenal glands, and the pancreas.

Pituitary Physiology The pituitary gland controls the function of many other endocrine glands, often being referred to as the “master gland.” Despite its

central role in the endocrine system, the pituitary is extremely small—about the size of a pea—and weighs only about 0.5 g. It is attached to the hypothalamus by the pituitary stalk (or infundibulum) and rests in the sella turcica, a small, bony cavity in the sphenoid bone at the base of the brain. The pituitary secretes at least 8 hormones that regulate organ function and are critical to survival. Both functionally and anatomically, the pituitary can be divided into the anterior lobe (or adenohypophysis) and the posterior lobe (or neurohypophysis). The lobes are different enough from one another that they can be considered as entirely different glands. In fact, consistent with their distinct structure and function, the embryonic origin of each lobe is entirely different: the anterior pituitary arises from the oral ectoderm whereas the posterior pituitary arises from the neuroectoderm.

Anterior Pituitary The anterior pituitary is a glandular secretory organ. The most important hormones produced by the anterior pituitary include adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), and the two gonadotropins, luteinizing hormone (LH) and folliclestimulating hormone (FSH). Melanocyte-stimulating hormone (MSH) is also produced by the anterior pituitary but is not required for homeostasis. The anterior pituitary is composed of 3 cell types, as identified with traditional aniline dye stains: acidophils, basophils (often collectively referred to as chromophils), and chromophobes. The chromophils are the principal secretory cell types whereas the chromophobes are not thought to have secretory function. Today, 5 cell types producing the 6 major hormones are best differentiated using immunohistochemical staining, as follows: • Somatotrophs, which produce GH (acidophilic) • Mammotrophs, which produce PRL (acidophilic) • Corticotrophs, which produce ACTH, MSH, and various endorphins (basophilic) • Thyrotrophs, which produce TSH (basophilic) • Gonadotrophs, which produce FSH and LH (basophilic) In general, the balance of releasing factors secreted by the hypothalamus and inhibiting factors secreted by each hormone’s target organ control the secretion of each hormone produced by the anterior pituitary. For example, TSH stimulates the thyroid to produce triiodothyronine (T3) and tetraiodothyronine (T4). The secretion of TSH by the anterior pituitary is stimulated by the secretion of thyrotropin-releasing hormone by the hypothalamus, but inhibited by both thyroid hormones (T3 and T4), creating a 693

CHAPTER 35  Endocrine Physiology 693.e1



Abstract

Keywords

This chapter reviews the normal physiology of the five major endocrine organs relevant to anesthesiology: the pituitary gland, parathyroid glands, thyroid gland, adrenal glands, and pancreas. Disturbances in endocrine hormone production from these glands lead to various endocrine disorders (such as thyroiditis, Cushing syndrome, and diabetes mellitus). The pathophysiology of the most common endocrine disorders and considerations for anesthetic management of patients with these disorders are discussed.

pituitary disease hyperthyroidism hypothyroidism diabetes hyperparathyroidism

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TABLE 35.1  Major Hormones of the Anterior Pituitary

Hormone

Acronym

Protein Structure

Releasing Factor (From Hypothalamus)

Inhibiting Factors

Anatomic Target

Adrenocorticotropic hormone

ACTH

Polypeptide

Corticotropin-releasing hormone

Glucocorticoids

Adrenal gland

Secretion of glucocorticoids

Thyroid-stimulating hormone

TSH

Glycoprotein

Thyrotropin-releasing hormone

T3 and T4

Thyroid gland

Secretion of thyroid hormones

Growth hormone

GH

Polypeptide

Growth hormone-releasing hormone

Growth hormone, insulin-like growth factor 1 (IGF-1), somatostatin

Liver, adipose tissue

Growth, anabolic, promotes lipid and carbohydrate metabolism

Prolactin

PRL

Polypeptide

See text

Dopamine

Ovaries, mammary glands

Milk production, lipid and carbohydrate metabolism

Luteinizing hormone

LH

Glycoprotein

Gonadotropin-releasing hormone

Estrogen, testosterone

Gonads

Sex hormone production

Follicle-stimulating hormone

FSH

Glycoprotein

Gonadotropin-releasing hormone

Estrogen, testosterone

Gonads

Sex hormone production

feedback loop. The releasing and inhibiting factors for each hormone are summarized in Table 35.1. The exception to this principle is prolactin, which is under tonic-inhibition by dopamine secreted by the hypothalamus. The action of releasing factors secreted by the hypothalamus is facilitated by the presence of a portal blood supply to the anterior pituitary. The hypothalamus secretes releasing factors into a primary capillary plexus from which they travel to a secondary capillary plexus in the anterior pituitary.

Hyperpituitarism and Anterior Lobe Tumors Essentially all cases of hyperpituitarism occur secondary to pituitary adenoma. These tumors are commonly encountered in clinical practice. They represent only 10% of diagnosed brain neoplasms; however, as many as 20% of people have a pituitary tumor on postmortem examination, suggesting that many pituitary adenomas are asymptomatic.1 Although the majority of pituitary adenomas are asymptomatic, most tumors present in 3 discrete ways: (1) hormonal hypersecretion, (2) local mass effects (including pituitary hypofunction due to compression of the normal gland), or (3) incidental discovery during cranial imaging for an unrelated condition. Approximately 75% of pituitary tumors are “functioning” and produce a single predominant hormone; these patients typically present with the signs and symptoms of hormone excess. For example, patients with a TSH-secreting adenoma have pituitary hyperthyroidism and present with the signs and symptoms of hyperthyroidism. Patients with Cushing disease (secondary to an ACTH-secreting adenoma) and acromegaly (secondary to a growth hormone-secreting adenoma) merit special attention and are discussed later. The perioperative management of patients with pituitary tumors undergoing surgery has been extensively reviewed.2 Pituitary adenomas are often classified based on their size at the time of discovery. Tumors larger than 10 mm in any dimension are classified as macroadenomas; tumors smaller than 10 mm are classified as microadenomas. The mass effects produced by pituitary tumors can be extensive and problematic given the location of the pituitary gland within

Effects

the brain. Patients can present with varying degrees of hypopituitarism secondary to compression of normal anterior pituitary tissue by the expanding intrasellar mass. Seventy percent to 90% of patients with nonfunctioning pituitary macroadenomas exhibit deficiencies in at least one pituitary hormone with formal testing.3 Thus, while it is easy to focus on the signs and symptoms of glucocorticoid excess in a patient with Cushing disease, for example, the patient with Cushing disease might also suffer from pituitary hypothyroidism. Furthermore, PRL is frequently elevated in patients with all varieties of pituitary tumors secondary to disruption in normal inhibitory tone from the hypothalamus. Regardless, posterior pituitary dysfunction is unusual, even among patients with very large tumors. Gigantism and Acromegaly

The unregulated hypersecretion of growth hormone by the anterior pituitary leads to increased production of insulin-like growth factor 1 (IGF-1) by the liver. Children in whom the epiphyses have not closed experience gigantism. In contrast, acromegaly develops in adults. Cardiac disease, hypertension, and ventricular hypertrophy are the most important causes of morbidity and mortality in acromegalic patients. Patients with acromegaly have a characteristic facies as the soft tissues of the nose, mouth, tongue, and lips become thicker and contribute to the acromegalic appearance. Airway obstruction and obstructive sleep apnea (OSA) can affect up to 70% of acromegalic patients.4 A high risk of perioperative airway compromise has been well documented in acromegalic patients.5 Other manifestations of acromegaly are summarized in Fig. 35.1. Cushing Disease

Cushing disease specifically results from the unregulated hypersecretion of ACTH by a pituitary adenoma and consequent hypercortisolism. Systemic hypertension is among the most common manifestations.2 Increased endogenous corticosteroids have been shown to cause systemic hypertension by a variety of mechanisms. Secondary to hypertension, a high prevalence of left ventricular hypertrophy and concentric remodeling has been reported. Glucose

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Increased Output Tumors Cushing disease Acromegaly Facial changes: Large lips, tongue, skin changes Airway obstruction Bony hypertrophy: prognathism, Obesity thick skull, jaw, hands cervical spine changes Septal hypertrophy Airway obstruction Laryngeal narrowing LV hypertrophy Cervical spine changes Hypertension Cardiomyopathy Diabetes mellitus Raynaud disease Barrel chest Bruising Chronic renal volume increase High adrenocorticoid output Mass Effect Cystic tumor Optic chiasm ICA Brainstem Headache Nausea DI-induced thirst Tumor expanding out of sella Optic tract defects Papilledema Basal brain pressure Arterial compromise Ischemic stroke

Acne Muscular atrophy Myopathy

Osteoporosis Cortisol Kidney stones

Hypothalamus pressure Residual functioning gland

Thinned or absent bone

• Fig. 35.1

  Manifestations of acromegaly. DI, Diabetes insipidus; ICA, internal carotid artery; LV, left ventricular. From: Nemergut EC, Dumont AS, Barry UT, Laws ER. Perioperative management of patients undergoing transsphenoidal pituitary surgery. Anesthesia & Analgesia. 2005;101(4):1170–1181.

intolerance occurs in at least 60% of patients, with overt diabetes mellitus (DM) present in up to one-third of all patients. Patients are typically obese, with characteristic “moon facies.” Although not as common as in acromegaly, patients frequently have OSA. Despite the association with OSA, endotracheal intubation is not usually more difficult.5 Other manifestations of Cushing disease are summarized in Fig. 35.1. Cushing syndrome is also frequently encountered in clinical practice but, unlike Cushing disease, results from iatrogenic corticosteroid medications (e.g., for asthma, inflammatory conditions, and so forth) and not from a pituitary adenoma. The unique aspects of Cushing syndrome are discussed in detail later. Prolactinomas

Prolactinomas are the most frequently observed type of hyperfunctioning pituitary adenoma, representing 20% to 30% of all clinically recognized pituitary tumors and half of all functioning tumors. Despite their frequency, prolactinoma is not associated with significant mortality. In women, hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido, and infertility. In men, symptoms of hyperprolactinemia are relatively nonspecific and include decreased libido, impotence, premature ejaculation, erectile dysfunction, and oligospermia.

Posterior Pituitary Unlike the anterior pituitary, the posterior pituitary gland (neurohypophysis) is not a secretory gland but rather a collection of axon terminals arising from the supraoptic and paraventricular nuclei of the hypothalamus. The posterior pituitary is principally

responsible for the secretion of oxytocin and vasopressin, also known as antidiuretic hormone (ADH). ADH is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. After initial synthesis, the precursor hormone is transported down the pituitary stalk into the posterior lobe of the pituitary where ADH undergoes final maturation to active hormone and is stored in vesicles for future release. Plasma osmolarity is the primary stimulus for ADH secretion; however, other factors—such as left atrial distention, circulating blood volume, exercise, and certain emotional states—can also alter ADH release. ADH is considerably more sensitive to small changes in osmolarity than to similar changes in blood volume. A 1% to 2% increase in osmolarity is sufficient to increase ADH secretion. ADH binds to vasopressin 2 (V2) receptors on the renal collecting ducts, which increases their permeability to water. This results in a significant increase in water reabsorption. Additionally, ADH increases blood pressure by increasing systemic vascular resistance through interaction with Vla receptors on blood vessels. The effect of ADH on blood pressure is mild in the healthy state, but becomes much more important in hypovolemic shock. It is used therapeutically as a vasopressor (see Chapter 25).

Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone The absence of ADH secretion results in pituitary diabetes insipidus (DI), whereas oversecretion or “inappropriately high” levels of ADH (or ADH-like hormones) results in the syndrome of inappropriate ADH (SIADH). DI is most commonly associated with pituitary surgery and is most often transient. Whereas 18% of 881 patients undergoing transsphenoidal surgery experienced early

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TABLE 35.2  Syndrome of Inappropriate Antidiuretic Hormone and Diabetes Insipidus

SIADH

DI

Associated conditions

1. 2. 3. 4.

1. Pituitary surgery 2. TBI 3. SAH (especially secondary to anterior communicating artery aneurysm)

Presentation

Hyponatremia

Polyuria

Plasma volume (awake patients)

Euvolemic (or slightly hypervolemic)

Euvolemic (practically speaking) Hypovolemic if not allowed access to fluids or unconscious

Serum osmolarity

Hypotonic (< 275 mOsm/L)

Hypertonic (> 310 mOsm/L)

Serum Na

Falling (< 135 mEq/L)

Rising (> 145 mEq/L)

Urine volume

Low (but not normally absent)

Voluminous (4–18 L/day)

Urine osmolarity

Relatively high (> 100 mOsm/L)

Relatively low (< 200 mOsm/L)

Urinary Na

> 30 mEq/L

Normal (or variable)

Treatment

Fluid restriction If Na+ < 120 mEq/L consider hypertonic saline to correct sodium (but no faster than 1 mEq/L/h) Intravenous urea Demeclocycline Lithium (rarely used)

Supportive DDAVP

+

+

Neurologic disease (SAH, TBI) Neoplasia (especially non–small cell lung cancer) Nonneoplastic lung disease Drugs (carbamazepine)

DDAVP, Desmopressin (1-desamino-8-D-arginine vasopressin); DI, diabetes insipidus; SAH, subarachnoid hemorrhage; SIADH, syndrome of inappropriate diuretic hormone; TBI, traumatic brain injury.

postoperative DI, only 2% had persistent DI 1 week after surgery.6 Its onset is heralded by the abrupt onset of polyuria, accompanied by thirst and polydipsia. SIADH is most commonly associated with central nervous system injury or trauma and certain cancers, especially lung cancer. Unlike DI, which typically presents with polyuria, SIADH typically presents with the signs and symptoms of hyponatremia. Characteristics of DI and SIADH are summarized in Table 35.2. Like ADH, oxytocin is also synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported down the pituitary stalk into the posterior pituitary for release. The principal physiologic functions of oxytocin are to stimulate cervical dilation and uterine contraction during labor and to allow milk to be let down into the subareolar sinuses during lactation. Oxytocin is one of the few hormones involved in a positive feedback loop. For example, uterine contractions stimulate oxytocin release from the posterior pituitary, which, in turn, increases uterine contractions.

Parathyroid Physiology The parathyroid glands generally consist of 4 pea-sized glands located posterior to the thyroid gland in the neck; however, many variations in location, and even number, of the glands exist. The glands possess a rich vascular supply via the inferior thyroid artery and consist mainly of chief cells primarily responsible for secreting parathyroid hormone (PTH) in response to hypocalcemia. PTH plays a chief role in bone remodeling and Ca2+ homeostasis. PTH stimulates bone resorption and consequently release of Ca2+ into the bloodstream. In addition, PTH causes renal Ca2+ reabsorption in the distal tubule and phosphate excretion in the proximal

tubule.7,8 Note that while the majority of renal Ca2+ reabsorption occurs in the proximal tubule, reabsorption at this site is not under hormonal control.7 PTH facilitates vitamin D conversion to its activated form such that it facilitates intestinal and renal absorption of Ca2+. Activated vitamin D also acts on bone to increase resorption, thus leading to further Ca2+ release into the bloodstream. Primary control of the release of PTH comes via negative feedback inhibition once elevated vitamin D and plasma Ca2+ levels are detected by a parathyroid Ca2+-sensing receptor.7 Other mechanisms also affect the release of PTH: (1) increased phosphate levels lead to increases in production and release of PTH; (2) hypomagnesemia, like hypocalcemia, causes release of PTH; and (3) adrenergic agonists, such as epinephrine, increase PTH release through β-adrenergic receptors on parathyroid cells.8 Indeed, this effect of adrenergic agonists is more pronounced at lower Ca2+ levels while it is transient and very mild in the setting of hypercalcemia.8 In addition, β-adrenergic antagonists, such as propranolol, decrease PTH in normal patients but are less likely to cause secondary hyperparathyroidism.8 Calcitonin counteracts the effects of PTH, as it inhibits bone resorption and increases excretion of Ca2+ through the kidneys.

The net result of the interactions of PTH, Ca2+, vitamin D, and calcitonin is maintenance of normal plasma Ca2+ concentration, which, in turn, helps maintain normal cellular function, nerve transmission, membrane stability, bone integrity, coagulation, and intracellular signaling. Normal plasma Ca2+ levels are 8.5 to 10.5 mg/ dL (2.1–2.6 mM). The majority of Ca2+ is stored in the bones and teeth. Only 1% is found in plasma in one of the following forms: ionized or unbound Ca2+ (50%; normally 1.0–1.2 mM), protein-bound Ca2+ (40%), and Ca2+ bound to citrate and phosphate (10%). The ionized, or unbound, Ca2+ is the form sensed by the Ca2+ receptors in the parathyroid gland. Protein-bound Ca2+ is



primarily bound to albumin with implications for changes in blood pH. Acidosis causes a decrease in protein binding, thus leading to higher ionized Ca2+, whereas alkalosis results in higher protein binding, thus reducing the free Ca2+ fraction in blood.9

Primary Hyperparathyroidism Primary hyperparathyroidism is excess PTH production and release most often due to parathyroid gland hyperplasia or tumor. The elevated PTH increases bone resorption and extracellular Ca2+. It occurs most commonly in patients aged 30 to 50 years and is more common in women than men.10 Clinically, patients exhibit increased intact PTH levels, hypercalcemia, hypercalciuria, hypophosphatemia, nephrolithiasis, osteoporosis, and neuromuscular changes, such as fatigue, weakness, and difficulties with cognition. Nausea, vomiting, constipation, and anorexia are common symptoms of hypercalcemia and patients may also complain of depression, confusion, and psychosis. Despite these manifestations, primary hyperparathyroidism is most often asymptomatic and detected incidentally on routine laboratory analysis as isolated hypercalcemia. Treatment of primary hyperparathyroidism centers on surgical excision of the parathyroid glands or tumor because there is increased risk of morbidity and cardiovascular mortality with long-standing hypercalcemia and untreated hyperparathyroidism.8

Multiple Endocrine Neoplasia Hyperparathyroidism may also present in concert with one of the multiple endocrine neoplasia (MEN) familial syndromes. MEN1 is a rare, autosomal-dominant syndrome in which tumors develop in the parathyroid glands, pancreas, and anterior pituitary gland of affected individuals. Most patients with MEN1 present with hyperparathyroidism. MEN2 is also an autosomal-dominant syndrome but has incomplete penetrance and variable expression. MEN2A is associated with medullary thyroid carcinoma (develops in essentially 100% of these patients), pheochromocytoma (50% incidence), and hyperparathyroidism (10%–30% incidence). Hyperparathyroidism is not a component of MEN2B.8,11,12 MEN4 is a rare familial endocrine syndrome associated with hyperparathyroidism and pituitary adenoma, which has only recently been described.13

Secondary Hyperparathyroidism Secondary hyperparathyroidism is a complication most commonly due to chronic renal failure but can result from any disease that causes chronic hypocalcemia. Early in the course of renal failure, decreased vitamin D and ionized Ca2+ levels cause increased production and release of PTH. The kidneys are also unable to excrete the phosphate load, which contributes to low serum Ca2+. Over time, the parathyroid glands become more resistant to the negative feedback mechanism of vitamin D and Ca2+ on PTH release, such that an increase in Ca2+ results in less efficient inhibition of PTH release. Hyperphosphatemia also further results in uremia-induced parathyroid gland hyperplasia, and PTH production and release. Goals of treatment of secondary hyperparathyroidism include maintaining Ca2+ and phosphate levels close to normal, reducing PTH secretion, and treating preexisting bone disease. These treatments focus on dietary phosphate restriction, maintaining daily Ca2+ intake greater than or equal to 1500 mg, administration of phosphate binder agents, and vitamin D replacement.

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Anesthetic considerations for patients with hyperparathyroidism (whether primary or secondary) focus on the effects of hypercalcemia. Preoperative evaluation should focus on eliciting the cause of the hyperparathyroidism and the degree of hypercalcemia. If hypercalcemia is mild to moderate and patients are without severe cardiovascular or renal complications, most surgery can proceed without further evaluation. Patients can have polydipsia and polyuria, and may present for surgery to remove renal calculi, as nephrolithiasis is common. Commonly observed electrocardiographic (ECG) changes in hypercalcemia include shortened PR interval, shortened QT interval, and cardiac arrhythmias.8 Patients with hyperparathyroidism can be hypertensive, and severe hypercalcemia can cause significant hypovolemia such that volume resuscitation is required. Severe hypercalcemia should be treated preoperatively. Aggressive volume resuscitation with subsequent diuretic administration can be used to acutely lower serum Ca2+ levels. Loop diuretics, such as furosemide, decrease the reabsorption of Ca2+ from the proximal tubules. For patients with renal dysfunction or failure, hemodialysis is immediately effective to reduce Ca2+ levels. Medications such as mithramycin and calcitonin can also be used but have significant side-effect profiles and should be administered with caution. Induction and maintenance of anesthesia should proceed carefully but there are no specific requirements as to choice of agent. Most anesthetic concerns for parathyroid surgery focus on emergence and postoperative care. After surgery of the thyroid and parathyroid glands, recurrent laryngeal nerve damage, airway swelling, and hematoma formation are serious potential complications with severe implications. The recurrent laryngeal nerves innervate all muscles of the larynx with the exception of the cricothyroid, which is supplied by the external laryngeal nerve. If the recurrent laryngeal nerve is completely paralyzed, the vocal cord will be abducted, resulting in stridor and hoarseness.8 If the recurrent laryngeal nerve is partially paralyzed, the vocal cord will be adducted. Thus, a partial lesion is more concerning for airway obstruction and a complete lesion more concerning for possible aspiration risk.8 Hypocalcemia can occur quickly after parathyroid removal; therefore, patients should be monitored with serial Ca2+, Mg2+, phosphate, and PTH levels. Hypocalcemia can also present with rapid onset of weakness and airway compromise.

Hypoparathyroidism Hypoparathyroidism is associated with other endocrine disorders and neoplasias or may result from surgical removal of the parathyroid glands. Hypocalcemia is the major acute result of inadvertent removal of the parathyroid glands. Hypocalcemic tetany can manifest as painful spasms of the facial muscles and extremities and laryngeal muscle spasm with upper airway obstruction. ECG changes associated with hypocalcemia include prolonged QT interval and possible heart block. Pseudohypoparathyroidism is not due to reduced PTH levels, but instead to reduced target sensitivity to PTH due to a receptor defect. Patients exhibit low plasma Ca 2+ levels, high phosphate levels, and high PTH levels. Depending on the type of receptor defect, patients with pseudohypoparathyroidism demonstrate either complete, systemic resistance to PTH (and present with short stature and skeletal abnormalities) or simply manifest renal resistance to PTH. There are few anesthetic considerations for the patient with a history of hypoparathyroidism presenting for surgery. The patient should have baseline Ca2+, phosphate, and Mg2+ levels and an ECG to determine QT interval. Hypocalcemia can be treated with

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TABLE 35.3  Thyroid Cell Types and Functions

Cell Type

Function

Follicular cells

Thyroid hormone (T3 and T4) synthesis

Endothelial cells

Line capillaries Provide blood supply to follicles

Parafollicular cells (also called C cells)

Produce and secrete calcitonin

Fibroblasts, lymphocytes, and adipose tissue

Structural support for the thyroid

T3, Triiodothyronine; T4, thyroxine.

calcium gluconate or calcium chloride in order to maintain serum Ca2+ levels.

Thyroid Physiology The thyroid gland is an acinar gland positioned in the neck, just anterior to the trachea with a rich vascular supply from the superior and inferior thyroid arteries. Weighing up to 25 g, the thyroid gland has a right and left lobe connected by the thyroid isthmus. Table 35.3 reviews the various cell types found within the thyroid gland and their corresponding functions. Other structures close to the thyroid gland include the trachea and esophagus as well as the recurrent laryngeal nerves and superior laryngeal nerve. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and released in response to decreased free circulating thyroid hormone. TRH binds to a G protein–coupled receptor in the anterior pituitary, causing an increase in intracellular Ca2+. Increased intracellular Ca2+ then causes release of TSH into the bloodstream, which stimulates the thyroid gland to increase the synthesis and release of T4 and T3 into the systemic circulation. T4 and T3 inhibit further secretion of TSH by inhibiting secretion of TRH. Thus, thyroid hormone production and secretion are regulated via negative feedback by the hypothalamic-pituitaryadrenal (HPA) axis. Other mediators that inhibit TSH release include dopamine, somatostatin, and glucocorticoids. Iodide is required for thyroid hormone synthesis. The body readily absorbs the necessary iodine from dietary sources, which is converted to iodide before being absorbed by the thyroid gland.14 In the follicle of the thyroid, thyroglobulin, a glycoprotein possessing several tyrosine residues, is iodinated, yielding mono-iodinated tyrosine (MIT) and di-iodinated tyrosine (DIT) residues. MIT and DIT ultimately are synthesized to T3 and T4 via thyroid peroxidase. The thyroid gland releases more T4 than T3, and T4 is converted to T3, primarily in the liver, as a result of the deiodination of T4. T4 is less active than T3 in that it has decreased affinity for the thyroid hormone receptor, but both T3 and T4 are stored in the thyroid gland for a 2- to 3-month supply. Thyroid hormones circulate in the bloodstream bound to proteins, mainly to thyroidbinding globulin but also to albumin. A small amount of each hormone circulates in an unbound, free form ready to enter the cell and bind to the thyroid hormone receptor. T4 binds more avidly to plasma proteins and thus has a longer half-life of 7 days compared to T3, which has a half-life of only 1 day. Thyroid hormone metabolism involves the sequential removal of iodine. Thus, T4, a relatively inactive thyroid hormone, is deiodinated to

T3, the active thyroid hormone. Removal of an additional iodine molecule to T2 yields a completely inactive product. In addition, thyroid hormones can be conjugated in the liver to increase solubility and allow for biliary excretion. Thyroid hormone receptors are found in virtually all tissues. Thyroid hormones play a chief role in cellular energy metabolism and are involved in the following15: • Transcription of cell membrane sodium-potassium adenosine triphosphatase (ATPase), leading to increase in oxygen consumption • Transcription of uncoupling protein (UCP) • Fatty acid oxidation and heat generation with production of ATP • Protein synthesis and breakdown • Epinephrine-induced glycogenolysis and gluconeogenesis with effects on insulin-induced glycogen synthesis and glucose utilization • Cholesterol synthesis and lipoprotein receptor regulation Thyroid hormone plays a major role in normal growth and development. Specific systems to note include the skeletal system, in which thyroid hormone is essential for bone growth, and the cardiovascular system, in which thyroid hormone has inotropic and chronotropic effects. These effects are evidenced by increased cardiac output and effects on blood volume and systemic vascular resistance. Thyroid hormone differentiates adipose tissue and regulates triglyceride and cholesterol metabolism in the liver. Thyroid hormone also regulates production of pituitary hormones and expression of genes involved in central nervous system myelination, cell differentiation, migration, and signaling. Thyroid disease and dysfunction occurs as a result of alterations in thyroid hormone levels, impaired metabolism of thyroid hormones, or resistance to effects of thyroid hormones. The thyroid gland can undergo changes that contribute to altered thyroid function. Thyroid hyperplasia or enlargement occurs in Graves disease and thyroid destruction occurs in Hashimoto thyroiditis. Table 35.4 differentiates hypothyroidism from hyperthyroidism based on laboratory values and clinical manifestations.

Hypothyroidism Hypothyroidism is divided into primary and secondary hypothyroidism. Primary hypothyroidism refers to disease at the level of the thyroid gland itself. In adults, this is most often owing to autoimmune disease causing destruction of thyroid tissue. Surgical excision or radioactive iodine therapy are iatrogenic causes of hypothyroidism and require thyroid hormone replacement. Secondary hypothyroidism implies dysfunction outside of the thyroid gland, most commonly in the hypothalamus or pituitary gland, resulting in decreased TSH secretion from the pituitary gland and, thus, decreased thyroid hormone release from the thyroid gland. Medications such as lithium, amiodarone, iron, and cholestyramine can be iatrogenic causes of hypothyroidism.16 Symptoms of hypothyroidism are vague and nonspecific, including fatigue, lethargy, painful joints and muscles, cold intolerance, constipation, change in voice quality (rough or gravelly), bradycardia, low voltage of ECG, and heart failure symptoms. Myxedema coma refers to severe hypothyroidism characterized by decreased mental status and coma, hypothermia, bradycardia, hyponatremia, heart failure, and respiratory failure. Myxedema coma is rare, and most commonly presents in the postoperative period after a trigger such as infection, exposure to cold temperatures, and excessive sedation and analgesic medications.16 A patient

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TABLE 35.4  Disorders of Thyroid Function

Hypothyroidism

Hyperthyroidism

Laboratory values

Low free T4 Low or normal T3 High TSH

High T4 High T3 Low TSH

Clinical manifestations

Fatigue, lethargy

Hyperactivity, irritability Anxiety, insomnia

Impaired memory, depression Cold intolerance Bradycardia, ventricular arrhythmias Prolonged QT interval, ventricular arrhythmias Decreased blood volume Decreased stroke volume Decreased cardiac output Narrowed pulse pressure Muscle cramps Delayed reflexes Weight gain Constipation Brittle nails, dry skin Abnormal menses Dry hair, hair loss Periorbital edema

Heat intolerance Tachycardia, palpitations, arrhythmias Arrhythmias (often atrial fibrillation) Increased blood volume Increased stroke volume Increased cardiac output Widened pulse pressure Proximal muscle weakness Hyperreflexia, fine tremor Weight loss Diarrhea Warm, moist skin; excessive sweating Decreased or absent menses Fine hair, hair loss Exophthalmos

TSH, Thyroid-stimulating hormone.

with myxedema coma should be treated in the intensive care unit with supportive therapy and urgent administration of intravenous levothyroxine and glucocorticoids for likely concomitant adrenal insufficiency, as well as aggressive volume replacement.16–18

Hyperthyroidism Hyperthyroidism refers to excessive thyroid gland function such that excess thyroid hormone is produced and released. Patients most commonly experience increased metabolism and autonomic nervous system disturbances. For adults, the most common cause of hyperthyroidism is Graves disease or diffuse toxic goiter, an autoimmune disease in which thyroid hormone is produced in an autonomous fashion owing to TSH receptor stimulation by antibodies. Patients with Graves disease often have thyroid eye disease, which is characterized by exophthalmos (protrusion of the eyeballs) owing to lymphocyte and fibroblast infiltration of the extraocular tissues and eye muscles. Other conditions leading to hyperthyroidism include toxic nodular goiter, toxic adenomatous disease of the thyroid, administration of excessive thyroid hormone, excess iodine intake, thyroiditis, follicular carcinoma, and TSH-producing tumor

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of the pituitary gland. Clinical features of hyperthyroidism or thyrotoxicosis include weight loss, tremor, heat intolerance, sweating, diarrhea, nausea, vomiting, anxiety, irritability, insomnia, and depression. Cardiovascular manifestations of hyperthyroidism include tachycardia, cardiac arrhythmias (commonly atrial fibrillation), and increases in blood volume, stroke volume, and cardiac output, which may ultimately lead to severe systolic ventricular dysfunction without appropriate management.19 Patients with hyperthyroidism are typically treated with antithyroid drugs to achieve a euthyroid state. The antithyroid drugs propylthiouracil (PTU) and methimazole both work by inhibiting thyroid peroxidase. At high doses, PTU also decreases peripheral T4 conversion to T3.20 While PTU has traditionally been the first-line antithyroid drug, a US Food and Drug Administration (FDA) warning issued in 2010 associated PTU with potential severe liver dysfunction.21 Thus, methimazole is now the most common antithyroid drug used to treat patients with hyperthyroidism. PTU is generally reserved for treatment of pregnant patients in the first trimester because methimazole has been associated with birth defects.20 Thyroid storm presenting in the perioperative period can mimic malignant hyperthermia (MH). Thus, anesthesiologists need to be aware of and vigilant for this concerning complication of undiagnosed or undertreated hyperthyroidism. Initiation of antithyroid therapy (i.e., with methimazole) and preoperative β blockade has significantly decreased the incidence of thyroid storm, though has not completely eliminated it. Symptoms are nonspecific and similar to those of MH: hyperpyrexia (up to 41°C), tachycardia, weakness, and delirium. Treatment requires intensive care and is mainly supportive. Beta blockers such as propranolol help reduce the adrenergic surge whereas antithyroid medications and iodine aim to reduce thyroid gland output.22–24 Useful cooling measures include administration of antipyretics, cool fluids, and application of cooling blankets. As these patients are typically intubated and mechanically ventilated, increased carbon dioxide production during thyroid storm may be counteracted with increasing the patient’s minute ventilation.22 Sick euthyroid syndrome affects patients with chronic nonthyroid medical conditions and diseases as patients appear euthyroid clinically but have evidence of thyroid dysfunction on laboratory testing. Usually, patients have decreased T3 and T4, decreased T4 binding to thyroid-binding globulin, but normal TSH and otherwise normal imaging of the thyroid gland itself.15 Factors known to precipitate sick euthyroid syndrome include stress, starvation, malnutrition, surgical trauma, myocardial infarction, chronic renal failure, diabetic ketoacidosis, cirrhosis, sepsis, and hyperthermia. Medications such as propranolol and amiodarone can also induce sick euthyroid syndrome, as they impair conversion of T4 to T3.16

Thyroiditis Thyroiditis, or inflammation of the thyroid gland, can be acute or chronic and can lead to abnormalities of thyroid function. Acute thyroiditis is rare and infectious. Patients present with a painful thyroid gland, chills, and fever and appear hyperthyroid. Chronic thyroiditis (otherwise known as Hashimoto thyroiditis, chronic lymphocytic thyroiditis, or autoimmune thyroiditis) is an autoimmune condition of the thyroid gland in which there is lymphocytic infiltration of the thyroid gland and circulating autoimmune antibodies. The antibodies prevent iodide uptake and thyroid hormone synthesis. Autoimmune thyroiditis is the most common cause of adult hypothyroidism.16 Early in the course of the disease, patients can have variable levels of T3, T4, and TSH, but usually

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have antibodies to thyroid peroxidase and thyroglobulin. Once chronic hypothyroidism develops, patients manifest low T3 and T4 and high TSH levels, although the increased TSH usually dissipates over time. Although hypothyroidism does not reduce the minimum alveolar concentration (MAC) for volatile anesthetics, hypothyroid patients presenting for surgery can be more sensitive to the effects of anesthetic agents and can have a prolonged recovery from anesthesia. Patients with mild to moderate hypothyroidism are at low risk for complications when undergoing surgery and anesthesia. 10,25 If possible, patients should be rendered euthyroid before surgery and patients should receive their thyroid supplementation medication on the day of surgery. It is important to maintain body temperature in hypothyroid patients because hypothermia puts patients at risk for such complications as delayed recovery from anesthesia, impaired wound healing, and coagulopathy. Major anesthetic considerations for patients with history of hyperthyroidism include determining their current thyroid status and obtaining a medication history. It is important to review the most recent thyroid function tests and inquire about symptoms of hyperthyroidism, such as tachycardia, atrial fibrillation, diarrhea, and weight loss. In patients presenting for thyroid surgery, it is vital to consider the size of the thyroid gland and elicit from patients whether they have experienced compressive symptoms due to an enlarged gland or goiter, such as dysphagia, or respiratory symptoms, such as dyspnea, stridor, or respiratory distress. Imaging of the neck may be helpful to reveal tracheal compression or deviation as well as retrosternal extension of the thyroid gland.22 Patients with severe tracheal compression may require awake, fiberoptic intubation with maintenance of spontaneous ventilation. Thyroid surgery for patients with retrosternal extension may require sternal splitting and partial sternotomy. In patients having emergency surgery in which there is concern for possible untreated or inadequately treated hyperthyroidism, a short-acting β blocker, such as esmolol, can be used to control tachycardia. During surgery in the neck, manipulation of the carotid sinus and bodies can induce hemodynamic instability that may not be well tolerated by patients who have coexistent cardiovascular disease. Other anesthetic considerations for the intraoperative and postoperative period, especially with regard to vocal cord dysfunction, are reviewed in the earlier section on anesthetic considerations, in the parathyroid disease discussion. Postoperative complications related to thyroid surgery are critical for every anesthesiologist to be vigilant of and understand how to treat quickly. Airway obstruction owing to hemorrhage in the neck, recurrent laryngeal nerve injury, and tracheal compression must be treated immediately. Hemorrhage or hematoma is the most common cause of airway obstruction within the first 24 hours after surgery. It is best treated by opening the neck, allowing drainage of the blood and clot, with consideration given to early endotracheal reintubation. Stitch and staple removers should be present at the bedside of every patient after thyroid surgery.22 After release of the airway compression, the neck wound can be explored and the hemorrhage treated surgically. The most common cause of airway obstruction occurring more than 24 hours after surgery is hypocalcemia, which occurs secondary to inadvertent parathyroid injury or removal. Hypocalcemia is treated with intravenous calcium, as described earlier.

Adrenal Gland Physiology The adrenal glands are small (3–5 cm in length) and are located just superior to each kidney. There are 2 parts to each adrenal

gland: the outer adrenal cortex derives from mesodermal tissue and the inner medulla derives from neural crest cells. The cortex makes up 90% of the adrenal mass and produces the steroid hormones glucocorticoids, mineralocorticoids, and androgens (cortisol, aldosterone, and dehydroepiandrosterone) as a result of HPA stimulation. The medulla makes up the remaining 10% of adrenal mass and synthesizes and releases the catecholamines epinephrine and norepinephrine as a result of sympathetic stimulation. Blood supply of the adrenal glands comes from branches of the suprarenal arteries. The venous drainage includes a renal vein for each adrenal gland. Steroid hormones are all synthesized from the same initial first step, the conversion of cholesterol to pregnenolone by cytochrome P450 enzymes.

Adrenal Cortex Physiology Cortisol is released from the adrenal gland in a pulsatile fashion— following a circadian rhythm sensitive to light, sleep, stress, and disease—owing to stimulation by ACTH from the anterior pituitary gland. Cortisol is mainly bound to a carrier protein called transcortin; some cortisol is also bound to albumin and a minimal amount of cortisol circulates unbound, which is the biologically active portion. Glucocorticoids such as cortisol have a multitude of actions, such as protein breakdown and gluconeogenesis, fatty acid mobilization, and prevention of muscle protein synthesis (Table 35.5). The main effect of glucocorticoids is to increase serum glucose concentration. At high circulating levels, glucocorticoids cause catabolism and breakdown of lean body mass, including bone and muscle. They also affect the immune response by exerting an antiinflammatory effect. Aldosterone is synthesized and released from the adrenal cortex zona glomerulosa, regulated not by the HPA axis but instead by the renin-angiotensin-aldosterone system, which is responsible for maintaining salt and water homeostasis. When intravascular volume and renal perfusion are decreased, renin is released and, through the angiotensin-converting enzyme (ACE), angiotensin II is released, which binds to a G protein–coupled receptor and stimulates aldosterone release. Aldosterone increases Na+ and water absorption through the kidneys and K+ is excreted. The other main stimulant for aldosterone release is K+. Aldosterone helps maintain K+ homeostasis and is responsible for preventing hyperkalemia by increasing K+ excretion via the kidneys, gastrointestinal tract, diaphoresis, and salivation.

Cushing Syndrome Glucocorticoid excess (Cushing syndrome) can occur for a number of reasons, including overproduction of cortisol by an adrenal mass, excessive stimulation of a normal adrenal gland to produce cortisol due to excessive ACTH production by the pituitary gland, or iatrogenic administration of glucocorticoids. Cushing syndrome manifests initially by a large increase in weight, usually central in the abdominal region. Patients also can appear to have moon facies and a buffalo hump of adipose tissue at the posterior cervical region. Other characteristics of Cushing syndrome include hypertension, glucose intolerance, decreased or absent menses in women, decreased libido, spontaneous ecchymoses, muscle wasting and weakness, thin friable skin, and osteoporosis due to bone resorption. Anesthetic considerations for patients with Cushing syndrome revolve around managing the effects of glucocorticoid excess during the perioperative period. The resultant obesity often portends increased risk of difficult airway management and problems with positioning. Osteoporosis also presents risk during positioning of

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TABLE 35.5  Glucocorticoid Effects

Metabolism

Hemodynamic

Immune Function

Central Nervous System

Muscle protein breakdown

Maintains vascular integrity

Increases antiinflammatory cytokines

Regulates perception and emotion

Increases nitrogen excretion

Maintains vascular reactivity

Decreases proinflammatory cytokines

Decreases corticotropin-releasing hormone

Increases gluconeogenesis

Maintains responsiveness to catecholamines

Decreases inflammation

Decreases adrenocorticotropic hormone release

Increases plasma glucose

Maintains fluid volume

Inhibits prostaglandin and leukotriene production

Increases hepatic glycogen synthesis

Inhibits bradykinin and serotonin inflammatory effects

Decreases glucose utilization

Decreases eosinophil, basophil, and lymphocyte counts

Decreases amino acid utilization

Impairs cell-mediated immunity

Increases fat mobilization

Increases neutrophil, platelet, and red blood cell counts

Redistributes fat

inadvertent bony fractures. Patients can have preexisting muscle weakness and be sensitive to the effects of neuromuscular blocking agents. Patients with Cushing syndrome tend to be hypervolemic with hypokalemic metabolic alkalosis. Many patients are on chronic diuretic therapy with potassium replacement.

Glucocorticoid Deficiency Glucocorticoid deficiency (Addison disease) is less common and results from dysfunction of the adrenal gland (primary deficiency) or from lack of ACTH stimulation of adrenal glucocorticoid production (secondary deficiency). Clinical manifestations include weakness, fatigue, hypoglycemia, hypotension, and weight loss. Exogenous administration of glucocorticoids in the treatment of many chronic medical conditions results in downregulation of corticotropin-releasing hormone and ACTH. Thus, sudden withdrawal of exogenous glucocorticoids during a stressful period or critical illness can precipitate an Addisonian crisis (acute adrenal failure), which is a medical emergency. Patients can experience circulatory collapse, fever, hypoglycemia, and mental obtundation as a result of the acute decrease in cortisol and the inability to secrete cortisol in response to stress. Anesthetic considerations for patients with glucocorticoid deficiency (whether chronic or acute) mainly focus on steroid replacement therapy during the perioperative period—a time of acute physiologic stress. Patients given the equivalent dose of prednisone 20 mg for 5 days may experience suppression of their HPA axis and their adrenal glands might not be able to respond to physiologic stress by production of cortisol.26,27 Exogenous glucocorticoid therapy for a 1-month period places patients at risk for HPA axis suppression for 1 year after the treatment is discontinued.26,27 Thus “stress-dose” steroids should be considered for these patients during the perioperative period. Historically, stressdose steroid therapy consisted of hydrocortisone 100 mg every 8 hours. However, this dose can precipitate hyperglycemia and decreased wound healing in some patients. Thus, a lower-dose regimen might be considered: hydrocortisone 25 mg at induction

of anesthesia, followed by a total of 100 mg of hydrocortisone over the next 24 hours.16 This lower-dose regimen decreases the risks of excessive steroid replacement and allows for plasma cortisol levels equal to that of healthy patients undergoing elective surgery. The initial bolus dose of hydrocortisone can be increased based on the urgency and complexity of the surgical procedure.28

Hyperaldosteronism Aldosterone excess can take several forms based on the pathophysiology. Primary hyperaldosteronism, or Conn syndrome, is due to adrenal oversecretion of aldosterone by benign adrenal tumors. Patients exhibit hypertension owing to Na+ and water retention, and exhibit hypokalemia owing to K+ excretion, muscle weakness, and metabolic alkalosis. Secondary hyperaldosteronism usually results from another pathologic state that reduces the effective circulating blood volume, such as cirrhosis with ascites or congestive heart failure. This decrease in the effective circulating volume causes continuous stimulation of the renin-angiotensin-aldosterone system with overproduction of aldosterone.29 Tertiary hyperaldosteronism, or Bartter syndrome, is a renal disorder that leads to increased renin release in order to compensate for excessive Na+ loss. The excess renin causes excess production of angiotensin II and aldosterone. Anesthetic considerations include correction of fluid and electrolyte abnormalities preoperatively. Potassium-sparing diuretics, such as spironolactone, are often prescribed to help manage the hypokalemia and hypervolemia and to control hypertension. Hypoaldosteronism Aldosterone deficiency also can take several forms. Primary hypoaldosteronism, or Addison disease, occurs as a result of destruction of the adrenal gland due to infection, injury, autoimmune problems, or genetic disorders. In Addison disease, renin activity is increased, which helps differentiate primary hypoaldosteronism from the other forms of deficiency. Clinical manifestations include hyponatremia, hypovolemia, hypotension, hyperkalemia, and metabolic acidosis. Secondary hypoaldosteronism results from

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decreased renin stimulation, usually from renal insufficiency, but the adrenal glands function normally. Anesthetic considerations include preoperative mineralocorticoid therapy, such as fludrocortisone, which helps correct the hypovolemia and hyperkalemia.

Adrenal Medulla Physiology The adrenal medulla is the inner part of the adrenal gland and is highly vascular, made up of 2 types of chromaffin cells: those that produce epinephrine and those that produce norepinephrine. Catecholamines such as epinephrine and norepinephrine are made from the amino acid tyrosine through multiple enzymatic conversions: Tyrosine ⇒ L-DOPA ( L-3,4-dihydroxyphenylalanine) ⇒ dopamine ⇒ norepinephrine ⇒ epinephrine The synthesis of catecholamines can be regulated by changes in the first enzymatic reaction of the pathway (tyrosine hydroxylase) such that the enzyme is inhibited acutely by increase in catecholamine production and chronically by an increase in tyrosine hydroxylase synthesis. Catecholamines are released in direct response to sympathetic nervous stimulation of the adrenal medulla. Acetylcholine released from the preganglionic sympathetic nerve terminals binds to nicotinic receptors in the chromaffin cells of the adrenal medulla. Depolarization of these cells leads to activation of Ca2+ channels. The influx of Ca2+ causes the vesicles containing the catecholamines to release their contents, including the catecholamines and other molecules, such as chromogranins, ATP, and various peptides. Catecholamines have a very short half-life, on the order of just 10 seconds up to about 2 minutes, and undergo uptake at extraneuronal sites and degradation by catecholO-methyltransferase (COMT) or monoamine oxidase (MAO). The degradation by COMT and MAO of norepinephrine and epinephrine, mostly in the liver, produces the metabolite vanillylmandelic acid (VMA), which is excreted in the urine and can be measured as an index of cumulative catecholamine secretion. The physiologic effects of the catecholamines epinephrine and norepinephrine are mediated by G protein–coupled receptors found in many tissues (Table 35.6, and see Chapter 13). α-Adrenoreceptor

TABLE 35.6  Physiologic Effects of Adrenergic Stimulation

α-Adrenergic Receptor Stimulation

β-Adrenergic Receptor Stimulation

Vasoconstriction

Vasodilation

Intestinal relaxation

Intestinal relaxation

Bladder and intestinal sphincter contraction

Bladder wall relaxation

Pilomotor contraction Bronchoconstriction

Bronchodilation

Uterine smooth muscle contraction

Uterine relaxation

Increased cardiac contractility

Increased chronotropy, increased dromotropy, increased contractility

Hepatic glucose production

Glycogenolysis, lipolysis

Iris dilation

activation causes activation of phospholipase C, which then activates protein kinase C via diacylglycerol. This causes an increase in intracellular Ca2+ and corresponding increase in smooth muscle contraction. β-Adrenoceptor stimulation leads to an increase in cyclic adenosine monophosphate (cAMP) and, depending on which subtype of β receptor is stimulated, effects vary from increasing myocardial contractility, vasodilation, bronchial smooth muscle relaxation, and lipolysis. Sympathetic stimulation leads to secretion of catecholamines, which play a chief role in the stress response to perceived or real physical or psychological injury, including hemorrhage, severe hypoglycemia, trauma, surgical trauma, and fear. The basic physiologic effects attributed to catecholamine secretion are mental arousal and alertness, pupillary dilation, diaphoresis, bronchial smooth muscle dilation, tachycardia, reduced activity of gastrointestinal tract, sphincter constriction, and uterine muscle relaxation. Catecholamines activate catabolism for the expenditure of energy in order to provide substrate for the stress response. As such, glucose is mobilized from the liver through glycogen breakdown and fat breakdown.

Pheochromocytoma Pheochromocytoma represents the most significant disease associated with adrenal medullary tissue. This tumor causes overproduction of catecholamines. As a result, patients with pheochromocytoma present with severe (sustained or paroxysmal) hypertension, headaches, sweating, and palpitations. Most pheochromocytomas are benign and located unilaterally in an adrenal gland, but approximately 10% can be malignant and 10% can be bilateral/ extra-adrenal in origin.30 Unrecognized pheochromocytoma can present intraoperatively due to sympathetic stimulation or surgical stimulation in the area of the undiagnosed tumor. Under general anesthesia, the signs of undiagnosed pheochromocytoma include tachycardia and hypertension. Preoperative evaluation and assessment should concentrate on treatment with α-adrenergic blockers and volume replacement. Arterial blood pressure, orthostatic blood pressure measurements, heart rate, and ECG are critical and might warrant further cardiovascular evaluation, including echocardiography. At the time of diagnosis, patients with pheochromocytoma are usually hypovolemic with a normal to elevated hematocrit. Preoperative α-adrenergic blocker therapy with phenoxybenzamine or phentolamine helps correct the hypertension and vasoconstriction as well as reduce the intravascular volume deficit. A drop in hematocrit usually signals adequate α blockade. Beta-blocker therapy is typically started after initiation of α-adrenergic blocker therapy to help control heart rate and blood pressure.31 There is a theoretical risk of unopposed α-adrenoreceptor agonism with massive vasoconstriction if β-blocker therapy is initiated prior to α-adrenoreceptor antagonists.16 Some studies have questioned the primacy of α-adrenergic blocker therapy in favor of treatment with Ca2+ channel blockers with favorable results. Management of pheochromocytoma resection mandates intraarterial blood pressure monitoring for immediate evaluation of rapid changes in blood pressure, which may aid in titration of any necessary vasopressor or vasodilator therapy, and frequent laboratory analysis to assess acid–base status, hematocrit, and electrolyte values. Central venous access may be helpful to allow infusion of vasoactive substances and large volumes of fluid and blood products if required. Induction should proceed thoughtfully, with strict blood pressure control. A deep plane of anesthesia should be established prior to laryngoscopy and endotracheal intubation in order to prevent

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sympathetic activation. Intraoperative hypertension can be treated with phentolamine, nitroprusside, or nicardipine. Phentolamine blocks α-adrenergic receptors, is relatively short acting, and prevents effects of catecholamines. Nitroprusside is easily titratable, with rapid onset and offset, but can result in cyanide accumulation with high doses. Potential anesthetic drugs to avoid include those that stimulate sympathetic nervous system activity or block parasympathetic activity, such as ketamine, ephedrine, and pancuronium. After the tumor is resected, hypotension can complicate the intraoperative and postoperative course owing to a decrease in circulating catecholamines and residual antihypertensive therapies. However, in some patients, hypertension continues to be problematic and requires treatment.32 If present, the resultant hypotension is usually responsive to fluid resuscitation and adrenergic agonist therapy if necessary. Persistent hypertension is treated with antihypertensive medications as well as serial surveillance for recurrence of the pheochromocytoma.32

Pancreas Physiology The pancreas plays a key role in digestion, metabolism, utilization, and storage of energy substrate with exocrine and endocrine capacities. The pancreas is located in the retroperitoneal space, near the duodenum. Most of the mass of the pancreas is made up of exocrine cells, which secrete an alkaline digestive fluid into the pancreatic duct and duodenum. Comprising 1% to 2% of the mass of the pancreas, within the pancreatic lobules, are small clusters of endocrine cells—the islets of Langerhans—which include α, β, and δ cells. The β cells make up about 75% of the total mass of the islets and secrete insulin. Of endocrine cells, 18% to 20% are α cells, which secrete glucagon, and the remaining 5% are δ cells, which secrete somatostatin. The arterial blood supply to the pancreas consists of branches from the splenic artery and the superior and inferior pancreaticoduodenal arteries. The islets receive 10% to 15% of the pancreatic blood flow; thus, their rich vascularization allows easy access for the hormones to be secreted by the islet cells into the bloodstream. Venous drainage leads directly to the portal vein of the liver; therefore, the pancreatic hormones undergo first-pass metabolism in the liver before being released into the systemic circulation. Insulin synthesis begins with an inactive protein, pre-proinsulin, which undergoes cleavage to proinsulin and then to insulin by cleavage of the C-peptide linkage structure. Insulin is thus made up of 2 amino acid peptides, α and β linked by a disulfide bond. The insulin and C peptide make up secretory granules that are

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stored in β cells and released in response to increased blood glucose. Glucose enters β cells via the GLUT-2 receptor, where it is used to generate ATP. ATP causes closure of the ATP-sensitive K+ channels, membrane depolarization, and Ca+ influx, which then triggers exocytosis of insulin secretory granules into the circulation. Overall, insulin has an anabolic effect on target organs and stimulates the synthesis of carbohydrates, fats, and proteins (Table 35.7). Glucose transporters play a key role in the utilization of glucose mediated by insulin. There are several glucose transporters with variable tissue distributions and functions.33 Table 35.8 reviews the specific glucose transporters along with their primary locations and functions. Glucagon is an amino acid polypeptide hormone secreted by the α cells of the islets of Langerhans and plays a vital role in glucose homeostasis by antagonizing the effects of insulin. Glucagon release is stimulated by hypoglycemia, high amino acid levels after amino acid–rich food intake, epinephrine, and vagal stimulation and is inhibited by increased blood glucose levels and somatostatin. The primary target tissues for the effects of glucagon are the liver

TABLE 35.7  Effects of Insulin

Carbohydrate metabolism

Glucose Transport Into Fat and Muscle

Glycogen Breakdown in Muscle and Liver

Glycolysis in fat and muscle

Glycogenolysis and gluconeogenesis in liver

Glycogen synthesis in fat, muscle, and liver Lipid metabolism

Fatty acid synthesis Uptake of triglycerides from circulation into fat and muscle Cholesterol synthesis in liver

Protein metabolism

Amino acid transport into tissues Protein synthesis in muscle, fat, and liver

Lipolysis in fat (causes decreased plasma fatty acids) Fatty acid oxidation in muscle and liver Ketogenesis Protein breakdown in muscle Urea formation

TABLE 35.8  Glucose Transporters

Transporter

Location

Function

GLUT-1

Widely distributed; highest concentration in red blood cells and endothelial cells of the brain

Glucose uptake by skeletal muscle and fat under basal conditions; allows glucose to cross blood–brain barrier

GLUT-2

Pancreatic β cells, liver, small intestine, kidney

Ensures that glucose uptake by β cells and hepatocytes occurs only when serum glucose concentration is elevated

GLUT-3

Neurons, placenta

Glucose uptake under basal conditions; allows glucose to cross blood–brain barrier

GLUT-4

Skeletal and cardiac muscle, adipose tissue

Mediates insulin-stimulated glucose transport into striated muscle cells and adipocytes

GLUT-5

Spermatozoa, small intestine

Transports fructose primarily; very low affinity for glucose

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and adipose tissues. The main effect of glucagon is to increase serum glucose concentration by causing hepatic gluconeogenesis and glycogen breakdown. The effects of glucagon on adipose tissue primarily occur during periods of stress and food deprivation.

