Goldfrank's Clinical Manual of Toxicologic Emergencies [2 ed.] 9781260475005, 126047500X, 9781260474992, 1260474992

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Goldfrank’s

2ND EDITION

CLINICAL MANUAL OF

TOXICOLOGIC EMERGENCIES

Robert S. Hoffman

Sophie Gosselin

Heroin

Lewis S. Nelson

Mary Ann Howland

Mc G r aw Hill

Neal A. Lewin Silas W. Smith

Lewis R. Goldfrank

Naloxone

Goldfrank’s

CLINICAL MANUAL OF TOXICOLOGIC EMERGENCIES

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EDITORS Robert S. Hoffman, MD, FAACT, FRCP Edin, FEAPCCT Professor of Emergency Medicine and Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Emergency Physician Bellevue Hospital Center and NYU Langone Health New York, New York Sophie Gosselin, MD, CSPQ, FRCPC, FACMT, FAACT Emergency Physician and Medical Toxicologist Consultant, Centre antipoison du Québec, Québec, Canada Chief of Department of Emergency Medicine, Centre intégré de santé et services Sociaux de la Montérégie-Centre, Hôpital Charles Lemoyne, Greenfield Park, Québec, Canada. Professor, Department of Family Medicine and Emergency Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada Lewis S. Nelson, MD, MBA, FAACT, FACEP, FACMT, FASAM Professor and Chair, Department of Emergency Medicine Professor of Pharmacology, Physiology, and Neuroscience Rutgers New Jersey Medical School Director, Division of Medical Toxicology and Addiction Medicine Chief of Service, Emergency Department, University Hospital of Newark Senior Consultant, New Jersey Poison Information & Education System Newark, New Jersey Mary Ann Howland, PharmD, DABAT, FAACT Professor of Pharmacy St. John’s University College of Pharmacy and Health Sciences Adjunct Professor of Emergency Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health Senior Consultant in Residence New York City Poison Control Center New York, New York

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Neal A. Lewin, MD, FACEP, FACMT, FACP Druckenmiller Professor of Emergency Medicine and Professor of Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Director, Didactic Education Emergency Medicine Residency Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Silas W. Smith, MD, FACEP, FACMT JoAnn G. and Kenneth Wellner Associate Professor of Emergency Medicine Chief, Division of Quality, Safety, and Practice Innovation Affiliate Faculty, Institute for Innovations in Medical Education Emergency Physician Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Lewis R. Goldfrank, MD, FAAEM, FAACT, FACEP, FACMT, FACP Professor of Emergency Medicine New York University Grossman School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health Medical Director, New York City Poison Control Center New York, New York

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Goldfrank’s

CLINICAL MANUAL OF TOXICOLOGIC EMERGENCIES Second Edition

Robert S. Hoffman, MD, FAACT, FRCP Edin, FEAPCCT Sophie Gosselin MD, CSPQ, FRCPC, FACMT, FAACT Lewis S. Nelson, MD, MBA, FAACT, FACEP, FACMT, FASAM Mary Ann Howland, PharmD, DABAT, FAACT Neal A. Lewin, MD, FACEP, FACMT, FACP Silas W. Smith, MD, FACEP, FACMT Lewis R. Goldfrank, MD, FAAEM, FAACT, FACEP, FACMT, FACP

New York  Chicago  San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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Copyright © 2024 by McGraw Hill LLC. All rights reserved. Except as permitted under the Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of publisher. ISBN: 978-1-26-047500-5 MHID: 1-26-047500-X The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-047499-2, MHID: 1-26-047499-2. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw Hill eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Library of Congress Cataloging-in-Publication Data Names: Hoffman, Robert S. (Robert Steven), 1959- author. | Nelson, Lewis S. 1963- Goldfrank’s toxicologic emergencies. Title: Goldfrank’s Clinical manual of toxicologic emergencies / Robert S. Hoffman, Sophie Gosselin, Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Silas W. Smith, Lewis R. Goldfrank. Other titles: Manual of toxicologic emergencies Description: Second edition. | New York : McGraw Hill, [2023] | Preceded by: Goldfrank’s manual of toxicologic emergencies / Robert S. Hoffman ... [et al.]. c2007. | Summary: “The condensed, clinically focused companion to the world-renowned Goldfrank’s Toxicologic Emergencies. The Manual portable and ideal for students, nurses, pharmacists, and physicians in the clinical practice setting. It focuses on assessment and management for immediate care of poisoned patients. Many tables and figures throughout facilitate quick referencing of critical information”—Provided by publisher. Identifiers: LCCN 2023007491 (print) | LCCN 2023007492 (ebook) | ISBN 9781260474992 (paperback ; alk. paper) | ISBN 1260474992 (paperback ; alk. paper) | ISBN 9781260475005 (ebook) Subjects: MESH: Emergencies | Poisoning | Poisons | Handbook Classification: LCC RA1224.5 (print) | LCC RA1224.5 (ebook) | NLM QV 607 | DDC 615.9/08—dc23/eng/20230429 LC record available at https://lccn.loc.gov/2023007491 LC ebook record available at https://lccn.loc.gov/2023007492 TERMS OF USE This is a copyrighted work and McGraw Hill (“McGraw Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw Hill’s prior consent. 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Neither McGraw Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