Diabetes Mellitus DM results from impaired secretion of insulin from the pancreas and/or reduced tissue sensitivity. Type 1 DM has been referred to as insulin-dependent DM owing to the destruction of the β cells in the pancreas, thus necessitating administration of exogenous insulin to avoid diabetic ketoacidosis. It is associated with onset in younger-age patients and makes up 2% to 5% of cases of DM. Type 2 DM is more frequent and results from loss of normal regulation of insulin secretion from the pancreas and insulin sensitivity. It is associated with adult onset, obesity, mild levels of hyperglycemia, and insulin resistance. The mean normal blood glucose is about 72 mg/dL (4 mM). The diagnosis of DM is made when fasting serum glucose is greater than 126 mg/dL (7 mM), or random glucose levels are greater than 200 mg/dL (11 mM) with associated symptoms of DM such as polyuria, polydipsia, and polyphagia. With type 1 DM, there is impaired insulin release such that cells cannot take up glucose as energy substrate; thus, serum glucose levels are elevated. Increased serum glucose concentrations cause elevated plasma osmolarity and glycosuria, accompanied by water and Na+ loss in the urine (polyuria). Patients become very dehydrated; increased thirst (polydipsia) as well as hunger (polyphagia) are compensatory mechanisms for the “starving” cells that are unable to utilize glucose. Diabetic ketoacidosis (DKA) can occur perioperatively; it is an acute event that anesthesiologists must understand and for which they must be vigilant. DKA is characterized by elevated blood glucose, ketone body formation (both acetoacetate and β-hydroxybutyrate), and anion gap metabolic acidosis that result from decreased availability of insulin and elevated levels of the counter-regulatory hormones glucagon, catecholamines, cortisol, and growth hormone. Lactic acidosis can coexist with the anion gap metabolic acidosis with DKA. DKA can be precipitated by infection, stress, surgery, inadequate doses of exogenous insulin, and untreated DM. Patients manifest tachypnea, severe abdominal pain, nausea, vomiting, and altered mental status. Treatment of DKA involves aggressive fluid volume resuscitation, insulin to treat the hyperglycemia, and replacement of K+ deficit. Patients with DKA require intensive care and frequent laboratory analysis for glucose, K+, serum ketones, and acid–base status. There are 3 main defects involved in type 2 DM. First, there is inadequate response of the β cells of the pancreas to glucose loads. That is, at basal conditions, patients produce and secrete insulin; however, with serum glucose elevation (such as with meals), there is much less secretion of insulin than in normal patients. Second, type 2 DM patients also have a decreased response of peripheral tissues to the actions of insulin. Third, patients with type 2 DM have increased hepatic glucose production.34 These impairments contribute to an overall higher fasting glucose level. Approximately 80% of patients with type 2 DM are considered obese and have a sedentary lifestyle, both of which are well-known risk factors.35,36 Anesthetic considerations for patients with DM include a thorough preoperative evaluation to determine whether the patient requires insulin and to determine end-organ damage. Hemoglobin A1C levels are helpful in preoperative evaluation for identifying patients at risk for perioperative hyperglycemia and further

complications. Hemoglobin A1C levels less than 6% are considered normal (with good glycemic control); those patients with levels greater than 8% are considered to have poorly controlled DM and often have postoperative complications.37,38 Patients with DM are at high risk for cardiovascular complications, including myocardial ischemia and infarction; thus, a preoperative ECG should be obtained. Diabetic autonomic dysfunction has many implications for the patient undergoing surgery and anesthesia, as it limits the ability of the myocardium to compensate for changes in volume status (such as reduced preload) and predisposes patients to cardiovascular instability, hypotension, and sudden cardiac death. Delayed gastric emptying and risk for aspiration can also be attributed to autonomic dysfunction and the attendant gastroparesis. Long-standing DM also places patients at risk for renal dysfunction and failure. Additionally, patients with DM have decreased immune system function and microvascular disease. Consequently, they are at risk for infections and delayed or impaired wound healing. The intraoperative care of the patient with DM focuses on control of blood glucose. There has been controversy surrounding what level of glucose should be targeted for patients with DM undergoing surgery. Hyperglycemia in surgical patients is a common problem in the perioperative period for patients with and without known DM. There are many reasons postulated for this hyperglycemia, including poorly controlled DM preoperatively, insulin resistance, increased inflammatory response associated with surgical trauma, increased stress response characterized by increased secretion of counter-regulatory hormones, and requirement for catecholaminebased vasopressors, such as epinephrine.16,39,40 The effects of these changes lead to increased gluconeogenesis, glycogenolysis, and insulin resistance in the periphery. Multiple studies have illustrated the importance of good glycemic control in surgical patients. The Portland Diabetes Project demonstrated the connection between hyperglycemia in the perioperative period and increased morbidity in the form of increased infections and deep sternal wound infections as well as increased mortality.41,42 In addition, intensive insulin therapy to control serum glucose to levels less than 110 mg/dL (6.1 mM) in the intensive care unit population was shown to significantly reduce morbidity and mortality.43 However, concerns over tight glycemic control have surfaced as a result of studies showing that intensive glucose control intraoperatively led to an increased incidence of stroke and death.44,45 Thus, no single, generalizable serum glucose goal exists for all patients with DM. One approach for serum glucose management in this patient population involves learning about each patient’s glycemic control before surgery. If a patient has a hemoglobin A1C of 9%, there is likely very poor control and rapidly controlling that patient’s blood glucose to a narrow, strict or “low” target range could lead to complications, such as severe hypoglycemia and even stroke or death. Instead, a patient whose DM is poorly controlled can be treated in a moderate fashion, aiming to reduce the blood glucose slowly over time to less than 180 mg/dL (10 mM) intraoperatively via an insulin infusion. Insulin infusions are more physiologic, rapidly titratable, and easier to control than intravenous insulin boluses.46 Currently, there is a paucity of evidence-based data to demonstrate that strict glucose control is superior to more moderate control intraoperatively. Refer to several other sources on blood glucose management.16,17,45,47

Emerging Developments Etomidate is an intravenous anesthetic agent typically used for the induction of general anesthesia, with the advantage of maintenance

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of hemodynamic stability. Etomidate’s hypnotic effects are believed to result from enhancement of γ-aminobutyric acid type A (GABA-A) receptor function. Etomidate has been shown to suppress adrenocortical function through inhibition of 11β-hydroxylase, which is a required enzyme to produce cortisol, corticosterone, and aldosterone. The mechanism underlying etomidate’s well-described suppression of adrenal steroid synthesis relates to the imidazole ring in its chemical structure. Some imidazole ring–containing drugs are known to produce a “chemical adrenalectomy” that can be long lasting. In the case of etomidate, x-ray crystallographic studies suggest that the nitrogen molecule on the imidazole ring forms a “coordination bond” with the heme iron of the 11β-hydroxylase enzyme, thus occupying the enzyme’s active site and preventing the enzyme from interacting with its usual substrates (Fig. 35.2).48 Recent work has resulted in the development of etomidate analogs that retain the hemodynamic stability of etomidate yet reduce the risks of adrenal suppression.48 Investigators have characterized the hypnotic potency of etomidate and 22 other etomidate analogs using in vivo and in vitro assays and found that the hypnotic potencies were significantly correlated with GABA-A receptor potencies.49 Several structural elements in the etomidate analogs can be modified with GABA-A receptor enhancement leading to an increase in the hypnotic potency of these etomidate analogs.49 These investigators also developed a strategy to reduce the problem of adrenocortical steroid suppression associated with etomidate. They synthesized and evaluated cyclopropyl methoxycarbonyl metomidate (CPMM) and carboetomidate, etomidate analogs that have similar hypnotic effects to etomidate but are either broken down rapidly to a metabolite with low affinity for 11β-hydroxylase (CPMM) or bind poorly to 11β-hydroxylase (carboetomidate).50 CPMM leads to reduced adrenocortical suppression as compared to etomidate because it is metabolized more rapidly and binds to 11β-hydroxylase with less affinity than etomidate. 50 Carboetomidate and other intravenous

705

Etomidate O O N N

N N

Fe

N N

Heme group

• Fig. 35.2

A proposed mechanism for the adrenocorticoid suppression associated with etomidate. The interaction between the basic nitrogen in the imidazole ring of etomidate and the heme iron at the active site of 11β-hydroxylase forms a coordination bond that prevents the active site of the enzyme from interacting with its usual substrates. (Adapted from Cotten JF, Forman SA, Laha JK, et al. Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function. Anesthesiology. 2010 Mar;112(3):637–644.)  

anesthetics—such as dexmedetomidine, ketamine, and propofol— bind to 11β-hydroxylase with very low affinity. Thus, at hypnotic doses, they produce nominal adrenocortical suppression.50 Carboetomidate was found to elicit 3 orders of magnitude less potent inhibition of cortisol synthesis by adrenocortical cells as compared to etomidate.48 This reduced binding affinity for 11β-hydroxylase likely relates to carboetomidate’s inability to bind with the heme iron on the active site of the enzyme, as with other imidazole ring–containing drugs. Thus, alterations in the structure of the basic etomidate molecule represent a path toward increased hypnotic potency, shorter-acting clinical profile, and less adrenal suppression.

Key Points • The most important hormones produced by the anterior pituitary include ACTH, TSH, GH, PRL, and the 2 gonadotropins, LH and FSH. • The balance of releasing factors secreted by the hypothalamus and inhibiting factors secreted by each hormone’s target organ control the secretion of each hormone produced by the anterior pituitary. • Cardiac disease, hypertension, and ventricular hypertrophy are the most important causes of morbidity and mortality in acromegalic patients. • ADH, produced by the posterior pituitary gland in response to a very mild increase in osmolarity, binds to vasopressin receptors on the renal collecting ducts and causes an increase in water reabsorption. • The end result of the interactions between PTH, calcium, vitamin D, and calcitonin is to maintain normal plasma calcium concentration, which, in turn, helps maintain normal cellular function, nerve transmission, membrane stability, bone integrity, coagulation, and intracellular signaling. • Thyroid hormones play a major role in normal growth and development, controlling the rate of metabolism and many body functions.

• Glucocorticoids, such as cortisol, have a multitude of actions, including protein breakdown and gluconeogenesis, fatty acid mobilization, and prevention of muscle protein synthesis. • Sympathetic stimulation leads to secretion of catecholamines (e.g., epinephrine and norepinephrine), which are produced in the adrenal medulla. Catecholamine release plays a crucial role in the stress response to perceived or real physical or psychological injury, including hemorrhage, severe hypoglycemia, trauma, surgical trauma, and fear. • Insulin, secreted by the β cells of the pancreas, has an anabolic effect on target organs and stimulates the synthesis of carbohydrates, fats, and proteins. • Type 2 DM involves 3 main defects in glucose and insulin metabolism: inadequate response of the pancreatic β cells to glucose, decreased response of the peripheral tissues to effects of insulin, and increased hepatic glucose production. • Alterations in the structure of the etomidate molecule may represent a path toward the development of an etomidate analog associated with less adrenocortical steroid suppression.

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Key References Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med. 2007;146:233–243. This study called into question the safety of the adoption of strict glucose control for all patients by demonstrating an increased incidence of death and stroke in patients having cardiac surgery managed with intensive glucose control (serum glucose < 110 mg/dL). (Ref. 44). Henzen C, Suter A, Lerch E, et al. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet. 2000;355:542545. Acute and chronic treatments with glucocorticoid therapy and adrenal gland suppression often become concerns for anesthesiologists in the perioperative period. This study reported the recovery of adrenal function after short-term, high-dose glucocorticoid treatment and use of the low-dose corticotropin test for evaluation of adrenal recovery. (Ref. 26). Mihai R, Farndon JR. Parathyroid disease and calcium metabolism. Br J Anaesth. 2000;85:29–43. This well-written article provides a thorough review of parathyroid anatomy, calcium homeostasis, and parathyroid hormone regulation. In addition, it contains the various classifications of hyperparathyroidism, accompanied by treatment options and anesthetic considerations for parathyroid surgery. (Ref. 8). Nemergut EC, Dumont AS, Barry UT, et al. Perioperative management of patients undergoing transsphenoidal pituitary surgery. Anesth Analg. 2005;101:1170–1181. This review covers a variety of conditions, including Cushing disease, acromegaly, and hyperthyroidism and the implications of transsphenoidal surgery to resect pituitary masses. (Ref. 2). NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283–1297. This landmark study found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg/dL resulted in lower mortality than did a target of 81 to 108 mg/dL. (Ref. 45).

References 1. Burrow GN, Wortzman G, Rewcastle NB, et al. Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N Engl J Med. 1981;304:156–158. 2. Nemergut EC, Dumont AS, Barry UT, et al. Perioperative management of patients undergoing transsphenoidal pituitary surgery. Anesth Analg. 2005;101:1170–1181. 3. Singer PA, Sevilla LJ. Postoperative endocrine management of pituitary tumors. Neurosurg Clin N Am. 2003;14:123–138. 4. Guilleminault C, van den Hoed J. Acromegaly and narcolepsy. Lancet. 1979;2:750–751. 5. Nemergut EC, Zuo Z. Airway management in pituitary disease: a review of 746 patients. J Neurosurg Anesth. 2006;18:73–77. 6. Nemergut EC, Zuo Z, Jane JA Jr, et al. Predictors of diabetes insipidus after transphenoidal surgery: a review of 881 patients. J Neurosurg. 2005;103:448–454. 7. Bringhurst FB, Demay MB, Kronenberg HM. Hormones and disorders of mineral metabolism. In: Kronenberg HM, ed. Williams Textbook of Endocrinology. 13th ed. Philadelphia: Elsevier; 2016:1253– 1322. 8. Mihai R, Farndon JR. Parathyroid disease and calcium metabolism. Br J Anaesth. 2000;85:29–43. 9. Molina PE. Parathyroid gland & Ca2+ & PO4– regulation. In: Molina PE, ed. Endocrine Physiology. 4th ed. New York: McGraw-Hill Education; 2013. Available at: http://accessmedicine.mhmedical.com/ content.aspx?bookid=507§ionid=42540504. 10. Edwards R. Thyroid and parathyroid disease. Int Anesthesiol Clin. 1997;35:63–83. 11. Thakker RV. Mutliple endocrine neoplasia type 1. Best Pract Res Clin Endocrinol Metab. 2010;24:355–370.

12. Wohllk N, Schweizer H, Erlic Z, et al. Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab. 2010;24:371–387. 13. Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Front Horm Res. 2013;41:63–78. 14. Leung AM, Pearce EN, Braverman LE. Perchlorate, iodine, and the thyroid. Best Pract Res Clin Endocrinol Metab. 2010;24:133–141. 15. Molina PE. Thyroid gland. In: Molina PE, ed. Endocrine Physiology. 4th ed. New York: McGraw-Hill Education; 2013. Available at: http://accessmedicine.mhmedical.com/content.aspx?bookid=507&s ectionid=42540504. 16. Kohl BA, Schwartz S. How to manage perioperative endocrine insufficiency. Anesthesiol Clin. 2010;28:139–155. 17. Mercado DL, Petty BG. Perioperative medication management. Med Clin N Am. 2003;87:41–57. 18. Bennett-Guerrero E, Kramer DC, Schwinn DA. Effect of chronic and acute thyroid hormone reduction on perioperative outcome. Anesth Analg. 1997;85:30–36. 19. Ertek S, Cicero AF. Hyperthyroidism and cardiovascular complications: a narrative review on the basis of pathophysiology. Arch Med Sci. 2013;9:944–952. 20. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388:906–918. 21. Food and Drug Administration. Propylthiouracil tablets. 2010. http:// www.fda.gov/Safety/MedWatch/SafetyInformation/ucm209256.htm. Accessed June 21, 2016. 22. Farling PA. Thyroid disease. Br J Anaesth. 2000;85:15–28. 23. Graham GW, Unger BP, Coursin DB. Perioperative management of selected endocrine disorders. Int Anesthesiol Clin. 2000;38:31–67. 24. Carroll R, Matfin G. Endocrine and metabolic emergencies: thyroid storm. Ther Adv Endocrinol Metab. 2010;1:139–145. 25. Weinberg AD, Brennan MD, Gorman CA, et al. Outcome of anesthesia and surgery in hypothyroid patients. Arch Int Med. 1983;143:893–897. 26. Henzen C, Suter A, Lerch E, et al. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet. 2000;355:542–545. 27. Hopkins RL, Leinung MC. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol Met Clin N Am. 2005;34:371–384. 28. Kohl BA, Schwartz S. Surgery in the patient with endocrine dysfunction. Anesthesiol Clin. 2009;27:687–703. 29. Molina PE. Adrenal gland. In: Molina PE, ed. Endocrine Physiology. 4th ed. New York: McGraw-Hill Education; 2013. Available at: http://accessmedicine.mhmedical.com/content.aspx?bookid=507&s ectionid=42540504. 30. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet. 2005;366:665–675. 31. Roizen MF, Schreider BD, Hassan SZ. Anesthesia for patients with pheochromocytoma. Anesthesiol Clin N Am. 1987;5:269–275. 32. Plouin P-F, Amar L, Lepoutre C. Phaeochromocytomas and functional paragangliomas: clinical management. Best Pract Res Clin Endocrinol Met. 2010;24:933–941. 33. Shepherd PR, Kahn BB. Glucose transporters and insulin action— implications for insulin resistance and diabetes mellitus. N Engl J Med. 1999;341:248–257. 34. Lin Y, Sun Z. Current views on type 2 diabetes. J Endocrinol. 2010;204:1–11. 35. Venables MC, Jeukendrup AE. Physical inactivity and obesity: links with insulin resistance and type 2 diabetes mellitus. Int J Exp Diabetes Res. 2009;25:S18–S23. 36. Weinstein AR, Sesso HD, Lee IM, et al. Relationship of physical activity vs body mass index with type 2 diabetes in women. J Am Med Assoc. 2004;292:1188–1194. 37. Nathan DM, Singer DE, Hurxthal K, et al. The clinical information value of the glycosylated hemoglobin assay. N Engl J Med. 1984;310:341–346. 38. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978–982.



39. Friedberg SJ, Lam YW, Blum JJ, et al. Insulin absorption: a major factor in apparent insulin resistance and the control of type 2 diabetes mellitus. Metab Clin Exp. 2006;55(5):614–619. 40. Furnary AP. Clinical benefits of tight glycaemic control: focus on the perioperative setting. Best Pract Res Clin Anaesthesiol. 2009;23(4):411–420. 41. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg. 1997;63(2):356–361. 42. Furnary AP, Zerr KJ, Grunkmeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67(2):352–360. 43. Van Den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–1367. 44. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med. 2007;146:233–243. 45. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283–1297.

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46. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–e137. 47. Garber AJ, Moghissi ES, Bransome ED Jr, et al. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocrinol Pract. 2004;10(suppl 2):4–9. 48. Cotten JF, Forman SA, Laha JK, et al. Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function. Anesthesiology. 2010;112(3):637–644. 49. Pejo E, Santer P, Wang L, et al. γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs. Anesthesiology. 2016;124(3): 651–663. 50. Pejo E, Zhou X, Husain SS, et al. Sedative-hypnotic Binding to 11β-hydroxylase. Anesthesiology. 2016;125(5):943–951.

36 

Endocrine Pharmacology MARK T. KEEGAN

CHAPTER OUTLINE Drugs to Treat Disorders of the Endocrine Pancreas Insulin Basic Pharmacology Clinical Pharmacology Individual Insulin Preparations Regular Insulin Rapidly Acting Insulin Analogues Intermediate-Acting Insulin Long-Acting Insulins Inhaled Insulin Clinical Application Oral Hypoglycemic Agents: Sulfonylureas, Biguanides, Thiazolidinediones Basic Pharmacology Sulfonylureas Biguanides Thiazolidinediones Clinical Pharmacology and Clinical Application Sulfonylureas Biguanides Thiazolidinediones Other Oral Hypoglycemic Agents Glucagon Basic Pharmacology Clinical Pharmacology and Clinical Application Somatostatin Analogs Basic and Clinical Pharmacology Clinical Application Drugs to Treat Disorders of the Hypothalamic-Pituitary-End-Organ Axis Thyroid Hormones Basic Pharmacology Clinical Pharmacology Clinical Application Thioureylene Antithyroid Drugs Basic and Clinical Pharmacology Clinical Application Other Antithyroid Drugs Preparing a Patient With Hyperthyroidism for Surgical Intervention Drugs Used in the Treatment of Pheochromocytoma Basic and Clinical Pharmacology α Antagonists α-Methyl-para-tyrosine (Metyrosine) Clinical Application 708

Corticosteroids Basic Pharmacology Clinical Pharmacology Adverse Effects Clinical Application Adrenal Insufficiency Reactive Airways Disease Corticosteroid Therapy in Neurologic Critical Care Nausea and Vomiting Immunosuppression Treatment of Inflammatory Conditions Airway Edema Allergy Perioperative Steroid Supplementation Adrenocorticotropic Hormone and Steroid Antagonists Posterior Pituitary Hormones, Analogs, and Antagonists Basic and Clinical Pharmacology Vasopressin and Desmopressin Oxytocin Clinical Application Vasopressin and Desmopressin Oxytocin Other Agents Growth Hormone, Prolactin, and Related Drugs Growth Hormone Basic Pharmacology Clinical Pharmacology Clinical Application Drugs Related to Growth Hormone Drugs Affecting Prolactin Physiology Sex Hormones and Related Drugs Basic and Clinical Pharmacology The Gonadotropins Sex Steroids Clinical Application Gonadotropins Estrogens Hormonal Contraceptives Parathyroid Hormone and Drugs Affecting Calcium Metabolism Emerging Developments Glycemic Control in the Perioperative Period and in the Critically Ill Steroid Supplementation During Critical Illness Hormone Supplementation in Potential Organ Donors

CHAPTER 36  Endocrine Pharmacology 708.e1



Abstract

Keywords

Dysfunction of the complex physiologic processes of the endocrine systems can lead to significant and potentially life-threatening problems. Administration of exogenous hormones or drugs that mimic or antagonize hormonal effects to manipulate the metabolic milieu is important in many therapies. Endocrine pharmacotherapeutics range from simple supplementation of a missing hormone, such as insulin in the case of patients with type 1 diabetes mellitus (DM), to careful manipulation of physiologic processes with advanced pharmaceuticals in the case of assisted reproduction techniques. Many of these agents have implications for the practice of anesthesia, critical care, and pain medicine.

Endocrinology Pharmacology Diabetes mellitus Thyroid Adrenal Hormones

CHAPTER 36  Endocrine Pharmacology



D

ysfunction of the complex physiologic processes of the endocrine systems can lead to significant and potentially life-threatening problems. Administration of exogenous hormones or drugs that mimic or antagonize hormonal effects to manipulate the metabolic milieu is important in many therapies. Endocrine pharmacotherapeutics range from simple supplementation of a missing hormone, such as insulin in the case of patients with type 1 diabetes mellitus (DM), to careful manipulation of physiologic processes with advanced pharmaceuticals in the case of assisted reproduction techniques. Many of these agents have implications for the practice of anesthesia, critical care, and pain. Historical perspectives are highlighted with the discussion of individual drug classes.

DRUGS TO TREAT DISORDERS OF THE ENDOCRINE PANCREAS

Insulin The discovery of insulin by Banting and Best represents a major milestone in modern medicine.1 Within a few years of its discovery insulin had been purified and crystallized. Its amino acid sequence was established by Sanger in 1960. The protein was synthesized in 1963 and its three-dimensional structure elucidated in 1972. The first biosynthetic human insulin was approved by the U.S. Food and Drug Administration (FDA) in 1982.2

Basic Pharmacology Insulin is synthesized in β cells of the pancreatic islets of Langerhans. Pre-proinsulin (a single-chain, 110–amino acid precursor) is initially formed. Subsequently the N-terminal 24–amino acid peptide is cleaved to form proinsulin. Removal of four basic amino acids and a connecting (C) peptide gives rise to insulin itself. The insulin molecule contains A and B peptide chains, usually composed of 21 and 30 amino acid residues, respectively. In most species a single insulin gene gives rise to a single protein product. When pancreatic β cells are stimulated, insulin and C-peptide are released into the circulation in equimolar amounts. Therefore functional activity of pancreatic β cells is reflected by plasma C-peptide concentrations. It is also possible to differentiate endogenous from exogenous insulin by evaluating plasma C-peptide content. Human insulin, made by recombinant DNA techniques, is used exclusively in the United States. “Purified” insulin contains less than 10 ppm of proinsulin. Refrigeration is recommended but is not crucial. Insulin is a member of a family of peptides known as insulin-like growth factors (IGFs). IGFs are produced in many tissues and regulate cellular growth and metabolism. Specific insulin receptors in the plasma membrane are similar to IGF receptors. The insulin receptor is a large transmembrane glycoprotein that mediates its actions through intracellular tyrosine kinase activity. Insulin binding leads to autophosphorylation of intracellular insulin receptor sites, causing recruitment of numerous enzymes and mediating molecules that are activated or inactivated, leading to a myriad of intracellular events. Importantly, glucose transporters type 4 are translocated to the plasma membrane where they facilitate diffusion of glucose into cells. Other signals activate glycogen synthase, stimulate uptake of amino acids and protein synthesis, and regulate gene expression (see Chapter 30 for more information on the physiology of insulin).

709

TABLE 36.1  Hypoglycemic Actions of Insulin

Liver

Muscle

Adipose Tissue

Inhibits hepatic glucose production (decreases gluconeogenesis and glycogenolysis)

Stimulates glucose uptake

Stimulates glucose uptake (amount is small compared to muscle)

Stimulates hepatic glucose uptake

Inhibits flow of gluconeogenic precursors to the liver (e.g., alanine, lactate, pyruvate)

Inhibits flow of gluconeogenic precursors to liver (glycerol) and reduces energy substrate for hepatic gluconeogenesis (nonesterified fatty acids)

Modified from Table 60.2 in Brunton LL, ed. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 11th ed. New York, NY: McGraw Hill; 2006.

Insulin’s hypoglycemic actions on liver, muscle, and adipose tissue are most important (Table 36.1). When injected intravenously, insulin has a plasma half-life of 5 to 6 minutes. It is degraded in liver, kidney, and muscle. When renal function is severely impaired, insulin requirements decrease because of reduced breakdown. Liver metabolism of insulin operates at near-maximal capacity and cannot compensate for loss of renal function. Although insulin is cleared relatively quickly from the circulation, its biologic effects persist for 30 to 60 minutes because it binds tightly to insulin receptors. Subcutaneous injection of insulin leads to slow release into the circulation and a sustained pharmacologic effect.

Clinical Pharmacology Insulin is most commonly administered subcutaneously, but it can also be administered intravenously. In contrast to physiologic secretion of insulin, subcutaneous administration delivers insulin to the peripheral tissues rather than the portal system, and the pharmacokinetics do not reproduce a normal rise and fall associated with ingestion of nutrients. Nonetheless, insulin treatment is lifesaving for patients with DM. Insulin preparations are characterized by their duration of action or their species of origin. This latter classification is less relevant now owing to the wide availability of synthetic human preparations. For historical reasons, doses and concentrations of insulin are expressed in units. In the past, preparations of the hormone were impure and were standardized by bioassay. One unit of insulin is equal to the amount of insulin required to reduce blood glucose concentration in a fasting rabbit to 45 mg/dL (2.5 mM). Insulin is supplied in solution or suspension at a concentration of 100 units/mL. Typically, a patient with type 1 DM requires between 20 and 60 units of exogenously administered insulin per day. Higher-concentration insulin preparations are available for patients who are resistant to insulin. Table 36.2 details currently available insulin preparations, and Fig. 36.1 shows typical pharmacokinetic profiles of insulin and insulin analogs following subcutaneous administration. Insulin is among the drugs highlighted by the Institute for Safe Medication Practices as having an increased risk for patient harm

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Gastrointestinal and Endocrine Systems

SE C T I O N V

TABLE 36.2  Insulin Preparations

Preparation

Onset (hr)

Peak (hr)

Effective Duration (hr)

Aspart Glulisine Lispro Regular

120 kg. The repeat dose remains the same: 1 g every 4 hours intraoperatively. Used with permission from University of Utah Health. b

and cephalosporins—increase the risk of C. difficile infection;64–66 the spore-forming, toxin-producing, gram-positive anaerobe behind antibiotic-associated diarrhea and pseudomembranous colitis. C. difficile infection is one of the most common nosocomial infections and is a significant cause of morbidity and mortality, especially among older adult hospitalized patients.67 The incidence of C. difficile infection among hospitalized adults in the United States nearly doubled between 2001 and 2010.68 Among the established risk factors (advanced age, hospitalization, and severe illness) antibiotic use is the most widely recognized and modifiable risk factor.69–72 Though any antibiotic can predispose

to colonization by C. difficile, the increased duration of therapy by multiple broad-spectrum antimicrobials significantly increases incidence.73 Antimicrobials disrupt the normal colonic flora and facilitate the growth and colonization of the gram-positive bacteria; exotoxins then bind to receptors on intestinal epithelial cells, leading to inflammation and diarrhea. The management of C. difficile–induced diarrhea involves oral vancomycin/fidaxomicin, supportive care, and discontinuation of the inciting antibiotic as soon as possible; antimotility agents, such as loperamide and opiates, are also usually avoided. C.

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Immunity and Infection

TABLE Drugs and Doses Available Routinely for Antibiotic Prophylaxis—Re-dose for Therapeutic Antibiotics 39.4  Started Preoperativelya

Initial Dose (< 80 kg)

Initial Dose (≥ 80 kg)

Piperacillin/Tazobactam (Zosyn)

3.375 g

Ampicillin/Sulbactam (Unasyn)

Initial Dose (≥ 120 kg)

Repeat Dose Interval for SCr >3

Timing

Repeat Doseb (Interval)

3.375 g

Infuse over 30 min1

Re-dose prior to incision if most recent dose > 2 h before incision; then re-dose at 2 h intervals.

12 h

3 g

3 g

Infuse over 30 min1

Re-dose prior to incision if most recent dose > 2 h before incision; then re-dose at 4 h (1.5 g).

12 h

Meropenem

500 mg

500 mg

Infuse over 30 min1

Re-dose prior to incision if most recent dose > 2 h before incision; then re-dose at 4 h.

12 h

Cefazolin

1 g

2 g

Slow IV push 0–60 min before incision

Re-dose prior to incision if most recent dose > 2 h before incision; then re-dose 1 g at 4 h.

12 h

Cefepime

1 g

2 g

Infuse over 30 min1

Re-dose prior to incision if most recent dose > 2 h before incision; then re-dose 1 g at 4 h.

-

Drug

3 g

a Protocol used when therapeutic antibiotics are started preoperatively (e.g., in the emergency department) to treat actual or presumed infection, for example, appendicitis or acute cholecystitis. Either the same drug can be continued or the usual prophylactic antibiotic agent for that procedure may be used. Note that, procedurally, these cases are not counted in our compliance monitoring, because these are therapeutic rather than prophylactic guidelines. This table is created to provide guidance to providers in determining when to re-dose the antibiotics from the perspective of patient benefit. b Note that dosing schedule is more frequent than for therapeutic use to maintain wound tissue levels throughout surgery and ongoing contamination. Additional intraoperative doses should be given when there is significant blood loss (~ half to 1 blood volume). Use the recommended second dose for this purpose. Used with permission from University of Utah Health.

difficile is easily spread; thus, implementing infection-control policies to minimize cross-contamination is critical. Of note, C. difficile spores are not susceptible to alcohol; thus, hand-washing with soap and water is required to prevent cross-contamination from infected patients.

Cost Containment Although antimicrobial prophylaxis plays an important role in reducing the rate of SSI, other factors—such as attention to basic infection-control strategies,74 the surgeon’s experience, duration of the procedure, operating room environments, instrument sterilization, perioperative temperature and glycemic control, and the underlying medical condition of the patient—all impact SSI rates.75,76 The costs of SSI are thousands of dollars per infection, especially those involving prosthetic joint implants17,77 or antimicrobialresistant organisms.78 The cost of treatment in patients who develop MRSA infection is twice as high as in patients with methicillinsusceptible staphylococcal infections. Patients with MRSA infections also have double the mortality.79

Summary The prevention of SSI remains a high priority, particularly as the number of patients at risk for SSI continues to increase. Anesthesiologists can make a major contribution to preventing SSI and should work in consultation with the surgical team to implement guidelines determined by the local infection-control committee. Surgical antibiotic prophylaxis is cost-effective in reducing SSI. The ideal prophylactic agent should prevent SSI, prevent SSI-related morbidity and mortality, be cost-effective, avoid adverse effects, and have no adverse consequences on the microbial flora of the

patient or the hospital.21 Cefazolin remains the drug of choice for prophylaxis in most procedures because it is safe and has proven efficacy. Anesthesiologists play a major role in preventing SSI and should contribute to the development of local guidelines based on national guidelines, local patterns of resistance, cost, and surgeon preference.

Emerging Developments While the efficacy of perioperative prophylactic antibiotics is well established, a number of opportunities remain to optimize both antibiotic prophylaxis and other approaches to preventing SSIs. Development of standardized decision support systems within electronic health records to optimize antibiotic choice and provide recommended initial doses and considerations in administration would advance the quality of patient care delivered across all health care environments. Questions remain related to weight-based antibiotic administration, re-dosing schedule, and antimicrobial efficacy in pedriatric populations, including dosing in newborns as well as antibiotic choice and dosing across all age groups. Given the increasing prevalence of antibiotic-resistant organisms, the development of new antibiotics and antibiotic classes with enhanced spectrum of activity will become increasingly important. While preoperative MRSA and MSSA screening is increasingly used, particularly for cases such as joint replacement and cardiac surgery, further studies to evaluate the cost-effectiveness and rational use of such testing would provide evidence for better management of decontamination during the perioperative period. Recent studies have demonstrated that many antibiotics induce changes in bacterial metabolism that promote the formation of reactive oxygen species that lead to bacterial cell death.80 Thus, antibiotics appear to require

CHAPTER 39  Infection, Antimicrobial Drugs, and Anesthesia



777

TABLE 39.5  Drugs and Doses Available Routinely for Preoperative Antibiotic Prophylaxis

Repeat Dose (Interval)

Drug

Initial Dose

Timing

Ciprofloxacin IV

400 mg

Infuse over 60 min. Start 0–60 min prior to incision.

400 mg (6 h)

Levofloxacin

500 mg

Infuse over 60 min. Start 0–120 min prior to incision.

500 mg (12 h)

Vancomycina (2

Vancomycina (70–110 kg)

1.5 g

Infuse at 1 g/h. Start 0–120 min prior to incision.c

Single re-dose at 8 h No repeat dose for serum creatinine>2

Vancomycina (≥ 110 kg)

2 g

Infuse at 1 g/h. Start 0–120 min prior to incisionc

Single re-dose at 8 h No repeat dose for serum creatinine >2

Ciprofloxacin (oral)b

500 mg

Take PO 0–60 min prior to incision.

400 mg IV (6 h)

a Vancomycin is indicated only for patients per protocol undergoing cardiac, orthopedic, or abdominal wall reconstruction surgery and at high risk with a positive screen or no screen. These patients should be identified in the preoperative clinic. They should never be scheduled as the first case, and should be asked to come in 3–4 hours before surgery so that vancomycin can be initiated in preoperatively. b Oral administration of ciprofloxacin is acceptable for urology cases, but IV is preferable when IV access is available. c To avoid having a SCIP fallout when the infusion is started more than 120 minutes prior to incision (60 minutes for ciprofloxacin), patients should receive either cefazolin or clindamycin 0–60 minutes prior to incision in the operating room. Notes Penicillin allergy is almost never a contraindication to cefazolin or other cephalosporin administration. A documented history of anaphylaxis or other serious reaction (angioedema, hives, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis) is the only exception. Always confirm the antibiotic plan with surgeons at the time-out or earlier. The surgeon may wish to delay antibiotics until after culture. Antibiotics may not be indicated. Make sure to record the reason for not giving antibiotics on the record. Ideally, an antibiotic infusion should be completed before incision, but Centers for Medicare and Medicaid guidelines consider starting the infusion before incision adequate. When possible, for drugs requiring slow (> 30 min) infusion, the infusion should be initiated in preop. When a tourniquet is used, the dose must be completed at least 5 minutes before the tourniquet is inflated. Additional intraoperative doses should be given when there is significant blood loss (~ half to 1 blood volume). Use the recommended second dose for this purpose. When therapeutic antibiotics are given for an infection or presumed infection (e.g., acute appendicitis), prophylactic antibiotics are not required. Each situation should be examined individually: When was the antibiotic given? Which antibiotic was used? In some cases, coverage of skin flora may be appropriate prior to skin incision, but often continuation of the therapeutic antibiotics is all that is required. Used with permission from University of Utah Health.

oxygen for optimal function; the dose-dependence of this relationship is an area for future research. Developing technology to monitor antimicrobial serum and tissue concentrations could create the opportunity for personalized approaches to antibiotic prophylaxis. Similarly, identifying pharmacogenomic influences on antibiotic metabolism and efficacy—as well as rapid, accurate tests for a patient’s resident flora—would allow personalization of perioperative prophylactic antibiotic selection and dosing. While antibiotic prophylaxis is a critical component of current perioperative surgical management, other factors—including improved antisepsis, reduction of cross-transmission of pathogens, and enhancement of host defenses—are complementary. Improvements in all aspects of perioperative infection control are required to further reduce SSI rates. For example, recent studies have demonstrated that increasing the rate of hand hygiene by

anesthesiologists from less than 1 to 7 times an hour reduces workspace contamination, intravenous stopcock contamination, and health care–associated infection rates.81 Increasing compliance of anesthesiologists with the World Health Organization’s Five Moments of Hand Hygiene82 might increase the efficacy of antibiotic prophylaxis. Similarly, inattention to requirements for sterile compounding and handling of intravenous medications by anesthesiologists may lead to individual cases or outbreaks of infectious complications. For example, there have been documented outbreaks involving bupivacaine and steroids used for joint injections in pain clinics.83 The lipid nature of propofol supports the growth of bacteria and provides an opportunity for both intrinsic and extrinsic contamination. Soon after its introduction, improper handling of propofol was associated with sepsis and even death; more recent reports of similar propofol-associated infections and sepsis suggest that manufacturer guidelines are not universally followed.84

Key Points • Surgical antibiotic prophylaxis is indicated for most operations and is a keystone for the prevention of SSI. • The antimicrobial of choice for prophylaxis should prevent SSI, prevent SSI-related morbidity and mortality, be cost-effective,

avoid adverse effects, and be chosen based on the microbial flora of the patient or the hospital. • The American Society of Health-System Pharmacists (ASHP) recommends administering doses within 60 minutes of surgical

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Immunity and Infection

incision for most antibiotics and within 120 minutes for vancomycin and fluoroquinolones. • Anesthesiologists are in the best position to administer most prophylactic antibiotics; therefore, they make a major

Key References Miles AA, Miles EM, Burke J. The value and duration of defence reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol. 1957;38(1):79–96. This research in a guinea pig model developed the basis for routine surgical antibiotic prophylaxis. (Ref. 1). Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281–286. This clinical study demonstrated that the timing established in the guinea pig model applied in human surgery as well and led to the establishment of antibiotic prophylaxis within 60 minutes of incision as the standard of care in surgical patients. (Ref. 5). Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. These are the most recent and comprehensive guidelines for surgical antibiotic prophylaxis. This is a valuable resource in establishing local practice guidelines. (Ref. 21). Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152(8):784–791. This is the most recent compilation by the CDC of all guidelines for prevention of SSI, including antibiotic prophylaxis. (Ref. 30). Blumenthal KG, Ryan EE, Li Y, et al. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018;66:329–366. This recent study demonstrated a 50% increase in SSI in patients who report penicillin allergy, which is attributable to the use of alternative agents, including vancomycin, clindamycin, and gentamicin. Thus, alternatives should be used only in patients with a documented, severe, IgE-mediated reaction to penicillin. (Ref. 41).

References 1. Miles AA, Miles EM, Burke J. The value and duration of defence reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol. 1957;38(1):79–96. 2. Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic. The effect of inspired oxygen on infection. Arch Surg. 1984;119(2):199–204. 3. Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic. A comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg. 1986;121(2):191–195. 4. Bernard HR, Cole WR. The prophylaxis of surgical infection: the effect of prophylactic antimicrobial drugs on the incidence of infection following potentially contaminated operations. Surgery. 1964;56:151– 157. 5. Classen DC, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281–286. 6. DiPiro JT, Vallner JJ, Bowden TA, et al. Intraoperative serum and tissue activity of cefazolin and cefoxitin. Arch Surg. 1985;120:829–832. 7. Mu Y, et al. Improving risk-adjusted measures of surgical site infection for the national healthcare safety network. Infect Control Hosp Epidemiol. 2011;32(10):970–986. 8. Anderson DJ, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(6):605–627. 9. National Healthcare Safety Network. Centers for Disease Control and Prevention. Surgical site infection (SSI) event. Published January 2018. http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf. Accessed April 16, 2018.

contribution to preventing SSI. Anesthesiologists should work in consultation with the surgical team and the local infectioncontrol committee to implement guidelines for antibiotic prophylaxis. 10. Smyth ET, Emmerson AM. Surgical site infection surveillance. J Hosp Infect. 2000;45(3):173–184. 11. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. National Health Statistics Reports 11. Revised September 4, 2009. http://www.cdc.gov/nchs/data/nhsr/nhsr011.pdf. Accessed October 2, 2017. 12. DeFrances CJ, Podgornik MN. 2004 National hospital discharge survey. Adv Data. 2006;371:1–19. 13. Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43(3):322–330. 14. Barie PS, Eachempati SR. Surgical site infections. Surg Clin North Am. 2005;85(6):1115–1135, viii–ix. 15. De Lissovoy G, Fraeman K, Hutchins D, et al. Surgical site infection: incidence and impact on hospital utilization and treatment cost. Am J Infect Control. 2009;37:387–397. 16. Dellinger EP. Prophylactic antibiotics: administration and timing before operation are more important than administration after operation. Clin Infect Dis. 2007;44:928–930. 17. Umscheid Craig A, et al. Estimating the proportion of healthcareassociated infections that are reasonably preventable and the related mortality and costs. Infect Control Hosp Epidemiol. 2011;32(2):101– 114. 18. Fry DE. Surgical site infections and the surgical care improvement project (SCIP): evolution of national quality measures. Surg Infect (Larchmt). 2008;9:579–584. 19. Myles JL, Shamanski F, Witte D. The physicians quality reporting initiative: measure development, implementation and current procedural terminology coding. Adv Anat Pathol. 2010;17:49–52. 20. Callcut RA, Breslin TM. Shaping the future of surgery: the role of private regulation in determining quality standards. Ann Surg. 2006;243:304–312. 21. Bratzler DW, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195–283. 22. Nelson RL, Glenny AM, Song F. Antimicrobial prophylaxis for colorectal surgery. Cochrane Database Syst Rev. 2009;(1):CD001181. 23. Ortega G, et al. An evaluation of surgical site infections by wound classification system using the ACS-NSQIP. J Surg Res. 2012;174(1):33–38. 24. Hidron AI, et al. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the national healthcare safety network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol. 2008;29(11):996–1011. 25. Kluytmans JA, et al. Reduction of surgical-site infections in cardiothoracic surgery by elimination of nasal carriage of staphylococcus aureus. Infect Control Hosp Epidemiol. 1996;17:780–785. 26. Kalmeijer MD, et al. Surgical site infection in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis. 2002;35:353–358. 27. Stratchounski LS, Taylor EW, Dellinger EP, et al. Antibiotic policies in surgery: a consensus paper. Int J Antimicrob Agents. 2005;26:312– 322. 28. Garey KW, et al. Timing of vancomycin prophylaxis for cardiac surgery patients and the risk of surgical site infections. J Antimicrob Chemother. 2006;58:645–650. 29. van Kasteren ME, Mannien J, Ott A, et al. Antibiotic prophylaxis and the risk of surgical site infections following total hip arthroplasty: timely administration is the most important factor. Clin Infect Dis. 2007;44:921–927. 30. Berríos-Torres SI, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152(8):784–791.



CHAPTER 39  Infection, Antimicrobial Drugs, and Anesthesia

31. Beauduy CE, Winston LG. Beta-Lactam & other cell wall- & membrane-active antibiotics. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:795–814. 32. Poeran J, Wasserman I, Zubizarreta N, et al. Characteristics of antibiotic prophylaxis and risk of surgical site infections in open colectomies. Dis Colon Rectum. 2016;59:733–742. 33. Beauduy CE, Winston LG. Aminoglycosides & spectinomycin. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:826–833. 34. Beauduy CE, Winston LG. Sulfonamides, trimethoprim, & quinolones. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:834–841. 35. Jackson MA, Schutze GE. The use of systemic and topical fluoroquinolones. Pediatrics. 2016;138(5). 36. Beauduy CE, Winston LG. Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:815–825. 37. Beauduy CE, Winston LG. Miscellaneous antimicrobial agents; disinfectants, antiseptics, & sterilants. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:895–903. 38. Lampiris HW, Maddix DS. Antifungal agents. In: Katzung BG, ed. Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Education; 2018:853–862. 39. Cunha BA. Antibiotic selection in the penicillin-allergic patient. Med Clin North Am. 2006;90:1257–1264. 40. Pichichero ME. Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagn Microbiol Infect Dis. 2007;57(3 suppl):13S–18S. 41. Blumenthal KG, Ryan EE, Li Y, et al. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018;66:329–366. 42. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498–2505. 43. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009;43(2):304–315. 44. Jain R, et al. Veterans affairs initiative to prevent methicillin resistant staphylococcus aureus infections. N Engl J Med. 2011;364:1419– 1430. 45. Harbarth S, Fankhauser C, Schrenzel J, et al. Universal screening for methicillin-resistant staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA. 2008;299:1149–1157. 46. Hebert C, Robicsek A. Decolonization therapy in infection control. Curr Opin Infect Dis. 2010;23(4):340–345. 47. Alphonso N, et al. Perioperative antibiotic prophylaxis in paediatric cardiac surgery. Cardiol Young. 2007;17(1):12–25. 48. Maher KO, et al. A retrospective review of three antibiotic prophylaxis regimens for pediatric cardiac surgical patients. Ann Thorac Surg. 2002;74(4):1195–1200. 49. Johnson PN, Miller JL, Boucher EA. Medication dosing in overweight and obese children. http://www.ppag.org/obesedose/. Accessed October 2, 2017. 50. Hendren S, Fritze D, Banerjee M, et al. Antibiotic choice is independently associated with risk of surgical site infection after colectomy: a population-based cohort study. Ann Surg. 2013;257:469e475. 51. Cannon JA, Altom LK, Deierhoi RJ, et al. Preoperative oral antibiotics reduce surgical site infection following elective colorectal resections. Dis Colon Rectum. 2012;55:1160e1166. 52. Deierhoi RJ, Dawes LG, Vick C, et al. Choice of intravenous antibiotic prophylaxis for colorectal surgery does matter. J Am Coll Surg. 2013;217:763e769. 53. Trent Magruder J, et al. Continuous intraoperative cefazolin infusion may reduce surgical site infections during cardiac surgical procedures: a propensity-matched analysis. J Cardiothorac Vasc Anesth. 2015;29(6):1582–1587.

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54. Adembri C, Ristori R, Chelazzi C, et al. Cefazolin bolus and continuous administration for elective cardiac surgery: improved pharmacokinetic and pharmacodynamic parameters. J Thorac Cardiovasc Surg. 2010;140:471–475. 55. Buijk SE, Gyssens IC, Mouton JW, et al. Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients. J Antimicrob Chemother. 2004;54:199–205. 56. Kasiakou SK, Lawrence KR, Choulis N, et al. Continuous versus intermittent intravenous administration of antibacterials with timedependent action: a systematic review of pharmacokinetic and pharmacodynamic parameters. Drugs. 2005;65:2499–2511. 57. Bertholee D, et al. Blood concentrations of cefuroxime in cardiopulmonary bypass surgery. Int J Clin Pharm. 2013;35:798–804. 58. Anaya DA, Dellinger EP. The obese surgical patient: a susceptible host for infection. Surg Infect (Larchmt). 2006;7:473–480. 59. Gendall KA, Raniga S, Kennedy R, et al. The impact of obesity on outcome after major colorectal surgery. Dis Colon Rectum. 2007;50:2223–2237. 60. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71–87. 61. Edmiston CE, Krepel C, Kelly H, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Surgery. 2004;136:738–747. 62. Zelenitsky SA, Silverman RE, Duckworth H, et al. A prospective, randomized, double-blind study of single high dose versus multiple standard dose gentamicin both in combination with metronidazole for colorectal surgical prophylaxis. J Hosp Infect. 2000;46:135– 140. 63. Rybak MJ, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325–327. 64. Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for clostridium difficile-associated diarrhea: a cohort study during an epidemic in quebec. Clin Infect Dis. 2005;41:1254. 65. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68:1951. 66. Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated clostridium difficile infection. Antimicrob Agents Chemother. 2013;57:2326. 67. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66:e1. 68. Reveles KR, Lee GC, Boyd NK, et al. The rise in clostridium difficile infection incidence among hospitalized adults in the United States: 2001-2010. Am J Infect Control. 2014;42:1028. 69. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother. 2003;51:1339. 70. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for clostridium difficile infection and colonization. N Engl J Med. 2011;365:1693. 71. Guh AY, Hocevar Adkins S, Li Q, et al. Risk factors for communityassociated clostridium difficile infection in adults: a case-control study. Open Forum Infect Dis. 2017;4:ofx171. 72. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for clostridium difficile infection and colonization. N Engl J Med. 2011;365:1693. 73. Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of clostridium difficile infection. Clin Infect Dis. 2011;53:42.

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Immunity and Infection

74. Ehrenkranz NJ, Pfaff SJ. Mediastinitis complicating cardiac operations: evidence of postoperative causation. Rev Infect Dis. 1991;13:803–814. 75. Anderson DJ, et al. Strategies to prevent surgical site infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(suppl 1):S51–S61. 76. Antimicrobial prophylaxis for surgery. Treat Guidel Med Lett. 2009;7(82):47–52. 77. Kurtz SM, et al. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8 suppl):61–65, e1. 78. Engemann John J., et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with staphylococcus aureus surgical site infection. Clin Infect Dis. 2003;36(5):592–598. 79. Henteleff HJ, et al. Universal screening for methicillin-resistant staphylococcus aureus in surgical patients. J Am Coll Surg. 2010; 211(6):833–835.

80. Dwyer DJ, Collins JJ, Walker GC. Unraveling the physiological complexities of antibiotic lethality. Annu Rev Pharmacol Toxicol. 2015;55:313–332. 81. Koff MD, Loftus RW, Burchman CC, et al. Reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a novel device. Anesthesiology. 2009;110:978–985. 82. Sax H, Allegranzi B, Uçkay I, et al. My five moments for hand hygiene’: a user-centered design approach to understand, train, monitor and report hand hygiene. J Hosp Infect. 2007;67: 9–21. 83. CDC. Invasive staphylococcus aureus infections associated with pain injections and reuse of single-dose vials – Arizona and Delaware, 2012. MMWR Morb Mortal Wkly Rep. 2012;61:501–504. 84. Muller AE, et al. Outbreak of severe sepsis due to contaminated propofol: lessons to learn. J Hosp Infect. 2010;76(3):225–230.

40 

Renal Physiology JOSEPH S. MELTZER

CHAPTER OUTLINE Renal Blood Flow and Glomerular Filtration Rate Renal Blood Flow Renal Clearance Renal Plasma Flow Glomerular Filtration Rate Age-Related Renal Changes The Nephron Water and the Kidney Salt and the Kidney Potassium and the Kidney

or acute renal failure can complicate surgery. The elimination of toxins and metabolites is important in the perioperative period; this function also includes the elimination of many anesthetic drugs, which can be viewed as exogenous toxins given their narrow therapeutic margin. Electrolyte balance is key for cardiovascular stability and prevention of dysrhythmias. Acid–base balance is vital for proper enzyme and cellular function. Hormones such as renin and erythropoietin play critical roles in blood pressure regulation and red blood cell production, critical concerns during the perioperative period. These many functions of the kidney help maintain homeostasis during periods of changing fluid and electrolyte intake and losses. Fig. 40.1 shows the anatomy and blood supply of the kidneys.

Acid–Base Balance

Renal Blood Flow and Glomerular Filtration Rate

Renal Hormone Production Defining Renal Failure

Renal Blood Flow

Risk of Perioperative Acute Kidney Injury

The kidney is the most robustly perfused organ per gram of tissue in the human body, receiving 20% to 25% of cardiac output. Renal blood flow (RBF) is directly proportional to the transrenal gradient, the pressure difference between the renal artery and renal vein, and inversely proportional to the resistance of the renal vasculature. Autoregulation of RBF is accomplished by changing renal vascular resistance as arterial pressure changes, thereby maintaining constant blood flow across a range of mean arterial pressure from 50 to 150 mm Hg in normotensive people.1 While global RBF is relatively constant, its distribution within the kidney is quite heterogeneous. The renal cortex and renal cortical nephrons receive 90% of RBF while the renal medulla and its juxtamedullary nephrons receive only about 10%. This great disparity in regional blood flow makes the renal medulla sensitive to ischemic injury. RBF is calculated by determining both the clearance of a given substance from the plasma and the renal plasma flow (RPF).

Toxin and Metabolite Excretion

Acute Kidney Injury in Surgical Patients Assessment and Management of Acute Kidney Injury Preoperative Approach Intraoperative Management of Renal Function Anesthetic Drugs and Impaired Renal Function Common Perioperative Medications That Impair Renal Function Perioperative Renal Replacement Therapy Hepatorenal Syndrome Emerging Developments Prevention and Biomarkers for Acute Kidney Injury

T

he kidney is a complex multifunctional organ that can be affected by anesthesia and the physiologic alterations of the perioperative period. The main functions of the kidney in the context of anesthesiology include (1) regulation of salt and water balance, (2) toxin and metabolite elimination (including drugs), (3) electrolyte homeostasis, (4) acid–base balance, and (5) hormone production. These functions must be understood and recognized for optimal patient care during and after surgery or intensive care. The anesthetist must understand the kidney’s role in salt and water balance; otherwise, hypovolemia, volume overload, 782

Renal Clearance The renal clearance of a substance is the volume of plasma completely cleared of the substance per unit time. [1] C = U × V P, where C = clearance in mL/min, U = urine concentration in mg/mL, V = urine volume/time in mL/min, and P = plasma concentration in mg/mL.

CHAPTER 40  Renal Physiology 782.e1



Abstract

Keywords

The main functions of the kidney are (1) regulation of salt and water balance, (2) toxin and metabolite elimination, (3) electrolyte homeostasis, (4) acid–base balance, and (5) hormone production. Renal blood flow is directly proportional to the transrenal gradient, the pressure difference between the renal artery and the renal vein. Autoregulation mechanisms maintain constant renal blood flow over a range of blood pressures.

clearance glomerular filtration rate renin acid-base balance electrolyte homeostasis acute kidney injury

CHAPTER 40  Renal Physiology



Superior vena cava

Normal GFR is about 120 mL/min in men and 100 mL/min in women. GFR can also be estimated with blood urea nitrogen (BUN) and plasma creatinine. BUN and plasma creatinine increase as GFR decreases. Notably, GFR decreases with age although plasma creatinine remains relatively constant owing to a decrease in muscle mass. Creatinine clearance is less accurate than inulin clearance but much more practical to measure.

Aorta

Heart

Inferior vena cava

Descending aorta

Right kidney

Left kidney

• Fig. 40.1  The anatomy of the kidneys. The kidneys are retroperitoneal organs attached to the abdominal aorta and inferior vena cava by the renal arteries and veins, respectively. The right kidney most often lies caudal to the left kidney, inferior to the liver.

Renal Plasma Flow RPF is calculated by the clearance of para-aminohippuric acid (PAH), as at low concentrations this compound is completely cleared from the plasma by renal tubular filtration and secretion in a single pass. RPF = CPAH

783

[2] = U PAH × V PPAH,

where RPF = renal plasma flow in mL/min, CPAH = clearance of PAH in mL/min, UPAH = urine concentration of PAH in mg/mL, V = urine flow rate in mL/min, and PPAH = plasma concentration of PAH in mg/mL. RBF (in mL/min) is determined via the following equation: [3] RBF = RPF 1 − hematocrit.

Glomerular Filtration Rate Glomerular filtration rate (GFR) is measured by the clearance of inulin, a fructose polysaccharide that is readily filtered but not resorbed or secreted by the renal tubule, therefore being directly proportional to GFR. [4] GFR = U inulin × V Pinulin = C inulin , where GFR = glomerular filtration rate in mL/min, Uinulin = urine concentration of inulin in mg/mL, V = urine flow rate in mL/ min, Pinulin = plasma concentration of inulin in mg/mL, and Cinulin = clearance of inulin in mL/min.

[5] GFR ≈ U creatinine × V Pcreatinine = C creatinine, where GFR = glomerular filtration rate in mL/min, Ucreatinine = urine concentration of creatinine in mg/mL, V = urine flow rate in mL/min, Pcreatinine = plasma concentration of creatinine in mg/ mL, and Ccreatinine = clearance of creatinine in mL/min. The filtration fraction (FF) is the fraction of RPF that is filtered across the glomerular capillaries and is normally about 0.20. Therefore, 20% of the RPF is filtered, leaving 80% of the RPF to leave the glomerulus via the efferent arterioles, making up the peritubular capillary circulation. [6] FF = GFR RPF , where FF = filtration fraction, GFR = glomerular filtration rate, and RPF = renal plasma flow. Blood flow to the glomerulus is regulated by the afferent and efferent arteriolar vascular tone, which adjusts glomerular filtration pressure. Afferent arteriolar dilation or efferent arteriolar constriction increases the FF and GFR. This autoregulatory mechanism is capable of maintaining GFR across a wide range of blood pressures and is achieved, in part, by the juxtaglomerular apparatus (see later discussion). If blood pressure falls, there is a concomitant reduction in afferent arteriolar pressure with a fall in RBF and in filtered solute. This triggers release of renin in the juxtaglomerular apparatus. Renin, a selective protease, cleaves angiotensinogen to angiotensin I, which is subsequently cleaved to angiotensin II by angiotensin-converting enzyme (ACE) in the lungs. Angiotensin II causes thirst (and water intake), vasoconstriction, and Na+ and water retention (via aldosterone), all of which increase blood volume and pressure, renal perfusion pressure, and thus RBF. Additionally, the kidney responds to low levels of catecholamines circulating when blood pressure drops by preferential efferent arteriolar vasoconstriction, which acts to maintain GFR.2

Age-Related Renal Changes RBF decreases by 10% per decade of life after age 50 years; parallel changes occur in the kidney’s ability to handle acid and Na+. Creatinine becomes increasingly unreliable as a marker of GFR in older adults owing to loss of muscle and malnutrition. The National Kidney Foundation recommends using the CockcroftGault formula for calculation of GFR.3 [7] GFR men = 140 − age ( years) × weight ( kg ) serum creatinine (mg dL ) × 72 [8] GFR women = 140 − age ( years ) × weight ( kg ) × 0.85 serum creatinine (mg dL)× 72

784

SE C T I O N VII

Fluid, Electrolyte, and Hematologic Homeostasis

TABLE 40.1  Normal Values of Serum Potassium

Age

Serum Potassium Range (mEq/L)

0–1 mo

4.0–6.0

1 mo–2 y

4.0–5.5

2–17 y

3.8–5.0

>18 y

3.2–4.8

In neonates, when adjusted for body surface area (BSA), RBF doubles during the first 2 weeks of postnatal life and continues to increase until it reaches adult values at about 2 years of age. This change is thought to be secondary to increasing cardiac output and decreasing systemic vascular resistance. GFR parallels this rise in RBF. GFR can be estimated in children based on serum creatinine level and height, as follows: [9] GFR = height (cm) × k serum creatinine (mg dL ) where k = 0.45 for infants, k = 0.55 for children, and k = 0.70 for adolescents. Neonates are unable to excrete K+ efficiently; therefore, the normal range of serum potassium tends to be higher than in older children and adults. The normal serum potassium by age is summarized in Table 40.1.

The Nephron Each kidney contains 1.0 to 1.3 million nephrons, the functional unit of the kidney.4 The glomerulus is made up of a tuft-like network of branching capillaries covered with epithelial cells that arc into the Bowman capsule, providing a large surface area for blood filtration (Fig. 40.2).5 Blood enters the glomerulus by an afferent arteriole and exits by an efferent arteriole. The basement membrane of the glomerulus acts as a filter. This membrane allows water, amino acids, free ions, and other solutes to pass through into the Bowman capsule; large proteins, and cellular elements, including blood cells, cannot pass. Fluid from the Bowman capsule flows into the proximal tubule. The main function of the proximal tubule is to resorb Na+ and water, but bicarbonate, Cl−, glucose, amino acids, phosphate, and lactate are also transported. The loop of Henle leads from the proximal convoluted tubule to the distal convoluted tubule. Its main function is to create and maintain an increasing osmolality gradient within the renal medullary interstitium, thereby providing the downstream collecting ducts with the ability to concentrate urine by osmotic forces. The loop of Henle is also responsible for Ca2+ and Mg2+ resorption. The distal convoluted tubule carries hypotonic fluid from the loop of Henle to the collecting ducts and is responsible for final changes in Na+, K+, Ca2+, phosphate, and acid–base homeostasis. The collecting ducts run down the steep osmotic gradient created by the loop of Henle and allow significant water resorption and thereby creation of concentrated, hypertonic urine. The juxtaglomerular apparatus is a small structure made up of the macula densa (a portion of modified ascending limb of the loop of Henle), mesangial cells, and juxtaglomerular cells (Fig. 40.3). The juxtaglomerular cells release renin in response to

TABLE 40.2  Functional Divisions of the Nephron

Segment

Function

Proximal tubule

Reabsorption: Na+, Cl−, water, bicarbonate, glucose, protein, amino acids, K+, Mg2+, Ca2+, phosphate, uric acid, urea Secretion: Organic anions and cations Ammonia production

Loop of Henle

Reabsorption: Na+, Cl−, water, K+, Ca2+, Mg2+ Establishes concentration gradient within medulla

Distal tubule

Reabsorption: Na+, Cl−, water, K+, Ca2+, bicarbonate Secretion: H+, K+, Ca2+

Collecting duct

Reabsorption: Na+, Cl−, water, K+, bicarbonate Secretion: H+, K+ Ammonia production

Juxtaglomerular apparatus

Secretion of renin

β-adrenergic stimulation, a decrease in afferent arteriolar perfusion pressure (sensed by a baroreceptor mechanism), and changes in Cl− flow within the loop of Henle (sensed by chemoreceptors).6 The role of each segment of the nephron is summarized in Table 40.2.

Water and the Kidney Regulation of plasma osmolarity is accomplished by varying the amount of water excreted by the kidney. Concentrated hyperosmotic urine is produced when circulating levels of antidiuretic hormone (ADH) are high. ADH, also known as vasopressin (see Chapter 35). ADH is released from the posterior pituitary (neurohypophysis) in response to increased osmolality (sensed by magnocellular neurons in the hypothalamus), decreased circulating plasma volume and/ or angiotensin II. ADH increases the number of aquaporin channels in the collecting ducts of the nephron, facilitating water reabsorption by osmosis. ADH secretion occurs in times of water deprivation or hemorrhage, or with syndrome of inappropriate ADH (SIADH). Without ADH, dilute urine is excreted owing to reduced permeability of the distal tubules and collecting ducts to water, leading to little water reabsorption and the potential for hypernatremia (see Chapter 42).

Salt and the Kidney Sodium is resorbed all along the nephron, but the majority is resorbed isosmotically in the proximal convoluted tubule. Sodium regulation is controlled by two main mechanisms: (1) reninangiotensin-aldosterone (Fig. 40.4) and (2) atrial natriuretic peptide (ANP). Angiotensin II is the most powerful Na+-retaining hormone. Its plasma levels increase with low blood pressure, hypovolemia, or salt and water loss. Angiotensin II stimulates aldosterone secretion, which increases Na+ absorption. Additionally, angiotensin II constricts efferent arterioles, thereby raising the filtration fraction,

CHAPTER 40  Renal Physiology



Efferent arteriole Glomerulus

Proximal

Convoluted tubules

785

Distal

Glucose amino acids Cl– H2O

HCO3– Afferent arteriole

Bowman capsule

NH3 H+ K+ Na+

Filtered through glomerulus • Water • Electrolytes • Glucose • Amino acids • Urea • Uric acid • Creatinine

H+ Creatinine Uric acid Electrolytes Penicillin Cl– HPO4–2 Urea HCO3 H2O

Urea H2O

Collecting

NaCI

Loop of Henle

NaCI

Duct U R I N E NH4+ H2PO4

• Fig. 40.2

  The structure of the nephron. The structure of the nephron, and its specialized tubular segments in particular, is uniquely suited to sodium, water, electrolyte, and H+ ion handling. The afferent arteriole brings blood into the glomerulus while the efferent arteriole carries blood away from the glomerulus. The Bowman capsule (or glomerular capsule) is a cup-like sac that cradles the tuft-like glomerular capillaries at the beginning of the tubular component of the nephron that performs the first step in the filtration of blood to form urine. This leads to the proximal convoluted tubule, the most proximal segment of the renal tubule. It is responsible for the reabsorption of glucose, amino acids, and the majority of ions and water that is reabsorbed. The loop of Henle separates the proximal and distal convoluted tubules. Its main function is to create an osmotic gradient in the renal medulla. By means of a countercurrent multiplier, the loop of Henle creates an area of high urine concentration deep in the medulla in the zone of the collecting duct, establishing a concentration gradient. Water present in the filtrate in the collecting duct flows down this concentration gradient (via aquaporin channels) out of the collecting duct. This process reabsorbs water and creates concentrated urine for excretion. The distal convoluted tubule follows the loop of Henle and is involved in the secretion of ammonia and urea as well as the regulation of potassium, sodium, calcium, and pH. From the distal convoluted tubule, filtrate drains into collecting ducts. Each duct receives filtrate from the distal convoluted tubules of many nephrons. Inside these collecting ducts, water can be absorbed to regulate the final concentration of urine produced by the kidneys. On leaving the collecting ducts, urine enters the renal pelvis and flows into the ureters.

and directly stimulates Na+ resorption in the proximal tubule. In times of salt and water overload and plasma volume expansion, the cardiac atria become distended and secrete ANP. ANP dilates the afferent arterioles in the glomerulus and constricts efferent arterioles, thus increasing GFR and increasing salt and water excretion. ANP also inhibits renin secretion, resulting in reduced angiotensin I, angiotensin II, and aldosterone production.6

Potassium and the Kidney Potassium is filtered, resorbed, and secreted by the nephron. Potassium excretion can vary widely, from 1% to 110% of the filtered load depending on dietary K+ intake, aldosterone levels, tubular flow rate, and acid–base balance. The proximal tubule reabsorbs 67% of filtered K+ along with Na+ and water. The loop

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Glomerulus

Glomerular capsule Afferent arteriole

Efferent arteriole

Foot processes of podocytes

Podocyte cell body (visceral layer) Red blood cell Proximal tubule cell

Parietal layer of glomerular capsule

Capsular space

Afferent arteriole Granular cells Extraglomerular mesangial cells Macula densa cells of the ascending limb of loop of Henle

Lumens of glomerular capillaries Endothelial cell of glomerular capillary

Efferent arteriole

Mesangial cells between capillaries Renal corpuscle

• Fig. 40.3

Juxtaglomerular apparatus

The structure of the glomerulus and macula densa (see text for a detailed explanation). The upper left shows the position of the glomerulus and juxtaglomerular apparatus relative to the entire nephron.  

+ Kidney Lungs Surface of pulmonary and renal endothelium: ACE

Liver

Angiotensin I

Angiotensin II

Decrease in Renin renal perfusion + (juxtaglomerular apparatus)

Aldosterone secretion

Arteriolar

+ vasoconstriction.

Increase in blood pressure

– +

Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases.

Arteriole

ADH secretion

Pituitary gland: posterior lobe

+

Collecting duct: H2O absorption

• Fig. 40.4

Reaction Active transport Passive transport

Adrenal gland: +

+ cortex

+

Kidney

Na+ K+ Cl– H2O

Tubular Na+ Cl– and K+ + reabsorption excretion. H2O retention

+ Angiotensinogen

Legend Secretion from an organ + Stimulatory signal – Inhibitory signal

Sympathetic activity

H2O

  Renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system regulates blood pressure and fluid balance. When blood volume is low, juxtaglomerular cells secrete renin into the circulation. Plasma renin then converts angiotensinogen released by the liver to angiotensin I. Angiotensin I is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE) found in the lungs. Angiotensin II is a potent vasoactive peptide that causes blood vessels to constrict, resulting in increased blood pressure. Angiotensin II promotes antidiuretic hormone secretion by the posterior pituitary, increasing water reabsorption by the kidneys, resulting in decreased urinary output. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which also increases blood pressure, closing the feedback loop.

CHAPTER 40  Renal Physiology



TABLE 40.3  Causes of Hyperkalemia

Transcellular Shifts

Decreased Excretion

Increased Uptake

Acidosis β-Blockers Insulin deficiency Burns Tumor lysis syndrome Rhabdomyolysis

Renal failure K+-sparing diuretics Cyclosporin NSAIDs ACE inhibitors Mineralocorticoid deficiency/resistance

K+ supplements Blood transfusions K+-containing medications

ACE, Angiotensin-converting enzyme; NSAIDs, nonsteroidal antiinflammatory drugs.

TABLE 40.4  Causes of Hypokalemia

Transcellular Shifts

Increased Excretion

Decreased Uptake

Insulin

Vomiting

Malnutrition

β-Agonists

Diarrhea Nasogastric suction Laxatives Diuretics Cisplatin Amphotericin B Renal tubular acidosis Corticosteroids

of Henle resorbs an additional 20% of filtered K+. The distal convoluted tubule and collecting duct reabsorb and secrete K+ and are responsible for regulation of K+ balance. Aldosterone stimulates K+ secretion by increasing Na+ entry into principal cells in the distal tubules. Acidosis decreases K+ excretion and alkalosis increases K+ secretion. The primary mechanism by which increased hydrogen ion concentration inhibits K+ secretion is via the Na+, K+ ATPase (Na+ pump).7 Sodium ions and K+ effectively exchange for each other across the cell membrane via this pump. Urine flow rates also affect K+ secretion, and drugs that increase urine flow, such as loop and thiazide diuretics, cause dilution of luminal K+ concentration and increase the driving force for K+ secretion (see Chapter 42). The common causes of hyperkalemia and hypokalemia are summarized in Tables 40.3 and 40.4, respectively.

Toxin and Metabolite Excretion The kidney plays a major role in the excretion of drugs, hormones, and toxins. Uremic toxins and metabolites are cleared from the blood by filtration and secretion. The kidney freely filters watersoluble toxins, such as creatinine and urea, which are excreted in the urine. Other toxins are removed from the blood and actively secreted. Multiple pathways are used to metabolize drugs to more water-soluble metabolites, including oxidation, dealkylation, reduction, hydrolysis, glucuronidation, sulfation, methylation, acetylation, and conjugation (see Chapter 4).8

Acid–Base Balance The lungs and kidneys are the main organs involved in acid–base balance. The lungs excrete a volatile acid, carbon dioxide; the

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kidneys are responsible for handling nonvolatile acids. The kidneys help regulate acid–base balance by excreting either acidic or basic urine. This is achieved by precise handling of the large amount of bicarbonate and acidic ions filtered continuously into the renal tubules. Volume depletion is associated with Na+ retention, which enhances bicarbonate reabsorption. Hypokalemia enhances bicarbonate reabsorption, leading to alkalemia (contraction alkalosis).9 There is ongoing controversy as to whether the kidney maintains acid–base homeostasis via ammonium (acid) excretion or chloride excretion.10

Renal Hormone Production The kidney secretes 2 hormones, erythropoietin (EPO) and calcitriol (1,25 [OH]2 vitamin D3), as well as the enzyme renin. EPO is a glycoprotein that acts on the bone marrow to increase red blood cell production in response to any condition that reduces the quantity of oxygen to the tissues. Most often, EPO production is increased owing to anemia, low blood volumes, or hypoxemia such as that experienced by people living at high altitudes, or with prolonged cardiac or pulmonary failure. Calcitriol is the activated form of vitamin D that acts to increase the absorption of Ca2+ from the intestine, to mobilize stored Ca2+ from bone, and to reabsorb phosphate in the kidney. It is the downstream product of calciferol, which is synthesized from ingested vitamin D in skin exposed to ultraviolet light. Calciferol is subsequently converted by the liver to 25-[OH]-vitamin D3 and transported to the kidney. There, it is converted to calcitriol in response to parathyroid hormone. The release and function of the renal hormone renin has been described earlier.

Defining Renal Failure Acute kidney injury (AKI; formerly known as acute renal failure) is associated with increased perioperative morbidity, mortality, increased length of hospital stay, and increased cost.11,12 Arriving at a standardized definition of renal failure has been surprisingly difficult. Renal failure is usually classified as either AKI or chronic kidney disease (CKD; previously termed chronic renal insufficiency or chronic renal failure).13 More than 35 definitions exist for renal failure.14 The absence of a consensus definition has had a negative impact on basic science as well as clinical research in the field of AKI. There is no consensus on the most effective way to assess renal function, either by defining the best markers to gauge renal function or the level of any biomarker that differentiates normal from abnormal renal function. Only recently has a unified standard for classifying and diagnosing AKI been accepted. The diagnosis of AKI requires both clinical history and relevant laboratory data. The Acute Kidney Injury Network (AKIN) introduced specific criteria for diagnosis of AKI, including a rapid time course (< 48 hours) and decrement of kidney function.15 Reduction of kidney function was defined as either an absolute increase in serum creatinine of greater than 0.3 mg/dL, percentage increase in serum creatinine of greater than 50%, or reduction in urine output to less than 0.5 mL/kg/hr for more than 6 hours. In addition to the AKIN, the Acute Dialysis Quality Initiative (ADQI) has attempted to uniformly define and stage AKI with the RIFLE criteria (Risk, Injury, Failure, Loss, End-stage kidney disease).16 These five categories represent three grades of increasing severity of AKI (risk, injury, and failure) and two outcome classes (loss and end-stage kidney

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GFR Criteria Increased SCreat x 1.5 or GFR decrease >25%

Risk

Injury

• Fig. 40.5  RIFLE criteria (Risk, Injury, Failure, Loss, End-stage kidney disease). SCreat, Serum creatinine; GFR, glomerular filtration rate; UO, urine output; AKI, acute kidney injury.

Increased SCreat x 2 or GFR decrease >50%

Increase SCreat x 3 or GFR decrease 75% Failure or SCreat ≥4 mg/dL

Urine Output Criteria UO 1.5 mg/dL No shock, ongoing bacterial infection, nephrotoxic agents, or fluid losses No improvement after diuretic withdrawal and fluid resuscitation Proteinuria < 500 mg/day, normal renal sonography

Pump

To patient

Adapted from Meltzer J, Brentjens TE. Renal failure in patients with cirrhosis: hepatorenal syndrome and renal support strategies. Curr Opin Anaesthesiol. 2010;23:139–144.

Diffusion across concentration gradient From patient Pump Pump Anticoagulant Effluent/ filtrate

Continuous venovenous hemodialysis (CVVHD)

• Fig. 40.6

  Continuous venovenous hemodialysis (CV  VHD) circuit. CV VHD is similar to standard dialysis except that it is performed continuously over a longer period of time. Red tubing is the access line; it takes blood from the patient to the hemofilter. Blue tubing is the return line; it takes blood from the hemofilter back to the patient. Green tubing is the dialysate line; it takes dialysate from the source into the hemofilter. Yellow tubing is the effluent line; it takes effluent from the dialyzer into a waste or effluent bag.

hypotension.46 There are several forms of CRRT, including, but not limited to, slow continuous ultrafiltration, continuous venovenous hemofiltration, CVVHD, and continuous venovenous hemodiafiltration. These forms of RRT use ultrafiltration, hemofiltration, and/or hemodialysis for solute and fluid removal. Despite development of these renal replacement therapies that can rapidly correct the metabolic and biochemical derangements of AKI, improvements in mortality have not materialized. The typical CVVHD circuit is represented in Fig. 40.6. Studies of differing dialysis dose, changing frequency, or alternate modalities (CRRT, iHD) have not shown consistent benefit of one technique over another.

Hepatorenal Syndrome Patients with liver cirrhosis are at risk for all three types of AKI, but they can also develop a unique entity known as hepatorenal syndrome (HRS).47 HRS is a form of prerenal AKI thought to be the result of circulatory dysfunction secondary to an imbalance of circulating vasodilatory and vasoconstrictive factors. This dysfunction is likely the result of a decrease in systemic vascular resistance arising from splanchnic vasodilatation due to nitric oxide, prostaglandins, and other vasoactive substances released in patients with portal hypertension and advanced cirrhosis.48 The vasodilatation triggers activation of the renin-angiotensin system and, along with sympathetic stimulation, results in intense renal vasoconstriction. In compensated cirrhosis, cardiac output and plasma volume both increase to restore effective arterial volume; thereby, renal perfusion

and function are preserved. However, in decompensated cirrhosis, cardiac output and heart rate are already maximal and cannot increase further to augment blood pressure, resulting in a further increase in circulating vasoconstrictors and renal vasoconstriction, Na+ and water retention, and ascites formation.49 This results in decreased renal perfusion pressure and reduced GFR. Two types of HRS exist: type 1 HRS is characterized by a rapid decline in renal function, while type 2 HRS entails a more chronic deterioration in renal function that is associated with ascites formation. Differentiating HRS from ATN can be difficult because diagnosing the former involves excluding other causes of AKI and there is no single test that confirms HRS.50 Although mortality is very high among patients with cirrhosis and renal failure, patients with type 1 HRS seem to have the worst prognosis—50% survival at 1 month and 20% survival at 6 months.51 Therapeutic options are limited for patients with HRS. Vasopressors are effective in AKI, primarily in the setting of type 1 HRS.50,52 The mechanism seems to be reversal of splanchnic vasodilatation and restoration of central blood volume and renal perfusion. Several vasoconstrictors have been studied, including terlipressin (a vasopressin analog), octreotide, norepinephrine, and midodrine. The strongest evidence, including recent randomized controlled trials, favors vasopressin analogs, with possible added benefit with coadministration of intravenous albumin.52 Although they should be considered first-line therapy, vasopressin analogs can be associated with cardiovascular and ischemic complications—over 10% in some studies. Overall, vasopressin analogs can be effective in 40% to 50% of patients with HRS, but 3- and 6-month mortality benefits in these studies are lacking.50,52 Despite maximum pharmacologic therapy, AKI and/or HRS can cause renal function to decline to the point of metabolic disarray, acidosis, severe electrolyte abnormalities, and/or volume overload. Once renal function has reached this level of severity, the patient should be treated with renal replacement therapy. While albumin combined with vasopressin (or its analogs) is of some benefit, optimal medical management should include evaluation for liver transplantation. Diagnostic criteria for HRS are summarized in Table 40.5.

Emerging Developments Prevention and Biomarkers for Acute Kidney Injury Renal function and dysfunction is an important determinant and indicator of perioperative outcome. Anesthetists often give fluid in an attempt to increase renal perfusion and reduce perioperative AKI. There is very little evidence to suggest that a particular fluid

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should be used for resuscitation of patients with or at risk of AKI; however, there is some evidence that 6% hydroxyethyl starch should be avoided in the setting of AKI. This is because of an emerging body of experiments and clinical studies that show that hydroxyethyl starch can induce and/or exacerbate renal injury.53,54,54a Detection and understanding of AKI is improving with time. There has been a promising search for biomarkers of renal function and injury. Serum cystatin C, a protein produced by all nucleated cells, is independent of age, sex, race, and muscle mass and is a better marker of GFR than creatinine55; further studies are needed for validation. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein produced by renal tubular cells in the setting of renal injury.56 It can be detected easily in the urine within minutes of induced injury and is highly sensitive and specific to AKI—levels

are much less increased in CKD. Although NGAL has been used in a variety of clinical scenarios, further research is necessary before it becomes widely accepted and used in clinical practice. Many vasoactive drugs have been studied in hopes of finding a pharmacologic approach to prevention or treatment of renal injury. Renal vasoactive medications, such as dopamine and prostaglandin infusions, have not been effective. However, fenoldopam mesylate, a dopamine-1 receptor agonist originally approved for hypertensive emergencies, has shown some potential benefit (see Chapter 26). In a variety of surgical and ICU populations, fenoldopam has been shown to reduce the risk of AKI but only in small randomized trials or meta-analyses of these trials.58–60 Current efforts focus on the development of novel renal protection approaches, including possible protective effects of volatile anesthetics.60a,60b

Key Points • The main functions of the kidney are (1) regulation of salt and water balance, (2) toxin and metabolite elimination, (3) electrolyte homeostasis, (4) acid–base balance, and (5) hormone production. • Renal blood flow is directly proportional to the transrenal gradient, the pressure difference between the renal artery and the renal vein. Autoregulation mechanisms maintain constant renal blood flow over a range of blood pressures. • Normal glomerular filtration rate is around 120 mL/min in men and 100 mL/min in women. • Renal blood flow decreases by about 10% per decade of life after age 50 years; parallel changes occur in the kidney’s ability to handle acid and Na+. • Regulation of plasma osmolarity is accomplished by varying the amount of water excreted by the kidney. Concentrated, hyperosmotic urine is produced when circulating levels of antidiuretic hormone are high. • Na+ regulation is controlled by 2 main mechanisms: (1) reninangiotensin-aldosterone and (2) atrial natriuretic peptide. • Potassium (K+) excretion can vary widely, from 1% to 110% of the filtered load depending on dietary K+ intake, aldosterone levels, tubular flow rate, and acid–base balance.

• Risk factors for AKI include advanced age, revised cardiac risk index score greater than 2, American Society of Anesthesiologists Physical Status 4 or 5, male sex, active congestive heart failure, hypertension, emergency surgery, high-risk surgery, elevated preoperative creatinine, and diabetes mellitus. • Procedures associated with the highest risk of AKI are cardiac surgery, aortic surgery, and liver transplantation. • There is no evidence-based support for one anesthetic technique over another in regard to optimal renal function. Important goals include support of normal blood pressure and, therefore, renal perfusion; maintenance of euvolemia to ensure adequate perfusion and oxygen delivery to all tissues; and avoidance of nephrotoxins. • Norepinephrine profoundly constricts the glomerular afferent arteriole, dropping filtration pressure, and can contribute to and prolong the course of AKI. • Arginine vasopressin constricts the glomerular efferent arteriole; therefore, it can increase filtration pressure and GFR.

Key References

versus colloids for fluid resuscitation in ICU patients revealing that the use of albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days. Subgroup analysis supported albumin resuscitation for sepsis and saline resuscitation for brain injury. (Ref. 55). Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279–1290. An outstanding review of the connection between renal failure and liver failure. (Ref. 49). Kheterpal S, Tremper K, Heung M, et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Anesthesiology. 2009;110:505–515. An investigation into the incidence and risk factors for AKI. (Ref. 18). McLean DJ, Shaw AD. Intravenous fluids: effects on renal outcomes. Br J Anaesth. 2018;120:397–402. An up to date review of the impact of fluid therapy on renal function. (Ref. 54a). Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–1377. A protocolized, goal-directed approach to the management of patients early in the course of severe, overwhelming infections improved survival significantly. The cornerstones of this early, goal-directed approach were monitoring, fluid resuscitation, and hemodynamic management. (Ref. 66).

Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356:2139–2143. Administration of low-dose dopamine by continuous infusion to critically ill patients at risk of renal failure did not confer clinically significant protection from renal dysfunction. (Ref. 29). Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212. An introduction to the changing classification and nomenclature of AKI. (Ref. 16). Borthwick E, Ferguson A. Perioperative acute kidney injury: risk factors, recognition, management, and outcomes. Br Med J. 2010;340:85–91. A good general review of which patients are at highest risk of perioperative renal injury. (Ref. 20). Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–2256. A well-performed landmark trial of crystalloids



References 1. Loutzenhiser R, Griffin K, Williamson G, et al. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1153–R1167. 2. McIlroy D, Sladen RN. Renal physiology, pathophysiology, and pharmacology. In: Miller R, ed. Miller’s Anesthesia. 8th ed. Philadelphia: Elsevier; 2015:545–589. 3. Stefan M, Iglesia LL, Fernandez G. Medical consultation and best practices for preoperative evaluation of elderly patients. Hosp Pract. 2011;39:41–51. 4. Rose BD, Post T. Clinical Physiology of Acid-Base and Electrolyte Disorders. 4th ed. New York: McGraw-Hill; 2001. 5. Guyton AC, Hall JE. Urine formation by the kidneys: I. Glomerular filtration, renal blood flow, and their control. In: Guyton AC, Hall JE, eds. Textbook of Medical Physiology. 9th ed. Philadelphia: WB Saunders; 1996:315–329. 6. Widmaier E, Raff H, Strang KT. Vander’s Human Physiology. 14th ed. New York: McGraw-Hill; 2016. 7. Hall JE. Unit V: the body fluids and kidneys. In: Hall JE, ed. Guyton and Hall Textbook of Medical Physiology. 13th ed. Philadelphia: Elsevier; 2016:367–382. 8. Lohr JW, Willsky GR, Acara MA. Renal drug metabolism. Pharmacol Rev. 1998;50:107–141. 9. Brandis K Acid-base physiology. Available at http://www.anaesthesia MCQ.com. 10. Bellomo R, Ronco C. New paradigms in acid-base physiology. Curr Opin Crit Care. 1999;5:427. 11. Bihorac A. Acute kidney injury in the surgical patient: recognition and attribution. Nephron. 2015;131:118–122. 12. Goren O, Matot I. Perioperative acute kidney injury. Br J Anaesth. 2015;115:ii3–ii14. 13. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334:1448–1460. 14. Kellum JA, Levin N, Bouman C, et al. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care. 2002;8:509–514. 15. Mehta RL, Kellum JA, Shah SV. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. 16. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212. 17. Cholongitas E, Calvaruso V, Senzolo M, et al. RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit. J Gastroenterol Hepatol. 2009;24:1639–1647. 18. Kheterpal S, Tremper K, Heung M, et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Anesthesiology. 2009;110:505–515. 19. Abelha FJ, Botelho M, Fernandez V, et al. Determinants of postoperative acute kidney injury. Crit Care. 2009;13:R79. 20. Borthwick E, Ferguson A. Perioperative acute kidney injury: risk factors, recognition, management, and outcomes. Br Med J. 2010;340:85–91. 21. Vaughn SB, LeMaire SA, Collard D. Case scenario: anesthetic considerations for thoracoabdominal aortic aneurysm repair. Anesthesiology. 2011;115:1093–1102. 22. Rymarz A, Serwacki M, Rutkowski M. Prevalence and predictors of acute renal injury in liver transplant recipients. Transplant Proc. 2009;15:475–483. 23. Wagener G, Brentjens TE. Anesthetic concerns in patients presenting with renal failure. Anesthesiol Clin. 2010;28:39–54. 24. The Prism Investigators. Early, goal-directed therapy for septic shock – patient-level meta-analysis. N Engl J Med. 2017;376:2223–2234. 25. The Acute Respiratory Distress Syndrome Network Investigators. Ventilation with lower tidal volumes as compared with traditional

CHAPTER 40  Renal Physiology

793

tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308. 26. Finfer S, Chittock DR, Su SY. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360: 1283–1297. 27. Sprung CL. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124. 28. Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327. 29. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356:2139–2143. 30. Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med. 2005;142:510–524. 31. Lassnigg A, Donner E, Grubhofer G, et al. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol. 2000;11:97–104. 32. Ho KM, Sheridan DJ. Meta-analysis of furosemide to prevent or treat acute renal failure. Br Med J. 2006;333:420–424. 33. Kusudo K, Ishii K, Rahman M. Blood flow-dependent changes in intrarenal nitric oxide levels during anesthesia with halothane or sevoflurane. Eur J Pharmacol. 2004;498:267–273. 34. Gentz BA, Malan TP. Renal toxicity with sevoflurane: a storm in a teacup? Drugs. 2001;61:2155–2162. 35. Doherty D, Sladen RN. Effects of positive airway pressure on renal function. In: Lumb PL, ed. Postoperative Mechanical Ventilation. Philadelphia: JB Lippincott; 1990:369–386. 36. Nahas GG, Sutin KM, Fermon C. Guidelines for the treatment of acidaemia with THAM. Drugs. 1998;55:191–224. 37. Solus-Biguenet H, Fleyfel M, Tavernier B. Non-invasive prediction of fluid responsiveness during major hepatic surgery. Br J Anaesth. 2006;97:808–816. 38. Biais M, Nouette-Gaulain K, Roullet S, et al. A comparison of stroke volume variation measured by Vigileo/FloTrac system and aortic Doppler echocardiography. Anesth Analg. 2009;109:466–469. 39. Brienza N, Giglio MT, Marucci M, et al. Does perioperative hemodyanamic optimization protect renal function in surgical patients? A meta-analytic study. Crit Care Med. 2009;37:2079–2090. 40. Robertson EN, Driessen JJ, Booij LH. Pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure. Eur J Anaesthesiol. 2005;22:4–10. 41. Shihab FS. Cyclosporin nephropathy: pathology and clinical impact. Semin Nephrol. 1996;16:536–547. 42. Nolin TD, Himmelfarb J. Mechanisms of drug-induced nephrotoxicity. In: Uetrecht J, ed. Adverse Drug Reactions. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag; 2010:111–130. 43. Itoh Y, Yano T, Sendo T. Clinical and experimental evidence for prevention of acute renal failure induced by radiographic contrast media. J Pharmacol Sci. 2005;97:473–488. 44. Schweiger MJ. Prevention of contrast induced nephropathy: recommendations for the high risk patient undergoing cardiovascular procedures. Catheter Cardiovasc Interv. 2007;69:135–160. 45. Thiele H, Hildbrand L, Schuler G. Impact of high-dose N-acetylcysteine versus placebo on contraST-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: the LIPSIA-N-ACC trial. J Am Coll Cardiol. 2010;55:2201–2209. 46. Petroni KC, Cohen NH. Continuous renal replacement therapy: anesthetic implications. Anesth Analg. 2002;94:1288–1297. 47. Meltzer J, Brentjens TE. Renal failure in patients with cirrhosis: hepatorenal syndrome and renal support strategies. Curr Opin Anaesthesiol. 2010;23:139–144. 48. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339:533–541.

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49. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279–1290. 50. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56:1310–1318. 51. Alessandria C, Ozdogan O, Guevara M. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005;41:1282–1289. 52. Martin-Llahi M, Pepin MN, Guevara M. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134:1352–1359. 53. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004;351:159–169. 54. Schortgen F, Lacherade JC, Bruneel F. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911–916. 54a.  McLean DJ, Shaw AD. Intravenous fluids: effects on renal outcomes. Br J Anaesth. 2018;120:397–402. 55. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–2256. 56. Hojs R, Bevc S, Ekart R, et al. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function. Nephrol Dial Transplant. 2006;21:1855–1862. 57. Wagener G, Minhaz M, Mattis FA, et al. Urinary neutrophil gelatinaseassociated lipocalin as a marker of acute kidney injury after orthotopic liver transplantation. Nephrol Dial Transplant. 2011;26:1717–1723. 58. Jones DT, Lee HT. Surgery in the patient with renal dysfunction. Anesthesiol Clin. 2009;27:739–749.

59. Morelli A. Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo controlled pilot trial. Crit Care Med. 2005;33:2681–2683. 60. Landoni G. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis. 2007;1:56–68. 60a.  Motayagheni N, Phan S, Eshraghi C, et al. A review of anesthetic effects on renal function: potential organ protection. Am J Nephrol. 2017;46:380–389. 60b. Fukazawa K, Lee HT. Volatile anesthetics and AKI: risks, mechanisms, and a potential therapeutic window. J Am Soc Nephrol. 2014;25:884–892. 61. Tuttle KR, Worrall NK, Dahlstrom LR. Predictors of ARF after cardiac surgical procedures. Am J Kidney Dis. 2003;41:76–83. 62. Shoyer AL, Coombs LP, Peterson ED, et al. The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk models. Ann Thorac Surg. 2003;75:1856–1864. 63. O’Neal JB, Shaw AD, Billings FT. Acute kidney injury following cardiac surgery: current understanding and future directions. Crit Care. 2016;20:187–196. 64. Meltzer J, Guenzer JR. Anticoagulant reversal and anesthetic considerations. Anesthesiol Clin. 2017;35:191–205. 65. Spanjer MRK, Bakker NA, Absalom AR. Pharmacology in the elderly and newer anaesthesia drugs. Best Pract Res Clin Anaesthesiol. 2011;25:355–365. 66. Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345: 1368–1377.

41 

Intravascular Volume Replacement Therapy CHRISTER SVENSEN AND PETER R ODHE

CHAPTER OUTLINE Historical Perspective Conventional Concepts Body Water Measurement of Body Fluid Spaces Maintenance Requirements for Water, Sodium, and Potassium Interstitium Third Space Fluid Shifts and Losses During Surgery, and Their Replacement Conventional Indices of Resuscitation Response to Fluid Challenge Static Measurements of Intravascular Volume Pulmonary Artery Occlusion Pressure Transesophageal Echocardiography Intrathoracic Blood Volume Index and Global End-Diastolic Volume Index Stroke Volume Variation and Pulse Pressure Variation Esophageal Doppler Catheter Passive Leg Raising Test Oxygen Delivery and the Microcirculation Body Fluid Dynamics (Modeling Fluid Therapy) Plasma Volume Expansion Volume Kinetics for Infusion Fluids Estimation of Volume Kinetic Parameters Population Kinetics for Infusion Fluids Pharmacodynamics of Infusion Fluids Guiding Principles and Clinical Implications Crystalloids Colloids Sepsis and Critical Illness Clinical Fluid Therapy Guidelines Basal Requirements and Rehydration Day Surgery Cases: Minor Surgery Surgery Performed With Spinal or Epidural Block Gastrointestinal Surgery Emerging Developments

Historical Perspective Plasma volume replacement is important in the perioperative period. The body and cardiovascular system are exposed to many challenges, such as neurohumoral adaptations, evaporation, fluid redistribution, and blood loss, that necessitate interventions. To achieve this, fluids are administered intravenously following protocols based on tradition, expert recommendations, and often limited evidence. There is an ongoing debate concerning the ideal composition and amount of intravenous fluids necessary for perioperative management.1–6 In the past century, recommendations varied from fluid restriction to giving liberal amounts for resuscitation.7–12 Surprisingly, intravenous (IV) fluids have been regarded as rather harmless, resulting in nothing worse than volume overload, which is often viewed as a minor problem.13 However, IV fluids can be deleterious in large amounts if not timed according to patient needs.3–5,14,15 In the late 1970s and early 1980s, acute lung injury caused by increased filtration rate across pulmonary capillaries and subsequent pulmonary inflammation was suggested as a plausible consequence.16 It has never been proven that large amounts of crystalloids cause acute respiratory distress syndrome; however, the link to abdominal compartment syndrome, which can be the result of large-volume crystalloid resuscitation, is compelling.14 Traditionally, the rationale supporting liberal perioperative fluid administration included assumptions that preoperative fasting resulted in hypovolemia, that insensible losses increased considerably during surgery, and that some fluid was distributed to a “third space.”11,17 Any resulting fluid overload was considered harmless because the kidneys had the capacity to eliminate the excess.18 The primary problem the clinician faces is that individual hydration and volume states are unknown before surgery. There are a few simple tests or physical maneuvers that can assess reliably either the level of hydration or the intravascular volume status. The clinician usually must rely on indirect nonspecific clinical signs to estimate the volume status of the cardiovascular system. Because the vascular system is highly reactive to neurohumoral changes and positioning, predicting the disposition of IV fluids is difficult. Very few healthy stable surgical patients admitted for elective minor operations require significant amounts of fluid, and thus the perioperative fluid management of these patients is straightforward.4,15,19 In contrast, fluid management of critically ill patients can be extremely demanding, and timing is very important.20 These patients sometimes require volume support, usually with extensive 795



CHAPTER 41  Intravascular Volume Replacement Therapy 795.e1

Abstract

Key words

This chapter describes conventional concepts about body fluid spaces. It carefully describes physiological principles about fluid shifting in the body and responses to fluid challenges. It further describes different monitoring principles on how to estimate fluid volumes. Furthermore it gives a body fluid dynaimic theory in a mathematical way. Finally, it gives recommendations on how to handle fluid requirements in daily practice

body water fluid spaces fluid challenge monitoring of fluid status body fluid dynamics and volume kinetics guiding principles for fluid

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TBW ~ 0.60 • BW ICF ~ 0.4 • BW

IFV ~ 0.15 • BW

PV ~ 0.05 • BW

ECF ~ 0.2 • BW

• Fig. 41.1  A static schematic of the distribution of body water. Water constitutes about 60% of body weight and is unequally distributed between extracellular and intracellular spaces. BW, Body weight in kilograms; ECF, extracellular fluid; ICF, intracellular fluid; IFV, interstitial fluid volume; PV, plasma volume; TBW, total body water. monitoring to guide fluid resuscitation. However, evidence suggests that several currently used monitors have limitations in measuring the adequacy of intravascular volume.21,22

Conventional Concepts Body Water With respect to traditional fluid therapy, the body is conceptualized as an interconnected group of anatomic spaces among which fluids distribute. However, this static concept hardly reflects the complexity of how fluids dynamically distribute over time. Total body water (TBW) is the amount of sodium-free water in the whole body, commonly divided into the extracellular fluid (ECF) space and the intracellular fluid (ICF) space. Under normal conditions, ECF constitutes 20% of total body weight and ICF 40% of TBW for an adult. The ECF consists of the plasma volume and interstitial fluid volume (Fig. 41.1). The plasma volume (PV) is relatively small, which is important to understand when boluses of fluids are given. The interstitial fluid volume contains water but is mainly bound by a gel-like composition of proteoglycan filaments and collagen fibers. Infused sodium ion (Na+) distributes mainly within ECF, which contains equal Na+ concentrations in PV and interstitial fluid volume (approximately 140 mM). The predominant intracellular cation K+ (potassium ion) has an intracellular concentration of approximately 150 mM.

Measurement of Body Fluid Spaces There are several methods to measure the various fluid spaces. TBW can be estimated by anthropometric formulae, commonly validated from tracer dilution methods. Anthropometric predictions of various physiologic properties depend on height, weight, age, gender, and race; these population models naturally result in various degrees of inaccuracy when applied to individuals. For example, TBW in liters can be estimated by the formulas23: Male TBW = 2.447 − (0.09156 × age ) + (0.1074 × height ) + (0.3362 × weight ) Female TBW = −2.097 + (0.1069 × height ) + (0.2466 × weight ) Inaccuracy when applied to the individual can be substantial. This equation does not take into account that TBW decreases with

age.24 The amount of body fat also influences TBW; fat varies inversely with water.25 TBW can be measured by isotope dilution techniques, preferably with nonradioactive isotopes such as the stable water isotopes 2H2O and H218O, and the precision can be as high as 1%.26 However, these methods are not clinically feasible owing to the complex experimental setup and mixing time required for the tracer.27 Another technique of estimating TBW is by bioelectrical impedance analysis. Although simple, quick, and cheap, there are many potential sources of error.28 ECF can also be estimated by tracer techniques. The most commonly used tracer is the bromide anion (Br−). Two drawbacks of using bromide as a dilution tracer are that it requires a long mixing time and does not distribute equally through the ECF.29 The blood volume is commonly predicted by anthropometric formulae but individual variation can be considerable.30 Because the blood volume includes erythrocytes (in ICF) and the PV, the two components can be estimated individually. The volume of erythrocytes can be determined by isotope labeling with chromium 51 (51Cr) and technetium 99 (99Tc), for example, but there are other nonradioactive methods such as labeling erythrocytes with fluorescein.29 Another methods uses a semiautomated blood volume analyzer that can provide rapid and fairly accurate information when assessing blood volume in blood loss situations and making critical transfusion decisions. It uses albumin–iodine 131 (131I) and results are available in 20 minutes.31

Maintenance Requirements for Water, Sodium, and Potassium TBW content is regulated by the intake and output of water. Water intake includes ingested liquids plus an average of 750 mL ingested in solid food and 350 mL generated metabolically. Perspiration losses are approximately 1000 mL/day and gastrointestinal losses are about 200 mL/day (Fig. 41.2). Thirst is the primary mechanism of controlling water intake and is triggered by an increase in plasma tonicity or by a decrease in ECV (see Chapter 42). Reabsorption of filtered water and Na+ is enhanced by changes mediated by the hormonal factors antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), and aldosterone (see Chapters 40 and 42). Renal water handling has three important components: (1) delivery of tubular fluid to the diluting segments of the nephron, (2) separation of solute and water in the diluting segment, and (3) variable reabsorption of water in the collecting ducts.32 In the descending loop of Henley, water is reabsorbed while solute is retained to achieve a final osmolality of tubular fluid of ~1200 mOsm/kg. This concentrated fluid is then diluted by active reabsorption of electrolytes in the ascending limb of the loop of Henle and distal tubule, both of which are relatively impermeable to water. As fluid exits the distal tubule and enters the collecting duct, osmolality is ~50 mOsm/ kg. Within the collecting duct water reabsorption is modulated by ADH (also called vasopressin). Vasopressin binds to V2 receptors along the basolateral membrane of the collecting duct cells and stimulates synthesis and insertion of aquaporin-2 water channels into the luminal membrane of collecting duct cells to facilitate water permeability. Plasma hypotonicity suppresses ADH release, resulting in excretion of dilute urine. Hypertonicity stimulates ADH secretion, which increases the permeability of the collecting duct to water and enhances water reabsorption. In response to changing plasma Na+, differences in the secretion of ADH can change urinary osmolality from 50 to 1200 mOsm/kg and urinary volume from 0.4 to 20 L/day. Other factors that stimulate ADH secretion, though

CHAPTER 41  Intravascular Volume Replacement Therapy



In healthy adults, sufficient water is required to offset gastrointestinal losses of 50 to 200 mL/day, insensible losses of 850 to 1200 mL/day (half of which is respiratory and half cutaneous), and urinary losses of about 1000 mL/day (see Fig. 41.2). Urinary losses exceeding 1000 mL/day can represent an appropriate physiologic response to ECV expansion or an inability to conserve salt or water. Daily requirements for Na+ and K+ are approximately 75 mEq/ day and 40 mEq/day, respectively, although wider ranges of Na+ intake than K+ intake are physiologically tolerated because conservation and excretion of Na+ are more efficient than of K+. Therefore healthy 70-kg adults require 2500 mL/day of water containing a Na+ of 30 mM and a K+ of 15 to 20 mM. Intraoperatively, fluids containing Na+-free water (i.e., Na+ 295 mOsm/kg). Calculated plasma osmolality is determined by the following formula: Posm = 2.0 × [Na + ] + Glucose 18 + BUN 2.8 , where serum Na+ is measured in millimoles, and blood glucose and blood urea nitrogen (BUN) are expressed as milligrams per deciliter. Other minor solutes such as Ca2+, Mg2+, and K+ make a small contribution to plasma osmolality. Considering plasma is

Normonatremia

Hyponatremia No Volume Regulation

Brain water 100%

Water

Brain solute 100%

Plasma Na+ 100 mEq/L

B

Hyponatremia after Rapid Correction Brain water 95%

Water

Brain solute 88% Sodium

D

Hyponatremia with Volume Regulation

Plasma Na 130 mEq/L

Brain water 104%

Water

Amino acids

Amino acids

Brain solute 74%

Potassium +

Brain water 140% Brain solute 100%

Plasma Na+ 140 mEq/L

A

815

Sodium

C

Potassium +

Plasma Na 100 mEq/L

• Fig. 42.1  Brain water and solute concentrations in hyponatremia. If normal plasma sodium (Na+) (A) suddenly decreases, the theoretical increase in brain water is proportional to the decrease in plasma Na+ (B). However, because of adaptive loss of cerebral intracellular solute, cerebral edema is minimized in chronic hyponatremia (C). Once adaptation occurs, a rapid return of plasma Na+ concentration toward normal results in brain dehydration (D).

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TABLE 42.2  Causes of True Hypo-osmotic Hyponatremia

Hypovolemia Renal losses (urinary sodium > 20 mEq/L) Diuretic therapy Mineralocorticoid deficiency Cerebral salt-wasting syndrome (e.g., subarachnoid hemorrhage) Renal disease Renal tubular acidosis (bicarbonaturia with renal tubular acidosis and metabolic alkalosis) Renal tubular defect (salt-wasting nephropathy) External losses (urinary sodium 20 mEq/L) Renal failure Other causes (urinary sodium 20 mEq/L) Glucocorticoid deficiency

Hypothyroidism

TABLE Causes of Syndrome of Inappropriate Secretion 42.4  of Antidiuretic Hormone

Malignancy Lung (especially small cell carcinoma) Central nervous system Pancreas

Pulmonary Pneumonia Tuberculosis Fungal Abscess

Neurologic Infection Trauma Cerebrovascular accident

Drugs Amitriptyline Chlorpropamide Cyclophosphamide Desmopressin Morphine Nicotine Nonsteroidal antiinflammatory drugs Oxytocin Selective serotonin reuptake inhibitors Vincristine

Syndrome of inappropriate antidiuretic hormone Reset osmostat—psychosis, malnutrition

TABLE 42.3  Causes of Pseudohyponatremia

Normal Plasma Osmolality Hyperlipidemia Hyperproteinemia Transurethral resection of prostate, hysteroscopy

Increased Plasma Osmolality Hyperglycemia Mannitol administration

93% water and Na+ is not completely dissociated into solution, these factors tend to cancel out. Patients with disorders such as hypoproteinemia or hyperlipidemia that cause increased osmolality and pseudohyponatremia have an abnormal osmolality gap. These disorders highlight the importance of measuring plasma osmolality in hyponatremic patients. Hyponatremia with a normal or high serum osmolality results from the presence of a nonsodium solute, such as glucose or mannitol, that holds water within the extracellular space and results in dilutional hyponatremia. The presence of a nonsodium solute resulting in “factitious” hyponatremia can be inferred if measured osmolality exceeds calculated osmolality by more than 10 mOsm/kg. For example, plasma Na+ decreases approximately 2.4 M for each 100-mg/dL rise in glucose concentration, with perhaps even greater decreases for glucose concentrations higher than 400 mg/dL.5

In anesthesia practice, a common cause of hyponatremia associated with a normal osmolality is the absorption of large volumes of sodium-free irrigating solutions (containing mannitol, glycine, or sorbitol) during transurethral resection of the prostate.6 Neurologic symptoms are minimal if mannitol is used because the agent does not cross the blood-brain barrier and is excreted with water in the urine. In contrast, as glycine or sorbitol is metabolized, hypoosmolality can gradually develop and cerebral edema can appear as a late complication. Consequently, hypoosmolality is more important in generating symptoms than hyponatremia per se.6 The problem of excessive fluid absorption during transurethral resection of the prostate can be monitored by using small amounts of alcohol in the irrigating fluid; the level of alcohol can be detected in expired air as a quantitative measure of irrigating fluid absorption.7 True hyponatremia with a normal or elevated serum osmolality also can accompany renal insufficiency. BUN, included in the calculation of total osmolality, distributes throughout both ECV and intracellular volume (ICV). Calculation of effective osmolality (2 Na+ + glucose/18) excludes the contribution of urea to tonicity and demonstrates true hypotonicity. True hyponatremia (Fig. 42.2, Table 42.5) with low serum osmolality can be associated with a high, low, or normal total body Na+ and PV. Therefore hyponatremia with hyposmolality is evaluated by assessing total body Na+ content, BUN, serum creatinine (SCr), urinary osmolality, and urinary Na+. Hyponatremia with increased total body Na+ is characteristic of edematous states—that is, congestive heart failure (CHF),8 cirrhosis, nephrosis, and renal failure. Aquaporin 2, the vasopressin-regulated water channel, is upregulated in experimental CHF9 and cirrhosis10 and decreased by chronic vasopressin stimulation. In patients with renal insufficiency, reduced

CHAPTER 42  Electrolytes and Diuretics



817

TABLE 42.5  Classification of Hypotonic Hyponatremia by Volume Status HYPOVOLEMIC

EUVOLEMIC

HYPERVOLEMIC

Extrarenal Na+ Loss (FENa < 1%, UNa < 20 mEq/L)

Renal Na+ Loss (FENa > 2%, UNa > 20 mEq/L)

(FENa < 1%, UNa > 20 mEq/L)

(UNa < 20 mEq/L)

Dehydration Diarrhea Vomiting Gastrointestinal suctioning Skin losses Trauma Pancreatitis

Diuretics Osmotic diuresis Salt-losing nephropathy Mineralocorticoid deficiency

Glucocorticoid deficiency SIADH Hypothyroidism Psychogenic polydipsia (>15 L/day) Beer potomania/malnutrition (alcoholism, anorexia)

CHF Liver disease Nephrotic syndrome Pregnancy

CHF, Congestive heart failure; FENa, fractional excretion of sodium; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; UNa, urine sodium.

Hyponatremia

History and physical

Exclude thiazide diuretics

Equivocal volume status by H/P

History of fluid loss Prerenal azotemia

Exclude renal failure

Edematous condition

Congestive heart failure

Cirrhosis Nephrotic syndrome

Urinary Sodium 150 mM) indicates an absolute or relative water deficit. The condition can exist in several forms categorized in terms of the adequacy of intravascular volume. Hypovolemic hypernatremia (water deficit > Na+ deficit). Adipsic hypernatremia is secondary to decreased thirst. This can be behavioral or, rarely, secondary to damage to the hypothalamic thirst centers. Hypovolemia can result from extrarenal losses (e.g., diarrhea, vomiting, fistulas, and significant burns) and renal losses (e.g., osmotic diuretics, diuretics, postobstructive diuresis, and intrinsic renal disease).