DEDICATION To the staffs of our hospitals, emergency departments, intensive care units, and outpatient sites, who have worked with remarkable courage, concern, compassion, and understanding in treating the patients discussed in this text and many thousands more like them.

youthful insight, and appreciation of my passion; to my parents Myrna of blessed memory and Dr. Irwin Nelson for the foundation they provided; and to my family, friends, and colleagues who keep me focused on what is important in life. (L.N.)

To the Emergency Medical Services personnel who have worked so faithfully and courageously to protect our patients’ health and who have assisted us in understanding what happens in the home and the field.

To my husband Bob; to my children Robert, Marcy and her husband Doug, and my grandchildren Joey and Kenzie; to the loving memory of my father and mother; and to family, friends, colleagues, and students for all their help and continuing inspiration. (M.A.H.)

To the Poison Center staff, who have quietly and conscientiously integrated their skills with ours to serve these patients and prevent many patients from ever requiring a hospital visit. To all the faculty, fellows, residents, nurses, nurse practitioners, physician assistants, and medical and pharmacy students who have studied toxicology with us, whose inquisitiveness has helped us continually strive to understand complex and evolving problems and develop methods to teach them to others. (Editors) To my wife Ali; my children Casey and Jesse; my parents; and my friends, family, and colleagues for their never-ending patience and forgiveness for the time I have spent away from them; to the many close colleagues and committee members who have helped me understand the fundamentals of evidence-based medicine and challenged me to be clear, precise, and definitive when making treatment recommendations. (R.S.H.) To my husband Daniel, my friends and family for understanding “me-time” spent on this book; to colleagues and students for continually asking interesting questions to help find better ways to care for our patients. (S.G.) To my wife Laura for her unwavering support; to my children Daniel, Adina, and Benjamin for their fresh perspective,

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To my wife Gail Miller; my sons Jesse Miller Lewin, MD, and Justin Miller Lewin, MD, and my daughters-in-law Alana Amarosa Lewin, MD, and Alice Tang, MD; my granddaughter Isabelle Rose Lewin; my grandsons Charles Andrew Lewin and Parker Tang Lewin, and in memory of my parents. To all my patients, students, residents, fellows, and colleagues who constantly stimulate my being a perpetual student. (N.L.) To my wife Helen, for her resolute support, understanding, and patience; to my children Addison and Alston, for their boundless enthusiasm, inquisitiveness, and spirit; and to my parents. (S.W.S.) To my children Rebecca and Ryan, Jennifer, Andrew and Joan, Michelle (deceased) and James; to my grandchildren Benjamin, Adam, Sarah, Kay, Samantha, Herbert, Jonah, Susie, and Sasha, who have kept me acutely aware of the ready availability of possible poisons; and to my wife, partner, and best friend Susan (deceased) whose support was essential to help me in the development of the first ten editions and whose contributions continue to inspire me and will be found throughout the text. (L.G.)

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CONTENTS Contributors to Goldfrank’s Toxicologic Emergencies, 11th Edition from which this Manual is derived................................................................. xi

16. Plant- and Animal-Derived Dietary Supplements................143

Preface ......................................................................................................xxiii

18. Iron...................................................................................163

THE GENERAL APPROACH TO THE PATIENT

17. Vitamins............................................................................155 A7. DEFEROXAMINE..............................................................................166 C. PHARMACEUTICALS 

1. Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes....................................................................1 2. Principles of Managing the Acutely Poisoned or Overdosed Patient.................................................................4 3. Techniques Used to Prevent Gastrointestinal Absorption..........................................................................11

19. Pharmaceutical Additives...................................................168

SC1. DECONTAMINATION PRINCIPLES: PREVENTION OF DERMAL, OPHTHALMIC AND INHALATIONAL ABSORPTION.................... 19

A10. l-CARNITINE...................................................................................195

20. Antidiabetics and Hypoglycemics/Antiglycemics.................173 A8. DEXTROSE (d-GLUCOSE).................................................................181 A9. OCTREOTIDE...................................................................................184

21. Antiepileptics....................................................................186 22. Antihistamines and Decongestants....................................197