Hypervolemic hypernatremia (Na+ gain > water gain). Hypernatremia with hypervolemia is often iatrogenic (e.g., administration of excessive hypertonic saline solution or sodium bicarbonate) or accidental (e.g., ingestion of seawater or high–salt content infant formula because of an error in formula preparation). Less common pathologic causes include excess mineralocorticoid (i.e., Cushing disease or syndrome). Euvolemic hypernatremia (Na+ gain without volume change). Hypernatremia with normal volume status can be divided into causes stemming from extrarenal water losses and renal water losses. A common pathologic condition resulting in excessive renal losses of free water is diabetes insipidis (DI), both central and nephrogenic. Although rare, extrarenal loss of free water sufficient to produce hypernatremia can result from excessive insensible fluid loss such as with prolonged hyperventilation. Normally, even slight increases in tonicity or Na+ stimulate thirst and ADH secretion. Therefore severe, persistent hypernatremia occurs only in patients who cannot respond to thirst by voluntary ingestion of fluid such as obtunded patients, anesthetized patients, and infants. Hypernatremia produces neurologic symptoms (including stupor, coma, and seizures), hypovolemia, renal insufficiency (occasionally progressing to renal failure), and decreased urinary concentrating ability.28,29 Because hypernatremia frequently results from DI or osmotically induced losses of Na+ and water, many patients are hypovolemic or bear the stigmata of renal disease. Postoperative neurosurgical patients who have undergone pituitary surgery are at risk of developing transient or prolonged DI. Polyuria can be present for only a few days within the first week of surgery, can be permanent, or can demonstrate a triphasic sequence: early DI, return of urinary concentrating ability, then recurrent DI. The clinical consequences of hypernatremia are most serious at the extremes of age and when hypernatremia develops abruptly. Geriatric patients are at increased risk of hypernatremia because of decreased renal concentrating ability and thirst.30 Brain shrinkage secondary to rapidly developing hypernatremia can damage delicate cerebral vessels, leading to subdural hematoma, subcortical parenchymal hemorrhage, subarachnoid hemorrhage, and venous thrombosis. Polyuria can cause bladder distention, hydronephrosis, and permanent renal damage.31 At the cellular level, restoration of cell volume occurs remarkably quickly after normal tonicity is restored.32 Although the mortality of hypernatremia rate is 40% to 55%, it is unclear whether hypernatremia is the cause or a marker of severe associated disease. Surprisingly, if plasma Na+ is initially normal, moderate acute increases in plasma Na+ do not appear to precipitate osmotic demyelination (which is much more likely in the setting of correcting hyponatremia). However, larger accidental increases in plasma Na+ have produced severe consequences in children. In experimental animals, acute severe hypernatremia (acute increase from 146 to 170 mM) caused neuronal damage at 24 hours, suggestive of early osmotic demyelination.33 Hypernatremia indicates an absolute or relative water deficit and is always associated with hypertonicity. Hypernatremia can be generated by hypotonic fluid loss, as in burns, gastrointestinal losses, diuretic therapy, osmotic diuresis, renal disease, mineralocorticoid excess or deficiency, and iatrogenic causes, or can be generated by isolated water loss, as in central or nephrogenic DI. The acquired form of nephrogenic DI is more common and usually less severe than the congenital form. As chronic renal failure advances, most patients have defective concentrating ability resulting in resistance to ADH with hypotonic urine. Because hypovolemia accompanies most pathologic water loss, signs of hypoperfusion

CHAPTER 42  Electrolytes and Diuretics

819

TABLE 42.6  Acute Treatment of Hypernatremia

Sodium Depletion (Hypovolemia) Hypovolemia correction (0.9% saline solution) Hypernatremia correction (hypotonic fluids)

Sodium Overload (Hypervolemia) Enhance sodium removal (loop diuretics, dialysis) Replace water deficit (hypotonic fluids)

Normal Total Body Sodium (Euvolemia) Replace water deficit (hypotonic fluids) Control diabetes insipidus Central diabetes insipidus: DDAVP, 10-20 µg intranasally; 2-4 µg SC Aqueous vasopressin, 5 U every 2-4 hr IM or SC Nephrogenic diabetes insipidus: Restrict sodium, water intake Thiazide diuretics DDAVP, Desmopressin; IM, intramuscularly; SC, subcutaneously.

also can be present. In many patients, preceding the development of hypernatremia, an increased volume of hypotonic urine suggests an abnormality in water balance. Although uncommon as a cause of hypernatremia, isolated Na+ gain occasionally occurs in patients who receive large quantities of Na+, such as treatment of metabolic acidosis with 8.4 % sodium bicarbonate, in which Na+ is approximately 1000 mM, or perioperative or prehospital treatment with hypertonic saline solution resuscitation solutions. In large randomized trials in the prehospital area, harmful effects of transiently increased Na+ have not been seen.34 Plasma Na+ does not reflect total body Na+, which must be estimated separately based on signs of the adequacy of ECV. For polyuric hypernatremic patients, the differential diagnostic decision is between solute diuresis and DI. Measurement of urinary Na+ and osmolality can help differentiate the various causes. Urinary osmolality less than 150 mOsm/kg in the setting of hypertonicity and polyuria is diagnostic of DI. Treatment of hypernatremia produced by water loss consists of repletion of water and correction of associated deficits in total body Na+ and other electrolytes (Table 42.6). Common errors in treating hypernatremia include excessively rapid correction, failure to appreciate the magnitude of the water deficit, and failure to account for ongoing maintenance requirements and continued fluid losses. The first step in treating hypernatremia is to estimate the TBW deficit, which can be accomplished using the measured plasma Na+ and the following equation: TBW deficit = 0.6 × body weight ( kg ) × ( Na + − 140) 140 , where 140 is the middle of the normal range for Na+. Hypernatremia must be corrected slowly because of the risk of neurologic sequelae such as seizures or cerebral oedema (see Fig. 42.1).35 At the cellular level, restoration of cell volume occurs remarkably quickly after tonicity is altered; as a consequence, acute treatment of hypertonicity can result in overshooting the original, normal tonic cell volume.35 The water deficit should be replaced over 24 to 48 hours, and plasma Na+ should not be reduced by more than 1 to 2 mM/hr. Reversible underlying causes should be treated. Hypovolemia should be corrected promptly with 0.9 % saline solution. Although the Na+ of 0.9 % saline solution is

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154 mM, the solution is effective in treating volume deficits and will reduce Na+ that exceeds 154 mM. Once hypovolemia is corrected, water can be replaced orally or with IV hypotonic fluids depending on the ability of the patient to tolerate oral hydration. In the occasional sodium-overloaded patient, Na+ excretion can be accelerated using loop diuretics or dialysis. The management of hypernatremia secondary to DI varies according to whether the cause is central or nephrogenic. The two most suitable agents for correcting central DI (an ADH deficiency syndrome) are desmopressin (DDAVP) and aqueous vasopressin. DDAVP, given subcutaneously in a dose of 1 to 4 µg or intranasally in a dose of 5 to 20 µg every 12 to 24 hours, is effective in many patients. It is less likely than vasopressin to produce vasoconstriction and abdominal cramping.36 Incomplete ADH deficits (partial DI) often are effectively managed with pharmacologic agents that stimulate ADH release or enhance the renal response to ADH. Chlorpromazine, which potentates the renal effects of vasopressin, and carbamazepine, which enhances vasopressin secretion, have been used to treat partial central DI, but are associated with clinically important side effects. In nephrogenic DI, salt and water restriction or thiazide diuretics induce contraction of ECV, thereby enhancing fluid reabsorption in the proximal tubules. When less filtrate passes through the collecting ducts, less water is excreted.

Potassium

TABLE 42.7  Causes of Renal Potassium Loss

Drugs

Bicarbonaturia

Diuretics

Distal Renal Tubular Acidosis

Thiazide diuretics Loop diuretics Osmotic diuretics

Correction Phase of Metabolic Alkalosis

Antibiotics Penicillin and penicillin analogs Amphotericin B Aminoglycosides

Hormones Aldosterone Glucocorticoid-excess states

Magnesium Deficiency Other Less Common Causes Cisplatin Carbonic anhydrase inhibitors Leukemia Diuretic phase of acute tubular necrosis

Intrinsic Renal Transport Defects Barter syndrome Gitelman syndrome

β2-Adrenergic agent

Physiologic Role Potassium ion (K+) is perhaps the most frequently supplemented electrolyte.37 Potassium plays an important role in cell membrane physiology, especially in maintaining resting membrane potential and in generating action potentials in the nervous system and heart. Potassium is actively transported into cells by sodium potassium adenosine triphosphatase (Na,K-ATPase; Na+ pump), which maintains intracellular K+ at least 30-fold greater than extracellular K+. Intracellular K+ concentration (K+) is normally 150 mM, while the extracellular concentration is only 3.5 to 5.0 mM. Serum K+ measures about 0.5 mM higher than plasma K+ owing to cell lysis during clotting. Total body K+ in a 70-kg adult is approximately 4256 mEq, of which 4200 mEq is intracellular; of the 56 mEq in the ECV, only 12 mEq is in the PV. Common causes of K+ losses are shown in Table 42.7. The ratio of intracellular to extracellular K+ contributes to the resting potential difference across cell membranes and therefore to the integrity of cardiac and neuromuscular transmission. Extracellular K+ is determined by catecholamines, the reninangiotensin-aldosterone system, glucose, and insulin, as well as direct release from exercising or injured muscle.37 The primary mechanism that maintains K+ inside cells is transport of three Na+ ions out of the cell for every two K+ ions transported in by the Na,K-ATPase pump.38 Both insulin and β- adrenergic agonists promote K+ entry into cells38 (Fig. 42.3). In contrast, α-adrenergic agonists impair cellular K+ uptake.39 Metabolic acidosis tends to shift K+ out of cells, whereas metabolic alkalosis favors movement into cells. Usual K+ intake is 50 to 150 mEq/day. Freely filtered at the glomerulus, most K+ excretion is urinary with some fecal elimination. Most filtered K+ is reabsorbed; excretion is usually approximately equal to intake. As long as GFR is greater than > 8 mL/kg, dietary K+ intake, unless greater than normal, can be excreted. Assuming plasma K+ of 4.0 mM and normal GFR of 180 L/day, 720 mEq of K+ is filtered daily, of which 85% to 90% is reabsorbed in the proximal convoluted tubule and loop of Henle. The remaining

Treatment of Proximal Renal Tubular Acidosis

Na+ +

3Na+

2K+

A

Na+ + Insulin

Na+ H+

3Na+

2K+

B

• Fig. 42.3

Extracellular signals that shift potassium into cells. (A) β2Adrenergic agents and insulin. (B) adrenergic agents. H+, Hydrogen ion; K+, potassium ion; Na+, sodium ion.  

10% to 15% reaches the distal convoluted tubule, which is the major site at which K+ excretion is regulated. Excretion of K+ ions is a function of open K+ channels and the electrical driving force in the cortical collecting duct.38 The two most important regulators of K+ excretion are plasma + K and aldosterone, although there is some evidence to suggest involvement of the CNS and of an enteric reflex mediated by potassium-rich meals. Potassium secretion into the distal convoluted tubules and cortical collecting ducts is increased by hyperkalemia, aldosterone, alkalemia, increased delivery of Na+ to the distal tubule and collecting duct, high urinary flow rates, and the presence in luminal fluid of non-reabsorbable anions such as carbenicillin, phosphates, and sulfates. As Na+ reabsorption increases, the electrical driving force opposing reabsorption of K+ is increased. Aldosterone increases Na+ reabsorption by inducing opening of the epithelial Na+ channel40; potassium-sparing diuretics (amiloride and triamterene) and trimethroprim block the epithelial Na+ channel, thereby increasing K+ reabsorption. Magnesium depletion contributes to renal K+ wasting.

Hypokalemia Uncommon among healthy persons, hypokalemia (K+ < 3.0 mM) is a frequent complication of treatment with diuretic drugs (see the



“Diuretics” section) and occasionally complicates other diseases and treatment regimens. Generally, a chronic decrement of 1.0 mM in plasma K+ corresponds to a total body deficit of approximately 200 to 300 mEq. In uncomplicated hypokalemia, the K+ deficit exceeds 300 mEq if plasma K+ is less than 3.0 mM and 700 mEq if plasma K+ is less than 2.0 mM. Plasma K+ poorly reflects total body K+; hypokalemia can occur with normal, low, or high total body K+. Hypokalemia causes muscle weakness and, when severe, even paralysis. With chronic K+ loss, the ratio of intracellular to extracellular K+ remains relatively stable; in contrast, acute redistribution of K+ from the extracellular to the intracellular space substantially changes resting membrane potential. Cardiac rhythm disturbances are among the most dangerous complications of hypokalemia. Acute hypokalemia causes hyperpolarization of cardiac cells that can lead to ventricular escape activity, reentrant phenomena, ectopic tachycardias, and delayed conduction. In patients taking digoxin, hypokalemia increases toxicity by increasing myocardial digoxin binding and pharmacologic effectiveness. Hypokalemia contributes to systemic hypertension, especially when combined with a high-sodium diet.41 In diabetic patients, hypokalemia impairs insulin secretion and end-organ sensitivity to insulin. Although no clear threshold has been defined for a level of hypokalemia below which safe conduct of anesthesia is compromised, K+ less than 3.5 mM has been associated with an increased incidence of perioperative dysrhythmias, especially atrial fibrillation/flutter, in cardiac surgical patients.42 Potassium depletion also induces defects in renal concentrating ability, resulting in polyuria and a reduction in GFR. Potassium replacement improves GFR, although the concentrating deficit might not improve for several months after treatment. If hypokalemia is sufficiently prolonged, chronic renal interstitial damage can occur. In experimental animals, hypokalemia is associated with intrarenal vasoconstriction and a pattern of renal injury similar to that produced by ischemia. Hypokalemia can result from chronic depletion of total body K+ or from acute redistribution of K+ from the ECV to the ICV. Redistribution of K+ into cells occurs when the activity of the Na,K-ATPase pump is acutely increased by hyperkalemia or increased intracellular concentration of Na+, as well as by insulin, carbohydrate loading (which stimulates release of endogenous insulin), β2-adrenergic agonists, or aldosterone.38 Both metabolic and respiratory alkalosis lead to decreases in plasma K+.38 Causes of chronic hypokalemia include those associated with renal K+ conservation (extrarenal K+ losses; low urinary K+) and those with renal K+ wasting.38 Low urinary K+ suggests inadequate dietary intake or extrarenal depletion (in the absence of recent diuretic use). Diuretic-induced urinary K+ losses are frequently associated with hypokalemia secondary to increased aldosterone secretion, alkalemia, and increased renal tubular flow. Aldosterone does not cause renal K+ wasting unless Na+ is present (i.e., aldosterone primarily controls Na+ reabsorption, not K+ excretion). Renal tubular damage owing to nephrotoxins such as aminoglycosides or amphotericin B can also cause renal K+ wasting. Initial evaluation of hypokalemia includes a medical history (diarrhea, vomiting, diuretic or laxative use), physical examination (hypertension, cushingoid features, and edema), measurement of serum electrolytes (Mg2+), arterial pH assessment, and evaluation of the electrocardiogram (ECG). Many trauma patients develop hypokalemia that returns to normal within 24 hours without specific therapy. Measurement of 24-hour urinary excretion of Na+ and K+ can distinguish extrarenal from renal causes. Magnesium deficiency, associated with aminoglycoside and cisplatin therapy, can generate hypokalemia that is resistant to replacement therapy.

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TABLE 42.8  Treatment of Hypokalemia

Correct Precipitating Factors Increased pH Decreased Mg2+ Drugs

Mild Hypokalemia (K+ > 2 mEq/L)   Intravenous KCl infusion ≤ 10 mEq/hr

Severe Hypokalemia (K+ ≤ 2 mEq/L, Paralysis or ECG Changes) Intravenous KCl infusion ≤40 mEq/hr Continuous ECG monitoring If life-threatening, 5-6 mEq bolus ECG, Electrocardiograml K+, potassium ion; KCl, potassium chloride; Mg2+, magnesium cation.

Plasma renin and aldosterone levels can be helpful in the differential diagnosis. Characteristic electrocardiographic changes associated with hypokalemia include flat or inverted T waves, prominent U waves, and ST-segment depression.43 The treatment of hypokalemia consists of K+ repletion, correction of alkalemia, and removal of offending drugs (Table 42.8). Hypokalemia secondary only to acute redistribution might not require treatment. There is no urgent need for K+ replacement therapy in mild to moderate hypokalemia (3–3.5 mM) in asymptomatic patients. If total body K+ is decreased, oral K+ supplementation is preferable to IV replacement. Potassium is usually replaced as the chloride salt because coexisting chloride deficiency can limit ability of the kidney to conserve K+. Potassium repletion must be performed cautiously, usually at a rate of 10 to 20 mEq/hr or lower, because the magnitude of K+ deficits is unpredictable. Plasma K+ and the ECG must be monitored during rapid repletion (10–20 mEq/hr) to avoid hyperkalemic complications.44 Particular attention should be given to patients with concurrent acidemia, type IV renal tubular acidosis, diabetes mellitus (DM), or those receiving nonsteroidal antiinflammatory agents, angiotensin-converting enzyme (ACE) inhibitors, or β blockers, all of which delay movement of extracellular K+ into cells. In patients with life-threatening dysrhythmias secondary to hypokalemia, serum K+ must be rapidly increased. Assuming PV in a 70-kg adult is 3.0 L, administration of 6.0 mEq of potassium over a minute will increase serum K+ by no more than 2.0 mM because redistribution into interstitial fluid will decrease the quantity remaining in plasma.38 Hypokalemia associated with hyperaldosteronemia (e.g., primary aldosteronism, Cushing syndrome) usually responds favorably to reduced Na+ intake and increased K+ intake. Hypomagnesemia, if present, aggravates the effects of hypokalemia, impairs K+ conservation, and should be treated. Potassium supplements or potassiumsparing diuretics should be given cautiously to patients who have DM or renal insufficiency, which limit compensation for acute hyperkalemia. In patients who are both hypokalemic and acidemic, such as those who have diabetic ketoacidosis, K+ administration should precede correction of acidosis to avoid a precipitous decrease in plasma K+ as pH increases.

Hyperkalemia The most lethal manifestations of hyperkalemia (K+ > 5.0 mM) involve the cardiac conduction system: dysrhythmias, conduction

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abnormalities, and cardiac arrest. A classic example of hyperkalemic cardiac toxicity is associated with the administration of succinylcholine to paraplegic, quadriplegic, or severely burned45 patients. If plasma K+ is less than 6.0 mM, cardiac effects are negligible. As K+ increases further, the ECG shows tall peaked T waves, especially in the precordial leads. With further increases, the PR interval becomes prolonged, followed by a decrease in the amplitude of the P wave. Finally, the QRS complex widens into a pattern resembling a sine wave as a prelude to cardiac standstill.45 Hyperkalemic cardiotoxicity is enhanced by hyponatremia, hypocalcemia, or acidosis. Because progression to fatal cardiotoxicity is unpredictable and often swift, the presence of hyperkalemic electrocardiographic changes mandates immediate therapy. The life-threatening cardiac effects usually require more urgent treatment than other manifestations of hyperkalemia. However, ascending muscle weakness appears when plasma K+ approaches 7.0 mM and can progress to flaccid paralysis, inability to phonate, and respiratory arrest. The most important diagnostic issues are history, emphasizing recent drug therapy, and assessment of renal function. If hyponatremia is also present, adrenal function should be evaluated. Although the ECG can provide the first suggestion of hyperkalemia in some patients, and despite the well-described effects of hyperkalemia on cardiac conduction and rhythm, the ECG is an insensitive and nonspecific method of detecting hyperkalemia.46 Hyperkalemia can occur with normal, high, or low total body K+ stores. Deficiency of aldosterone, a major regulator of K + excretion, leads to hyperkalemia in adrenal insufficiency and hyporeninemic hypoaldosteronism, a state associated with DM, renal insufficiency, and advanced age. Because the kidneys excrete K+, severe renal insufficiency commonly causes hyperkalemia. Patients with chronic renal insufficiency can maintain normal plasma K+ despite markedly decreased GFR because urinary K+ excretion depends on tubular secretion rather than glomerular filtration when the GFR exceeds 8 mL/min. Drugs are now the most common cause of hyperkalemia, especially in elderly patients. Drugs that can limit K+ excretion include nonsteroidal antiinflammatory drugs, ACE inhibitors, cyclosporin, and potassium-sparing diuretics such as triamterene. Drug-induced hyperkalemia most commonly occurs in patients with other predisposing factors, such as DM, renal insufficiency, advanced age, or hyporeninemic hypoaldosteronism. ACE inhibitors are particularly likely to produce hyperkalemia in patients who have CHF.47 In patients with normal total body K+, hyperkalemia can accompany a sudden shift of K+ from the ICV to the ECV because of acidemia, increased catabolism, or rhabdomyolysis. Metabolic acidosis and respiratory acidosis can also cause an increase in plasma K+. However, organic acidosis (lactic acidosis, ketoacidosis) has little effect on K+, whereas mineral acids cause significant cellular shifts. In response to increased hydrogen ion activity because of addition of acids, K+ will increase if the anion remains in the extracellular volume.38 Neither lactate nor ketoacids remain in the extracellular fluid (ECF). Therefore hyperkalemia in these circumstances reflects tissue injury or lack of insulin.38 Pseudohyperkalemia, which occurs when K+ is released from cells in blood collection tubes, can be diagnosed by comparing serum and plasma K+ levels from the same blood sample. Hyperkalemia usually accompanies malignant hyperthermia. The treatment of hyperkalemia is aimed at eliminating the cause, reversing membrane hyperexcitability, and removing K+ from the body.38 Emergent management of severe hyperkalemia is shown in Table 42.9. Hyperkalemia is best treated with insulin plus glucose, β agonists (see Fig. 42.3), and furosemide.37

TABLE a 42.9  Treatment of Severe Hyperkalemia

Reverse Membrane Effects   Calcium (10 mL of 10% calcium chloride IV over 10 min)

Transfer Extracellular K+ Into Cells Glucose and insulin (D10W + 5-10 U regular insulin per 25-50 g glucose) Sodium bicarbonate (50-100 mEq over 5-10 min) β2 agonists

Remove Potassium From Body Diuretics, proximal or loop Potassium-exchange resins (sodium polystyrene sulfonate) Hemodialysis Monitor ECG and Serum K+ ECG, Electrocardiogram; IV, intravenously; K+, potassium ion. a Potassium concentration (K+) > 7 mEq/L or electrocardiographic changes.

Mineralocorticoid deficiency can be treated with 9-ααfludrocortisone (0.025–0.10 mg/day). Hyperkalemia secondary to digitalis intoxication can be resistant to therapy because attempts to shift K+ from the ECV to the ICV are often ineffective. In this situation, use of digoxin-specific antibodies has been successful. Membrane hyperexcitability can be antagonized by translocating K+ from the ECV to the ICV, removing excess K+, or (transiently) by infusing calcium chloride to depress the membrane threshold potential. Pending definitive treatment, rapid infusion of calcium chloride (1 g over 3 minutes, or 2–3 ampoules of 10% calcium gluconate over 5 minutes) can stabilize cardiac rhythm. Calcium should be given cautiously if digitalis intoxication is likely. Acute alkalinization using sodium bicarbonate (50–100 mEq over 5-10 minutes in a 70-kg adult) transiently promotes movement of K+ from the ECV to the ICV. Bicarbonate can be administered even if pH exceeds 7.40; however, it should not be administered to patients with congestive cardiac failure or hypernatremia. When used alone, bicarbonate is relatively ineffective and is no longer favored. Insulin, in a dose-dependent fashion, causes cellular uptake of K+ by increasing the activity of the Na,K-ATPase pump. Insulin increases cellular uptake of K+ best when high insulin levels are achieved by IV injection of 5 to 10 U of regular insulin, accompanied by 50 mL of 50% glucose.47 β2-Adrenergic drugs such as salbutamol and albuterol also increase K+ uptake by skeletal muscle and reduce plasma K+, an action that can explain hypokalemia with severe acute illness. Potassium can also be removed from the body by the renal or gastrointestinal routes. Furosemide promotes kaliuresis in a dosedependent fashion. Sodium polystyrene sulfonate resin (Kayexalate), which exchanges Na+ for K+, can be given orally (30 g) or as a retention enema (50 g in 200 mL of 20% sorbitol). However, Na+ overload and hypervolemia are potential risks. Rarely, when temporizing measures are insufficient, emergency hemodialysis can remove 25 to 50 mEq/hr. Peritoneal dialysis is less efficient.

Calcium Physiologic Role Calcium is a divalent cation found primarily in the ECF. The free calcium concentration Ca2+ in ECV is approximately 1 mM, whereas

CHAPTER 42  Electrolytes and Diuretics



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Intestine Liver

− − +

+

Bone −

Ca2+, PO4

Kidney

Ca2+, PO4

ECF 2+ Ca

Vitamin D

−

+ 25(OH)D

1,25 (OH)2D3

Ca2+ +

−

− +

+

PO4, cAMP

+ + PTH

• Fig. 42.4  Regulatory system maintaining extracellular Ca2+ homeostasis. The solid arrows and lines delineate effects of parathyroid hormone and 1,25 (OH)2D3 on their target tissues; dashed arrows and lines show examples of how extracellular Ca2+ or phosphate ions act directly on tissues regulating mineral ion metabolism. Ca, Calcium; Ca2+, calcium ion; cAMP, cyclic adenosine monophosphate; PO4, phosphate; ECF, extracellular fluid; PTH, parathyroid hormone; 1,25 (OH)2D3, 1,25 dihydroxyvitamin D; 25(OH) D, 25-hydroxyvitamin D; negative signs indicate inhibitory actions and plus signs indicate stimulatory effects. the free Ca2+ in the ICV approximates 100 nM, a gradient of 10,000 to 1. Circulating Ca2+ consists of a protein-bound fraction (40%), a chelated fraction (10%), and an ionized fraction (50%), which is the physiologically active and homeostatically regulated component.48 Acute acidemia increases and acute alkalemia decreases ionized Ca2+. Because mathematical formulae that “correct” total Ca2+ measurements for albumin concentration are inaccurate in critically ill patients, ionized Ca2+ should be directly measured. In general, Ca2+ is essential for all movement that occurs in mammalian systems. Essential for normal excitation-contraction coupling, Ca2+ is also necessary for proper function of muscle tissue, swallowing, mitosis, neurotransmitter release, enzyme secretion, and hormonal secretion. cAMP and phosphoinositides, which are major second messengers regulating cellular metabolism, function primarily through the regulation of Ca2+ movement. Activation of numerous intracellular enzyme systems requires Ca2+. Calcium is important both for generation of cardiac pacemaker activity and for generation of the cardiac action potential for which it is the primary ion responsible for the plateau phase of the action potential. Calcium also plays vital functions in membrane and bone structure.

Serum Ca2+ is regulated by multiple factors (Fig. 42.4), including a Ca2+ receptor and several hormones. Parathyroid hormone (PTH) and calcitriol, the most important neurohumoral mediators of serum Ca2+,49 mobilize Ca2+ from bone, increase renal tubular reabsorption of Ca2+, and enhance intestinal absorption of Ca2+. Vitamin D, after ingestion or cutaneous manufacture under the stimulus of ultraviolet light, is 25-hydroxylated to calcidiol in the liver and then is 1-hydroxylated to calcitriol, the active metabolite, in the kidney. Even in the absence of dietary Ca2+ intake, PTH and vitamin D can maintain a normal circulating Ca2+ by mobilizing Ca2+ from bone.

Hypocalcemia Hypocalcemia occurs frequently in critical care, affecting 80% to 90% of patients, and is associated with increased mortality in this population.37 Hypocalcemia (ionized Ca2+ < 4.0 mg/dL or < 1.0 mM) occurs as a result from failure of PTH or calcitriol action or because of Ca2+ chelation or precipitation, not because of Ca2+ deficiency alone. PTH deficiency can result from surgical damage or removal of the parathyroid glands or from suppression of the

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parathyroid glands by severe hypomagnesemia or hypermagnesemia. Burns, sepsis, and pancreatitis can suppress parathyroid function and interfere with vitamin D action. Vitamin D deficiency can result from lack of dietary vitamin D or vitamin D malabsorption in patients with low sunlight exposure. Hyperphosphatemia-induced hypocalcemia can occur as a consequence of overzealous phosphate therapy, from cell lysis secondary to chemotherapy, or as a result of cellular destruction from rhabdomyolysis. Precipitation of calcium hydrogen phosphate (CaHPO4) complexes occurs with hyperphosphatemia. However, ionized Ca2+ decreases only approximately 0.019 mM for each 1.0-mM increase in phosphate concentration. In massive transfusion, citrate can produce hypocalcemia by chelating Ca2+; however, decreases are usually transient and produce no cardiovascular effects. A healthy, normothermic adult who has intact hepatic and renal function can metabolize the citrate present in 20 units of blood per hour without becoming hypocalcemic. However, when citrate clearance is decreased (e.g., by hepatic or renal disease or hypothermia) and when blood transfusion rates are rapid (e.g., >2 mL/ kg per minute), hypocalcemia and cardiovascular compromise can occur. Alkalemia resulting from hyperventilation or sodium bicarbonate injection can acutely decrease Ca2+. Furthermore, resuscitation-induced hemodilution is an important causative factor of early hypocalcemia in trauma patients.37 This is an iatrogenic rather than adaptive complication of treatment and can have deleterious effects on blood coagulation and cardiovascular function. The hallmark of hypocalcemia is increased neuronal membrane irritability and tetany (Table 42.10). Early symptoms include sensations of numbness and tingling involving fingers, toes, and the circumoral region. In frank tetany, tonic contraction of respiratory muscles can lead to laryngospasm, bronchospasm, or respiratory arrest. Smooth muscle spasm can result in abdominal cramping and urinary frequency. Mental status alterations include irritability, depression, psychosis, and dementia. Hypocalcemia can impair cardiovascular function and has been associated with heart failure, hypotension, dysrhythmias, insensitivity to digitalis, and impaired β-adrenergic action. Reduced ionized serum Ca2+ occurs in as many as 88% of critically ill patients, 66% of less severely ill patients in intensive care units (ICUs), and 26% of non-ICU hospitalized patients.50 Patients at particular risk include patients after multiple trauma and cardiopulmonary bypass. In most patients, ionized hypocalcemia is clinically mild (Ca2+ 0.8– 1.0 mM). TABLE 42.10  Clinical Manifestations of Hypocalcemia

Cardiovascular Dysrhythmias Digitalis insensitivity Electrocardiographic changes Heart failure Hypotension

Neuromuscular Tetany Muscle spasm Papilledema Seizures Weakness Fatigue

Respiratory Apnea Laryngeal spasm Bronchospasm

Psychiatric Anxiety Dementia Depression Psychosis

Initial diagnostic evaluation should concentrate on history and physical examination, laboratory evaluation of renal function, and measurement of serum phosphate concentration. Latent hypocalcemia can be diagnosed by tapping on the facial nerve to elicit the Chvostek sign or by inflating a sphygmomanometer to 20 mm Hg above systolic pressure, which produces radial and ulnar nerve ischemia and causes carpal spasm known as the Trousseau sign. The differential diagnosis of hypocalcemia can be approached by addressing four issues: age, serum phosphate concentration, general clinical status, and duration of hypocalcemia.51 High phosphate concentrations suggest renal failure or hypoparathyroidism. In renal insufficiency, reduced phosphorus excretion results in hyperphosphatemia, which downregulates the 1α-hydroxylase responsible for renal conversion of calcidiol to calcitriol. This, combined with decreased production of calcitriol secondary to reduced renal mass, causes reduced intestinal absorption of Ca2+ and hypocalcemia.49 Low or normal phosphate concentrations imply vitamin D or Mg2+ deficiency. An otherwise healthy patient with chronic hypocalcemia probably is hypoparathyroid. Chronically ill adults with hypocalcemia often have disorders such as malabsorption, osteomalacia, or osteoblastic metastases. The definitive treatment of hypocalcemia necessitates identification and treatment of the underlying cause (Table 42.11). Symptomatic hypocalcemia usually occurs when serum ionized Ca2+ is less than 0.7 mM. The clinician should carefully consider whether mild, asymptomatic ionized hypocalcemia requires therapy, particularly in ischemic and septic states in which experimental evidence suggests that Ca2+ can increase cellular damage. Unnecessary offending drugs should be discontinued. Hypocalcemia resulting from hypomagnesemia or hyperphosphatemia is treated by repletion of Mg2+ or removal of phosphate. Treatment of a patient with tetany and hyperphosphatemia requires coordination of therapy to avoid the consequences of metastatic soft tissue calcification.52 Potassium and other electrolytes should be measured and abnormalities corrected. Hyperkalemia and hypomagnesemia potentiate hypocalcemia-induced cardiac and neuromuscular irritability. In contrast, hypokalemia protects against hypocalcemic tetany; therefore correction of hypokalemia without correction of hypocalcemia can provoke tetany. Mild, ionized hypocalcemia should not be overtreated. For instance, in most patients after cardiac surgery administration of Ca2+ only increases blood pressure53 and actually attenuates the β-adrenergic effects of epinephrine.53 In normocalcemic dogs,

TABLE 42.11  Acute Treatment Hypocalcemia

Administer Calcium IV: 10 mL 10% calcium gluconatea over 10 min, followed by elemental calcium 0.3-2 mg/kg per hour Oral: 50-100 mg elemental calcium every 6 hr

Administer Vitamin D Ergocalciferol: 1200 µg/day (t1/2 = 30 days) Dihydrotachysterol: 200-400 µg/day (t1/2 = 7 days) 1,25-dihydroxycholecalciferol: 0.25-1 µg/day (t1/2 = 1 day)

Monitor Electrocardiogram t1/2, Half-life. a Calcium gluconate contains 93 mg elemental calcium per 10-mL vial.



calcium chloride primarily acts as a peripheral vasoconstrictor, with transient reduction of myocardial contractility; in hypocalcemic dogs, Ca2+ infusion significantly improves contractile performance and blood pressure.54 Therefore Ca2+ infusions should be of limited value in surgical patients unless there is evidence of hypocalcemia.54 Calcium salts appear to confer no benefit to patients already receiving inotropic or vasoactive agents. The cornerstone of therapy for confirmed, symptomatic, ionized hypocalcemia (Ca2+ < 0.7 mM) is Ca2+ administration. In patients who have severe hypocalcemia or hypocalcemic symptoms, Ca2+ should be administered intravenously. In emergency situations in an average-sized adult, the “rule of 10s” advises infusion of 10 mL of 10% calcium gluconate (93 mg elemental calcium) over 10 minutes, followed by a continuous infusion of elemental calcium of 0.3 to 2 mg/kg per hour (i.e., 3–16 mL/h of 10 % calcium gluconate for a 70-kg adult). Calcium salts should be diluted in 50 to 100 mL of dextrose 5% in water (D5W) (to limit venous irritation and thrombosis), should not be mixed with bicarbonate (to prevent precipitation), and must be given cautiously to patients using digoxin because Ca2+ increases its toxicity. Continuous ECG monitoring during initial therapy will detect cardiotoxicity (e.g., heart block, ventricular fibrillation). During Ca2+ replacement, serum Ca2+, Mg2+, phosphate, K+, and creatinine should be monitored. Once the ionized Ca2+ is stable in the range of 4 to 5 mg/dL (1.0–1.25 mM), oral calcium supplements can substitute for parenteral therapy. Urinary Ca2+ should be monitored in attempt to avoid hypercalciuria (>5 mg/kg per 24 hours) and possible urinary tract stone formation. When supplementation fails to maintain normal serum Ca2+, or if hypercalciuria develops, vitamin D can be added. Although the principal effect of vitamin D is to increase enteric Ca2+ absorption, osseous Ca2+ resorption is also enhanced. When rapid changes in dosage are anticipated or an immediate effect is required (e.g., postoperative hypoparathyroidism), shorter-acting calciferols such as dihydrotachysterol are preferable. Because the effect of vitamin D is not regulated, the dosages of Ca2+ and vitamin D should be adjusted to raise serum Ca2+ into the low normal range. Adverse reactions to Ca2+ and vitamin D include hypercalcemia and hypercalciuria. If hypercalcemia develops, Ca2+ and vitamin D should be discontinued and appropriate therapy given. The toxic effects of vitamin D metabolites persist in proportion to their biologic half-lives (ergocalciferol, 20–60 days; dihydrotachysterol, 5–15 days; calcitriol, 2–10 days). Glucocorticoids can antagonize the toxic effects of vitamin D metabolites.

Hypercalcemia Although ionized Ca2+ most accurately demonstrates hypercalcemia (ionized Ca2+ > 1.5 mM or total serum Ca2+ > 10.5 mg/dL), hypercalcemia customarily is defined in terms of total serum Ca2+. In hypoalbuminemic patients, total serum Ca2+ can be estimated by assuming an increase of 0.8 mg/dL for every 1 g/dL of albumin concentration below 4.0 g/dL. Patients with total serum Ca2+ less than 11.5 mg/dL are usually asymptomatic. Patients with moderate hypercalcemia (total serum Ca2+ 11.5–13 mg/dL) can show symptoms of lethargy, anorexia, nausea, and polyuria. Severe hypercalcemia (total serum Ca2+ > 13 mg/dL) is associated with more severe neuromyopathic symptoms, including muscle weakness, depression, impaired memory, emotional lability, lethargy, stupor, and coma. The cardiovascular effects of hypercalcemia include hypertension, arrhythmias, heart block, cardiac arrest, and digitalis sensitivity. Skeletal disease occurs secondary to direct osteolysis or humoral bone resorption.

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Hypercalcemia impairs urinary concentrating ability and renal excretory capacity for Ca2+ by irreversibly precipitating Ca2+ salts within the renal parenchyma and by reducing renal blood flow and GFR. In response to hypovolemia, renal tubular reabsorption of Na+ enhances renal Ca2+ reabsorption. Effective treatment of severe hypercalcemia is necessary to prevent progressive dehydration and renal failure leading to further increases in total serum Ca2+, because volume depletion exacerbates hypercalcemia.55 Hypercalcemia occurs when Ca2+ enters the ECV more rapidly than the kidneys can excrete the excess. Clinically, hypercalcemia most commonly results from an excess of bone resorption over bone formation, usually secondary to malignant disease, hyperparathyroidism, hypocalciuric hypercalcemia, thyrotoxicosis, immobilization, and granulomatous diseases. Granulomatous diseases produce hypercalciuria and hypercalcemia as the result of conversion by granulomatous tissue of calcidiol to calcitriol.56 Malignancy can produce hypercalcemia either through bone destruction or secretion by malignant tissue of hormones that promote hypercalcemia.57 Although weakness, weight loss, and anemia associated with primary hyperparathyroidism might suggest malignancy, these can result simply from the primary disease process. Hypercalcemia associated with granulomatous diseases (e.g., sarcoidosis) results from the production of calcitriol by granulomatous tissue. To compensate for increased gut absorption or bone resorption of Ca2+, renal excretion can readily increase from 100 to more than 400 mg/day. Factors that promote hypercalcemia might be offset by coexisting disorders such as pancreatitis, sepsis, or hyperphosphatemia that cause hypocalcemia. Although definitive treatment of hypercalcemia requires correction of underlying causes, temporizing therapy can be necessary to avoid complications and to relieve symptoms. Total serum Ca2+ exceeding 14 mg/dL represents a medical emergency. General supportive treatment includes hydration, correction of associated electrolyte abnormalities, removal of offending drugs, dietary Ca2+ restriction, and increased physical activity. Because anorexia and antagonism by Ca2+ of ADH action invariably lead to Na+ and water depletion, infusion of 0.9 % saline solution will dilute serum Ca2+, promote renal excretion, and can reduce total serum Ca2+ by 1.5 to 3 mg/dL. Urinary output should be maintained at 200 to 300 mL/hr. As GFR increases, Na+ increases Ca2+ excretion by competing with Ca2+ for reabsorption in the proximal renal tubules and loop of Henle. Furosemide further enhances Ca2+ excretion by increasing tubular + Na . Patients who have renal impairment require higher doses of furosemide. During saline solution infusion and forced diuresis, careful monitoring of cardiopulmonary status and electrolytes, especially Mg2+ and K+, is required. Intensive diuresis and saline administration can achieve net Ca 2+ excretion of 2000 to 4000 mg/24 hr, a rate eight times greater than saline solution alone but still somewhat less than the rate of removal achieved by hemodialysis (6000 mg/8 hr). Patients treated with phosphates should be well hydrated. Bone resorption, the primary cause of hypercalcemia, can be minimized by increasing physical activity and initiating drug therapy. Bisphosphonates, currently the first-line therapy for acute hypercalcemia, inhibit osteoclast function and viability. Bisphosphonates are the principal drugs for the management of hypercalcemia mediated by osteoclastic bone resorption.58 Pamidronate, unlike earlier biphosphonates, does not appear to worsen renal insufficiency. More recently released biphosphonates include alendronate, risedronate, and zoledronic acid. Risedronate has been associated with fewer nonvertebral fractures than alendronate.59 Zoledronic

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acid has the most rapid onset of action among the biphosphonates and prolongs the duration before relapse of hypercalcemia; however, it has been associated with compromised renal function.60 Other osteoclast-inhibiting agents used to treat hypercalcemia include mithramycin and calcitonin.61 Mithramycin, a cytotoxic agent, lowers serum Ca2+ primarily by inhibiting bone resorption, probably because of toxicity to osteoclasts. The hypocalcemic effect, usually seen within 12 to 24 hours after a single IV dose of 25 µg/ kg, peaks at 48 to 72 hours and persists 5 to 7 days. Major toxic effects of mithramycin, more likely to occur in patients with renal insufficiency, include thrombocytopenia, nephrotoxicity, and hepatotoxicity. Calcitonin lowers serum Ca2+ within 24 to 48 hours and is more effective when combined with glucocorticoids.60 Usually calcitonin reduces total serum Ca2+ by only 1 to 2 mg/dL. Although calcitonin is relatively nontoxic, more than 25% of patients do not respond. Thus calcitonin is unsuitable as a first-line drug during life-threatening hypercalcemia. Hydrocortisone is effective in treating hypercalcemic patients with lymphatic malignancies, vitamin D or A intoxication, and diseases associated with production by tumor or granulomas of 1,25-dihydroxyvitamin D (1,25(OH)2D) or osteoclast-activating factor. Glucocorticoids rarely improve hypercalcemia secondary to malignancy or hyperparathyroidism. In the future, Ca2+ receptor agonists could become treatments of choice for suppressing primary and secondary hyperparathyroidism. Currently undergoing initial clinical trials, these agents also reduce inorganic phosphate concentration and the calcium × phosphate product.62 Phosphates lower serum Ca2+ by causing deposition of Ca2+ in bone and soft tissue. Because the risk of extraskeletal calcification of organs such as the kidney and myocardium is less if phosphates are given orally, the IV route should be reserved for patients with life-threatening hypercalcemia or patients in whom other measures have failed.

Phosphate Physiologic Role Inorganic phosphate (PO43−; Pi) is distributed in similar concentrations throughout intracellular and ECF. Of total body phosphorus, 90% is in bone, 10% is intracellular, and less than 1% is in the ECF. Phosphate circulates as the free ion (55%), complexed ion (33%), and in a protein-bound form (12%). Plasma levels vary widely; normal total Pi ranges from 2.7 to 4.5 mg/dL in adults. Control of Pi is achieved by altered renal excretion and redistribution between body compartments. Absorption occurs in the duodenum and jejunum and is largely unregulated. Phosphate reabsorption in the kidney is primarily regulated by PTH, dietary intake, and insulinlike growth factor.63 Phosphate is freely filtered at the glomerulus and its concentration in the glomerular ultrafiltrate is similar to plasma. Filtered phosphate is then reabsorbed in the proximal tubule, where it is passively cotransported with Na+.63,64 Cotransport is regulated by phosphorus intake and PTH.65 Phosphate excretion is increased by volume expansion and decreased by respiratory alkalosis. Phosphoryl bonds provide the primary energy bond in ATP and creatine phosphate. Therefore severe phosphate depletion can result in cellular energy depletion. Phosphate is an essential component of second-messenger systems, including cAMP and phosphoinositides, and of nucleic acids, phospholipids, and cell membranes. As part of 2,3-diphosphoglycerate, phosphate promotes release of oxygen from hemoglobin. Phosphate also functions in protein phosphorylation and acts as a urinary buffer.

Hypophosphatemia Hypophosphatemia is characterized by low levels of phosphatecontaining cellular components, including ATP, 2,3-diphosphoglycerate, and membrane phospholipids. Serious life-threatening organ dysfunction can occur when serum Pi falls below 1 mg/dL. Neurologic manifestations of hypophosphatemia include paresthesias, myopathy, encephalopathy, delirium, seizures, and coma.66 Hematologic abnormalities include dysfunction of erythrocytes, platelets, and leukocytes. Because hypophosphatemia limits the chemotactic, phagocytic, and bactericidal activity of granulocytes, associated immune dysfunction contributes to the susceptibility of hypophosphatemic patients to sepsis. Muscle weakness and malaise are common. Respiratory muscle failure and myocardial dysfunction are potential problems of concerns in anesthesiology. Rhabdomyolysis is a complication of severe hypophosphatemia.67 Common in postoperative and traumatized patients, hypophosphatemia (Pi < 2.5 mg/dL) is caused by three primary abnormalities in Pi homeostasis: intracellular shift of Pi, increase in renal Pi loss, or reduced gastrointestinal Pi absorption. Carbohydrate-induced hypophosphatemia (refeeding syndrome),68 mediated by insulininduced cellular Pi uptake, is the type most commonly encountered in hospitalized patients. Hypophosphatemia also occurs as catabolic patients become anabolic, and during medical management of diabetic ketoacidosis. Acute alkalemia, which can reduce serum Pi to 1 to 2 mg/dL, increases intracellular consumption of Pi by increasing the rate of glycolysis. Hyperventilation significantly reduces Pi and, importantly, the effect is progressive after cessation of hyperventilation.69 Acute correction of respiratory acidemia can also result in severe hypophosphatemia. Respiratory alkalosis probably explains the hypophosphatemia associated with gram-negative bacteremia and salicylate poisoning. Excessive renal loss of Pi explains the hypophosphatemia associated with hyperparathyroidism, hypomagnesemia, hypothermia, diuretic therapy, and renal tubular defects in Pi absorption. Excess gastrointestinal loss of Pi is most commonly secondary to use of Pi-binding antacids or to malabsorption syndromes. Measurement of urinary Pi aids in differentiation of hypophosphatemia owing to renal losses from that owing to excessive gastrointestinal losses or redistribution of Pi into cells. Extrarenal causes of hypophosphatemia cause avid renal tubular Pi reabsorption, reducing urinary excretion to less than 100 mg/day. Patients who have severe ( 5.0 mg/dL) relate primarily to development of hypocalcemia and ectopic calcification. Hyperphosphatemia is caused by three basic mechanisms: inadequate renal excretion, increased movement of Pi out of cells, and increased Pi or vitamin D intake. Rapid cell lysis from chemotherapy, rhabdomyolysis, and sepsis can cause hyperphosphatemia, especially when renal function is impaired. Renal failure is the most common cause of hyperphosphatemia.66 Renal excretion of Pi remains adequate until the GFR falls below 20 to 25 mL/min. Measurements of BUN, creatinine, GFR, and urinary Pi are helpful in the differential diagnosis of hyperphosphatemia. Normal renal function accompanied by high Pi excretion (>1500 mg/day) indicates an oversupply of Pi. Elevated BUN, elevated creatinine, and low GFR suggest impaired renal excretion of Pi. Normal renal function and Pi excretion less than 1500 mg/day suggest increased Pi reabsorption (i.e., hypoparathyroidism). Hyperphosphatemia is corrected by eliminating the cause of Pi elevation and correcting the associated hypocalcemia. Calcium supplementation of hypocalcemic patients should be delayed until serum phosphate has fallen below 2.0 mM (6.0 mg/dL).56 Serum Pi is reduced by restricting intake, increasing urinary excretion with saline solution and acetazolamide (500 mg every 6 hours), and increasing gastrointestinal losses by enteric administration of aluminum hydroxide (30–45 mL every 6 hours). Aluminum hydroxide absorbs Pi secreted into the bowel lumen and increases Pi loss even if none is ingested. Hemodialysis and peritoneal dialysis are effective in removing Pi in patients with renal failure.

Magnesium Physiologic Role Magnesium is a physiologically important, multifunctional, divalent cation present primarily in the intracellular space (intracellular Mg2+ ~ 2400 mg; extracellular Mg2+ ~ 280 mg). About 50% of Mg2+ is in bone, 25% in muscle, and less than 1 % of total body Mg2+ circulates in plasma. Of normal circulating total Mg2+ (1.5-1.9 mEq/L or 0.75–0.95 mM or 1.7–2.2 mg/dL),71 there are three components: protein-bound (30%), chelated (15%), and ionized (55%), of which only ionized Mg2+ is active. Magnesium is necessary for enzymatic reactions involving DNA and protein synthesis, energy metabolism, glucose utilization, and fatty acid synthesis and breakdown.72,73 As a primary regulator or cofactor in many enzyme systems, Mg2+ is important for regulation of the Na/K-ATPase, calcium adenosine triphosphatase (Ca-ATPase) enzymes, adenylyl cyclase, proton pumps, and Ca2+ channels. Magnesium has been called an endogenous Ca2+ antagonist, because modulation of Ca2+ channels contributes to maintenance of normal vascular tone, prevention of vasospasm, and perhaps to prevention of Ca2+ overload in many tissues. Because Mg2+ partially regulates PTH secretion and is important for maintenance of end-organ sensitivity to both PTH and vitamin D, abnormalities in ionized Mg2+ concentration (Mg2+) can result in abnormal Ca2+ metabolism. Magnesium functions in K+ metabolism primarily through regulating Na/K ATPase, which controls K+ entry into cells, especially in K+-depleted states, and controls reabsorption of K+ by the renal tubules. In addition, Mg2+ functions as a regulator of membrane excitability and serves as a structural component in both cell membranes and the skeleton.

CHAPTER 42  Electrolytes and Diuretics

827

Because Mg2+ stabilizes axonal membranes, hypomagnesemia decreases the threshold of axonal stimulation and increases nerve conduction velocity. Magnesium also influences release of acetylcholine at the neuromuscular junction by competitively inhibiting Ca2+ entry into presynaptic nerve terminals. The concentration of Ca2+ required to trigger Ca2+-induced Ca2+ release and the rate at which Ca2+ is released from the sarcoplasmic reticulum are inversely related to Mg2+ concentration. Thus the net effect of hypomagnesemia is muscle that contracts more in response to stimuli and is tetany prone. Magnesium is widely available in foods and is absorbed through the gastrointestinal tract, although dietary consumption appears to have decreased over several decades.73 The distal tubule is the major site of Mg2+ regulation. Plasma Mg2+ regulates Mg2+ reabsorption through the Ca2+/Mg2+–sensing receptor, located on the capillary side of cells in the thick ascending limb.74 Although both Mg2+ and Pi are primarily regulated by intrinsic renal mechanisms,72 PTH exerts a greater effect on renal loss of Pi. Magnesium has been used to help manage an array of clinical problems in patients who are not hypomagnesemic.75 Therapeutic hypermagnesemia is used to treat patients with premature labor, preeclampsia, and eclampsia. Because Mg2+ blocks release of catecholamines from adrenergic nerve terminals and the adrenal glands, it has been used to reduce the effects of catecholamine excess in patients with tetanus and pheochromocytoma. Magnesium administration can influence dysrhythmias by direct effects on myocardial membranes; by altering cellular K+ and Na+ concentrations; by inhibiting cellular Ca2+ entry; by improving myocardial oxygen supply and demand; by prolonging the effective refractory period; by depressing conduction, by antagonizing catecholamine action on the conducting system; and by preventing vasospasm. Administration of Mg2+ reduces the incidence of dysrhythmias after myocardial infarction and in patients with CHF.76 In humans with ischemic myocardium, Mg2+ prevents ischemic increases in action potential duration and membrane repolarization. After acute myocardial infarction, IV Mg2+ decreased short-term mortality.77 In addition, Mg2+ can be useful as treatment for torsades de pointes, even in normomagnesemic patients.78

Hypomagnesemia The clinical features of hypomagnesemia (Mg2+ < 1.8 mg/dL), like those of hypocalcemia, are characterized by increased neuronal irritability and tetany.79 Symptoms are rare when serum Mg2+ is 1.5 to 1.7 mg/dL; in most symptomatic patients serum Mg2+ is less than 1.2 mg/dL. Patients frequently complain of weakness, lethargy, muscle spasms, paresthesias, and depression. When severe, hypomagnesemia can induce seizures, confusion, and coma. Cardiovascular abnormalities include coronary artery spasm, cardiac failure, dysrhythmias, and hypotension. Severe hypomagnesemia can reduce the response of adenylyl cyclase to stimulation of the PTH receptor.80 Hypomagnesemia can aggravate digoxin toxicity and CHF. Rarely resulting from inadequate dietary intake, hypomagnesemia most commonly is caused by inadequate gastrointestinal absorption, excessive losses, or failure of renal conservation. Excessive Mg2+ loss is associated with prolonged nasogastric suctioning, gastrointestinal or biliary fistulas, and intestinal drains. Inability of the renal tubules to conserve Mg2+ complicates a variety of systemic and renal diseases, although advanced renal disease with decreased GFR can lead to Mg2+ retention. Polyuria, whether secondary to ECV expansion or to pharmacologic or pathologic diuresis, can

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result in excessive urinary Mg2+ excretion. Various drugs, including aminoglycosides, cis-platinum, cardiac glycosides, and diuretics, enhance urinary Mg2+ excretion. Intracellular shifts of Mg2+ as a result of thyroid hormone or insulin administration can also decrease serum Mg2+. Because the Na/K-ATPase pump is Mg2+-dependent, hypomagnesemia increases myocardial sensitivity to digitalis preparations and can cause hypokalemia as a result of renal potassium wasting. Attempts to correct potassium deficits with K+ replacement therapy alone might not be successful without simultaneous Mg2+ therapy. Magnesium is important in the regulation of K+ channels. The interrelationships of Mg2+ and K+ in cardiac tissue have probably the greatest clinical relevance in terms of arrhythmias, digoxin toxicity, and myocardial infarction. Both severe hypomagnesemia and hypermagnesemia suppress PTH secretion and can cause hypocalcemia. Severe hypomagnesemia can also impair end-organ response to PTH. Hypomagnesemia is associated with hypokalemia, hyponatremia, hypophosphatemia, and hypocalcemia. The reported prevalence of hypomagnesemia in hospitalized and critically ill patients varies from 11% to 61%, with the variability attributable to differences in measurement technique.81 Recent development of a specific electrode to measure ionized Mg2+ has demonstrated an association between hypomagnesemia, use of diuretics, and development of sepsis.81 Patients who develop hypomagnesemia while in intensive care have increased mortality.81 Of alcoholic patients admitted to the hospital, 30% are hypomagnesemic.82 Serum Mg2+ might not reflect intracellular Mg2+. Peripheral lymphocyte Mg2+ correlates well with skeletal and cardiac Mg2+ content. Measurement of 24-hour urinary Mg2+ excretion is useful in separating renal from nonrenal causes of hypomagnesemia. Normal kidneys can reduce Mg2+ excretion to less than 1 to 2 mEq/day in response to depletion. Hypomagnesemia accompanied by high urinary excretion (>3–4 mEq/day) suggests a renal cause. In the Mg2+-loading test, urinary Mg2+ excretion is measured for 24 hours after an IV load. Magnesium deficiency is treated by administration of Mg2+ supplements (Table 42.12). One gram of magnesium sulfate provides approximately 4 mmol (8 mEq, or 98 mg) of elemental magnesium. Mild deficiencies can be treated with diet alone. Replacement must be added to daily requirements (0.3–0.4 mEq/kg per day). Symptomatic or severe hypomagnesemia (Mg2+ < 1.0 mg/dL) should be treated with parenteral Mg2+: 1 to 2 g (8–16 mEq) of magnesium sulfate as an IV bolus over the first hour, followed by a continuous infusion of 2 to 4 mEq/hr. Therapy should be guided subsequently by serum Mg2+ level. The rate of infusion should not exceed 1 mEq/ min, even in emergency situations, and continuous cardiac monitoring is necessary to detect cardiotoxicity. Because Mg2+ antagonizes Ca2+, blood pressure and cardiac function should be monitored, although blood pressure and cardiac output usually change little during Mg2+ infusion. Treatment of hypomagnesemia during cardiopulmonary bypass was found to

TABLE 42.12  Acute Treatment of Hypophosphatemia Parenteral phosphate, 0.2 mM-0.68 mmol/kg (5-16 mg/kg) over 12 hr Potassium phosphate (93 mg/mL phosphate) Sodium phosphate (93 mg/mL phosphate)

decrease the incidence of postoperative ventricular tachycardia from 30% to 7% and increase the frequency of continuous sinus rhythm from 5% to 34%.83 During repletion, patellar reflexes should be monitored frequently and Mg2+ withheld if they become suppressed. Patients with renal insufficiency have a diminished ability to excrete Mg2+ and require careful monitoring. Repletion of systemic Mg2+ stores usually requires 5 to 7 days of therapy, after which daily maintenance doses should be provided. Magnesium can be given orally, usually in a dose of 60 to 90 mEq/day of magnesium oxide. Hypocalcemic, hypomagnesemic patients should receive Mg2+ as the chloride salt, because sulfate can chelate Ca2+ and further reduce serum Ca2+.

Hypermagnesemia Most cases of hypermagnesemia (Mg2+ > 2.5 mg/dL) are iatrogenic, resulting from administration of Mg2+ in antacids, enemas, or parenteral nutrition, especially to patients with impaired renal function. Other rarer causes of mild hypermagnesemia are hypothyroidism, Addison disease, lithium intoxication, and familial hypocalciuric hypercalcemia. Hypermagnesemia is rarely detected in routine electrolyte determinations.79,84,85 Hypermagnesemia antagonizes the release and effect of acetylcholine at the neuromuscular junction, depressing skeletal muscle function and enhancing neuromuscular blockade. Magnesium potentiates the action of nondepolarizing muscle relaxants and decreases K+ release in response to succinylcholine.79 The neuromuscular and cardiac toxicity of hypermagnesemia can be acutely, but transiently, antagonized by IV Ca2+ (5–10 mEq) to buy time while more definitive therapy is instituted.79 All Mg2+-containing preparations must be stopped. Urinary excretion of Mg2+ can be increased by expanding ECV and inducing diuresis with a combination of saline solution and furosemide. In emergency situations and in patients with renal failure, Mg2+ can be removed by dialysis.

Diuretics The most prominent property of diuretics is that they reduce reabsorption of Na+ and Cl− at different sites in the nephron, thereby increasing urinary Na+ and water losses. This makes them useful in treatment of a variety of conditions, such as edematous states, hypertension, heart failure, renal dysfunction, hypercalcemia, nephrolithiasis, glaucoma, and mountain sickness. Their efficacy, safety, and optimal dosing are, however, based on small and underpowered trials.86,87 They can be divided into three major classes depending on the site at which they impair Na+ reabsorption. Loop diuretics act in the thick ascending limb of the loop of Henle; thiazide-type diuretics act in the distal tubule and connecting segment; and potassium-sparing diuretics act in the aldosteronesensitive principal cells in the cortical collecting tubule. It is important to understand the general mechanism behind Na+ reabsorption (Fig. 42.5). The Na+-transporting cells contain Na,K-ATPase in the basolateral membrane.88 These pumps have two major functions. They return reabsorbed Na+ to the systemic circulation and maintain intracellular Na+ concentration at low levels. This is important because otherwise no Na+ transport occurs. Each of the major nephron segments has a unique Na+ entry mechanism; inhibition of this step is the major mechanism at which each of the different classes of diuretics acts. Approximately two-thirds of filtered Na+ is reabsorbed in the proximal tubule by primary and secondary active transport.

CHAPTER 42  Electrolytes and Diuretics



Glomerulus

Proximal convoluted tubule Acids

120 mL/min

Bases

Distal convoluted tubule Cl– PTH sensitive (ADH) Ca2+ 4

Na+ (60%)

Lumen 1 H2O 2

Cortex

Na+ (10%)

HCO3– (reabsorption)

829

Cl– (45%) K+ Ca2+ Mg2+

6 5

K+H+

Na+ (5%) 3

Medulla

Thick ascending loop

Cl– Na+ (25%)

(ADH) H2O

H2O

Collecting Ducts

H2O Thin descending loop

Thin ascending loop

Loop of Henle

H2O Na+

1 Carbonic anhydrase inhibitors 2 Osmotic diuretics 3 Loop diuretics 4 Thiazides 5 K+-sparing 6 Aldosterone antagonists

• Fig. 42.5  Action of diuretics at various renal tubular segments. ADH, Antidiuretic hormone; Ca2+, calcium ion; Cl−, chloride ion; HCO3−, bicarbonate; H2O, water; K+H+, ——————–; Na+, sodium ion; PTH, parathyroid hormone.

Proximal Convoluted Tubule–Carbonic Anhydrase Inhibitors Azetazolamide and dorzolamide inhibit the activity of carbonic anhydrase, which plays an important role in proximal HCO3−, Na+, and Cl− reabsorption. These agents thus produce NaCl and NaHCO3 loss. The net diuresis is small because most of the excess fluid is reclaimed at more distal segments, particularly at the loop of Henle. The diuretic action is also attenuated by the metabolic acidosis that results from the loss of HCO3− (Fig. 42.6). The major uses of these diuretics are for edematous states and metabolic alkalosis.89,90 Clinical uses are glaucoma (decrease of aqueous humor, which lowers intraocular pressure), acute mountain sickness (lowers the incidence of pulmonary as well as cerebral edema), metabolic alkalosis (such as caused by thiazide diuretics), and elimination of acidic drugs (such as aspirin, uric acid). Adverse effects are acidosis, bicarbonaturia, hypokalemia, paresthesias, and renal stones (hypercalciuria, phosphaturia).

Ascending Loop of Henle: Loop Diuretics Fluid entering the loop of Henle is isotonic (osmolarity 300 mOsm/L) but the volume is only a third of the volume originally filtered into Bowman capsule. The loop of Henle acts as a countercurrent multiplier (see Fig. 42.5), and as such creates a medullary interstitial osmolar gradient. The descending limb of the loop of Henle is permeable to water. Water diffuses into the

Proximal Convoluted Tubule Luminal membrane

Basolateral membrane K+ Na+

–

HCO3

H2CO3

Na+

Na+

H+

H+

HCO3– HCO3–

CA Acetazolamide CO2 + H2O

CA

CO2 + H2O

CO2 + H2O

• Fig. 42.6

  Actions of carbonic anhydrase inhibitors. CA, Carbonic anhydrase; Cl−, chloride ion; CO2, carbon dioxide; H+, hydrogen ion; HCO3−, bicarbonate; H2CO3, carbonic acid; H2O, water; Na+, sodium ion.

hyperosmolar medullary interstitium. The osmolarity can reach a maximum of 1200 mOsm/L at the tip of the medullary interstitium in antidiuresis. The ascending limb (where loop diuretics work) is impermeable to water. NaCl is pumped from the tubule into the interstitium in the ascending limb. The tubular osmolarity decreases

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Distal Tubule

Thick Ascending Loop Luminal membrane

Basolateral membrane

Loop diuretics 2Cl– Na+ K+

Luminal membrane

Basolateral membrane

K+ Cl– K+ Na+

K+ Na+

Na+

Thiazides

Cl–

Cl–

K+ Na+

Na+ Cl–

(+) Potential

Ca2+

• Fig. 42.7

  Actions of loop diuretics on the thick ascending loop of Henle. Cl−, Chloride ion; K+, potassium ion; Na+, sodium ion.

and fluid that leaves the loop is hypotonic. The collecting duct is impermeable to water without ADH. Loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid) can lead to excretion of 20% to 25% of filtered Na+ in large doses.91,92 They act principally in the medullary and cortical aspects of the thick ascending limb and the macula densa cells in the early distal tubule. Loop diuretics compete for the Cl− site, thereby diminishing net reabsorption.93,94 Sodium reabsorbed via the Na+/ K+/2Cl− transporter is transported back into the blood by the Na/K ATPase pump and by a Na+/Cl− cotransporter, the excess Cl− returning to blood via passive diffusion. High intracellular K+ results in its backdiffusion across the luminar membrane, providing a positive potential that drives reabsorption of both Mg2+ and Ca2+ (Fig. 42.7). Inhibition of this mechanism thus increases urinary Na+, K+, Ca2+, Mg+ and Cl−. Clinical uses of loop diuretics include acute pulmonary edema, acute renal failure, anion overdose, heart failure, hypercalcemia, hypertension, and refractory edema. Adverse effects are allergies, alkalosis, hypocalcemia, hypokalemia, hypomagnesemia, hyperuricemia, hypovolemia, and ototoxicity (ethancrynic acid > furosemide).

Thiazides Hydrochlorothiazide, indapamide, and metolazone are organic acids that are both filtered and secreted and inhibit the Na+/Cl− transporter on the luminal membrane of the distal convoluted tubule. Normally, the Na+ that is brought in by the Na+/Cl− cotransporter is exchanged for K+ that returns to blood via backdiffusion. Chloride also returns to blood by such a mechanism, whereas Ca2+ returns by a Ca2+/Na+ antiporter. If the Na+/Cl− cotransporter is inhibited by thiazides, hypokalemia and alkalosis occur. Hypercalcemia can occur as the result of increased activity of the Na+/ Ca2+ antiporter (Fig. 42.8). Clinical uses of thiazides are hypertension and heart failure. Their effects are improved by Na+ restriction and attenuated by low GFR. Adverse effects are allergies, alkalosis, hypokalemia, hyperuricemia, hypovolemia, hyperglycemia, hyperlipidemia, hypercalcemia, and sexual dysfunction.

Na+ Ca2+

• Fig. 42.8

2+   Actions of thiazides on the distal convoluted tubule. Ca , Calcium ion; Cl−, chloride ion; K+, potassium ion; Na+, sodium ion.

Potassium-Sparing Diuretics Spironolactone, amiloride, and triamterene are weak diuretics that act at the level of the collecting tubules and ducts. Most K+ is secreted in the collecting ducts. Normally, aldosterone exerts its mineralocorticoid action via interaction with specific receptors, increasing insertion of Na+ channels on the luminal membrane, thereby increasing activity of Na+/K+ and H+ exchangers. Na+ entering through the channels increases intracellular positive charge, and thereby extrusion of K+ into the lumen. Potassium-sparing diuretics prevent these effects. Spironolactone is an aldosterone receptor inhibitor, whereas amiloride and triamterene block Na+ channels. The result is a minor effect on Na+ reabsorption but a major effect on K+ retention. Thus they cause a minor increase in urinary Na+ but a substantial decrease in urinary K+ with possible hyperkalemia and acidosis. Clinical uses include hyperaldosteronism, hypertension, heart failure, and female hirsutism (spironolactone). The Na+ channel blockers can be used as adjuncts to other diuretics. Amiloride is used for treatment of diabetes insipidus. Adverse effects include acidosis, hyperkalemia, azotemia, gynecomastia, and libido changes (spironolactone) and nephrolithiasis (triamterene).

Osmotic Diuretics Mannitol is a non-reabsorbable sugar that acts as an osmotic diuretic, inhibiting water reabsorption in the proximal convoluted tubule (main site), thin descending loop of Henle, and the collecting ducts.95,96 Mannitol produces a profound water diuresis in which water is lost in excess of electrolytes. However, retention of the hypertonic mannitol can induce further volume expansion. This can potentially cause pulmonary edema in patients with heart failure. Major clinical uses include early stages of oliguria, early phases of brain edema, and postischemic acute renal failure. It is also commonly used in neurosurgical anesthesia to provide good operating conditions.

Diuretics in Heart Failure In acute decompensated heart failure, there are no differences between low and high furosemide dose strategies on outcome.

CHAPTER 42  Electrolytes and Diuretics



ACEIs, ARBs (RAAS inhibitors)

Distal convoluted tubule

Proximal tubule

2

6

3

A1RA

Adenosine

(+)

H+ Na+

BNP, dopamine

Na+

MRAs, BNP, NO 7

4

1

831

NHE3

Na+

Na+Cl–

K+

Thiazides

ATPase

Vasopressin (+)

Dopamine Thick ascending loop of Henle

NCCT

NKCC2

ATPase

Aldosterone

H+ Collecting duct

AQP2

H2O

(+)

Vasopressin

Na+K+ 2Cl–

5

(V2RAs, V1RAs/V2RAs)

Loop diuretics

• Fig. 42.9

112   Sites of action of drugs producing diuresis and natriuresis. Adenosine produces afferent arteriolar vasoconstriction and increases Na+ reabsorption in the proximal tubule. Aldosterone stimulates Na+ and K+ channels and Na+,K+-ATPase activity in the collecting tubules. Vasopressin stimulates activity of the Na+/K+/2Cl− cotransporter (NKCC2, also known as SLC12A1) and aquaporin 2 (AQP2). Step 1 corresponds to afferent arteriolar vasodilatation. Step 2 corresponds to efferent arteriolar vasodilation. Step 3 corresponds to the increase in the glomerular filtration rate. Step 4 corresponds to inhibition of Na+ reabsorption in the proximal tubule, and step 5 corresponds to the thick ascending loop of Henle. Step 6 corresponds to the distal tubule. Step 7 corresponds to the collecting ducts. Drugs that act at these sites are shown in colored boxes. A1RA, Adenosine A1 receptor antagonist; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin II type 1 receptor blocker; ATPase, adenosine triphosphatase; BNP; brain natriuretic peptide; Cl−, chloride ion; H+, hydrogen ion; H2O, water; K+, potassium ion; MRA, mineralocorticoid receptor antagonist; Na+, sodium ion; Na+,K+-ATPase, sodium potassium adenosine triphosphatase; NCCT, Na+/Cl− cotransporter; NHE3, Na+/H+ exchanger 3 (also known as SLC9A3); NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system; V1RA/V2RA, vasopressin receptor antagonist.

Because a high-dose strategy brings more relief of dyspnea, diuresis, and weight loss and a transient worsening of renal function without evidence of worse clinical outcome at 60 days, this regimen might be more beneficial.97 The action of drugs producing diuresis and natriuresis in patients with heart failure are shown in Fig. 42.9.

Adverse Effects of Diuretics At high doses diuretics produce adverse effects, such as hypotension, hypovolemia, electrolyte abnormalities, renal dysfunction, and neurohumoral activation. They can also contribute to longer hospitalization and higher mortality.98 Major fluid and electrolyte disturbances can occur within the first 2 to 3 weeks of diuretic administration owing to attainment and maintenance of a new steady state.99 Maximum diuresis always occurs with the first dose because as soon as fluid loss occurs, activation of Na+ retaining mechanisms takes place.100

Volume Depletion Although duration of Na+ loss is limited, some patients have a large initial response of volume loss, particularly in patients with

hypertension. In patients who remain edematous, the circulatory volume can be depleted and tissue perfusion reduced.

Azotemia If circulating volume is depleted, renal perfusion can fall, which lowers GFR and elevates BUN and serum creatinine. This is called prerenal azotemia because the defect is in renal perfusion rather than in renal function.101 Hypokalemia There is controversy whether mild hypokalemia caused by diuretics has any clinical significance. Some experts believe that hypokalemia can increase the risk of sudden death.102,103 There is increased risk of ventricular arrhythmia.104 A pertinent risk is when mild hypokalemia suddenly becomes profound. This can occur when epinephrine during a stress situation transfers K + into cells via β2-receptor agonism. Hyponatremia Hyponatremia is a common side effect in edematous patients with heart failure or cirrhosis. Volume loss enhances release of ADH

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and thereby causes dilution of Na+. This is almost solely due to thiazide diuretics, which do not impair concentration ability. Other diuretics reduce the medullary osmolal gradient and concentrating ability.

Emerging Developments In the perioperative period, maintenance IV solutions that minimize risks of deranged sodium and glucose homeostasis should be used. The fluid should have a sodium concentration close to the physiologic range to avoid perioperative hyponatremia, the most common complication of perioperative fluid therapy. The glucose content should be 1T to 2.5%, thereby avoiding hypoglycemia as well as hyperglycemia. The small amount of glucose in the solution also prevents lipolysis and the release of ketone bodies and free fatty

acids.105 Moreover, the solution should preferably have a balanced pH to avoid the hyperchloremic acidosis that occurs when larger amounts of 0.9% NaCl are given. Despite this, it is difficult to understand why 0.9% NaCl–based solutions are so frequently used worldwide. In recent years, several studies have confirmed the safety of balanced IV solutions with physiologic sodium concentrations and 1% glucose as the preferred perioperative fluid,106–109 which has been recommended by a European consensus statement from 2011 for intraoperative use.110,111 Such a solution has recently been registered in Sweden for pediatric use in the treatment of isotonic dehydration; it contains glucose 10 mg/mL and is balanced and isotonic. Although fluids of this type are adequate for most pediatric patients, individual patient characteristics must, as always, be considered when choosing the type of fluid to use.

Key Points • The major electrolytes (sodium, potassium, calcium, phosphate, and magnesium) are critical to basic physiologic functions, including action potential generation, cardiac rhythm control, muscle contraction, and energy storage, among many others. • Hyponatremia is the most common electrolyte disorder in hospitalized patients; it is sometimes associated with severe symptoms and even death, especially when the hyponatremia is corrected too rapidly. • New approaches differ from the previously advocated focus on separation between acute or chronic causes for hyponatremia. When seriously symptomatic, hyponatremia must be addressed expeditiously. • Hypernatremia is categorized in terms of the adequacy of intravascular volume. It is treated first with volume resuscitation when needed followed by repletion of the free water deficit, and by addressing the underlying cause (e.g., diabetes insipidus, iatrogenic causes, and so on). • No clear threshold has been defined for a level of hypokalemia below which safe conduct of anesthesia is compromised. There is no urgent need for K+ replacement therapy in mild to moderate hypokalemia (3–3.5 mEq/L) in asymptomatic patients. • Drugs are now the most common causes of hyperkalemia (e.g., nonsteroidal antiinflammatory drugs, ACE inhibitors, cyclosporin, and potassium-sparing diuretics) that occurs most commonly in patients with predisposing comorbidities (e.g.,

Key References Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. 2004;32:S146–S154. (Ref. 60). Ayus JC, Armstrong DL, Arieff AI. Effects of hypernatraemia in the central nervous system and its therapy in rats and rabbits. J Physiol. 1996;492:243–255. A study in animals showing the effect of untreated hypernatremia that results in brain lesions, myelinolysis, and cellular necrosis. (Ref. 33). Brooks MJ, Melnik G. The refeeding syndrome: an approach to understanding its complications and preventing its occurrence. Pharmacotherapy. 1995;15:713–726. The refeeding syndrome should be characterized as a syndrome of generalized fluid and electrolyte imbalance. Recommended electrolyte supplementation and laboratory monitoring can help prevent the disorder in susceptible patients. (Ref. 68). Overgaard-Steensen C. Initial approach to the hyponatremic patient. Acta Anaesthesiol Scand. 2011;55:139–148. This article presents a practical

•

•

•

• • •

DM, renal insufficiency). In anesthesia practice, hyperkalemic cardiac toxicity is associated with the administration of succinylcholine to patients with upper motor neuron lesions or severe burns. Definitive treatment of hypocalcemia necessitates identification and treatment of the underlying cause. Symptomatic hypocalcemia usually occurs when serum ionized Ca 2+ is less than 0.7 mM. The clinician should carefully consider whether mild, asymptomatic ionized hypocalcemia requires therapy, particularly in ischemic and septic states in which experimental evidence suggests that Ca2+ can increase cellular damage. Carbohydrate-induced hypophosphatemia (refeeding syndrome), mediated by insulin-induced cellular phosphate uptake, is the most commonly encountered type in hospitalized patients. Magnesium influences the release of neurotransmitters at the neuromuscular junction by competitively inhibiting the entry of Ca2+ into presynaptic nerve terminals. Diuretics reduce reabsorption of sodium chloride at different sites in the nephron, thereby increasing urinary Na+ and water losses. Diuretics are useful in a variety of conditions, such as edematous states, hypertension, heart failure, renal dysfunction, hypercalcemia, nephrolithiasis, glaucoma, and mountain sickness.

and unified approach based on a literature study of the physiology of plasma Na+, the brain’s response, and clinical and experimental studies of hyponatremia. (Ref. 1). Tamargo J, López-Sendón J. Novel therapeutic targets for the treatment of heart failure. Nat Rev Drug Discov. 2011;10:536–555. In recent years, new potential targets involved in the pathogenesis of heart failure have been identified. (Ref. 112). Wahr JA, Parks R, Boisvert D, et al. Preoperative serum potassium levels and perioperative outcomes in cardiac surgery patients. Multicenter Study of Perioperative Ischemia Research Group. JAMA. 1999; 281:2203–2210. Prospective, observational, case-control study of data. (Ref. 42). Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet. 1998;352:391–396. A summary of new findings regarding alterations of magnesium and phosphorus metaboilism are reviewed for the clinician. (Ref. 71).



References 1. Overgaard-Steensen C. Initial approach to the hyponatremic patient. Acta Anaesthesiol Scand. 2010;55:139–148. 2. Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol. 2009;29:227–238. 3. Tierney WM, Martin DK, Greenlee MC, et al. The prognosis of hyponatremia at hospital admission. J Gen Intern Med. 1986;1:380–385. 4. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol. 2008;295:F619–F624. 5. Kashyap AS. Hyperglycemia-induced hyponatremia: is it time to correct the correction factor? Arch Intern Med. 1999;159:2745–2746. 6. Gravenstein D. Transurethral resection of the prostate (TURP) syndrome: a review of the pathophysiology and management. Anesth Analg. 1997;84:438–446. 7. Hjertberg H. The use of ethanol as a marker to detect and quantify the absorption of irrigation fluid during transurethral resection of the prostate. Scand J Urol Nephrol Suppl. 1996;178:1–64. 8. Chatterjee K. Hyponatremia in heart failure. J Intensive Care Med. 2009;24:347–351. 9. Xu DL, Martin PY, Ohara M, et al. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J Clin Invest. 1997;99:1500–1505. 10. Fujita N, Ishikawa SE, Sasaki S, et al. Role of water channel AQP-CD in water retention in SIADH and cirrhotic rats. Am J Physiol. 1995;269(6 Pt 2):F926–F931. 11. Kumar S, Berl T. Sodium. Lancet. 1998;352:220–228. 12. Berendes E, Walter M, Cullen P, et al. Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet. 1997;349(9047):245–249. 13. Yamaki T, Tano-oka A, Takahashi A, et al. Cerebral salt wasting syndrome distinct from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Acta Neurochir (Wien). 1992;115(3–4):156–162. 14. Kim JK, Summer SN, Wood WM, et al. Osmotic and non-osmotic regulation of arginine vasopressin (AVP) release, mRNA, and promoter activity in small cell lung carcinoma (SCLC) cells. Mol Cell Endocrinol. 1996;123(2):179–186. 15. Chung HM, Kluge R, Schrier RW, et al. Postoperative hyponatremia. A prospective study. Arch Intern Med. 1986;146(2):333–336. 16. Ayus JC, Arieff AI. Brain damage and postoperative hyponatremia: the role of gender. Neurology. 1996;46(2):323–328. 17. Gomola A, Cabrol S, Murat I. Severe hyponatraemia after plastic surgery in a girl with cleft palate, medial facial hypoplasia and growth retardation. Paediatr Anaesth. 1998;8(1):69–71. 18. Arieff AI. Postoperative hyponatraemic encephalopathy following elective surgery in children. Paediatr Anaesth. 1998;8(1):1–4. 19. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med. 1997;126(1):20–25. 20. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29:282–299. 21. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120:S1–S21. 22. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. 2006;21:70–76. 23. Brown WD. Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol. 2000;13:691–697. 24. Overgaard-Steensen C, Stodkilde-Jorgensen H, Larsson A, et al. Regional differences in osmotic behavior in brain during acute hyponatremia: an in vivo MRI-study of brain and skeletal muscle in pigs. Am J Physiol Regul Integr Comp Physiol. 2010;299(2): R521–R532. 25. Deleted in review.

CHAPTER 42  Electrolytes and Diuretics

833

26. Ferguson-Myrthil N. Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan. Cardiol Rev. 2010;18:313–321. 27. Masuda T, Murakami T, Igarashi Y, et al. Dual impact of tolvaptan on intracellular and extracellular water in chronic kidney disease patients with fluid retention. Intern Med. 2016;55(19):2759–2764. 28. Ober KP. Endocrine crises. Diabetes insipidus. Crit Care Clin. 1991;7(1):109–125. 29. Bagshaw SM, Townsend DR, McDermid RC. Disorders of sodium and water balance in hospitalized patients. Can J Anaesth. 2009;56:151–167. 30. Rowe JW, Shock NW, DeFronzo RA. The influence of age on the renal response to water deprivation in man. Nephron. 1976;17(4):270–278. 31. Joelsson-Alm E, Nyman CR, Lindholm C, et al. Perioperative bladder distension – a prospective study. Scand J Urol Nephrol. 2009;43:58–62. 32. McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health and disease. N Engl J Med. 1995;333:1260–1266. 33. Ayus JC, Armstrong DL, Arieff AI. Effects of hypernatraemia in the central nervous system and its therapy in rats and rabbits. J Physiol. 1996;492(Pt 1):243–255. 34. Mattox KL, Maningas PA, Moore EE, et al. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The U.S. Multicenter Trial. Ann Surg. 1991;213:482–491. 35. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342(20):1493–1499. 36. Chanson P, Jedynak CP, Dabrowski G, et al. Ultralow doses of vasopressin in the management of diabetes insipidus. Crit Care Med. 1987;15(1):44–46. 37. Sedlacek M, Schoolwerth AC, Remillard BD. Electrolyte disturbances in the intensive care unit. Semin Dial. 2006;19:496–501. 38. Halperin ML, Kamel KS. Potassium. Lancet. 1998;352:135–140. 39. Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. New York: McGraw-Hill: Medical Pub. Division; 2001. 40. Rossier BC. 1996 Homer Smith Award Lecture. Cum grano salis: the epithelial sodium channel and the control of blood pressure. J Am Soc Nephrol. 1997;8:980–992. 41. Weiner ID, Wingo CS. Hypokalemia–consequences, causes, and correction. J Am Soc Nephrol. 1997;8:1179–1188. 42. Wahr JA, Parks R, Boisvert D, et al. Preoperative serum potassium levels and perioperative outcomes in cardiac surgery patients. Multicenter Study of Perioperative Ischemia Research Group. JAMA. 1999;281:2203–2210. 43. Osadchii OE. Mechanisms of hypokalemia-induced ventricular arrhythmogenicity. Fundam Clin Pharmacol. 2010;24:547–559. 44. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339:451–458. 45. Kuvin JT. Electrocardiographic changes of hyperkalemia. N Engl J Med. 1998;338:662. 46. Wrenn KD, Slovis CM, Slovis BS. The ability of physicians to predict hyperkalemia from the ECG. Ann Emerg Med. 1991;20: 1229–1232. 47. Kim HJ, Han SW. Therapeutic approach to hyperkalemia. Nephron. 2002;92:33–40. 48. Zaloga GP, Chernow B. Hypocalcemia in critical illness. J Am Med Assoc. 1986;256:1924–1929. 49. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet. 1998;352:306–311. 50. Zivin JR, Gooley T, Zager RA, et al. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am J Kidney Dis. 2001;37(4):689–698. 51. Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. 1995;80:1473–1478. 52. Sutters M, Gaboury CL, Bennett WM. Severe hyperphosphatemia and hypocalcemia: a dilemma in patient management. J Am Soc Nephrol. 1996;7(10):2056–2061. 53. Zaloga GP, Strickland RA, Butterworth JF IV., et al. Calcium attenuates epinephrine’s ⋅-adrenergic effects in postoperative heart surgery patients. Circulation. 1990;81:196–200.

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SE C T I O N VII

Fluid, Electrolyte, and Hematologic Homeostasis

54. Mathru M, Rooney MW, Goldberg SA, et al. Separation of myocardial versus peripheral effects of calcium administration in normocalcemic and hypocalcemic states using pressure volume (conductance) relationships. Anesth Analg. 1993;77:250–255. 55. Bilezikian JP. Clinical review 51: management of hypercalcemia. J Clin Endocrinol Metab. 1993;77:1445–1449. 56. Bushinsky DA, Monk RD. Calcium. Lancet. 1998;352: 306–311. 57. Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med. 1997;103:134–145. 58. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med. 1996;334:488–493. 59. Watts NB, Worley K, Solis A, et al. Comparison of risedronate to alendronate and calcitonin for early reduction of nonvertebral fracture risk: results from a managed care administrative claims database. J Manag Care Pharm. 2004;10:142–151. 60. Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. 2004;32:S146–S154. 61. Chan FKW, Koberle LMC, Thys-Jacobs S, et al. Differential diagnosis, causes, and management of hypercalcemia. Curr Probl Surg. 1997;34:449–523. 62. Urena P, Frazao JM. Calcimimetic agents: review and perspectives. Kidney Int Suppl. 2003;S91–S96. 63. Murer H, Werner A, Reshkin S, et al. Cellular mechanisms in proximal tubular reabsorption of inorganic phosphate. Am J Physiol. 1991;260:C885–C899. 64. Murer H, Markovich D, Biber J. Renal and small intestinal sodium-dependent symporters of phosphate and sulphate. J Exp Biol. 1994;196:167–181. 65. Peppers MP, Geheb M, Desai T. Endocrine crises. Hypophosphatemia and hyperphosphatemia. Crit Care Clin. 1991;7:201–214. 66. Peppers MP, Geheb M, Desai T. Hypophosphatemia and hyperphosphatemia. Crit Care Clin. 1991;7:201–214. 67. Knochel JP. Hypophosphatemia and rhabdomyolysis. Am J Med. 1992;92(5):455–457. 68. Brooks MJ, Melnik G. The refeeding syndrome: an approach to understanding its complications and preventing its occurrence. Pharmacotherapy. 1995;15(6):713–726. 69. Paleologos M, Stone E, Braude S. Persistent, progressive hypophosphataemia after voluntary hyperventilation. Clin Sci. 2000;98(5):619–625. 70. Rosen GH, Boullata JI, O’Rangers EA, et al. Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med. 1995;23(7):1204–1210. 71. Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet. 1998;352:391–396. 72. Whang R, Hampton EM, Whang DD. Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother. 1997;28:220–226. 73. Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569–1576. 74. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:1180–1195. 75. McLean RM. Magnesium and its therapeutic uses: a review. Am J Med. 1994;96:63–76. 76. Sueta CA, Clarke SW, Dunlap SH, et al. Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure. Circulation. 1994;89(2):660–666. 77. Teo KK, Yusuf S, Collins R, et al. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomised trials. Brit Med J. 1991;303:1499–1503. 78. Tzivoni D, Banai S, Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation. 1988;77:392–397. 79. Topf JM, Murray PT. Hypomagnesemia and hypermagnesemia. Rev Endocr Metab Disord. 2003;4(2):195–206. 80. Abbott LG, Rude RK. Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab. 1993;19:314–322.

81. Soliman HM, Mercan D, Lobo SS, et al. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med. 2003;31(4):1082–1087. 82. Elisaf M, Merkouropoulos M, Tsianos EV, et al. Pathogenetic mechanisms of hypomagnesemia in alcoholic patients. J Trace Elem Med Biol. 1995;9:210–214. 83. Wilkes NJ, Mallett SV, Peachey T, et al. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Anesth Analg. 2002;95(4):828–834, table of contents. 84. Whang R, Ryder KW. Frequency of hypomagnesemia and hypermagnesemia. Requested vs routine. J Am Med Assoc. 1990;263: 3063–3064. 85. Wong ET, Rude RK, Singer FR, et al. A high prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients. Am J Clin Pathol. 1983;79:348–352. 86. Dickstein K, Vardas PE, Auricchio A, et al. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Europace. 2010;12(11): 1526–1536. 87. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):e1–e90. 88. Katz AI. Distribution and function of classes of ATPases along the nephron. Kidney Int. 1986;29(1):21–31. 89. Leaf A, Schwartz WB, Relman AS. Oral administration of a potent carbonic anhydrase inhibitor (diamox). I. Changes in electrolyte and acid-base balance. N Engl J Med. 1954;250(18):759–764. 90. Preisig PA, Toto RD, Alpern RJ. Carbonic anhydrase inhibitors. Ren Physiol. 1987;10(3–4):136–159. 91. Rose BD. Diuretics. Kidney Int. 1991;39(2):336–352. 92. Stanton BA, Kaissling B. Adaptation of distal tubule and collecting duct to increased Na delivery. II. Na+ and K+ transport. Am J Physiol. 1988;255(6 Pt 2):F1269–F1275. 93. O’Grady SM, Palfrey HC, Field M. Characteristics and functions of Na-K-Cl cotransport in epithelial tissues. Am J Physiol. 1987;253(2 Pt 1):C177–C192. 94. Amsler K, Kinne R. Photoinactivation of sodium-potassium-chloride cotransport in LLC-PK1/Cl 4 cells by bumetanide. Am J Physiol. 1986;250(5 Pt 1):C799–C806. 95. Seely JF, Dirks JH. Micropuncture study of hypertonic mannitol diuresis in the proximal and distal tubule of the dog kidney. J Clin Invest. 1969;48(12):2330–2340. 96. Mathisen O, Raeder M, Kiil F. Mechanism of osmotic diuresis. Kidney Int. 1981;19(3):431–437. 97. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797–805. 98. Felker GM, O’Connor CM, Braunwald E. Loop diuretics in acute decompensated heart failure: necessary? Evil? A necessary evil? Circ Heart Fail. 2009;2(1):56–62. 99. Maronde RF, Milgrom M, Vlachakis ND, et al. Response of thiazide-induced hypokalemia to amiloride. JAMA. 1983;249(2): 237–241. 100. Rudy DW, Voelker JR, Greene PK, et al. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med. 1991;115(5):360–366. 101. Dossetor JB. Creatininemia versus uremia. The relative significance of blood urea nitrogen and serum creatinine concentrations in azotemia. Ann Intern Med. 1966;65(6):1287–1299.



102. Kuller LH, Hulley SB, Cohen JD, et al. Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis. Circulation. 1986;73(1):114–123. 103. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994;330(26):1852–1857. 104. Cohen JD, Neaton JD, Prineas RJ, et al. Diuretics, serum potassium and ventricular arrhythmias in the Multiple Risk Factor Intervention Trial. Am J Cardiol. 1987;60(7):548–554. 105. Nishina K, Mikawa K, Maekawa N, et al. Effects of exogenous intravenous glucose on plasma glucose and lipid homeostasis in anesthetized infants. Anesthesiology. 1995;83(2):258–263. 106. Sumpelmann R, Mader T, Dennhardt N, et al. A novel isotonic balanced electrolyte solution with 1% glucose for intraoperative fluid therapy in neonates: results of a prospective multicentre observational postauthorisation safety study (PASS). Paediatr Anaesth. 2011;21(11):1114–1118. 107. Sumpelmann R, Mader T, Eich C, et al. A novel isotonic-balanced electrolyte solution with 1% glucose for intraoperative fluid therapy

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in children: results of a prospective multicentre observational post-authorization safety study (PASS). Paediatr Anaesth. 2010;20(11): 977–981. 108. McNab S, Duke T, South M, et al. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet. 2015;385(9974):1190–1197. 109. Choong K, Arora S, Cheng J, et al. Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial. Pediatrics. 2011;128(5):857–866. 110. Sumpelmann R, Becke K, Crean P, et al. European consensus statement for intraoperative fluid therapy in children. Eur J Anaesthesiol. 2011;28(9):637–639. 111. Moritz ML, Ayus JC. Maintenance intravenous fluids in acutely ill patients. N Engl J Med. 2016;374(3):290–291. 112. Tamargo J, Lopez-Sendon J. Novel therapeutic targets for the treatment of heart failure. Nat Rev Drug Discov. 2011;10(7): 536–555.

43 

Blood and Coagulation JERROLD H. LEVY, ROMAN M. SNIECINSKI, AND IAN WELSBY

CHAPTER OUTLINE Normal Hemostatic Mechanisms Hypercoagulability Inherited Risk Factors Increased Procoagulant Effects Reduction of Natural Anticoagulant Factors Fibrinolysis Modulation Other Inherited Conditions Acquired Risk Factors Disease States Associated With Hypercoagulability Heparin-Induced Thrombocytopenia Hypocoagulability: Perioperative Bleeding Risk Factors for Bleeding Patient-Related Causes of Bleeding Common Inherited Hemostatic Disorders Physician-Related Factors Procedure-Related Factors Pharmacologic Factors Disorders of Hemostasis: Disseminated Intravascular Coagulation Thrombocytopenia Coagulopathy Fibrinogen Consumption Reductions in Coagulation Inhibitors Fibrinolysis Indicators Hemostatic Testing Point-of-Care Coagulation Testing Transfusion Algorithms and Massive Transfusion Blood Conservation

H

emostasis is a critical homeostatic mechanism of survival that involves vascular, cellular, and plasma components that interact to stop bleeding.1,2 Vascular effects include vasoconstriction, expression of procoagulant factors such as tissue factor, and loss of normal anticoagulant functions of the endothelium.2,3 Coagulation and clot formation occur by cellular and humoral factors that interact together with local and systemic factors. Surgery produces complex alterations and defects in hemostatic mechanisms, particularly in trauma, cardiac surgery with or without cardiopulmonary bypass, major orthopedic surgery, and neurosurgery. In many patients, multiple quantitative and qualitative hemostatic abnormalities develop as part of surgery, tissue injury, and complex underlying medical conditions.

Additionally, the increasing use of multiple anticoagulation agents to treat cardiovascular disease contributes to preexisting perioperative hemostatic defects and increases the potential for bleeding. Furthermore, massive bleeding can produce an acquired hemostatic defect called massive transfusion coagulopathy that is characterized by tissue injury, dilutional hemostatic changes, hypothermia, acidosis, and multiorgan dysfunction.2 Managing hemostatic dysfunction and bleeding perioperatively requires an understanding of underlying hemostatic mechanisms. Tissue injury and the stress response activate fibrinolysis that can further contribute to coagulopathy and bleeding.3 This chapter reviews the basis of normal hemostasis, the procoagulant and anticoagulant changes that occur in surgical patients, as well as perioperative coagulation testing and treatment of bleeding.

Normal Hemostatic Mechanisms Complex interactions among coagulation proteins, platelets, and the vascular endothelium maintain normal hemostasis (Fig. 43.1). The vascular endothelium plays a major role in preventing clotting; it presents an important anticoagulation interface with circulating blood. Multiple substances are released to prevent activation of both cellular and humoral components of hemostasis. Understanding hemostasis, perioperative bleeding, and treatment of coagulopathy in the current era requires knowledge of the multiple interactions that occur between molecular and cellular components of the coagulation cascade. Hemostasis, which means the “halting of blood,” protects the individual from massive bleeding secondary to minor trauma. In pathologic states, however, thrombosis can occlude the microvasculature, leading to organ ischemia. Hemostasis is therefore highly regulated by a number of factors, including (1) vascular extracellular matrix and alterations in endothelial reactivity, (2) platelets, (3) coagulation proteins, (4) inhibitors of coagulation, and (5) fibrinolysis. These involve tissue factor release, generation of factor VIIa, platelet activation, and multiple cellular and humoral amplification pathways.2–6 Prostacyclin, tissue plasminogen activator (tPA), heparan sulfate, antithrombin III, protein C, and endothelium-derived relaxing factor are normally expressed or secreted to inhibit platelet activation, fibrin formation, and to provide vascular patency.1,2 However, if a blood vessel is cut or damaged, tissue factor and other promoters of coagulation are released or exposed to provide a thrombotic surface. Exposure of subendothelial vascular basement membrane activates platelets, and expression of tissue factor also activates thrombin generation and signals other inflammatory pathways. Platelet activation is an important mechanism for initiation of the coagulation cascade. Receptors on platelets bind to the damaged 837

CHAPTER 43  Blood and Coagulation 837.e1



Abstract

Keywords

Hemostasis is a critical homeostatic mechanism of survival that involves vascular, cellular, and plasma components that interact to stop bleeding. Vascular effects include vasoconstriction, expression of procoagulant factors such as tissue factor, and loss of normal anticoagulant functions of the endothelium. Coagulation and clot formation occur by cellular and humoral factors that interact together with local and systemic factors. Surgery produces complex alterations and defects in hemostatic mechanisms, particularly in trauma, cardiac surgery with or without cardiopulmonary bypass, major orthopedic surgery, and neurosurgery. In many patients, multiple quantitative and qualitative hemostatic abnormalities develop as part of surgery, tissue injury, and complex underlying medical conditions. Additionally, the increasing use of multiple anticoagulation agents to treat cardiovascular disease contributes to preexisting perioperative hemostatic defects and increases the potential for bleeding. Furthermore, massive bleeding can produce an acquired hemostatic defect called massive transfusion coagulopathy that is characterized by tissue injury, dilutional hemostatic changes, hypothermia, acidosis, and multiorgan dysfunction.

bleeding blood conservation coagulation testing coagulopathy disseminated intravascular coagulation hemostasis hypercoagulability

838

SE C T I O N VIII

Blood and Hemostasis

PLT PLT

Platelet activation

PLT

AT APC

Thrombin

TFPI

Va

Fibrin production

Plasmin PLT

Fibrinolysis VIIa + TF

PLT

vW F

PLT

vW F

vW F

PLT

tPA

than separate clinical entities.8-10 In the perioperative environment, clinicians are usually aware and concerned about the risk of bleeding; however, hypercoagulability is also a potential cause of postoperative adverse outcomes that is often overlooked.6,11,12 Risk factors for hypercoagulability can be inherited or acquired, and are caused by either increasing procoagulant activity and/or decreasing anticoagulant or fibrinolytic activity.6,13 About 80% of patients with venous thromboembolism (VTE) have at least one underlying risk factor.14 Because of this increased risk, hypercoagulable patients often receive prophylactic anticoagulation therapy.15,16

Inherited Risk Factors Endothelium

• Fig. 43.1

  Schematic summary of procoagulant and anticoagulant processes. Initial plug formation begins with von Willebrand factor (vWF) binding to collagen at the site of injury, which acts as a bridge for platelets to adhere. At the same time, exposed tissue factor (TF) at the site of injury binds with small amounts of circulating activated factor VII (FVIIa) to produce thrombin via the tissue factor (extrinsic) pathway. Thrombin activates a positive feedback loop by producing more of itself, cleaves fibrinogen to insoluble fibrin, and activates platelets that release more procoagulant and inflammatory factors. The process is kept in check by anticoagulant forces. Away from the site of injury, antithrombin (AT) inhibits thrombin. Additionally, activated protein C (APC) destroys factor V (Va— needed for the tissue factor pathway), and tissue factor pathway inhibitor (TFPI) destroys TF-FVIIa complexes. The endothelium releases tissue plasminogen activator (tPA) that cleaves plasminogen into plasmin to initiate fibrinolysis. PLT, Platelet.

blood vessel by forming a bridge with von Willebrand factor (vWF) to initiate platelet adhesion. Once platelets adhere, they undergo surface receptor changes that cause platelets to aggregate. Once platelets aggregate, they expose factors on their surface that provides a substrate for activation of the coagulation cascade and formation of the early hemostatic plug. Platelets play vital roles in maintaining vascular hemostasis. Any abnormality in platelet number or function poses a significant risk for perioperative coagulopathy.

Hypercoagulability Normal hemostasis is a balance between procoagulant and anticoagulant mechanisms. The coagulation system ensures that bleeding does not continue indefinitely after vascular injury. This is balanced by thromboresistant forces involving anticoagulant proteins to control clot formation and fibrinolytic proteins to remove clot once vascular injury has been repaired. A proper balance between these systems must be maintained to ensure the fluid nature of blood, yet be readily activated when pathologic activation occurs.6 In surgical patients, especially postoperatively, there is potential for a hypercoagulable state. Hypercoagulability, also known as thrombophilia or a prothrombotic state, is a condition in which blood clots more readily than normal. It results from a shift of the normal equilibrium of procoagulant and anticoagulant forces in favor of coagulation.6,7 Although arterial and venous thrombi were once thought to represent distinct problems, patients with hypercoagulability can be at risk for both, and it has been suggested that hypercoagulability represents a spectrum of disease rather

Most patients with inherited risk factors for hypercoagulability are at risk to develop venous thromboembolic events early in life.17 One of the most common risk factors is inherited antithrombin deficiency.7 Other conditions, for example, the prothrombin G20210A mutation, are continually being discovered.2,7,18 Inherited risk factors can enhance procoagulant effects, reduce natural anticoagulation, impair fibrinolysis, or have other potential effects.7 Fig. 43.2 presents an overview of the interaction of coagulation and fibrinolytic pathways and illustrates how different inherited risk factors modify hemostasis.

Increased Procoagulant Effects The most common inherited risk factors for VTE are factor V (FV) Leiden, present in approximately 5% of the population, and the prothrombin G20210A mutation, present in approximately 2% of Caucasians.19,20 In the FV Leiden mutation, an amino acid replacement modifies activated procoagulant FV so that it is no longer inactivated or inhibited by activated protein C. In patients with FV Leiden, thrombotic risk is increased approximately 3-fold in heterozygotes, 18-fold in homozygotes, and 9-fold overall compared with individuals without the mutation.6 Patients heterozygous for the prothrombin G20210A mutation have higher plasma levels of prothrombin, the precursor for thrombin, and an approximately threefold greater risk for VTE; homozygous individuals for the G20210A mutation are rare.6,21,22 Whether FV Leiden and prothrombin G20210A carriers have increased risk for arterial thrombosis is less clear.23 Other common procoagulant effects include fibrinogen abnormalities caused by increased levels or structural variants that are either more or less susceptible to clot formation, known as dysfibrinogenemia. Fibrinogen is an increasingly important target for therapeutic interventions in bleeding and coagulopathy. Similarly, patients with the highest plasma fibrinogen concentration have an approximately twofold increased risk for arterial thrombosis, and stroke patients with fibrinogen levels of 450 mg/dL or greater have poorer functional outcomes.24,25 Hyperfibrinogenemia also increases the risk for VTE.26,27 Dysfibrinogenemias can also cause hypercoagulability if the resulting fibrin molecules fail to inhibit thrombin or are less susceptible to cleavage by plasmin.28,29 Elevated coagulation factor levels, including vWF and FVIII, can occur in patients with unexplained VTE, and increased FVIII levels are a risk factor for arterial vascular events.30–32

Reduction of Natural Anticoagulant Factors Two important circulating anticoagulants are protein C and protein S. These are vitamin K–dependent proteins that inhibit the activated

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Hyperhomocysteinemia

Reduced anticoagulant levels • Protein C • Protein S • Antithrombin • TFPI

Tissue injury

Contact activation

TF + VIIa

XII + Kallikrein

Enhanced procoagulant levels • Fibrinogen • Factor VIII • von Willebrand factor • Factor XI

TFPI Xa Protein C + Protein S

Factor V Leiden Thrombomodulin

Plasminogen activator inhibitor

Prothrombin G20210A mutation

Antithrombin

V

IIa (thrombin)

Platelet activation

XIII Increased levels

Increased prothrombin levels

VIII

Fibrin formation

PAI-1 4G/5G polymorphism

839

Increased aggregation

Clot

Platelet glycoprotein polymorphisms

Fibrinolysis High levels lipoprotein(a)

Plasminogen activator Plasminogen

α2-antiplasmin Plasmin

• Fig. 43.2  Inherited risk factors for hypercoagulability. Procoagulant forces (red) and natural anticoagulant/fibrinolytic forces (blue) are shown. Dashed lines indicated an inhibitory effect. Inherited risk factors are presented in diamond shapes with lettering and arrows indicating the mechanism for the hypercoagulable effect. “X” denotes a specific block in a pathway. See text for full details. PAI, Plasminogen activator inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor. (Modified with permission from Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg. 2010;112:46–58.) procoagulant FV and FVIII.6 Inherited qualitative or quantitative deficiencies of protein C and protein S increase the risk for VTE by 5- to 10-fold.33 Importantly, large loading doses of the vitamin K antagonist warfarin, without concomitant heparin therapy, can result in a transient procoagulant state by depleting proteins C and S. This most commonly manifests as microthrombi within cutaneous vessels, a condition known as “warfarin skin necrosis.” Antithrombin (formerly called antithrombin III) is a serine protease inhibitor that avidly binds to thrombin; this interaction is facilitated by heparin and, along with its inhibition of FXa, the primary mechanism for heparin’s anticoagulant action. Heparin and related glycosaminoglycans are normally present on endothelial surfaces or administered therapeutically. Heterozygous antithrombin deficiency is associated with approximately 50% of normal levels, whereas homozygous antithrombin deficiency is likely always fatal in the newborn or in utero, and is exceedingly rare.34 Acquired antithrombin deficiency can also occur after prolonged heparin administration, or in patients with sepsis or disseminated intravascular coagulation (DIC).35 Patients with antithrombin deficiency are at an increased risk for thrombotic events. 36 Whether

antithrombin should be replaced in prolonged cardiopulmonary bypass operations remains an area of active investigation.

Fibrinolysis Modulation Fibrinolysis regulates the extent of clot formation and vascular patency as part of hemostatic regulation. After tissue and vascular injury, multiple hemostatic mechanisms are initiated to modulate fibrinolysis. An important circulating serine protease inhibitor that regulates fibrinolysis is plasminogen activator inhibitor-1 (PAI-1) and a specific polymorphism (4G/5G) correlates with higher plasma levels.37 The 4G allele is associated with an increased risk of VTE but only when combined with another genetic risk factor for thromboembolic complications.38 Abnormalities in tPA, another important regulator of fibrinolysis, are associated with a twofold to threefold increased risk of myocardial infarction and thrombotic stroke.6 Inherited deficiencies of plasminogen and polymorphisms affecting plasma levels of thrombin-activatable fibrinolysis inhibitor are reported, but their associations with thrombotic risk remain unclear.6

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disease despite their relative platelet dysfunction, although some reports suggest reduced cardiovascular risk.11,39

Other Inherited Conditions Increased levels of homocysteine are thought to produce endothelial dysfunction and could have variable effects on arterial or venous thrombosis and potentially other vascular ischemic events.6 Hyperhomocystinemia can also be acquired in individuals with folic acid deficiency, and folate therapy was once thought to reduce ischemic cardiovascular disease. Other important polymorphisms exist for regulatory glycoproteins on platelets. Lack of the glycoprotein Ib/IX complex or vWF receptor results in Bernard-Soulier disease. Common deficiencies include abnormalities of the IIb/ IIIa receptor that binds fibrinogen and allows platelet cross-linking, known as Glanzmann thrombasthenia. Patients with these platelet glycoprotein genetic variants can still have ischemic cardiovascular

Acquired Risk Factors Acquired risk factors are usually transient, yet can confer higher thrombotic risk than genetic disorders. Like inherited factors, some acquired conditions enhance procoagulant effects (e.g., heparininduced thrombocytopenia), whereas others decrease levels of natural anticoagulants (e.g., antiphospholipid antibodies). However, most acquired risk factors are multifactorial and have mechanisms that remain to be fully characterized. We have grouped the acquired risk factors into three broad categories: disease states, patient-related causes, and pharmacologic causes (Fig. 43.3).

• Surgery • Trauma • Inflammation

Increased TF expression Bovine thrombin

Tissue injury

Contact activation

TF + VIIa

XII + Kallikrein

TFPI

rFVIIa Xa

Antiphospholipid antibodies Protein C + Protein S

CPB

VIII Antithrombin

V

Down-regulation Thrombomodulin Decreased levels of protein C and/or S • Warfarin therapy • Estrogen therapy • Liver disease • Nephrotic syndrome • Acute thrombosis

DIC

XIII High levels

DDAVP Platelet activation

Clot

Plasminogen activator inhibitor

Heparin therapy

Increased VIII release

IIa (thrombin)

Fibrin formation

↓ Levels

HIT

Increased vWF release

Fibrinolysis α2-antiplasmin

Plasminogen activator Liver disease

↓ Levels

Plasminogen

Plasmin

Lysine analogs

Noncompetitive inhibition

• Fig. 43.3

  Acquired risk factors for hypercoagulability. Procoagulant forces (red) and natural anticoagulant/fibrinolytic forces (blue) are diagrammed. Dashed lines indicate an inhibitory effect. Acquired risk factors are presented in diamond shapes with lettering and arrows indicating the mechanism for the hypercoagulable effect. “X” denotes a specific block in a pathway. Note that some acquired risk factors have multiple effects; see text for full details. CPB, Cardiopulmonary bypass; DDAVP, desmopressin; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; rFVIIa, recombinant factor VIIa; TF, tissue factor; TFPI, tissue factor pathway inhibitor. (Modified with permission from Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg. 2010;112:46–58.)