A1. ACTIVATED CHARCOAL.....................................................................22



A2. WHOLE-BOWEL IRRIGATION AND OTHER INTESTINAL EVACUANTS......................................................25



4. Principles and Techniques Applied to Enhance Elimination............................................................28

24. Methotrexate, 5-Fluorouracil, and Capecitabine.................213

5. Principles of Diagnostic Imaging..........................................35

A13. GLUCARPIDASE (CARBOXYPEPTIDASE G2).....................................220

SC2.  TRANSDERMAL TOXICOLOGY................................................... 52 SC3.  PATIENT VIOLENCE................................................................. 54

A14. URIDINE TRIACETATE......................................................................223



THE CLINICAL BASIS OF MEDICAL TOXICOLOGY A. ANALGESICS AND ANTIINFLAMMATORY MEDICATIONS 

6. Acetaminophen...................................................................57 A3. N-ACETYLCYSTEINE..........................................................................66



7. Colchicine, Podophyllin, and the Vinca Alkaloids...................71



8. Nonsteroidal Antiinflammatory Drugs..................................75

9. Opioids................................................................................79 A4. OPIOID ANTAGONISTS......................................................................90

A11. PHYSOSTIGMINE SALICYLATE........................................................206

23. Chemotherapeutics...........................................................208 A12. FOLATES: LEUCOVORIN (FOLINIC ACID) AND FOLIC ACID...............217



SC6.  INTRATHECAL ADMINISTRATION OF XENOBIOTICS................ 225



SC7.  EXTRAVASATION OF VESICANT XENOBIOTICS ........................ 227

25. Antimigraine Medications..................................................229 26. Thyroid and Antithyroid Medications..................................233 D.  ANTIMICROBIALS 

27. Antibacterials, Antifungals, and Antivirals..........................238 28. Antimalarials.....................................................................247 29. Antituberculous Medications..............................................255 A15. PYRIDOXINE...................................................................................262 E.  C ARDIOPULMONARY MEDICATIONS 

SC4.  INTERNAL CONCEALMENT OF XENOBIOTICS............................ 93

30. Antidysrhythmics...............................................................264



A16. MAGNESIUM...................................................................................271

SC5.  PREVENTION, TREATMENT, AND HARM REDUCTION APPROACHES TO OPIOID OVERDOSES..................................... 96

10. Salicylates...........................................................................98 A5. SODIUM BICARBONATE..................................................................104 B.  FOOD, DIET, AND NUTRITION 

31. Antithrombotics................................................................273 A17. PROTHROMBIN COMPLEX CONCENTRATES AND DIRECT ORAL ANTICOAGULANT ANTIDOTES..................................285 A18. VITAMIN K1.....................................................................................289

11. Botulism...........................................................................108

A19. PROTAMINE....................................................................................291

A6. BOTULINUM ANTITOXIN.................................................................114

32. a-Adrenergic Antagonists..................................................293

12. Food Poisoning..................................................................117

A20. GLUCAGON.....................................................................................301

13. Dieting Xenobiotics and Regimens.....................................125

33. Calcium Channel Blockers...................................................303

14. Athletic Performance Enhancers.........................................131

A21. HIGH-DOSE INSULIN......................................................................307

15. Essential Oils.....................................................................137

34. Other Antihypertensives....................................................309

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viii

CONTENTS

35. Cardioactive Steroids.........................................................314

65. Copper...............................................................................471

A22. DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS...................................319

66. Lead..................................................................................474

36. Methylxanthines and Selective a2-Adrenergic Agonists........323

A29. SUCCIMER (2,3-DIMERCAPTOSUCCINIC ACID) AND DMPS (2,3-DIMERCAPTO-1-PROPANESULFONIC ACID)...........................485

F.  ANESTHETICS AND RELATED MEDICATIONS 

37. Local Anesthetics...............................................................327 A23. LIPID EMULSION............................................................................331

38. Inhalational Anesthetics....................................................335 39. Neuromuscular Blockers.....................................................339 A24. DANTROLENE SODIUM...................................................................346 G.  PSYCHOTROPIC MEDICATIONS 

40. Antipsychotics...................................................................348

A30. EDETATE CALCIUM DISODIUM (CaNa2EDTA)...................................488

67. Manganese........................................................................490 68. Mercury.............................................................................493 69. Nickel................................................................................497 70. Selenium...........................................................................500 71. Silver.................................................................................503 72. Thallium............................................................................505 A31. PRUSSIAN BLUE..............................................................................508