Disease States Associated With Hypercoagulability Antiphospholipid antibodies, including lupus anticoagulants, anticardiolipin antibody, and anti–β2-glycoprotein 1 antibody are associated with increased risk of thrombosis.6 Patients with lupus anticoagulants are actually hypercoagulable despite increased prothrombin times, and have increased risk for both arterial and venous thrombosis and miscarriage.6 Multiple mechanisms are responsible for increased thrombotic risk with antiphospholipid antibodies and are thought to be due to decreased thrombomodulin expression, increased tissue factor expression, and impairment of the protein C anticoagulant pathway.40 Patients with thrombosis (arterial or venous) or repeated pregnancy loss plus antiphospholipid antibody detected on at least two occasions at least 12 weeks apart meet diagnostic criteria for antiphospholipid syndrome.41 Patients with known antiphospholipid antibodies are at risk for recurrent thrombotic events and require ongoing anticoagulation, usually with warfarin.6 Other important factors that contribute to hypercoagulability include renal and hepatic dysfunction, although these are commonly considered risks for bleeding. Severe hepatic dysfunction and cirrhosis lead to decreased synthetic capabilities and decreased levels of anticoagulant factors, including antithrombin, protein C, protein S, and plasminogen.6 Endothelial dysfunction, especially with renal failure and often pulmonary and portal vascular dysfunction, also occur. This, in turn, increases platelet activation and is an important cause of hypercoagulability.6 In nephrotic syndrome, fibrinogen levels are increased and antithrombin levels are low, increasing the potential for thrombosis.6 Another important clinical setting is blood stasis, which commonly occurs with postoperative immobility or low cardiac output associated with heart failure—important risk factors for hypercoagulability. Although a low-flow state is a component of the Virchow triad, it alone does not create thrombosis. The importance of the other two Virchow factors— vessel wall abnormalities and dysfunctional blood constituents—is now becoming clear at the molecular level.6 Metabolic syndrome characterized by abdominal obesity, hypertension, elevated glucose, and increased cholesterol levels is associated with endothelial dysfunction and increased platelet aggregation.42 Cancer can have multiple causes for hypercoagulability, including cells that release microparticles to promote fibrin deposition.43 Advanced age is associated with procoagulant changes, including vascular dysfunction, increased fibrinogen levels, increased FVII, impaired fibrinolytic activity, and increased platelet aggregation.6 Many of these factors can be additive with complex interactions that are not well understood. Routine VTE prophylaxis is therefore an important part of perioperative management. Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) is an important antibody-mediated prothrombotic complication of heparin therapy that occurs in 0.5% to 5% of patients treated with heparin for at least 5 days (see Chapter 45).16,44 HIT is characterized by an otherwise unexplained drop in platelet count by 50% or more, often to less than 150,000/µL and frequently accompanied by thrombosis, plus the presence of HIT antibodies.44 When HIT is suspected, heparin, including low-molecular-weight heparin treatment, should be discontinued, and alternative anticoagulation therapy initiated even before laboratory confirmation.16,44 HIT is mediated by antibodies to a complex of heparin and platelet factor 4 (PF4). Antibodies recognize antigenic sites newly exposed on PF4 when it is conformationally modified by binding

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to heparin. Platelets are activated by the Fc domain of the immunoglobulin G (IgG) in the heparin-PF4 immune complexes, and release microparticles that promote thrombin formation and thrombosis. Thrombocytopenia, excessive thrombin generation, and a prothrombotic state ensue. Antibody-mediated endothelial injury and tissue factor production further increase the prothrombotic state.44 Up to 7% to 50% of heparin-treated patients generate heparinPF4 antibodies, especially after cardiovascular surgery. HIT antibodies circulate with a median half-life of approximately 90 days. The presence and level of HIT antibodies, regardless of thrombocytopenia, are associated with increased morbidity or mortality in various clinical settings. Clinical HIT occurs in 1% to 5% of patients administered unfractionated heparin and less than 1% of patients administered low-molecular-weight heparin. Cardiac transplant and neurosurgery patients (11% and 15%, respectively), as well as orthopedic patients, are at increased risk of HIT.44 HIT increases the risk of thrombosis, including deep VTE, pulmonary embolism, myocardial infarction, stroke, and limb artery occlusion requiring amputation. The overall risk for thrombosis in patients with HIT is 38% to 76%. Other risk factors for HITrelated thrombosis include female gender, malignancy, higher-titer heparin-PF4 antibodies, and more severe thrombocytopenia. Other complications include skin lesions at heparin injection sites, DIC, warfarin-associated venous limb ischemia, and acute systemic reactions after heparin bolus. Although counterintuitive, bleeding is rare even in the presence of severe thrombocytopenia.44 HIT should be suspected whenever the platelet count drops by 50%, or new thrombosis occurs in a patient 5 to 14 days after the start of heparin therapy. Other causes of thrombocytopenia (e.g., sepsis, mechanical destruction with an intraaortic balloon pump or with extracorporeal circulation, or another drug-induced thrombocytopenia) should be excluded. In “rapid-onset” HIT, the platelet count begins to drop minutes to hours after heparin exposure, usually owing to heparin-PF4 antibodies from a previous heparin exposure within the prior 3 months. HIT should also be suspected if acute systemic reactions, such as hypotension, pulmonary hypertension, and/or tachycardia, occur 2 to 30 minutes after intravenous heparin bolus. This can be observed intraoperatively and can present as anaphylaxis, usually accompanied by acute thrombocytopenia.16,44,45 HIT can also occur days to weeks after stopping heparin (“delayed-onset HIT”), and should be considered if a recently hospitalized, heparin-treated patient presents with thrombosis.44 For suspected HIT, laboratory testing for heparin-PF4 antibody is recommended. Because of the high thrombotic risk early in HIT, treatment should not be withheld while awaiting laboratory results.44 The recommended treatment for strongly suspected or confirmed HIT, with or without complicating thrombosis, is stopping heparin and initiating a nonheparin alternative anticoagulant. The mainstay agents include intravenous administration of a direct thrombin inhibitor, either argatroban or bivalirudin.46 Other heparin sources such as catheter flushes and heparin-coated devices should be eliminated. Different direct thrombin inhibitors are approved in the United States for use in HIT patients without initial thrombosis (argatroban), in HIT patients with thrombosis (argatroban), and in patients with or at risk of HIT undergoing percutaneous coronary intervention (argatroban, bivalirudin). Previously used agents that were derivatives of the leech protein hirudin are no longer available (desirudin, lepirudin). The more recently approved direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) provide potential alternatives for venous thromboembolic prophylaxis in

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patients but not as immediate therapies for HIT therapy. Recent evidence-based guidelines from the American College of Chest Physicians for the use of these alternative anticoagulants in patients with HIT in noninterventional and interventional settings have been reported.16 Alternative nonheparin anticoagulant strategies are required in HIT patients who need intraoperative anticoagulation. If heparin use is unavoidable or planned, the heparin exposure should be limited to the surgery itself, with alternative anticoagulation used preoperatively and postoperatively. If cardiac surgery is required, prospective studies have evaluated bivalirudin as the most investigated and useful alternative, although plasmapheresis has also been reported.16

Hypocoagulability: Perioperative Bleeding Bleeding in surgical patients is a common and multifactorial problem. Surgery-induced tissue injury with both large vessel bleeding and microvascular bleeding can occur. Patients often have acquired defects that can be complicated by the surgical insult, or coagulation abnormalities that occur owing to antiplatelet or anticoagulant drug use or massive blood loss. Major coagulation abnormalities occur perioperatively and are influenced by multiple factors, including type of surgery, cardiopulmonary bypass, and preexisting abnormalities. Coagulopathic states and risk factors predisposing to surgical bleeding are listed in Tables 43.1 and 43.2. Patients with atherosclerotic cardiovascular disease often receive anticoagulation and/or antiplatelet therapies that interfere with hemostasis (see Chapter 45).47-50 Patients can also receive prophylactic anticoagulation therapy for atrial fibrillation, VTE prophylaxis, or prosthetic cardiac valves. Surgical patients have acquired changes in hemostasis that contribute to postoperative bleeding, including activation of coagulation, fibrinolytic, and inflammatory pathways.46,47,51–53 Trauma and obstetric patients can also develop massive hemorrhage.4,53,54 Therapies that prevent clot from forming in TABLE Coagulopathic States Associated With 43.1  Increased Risk for Bleeding Hemophilia Inherited platelet disorders von Willebrand disease Liver failure Renal failure (uremia) Disseminated intravascular coagulation Dilutional coagulopathy Anticoagulant and antiplatelet therapy Other coagulation disorders (factor deficiencies)

TABLE 43.2  Risk Factors for Bleeding in Surgical Patients Advanced age Small body size or preoperative anemia (low red cell volume) Antiplatelet or antithrombotic drugs Preexisting coagulopathy Prolonged operation including prolonged cardiopulmonary bypass time Emergency operation Comorbidities: heart failure, chronic obstructive pulmonary disease, hypertension, peripheral vascular disease, renal failure, liver failure

pathologic states also interfere with normal hemostasis, an important mechanism protecting patients from exsanguination during surgery.

Risk Factors for Bleeding Perioperative bleeding with increased transfusion requirements is caused by patient-related, procedure-related, and process-related factors.55 However, most studies do not distinguish between red blood cell (RBC) and hemostatic factor transfusion. Important indicators of high risk for bleeding and transfusion requirements include (1) advanced age, (2) low preoperative RBC volume (preoperative anemia or small body size), (3) preoperative antiplatelet or antithrombotic treatment, (4) reoperation or complex procedures, (5) emergency operations, and (6) noncardiac patient comorbidities (see Table 43.2).55

Patient-Related Causes of Bleeding Risk for bleeding is increased by acquired or congenital coagulopathies, including hemophilia, complex procedures (e.g., multilevel spine surgery, combined valve/coronary revascularization, aortic dissection, and major aortic surgery), repeat cardiac and orthopedic procedures, and sepsis with thrombocytopenia. Certain patients have an accentuated response to antiplatelet drugs. Thrombocytopenia from whatever cause (defined as platelet count 65% aggregation in response to the platelet activators adenosine diphosphate, epinephrine, collagen, ristocetin, and arachidonic acid.

Overview Platelet aggregation studies are used to classify qualitative platelet abnormalities. Abnormalities can be in adhesion, release, or aggregation.

Method Platelet aggregation is stimulated by introducing activators in vitro. Aggregation is measured using a turbidimeter and expressed graphically by wave patterns.

Important Notes Platelet aggregation studies are rarely useful in evaluating acquired bleeding disorders.

These systems measure multiple aspects of the clotting process, including hemostatic factor and platelet interactions, fibrin formation, clot retraction, and fibrinolysis. The tests are routinely evaluated in whole blood, allowing potential evaluation of platelet function, although fibrinogen highly influences these tests. This type of hemostatic testing is increasingly used in managing patients after trauma and massive hemorrhage or other major surgery. When viscoelastic testing is normal, surgical bleeding should be considered; however, these tests can also be used to guide transfusion of procoagulant therapies.

Transfusion Algorithms and Massive Transfusion Most studies demonstrate that transfusion algorithms based on coagulation testing reduce the need for platelets, fresh frozen plasma, or cryoprecipitate. Indeed, any test that prevents empirical administration likely will reduce transfusions. Most transfusion algorithms suggest transfusion when bleeding is accompanied by a PT or aPTT greater than 1.5 times the normal value, thrombocytopenia with a platelet count less than 50,000 to 100,000/µL, or fibrinogen concentration less than 100 mg/dL (or 1 g/L). Because most

845

laboratory testing is slow, POC viscoelastic testing has become the focus of most transfusion algorithms.72 Prospective algorithms using platelet function data have also been reported. However, platelet function testing is problematic in that most tests need a relatively higher number of platelets to work and it is unclear whether they are applicable to the platelet dysfunction encountered after cardiopulmonary bypass. Battlefield trauma can cause massive bleeding, and extensive information on massive transfusion has come from experience in the Iraq War. Massive transfusion is commonly defined as 10 or more units of RBC transfusions in a 24-hour period, but use of 4 or more red cell units within 1 hour when the ongoing need is foreseeable; or replacing 50% of the total blood volume within 3 hours might also be appropriate in the acute clinical setting.73,74 Blood transfusion is the main therapeutic option for treating acute hemorrhage, and in trauma patients the ideal solution is fresh whole blood, although this is not widely available.6 With lifethreatening bleeding, multiple blood volumes may be transfused, leading to coagulopathy if sufficient factors are not replaced. The etiology of coagulopathy during massive transfusion is complex, involving dilution of factors, hypothermia, tissue hypoperfusion/ ischemia, acidosis, and potential DIC.75 Because coagulation test results are not often available, massive transfusion protocols often use fixed doses of component therapies that include fresh frozen plasma and platelets after transfusion of a defined number of RBCs, often in an attempt to mimic the transfusion of fresh whole blood. In addition to fixed ratios, antifibrinolytic agents are also considered if fibrinolysis is present and are an important consideration of multimodal therapy as demonstrated in surgical patients and trauma. The role of factor concentrates to manage bleeding is increasingly evolving in clinical algorithms.76–78

Blood Conservation Blood conservation is often discussed in many perioperative settings, but not actively practiced, in part because of the additional work involved. Pharmacologic management of hemostasis in patients undergoing surgery represents an important therapeutic approach in the management of complex surgical patients and for blood conservation. Because surgery represents a major consumer of blood products and because agents can be administered prophylactically, pharmacologic approaches are an important aspect of blood conservation. Unfortunately, many studies have reviewed issues related to RBC use and not hemostatic factor use. Of the major preoperative patient risk factors for transfusion, low RBC mass owing to small body size or from preoperative anemia is important. Additional important considerations for perioperative blood conservation are the preoperative treatment of anemia, especially for elective surgery. A low starting RBC volume, calculated by hematocrit multiplied by estimated blood volume, correlates with bleeding and the need for allogeneic RBC transfusion. Blood conservation guidelines should reduce hemodilution and conserve red cells. The judicious use of preoperative erythropoietin and supplemental iron can increase RBC mass, but this requires interventions weeks before surgery. Minimizing extracorporeal circuits with circuits that require reduced priming volumes may be useful in cardiopulmonary bypass. Additional strategies before surgical intervention include normovolemic hemodilution, salvage of RBCs from the operative field, and use of pharmacologic agents that reduce bleeding. In cardiac surgical patients, additional considerations include modified ultrafiltration.

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Multimodal interventions provide the best opportunity to reduce bleeding and the need for allogenic transfusion. An important aspect of preoperative risk evaluation is the management of preoperative therapies that interfere with normal hemostasis. Surgical patients are increasingly receiving both antiplatelet agents and anticoagulation for perioperative thromboprophylaxis and as therapy for ischemic cardiovascular disease (see Chapter 45). As a result, patients often present for surgery with an acquired hemostatic imbalance because of preexisting anticoagulation. These agents should be discontinued before surgery, including the thienopyridines, drugs that inhibit P2Y12 receptor binding. For drugs like clopidogrel, there is variability in patient response to their use; however, newer P2Y12 inhibitors such as prasugrel are more potent than clopidogrel and have a much lower incidence of resistance. Specific laboratory assays that include POC testing, such as VerifyNow (Accriva Diagnostics, San Diego, CA), might help identify patients who can safely undergo urgent operations. Managing blood resources with a multidisciplinary team of anesthesiologists, blood bankers, surgeons, and intensivists should be considered when developing blood conservation strategies.46 Patients with known coagulopathies or hereditary deficiencies should be optimized preoperatively as illustrated in Table 43.7. Most studies suggest that developing a transfusion algorithm that all team members agree with, and the use of laboratory and/or POC testing

TABLE Management of Patients With Hemophilia for 43.7  Elective Surgery Surgical procedures should be performed in coordination with a team experienced in the management of hemophilia. Procedures should take place in a center with adequate laboratory support for reliable monitoring of clotting factor levels. Preoperative assessment should include inhibitor screening. Surgery should be scheduled early in the week and early in the day for optimal laboratory and blood bank support, if needed. Availability of sufficient quantities of clotting factor concentrates should be ensured before undertaking major surgery. The dosage and duration of clotting factor concentrate coverage depends on the type of surgery performed. Modified from Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1–e47.

to guide transfusion decisions, are important aspects of blood conservation. Treatment of the coagulopathy includes volume replacement, normothermia, resolution of acid-base abnormalities, and blood component therapy. Because of fibrinolysis, antifibrinolytic drugs should be considered for dosing.

Key Points • Hemostasis is a complex process that involves interactions between vascular components with blood cellular and plasma components. • Coagulopathy in surgical patients can result from consumption/ loss of coagulation components, drug effects, surgical trauma, and preexisting hemostatic defects. • The growing use of anticoagulants and antiplatelet agents poses potential problems in the perioperative period. • Both congenital and acquired forms of hypercoagulability can occur in surgical patients. • Heparin-induced thrombocytopenia is a hypercoagulable state complicating anticoagulation therapy and is a major risk factor for adverse events. • Acquired hemostatic disorders related to anticoagulation agents are common perioperative considerations requiring factor therapy.

• Inherited bleeding disorders such as hemophilia and von Willebrand disease require specific perioperative management. • Disseminated intravascular coagulation is a severe consumptive hemostatic disorder that can occur in diverse settings. • The etiology of coagulopathy associated with massive transfusion is complex and involves dilution of factors, hypothermia, tissue hypoperfusion, acidosis, and possible disseminated intravascular coagulation. • Although transfusion therapies remain important, blood conservation has gained priority to minimize adverse effects. • Laboratory testing and objective algorithms are important approaches to reduce transfusion of banked blood products.

Key References

hematology, critical care, and surgery of hemostasis and management of the bleeding patient across different clinical settings, with a focus on perioperative considerations. This review focuses on advances in hemostasis research and the need for a multidisciplinary approach to improve patient care and develop management strategies. (Ref. 48). Levy JH, Spyropoulos AC, Samama CM, et al. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv. 2014;7:1333–1351. With the increasing use of new and older anticoagulation agents, this review describes clinical studies, pharmacokinetics, and pharmacodynamics of new anticoagulation agents and current management strategies for perioperative consideration of patients receiving them. (Ref. 69). Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e495S–530S. Management of HIT using evidence-based medicine. (Ref. 17).

Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007;100:158–173. Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007;100:174–190. A two-part review of endothelial cells, the vascular tree, properties of endothelium, and hemostatic interactions as described by a hematologist/vascular biologists who have made many contributions to this area. (Refs. 54 and 55). Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–965. An important description of a novel model to describe hemostatic function not using standard intrinsic and extrinsic coagulation pathways, but rather the complex cellular and protein interactions that more likely occur in vivo. (Ref. 1). Levy JH, Dutton RP, Hemphill JC 3rd, et al. Multidisciplinary approach to the challenge of hemostasis. Anesth Analg. 2010;110:354–364. A multidisciplinary review by experts in anesthesiology, blood banking,



Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg. 2010;112:46–58. A recent review of hemostatic interactions based on a multidisciplinary approach. This review describes common hypercoagulability issues and perioperative considerations. (Ref. 7).

References 1. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–965. 2. Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin regulation. Anesth Analg. 2009;108:657–670. 3. Levy JH, Koster A, Quinones QJ, et al. Antifibrinolytic therapy and perioperative considerations. Anesthesiology. 2018;128:657–670. 4. Ghadimi K, Levy JH, Welsby IJ. Perioperative management of the bleeding patient. Br J Anaesth. 2016;117(suppl 3):iii18–iii30. 5. Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009;108:1447–1452. 6. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381(9880):1845–1854. 7. Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg. 2010;112:46–58. 8. Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: basic pathophysiology. Crit Care Med. 2010;38:S3–S9. 9. Franchini M, Mannucci PM. Venous and arterial thrombosis: different sides of the same coin? Eur J Intern Med. 2008;19:476–481. 10. Lowe GD. Common risk factors for both arterial and venous thrombosis. Br J Haematol. 2008;140:488–495. 11. Lowe GD. Arterial disease and venous thrombosis: are they related, and if so, what should we do about it? J Thromb Haemost. 2006;4: 1882–1885. 12. Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation. 2008;118:2286–2297. 13. Kfoury E, Taher A, Saghieh S, et al. The impact of inherited thrombophilia on surgery: a factor to consider before transplantation? Mol Biol Rep. 2009;36:1041–1051. 14. Mannucci PM. Laboratory detection of inherited thrombophilia: a historical perspective. Semin Thromb Hemost. 2005;31:5–10. 15. Whitlatch NL, Ortel TL. Thrombophilias: when should we test and how does it help? Semin Respir Crit Care Med. 2008;29:25–39. 16. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2008;133:381S–453S. 17. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e495S–530S. 18. Parker RI. Thrombosis in the pediatric population. Crit Care Med. 2010;38:S71–S75. 19. Bezemer ID, Bare LA, Doggen CJ, et al. Gene variants associated with deep vein thrombosis. J Am Med Assoc. 2008;299:1306–1314. 20. De Stefano V, Chiusolo P, Paciaroni K, et al. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost. 1998;24: 367–379. 21. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79:706–708. 22. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703. 23. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009;102:360–370.

CHAPTER 43  Blood and Coagulation

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24. Ye Z, Liu EH, Higgins JP, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006;367:651–658. 25. Maresca G, Di Blasio A, Marchioli R, et al. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999;19:1368–1377. 26. del Zoppo GJ, Levy DE, Wasiewski WW, et al. Hyperfibrinogenemia and functional outcome from acute ischemic stroke. Stroke. 2009;40:1687–1691. 27. van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost. 2003;1:2677–2678. 28. Tsai AW, Cushman M, Rosamond WD, et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162:1182–1189. 29. Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol. 1997;4:357–365. 30. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost. 1999;25:311–319. 31. O’Donnell J, Tuddenham EG, Manning R, et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost. 1997;77:825–828. 32. O’Donnell J, Mumford AD, Manning RA, et al. Elevation of FVIII: c in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost. 2000;83:10–13. 33. Bank I, van de Poel MH, Coppens M, et al. Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:C. A prospective family cohort study. Thromb Haemost. 2007;98:1040–1044. 34. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost. 2009;7(suppl 1):301–304. 35. Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018;131:845–854. 36. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14:1229–1239. 37. Moll S. Thrombophilias–practical implications and testing caveats. J Thromb Thrombolysis. 2006;21:7–15. 38. Tsantes AE, Nikolopoulos GK, Bagos PG, et al. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res. 2008;122:736–742. 39. van der Bom JG, de Knijff P, Haverkate F, et al. Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation. 1997;95:2623–2627. 40. Franchini M, Veneri D, Salvagno GL, et al. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006;43:249–290. 41. Todorova M, Baleva M. Some recent insights into the prothrombogenic mechanisms of antiphospholipid antibodies. Curr Med Chem. 2007;14:811–826. 42. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306. 43. Franchini M, Targher G, Montagnana M, et al. The metabolic syndrome and the risk of arterial and venous thrombosis. Thromb Res. 2008;122:727–735. 44. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6:401–410. 45. Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg. 2007;105:570–582. 46. Levy JH, Adkinson NF Jr. Anaphylaxis during cardiac surgery: implications for clinicians. Anesth Analg. 2008;106:392–403. 47. Koster A, Faraoni D, Levy JH. Argatroban and bivalirudin for perioperative anticoagulation in cardiac surgery. Anesthesiology. 2018;128:390–400. 48. Levy JH, Dutton RP, Hemphill JC 3rd, et al. Multidisciplinary approach to the challenge of hemostasis. Anesth Analg. 2010;110:354–364.

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SE C T I O N VIII

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49. Steinhubl SR, Schneider DJ, Berger PB, et al. Determining the efficacy of antiplatelet therapies for the individual: lessons from clinical trials. J Thromb Thrombolysis. 2007;26:8–13. 50. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e120S–e151S. 51. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med. 2007;356:2301–2311. 52. Lawson JH, Murphy MP. Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol. 2004;41:55–64. 53. Achneck HE, Sileshi B, Lawson JH. Review of the biology of bleeding and clotting in the surgical patient. Vascular. 2008;16(suppl 1):S6–S13. 54. Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007;100:174–190. 55. Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007;100:158–173. 56. Faerraris VA, Ferraris SP, Saha SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83:S27–S86. 57. Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 2004;351:683–694. 58. Lison S, Dietrich W, Spannagl M. Unexpected bleeding in the operating room: the role of acquired von Willebrand disease. Anesth Analg. 2012;114:73–81. 59. Ott E, Mazer CD, Tudor IC, et al. Coronary artery bypass graft surgery—care globalization: the impact of national care on fatal and nonfatal outcome. J Thorac Cardiovasc Surg. 2007;133:1242– 1251. 60. Stover EP, Siegel LC, Parks R, et al. Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: a 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology. 1998;88:327–333. 61. Johnson RG, Thurer RL, Kruskall MS, et al. Comparison of two transfusion strategies after elective operations for myocardial revascularization. J Thorac Cardiovasc Surg. 1992;104:307–314. 62. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol. 2005;46:872–882. 63. Cheng DC, Bainbridge D, Martin JE, et al. Does off-pump coronary artery bypass reduce mortality, morbidity, and resource utilization when compared with conventional coronary artery bypass? A metaanalysis of randomized trials. Anesthesiology. 2005;102:188–203.

64. Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg. 2011;112:292–318. 65. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med. 2001;29:2271–2275. 66. Hongo RH, Ley J, Dick SE, et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol. 2002;40:231–237. 67. Ray JG, Deniz S, Olivieri A, et al. Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel. BMC Cardiovasc Disord. 2003;3:3. 68. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):2354– 2394. 69. Levy JH, Spyropoulos AC, Samama CM, et al. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv. 2014;7(12):1333–1351. 70. Squizzato A, Hunt BJ, Kinasewitz GT, et al. Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost. 2016;115(5):896–904. 71. Avidan MS, Alcock EL, Da Fonseca J, et al. Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery. Br J Anaesth. 2004;92:178–186. 72. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366–1375. 73. Steiner ME, Despotis GJ. Transfusion algorithms and how they apply to blood conservation: the high-risk cardiac surgical patient. Hematol Oncol Clin North Am. 2007;21:177–184. 74. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma. Crit Care. 2016;20:100. 75. Harris T, Davenport R. The evolving science of trauma resuscitation. 2018;Feb, PMID: 29132583. 76. Chang R, Cardenas JC, Wade CE, et al. Advances in the understanding of trauma-induced coagulopathy. Blood. 2016;128(8):1043–1049. 77. Levy JH, Ghadimi K, Quinones QJ, et al. Adjuncts to blood component therapies for the treatment of bleeding in the intensive care unit. Transfus Med Rev. 2017;31(4):258–263. 78. Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology. 2015;122(4):923–931.

44 

Transfusion and Coagulation Therapy KENICHI A. TANAKA AND DANIEL BOLLIGER

CHAPTER OUTLINE Hemoglobin and Volume Replacement Therapies Historical Aspects of Transfusion Packed Red Blood Cells Clinical Uses Side Effects Erythropoietin Side Effects Blood Substitutes Albumin Synthetic Colloids Hemostatic Interventions and Coagulation Therapies Platelet Concentrates Clinical Uses Side Effects Plasma Solvent-Detergent (S/D) Plasma Lyophilized Plasma Clinical Uses Side Effects Cryoprecipitate Clinical Uses Side Effects Fibrinogen Concentrate Clinical Use Side Effects Recombinant Factor VIIa Clinical Uses Side Effects Prothrombin Complex Concentrate Clinical Uses Side Effects Antithrombin Concentrate Protein C Concentrate Antifibrinolytic Agents Clinical Uses Side Effects Desmopressin Side Effects Topical Hemostatic Agents Special Considerations Liver Failure Jehovah’s Witnesses Emerging Developments

Hemoglobin and Volume Replacement Therapies Historical Aspects of Transfusion The observation by Harvey in 1628 that blood circulates in a closed vascular system was pivotal in the practice of blood transfusion.1 As blood was recognized as vital to sustain life, Denis in Paris and Lower in Oxford attempted xeno-transfusion (animal blood to humans) with little success in the 17th century. The first documented transfusion of human blood was made in 1818 by Blundell, an obstetrician in London, who recognized the need for transfusion in women suffering from postpartum hemorrhage. His results were not reproducible owing to the lack of knowledge of blood types and anticoagulants. Major advances were made in the beginning of 20th century when Landsteiner identified blood groups A, B, and C (later renamed group O). Transfusion of fresh whole blood was reported as a treatment for epistaxis due to thrombocytopenia in 1910. Storage and distribution of donated blood became possible after sodium citrate was developed as an anticoagulant during World War I. The infrastructure of the modern blood banking system was established by World War II; use of fresh whole blood transfusion saved many wounded soldiers. However, the risk of pathogen transmission, including hepatitis via blood transfusion, was recognized later. During World War II, Cohn and colleagues developed the cold ethanol method to separate albumin, γ-globulin, and fibrinogen from plasma, which became the basic principle for commercial plasma fractionation. Pooling of random donor plasma to manufacture factor (F) VIII concentrates without effective donor screening or virus inactivation steps in the late 1970s and early 1980s led to transfusion-related transmission of viruses, particularly human immunodeficiency virus (HIV) and hepatitis C to a large number of hemophiliac patients worldwide. Many precautions for bloodborne pathogens have been implemented, including vapor heat treatment and nanofiltration, since the mid-1980s; recombinant coagulation factors became available in the 1990s. The risk of infectious transmission also fueled efforts to develop synthetic oxygen carriers.2,3 Over the years, clinicians have recognized the importance and potential harms of blood component therapies, fostering the creation of patient blood management programs.4 Preoperative anemia management is a critical part of patient blood management; iron supplementation and/or erythropoietin therapy can be used in appropriate patient groups.5,6 Perioperative cessation of antithrombotic agents, intraoperative blood salvage, and antifibrinolytic therapy are also utilized to minimize the need for allogeneic blood 849

850

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TABLE Characteristics of Allogeneic 44.1  Blood Components

Normal artery

Volume

Shelf Life

Red blood cells

220–340 mL

42 days

1–6°C

Apheresis platelets

250–300 mL

5 days

20–24°C

50–70 mL

5 days

20–24°C

200–250 mL

1y

< −18°C

10–15 mL

1y

< −18°C

Plasma Cryoprecipitate

Normal vein 75 SO2 (%)

Component

Random donor platelets

100

Storage Temperature

Note: Plasma frozen within 8 hours is called FFP and plasma frozen between 8–24 hours of collection is called FP24.

50

25

0

transfusion along with point-of-care coagulation monitors.7 The rational and cost-effective uses of blood components are now the subject of published transfusion guidelines.7–12

Packed Red Blood Cells Circulating red blood cells (RBCs) are anuclear, hemoglobin-carrying cells of about 7 to 8 µm in diameter. The biconcave and discoid shape of RBCs confers advantages in increasing surface area for gas exchange and flexibility in passing through capillaries. On average, RBCs remain in the circulation for 120 days. Senescent or abnormal RBCs are eliminated by the spleen. The synthesis of RBCs (erythropoiesis) is regulated by erythropoietin, which is elevated in anemia and hypoxia. Erythropoiesis is also affected by the availability of iron, an integral component of hemoglobin. Packed RBCs (PRBCs) are prepared by separating most plasma components of donated whole blood by centrifugation. One unit of RBCs collected in anticoagulant-preservative solution is about 300 mL with a hematocrit of 50% to 70%. Dextrose is added to maintain glucose metabolism, and adenine and phosphate allow synthesis of adenosine triphosphate (ATP; Table 44.1). Additive solutions (adenine, glucose, mannitol, sodium chloride) are also used to extend shelf life up to 42 days.13 Depending on the storage solution, RBCs have a shelf life of 28 to 42 days at 1°C to 6°C. During storage, intracellular 2,3-diphosphoglycerate (DPG) is reduced to < 10% of normal at 5 weeks such that release of oxygen from hemoglobin is significantly impaired (Fig. 44.1). Nonetheless, no differences in morbidity and mortality were detected between short-term storage (6–11 days) and long-term storage (21–28 days) in prospective randomized studies in premature infants, adult cardiac surgical patients, and critically ill adult subjects.14–17

Clinical Uses Transfusion of RBCs is indicated to restore the oxygen-carrying capacity in patients with severe anemia or major blood loss. There is no absolute level of hemoglobin that indicates a threshold for transfusion (“transfusion trigger”); underlying clinical conditions and laboratory data for each patient should be considered. Acute anemia is less well tolerated compared to chronic anemia, in which peripheral oxygen delivery is compensated by elevated 2,3-DPG levels in RBCs and higher cardiac output (see Fig. 44.1). In patients with moderate to severe cardiovascular dysfunction, anemia might not be well tolerated. The extent and duration of clinical bleeding are also important criteria for transfusion in major trauma and

0

20 P50

40

60

80

100

PO2 (mm Hg) Normal dissociation curve

↓ pH ↑ 2,3-DPG ↑ temperature

• Fig. 44.1

  Oxygen-dissociation curve. The oxygen-dissociation curve of hemoglobin at normal pH is shown in blue. The dissociation of oxygen from hemoglobin can be increased (red) by acidosis, elevated 2,3-DPG (2,3-diphosphoglycerate), or higher temperature. Conversely, the curve can be shifted to the left by alkalosis, low 2,3-DPG, or hypothermia. The partial pressure of oxygen (PO2) when hemoglobin is 50% saturated (P50) is about 26.6 mm Hg.

surgery. According to the American Society of Anesthesiologists (ASA) guidelines for blood component therapy, transfusion of RBCs is almost always indicated for hemoglobin less than 6 g/dL, whereas it is rarely indicated for hemoglobin greater than 10 g/ dL. For hemoglobin between 6 g/dL and 10 g/dL, transfusion should be considered if complications due to inadequate oxygenation are anticipated.8 It remains controversial as to whether liberal or restrictive transfusion strategy is preferable in various surgical and medical settings.18 Restrictive transfusion (hemoglobin triggers < 7–8 g/dL) appears to increase mortality and ischemic events relative to a liberal strategy (triggers < 9–10 g/dL) in cardiovascular surgery patients19 and elderly orthopedic surgical patients.20 There was no difference in adverse event rates between liberal and restrictive strategies in nonsurgical critically ill patients.18 ABO and Rh blood group–specific packed RBCs should be administered whenever possible (Fig. 44.2). In the case of lifethreatening hemorrhage without time for formal cross-matching, either Rh-positive or Rh-negative group O RBCs can be transfused in principle. In Rh-negative women of childbearing age, Rh-negative group O RBCs should be preferred for reducing the risk of alloantibody (anti-D) development, which can cause anemia in an Rh-positive fetus. Transfusion of mismatched RBCs, typically related to ABO, can induce immunoglobulin M (IgM) antibody–mediated acute hemolysis, but in less serious mismatches of minor antigens such as Rh, Kell, and Duffy, survival of transfused RBCs is shortened.

Side Effects Acute hemolytic transfusion reactions are usually caused by ABO incompatibility. This potentially fatal complication occurs in about

CHAPTER 44  Transfusion and Coagulation Therapy



RBC compatibility

Plasma compatibility

O

AB

A

B

Y

Y

YA Y

YB Y Y

Y

Y

AB

Y

O Y

Y

• Fig. 44.2

  ABO compatibility. For RBC transfusion, the recipient can receive the same blood type or blood group(s) specified by the arrow(s). Blood group O recipients can be transfused only with group O blood whereas group AB recipient can be transfused with O, A, B, or AB group RBCs. Rh-positive or Rh-negative RBCs can be transfused in an Rhpositive recipient, and Rh-negative RBCs should be given to an Rhnegative recipient. For plasma product transfusion, the recipient can receive the same plasma type or plasma group(s) specified by the arrow(s). Blood group AB recipients can be transfused only with group AB plasma whereas type O recipients can be transfused with O, A, B, or AB group plasma. Rh types are not considered for plasma product transfusion. Orange arrow, anti-B antibody; green arrow=anti-A antibody.

1 in 30,000 transfusions. As little as 20 to 30 mL of incompatible RBCs can cause agitation, nausea/vomiting, dyspnea, fever, flushing, hypotension, tachycardia, and hemoglobinuria. Two major complications of intravascular hemolysis include renal failure from acute tubular necrosis and disseminated intravascular coagulation (DIC). Febrile nonhemolytic transfusion reaction is relatively common (0.1–1% of RBC transfusions). Other immunologic complications of transfusion include human leukocyte antigen (HLA) alloimmunization, graft-versus-host disease, and immunosuppression triggered by donor leukocytes.21 The risk of these complications can be partially reduced by use of leukocyte adsorption (leukoreduction) filters at blood collection and γ-irradiation after collection to prevent lymphocyte proliferation. The leukoreduction process presumably reduces virologic risks associated with leukocytes, including cytomegalovirus, Epstein-Barr virus, and human T-cell leukemia virus I and II. Transmission of emerging virus (e.g., Zika) through transfusion is possible; thus, careful donor screening and implementation of available pathogen reduction techniques are recommended.22 Although transfusion-related variant CreutzfeldtJakob diseases (vCJDs) and bovine spongiform encephalopathy (BSE) are rare, there is a theoretical advantage in leukodepletion to prevent prion transmission.23

Erythropoietin Erythropoietin is a hormone produced in the kidney in response to hypoxemia, such as in chronic pulmonary disease and at high altitudes. Recombinant human erythropoietin products are available for intravenous (IV) or subcutaneous (SC) injection. The primary indication for recombinant erythropoietin is anemia associated with chronic renal insufficiency. Other indications for erythropoietin include treatment of anemia related to the antiviral zidovudine in HIV-infected patients and treatment of chemotherapy-induced anemia in patients with metastatic, nonmyeloid malignancies.

851

Preoperative erythropoietin treatment of anemia has been shown to reduce allogeneic RBC transfusion,24 but its high cost hinders easy access for perioperative anemic patients. There are a variety of perioperative dosing regimens in conjunction with iron supplementation.24 One example is a weekly dose of 600 units/kg SC started 3 weeks before surgery and the 4th dose given on the day of surgery. A single dose of 80,000 IU SC dose 2 days before cardiovascular surgery reduced the overall transfusion rate from 39% to 17% in a prospective randomized placebo-controlled study involving 600 patients.25

Side Effects Erythropoietin therapy induces a marked expansion of erythroid cells, which can result in iron deficiency; thus, iron should be supplemented as appropriate. Target hemoglobin levels should not be set above 13 g/dL because the risk for cardiovascular events and stroke is increased. Hypertension can be worsened by erythropoietin, especially in patients with chronic renal failure. Erythropoietin therapy can adversely affect the survival of cancer patients, with progression or recurrence of certain tumors.

Blood Substitutes The limited availability of blood and infection risks are the driving forces in developing oxygen-carrying blood substitutes. Two major classes of substitutes are hemoglobin-based oxygen carriers (HBOC) and perfluorocarbon (PFC) emulsions. Bovine-derived hemoglobin glutamer-200 (Oxyglobin, Biopure, Cambridge, MA) is currently approved for canine anemia in the United States. In South Africa, bovine hemoglobin glutamer-250 (Hemopure, Biopure, Cambridge, MA) is approved for treatment of human anemia. Free hemoglobin solutions have a higher affinity for oxygen compared to RBCs (P50 of 12–14 mm Hg for HBOC vs. 27 mm Hg for RBCs).26,27 The modification of hemoglobin by pyridoxal phosphate increases P50 to 32 mm Hg, improving release of oxygen.3 Potential benefits of HBOCs include sparing allogeneic RBC transfusion in anemia, trauma, and major surgery, and reduction of transfusionrelated infection and other complications. Compassionate use of HBOC has been reported in a Jehovah’s Witness patient with acute lymphoblastic leukemia who survived severe anemia (lowest hemoglobin, 3.1 g/dL).28 However, vasoconstrictive properties of HBOC remain a major concern for further clinical development.2,3 PFC emulsions consist of halogen-substituted hydrocarbons that enhance plasma oxygen solubility. Hydrophobic PFC molecules are dissolved in plasma using emulsifiers. Unlike hemoglobin, the oxygen-carrying capacity of PFC is directly proportional to oxygen partial pressure.2 Febrile reactions or flu-like symptoms can occur as PFC emulsion is taken up by the reticuloendothelial system. PFC is not clinically available at present, but potential perioperative uses include acute lung injury and acute normovolemic hemodilution to spare RBCs from extracorporeal circuits.

Albumin Albumin is a 69-kDa plasma protein synthesized in the liver and present in plasma at 3 to 5 g/dL (~60% of plasma protein). Plasma-derived, pasteurized (60°C for 10 hours) fractions are available in iso-oncotic (5%) or hyper-oncotic (25%) solutions. Albumin exerts oncotic activity (colloid osmotic pressure) to retain intravascular water. The oncotic pressure of 5% albumin is equivalent to plasma. Albumin also serves to carry poorly

852

Blood and Hemostasis

SE C T I O N VIII

4 (

6

O 5

RO 3

2

R1

O

O 1 O O R

RO O RO

R O

O

O

R1 O

1

OR α-amylase

1 RO O R O 4

O R1

O

R O O RO

O R O

O

)n

O R1

• Fig. 44.3  Hydroxyethyl substitution of hydroxyethyl starch (HES). The structural formula of HES poly(O-2-hydroxyethyl)starch. R = –H, –CH2CH2OH. R1 = –H, CH2CH2OH, or glucose unit. Enzymatic cleavage site of α-amylase (yellow arrow) is at C1 and C4 atoms. Hydroxyethyl groups at position C2 inhibit the access of α-amylase to the substrate more effectively than those at C6. HES products with high C2/C6 ratios are more slowly degraded. (From Kozek-Langenecker SA: Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005; 103: 654-660.)

water-soluble molecules (apoprotein, bilirudin, transferrin, and so on) and can bind a number of drugs. In hypovolemic patients, there is no evidence that albumin reduces mortality compared with crystalloid or colloid solutions.29 There are a few indications for albumin use, including fluid replacement for hypovolemic shock with lack of response to crystalloids or colloids, priming for extracorporeal circuits, and plasma exchange therapy. In acute liver failure, albumin can be used to restore oncotic pressure. The intravascular retention of albumin is affected by increased vascular permeability (e.g., first 24 hours of thermal injury) and excretion (e.g., nephrotic syndrome). Albumin does not affect hepatic or renal function.

TABLE Synthetic Hydroxyethyl Starch Colloid 44.2  Solutions

Type of HES

600/0.7

670/0.75

260/0.45

130/0.4

Product name

Hespan

Hextend

Pentaspan

Voluven

Concentration

6%

6%

10%

6%

Solvent

Saline

LR

Saline

Saline

Oncotic pressure (mm Hg)

25–30

25–30

55–60

36

Mean molecular mass (kDa)

600

670

260

130

Synthetic Colloids

Molar substitution

0.7

0.75

0.45

0.4

Synthetic colloid solutions include hydroxyethylstarches (HESs), in which rapid degradation by α-amylase is prevented by hydroxyethylation of glucose subunits (Fig. 44.3). The molar replacement ratio indicates the proportion of glucose molecules replaced with hydroxyethyl units (e.g., 0.4 = 40% replacement). The C2/ C6 ratio indicates the number of hydroxyethyl units at the C2 relative to the C6 position. HES with higher molar replacement and C2/C6 ratios is retained longer owing to slower metabolism (Table 44.2). HES is excreted by the kidneys after degradation. Differences between albumin and HES in efficacy and safety are controversial. HES products are available in iso-oncotic (6%) or hyper-oncotic (10%) solutions. The most commonly used are 6% HES solutions, with an average molecular weight of 600 to 670 kDa (Hespan, Hextend, B. Braun, Bethlehem, PA), but lowmolecular-weight HES (130 kDa, Voluven, Fresenius Kabi, Halden, Norway) has recently become available in the United States.30 HES products are as effective as albumin as fluid replacements, but large doses of HES (particularly, Hespan) can adversely affect coagulation (fibrin polymerization)31 and exacerbate renal dysfunction in sepsis.32 Excess HES can falsely elevate turbidometric fibrinogen measurements.33Recently, the European Medical Association has recommended suspending marketing authorization for HES colloids in patients with sepsis or at risk for renal insufficiency. Colloid replacement therapy might still be indicated in early volume resuscitation after acute blood loss (e.g., trauma).

C2/C6 ratio

5

4.5

6

9

Maximum daily dose (mL/kg)

20

20

20

33

LR, Lactated Ringer’s Solution.

Hemostatic Interventions and Coagulation Therapies Platelet Concentrates Platelets are anuclear, granulated cells 2 to 4 µm in diameter derived from bone marrow megakaryocytes. The normal half-life of platelets is 7 to 10 days. There are 150 to 350 × 109/L platelets in the circulation, but their concentration near arterial vessel walls is significantly higher owing to the margination of platelets by larger RBCs.34 Platelets rapidly respond to disruption of normal endothelium, contributing to the initial arrest of bleeding (primary hemostasis), and support of localized thrombin generation and fibrin formation (secondary hemostasis or coagulation; Fig. 44.4).35

CHAPTER 44  Transfusion and Coagulation Therapy



Vascular injury

Primary hemostasis

Coagulation

S-E-A

S-E-A

A

B

853

C

Event

Vascular injury Bleeding

Primary hemostasis Localization of factors

Thrombin generation Fibrin polymerization

Elements

Collagen Tissue factor

Platelets ADP, Thromboxane vWF, Fibrinogen FVII, FX, FII

Platelets (S) Fibrinogen (E) FII, FIX, FX, FXI, FXII (A) FV, FVIII

Interventions

Erythrocytes

Platelets Cryoprecipitate vWF concentrate Desmopressin

Plasma, PCC Cryoprecipitate Fibrinogen FXIII concentrate rFVIIa

• Fig. 44.4  Hemostatic processes and phase-specific interventions. (A) Hemorrhage occurs after vascular injury. Extravascular (subendothelial) collagen and tissue factor are exposed to the flowing blood. Transfusion of erythrocytes/red blood cells is the initial intervention. The intact vascular wall (blue), platelets (white ovals), erythrocytes (red circles), and fibrin (green) are depicted. (B) Platelets adhere to the vascular injury site by interacting with von Willebrand factor (vWF) by glycoprotein Ib/IX receptors. Mural platelets are activated by collagen and trace thrombin (by the extrinsic pathway involving factors VII [FVII], X [FX], and II [FII]). They release adenosine-5-diphosphate (ADP) and thromboxane, stabilizing platelet–platelet interactions with fibrinogen. Thus, the primary (hemostatic) plug is established. Platelet transfusion and measures to increase von Willebrand factor can augment this process. (C) Activated platelet aggregates serve as a catalytic surface and binding sites for coagulation responses. Substrates (S; fibrinogen), proenzymatic factors (E; factors II, IX [FIX], X, XI [FXI], and XIII [FXIII]), and accelerators (A; factors V [FV] and VIII [FVIII]) are congregated. These factors can be replaced using plasma transfusion or specific factor concentrates (see text for details). PCC, Prothrombin complex concentrate; rFVIIa, recombinant factor VIIa. (From Tanaka KA, Bolliger D, Vadlamudi R, Nimmo A. Rotational thromboelastometry (ROTEM)-based coagulation management in cardiac surgery and major trauma. J Cardiothorac Vasc Anesth. 2012;26: 1083–1093.)

Since the first platelet transfusion in the 1950s, platelet concentrate remains the mainstay therapy for thrombocytopenia.36 Platelet concentrates are prepared by centrifugation of citrated whole blood within 8 hours of collection. After separating RBCs from platelet-rich plasma, further centrifugation yields 1 unit of platelet concentrate and plasma. Each unit of platelets, referred to as random-donor platelets, contains 5.5 × 1010 platelets in 50 to 70 mL of plasma. Four to 8 random-donor units are pooled to increase platelet count by 5 to 10 × 109/L in the adult. In order to decrease multiple donor exposures, single-donor platelet apheresis is increasingly used. During the apheresis procedure, donor blood is placed in the extracorporeal circuit and centrifuged to separate platelets. One platelet apheresis unit contains 30 to 50 × 1010 platelets in 250 to 300 mL of plasma. Platelet concentrates are agitated and stored at room temperature (20–24°C) for up to 5 days (see Table 44.1).

Clinical Uses Platelet transfusion is used to prevent or treat bleeding due to platelet dysfunction or thrombocytopenia. Hereditary platelet dysfunction is rare, but adhesion defects in Bernard-Soulier syndrome (GPIb/ IX deficiency), aggregation defects in Glanzmann thrombasthenia (GPIIb/IIIa deficiency), and a secretion defect in Hermansky–Pudlak syndrome (lack of dense granules) are prototypical hemorrhagic conditions resulting from decreased primary hemostasis.37 Platelet dysfunction in perioperative patients is usually due to antiplatelet therapy (see Chapter 45). Platelet transfusion can be required even with a normal platelet count if platelet dysfunction is clinically suspected or identified by platelet function testing.38,39 Perioperative platelet dysfunction is most commonly caused by acetylsalicylic acid (aspirin), thienopyridines, or GPIIb/IIIa

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inhibitors.40 For thrombocytopenia associated with bone marrow disorders, prophylactic platelet transfusion for a threshold below 10 × 109/L appears to reduce the risk of serious bleeding events.41,42 The recommended thresholds for platelet transfusion for nonbleeding, critically ill patients are also in the similar range (10–20 × 109/L).43 The trigger platelet count usually falls in the range of 50–100 × 109/L in trauma or major surgery.8-11 The trigger values are generally higher for neurosurgical and cardiovascular procedures (> 100 × 109/L).44 For other procedures, such as lumber puncture or central venous catheterization, a threshold of platelet count between 20 and 50 × 109/L is used, but supporting evidence is rather weak.45 Platelet transfusion is administered to mitigate microvascular bleeding due to thrombocytopenia or platelet dysfunction, but hypofibrinogenemia and hyperfibrinolysis need to be addressed separately as the latter are important causes of perioperative bleeding.46–48 It is often difficult to quantify hemostatic efficacy

Normal (EXTEM) mm 40 CT 40

A10

of platelet transfusion in the presence of multifactorial factor deficiency after major trauma or surgery.49 Platelet count does not reliably reflect functional recovery in the presence of platelet inhibitors and other pathologic conditions (e.g., extracorporeal circuit) that adversely affect platelet function.39,50 The timing and amount of platelet transfusion can be individualized using platelet function testing39,51 and/or thromboelastometry/thromboelastography (Fig. 44.5).52,53 Modified thromboelastometry/thromboelastography assays suitable for monitoring antiplatelet agents have been developed, but further clinical validations are warranted for the standardization and optimal thresholds for transfusion.38,39

Side Effects The risk of bacterial contamination is higher with platelet concentrates than other blood components since they are stored at room temperature. An immunoassay kit is available to test for aerobic or anaerobic gram-positive and gram-negative bacteria

Hyperfibrinolysis (EXTEM)

Normal (FIBTEM)

Maximal lysis (=100%)

MCF

A10

CFT

Pretreatment traces 10 20 30 mm

40

50 min

10

20

30

40

50 min

10

Low MCF, in vitro antifibrinolytic effect

Low MCF, fibrinolysis

20

MCF

30

40

50 min

No fibrin formation

40 40 APTEM

EXTEM CT 265 s

α 22°

CFT n.a.

A10 14 mm A20 19 mm MCF 19 mm

CT 210 s

FIBTEM α 26°

CFT 917 s

A10 16 mm A20 22 mm MCF 25 mm

CT n.a.

CFT n.a.

α n.a.

A10 n.a.

A20 n.a.

MCF n.a.

Posttreatment traces mm

10

20

30

40

50 min

10

20

30

40

50 min

10

No fibrinolysis

Near normal CT, normal MCF

20

30

40

50 min

Low FIBTEM-MCF

40 40 EXTEM CT 83 s

APTEM CFT 216 s

α 52°

A10 41 mm A20 52 mm MCF 58 mm

• Fig. 44.5

CT 82 s

FIBTEM CFT 237 s

α 49°

A10 39 mm A20 51 mm MCF 57 mm

CT 158 s A10 5 mm

CT n.a.

α n.a.

A20 6 mm MCF 6 mm

  Examples of rotational thromboelastometric tracings. Tissue factor–activated whole blood thromboelastometry (EXTEM) reflects the pattern of whole blood clotting, which is triggered by tissue factor. On the fibrin-specific (FIBTEM) test, fibrin-specific clotting after tissue factor activation is demonstrated by inhibiting platelet–fibrin interactions with the platelet inhibitor cytochalasin D. Normal ranges for EXTEM and FIBTEM are as follows: EXTEM-CT, 35 to 80 s; clot formation time (CFT), 35 to 160 s, angle, 63 to 818; A10, 50–71 mm; maximum clot firmness (MCF), 53 to 72 mm; FIBTEM-A10, 7–23 mm; MCF, 9 to 25 mm. Pretreatment: traces obtained from a bleeding patient with major blunt trauma. Prolonged computed tomography (CT) and early clot breakdown are notable on EXTEM. Fibrinolysis is corrected in vitro on APTEM, but CT and amplitude remain abnormal. Severe hypofibrinogenemia and fibrin breakdown are also observed on FIBTEM. Posttreatment: CT is nearly normal and MCF is within normal range on EXTEM after treatment with 2 g of intravenous tranexamic acid, and transfusion of 20 U cryoprecipitate and a unit of apheresis platelets. Hyperfibrinolysis is no longer detected (EXTEM = APTEM). Fibrin polymerization is improving, but FIBTEM-MCF remains below normal. (From Tanaka KA, Esper S, Bolliger D. Perioperative factor concentrate therapy. Br J Anaesth. 2013;111 Suppl 1:i35–i49.)



CHAPTER 44  Transfusion and Coagulation Therapy

855

(sensitivity, 103–105 colony formation units/mL). The lack of virus reduction procedures for platelet concentrates has been a major concern, and transmissions of Zika virus via platelet transfusion were recently reported.54 A recently US Food and Drug Administration (FDA)–approved pathogen- reduction system (Intercept Blood System, Cerus Corp., Concord, CA) uses the combination of amotosalen and ultraviolet A light to block DNA and RNA replication of various pathogens in plasma and platelet concentrates. Further clinical validations are needed as to its indications and efficacies against emerging pathogens.55 Alloimmunizations after platelet transfusion can result in antibodies against HLA class I antigens and platelet-specific antigens. Problems due to platelet alloimmunization include refractoriness to platelet transfusion and post-transfusion purpura. For those who require frequent platelet transfusions, the use of leukoreduced, HLA-matched, and ABO-compatible platelet units should be considered to reduce the risk of platelet alloimmunization.56 Hemolysis of RBCs can be caused by anti-A or anti-B antibody present in donor plasma of platelet concentrates. This typically occurs after group O platelet transfusion in non-group O recipients.57 The incidence of severe hemolysis is estimated to be in the range of 1 in 6600 (apheresis platelet transfusion) to 1 in 9000 (non–ABO-identical platelet transfusions). Other potential complications of platelet transfusion in surgical patients include transfusion-associated lung injury (TRALI) and thrombotic complications.58 Last, it is unclear whether there is a clinical difference in hemostatic efficacy and safety between pooled platelet concentrates and apheresis platelets. The increment in platelet count was higher after apheresis platelets compared to pooled concentrates, but without impacting clinical bleeding in hemato-oncology–related thrombocytopenia.59 Similarly, the clinical relevance of platelet preparation for bacterial contamination and donor exposure remains unclear.60

States. Large pools of donor plasma are collected in a blood type–specific batch (280 L from ~1500 donors) from countries at low risk for vCJD.65 The plasma pool is subsequently treated for 1 to 1.5 hours at 30°C (previously 4–4.5 hours) with a combination of solvent, 1% tri(n-butyl)phosphate (TNBP), and a detergent (1% Octoxynol-9), inactivating enveloped viruses.66 After extraction of S/D reagents, the product solution is passed through an affinity ligand column for intended removal of prions. The processes are presumed to remove emerging virus (e.g., Zika).22 The filtered plasma is aliquoted in 200-mL bags, and frozen to below −65°C. Octaplas LG is stored at < 18°C, and a specific type (A, B, AB, O) of bag is thawed before transfusion. The production steps decrease the levels of protein S and α2-plasmin inhibitor in the final plasma batch, but the duration of S/D treatment has recently been reduced,66 resulting in less significant deviations of protein S and α2-plasmin inhibitor from normal ranges in Octaplas LG compared to the older products. In a study comparing cryosupernatant (250 mL/bag) and Octaplas (200 mL/bag) in therapeutic plasma exchange (TPE) for thrombotic thrombocytopenic purpura (TTP), there was no statistical difference in the number of TPE treatments from admission to clinical remission between products.67 Citrate reactions (paresthesia, muscle cramps) were less frequent with Octaplas (6.9% vs. 18%) than with cryosupernant and, more important, allergic reactions were less common with Octaplas (3.1% vs. 9.3%).67 The risk of transfusion-related acute lung injury is also reduced with S/D plasma because anti-HLA/anti-granulocyte antibodies in donor units are significantly diluted by pooling of donor plasma.68 Third-generation S/D plasma is not blood-type specific (Uniplas LG, Octapharma). Uniplas/UniplasLG can be transfused universally in any recipient because anti-A and anti-B antibodies are removed. Other features of Uniplas LG are similar to Octaplas LG.

Plasma

Lyophilized Plasma

Plasma transfusion has been traditionally performed using fresh frozen plasma (FFP). FFP is prepared from whole blood (~500 mL) or apheresis donations and frozen at –18°C within 8 hours of collection. However, other plasma products have been increasingly used to make up the shortfall in plasma supply in the United States. Plasma frozen between 8–24 hours of phlebotomy (FP24) is a unit of plasma containing similar factor levels to FFP except for factor VIII (FVIII, up to 20% reduction).61,62 Each unit of FFP or FP24 is approximately 200 to 250 mL, and contains all components of donor plasma, including procoagulant and anticoagulant factors, albumin, and immunoglobulins. The recovery of coagulation factors after each plasma unit is about 2% to 3% in the adult but can vary with donors, clinical hemorrhage, and/ or ongoing consumption. Plasma products can be stored frozen up to 12 months. Thawed plasma (FFP and FP24) are maintained in the liquid state for up to 5 days at 1°C to 6°C for clinical use, but some degradations of plasma factors do occur, particularly for FV and FVIII.63,64 Donor plasma should be compatible with recipients’ ABO types (see Fig. 44.2), but Rh types do not need to be considered. Blood group AB and A plasma have been used as universal donors for emergency.48

Lyophilized (freeze-dried) plasma (LyoPlas N-w) is available in several countries. This blood type–specific, single-donor plasma is produced by the German Red Cross (DRK-Blutspendedienst West). Donor plasma is tested for viral hepatitis and parvovirus B19, and type-specific plasma (A, B, AB, O) is kept frozen in quarantine until the donor is retested negative after a minimum of 4 months. After the quarantine, frozen single plasma units are thawed and filtered to eliminate blood cells and cell debris, reducing the risk of leukocyte-associated cytomegalovirus (CMV) transmission. The bottles of plasma are sealed and refrozen (< −30°C) and subsequently dehydrated under vacuum and gradually rising temperature. The French Military Blood Institute (FMBI) has manufactured French lyophilized plasma (FLyP) since 1994.69 For the production of FLyP, apheresis plasma is collected from male/female donors who fulfill rigorous medical criteria. Leukoreduced plasma undergoes pathogen reduction steps, including amotosalen and ultraviolet light (Intercept Blood System). Mixing of 3000 mL of pathogeninactivated plasma from a maximum of 10 donors (mixture of A, B, and AB blood types) results in neutralization of anti-A and anti-B hemagglutinins). The plasma is subsequently aliquoted in an individual flask and freeze-dried over 4 days. The major advantage of this lyophilized plasma is that it can be kept at room temperature (range, 2–25°C) for 15 months (LyoPlas N-w) or 2 years (FLyP). Each bottle of powdered plasma is reconstituted with 200 mL of sterile water before transfusion. These plasma products can be transported to locations where a

Solvent-Detergent (S/D) Plasma Octaplas LG (Octapharma AG, Lachen, Switzerland) is a commercial S/D plasma licensed in many countries, including the United

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SE C T I O N VIII

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TABLE 44.3  Plasma Concentrations and Half-Lives of Coagulation Factors

Concentration (µM)

Half-Life (h) 72–120

Available Concentrate(s)

Fibrinogen

7.6

pd-fibrinogen, cryoprecipitate

Prothrombin

1.4

72

PCC, FEIBA

Factor V

0.03

36

None

Factor VII

0.01

3–6

pd-FVII, r-FVIIa, PCC, FEIBA

Factor VIII

0.00003

12

pd-FVIII, r-FVIII

Factor IX

0.09

24

pd-FIX, r-FIX, FEIBA

FX

0.17

40

pd-FX, PCC, FEIBA

Factor XI

0.03

80

pd-FXI

Factor XIII

0.03

120–200

pd-FXIII, r-FXIII, cryoprecipitate

vWF

0.03

10–24

pd-vWF, r-vWF, cryoprecipitate

Protein C

0.08

10

pd-Protein C, PCC

Protein S

0.14

42.5

PCC

Antithrombin

2.6

48–72

pd-antithrombin, r-antithrombin

Adapted from Bolliger D, Gorlinger K, Tanaka KA: Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology 2010; 113: 1205-1219. FEIBA, Factor eight inhibitor bypassing activity; PCC, prothrombin complex concentrate (some PCC products contain minimal levels of FVII, protein C, and protein S; see Table 44.3); pd, plasma-derived; r, recombinant; vWF, von Willebrand factor.

steady supply of safe plasma is not feasible. Type AB or universal lyophilized plasma can be stocked for emergencies. One study reported that FV and FVIII are 25% and 20% lower in FLyP than in FFP, respectively, but other factor levels, endogenous thrombin generation potential, and thromboelastometry profile are comparable between the two.70

Clinical Uses Plasma transfusion is mainly indicated for treatment of complex coagulopathies in which multiple coagulation factors and inhibitors are depleted. For congenital factor deficiency, plasma transfusion should be considered only if recombinant or plasma-derived factor concentrate is not available (Table 44.3). Plasma products are sometimes transfused prophylactically before invasive procedures when risk of bleeding is high, but there is limited evidence and no cut-off level for any coagulation test that clearly indicates the need for plasma.44 When the international normalized ratio (INR) is < 1.5, excessive bleeding is unlikely.71,72 Plasma transfusion is frequently used to treat bleeding conditions when prothrombin time (PT) is greater than 1.5 times the midpoint of the normal range or activated partial thromboplastin time (aPTT) is greater than 1.5 times the upper limit of normal.73 The most commonly used plasma dose is 2 units for adults, which amounts to 5 to 8 mL/kg.74,75 However, factor increments are generally 10% even after 12 mL/kg of plasma transfusion, and 15 to 30 mL/kg might be necessary to keep coagulation factors above 50% of normal.76,77 Plasma products need to be administered early rather than late to avoid fluid overload in cases of massive hemorrhage.78,79 However, larger plasma and platelet doses relative to RBCs (1 : 1 : 1 ratio) failed to improve the survival of major civilian trauma victims (n = 338) compared to lower doses (n = 342).49

It is feasible to implement targeted coagulation therapy after the first round of blood products in major trauma patients when rapid viscoelastic coagulation tests are used (see Fig. 44.5).48,80,81 Guidelines of the American Association of Blood Banks and the European task force recommend early plasma transfusion without a specific FFP:RBC ratio.11,73 For acute reversal of vitamin K antagonist (e.g., warfarin) therapy, FFP is used in conjunction with vitamin K, but plasma-derived, virus-inactivated prothrombin complex concentrate (PCC) is more effective for this indication, as described later.10,82 For congenital factor deficiencies, plasma-derived or recombinant factor concentrates are often available and are preferable to plasma transfusion in terms of safety and efficacy (Table 44.4). Plasma can be used as a replacement fluid (plasma exchange) in patients undergoing therapeutic plasma exchange (apheresis). 83 It is the first-line therapy to reduce mortality from thrombotic thrombocytopenia purpura (TTP) by providing metalloprotease (ADAMTS13) that cleaves high-molecular von Willebrand factor (vWF).84 Plasma exchange has also been used to remove antibodies relating to ABO-incompatible or donor-specific HLA antibodies in pretransplant patients and heparin-induced thrombocytopenia before cardiac surgery.85 Large amounts of plasma are required to achieve sufficient antibody removal, and 5% albumin is used as an exchange fluid to reduce unnecessary donor exposures and the risk of allergic reaction.86,87

Side Effects Allergic reactions to plasma are the most common complications, occurring in 1% to 3% of all transfusions. The risk of fluid overload owing to a large volume of plasma transfusion should be considered in patients with limited cardiovascular reserve.

CHAPTER 44  Transfusion and Coagulation Therapy



857

TABLE 44.4  Factor Contents of Commercially Available Prothrombin Complex Concentrates (PCCs)

FII IU/mL

FVII IU/mL

FIX IU/mL

FX IU/mL

PC IU/mL

PS IU/mL

Heparin U/mL

20–48

10–25

20–31

22–60

15–45

13–26

0.4–2

11–38

9–24

25

18–30

7–31

7–32

20

NQ

80 µg/kg), age, and coronary artery disease were contributing factors to thrombosis.

Prothrombin Complex Concentrate PCC is a sterile, lyophilized concentrate of factors II, VII, IX, and X and protein C and S. Prior to development of FIX concentrates, PCC with low amounts of FVII (3-factor PCC) was used to treat hemophilia B. There is a variety of commercial PCCs available in different countries, but the content of PCC is standardized to the amount of FIX in each vial (each vial contains at least 500 IU of FIX; see Table 44.4). Advantages of PCC include rapid availability (no need for blood typing, thawing), small volume of infusion, and avoidance of complications such as ABO incompatibility and TRALI associated with plasma. PCC containing clinically relevant FVII levels (4-factor PCC) has been approved by the FDA for acute reversal of vitamin K antagonists in the treatment of major bleeding122 and for prevention of bleeding prior to urgent surgery.82 PCCs increase thrombin generation by interacting with negatively charged phospholipids on activated platelets at the vascular injury site.123 Commercial PCCs are fractionated from pooled plasma and undergo multiple pathogen reduction steps, such as vapor heating, S/D treatment, and nano-filtration.

Clinical Uses PCC can be rapidly reconstituted with sterile water (20 mL per 500 IU) without the need for thawing and blood type matching. Dosing depends on the extent of anticoagulation. A high initial dose of 30 to 50 IU/kg (daily maximum, 5000 IU) is used in life-threatening bleeding associated with anticoagulation, including intracranial hemorrhage and retroperitoneal bleeding. A lower dose of 20 to 25 IU/kg is used for soft tissue bleeding, epistaxis, and

hematuria. Subsequent doses are based on PT/INR measurements. In acute bleeding, the major advantage of PCC is that procoagulant FII, FVII, FIX, and FX can be rapidly (< 30 minutes, Fig. 44.6) increased by 40% to 80% without dilution of RBCs and platelets.82,122,124 The vicious cycle of hematoma formation, tissue edema, and rebleeding can be prevented by prompt reestablishment of hemostasis.125 Adjunctive vitamin K is recommended to sustain PT/INR because plasma FVII falls quickly after a dose of PCC owing to its short half-life.124 There is a paucity of data on PCC for treatment of coagulopathy in trauma, major surgery, and hepatic dysfunction. There have been a number of retrospective studies on PCC in trauma and surgical patients who had suffered from major bleeds51,80,105,126,127 or those who were refractory to standard transfusion, including platelets, plasma, and cryoprecipitate.128,129 There are insufficient data regarding the optimal timing and dose of PCC outside the setting of acute reversal of vitamin K antagonists.

Side Effects Use of PCC is generally safe for acute reversal of anticoagulation and the incidence of thrombotic complications is about 0.9% to 2%.130,131 Thrombogenicity is still a concern in the case of blood stasis associated with congestive heart failure.132 PCC is contraindicated in patients with DIC,10 but the use of PCC is often considered in bleeding associated with hepatic cirrhosis and severe hemodilution.126,129,133 Thrombotic complications appear to be more commonly associated with off-label indications.113 Current antiviral protocols for factor concentrates are not effective against prions (e.g., vCJD) or nonlipid-enveloped, heatresistant viruses (e.g., parvovirus B19), but these risks are considered low.134

Antithrombin Concentrate Antithrombin (AT) is a serine protease inhibitor with a molecular weight of 58 kDa. Normal plasma AT is about 150 µg/ml (2.6 µM).

Blood and Hemostasis

SE C T I O N VIII

Fraction of patients without INR correction

860

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

4F-PCC (n = 87) Plasma (n = 81)

0

2

4

6

8

10 12 14 16 18 20 Time since start of study product infusion (h)

FII

120

200 P < 0.0001

P < 0.0001

100 80 60 40 20 0

24

26

28

FVII

P < 0.0001 P < 0.0001 P < 0.0001

P = 0.92

3 6 24 0.5 1 Timepoint after the start of infusion (h)

Pre-infusion

% of normal levels

% of normal levels

140

22

150 100

P = 0.0340 P = 0.0007 P < 0.0001 P = 0.0067

P = 0.97

50 0 –50

P = 0.72

0.51 3 6 24 Timepoint after the start of infusion (h)

Pre-infusion

• Fig. 44.6

  INR correction and coagulation factor levels in warfarin-treated patients who received 4-factor PCC or plasma transfusion. The mean plasma coagulation factor levels [% of normal activity (SD)] for FII (prothrombin) and FVII over 24 hours after injection of four-factor PCC (4F-PCC) or plasma transfusion. The elapsed time (h) from the treatment is indicated on the horizontal axis. Pre, Baseline; F, factor. P values indicate the significant difference in protein levels between groups. (From Goldstein JN, Refaai MA, Milling TJ, Jr., et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–2087.)

Anticoagulant activity of AT is potentiated by endothelial surface heparan sulfate or exogenously administered heparin. In congenital AT deficiency, AT is 40% to 60% of normal, resulting in prolonged half-life of FXa and thrombin (Fig. 44.7).135 The incidence of venous thromboembolism is increased in congenital AT deficiency during pregnancy and after major trauma or surgery. Replacement of AT using plasma-derived (Thrombate III, Grifols, Los Angeles, CA) and recombinant AT concentrate (ATryn, GTC Biotherapeutics, Framingham, MA) are indicated to prevent thrombotic complications in congenital deficiency. Recombinant AT is produced in transgenic goats and has different glycosylation and a shorter half-life (11 hours vs. 2.5 days). Whether the cost of higher doses is justified by the improved viral safety of recombinant AT is unknown. Acquired AT deficiency is frequently observed following treatment with intravenous heparin for more than 4 to 5 days. In cardiac surgical patients with heparin insensitivity (activated clotting time < 400 sec), plasma-derived or recombinant AT concentrates restore plasma AT activity effectively without the need for additional heparin or FFP.136,137 AT concentrates are less likely to decrease hematocrit and platelet count compared to FFP. Both plasma-derived

and recombinant AT concentrates contain trace amounts of heparin; thus, they should not be used in patients with heparin-induced thrombocytopenia (HIT).10

Protein C Concentrate Protein C is a vitamin K-dependent factor similar to prothrombin, FVII, FIX, and FX. Protein C activation by thrombin is limited in the presence of fibrinogen, FV, FVIII, and platelets at a vascular injury site, but is more efficiently activated by thrombin bound to thrombomodulin expressed on the endothelium (see Fig. 44.7). Elevated systemic thrombin activity thus increases protein C activation as observed in thrombophilia,138 sepsis,139 and traumatic injury.140 Activated protein C with protein S downregulates activated FV and FVIII and exerts antiinflammatory and cytoprotective functions by modulating endothelial protein C receptor and protease-activated receptor-1 (PAR-1, thrombin receptor).141 Antiinflammatory effects of activated protein C (recombinant) might be beneficial in patients with severe sepsis (Acute Physiologic Assessment and Chronic Health Evaluation [APACHE] score > 25), but serious bleeding is the major side effect.142 Homozygous

CHAPTER 44  Transfusion and Coagulation Therapy



861

Vascular injury site

IIa Fibrin AT

Xa

Heparin

Xa

IIa PC

IIa Free FXa, thrombin

IIa AT

Heparin

APC

Thrombomodulin Va VIIIa

PAR

Lysine analogs Plgn Fibrin Plasmin tPA

IIa

Endothelial cells

• Fig. 44.7

  Regulation of procoagulant responses. Local and systemic regulation of coagulation and fibrinolysis at a site of vascular injury are shown. Hemostasis is established as fibrin is polymerized by thrombin (FIIa) and activated FXIII. When thrombin or FXa is released (i.e., free thrombin) into the systemic circulation during hemostatic activation, antithrombin (AT) and thrombomodulin of intact endothelium bind to thrombin and reduce its procoagulant activity. Thrombomodulin-bound thrombin activates protein C (APC), which inactivates FVa and FVIIIa. Thrombin also causes the release of tissue plasminogen activator (tPA) from endothelium, which promotes plasminogen (Plgn) conversion to plasmin on the fibrin surface. Broken lines indicated inhibitory action of respective protease inhibitors. PAR, Protease-activated receptor (thrombin receptor on endothelium). (Adapted from Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth. 2010;24:96–106.)

protein C deficiency in newborns manifests as purpura fulminans with thrombosis in small vessels causing skin necrosis.143 Incidence of venous thromboembolism is 8- to 10-fold higher in individuals with heterozygous protein C deficiency.144 Lyophilized protein C concentrate (Ceprotin, Shire, Lexington, MA) is available for prevention and treatment of purpura fulminans and venous thrombosis in the North America. The initial dose for acute thrombosis is 100 to 120 IU/kg, followed by maintenance doses of 45 to 60 IU/kg every 6 to 12 hours. The infectious risk of plasma-derived protein C is low owing to viral inactivation steps, including polysorbate-80, vapor-heat, and ion exchange chromatography. Precautions for use include bleeding, sodium overload, rare allergic reactions and heparin-induced thrombocytopenia due to trace amounts of heparin.

Antifibrinolytic Agents The lysine analogs ε-aminocaproic acid (EACA) and tranexamic acid (TXA) are widely popular antifibrinolytic agents with hemostatic properties in many clinical areas.145 Both drugs prevent plasminogen from binding to fibrin by occupying the plasminogen lysine-binding site (see Fig. 44.7). Plasmin activation and subsequent fibrin degradation are inhibited because tissue plasminogen activator (tPA) and plasminogen can no longer co-localize on the surface of fibrin. Most clinical studies have been done with TXA because it is more potent and universally available. EACA and TXA have a low molecular weight (131 Da and 157 Da, respectively); thus, they are less antigenic compared to the bovine

plasmin inhibitor aprotinin (6512 Da), which acts as a direct plasmin inhibitor. Clinical use of aprotinin has been resumed but is limited to coronary bypass grafting surgery in Canada and Europe after its suspension from 2007 to 2012 owing to safety concerns.146,147

Clinical Uses Lysine analogs have been conventionally used to reduce bleeding in patients with hemophilia and von Willebrand disease.148 EACA is administered orally or intravenously for bleeding associated with fibrinolysis, with an initial dose of 5 g in adults. In hemophiliacs having dental extraction, TXA is given at a dose of 10 mg/ kg 3 to 4 times a day. Antifibrinolytic therapy appears to be useful in bleeding associated with menorrhagia 149 and chronic thrombocytopenia. Reduced perioperative blood loss and decreased usage of PRBCs has been reported in cardiac, hepatic, and orthopedic surgeries without increased rate of thromboembolic events with the use of TXA. Multiple TXA regimens have been clinically used and the optimal dosage and route for any specific indication are unclear. The reported studies are largely underpowered for safety issues.150,151 In cardiac surgery with cardiopulmonary bypass, the typical loading dose of intravenous EACA and TXA is 50 mg/kg and 10 to 15 mg/kg, respectively, after systemic anticoagulation. Continuous infusion of EACA and TXA is commonly used at 15 mg/kg/hr for EACA and 7.5 mg/kg/hr for TXA until the end of surgery. A single high-dose of TXA (100 mg/kg) was used in a large randomized

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controlled trial (Aspirin and Tranexamic Acid for Coronary Artery Surgery [ATACAS]) involving 4631 patients undergoing coronary artery bypass grafting surgery.152 The incidence of surgical revision owing to major hemorrhage or cardiac tamponade and the total number of transfused allogeneic blood products were reduced by nearly 50%. In the trauma setting, TXA (1 g loading, followed by 1 g over 8 hours) improved mortality without increasing cardiovascular complications.153

Side Effects Systemic thrombosis is uncommon with EACA or TXA, but they should not be used in patients with DIC.10 Lysine analogs are mainly excreted by the kidneys, and dosage should be reduced based on serum creatinine level. EACA and TXA are eliminated by hemofiltration or dialysis. With renal or ureteral bleeding, lysine analogs can increase the risk of ureteral obstruction due to clot formation. Prolonged infusion of TXA is associated with seizures presumably owing to TXA crossing the blood–brain barrier and antagonizing GABA and glycine receptors.154 In the ATACAS trial, the incidence of seizures was 0.7% in cardiac surgery patients treated with TXA (100 mg/kg bolus) compared to 0.1% in the placebo control. Lowering the total TXA dose to 30 mg/kg or use of alternative agents (EACA) might reduce seizure risk in susceptible patients (e.g., valve replacement).155

Desmopressin Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic vasopressin analog with antidiuretic activity. In mild to moderate von Willebrand disease and hemophilia A, intravenous desmopressin (0.3–0.4 µg/kg) increases plasma vWF and FVIII by 2- to 3-fold within 60 to 90 minutes. Increased vWF might improve platelet adhesion to sites of vascular injury. Desmopressin is often administered to patients with preexisting platelet dysfunction related to antiplatelet drugs and uremia. Desmopressin appears to reduce blood loss, but most studies failed to demonstrate reduced RBC transfusion in nonhemophilic surgical patients.156 Inconsistent efficacy could be related to simultaneous release of tissue plasminogen activator and tachyphylaxis or exhaustion of stored vWF-FVIII in high-stress situations.

Side Effects Rapid intravenous administration of desmopressin causes flushing and mild hypotension via vasopressin V2 receptor stimulation. Vascular occlusion due to elevated vWF is rare in von Willebrand disease and hemophilia A but could be a concern in surgical patients with preexisting cardiovascular disease.156 Topical Hemostatic Agents Topical hemostatic agents are useful in controlling minor bleeding from bone (bone wax, Ostene, Baxter, Round Lake, IL) or small capillaries and venules (e.g., topical thrombin).157 Bovine thrombin has been clinically used for a long time but is associated with major immunologic reactions, including immunization against endogenous prothrombin, thrombin, FV, and cardiolipin. Acquired FV deficiency due to bovine thrombin exposure can result in serious bleeding.158 Plasma-derived thrombin (Evithrom, Ethicon, Somerville, NJ) or recombinant thrombin (Recothrom, Mallinckrodt, Hazelwood, MO) are preferred to bovine thrombin (Thrombin–JMI, Pfizer, New York, NY) as a topical agent. Oxidized cellulose (Surgicel, Ethicon) induces local hemolysis of RBCs by lowering pH and provides a physical matrix for

coagulation. Disadvantages include inactivation of natural clotting enzymes, such as thrombin, and potential for inflammation and delayed wound healing. Microfibrillar collagen (Avitene, Bard) increases local platelet adhesion and activation, leading to hemostasis within 5 minutes. The collagen particles do not cause much swelling and are reabsorbed within 8 weeks. It should be cautioned that microfibrillar collagen can pass through RBC salvage system filters. Platelet gel (Vitagel, Stryker) combines microfibrillar collagen and thrombin with the patient’s own platelet and plasma (fibrinogen) but requires centrifugation for preparation. Fibrin sealants (TISSEEL, Baxter; Crosseal, OMRIX Biopharmaceuticals, Ltd, Brussels; Evicel, Ethicon) are effective for venous oozing from raw surfaces. They are supplied with separate vials of fibrinogen, thrombin, and calcium chloride that are mixed at the wound by a dual-syringe applicator. Hemostasis results from topical fibrin formation. A patch sponge (TachoSil, Baxter) impregnated with lyophilized human fibrinogen and thrombin is also available for treatment of raw surface bleeding. To prevent viral transmission from the human plasma, fibrinogen and thrombin are treated with solvent-detergent, nanofiltration or vapor-heat. Recombinant aprotinin (TISSEEL) and tranexamic acid (Crosseal) are added for improved clot stability. Gelatin forms (Gelfoam, Pfizer; Gelfilm, Pfizer; Surgiform, Surgiform Technology, Ltd., Kershaw County, SC) provide a physical matrix for clot formation, and are effective in bleeding from small capillaries and venules. Another gelatin-based sealant (FloSeal, Baxter) is a mixture of human thrombin and bovine-derived gelatin-based matrix. Thrombin generates fibrin from blood fibrinogen and the gelatin particles expand to tamponade bleeding. Gelatin matrix is reabsorbed after 6 to 8 weeks. These topical agents are generally safe and useful adjuncts for hemostasis when used for appropriate indications and anatomic sites.157

Special Considerations Liver Failure Patients with liver failure often develop abnormal hemostasis since most coagulation factors and inhibitors are synthesized by hepatocytes. Hemophilia A and B can be cured by liver transplantation.159 The liver is also the major site for clearance of activated coagulation factors and plasminogen activators. The extent of coagulopathy varies with the type and stage of liver and biliary tract disease.160,161 PT/INR has been part of the outcome assessment for liver disease.162 Coagulopathy in end-stage liver disease is often viewed as a hemorrhagic condition, but recent clinical data indicate that the hypocoagulable state coexists with a potentially prothrombotic state due to generalized decreases in both procoagulant and anticoagulant proteins.160,161

Jehovah’s Witnesses Devout Jehovah’s Witnesses (JWs) do not accept transfusion of “primary components” including RBCs, white blood cells, platelets, and plasma. The use of immunoglobulins, albumin, and plasmaderived FVIII and FIX (“hemophiliac preparations” per religious leaders) have been allowed since 1978. The policy on blood transfusion was changed recently—acceptance of fractionated products of “primary components” was left to the individual believer (Table 44.7).

CHAPTER 44  Transfusion and Coagulation Therapy



Bispecific antibody

Antibody analog of Factor VIII (FVIII): ACE910/Emicizumab FIXa

FX

FIXa

A2

863

FX

Bispecific antibody substitution

A1 A3 Gla

C1

C2

Gla

FVIIIa Activated phospholipid membrane

Gla

Gla

Activated phospholipid membrane

• Fig. 44.8

Schematic illustration of the FVIII-mimetic cofactor action of emicizumab (ACE910), an antiFIXa/X bispecific antibody. Left: Activated FVIII (FVIIIa) supports the interaction between activated factor IX (FIXa) and factor FX (FX) through its binding to both factors on the activated phospholipid membrane at a coagulation site. Right: Emicizumab binds to FIXa and FX, promoting the interaction between FIXa and FX, enhancing the generation of activated FX (FXa) and exerting FVIII-mimetic cofactor activity. (Adapted from Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165–3171.)  

TABLE Primary Components and Fractionated 44.7  Products for Jehovah’s Witnesses

Primary Components

Fractionated Products of Primary Components

Not Acceptable

Up to the Individual Believer

Red blood cells White blood cells Platelets Plasma

Hemoglobin-based oxygen carrier Interleukins, Interferons Platelet gels Albumin, immunoglobulins, coagulation factor/inhibitor concentrates, recombinant human proteins, topical hemostatics

Many strategies for blood conservation for JW patients have been described, including preoperative administration of iron and erythropoietin, intraoperative use of normovolemic hemodilution and cell scavenging, and use of desmopressin, antifibrinolytics, and recombinant proteins, such as rFVIIa or other plasma-derived factor concentrates (see Table 44.3).163 Using such techniques, even complex cardiac surgical procedures can be successfully performed in JW patients. A recent meta-analysis in adult JW patients undergoing cardiac surgery showed a nonsignificant trend to better early outcomes—including mortality, reoperation owing to bleeding, and thromboembolic complications—than in controls with and without blood transfusion.164

Emerging Developments Special focus on patient blood management (PBM) to reduce inappropriate blood component use has reduced the plasma usage in the United States. Improved pathogen detection in donors and pathogen reduction treatments should allow increasingly safer supplies of allogeneic blood products.55 There are continuing efforts to improve techniques to utilize hematopoietic progenitors, embryonic stem cells, and pluripotent stem cells to achieve in vitro mass production of functional RBCs and platelets.165,166 In time, cultured autologous RBCs and platelets might become valid transfusion resources for those with rare antigens and multiple alloantibodies. Cultured RBCs and platelets might also be used as a carrier for the delivery of therapeutic agents to certain cells (e.g., cancer) or organs.167,168 A bispecific antibody targeting FIXa and FX has been developed to bypass FVIII activity in hemophilia patients who develop FVIII neutralizing antibody.169 The anti-FIXa/FX immunoglobulin G antibody (emicizumab; ACE910) aligns FIXa and FX into spatially appropriate positions, thus eliminating the need for FVIII (Fig. 44.8). Once-weekly subcutaneous injection of emicizumab was effective in reducing bleeding episodes in 18 Japanese hemophilia patients with or without anti-FVIII antibody.170 There is increasing interest in abrogating contact activation (intrinsic coagulation pathway) to reduce pathologic thrombosis associated with DIC and extracorporeal circulation.171 Two main targets are factor XI172,173 and factor XII.174 These pathways are hypothesized to cause minimal bleeding complications because normal tissue factor triggered hemostasis is maintained.

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Key Points • Transfusion of blood components can be lifesaving, but there are potentially serious complications. ABO-incompatible transfusion—transfusion-associated circulatory overload (TACO) and TRALI—are two of the most common causes of death after blood transfusion. Proper identifications of the donor unit and patient and careful risk–benefit assessments are essential prior to each component transfusion. • Transfusion of RBC concentrates should be determined not only by threshold hemoglobin values but also by the rate/extent of hemorrhage, clinical conditions (e.g., reduced cardiovascular reserve), and the risk–benefit ratio. • Hemodilution can be extensive in major trauma and surgery, affecting both procoagulant and anticoagulant factors. Reduced plasma levels of fibrinogen and factor XIII early during hemodilution result in fragile clot formation, which is susceptible to fibrinolysis. Fibrinogen can be replaced more efficiently by cryoprecipitate (or plasma-derived fibrinogen) than by FFP. • Plasma-based PT and aPTT are frequently used to evaluate coagulopathy but are not predictive of perioperative bleeding risks. Thromboelastography/thromboelastometry of whole blood is a useful adjunct to PT/aPTT and platelet count because the

stability of fibrin polymerization (i.e., activity of thrombin, fibrinogen, and FXIII) can be assessed. • Early plasma and platelet administration, along with RBCs, is indicated in major hemorrhage associated with severe trauma. Expedited surgical control of bleeding is crucial in improving morbidity and mortality, and there does not appear to be any specific ratio of blood products that can be recommended. The use of thromboelastography/thromboelastometry can be helpful in the selection of hemostatic product(s). • For certain hereditary deficiencies of coagulation factors or inhibitors, plasma-derived or recombinant concentrates are available and are preferable for safety (e.g., reduced risk of viral transmission) and efficacy. Use of factor concentrates in acquired factor deficiency is generally considered to be off-label, but there are some supportive data available for certain indications (e.g., PCC for vitamin K antagonist reversal and fibrinogen for dilutional coagulopathy). • Topical hemostatic agents are frequently used by surgeons, and can be potentially useful to reduce blood loss. The proper indication(s) and site(s) should be considered to reduce untoward complications (e.g., tissue swelling, necrosis, intravascular absorption).

Key References

grafting surgery. There was no difference between TXA (n = 2311) and placebo (n = 2320) in the primary outcomes consisting of death and thromboembolic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. Total number of units of blood products was reduced from 7994 with placebo to 4331 with TXA (P < 0.001). In addition, the incidences of major hemorrhage or cardiac tamponade leading to reoperation were reduced by 50% (P = 0.001). Seizures occurred in 0.7% and 0.1% in patients treated with and without TXA, respectively (P = 0.002). TXA seems to be safe and effective in reducing perioperative blood loss in cardiac surgery. However, caution should be exercised for postoperative seizures in some patients receiving high-dose TXA. (Ref. 152). Nakayama Y, Nakajima Y, Tanaka KA, et al. Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery. Br J Anaesth. 2015;114:91–102. The authors reported a prospective randomized study (n = 100) of conventional versus thromboelastometry (ROTEM)–guided hemostatic intervention in cardiac surgery for infants (median age, 10–13 months). Platelets and plasma were the only 2 products available for hemostatic therapy during the study. In the conventional group, platelets and plasma were transfused when platelet count was below 80 × 109/L, and activated clotting time (ACT) was over 150 seconds. Corresponding indications in the ROTEM group were platelets for EXTEM-A10 (10-minute amplitude) below 30 mm and plasma for FIBTEM-A10 below 5 mm. The amount of intraoperative plasma transfusion was higher in the ROTEM group than the conventional group (median, 21 mL/kg vs. 14 mL/kg; P < 0.005). This resulted in higher fibrinogen levels in the ROTEM group immediately after surgery (165 vs. 125 mg/ dL; P < 0.001). Reduced postoperative blood loss, RBC transfusion, and duration of ICU stay in the ROTEM group suggest that early plasma transfusion to maintain fibrin polymerization may be more effective than conventional management focused on clotting time (e.g., PT/INR, aPTT, or ACT). (Ref. 79). Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11:307–314. The authors investigated the incidence and extent of hyperfibrinolysis in 303 consecutive trauma patients using thromboelastometry (maximum lysis of > 15%) and fibrinolytic markers

Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–2087. The authors compared the efficacies of 4-factor PCC or plasma in a multicenter, open-label, phase 3b randomized trial involving 181 patients undergoing an urgent surgical or invasive procedure. The intention-to-treat efficacy population comprised 168 patients (PCC, n = 87; plasma, n = 81). Rapid INR reduction (≤ 1⋅3 at 0⋅5 hr after therapy) was achieved in 48 (55%) patients in the PCC group compared with 8 (10%) patients in the plasma group. Effective hemostasis was achieved in 78 (90%) patients in the PCC group compared with 61 (75%) patients in the plasma group. Both endpoints demonstrated noninferiority and superiority of PCC over plasma. The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving PCC had adverse events compared with 53 (60%) patients receiving plasma. Notably, fluid overload or similar cardiac events were more frequent in the plasma group (3% vs. 13% with PCC). (Ref. 82). Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471–482. The authors conducted a prospective randomized trial of 1:1:1 versus 1:1:2 ratio of plasma, platelets, and RBC administration (n = 338 vs. 342) in the early resuscitation of major civilian trauma victims. Improved hemostasis was more frequently observed in the 1:1:1 group than in the 1:1:2 group (86.1% vs. 78.1%). The increased donor exposure was evident in the 1:1:1 group (median 19 U plasma plus platelets vs. 11 U in the 1:1:2 group). This study failed to point to the optimal ratio (or volume) of plasma and platelet transfusion. Fibrinogen or fibrin polymerization was not continuously monitored and cryoprecipitate was seldom used in either group of patients (median, 0 unit). (Ref. 49). Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017;376:136–148. The authors compared the safety and efficacy of a single high-dose TXA regimen (100 mg/kg prior to cardiopulmonary bypass) in a multicenter randomized controlled trial in patients undergoing coronary artery bypass

CHAPTER 44  Transfusion and Coagulation Therapy



(plasmin–antiplasmin complex and D-dimer levels). Hyperfibrinolysis was evident on thromboelastometry in only 5% of patients, while plasma fibrinolysis markers were elevated in 57% of patients in proportion to the base deficit and hypotension on admission. The 28-day mortality of patients with hyperfibrinolysis on thromboelastometry was 40%, whereas it was 12% in those with elevated plasma fibrinolysis markers. These data suggest that hyperfibrinolysis on thromboelastometry represents a marker of worse prognosis and that antifibrinolytic therapy should be considered according to the injury severity regardless of the thromboelastometry findings. (Ref. 47).

References 1. Counts RB. A history of transfusion medicine. In: Spiess BD, Spence RK, Shander A, eds. Perioperative Transfusion Medicine. Baltimore: Lippincott Williams & Wilkins; 1997:3–12. 2. Spahn DR. Blood substitutes. Artificial oxygen carriers: perfluorocarbon emulsions. Crit Care. 1999;3:R93–R97. 3. Jahr JS, Walker V, Manoochehri K. Blood substitutes as pharmacotherapies in clinical practice. Curr Opin Anaesthesiol. 2007;20: 325–330. 4. Spahn DP, Moch H, Hofmann A, et al. Patient blood management the pragmatic solution for the problems with blood transfusions. Anesthesiology. 2008;109:951–953. 5. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia in the elective orthopedic surgical patient: NATA guidelines. Br J Anaesth. 2011;106:13–22. 6. Kotze A, Carter LA, Scally AJ. Effect of a patient blood management programme on preoperative anaemia, transfusion rate, and outcome after primary hip or knee arthroplasty: a quality improvement cycle. Br J Anaesth. 2012;108:943–952. 7. Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30:270–382. 8. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105:198–208. 9. Spahn DR, Cerny V, Coats TJ, et al. Management of bleeding following major trauma: a European guideline. Crit Care. 2007;11:R17. 10. German Medical Association. Cross-sectional guidelines for therapy with blood components and plasma derivatives. 4th revised edition. Transfus Med Hemother. 2009;36:419–436. 11. Rossaint R, Bouillon B, Cerny V, et al. Management of bleeding following major trauma: an updated European guideline. Crit Care. 2010;14:R52. 12. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–982. 13. Harris SB, Hillyer CD. Blood manufacturing: component preparation. In: Hillyer CD, ed. Storage, and Transportation, Blood Banking and Transfusion Medicine: Basic Principles and Practice, 2nd Ed. Philadelphia: Churchill-Livingstone, Elsevier; 2007:185–187. 14. Fergusson DA, Hebert P, Hogan DL, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308:1443–1451. 15. Steiner ME, Ness PM, Assmann SF, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med. 2015;372:1419–1429. 16. Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med. 2015;372:1410–1418. 17. Heddle NM, Cook RJ, Arnold DM, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med. 0:null. 18. Hovaguimian F, Myles PS. Restrictive versus liberal transfusion strategy in the perioperative and acute care settings: a context-specific

865

systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2016;125:46–61. 19. Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008. 20. Parker MJ. Randomised trial of blood transfusion versus a restrictive transfusion policy after hip fracture surgery. Injury. 2013;44:1916–1918. 21. Blumberg N, Heal JM. Blood transfusion immunomodulation: the silent epidemic. Arch Pathol Lab Med. 1998;122:117–119. 22. Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components–Guidance for Industry. Rockville, MD: Food and Drug Administration; 2016. 23. Murphy MF. New variant Creutzfeldt-Jakob disease (nvCJD): the risk of transmission by blood transfusion and the potential benefit of leukocyte-reduction of blood components. Transfus Med Rev. 1999;13:75–83. 24. Lin DM, Lin ES, Tran MH. Efficacy and safety of erythropoietin and intravenous iron in perioperative blood management: a systematic review. Transfus Med Rev. 2013;27:221–234. 25. Weltert L, Rondinelli B, Bello R, et al. A single dose of erythropoietin reduces perioperative transfusions in cardiac surgery: results of a prospective single-blind randomized controlled trial. Transfusion. 2015;55:1644–1654. 26. Goodnough LT, Brecher ME, Kanter MH, et al. Transfusion medicine. First of two parts–blood transfusion. N Engl J Med. 1999;340:438–447. 27. Goodnough LT, Brecher ME, Kanter MH, et al. Transfusion medicine. Second of two parts–blood conservation. N Engl J Med. 1999;340:525–533. 28. Donahue LL, Shapira I, Shander A, et al. Management of acute anemia in a Jehovah’s Witness patient with acute lymphoblastic leukemia with polymerized bovine hemoglobin-based oxygen carrier: a case report and review of literature. Transfusion. 2010;50:1561–1567. 29. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013. 30. Westphal M, James MF, Kozek-Langenecker S, et al. Hydroxyethyl starches: different products–different effects. Anesthesiology. 2009;111:187–202. 31. Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology. 2005;103:654–660. 32. Delaney AP, Dan A, McCaffrey J, et al. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39:386–391. 33. Fenger-Eriksen C, Moore GW, Rangarajan S, et al. Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders. Transfusion. 2010;50:2571–2576. 34. Aarts PA, van den Broek SA, Prins GW, et al. Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood. Arteriosclerosis. 1988;8:819–824. 35. Tanaka KA, Bolliger D, Vadlamudi R, et al. Rotational thromboelastometry (ROTEM)-based coagulation management in cardiac surgery and major trauma. J Cardiothorac Vasc Anesth. 2012;26: 1083–1093. 36. Stroncek DF, Rebulla P. Platelet transfusions. Lancet. 2007;370: 427–438. 37. George JN. Platelets. Lancet. 2000;355:1531–1539. 38. Mahla E, Suarez TA, Bliden KP, et al. Platelet function measurementbased strategy to reduce bleeding and waiting time in clopidogreltreated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrelassociated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv. 2012;5:261–269. 39. Ranucci M, Baryshnikova E, Soro G, et al. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines. Ann Thorac Surg. 2011;91:123–129. 40. Oprea AD, Popescu WM. Perioperative management of antiplatelet therapy. Br J Anaesth. 2013;111(suppl 1):i3–i17.

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41. Estcourt L, Stanworth S, Doree C, et al. Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation. Cochrane Database Syst Rev. 2012;CD004269. 42. Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013;368:1771–1780. 43. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup: surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39: 165–228. 44. Bolliger D, Mauermann E, Tanaka KA. Thresholds for perioperative administration of hemostatic blood components and coagulation factor concentrates: an unmet medical need. J Cardiothorac Vasc Anesth. 2015;29:768–776. 45. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162:205–213. 46. Karkouti K, Callum J, Crowther MA, et al. The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study. Anesth Analg. 2013;117:14–22. 47. Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11:307–314. 48. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg. 2016;263:1051–1059. 49. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471–482. 50. Susen S, Rauch A, Van Belle E, et al. Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis. J Thromb Haemost. 2015;13:1757–1767. 51. Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531–547. 52. Nuttall GA, Oliver WC, Santrach PJ, et al. Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology. 2001;94:773–781; discussion 5A–6A. 53. Kozek-Langenecker S. Management of massive operative blood loss. Minerva Anestesiol. 2007;73:401–415. 54. Motta IJ, Spencer BR, Cordeiro da Silva SG, et al. Evidence for transmission of Zika Virus by platelet transfusion. N Engl J Med. 2016;375:1101–1103. 55. Corash L, Benjamin RJ. The role of hemovigilance and postmarketing studies when introducing innovation into transfusion medicine practice: the amotosalen-ultraviolet A pathogen reduction treatment model. Transfusion. 2016;56(suppl 1):S29–S38. 56. Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology. 2007;172–178. 57. Fung MK, Downes KA, Shulman IA. Transfusion of platelets containing ABO-incompatible plasma: a survey of 3156 North American laboratories. Arch Pathol Lab Med. 2007;131:909–916. 58. Spiess BD, Royston D, Levy JH, et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion. 2004;44:1143–1148. 59. Triulzi DJ, Assmann SF, Strauss RG, et al. The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. Blood. 2012;119:5553–5562. 60. Vamvakas EC. COMMENTARY: relative safety of pooled whole blood–derived versus single-donor (apheresis) platelets in the United

States: a systematic review of disparate risks. Transfusion. 2009;49: 2743–2758. 61. Alhumaidan H, Cheves T, Holme S, et al. Stability of coagulation factors in plasma prepared after a 24-hour room temperature hold. Transfusion. 2010;50:1934–1942. 62. Benjamin RJ, McLaughlin LS. Plasma components: properties, differences, and uses. Transfusion. 2012;52(suppl 1):9S–19S. 63. Downes KA, Wilson E, Yomtovian R, et al. Serial measurement of clotting factors in thawed plasma stored for 5 days. Transfusion. 2001;41:570. 64. Scott E, Puca K, Heraly J, et al. Evaluation and comparison of coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6 degrees C storage. Transfusion. 2009;49:1584–1591. 65. Heger A, Svae TE, Neisser-Svae A, et al. Biochemical quality of the pharmaceutically licensed plasma OctaplasLG after implementation of a novel prion protein (PrPSc) removal technology and reduction of the solvent/detergent (S/D) process time. Vox Sang. 2009;97:219–225. 66. Neisser-Svae A, Bailey A, Gregori L, et al. Prion removal effect of a specific affinity ligand introduced into the manufacturing process of the pharmaceutical quality solvent/detergent (S/D)-treated plasma OctaplasLG. Vox Sang. 2009;97:226–233. 67. Scully M, Longair I, Flynn M, et al. Cryosupernatant and solvent detergent fresh-frozen plasma (Octaplas) usage at a single centre in acute thrombotic thrombocytopenic purpura. Vox Sang. 2007;93:154–158. 68. Riedler GF, Haycox AR, Duggan AK, et al. Cost-effectiveness of solvent/detergent-treated fresh-frozen plasma. Vox Sang. 2003;85:88–95. 69. Daban JL, Clapson P, Ausset S, et al. Freeze dried plasma: a French army specialty. Crit Care. 2010;14:412. 70. Martinaud C, Civadier C, Ausset S, et al. In vitro hemostatic properties of French lyophilized plasma. Anesthesiology. 2012; 117:339–346. 71. Stanworth SJ, Brunskill SJ, Hyde CJ, et al. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol. 2004;126:139–152. 72. Segal JB, Dzik WH. Transfusion Medicine/Hemostasis Clinical Trials Network: Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review.[see comment]. Transfusion. 2005;45: 1413–1425. 73. Roback JD, Caldwell S, Carson J, et al. Evidence-based practice guidelines for plasma transfusion. Transfusion. 2010;50: 1227–1239. 74. Triulzi D, Gottschall J, Murphy E, et al. III: a multicenter study of plasma use in the United States. Transfusion. 2015;55:1313–1319; quiz 1312. 75. Marshall AL, Levine M, Howell ML, et al. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost. 2016;14:324–330. 76. Chowdhury P, Saayman AG, Paulus U, et al. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol. 2004;125:69–73. 77. Muller MC, Juffermans NP. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy: reply. J Thromb Haemost. 2015;13:1943–1944. 78. Hiippala S. Replacement of massive blood loss. Vox Sang. 1998;74(suppl 2):399–407. 79. Nakayama Y, Nakajima Y, Tanaka KA, et al. Thromboelastometryguided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery. Br J Anaesth. 2015;114:91–102. 80. Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry



(ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14:R55. 81. Olde Engberink RH, Kuiper GJ, Wetzels RJ, et al. Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery. J Cardiothorac Vasc Anesth. 2014;28:210–216. 82. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–2087. 83. Shehata N, Kouroukis C, Kelton JG. A review of randomized controlled trials using therapeutic apheresis. Transfus Med Rev. 2002;16:200–229. 84. Fontana S, Kremer Hovinga JA, Lammle B, et al. Treatment of thrombotic thrombocytopenic purpura. Vox Sang. 2006;90:245–254. 85. Roman PE, DeVore AD, Welsby IJ. Techniques and applications of perioperative therapeutic plasma exchange. Curr Opin Anaesthesiol. 2014;27:57–64. 86. Brecher ME, Hay SN, Park YA. Theoretical efficacy of using albumin/ plasma versus full plasma replacement in TTP. J Clin Apher. 2011;26:58. 87. Reutter JC, Sanders KF, Brecher ME, et al. Incidence of allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of thrombotic thrombocytopenic purpura. J Clin Apher. 2001;16:134–138. 88. Pamphilon D. Viral inactivation of fresh frozen plasma. Br J Haematol. 2000;109:680–693. 89. Triulzi DJ. Transfusion-related acute lung injury: current concepts for the clinician. Anesth Analg. 2009;108:770–776. 90. Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet. 2007;370:439–448. 91. Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology. 2010;113:1205–1219. 92. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. British Committee for Standards in Haematology BTTF: guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126:11–28. 93. Charbit B, Mandelbrot L, Samain E, et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost. 2007;5:266–273. 94. Blome M, Isgro F, Kiessling AH, et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost. 2005;93:1101–1107. 95. Bolliger D, Szlam F, Molinaro RJ, et al. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model. Br J Anaesth. 2009;102:793–799. 96. Karlsson M, Ternstrom L, Hyllner M, et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost. 2009;102:137–144. 97. Fenger-Eriksen C, Jensen TM, Kristensen BS, et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost. 2009;7:795–802. 98. Solomon C, Cadamuro J, Ziegler B, et al. A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients. Transfusion. 2011;51:1695–1706. 99. Schlimp CJ, Solomon C, Ranucci M, et al. The effectiveness of different functional fibrinogen polymerization assays in eliminating platelet contribution to clot strength in thromboelastometry. Anesth Analg. 2014;118:269–276. 100. Fabbro M 2nd, Gutsche JT, Miano TA, et al. Comparison of thrombelastography-derived fibrinogen values at rewarming and

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following cardiopulmonary bypass in cardiac surgery patients. Anesth Analg. 2016;123:570–577. 101. Groner A. Reply. Pereira A. Cryoprecipitate versus commercial fibrinogen concentrate in patients who occasionally require a therapeutic supply of fibrinogen: risk comparison in the case of an emerging transfusion-transmitted infection. Haematologica 2007;92:846-9. Haematologica. 2008;93:e24–e26; author reply e27. 102. Stanworth SJ. The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology Am Soc Hematol Educ Program. 2007;179–186. 103. Tanaka KA, Esper S, Bolliger D. Perioperative factor concentrate therapy. Br J Anaesth. 2013;111(suppl 1):i35–i49. 104. Rahe-Meyer N, Pichlmaier M, Haverich A, et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth. 2009;102:785–792. 105. Fassl J, Matt P, Eckstein F, et al. Transfusion of allogeneic blood products in proximal aortic surgery with hypothermic circulatory arrest: effect of thromboelastometry-guided transfusion management. J Cardiothorac Vasc Anesth. 2013;27:1181–1188. 106. Rahe-Meyer N, Solomon C, Hanke A, et al. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology. 2013;118:40–50. 107. Tanaka KA, Egan K, Szlam F, et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional transfusion. Transfusion. 2014;54:109–118. 108. Jeppsson A, Waldén K, Roman-Emanuel C, et al. Preoperative supplementation with fibrinogen concentrate in cardiac surgery: a randomized controlled study. Br J Anaesth. 2016;116:208–214. 109. Ranucci M, Baryshnikova E, Crapelli GB, et al. Surgical clinical outcome RG: randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc. 2015;4:e002066. 110. Rahe-Meyer N, Levy JH, Mazer CD, et al. Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth. 2016;117:41–51. 111. Karkouti K, Callum J, Wijeysundera DN, et al. Point-of-care hemostatic testing in cardiac surgery: a stepped-wedge clustered randomized controlled trial. Circulation. 2016;134:1152–1162. 112. Fassl J, Lurati Buse G, Filipovic M, et al. Perioperative administration of fibrinogen does not increase adverse cardiac and thromboembolic events after cardiac surgery. Br J Anaesth. 2015;114:225–234. 113. Ekezue BF, Sridhar G, Ovanesov MV, et al. Clotting factor product administration and same-day occurrence of thrombotic events, as recorded in a large healthcare database during 2008-2013. J Thromb Haemost. 2015;13:2168–2179. 114. Key NS, Christie B, Henderson N, et al. Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy. Thromb Haemost. 2002;88:60–65. 115. Hardy JF, Belisle S, Van der Linden P. Efficacy and safety of recombinant activated factor VII to control bleeding in nonhemophiliac patients: a review of 17 randomized controlled trials. Ann Thorac Surg. 2008;86:1038–1048. 116. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005;59:8–15; discussion 15–18. 117. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69:489–500. 118. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–2137.

868

SE C T I O N VIII

Blood and Hemostasis

119. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009;120:21–27. 120. O’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–298. 121. Levi M, Levy JH, Andersen HF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363: 1791–1800. 122. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234– 1243. 123. Ogawa S, Ohnishi T, Hosokawa K, et al. Haemodilution-induced changes in coagulation and effects of haemostatic components under flow conditions. Br J Anaesth. 2013;111:1013–1023. 124. Riess HB, Meier-Hellmann A, Motsch J, et al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res. 2007;121:9–16. 125. Mayer SA, Rincon F. Ultra-early hemostatic therapy for acute intracerebral hemorrhage. Semin Hematol. 2006;43:S70–S76. 126. Kirchner C, Dirkmann D, Treckmann JW, et al. Coagulation management with factor concentrates in liver transplantation: a single-center experience. Transfusion. 2014;54:2760–2768. 127. Gorlinger K, Weber CF, Zacharowski K. In reply. Anesthesiology. 2013;118:988–990. 128. Tanaka KA, Mazzeffi MA, Grube M, et al. Three-factor prothrombin complex concentrate and hemostasis after high-risk cardiovascular surgery. Transfusion. 2013;53:920–921. 129. Joseph B, Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg. 2014;38:1875–1881. 130. Leissinger CA, Blatt PM, Hoots WK, et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008;83:137–143. 131. Hanke AA, Joch C, Görlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth. 2013;110:764–772. 132. Goldhammer JE, Bakowitz MJ, Milas BL, et al. Intracardiac thrombosis after emergent prothrombin complex concentrate administration for warfarin reversal. Anesthesiology. 2015; 123:458. 133. Schochl H, Voelckel W, Maegele M, et al. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care. 2014;18:R147. 134. Kleinman SH, Glynn SA, Lee TH, et al. A linked donor-recipient study to evaluate parvovirus B19 transmission by blood component transfusion. Blood. 2009;114:3677–3683. 135. Bauer KA, Rosenberg RD. Congenital antithrombin III deficiency: insights into the pathogenesis of the hypercoagulable state and its management using markers of hemostatic system activation. Am J Med. 1989;87:39S–43S. 136. Williams MR, D’Ambra AB, Beck JR, et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg. 2000;70:873–877. 137. Avidan MS, Levy JH, Scholz J, et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology. 2005;102:276–284. 138. Nicolaes GAF, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol. 2002;22:530–538.

139. Liaw PCY, Esmon CT, Kahnamoui K, et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood. 2004;104:3958–3964. 140. Cohen MJ, Bir N, Rahn P, et al. Protein C depletion early after trauma increases the risk of ventilator-associated pneumonia. J Trauma. 2009;67:1176–1181. 141. Riewald M, Petrovan RJ, Donner A, et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296:1880–1882. 142. Bernard GR, Vincent JL, Laterre PF, et al. Recombinant human protein CWEiSSsg: efficacy and safety of recombinant human activated protein C for severe sepsis.[comment]. N Engl J Med. 2001;344:699–709. 143. Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981;68: 1370–1373. 144. Franchini M, Veneri D, Salvagno GL, et al. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006;43:249–290. 145. Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth. 2013;111:549–563. 146. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.[see comment]. N Engl J Med. 2008;358:2319–2331. 147. McMullan V, Alston RP. III. Aprotinin and cardiac surgery: a sorry tale of evidence misused. Br J Anaesth. 2013;110:675–678. 148. Hvas AM, Sorensen HT, Norengaard L, et al. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A. J Thromb Haemost. 2007;5:2408–2414. 149. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000. 150. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054. 151. Ker K, Beecher D, Roberts I. Topical application of tranexamic acid for the reduction of bleeding. Cochrane Database Syst Rev. 2013. 152. Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017;376:136–148. 153. Shakur H, Roberts R, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. 154. Furtmuller R, Schlag MG, Berger M, et al. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gammaaminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther. 2002;301:168–173. 155. Murkin JM, Falter F, Granton J, et al. High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010;110:350–353. 156. Carless PA, Henry DA, Moxey AJ, et al. Desmopressin for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2004;CD001884. 157. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg. 2010;251:217–228. 158. Ortel TL, Mercer MC, Thames EH, et al. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg. 2001;233:88–96. 159. Wilde J, Teixeira P, Bramhall SR, et al. Liver transplantation in haemophilia. Br J Haematol. 2002;117:952–956. 160. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41:553–558. 161. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood. 2010;116: 878–885.



162. Tripodi A, Chantarangkul V, Primignani M, et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007;46:520–527. 163. Bolliger D, Sreeram G, Duncan A, et al. Prophylactic use of factor IX concentrate in a Jehovah’s Witness patient. Ann Thorac Surg. 2009;88:1666–1668. 164. Vasques F, Kinnunen E-M, Pol M, et al. Outcome of Jehovah’s Witnesses after adult cardiac surgery: systematic review and metaanalysis of comparative studies. Transfusion. 2016;56:2146–2153. 165. Giarratana MC, Rouard H, Dumont A, et al. Proof of principle for transfusion of in vitro-generated red blood cells. Blood. 2011;118:5071–5079. 166. Nakamura S, Takayama N, Hirata S, et al. Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells. Cell Stem Cell. 2014;14:535–548. 167. Sarkar S, Alam MA, Shaw J, et al. Drug delivery using platelet cancer cell interaction. Pharm Res. 2013;30:2785–2794. 168. Villa CH, Cines DB, Siegel DL, et al. Erythrocytes as carriers for drug delivery in blood transfusion and beyond. Transfus Med Rev. 2017;31:26–35.

CHAPTER 44  Transfusion and Coagulation Therapy

869

169. Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165–3171. 170. Shima M, Hanabusa H, Taki M, et al. Factor VIIIâ “mimetic function of humanized bispecific antibody in hemophilia a. N Engl J Med. 2016;374:2044–2053. 171. Gailani D, Bane CE, Gruber A. Factor XI and contact activation as targets for antithrombotic therapy. J Thromb Haemost. 2015;13:1383–1395. 172. van Montfoort ML, Knaup VL, Marquart JA, et al. Two novel inhibitory anti-human factor XI antibodies prevent cessation of blood flow in a murine venous thrombosis model. Thromb Haemost. 2013;110:1065–1073. 173. Gailani D, Gruber A. Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36:1316–1322. 174. Woodruff RS, Xu Y, Layzer J, et al. Inhibiting the intrinsic pathway of coagulation with a factor XII–targeting RNA aptamer. J Thromb Haemost. 2013;11:1364–1373. 175. Ide M, Bolliger D, Taketomi T, et al. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth. 2010;24:96–106.

45 

Anticoagulant and Antiplatelet Therapy DAVID ROYSTON

CHAPTER OUTLINE Normal Platelet Function and Hemostasis Mechanisms of Thrombin and Fibrin Generation Indirect Inhibitors of Thrombin Generation Historical Considerations Heparins Low-Molecular-Weight Heparin Pentasaccharide Vitamin K Antagonists Direct Thrombin Inhibitors Intravenous Direct Thrombin Inhibitors Oral Direct Thrombin Inhibitors Inhibitors of Activated Factor X Antiplatelet Agents Oral Agents Platelet Receptor Inhibitors Adenosine Diphosphate Analogs Glycoprotein IIb/IIIa Antagonists Protease Activated Receptor-1 (Thrombin Receptor) Emerging Developments Reversal of Novel Anticoagulants

A

rterial and venous thrombosis are major causes of morbidity and mortality. Venous thromboembolism (VTE) is the leading cause of preventable in-hospital mortality. Deep vein thrombosis (DVT) leading to VTE causes as many as 300,000 deaths annually in the United States and approximately 300,000 within the European Union as well.1,2 Arterial thrombosis is the most common cause of myocardial infarction (MI), ischemic stroke, and limb gangrene. Arterial thrombi, which typically form under high shear conditions, consist of platelet aggregates held together by small amounts of fibrin. Because of the predominance of platelets, strategies to inhibit arterial thrombogenesis focus mainly on drugs that block platelet function, but include anticoagulants for prevention of cardioembolic events in patients with atrial fibrillation or mechanical heart valves. DVT can lead to pulmonary thromboembolism (PE), which can be fatal, and to postphlebitic syndrome. Venous thrombi, which form under low shear, are composed mainly of fibrin and trapped 870

red blood cells, with relatively few platelets. With the predominance of fibrin in venous thrombi, anticoagulants are the agents of choice for the prevention and treatment of DVT and VTE. The incidence of VTE is about 20% higher in men than in women and increases with age in both sexes. Asian and Hispanic populations have a lower risk of VTE, whereas Caucasians and African Americans have a 2.5-fold higher risk. Agents such as vitamin K antagonists or dual antiplatelet therapy with aspirin and clopidogrel have addressed inappropriate thrombosis. Administration of these drugs significantly reduces the risk of thrombotic events but also increases bleeding. They also suffer from inconsistency in efficacy associated with pharmacogenetic factors and drug interactions. Recently there have been a number of additional anticoagulant and antiplatelet drugs3 based on a greater understanding of hemostasis mechanisms that are outlined in the following text.

Normal Platelet Function and Hemostasis A brief overview of the hemostatic system is provided as background for consideration of antiplatelet and anticoagulant drugs; further detail is provided in Chapters 43 and 44. The initial response of the hemostatic system to tissue or endothelial injury is to produce a platelet plug (primary hemostasis). Platelets have multiple surface receptors that, when stimulated, produce a shape change involving the energy-dependent actin-myosin system. Principal among these is the glycoprotein Ib (GpIb) receptor, which binds to von Willebrand factor (vWF), a large protein expressed on the abluminal side of endothelial cells that is exposed when there is endothelial injury. The glycoprotein Ib receptor is expressed at all times. There are also receptors for adenosine diphosphate (ADP), thrombin, and thromboxane A2. These receptors principally allow feedback amplification to enhance generation of the primary hemostatic plug. With the platelet shape change, the surface of the platelet also changes with expression of a second binding site, the glycoprotein IIb/IIIa (GpIIb/IIIa) receptor. The GpIIb/IIIa receptor binds fibrinogen to provide bridging between adjacent platelets. The surface of the platelet also becomes electronegatively charged and expresses binding sites for factor V, an essential cofactor in the generation of thrombin.

Mechanisms of Thrombin and Fibrin Generation The coagulation phase of hemostasis involves thrombin-catalyzed cleavage of fibrinogen to fibrin, which binds and stabilizes the

CHAPTER 45  Anticoagulant and Antiplatelet Therapy



Anion-binding exosite

S

D H

Active site

• Fig. 45.1

Thrombin structure. The thrombin active site (shown in aqua) is surrounded by a ring of negative charge and contains three conserved amino acid residues (serine 195 [S], aspartic acid 102 [D], and histidine 57 [H]). Fibrinogen interacts with the negatively charged ring around the active site as well as with the active site itself. Fibrinogen also interacts with the positively charged exosite shown on the right (Anion-binding exosite), which is likely important in both orienting fibrinogen correctly within the active site and maintaining a strong bond between enzyme and substrate. Upon recognition of the correct substrate sequence, the hydroxyl of Ser195 cleaves the postarginine peptide bond. The anionbinding site on the right will also bind hirudin-like proteins. The anionbinding exosite to the left binds to glycosaminoglycans (heparan and chondroitin) and to heparin.  

weak platelet hemostatic plug. Thrombin is highly specific in cleaving fibrinogen at only two arginine sites. The active site of thrombin is surrounded by negatively charged amino acid residues and away from this are positively charged exosites. This arrangement allows the very specific alignment and cleavage of fibrinogen (Fig. 45.1). There are no covalent bonds holding platelets together during formation of the primary hemostatic plug. If left in this state, the platelet plug disintegrates in a few hours, resulting in late bleeding. The process of blood coagulation, with soluble factors in the blood entering into a cascade of protease activation that leads to the formation of fibrin, is localized to the site where the original platelet plug was formed. This localization is achieved by two mechanisms. First, the chain of reactions that leads to cleavage of fibrinogen to fibrin is restricted to a surface, such as platelet phospholipids. Second, a series of inhibitors constrains the reaction to the site of injury and platelet deposition. Historically the blood coagulation system is separated into two initiating pathways: the tissue factor (extrinsic) pathway and the contact factor (intrinsic) pathway. These pathways meet in a final common pathway in which factor Xa converts prothrombin to thrombin, which then cleaves fibrinogen to fibrin. The prothrombin time (PT) is a plasma and test tube test of the integrity of the extrinsic pathway, and the activated clotting time or activated partial thromboplastin time (aPTT) are tests of the intrinsic system for blood and plasma, respectively. This model based on the concept of a waterfall or cascade is an oversimplification of the coagulation system, as proteins from each pathway influence one another. It is probably more correct to think of the coagulation system as an interactive network with carefully placed amplifiers and restraints. Fibrin formation involves a process of initiation and amplification. The specific properties of platelets and the coagulation system cooperate to ensure that fibrin formation occurs only at the localized site where it is required to initiate wound repair. This is achieved by the following physicochemical means. First, the surface of resting platelets contains acidic phospholipids such as phosphatidylserine that have their negatively charged pole directed inward. During irreversible shape change, this pole is flipped to the outside of the

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platelet to provide a negatively charged outer surface to anchor coagulation. Second, the coagulation system relies primarily on soluble factors synthesized in the liver that circulate in the plasma as inactive zymogen forms and become active after proteolytic cleavage. Apart from factor XIII, which is a transglutaminase, all active factors are serine proteases related to the digestive enzyme trypsin. Other factors in the coagulation process, such as tissue factor, factor V, factor VIII, and high-molecular-weight kininogen act as cofactors. Factors VII, IX, X, and prothrombin contain carboxylated glutamic acid residues at their N-terminal regions. Vitamin K acts as a cofactor for the enzyme that carboxylates glutamic acid, forming gamma-carboxy glutamic acid, with a resultant higher density of negative charges. This charged area interacts at the organizing surface of the platelet with ionized calcium ions (Ca2+), acting as a bridge with the negative surface charge on the activated platelet.

Indirect Inhibitors of Thrombin Generation Historical Considerations Heparin, one of the oldest anticoagulant drugs currently still in widespread clinical use, was discovered in 1916 by a second-year medical student, Jay McLean, and Professor Howell at Johns Hopkins University. McLean was investigating procoagulant preparations when he isolated a fat-soluble phosphatide anticoagulant in canine liver for which Howell coined the term heparin (from hepar, Greek for liver). In the early 1920s, Howell isolated a water-soluble polysaccharide anticoagulant, which was also termed heparin, although it was distinct from the phosphatide preparations previously isolated. Research on heparin continued into the 1930s. Jorpes described the structure of heparin in 1935, and the first heparin product for intravenous use was launched in 1936. Best perfected a technique for producing safe, nontoxic heparin that could be administered in a salt solution. The first human trials of heparin began in 1935, and by 1937 it was clear that heparin was a safe, easily available, and effective anticoagulant.

Heparins Heparins are available as unfractionated heparin (UFH) and lowmolecular-weight heparins (LMWHs), which are chemical modifications of unfractionated heparin. The pharmacology of both has been extensively reviewed.4–8

Unfractionated Heparin UFH is a naturally occurring glycosaminoglycan. It is a negatively charged sulfated polysaccharide formed from alternating residues of D-glucosamine and L-iduronic acid. Heparin is mostly located in lung, intestine, and liver in mammals. Standard preparations are derived from porcine intestine and prepared as calcium or sodium salts. The number and sequence of the saccharides are variable, producing a heterogeneous collection of polysaccharides. Molecular weights range from 3000 to 30,000 Da, with a mean of 15,000 Da representing 40 to 50 saccharides in length. There is no apparent difference between any of the available forms of UFH with respect to pharmacology or anticoagulant profile.6 Mechanism of Action Numerous physiologic actions have been proposed for heparin. Heparin has a direct antiinflammatory action in humans and a

Blood and Hemostasis

Antithrombin

+++

+

++

S

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S

872

Thrombin

A

+

18 Saccharides

S

S

S

B

C • Fig. 45.2  Effects of heparin chain length on antithrombin (AT) and its binding to thrombin. A, The pentasaccharide binds to AT to induce a conformational change, but the arginine-derived electropositivity (+++) remains to reduce affinity for thrombin. With increasing saccharide chain length contributing more anionic charge, this effect is reduced, as shown in B. The most avid reaction with thrombin requires heparin binding, not only to AT but also to thrombin itself, at the anionic binding site that normally binds glycosaminoglycans (shown as a lavender box) to form a ternary complex. Only heparin moieties with more than 18 saccharides are able to do this, as shown in C. wide spectrum of interactions with various enzymes, hormones, biogenic amines, and plasma proteins. The role of heparin as an antiinflammatory agent is strengthened when one considers that heparin alone has no effects on coagulation and is found in lower orders of the animal kingdom, such as mollusks, which lack a coagulation system. Heparin alone has no anticoagulant activity but requires a plasma cofactor, originally designated antithrombin III, and now simply called antithrombin or AT. AT has a low level of intrinsic anticoagulant activity mediated by a positively charged arginine center that binds to the catalytic serine of proteases of the coagulation cascade. Binding of heparin to AT is highly specific via a pentasaccharide sequence found in about one-third of molecules and is reversible. Binding of heparin and subsequent anticoagulant activity depend on saccharide chain length (Fig. 45.2). The binding of AT to thrombin is suicidal to the thrombin-antithrombin complex, but the heparin molecule is able to dissociate from this complex unchanged. Inhibition of thrombin activation also prevents feedback by thrombin on factors V and VIII, which normally amplifies the clotting cascade. In contrast, inhibition of factors IXa, Xa, and XIIa requires only that heparin bind AT to form the heparin-AT complex.6 This explains why LMWHs and the synthetic pentasaccharide fondaparinux act as inhibitors of factor Xa but not necessarily of thrombin.

Heparin has actions in addition to anticoagulant effects mediated via AT. At high blood levels (>4 IU/mL) heparin is capable of binding heparin cofactor II, potentiating its inactivation of bound activated thrombin.9 This action does not require the specific AT binding site but does require heparins of greater than 7200 Da or 24 saccharide units in length. The clinical importance of this action is unclear, but it might account for the need for higher doses of heparin to inhibit clot-bound thrombin. Much higher levels of heparin are needed to prevent the extension of venous thrombosis compared with those required to inhibit initiation of thrombosis.5,7 Heparin also stimulates release of tissue factor plasma inhibitor, which binds and neutralizes the tissue factor–FVIIa complex, reducing prothrombinase production via the extrinsic pathway. Plasma concentrations of tissue factor plasma inhibitor (TFPI) rise twofold to sixfold after injection of UFH and LMWH. Heparin also impairs platelet aggregation mediated by vWF and collagen, and inhibits platelet function by direct binding to platelets. The higher-molecular-weight heparins interfere most with platelet function.10 These actions might contribute to heparin-induced hemorrhage by a mechanism separate from its anticoagulant actions.

Metabolism and Elimination Elimination of heparin is nonlinear and occurs by two separate processes. The rapid saturable phase of heparin clearance is thought



to be due to cellular degradation. Macrophages internalize heparin, then depolymerize and desulfate it; saturation occurs when all receptors have been used and further clearance depends on new receptor synthesis. This process accounts for the poor bioavailability after low-dose subcutaneous injection, in that the slow rate of absorption barely exceeds the capacity of cellular degradation. Significant plasma levels can only be achieved once these cellular receptors have been saturated after a loading dose. The slower phase of heparin elimination is due to renal excretion. As the dose of heparin is increased, elimination half-life increases and the anticoagulant response is exaggerated. At a dose of 25 U/kg the half-life is about 30 minutes, increasing to about 150 minutes with a bolus dose of 400 U/kg. There are no consistent reports of the effects of renal or hepatic dysfunction on the pharmacokinetics of heparin.5,7

Clinical Pharmacology Pharmacokinetics and Pharmacodynamics

Heparins are usually administered by subcutaneous or intravenous injection as they are poorly absorbed from the gastrointestinal tract and cause hematomas after intramuscular injection. Safety of the two routes is comparable. Intravenous injection is the preferred route for a rapid anticoagulant effect; however, similar levels of anticoagulation can be achieved by the subcutaneous route with a delayed time to maximum effect.7 There is great variability in plasma concentration of heparin in relation to dose. After intravenous injection, more than 50% of heparin circulates bound to plasma proteins, including platelet factor 4, histidine-rich glycoprotein, vitronectin, fibronectin, and vWF. The first three of these neutralize heparin activity and its bioavailability. Increased levels of these proteins might account for heparin resistance sometimes seen in malignancy and inflammatory disorders.5 Plasma levels also decline rapidly owing to redistribution and uptake by endothelial cells and macrophages. Therapeutic Effects

Heparin is given to reduce thrombin generation and activity and therefore “anticoagulate” the patient. The therapeutic target dose depends on the indication and is tailored to patient need. For example, the degree of anticoagulation required to prevent thrombosis in a hemodialysis system is not as great as that required in cardiopulmonary bypass. Typically effectiveness of the dose is assessed at regular intervals using a coagulation test initiated by contact activation. The plasma version of this is the aPTT, which measures the effect of heparin on thrombin and factors IXa and Xa. The therapeutic range most commonly quoted is aPTT between 1.5 and 2.5 times the control value. However, commercially available kits for measurement of aPTT differ in their sensitivity to heparins. The whole blood version of the aPTT usually used when higher doses are administered is the automated or activated coagulation time (ACT), a standard of care in cardiac surgical practice; typically the ACT is maintained above 400 to 480 seconds. As there is a marked variation in response between individuals to the anticoagulant effect of a fixed dose of unfractionated heparin, regular monitoring of anticoagulation is routine.

Clinical Use For thromboembolic prophylaxis, UFH is administered either as “low dose” (5000 U subcutaneously 8 or 12 hourly) or “adjusted dose” (3500 U 8 or 12 hourly adjusted to maintain the aPTT about 3 to 5 seconds above control). For treatment of established thromboembolic disease, full therapeutic doses of heparin are used

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either by intravenous infusion or subcutaneous injection after an intravenous loading dose. Long-term heparin therapy is only used during pregnancy (unlike warfarin, neither UFH nor LMWH are able to cross the placenta) and for recurrent thromboembolic complications while the patient is taking adequate doses of warfarin. Low-dose UFH is safe and effective prophylactic treatment for surgical patients at risk for VTE. Low-dose subcutaneous UFH produces a greater than 50% reduction in the incidence of venous thrombosis and fatal or nonfatal PE.11 Although this is associated with an increased incidence of wound hematoma, there is no increase in major or fatal hemorrhage. Although relatively low doses of heparin are sufficient to provide thromboprophylaxis, much higher concentrations are needed to prevent thrombus propagation. Recommended regimens for the treatment of DVT with UFH include an intravenous loading dose of 5000 to 10,000 U followed by a continuous infusion of 1300 U/ hr, adjusted to maintain the aPTT 1.5 to 2.5 times control. This should be continued until warfarin therapy has prolonged the PT to a therapeutic range for at least 24 hours.12 This regimen reduces recurrence of venous thrombosis and mortality from PE. The most common reason for failure of treatment is inadequate anticoagulation, particularly within the first 24 hours, which is overcome by the large intravenous loading dose. These treatment protocols have been compared with twice-daily subcutaneous LMWHs without laboratory assessment, which is safer and more effective, with significant and important reductions in recurrence of thrombosis and major hemorrhage.13

Adverse Effects Until 2008, the standard of heparin potency was different between heparins marketed in North America, which used the United States Pharmacopeia (USP) standard, and heparins that used the World Health Organization (WHO)’s international standard or international unit. In 2008, the USP adopted new manufacturing controls for heparin, which included a modification to the reference standard for heparin unit dose. These changes were precipitated by a number of cases of severe hypotension, sometimes leading to death, reported in association with administration of heparin. In March 2008, the U.S. Food and Drug Administration (FDA) identified “oversulfated chondroitin sulfate” as a contaminant in heparin originating from China. This contaminant mimics heparin activity and behaves like UFH in standard USP tests. In vitro and in vivo studies showed that oversulfated chondroitin sulfate directly activates the kinin-kallikrein pathway in human plasma, which can lead to generation of bradykinin, a potent vasodilator.14 In addition, oversulfated chondroitin sulfate induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of oversulfated chondroitin sulfate in a similar manner. Oversulfated chondroitin sulfate–containing heparin and synthetically derived oversulfated chondroitin sulfate induce hypotension associated with kallikrein activation when administered by intravenous infusion in swine. Adopting the WHO international standard standards and introducing other safeguards allow early detection of this contaminant. The new standardized heparin now has a different strength that results in about a 10% reduction in “anticoagulant” potency compared with the previous USP standard. The current WHO standard has a potency of 122 IU/mg heparin. The reduced potency should have no clinical effect in that dosing regimens are tailored to individual patient needs.

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TABLE a 45.1  Scoring System for Diagnosing Type II Heparin-Induced Thrombocytopenia (HIT)

4 T’s

2 Points

1 Point

0 Point

Thrombocytopenia

Platelet count fall >50% and platelet nadir >20 × 109/L

Platelet count fall 30%–50% or platelet nadir 10–19 × 109/L

Platelet count fall 80%) and inhibition of platelet function.60 Skin bleeding time recovers within 12 hours of stopping the infusion. Although low levels of GpIIb/IIIa receptor blockade are present for more than 10 days after cessation of the infusion, platelet function typically returns to normal over a period of 24 to 48 hours. Tirofiban inhibits ADP-induced platelet aggregation ex vivo and prolongs bleeding time. After a loading dose of 0.4 µg/kg over 30 minutes, platelet aggregation was inhibited by more than 90% and bleeding time was prolonged about threefold. After discontinuation of an infusion of tirofiban, ex vivo platelet aggregation returns to near baseline in approximately 90% of patients in 4 to 8 hours.61 In clinical trials, eptifibatide inhibits platelet aggregation ex vivo induced by ADP and other agonists in a dose- and concentration-dependent manner.62 The effect of eptifibatide was observed immediately after administration. Platelet aggregation is inhibited by about 85% after bolus injection and more than 90% during the steady-state infusion. Platelet aggregation returns to less than 50% inhibition 4 hours after discontinuing the infusion, and bleeding time returns to baseline within 6 hours of discontinuing the drug. Therapeutic Effects

The benefit of GpIIb/IIIa inhibitors is mainly limited to high-risk patients with unstable angina or non–ST-elevation MI.63 The most notable conditions where benefit is shown are in troponin-positive patients, regardless of whether they undergo revascularization, and those with diabetes mellitus. The TARGET (Treatments Against RA and Effect on FDG-PET/CT) trial provides the only direct comparison of a small molecule (tirofiban) agent with abciximab, and this trial demonstrated superiority for abciximab in reducing ischemic endpoints. For diabetic patients, abciximab is the only GpIIb/IIIa inhibitor observed to provide a significant survival advantage in patients undergoing PCI with angioplasty or stent placement, and thus is singled out as the agent of choice for use in diabetic patients undergoing stent implantation. Abciximab also has the most data supporting safety in patients with severe renal insufficiency, likely because of its nonrenal mode of metabolism and elimination. Current American College of Cardiology/American Heart Association guidelines recommend a platelet GpIIb/IIIa antagonist in patients with moderate- to high-risk ACS in whom catheterization and PCI are planned (class I, level A). Patients receiving a bolus plus infusion of abciximab have a significant (35%–50%) reduction in the composite endpoint of death, nonfatal MI, refractory ischemia, or urgent revascularization within 30 days. Treatment

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benefits are observed within hours after intervention and are sustained through 6 to 12 months. Eptifibatide or tirofiban should be administered in patients with high-risk ACS in whom invasive management is not planned (class IIa, level A). In contrast to the data for abciximab, treatment with eptifibatide in the IMPACT II (Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II) study showed a treatment effect over 30 days that was lost at 6-month follow-up. Similarly in the RESTORE (Randomized Evaluation of Sedation Titration fOr Respiratory failure) study, the early treatment effect to prevent restenosis after angioplasty with tirofiban was lost at 6-month follow-up. An evidence-based approach would thus favor abciximab as the standard GpIIb/IIIa inhibitor for administration during PCI, especially in patients with ACS accompanied by high-risk features, including diabetes mellitus. Adverse Effects Bleeding.  As with all anticoagulant and antiplatelet agents,

bleeding is a risk. The main concern is when these agents are given with anticoagulants, especially heparin. With abciximab, the incidence of bleeding decreases to only about 2% when used with low-dose heparin (70 U/kg) and further studies have reported major bleeding rates that are at least as low, if not lower, than that owing to heparin alone. With tirofiban, the addition of heparin does not significantly alter inhibition of platelet aggregation, but it does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to more than 30 minutes. The principal site for bleeding is the femoral artery puncture site used for vascular access. To reduce the risk of bleeding, manufacturers recommend stopping heparin 3 to 4 hours before cannula withdrawal. Thrombocytopenia.  Thrombocytopenia can occur with all the GpIIb/IIIa receptor antagonists, with some variability related to the agent administered, dosage, duration of treatment, and the various drugs coadministered. Incidence of thrombocytopenia ranges from 1.1% to 5.6%. An immune mechanism is believed to be responsible. Binding of the antagonist to GpIIb/IIIa receptors might lead to exposure of ligand-induced binding sites to preexisting or induced antibodies. Another possible mechanism for thrombocytopenia is drug-induced activation of platelets. Thrombocytopenia induced by these mechanisms occurs within the first 24 hours of administration. All patients receiving parenteral GpIIb/IIIa antagonists should be monitored within 24 hours of initiation of therapy for development of thrombocytopenia and the drug discontinued if this occurs. Special Populations and Contraindications

Treatment with GpIIb/IIIa receptor antagonists is contraindicated in patients with severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled by antihypertensive therapy, major surgery or history of major trauma within the preceding 4 to 6 weeks, history of stroke within 30 days or any history of hemorrhagic stroke (for tirofiban and eptifibatide), increased to 2 years before the use of abciximab, or a history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm. For abciximab, additional contraindications are administration of oral anticoagulants within 7 days unless the PT is less than or equal to 1.2 times control, use of intravenous dextran before percutaneous coronary intervention, or intent to use it during intervention, or presumed or documented history of vasculitis.

Tirofiban is also contraindicated with a history, symptoms, or findings suggestive of aortic dissection or pericarditis. As both tirofiban and eptifibatide are principally cleared by the kidney, both should have the dose of the maintenance infusion reduced to half with an estimated creatinine clearance less than 50 mL/ min. Both are also contraindicated in patients receiving long-term renal dialysis, as is abciximab, but in this case because of a lack of safety data in this population. Special Populations and Unique Features

Except for patients with renal disease, there are no groups of patients in whom these drugs are associated with a relative increase in adverse effects. Administration of abciximab can result in the formation of human antichimeric antibodies that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia, or diminished benefit upon readministration.

Protease Activated Receptor-1 (Thrombin Receptor) Platelets have a specific surface G protein–coupled receptor known as protease-activated receptor-1 (PAR-1) receptor for thrombin. The extracellular portion is a long polypeptide, which has an arginine residue at position 41 and a serine at position 42. Thrombin cleaves this peptide at this position, resulting in a hexapeptide SFLLRN at the N-terminal end. This is the tethered ligand for the stimulation of the receptor. Compounds have been developed that inhibit the ligand-binding site on PAR-1. Because the proteolytic activity of thrombin to cleave fibrinogen is not inhibited, coagulation should be unaffected. Vorapaxar is the only currently licensed protease activated receptor 1 or thrombin receptor inhibitor for human use. It is a derivative of himbacine, which is found in the bark of the Australian magnolia tree. Himbacine’s marked activity as a muscarinic M2 receptor agonist made it a potential medication for Alzheimer disease but this action was engineered out of the current medication. Vorapaxar is available as a tablet containing 2.08 mg of vorapaxar sulfate. It is licensed as an adjunct to aspirin or clopidogrel therapy for reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral arterial disease. Vorapaxar was administered to more than 13000 patients in the TRA 2P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) (TIMI [Thrombolysis in Myocardial Infarction] 50) study to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. This study also showed an increased rate of intracranial bleeding, and the prescribing information has a black box warning that intracranial bleeding is more common with varapaxar and that it is contraindicated in patients with a history of stroke, TIA, intracranial hemorrhage, or active pathologic bleeding. At the recommended dose varapaxar achieves 80% or higher inhibition of thrombin receptor activation peptide–induced platelet aggregation by one week. Vorapaxar is 99% protein bound and is metabolized by cytochromes CYP 3A4 and CYP 2J2 to an active metabolite. The apparent terminal elimination half-life is about 8 days (range 5–13), and this is also the case for the metabolite. The manufacturers suggest that there will still be 50% inhibition of thrombin receptor activation peptide–induced platelet aggregation 4 weeks after discontinuation of the drug based on elimination kinetics. There is no known antidote, so this raises serious concerns about urgent surgical interventions.

CHAPTER 45  Anticoagulant and Antiplatelet Therapy



Emerging Developments Reversal of Novel Anticoagulants The introduction of orally administered direct thrombin and factor Xa inhibitors has produced a search for specific antidotes to these agents. Three lines of development are being pursued. The first is drug specific. Idarucizumab is a monoclonal antibody developed by the manufacturers of dabigatran etexilate and raised against fragments of the dabigatran molecule and its metabolites. It is given intravenously at a dose of 5 g. This dose will reverse the coagulation tests associated with dabigatran use (dilute thrombin time and ECT) within minutes of administration. However, there are some concerns if this is a biologically relevant endpoint in preventing bleeding. In animal studies of traumatic hepatic injury, idarucizumab did reverse the effect of dabigatran on blood loss but not to the values measured with no pharmaceutical intervention64 (Fig. 45.9). Early results of the ongoing RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study29 reported that, as determined by local investigators, hemostasis was restored in 35 patients presenting with serious bleeding by a median of 11.4 hours after administration of idarucizumab. This time is about the same as the half-life of dabigatran, leading to speculation as to the effectiveness of the antibody to provide very rapid reversal.

Idarucizumab (mg/kg) • Fig. 45.9  Effects of increasing dose of idarucizumab on mean blood loss 120 minutes after hepatic trauma in male pigs given dabigatran exilate 30 mg/kg twice daily for 3 days. Data show idarucizumab effectively reduces acute bleeding. However, mean total loss with the highest dose is greater than that in Sham (no dabigatran, no idarucizumab) animals.64

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Sorbitol at a high concentration is used as an excipient for the commercially available preparation, and thus this agent should be used with extreme caution in patients with inherited fructose intolerance. The drug is expensive with a wholesale cost of a single treatment of 5 g in the United States of $3500 (about £2600 or €3200). The second drug is a class-specific reversal agent for both direct and indirect factor Xa antagonists. Andexanet alfa is a recombinant factor Xa “decoy molecule” that has been designed so that it lacks the glutamic acid–rich membrane-binding domain, is enzymatically inactive as it has a serine to alanine substitution at the active cleavage site of factor Xa, and finally has deletion of the heavy-chain activation peptide (Fig. 45.10). The molecule inhibits all oral factor Xa inhibitors and is unique in being able to inhibit indirect inhibitors such as LMWH and fondaparinux. This agent has been extensively studied in animal models of traumatic hemorrhage and has been shown to fully reverse the effects of both the oral Xa inhibitors and enoxaparin.65 Data from studies to reverse rivaroxaban inhibition in a hepatic trauma model (Fig. 45.11) show complete reversal of the effect of rivaroxaban on blood loss. Initial studies have been reported in humans with bleeding and who were recently taking an Xa inhibitor.32 Of the 67 patients (mean age 77 years), 32 were receiving rivaroxaban, 31 apixaban, and 4 enoxaparin. The site of bleeding was gastrointestinal in 33 (49%) and intracranial in 28 (42%). Based on data from prior studies andexanet alfa was given as a bolus over 15 minutes followed by an infusion over 2 hours. Two doses were administered. In patients who had received rivaroxaban or apixaban more than 7 hours before hospital admission, a bolus of 400 mg and the total for infusion of 480 mg. For patients taking edoxiban, enoxaparin, or rivaroxaban within 7 hours of admission the dose was doubled to a bolus of 800 mg and an infusion of 960 mg. The rates for good or excellent hemostasis were more than 80% for both gastrointestinal and intracranial hemorrhage. The final agent being developed potentially has universal applicability. Ciraparantag has been developed to bind to specific portions of all of the novel anticoagulants and also LMWHs. Ciraparantag consists of two L-arginine units connected with a piperazine-containing linker chain. Binding to substrate is by electrostatic or hydrogen bonding. Phase II studies in humans showed that ciraparantag administration reversed the anticoagulant activity of enoxaparin. Phase III studies are currently underway. The spectrum of inhibitor activity (drug, class, or overall) is shown schematically in Fig. 45.12.

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• Fig. 45.10

  The structure of the ‘decoy’ factor Xa molecule andexanet. The molecule is factor Xa without the membrane binding domain. Andexanet is also enzymatically inactive owing to a serine to alanine substitution at the active pocket site.

Blood Loss (gram)

20

Ciraparantag

15 10 Andexanet alfa

5 0

Vehicle

• Fig. 45.11

Rivaroxaban Rivaroxaban + Andexanet

Vehicle + Andexanet

Effects of andexanet administration on mean blood loss in a rabbit hepatic laceration model of bleeding. Animals that were treated with rivaroxaban orally for 3 days showed a 3- to 4- fold increase in blood loss, which was totally prevented by administration of andexanet before trauma.65  

LMWH Oral direct Xa Inhibitors Apixaban Rivaroxaban Edoxaban

Heparin LMWH Oral direct thrombin Inhibitor Dabigatran

Idarucizumab

Fondaparinux

• Fig. 45.12

  Schematic representation of antidotes to anticoagulating agents. Idarucizumab is an antibody specific for dabigatran. Andexanet alfa is a “decoy” factor X analog that is class specific for direct- and indirect-acting factor Xa inhibitors. Ciraparantag is being developed to have a universal inhibitory action on all anticoagulants except the pentasaccharide fondaparinux.



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Key Points • Arterial and venous occlusion with thrombus is a major contributor to mortality and morbidity. • Improvements in physical chemistry have allowed targeting many receptors associated with the coagulation network and platelet function to inhibit coagulation and platelet aggregation. • Until recently the mainstay of anticoagulant therapy was heparin and vitamin K antagonists, and the mainstay for platelet inhibition was acetylsalicylic acid. • Understanding the receptor structure and function of platelets and the active proteolytic sites of coagulation proteins has allowed

Key References Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. Br Med J. 2002;324:71–86. Collated data from controlled trials show that therapy with antiplatelet agents, and especially aspirin, was able to reduce mortality and morbidity associated with high shear stress arterial occlusions found in patients with myocardial infarction and stroke. This observation paved the way for further drug development in this area. (Ref. 39). Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015;386:281–291. Commisioned review of the pharmacology of newer anticoagulant agents outlining their potential strengths and weaknesses, and their use in the management of venous thrombosis and thromboembolism. (Ref. 3). Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:199S–233S. Consensus evidence-based document outlining the best practice use of antiplatelet agents in the prevention and treatment of myocardial infarction and ischemia. (Ref. 51). Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–520. (Ref. 29) Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor XA inhibitors. N Engl J Med. 2016;375:1131–1141. (Ref. 32). Two milestone articles demonstrating the efficacy of novel agents that can inhibit the anticoagulant action of a direct thrombin and a direct factor Xa inhibitors in humans. These and similar agents being developed will reduce considerably the risk of bleeding during urgent interventions or when there is unexpected bleeding. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358:1037–1052. A review of low sheer stress venous thrombosis and thromboembolism. The article highlights risk factors for venous thrombosis that are being included in standard perioperative risk management strategies. (Ref. 2).

References 1. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98:756–764. 2. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358:1037–1052. 3. Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015;386(9990):281–291. 4. Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis. 1996;26(suppl 2):24–38. 5. Hirsh J. Heparin [see comments]. N Engl J Med. 1991;324(22): 1565–1574.

rational development of novel drugs to modify or inhibit thrombogenesis and coagulation. • However, the new direct oral anticoagulant drugs and new platelet-inhibiting agents increase bleeding risk associated with surgery and invasive procedures. • In the case of the new oral anticoagulants, there is no ability to monitor their effect using simple standard laboratory assays, and antiplatelet activity can be measured only by specialized methods. • Pharmacokinetics and pharmacodynamics of anticoagulant and antiplatelet drugs can differ significantly between patients depending on factors such as renal function, age, and frailty.

6. Hirsh J, Dalen JE, Deykin D, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1992;102(4 suppl):337s–351s. 7. Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79(1):1–17. 8. Hirsh J, Levine MN. Low molecular weight heparin: laboratory properties and clinical evaluation. A review. Eur J Surg Suppl. 1994;571:9–22. 9. Tollefsen DM, Majerus DW, Blank MK. Heparin cofactor II. Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem. 1982;257(5):2162–2169. 10. Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest. 1980;65(1):64–73. 11. Gallus AS. Anticoagulants in the prevention of venous thromboembolism. Baillieres Clin Haematol. 1990;3(3):651–684. 12. Litin SC, Gastineau DA. Current concepts in anticoagulant therapy. Mayo Clin Proc. 1995;70(3):266–272. 13. Green D, Hirsh J, Heit J, et al. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev. 1994;46(1):89–109. Issn: 0031-6997. 14. Kishimoto TK, Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008;358(23):2457–2467. 15. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention [see comments]. Am J Med. 1993;95(3):315–328. 16. Linkins LA, Warkentin TE. The approach to heparin-induced thrombocytopenia. Semin Respir Crit Care Med. 2008;29(1):66–74. 17. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759–765. 18. Fareed J, Walenga JM, Hoppensteadt D, et al. Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins [published erratum appears in Haemostasis 1988;18(4–6):following 389]. Haemostasis. 1988;18(suppl 3):3–15. 19. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecularweight heparin versus standard heparin in general and orthopedic surgery: a meta-analysis. Lancet. 1992;340(8812):152–156. 20. Turpie AG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833–1840. 21. Turpie AG, Bauer KA, Eriksson BI, et al. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest. 2004; 126(2):501–508. 22. Agnelli G, Bergqvist D, Cohen AT, et al. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005;92(10):1212–1220. 23. Buller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial

894

SE C T I O N VIII

Blood and Hemostasis

treatment of pulmonary embolism. N Engl J Med. 2003;349(18): 1695–1702. 24. Gage BF, Birman-Deych E, Radford MJ, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166(2):241–246. 25. Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011;72:581–592. 26. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. 27. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. 28. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res. 2010;126(3):175–182. 29. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520. 30. Padmanabhan K, Padmanabhan KP, Tulinsky A, et al. Structure of human des(1-45) factor Xa at 2.2 A resolution. J Mol Biol. 1993;232(3):947–966. 31. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8): 699–708. 32. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with Factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–1141. 33. Majerus PW. Arachidonate metabolism in vascular disorders. J Clin Invest. 1983;72(5):1521–1525. 34. Pedersen AK, FitzGerald GA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med. 1984;311(19):1206–1211. 35. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest. 1975;56(3):624–632. 36. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA. 1975;72(8):3073–3076. 37. Demers LM, Budin RE, Shaikh BS. The effects of aspirin on megakaryocyte prostaglandin production. Proc Soc Exp Biol Med. 1980;163(1):24–29. 38. Najean Y, Ardaillou N, Dresch C. Platelet lifespan. Annu Rev Med. 1969;20:47–62. 39. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71–86. 40. Patrono C, Garcia Rodriguez LA, Landolfi R, et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med. 2005;353(22):2373–2383. 41. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA. 2004;292(15):1867–1874. 42. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet. 2006;367(9510): 606–617. 43. Slattery J, Warlow CP, Shorrock CJ, et al. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin–analysis of gastrointestinal bleeding during the UK-TIA trial. Gut. 1995;37(4):509–511. 44. Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108(14):1682–1687. 45. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1–2):1–13. 46. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY

trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9(2):159–166. 47. Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgrad Med. 2011;123(1):73–79. 48. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373(9665):723–731. 49. Quinlan DJ, Eikelboom JW, Goodman SG, et al. Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes. Eur Heart J. 2011;32(18):2256–2265. 50. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003;107(1):32–37. 51. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):199S–233S. 52. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354–362. 53. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119(19):2553–2560. 54. Alexopoulos D, Xanthopoulou I, Mylona P, et al. Prevalence of contraindications and conditions for precaution for prasugrel administration in a real world acute coronary syndrome population. J Thromb Thrombolysis. 2011;32(3):328–333. 55. Keltai M, Tonelli M, Mann JF, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil. 2007;14(2):312–318. 56. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577–2585. 57. Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57(6):672–684. 58. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464–1476. 59. Schneider DJ. Anti-platelet therapy: glycoprotein IIb-IIIa antagonists. Br J Clin Pharmacol. 2011;72(4):672–682. 60. Saucedo JF, Lui HK, Garza L, et al. Comparative pharmacodynamic evaluation of eptifibatide and abciximab in patients with non-STsegment elevation acute coronary syndromes: the TAM2 study. J Thromb Thrombolysis. 2004;18(2):67–74. 61. Solinas E, Gobbi G, Dangas G, et al. Comparison of the effects of pretreatment with tirofiban, clopidogrel or both on the inhibition of platelet aggregation and activation in patients with acute coronary syndromes. J Thromb Thrombolysis. 2009;27(1):36–43. 62. Saucedo JF, Garza L, Wolford DC, et al. Comparative pharmacodynamic evaluation of eptifibatide and tirofiban HCl in patients undergoing percutaneous coronary intervention (the TAM1 Study). Am J Cardiol. 2004;93(10):1279–1282. 63. Friedland S, Eisenberg MJ, Shimony A. Meta-analysis of randomized controlled trials of intracoronary versus intravenous administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention for acute coronary syndrome. Am J Cardiol. 2011;108(9):1244–1251. 64. Grottke O, Honickel M, van Ryn J, et al. Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation. J Am Coll Cardiol. 2015;66(13):1518–1519. 65. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–451.

A Abciximab, as antiplatdet drug, 888, 889t Abdominal compartment syndrome, crystalloids and, 795. 799 Abilify (aripiprawle), as atypical antipsychotic, 255 Abuse, drugs of, 263-264 amphetamines as, 264 cocaine as, 263-264 ethanol as, 263 ABW: see Adjusted body weight Acetaminophen, 744 features of, 375--376 for postoperative analgesia,

3761--377t, 377/ Acctazolamide, 829 Acetic acid de.dvatives characteristics of, 372t molecular structure of, 371/ .Aretohc:xamide, as oral hypoglycemic, 712 Acecylator status, adverse drug reactions and, 132-133 .Aretylcholine (ACh) in cholinergic synapse, 273, 273/ muscarinic actions of, 295/,

295t in neuromuscular transmission, 413 receptors for, 157t, 159 rdease of, extracellular Ca2+ concentration and, 414 synthesis o f, 413-414 Acecylcholine receptors (AChRs), 416-419 dectroph~ology of, 417 immature, 417-418 re-expression of, after denervation or pathologic states, 419 postjunctional, mature and immature, 417.f-418/, 418-419 postsynaptic, 417-418 presynaptic, 418 structure of, 416-417, 416/-417/

Page numbers followed by /indicate figures, t indicate tables, and b indicate boxes.

types of, 417-419 upregulation and downregulation of, 419 Acetylcholinesterase, in neuromuscular junction, 416 Acecylsalicylic acid, as antiplatelet agent, 883, 884t ACh. see Acetylcholine Achalasia, 636 AChRs. see Acecylcholine receptors Acid-base balance, kidneys in, 787 Acide.mia, increased ventilation in, 595 ACLS drug chart, 576t Acromegaly, 694, 695/ Accin filaments, in vascular smooth muscle, 464-465, 465/, 467, 467/ Action potential(s) cardiac, 458-459 dectrocardiogram and,

559f impulse propagation and conduction in, 457/, 459-460,460/ nerve terminal, 415-416 of neuronal cdl membrane, in communication, 154, 155/-156/ Activated factor X inhibitors, as thrombin inhibitors, 881-882, 882/, 882t Activated partial thromboplastin time, in hemostatic testing, 844t Active zones, in terminal portion of nerve, 413/, 414 Acute doxorubicin toxicity, 755 Acute respiratory distress syndrome (ARDS), crystalloids and, 795, 799 ADD. see Attention deficit disorder Addison disease, 701-702 Additivity, in drug interactions, 113-114, 114/ isobologram of, 115/ Adenohypophys~,693

Adenosine, 542, 576t Adenosine diphosphate analogs, as anciplatdet drugs, 887-888 ADH. see Antidiuretic honnone ADHD. see Attention deficit/ hyperactivity disorder

Adjusted body weight (ABW), 94t Administration, of antimicrobial drugs, 774, 7751--777t Adrenal cortex, physiology of, 700-702, 701t Adrenal gland, physiology of, 700-702 Adrenal insufficiency, 720 Adrenal medulla catecholamines secreted by, 285,702 pheochromocytoma and, 702-703 physiology o f, 702-703, 702t in sympathetic nervous system, 276 Adrenergic agents, added to local anesthetics, 403, 403t arAdrenergic agonoo added to local anesthetics, 403 inhaled anesthetics and, interactions between, 122 Adrenergic agonists, rdative potency of, 286t Adrenergic blocking drugs, 291-293 Adrenergic G protein-coupled receptors (GPCRs), 283 Adrcnergic pn:synaptic terminal, 274/ Adrenergic receptor classification of, 274-275, 275/, 283 pharmacogenetics of, 523-525 scruccure and mechanism, 283-285,284/ in vascular smooth muscle regulation,469 Adrenergic receptor agonists/ antagonoo, cerebrovascular effects of, 180, 180f a-Adrenoceptor antagonoo of, 291 classification and al/a2 selectivity of, 288t epinephrine infusions and, 285-286 pharmacogenetics of, 523-525 a 1-Adrenoceptor activation and inhibition of, 283 agonoo of, 287-288 methoxamine as, 288 midodrine as, 288 phenylephrine as, 287-288 physiologic effects of, 285/

arAdrenoceptor, activation and inhibition of, 283 b-Adrenoceptor, pharmacogenetics of, 523-525 b 1-Adrenoceptor, 283-285 activation of, ph~ologic effects of, 286/ agonoo of dobutamine as, 289 isoproterenol as, 289 antagon~ts of, 291-293 epinephrine infusions and, 285-286 selective agonw of, 289 brAdrenoceptor, 283 activation of, physiologic effects of, 286/ in bronchial smooth muscle control, 587 epinephrine infusions and, 285-286 selective agonw of, 289 ritodrine as, 289 terbutaline as, 289 brAdrenoceptor agonises, 614-616 inhaled, for bronchospasm, 614-616 adverse effects, 615-616 clinical application, 616 clinical pharmacology, 615-616 clinical pharmacology of, 615-616 drug interactions of, 616 mcchan~ and metabolism of, 614-615 pharmacodynamics of, 615 pharmacokinctics of, 615 rationale drug selection and administration, 616 structure-activity, 614, 614t, 615/ b adrenoceptor blocking drugs, 539 Adrenocorticotropic hormone (ACTH), 721 hypersecretion of, Cushing disease from, 694-695 releasing and inhibiting factors for, 694t a-Adrenoreceptor agonists, 541

895

Index

a2-Adrenoreceptor agonists, 288-289, 541, 541.f. 547 clonidine as, 288, 288t dexmedetomidine as, 288-289, 288t Adverse drug reaction(s), 130-143 augmented (dose related), 131-132, 131~ 132/-133/ bizarre (idiosyncratic), 131 t, 132-137, 134(.137/ acetylator status and, 132-133 allergic drug reactions as, 135-137 cytochrome P450 variants and, 133 glucose-6-phosphate dehydrogenase deficiency and, 133-134 malignant hyperthermia and, 134-135, 135.f. 137/ plasma cholinesterase variants and, 133 porphyrias and, 134, 135/ chronic {direct organ damage), 131t, 137-138, 138/ classification of, 130, 13lt definition of. 130 delayed (time related), 131t, 138-140, 139/ drug f.tilure, 131t, 138-140, 139/ end of use (withdrawal), 13lt, 138 incidence of, 130-131 prevention of, emerging developments in, 140-141, 140/ types of, 131-140, 131t Advisory display systems, PK-PD, 37, 38/ Affinity developing concept of, 3 diswciation constant and, 4 Afterload, cardiac output and, 475, 477/

Age cerebrovascular effects of, 181 changes in neuromuscular junction related to, 420 minimum alveolar concentration of volatile anesthetics and, 229, 229/ opioid pharmacology and, 341-342,342/

Aging autonomic f.tilure and, 278 physiology and pharmacology of, 91-112 Agonism, 3, 4f. 6 inverse, 6 Agonist(s)

full, 6, 7/ interaction with additive agonist, response surf.ice for, 117/

Agonist{s) (Continued} interaction with competitive antagonist, response surfu:e for, 117/ interaction with infra-additive agonise, response surfu:e for, 117/ interaction with inverse agonist, response surf.ice for, 117/ interaction with partial agonise, response surf.ice for, 117/ interaction with supra-additive agonist, response surfu:e for, 117/ inverse, 6, 7f

partial. 6, 7f

l>-Agonists, inotropic mechanisms of, 522 Agranulocytosis, from second generation antipsychotics, 255 Airway{s) diameter cellular physiology and, 587-588 control of, 587. see also Bronchial smooth muscle, control of disease of, bronchoconstriction in, 589-590 remodding of, 596, 596t Airway collapse, risk of, 438/439.f. 439--440 Airway edema, corticosteroids for, 721 Airway to residual block, sensitivity of musculature of, 440 Akathisia, from first-generation antipsychotics, 251-254 Albumin transfusion of, 851-852 in volume replacement therapy, clinical recommendations on,807 Albuterol metabolism of, 615 structure of, 284/ Alcohol withdrawal syndrome, benmdiazepines for, 250 Aldosterone deficiency of, 701-702 excess of, 701 synthesis and rdease of, 700 in total body sodium regulation, 797 Alfentanil. see also Opioid(s) features of, 344 and midazolam with propofol, synergistic effects, 124-125 synergistic effecrs, 124-125 physicochemical and pharmacokinetic parameters of, 334t renal dysfunction and, 790 Aliphatic compounds, pharmacology of, 252.f.

252t-253t

Alkanes, 44-45, 45/ Alkylating agents cause DNNRNA damage, 754,

755.f-756/ side effects of, 754 subclass, 756t All or none phenomenon, dectrochemical impulse conduction as, 394 Allergic drug reactions, 135-137 to local anesthetics, 391 Allergy corticosteroid therapy for, 722 definition of, 135-136 to NSAIDs, 374 Alloconex, 161 Allodynia description of, 318 spinal mechanisms of, 318-321 Allosteric binding sites, 8, 1Of Allosteric drug interactions, 8, 10/ definition of, 8 Alpha interferons, 651 Alprazolam (Xanax), introduction of, 248 Alveolus, in oxygenation, 590 Alvimopan (Entereg) , 650-651 for postoperative nausea and vomiting,686--687,686/ properties of, 674~76t Alzheimer disease (AD), 232 lithium and, 256 Amantadine, for neurolepticinduced pseudoparkinsonism, 254 Ambriscntan, 552 Amide local anesthetics dosages of, recommended, 398t ester local anesthetics w:rsus, 391,391/ historical perspective on, 391 physicochemical properties of,

393t specific, 400-401 Amiloride, 546 Amino acids, for surgical patients, 666 e-Aminocaproic acid (EACA), transfusion of, 861 Aminoglutethimide, as steroid antagonist, 721 Aminoglycosides, as perioperative antimicrobial drugs, 772-773 Aminolevulinic acid (ALA) synthetase, induced activity of, adverse drug reactions and, 134 Amiodarone, 576t clinical applications of, 567-568 for ventricular fibrillation,

565 Amitriptyline chemical structure of, 242/ features of, 380-381 side effecrs of, 380t Amnesia, in anesthesia, 221

Amoxapine, chemical structure of, 242, 242f AMPA receptors in dorsal hom nociceptive circuits, 317, 318.f-319/ as targets of intravenous anesthetics in CNS, 197-198 Amphetamines abuse of, 264 as indirect-acting sympathomimetic, 290 as psychostimulant, 258, 259.f. 259t Amphotericin B, as perioperative antimicrobial drugs, 773 Amrinone, 548 Amygdala, in nociceptive physiology, 323 Amylin, as oral hypoglycemics, 713 Analgesia by inhaled anesthetics, 225 postoperative, opioids for, 346 postoperative, oral NSAIDs for, 376, 376.f. 376t Analgesics, nonopioid, 369-389. see also Nonopioid analgesics Analogs, 722-723 Anaphylactic shock, epinephrine fur, 525 Anaphylaxis, definition of, 136, 136t Andc:xanet, 892/ Androgens, basic and clinical pharmacology of, 724-725 Anesthesia, 753-780

balanced history of, 113, 193 opioids for, 346 cancer and, 765-766 local anesthetics, 766 opioids, 765 propofol, 765-766 volatile anesthetics, 765 high dose opioid, 346 Anesthetic drugs cerebral blood flow and, 177, 178/ effecrs, real-time display of, 125-126, 126/ impaired renal function and, 790 intravenous,647-648 and liver, 647-648 local, 390-411. see also Local anesthetics pharmacogenetics of, 70, 71/ Anesthetic pharmacology historical perspective on, 20-21 unique aspects, 21-22 Anesthetic posology, in obesity, 93-97 Anesthetic preconditioning, 348 Anesthetic techniques and agents, effecrs of, 303 Angina diltiazem for, 569 vcrapamil for, 569

Index

Angiotensin-converting enzyme inhibitors, 539-540, 540/, 546 Angiotensin II, in vascular smooth muscle regulation, 469-470 Angiotensin rc:ceptor antagonists, 539-540 Anorexia nervosa, sdective serotonin reuptake inhibitors for, 247 ANP. stt Atrial natriuretic peptide ANS. stt Autonomic nervous system Antagonism, 6--8, 7f competitive, 7, 7f in drug interactions, 114 isobologram of, 115/ Antagonists, 722--723 competitive, interaction of agonist with, response surface for, 117/ noncompetitive, 8 b-Antagonists, 291-293, 292t, 717 side effects of, 292 Anteparrum anticoagulation, 745-747. 7461, 747/ Anterior circulation, 175 Anterior pituitary, 693-695 hormones produced by, 693, 694t tumors of, hyperpiruitarism and, 694-695 Antiarrhythmic drug(s), 556-574 arrhythmogenic mechanisms and, 564-565 basic pharmacology of, 557-564 class I clinical application of, 565-566 mechanism of action of, 557, 557t sodiwn channels and, 557-560, 559f-560f class lb, clinical applications of, 566-567 class le, clinical applications of, 566-567 class II b receptors and, 560, 561/ clinical applications of, 567 mechanism of action of, 557, 557t class III clinical applications of, 567-568 mechanism of action of, 557, 557t potassium channels and, 560-561, 562/ class N calcium channds and, 563-564, 563/ clinical applications of, 568-569 mechanism of action of, 557, 557t

Antiarrhythmic drug(s) (Continutd) clinical application of, 565-569 clinical pharmacology of, 558t, 564-565 control of, 568/ emerging devdopments in, 569-571 historical perspective on, 556-557 sdection of, 569/ Singh-Vaughan William classification of, 557, 557t Antibiotic prophylaxis, 744 surgical, 770-771, 770/, 771t Antibiotics, antineoplastic cause DNA/RNA damage, 754-757. 757t topoisomerase inhibitors, 757-758, 758~ 759fi 760t Anticholinergics, 294 for bronchospasm, 616-618 adverse effects, 616-617 clinical application, 615/, 617-618 clinical pharmacology, 616--617 mechanism and metabolism, 616, 617/ pharmacodynamics of, 616 pharmacokinctics of, 616 structure-activity, 614t, 616, 618/ therapeutic effects of, 616 tricyclic interactions with, 244, 380 Anticholincsterascs, 294, 441-443 adverse effects, 442 dosing, 442--443, 442/ for myasthenia gravis, 260-261 pharmacokinetics and pharmacodynamics, 443 speed and adequacy of recovery, determinants of, 441-442 Anticoagulant factors, natural, from, 838-839 Anticoagulation, 745-747 Anticonvulsant effects, of ctomidate, 202 Anticonvulsant mood stabilizers, 257-258, 257/ Antidepressants, 242-248 aripiprazole as, 255 atypical, 248, 249t monoamine oxidase inhibitors as,248 sdective serotonin reuptake inh.ibitors as, 245-247. stt also Selective serotonin reuptake inhibitors (SSRis) tricyclic, 242-244 Antidiurctic hormone (ADH). stt also Vasopressin inappropriate, syndrome of, 695-696, 6961 Antidotes, novel, 17, 17t

Antiemetics, 744 errors in administration of, 131 h.istorical perspective on, 671 properties of, 674~76t Antiepileptic drugs, 261-263, 262t for neuropath.ic pain, 381. stt also Gabapentin, for neuropathic pain; Pregabalin, for neuropathic pain Antllibrinolytic agents, transfusion of, 861-862 Antihypertensive drugs, 535-555 adverse effects of, 543-548 emerging devdopments, 550-552 pharmacodynamics of, 543-548 pharmacokinetic of, 543-548 sites and mechanisms of, 537, 537/, 537i--538t Antimetabolites, DNA/RNA damage caused by, 754, 756/, 756t Antimetasrasis therapy, 764 Antimicrobial drugs, 769-780 cost containment, 776 dosing and administration, 774, 775i--777t emerging developments, 776-777 h.istorical perspective, 769 perioperativc aminoglycosides, 772-773 amphotericin B, 773 beta-lactam antibiotics, 772--773 carbapenems, 772 clindamycin, 773 fluoroquinoloncs, 773 metronidazole, 773 monobactams, 772 vancomycin, 773 renal function impairment from, 790 for SSI prevention, 773-774 summary, 776 Antimuscarinic drugs, 293t Antincoplastic antibiotics cause DNA/RNA damage, 754-757, 757t topoisomerase inhibitors, 757-758, 758t, 759fi 760t Antioxidants, for surgical patients, 666 Antiphospholipid antibodies, hypercoagulability and, 841 Antiplatdet agents, 882-890 adenosine diphosphate analogs as, 887-888 aspirin as, 883-884, 8841 dipyridamole as, 884 glycoprotcin Ilb/Illa antagonists as, 888-890, 889t oral,883-884 platelet receptor inhibitors as,

Antiplatdet agents (Continued) 884-887,885f--886f, 886t, 889t protease activated receptor-I , 890, 891/ sites of action of, 883/ Antipsychotics, 251-256 first-generation (typical), 251-254 pharmacology of, 251, 252i--253t side effects of, 251-254 se