73. Zinc...................................................................................511

41. Cyclic Antidepressants........................................................356

J.  HOUSEHOLD PRODUCTS 

42. Serotonin Reuptake Inhibitors and Atypical Antidepressants....................................................361

74. Antiseptics, Disinfectants, and Sterilants............................513

43. Lithium.............................................................................367

75. Camphor and Moth Repellents...........................................520

44. Monoamine Oxidase Inhibitors...........................................370

76. Caustics.............................................................................523

45. Sedative–Hypnotics...........................................................376

77. Hydrofluoric Acid and Fluorides..........................................529

A25. FLUMAZENIL..................................................................................381

A32. CALCIUM.........................................................................................532

H.  SUBSTANCES OF ABUSE 

46. Amphetamines..................................................................383 47. Cannabinoids.....................................................................389 48. Cocaine.............................................................................395 A26. BENZODIAZEPINES.........................................................................401

49. Ethanol.............................................................................405

78. Hydrocarbons....................................................................535 79. Toxic Alcohols....................................................................542 A33. FOMEPIZOLE...................................................................................548 A34. ETHANOL........................................................................................550

SC8.  DIETHYLENE GLYCOL............................................................ 553 K.  PESTICIDES 

A27. THIAMINE HYDROCHLORIDE..........................................................412

80. Barium..............................................................................556

50. Alcohol Withdrawal...........................................................416

81. Fumigants.........................................................................558

51. Disulfiram and Disulfiram-Like Reactions...........................420

82. Herbicides.........................................................................563

52. Hallucinogens....................................................................423

83. Insecticides: Organic Phosphorus Compounds and Carbamates.......................................................................577

53. g-Hydroxybutyric Acid........................................................428 54. Inhalants...........................................................................431 55. Nicotine............................................................................436 56. Phencyclidine and Ketamine..............................................440 I.  METALS 

A35. ATROPINE.......................................................................................586 A36. PRALIDOXIME.................................................................................588

84. Insecticides: Organic Chlorines, Pyrethrins/Pyrethroids, and Insect Repellents.........................................................590 85. Phosphorus.......................................................................597

57. Aluminum.........................................................................445

86. Sodium Monofluoroacetate and Fluoroacetamide...............600

58. Antimony..........................................................................448

87. Strychnine.........................................................................601

59. Arsenic..............................................................................453

L.  NATURAL TOXINS AND ENVENOMATIONS 

A28. DIMERCAPROL (BRITISH ANTI-LEWISITE OR BAL)........................457

88. Arthropods........................................................................603

60. Bismuth............................................................................459 61. Cadmium...........................................................................461 62. Cesium..............................................................................463 63. Chromium.........................................................................465 64. Cobalt...............................................................................468

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A37. ANTIVENOM: SPIDER......................................................................613 A38. ANTIVENOM: SCORPION.................................................................615

89. Marine Envenomations......................................................618 90. Mushrooms.......................................................................627 91. Plants................................................................................637

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CONTENTS

ix

92. Native (US) Venomous Snakes and Lizards..........................651

97. Methemoglobin Inducers...................................................695

A39. ANTIVENOM FOR NORTH AMERICAN VENOMOUS SNAKES (CROTALINE AND ELAPID)..............................................................658

A43. METHYLENE BLUE..........................................................................701



98. Chemical Weapons.............................................................703

SC9.  EXOTIC NONNATIVE SNAKE ENVENOMATIONS....................... 662

99. Biological Weapons............................................................710

M.  OCCUPATIONAL AND ENVIRONMENTAL TOXINS 

100. Radiation..........................................................................715

93. Smoke Inhalation..............................................................666 94. Simple Asphyxiants and Pulmonary Irritants......................671

A45. PENTETIC ACID OR PENTETATE (ZINC OR CALCIUM) TRISODIUM (DTPA).........................................................................726

95. Carbon Monoxide...............................................................678

101. Hazardous Materials Incident Response..............................728

A44. POTASSIUM IODIDE........................................................................724

A40. HYPERBARIC OXYGEN....................................................................683



SC10.  ASSESSMENT OF ETHANOL-INDUCED IMPAIRMENT.............. 734

96. Cyanide and Hydrogen Sulfide............................................686



SC11.  ORGAN PROCUREMENT FROM POISONED PATIENTS.............. 737

A41. HYDROXOCOBALAMIN...................................................................691

Index ..........................................................................................................739

A42. NITRITES (AMYL AND SODIUM) AND SODIUM THIOSULFATE........693

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CONTRIBUTORS to GOLDFRANK’S TOXICOLOGIC EMERGENCIES, 11TH EDITION from which this Manual is derived Theodore C. Bania, MD, MS Assistant Professor of Emergency Medicine Director of Research and Toxicology Mt. Sinai West and Mt. Sinai St. Luke’s Hospitals Department of Emergency Medicine Associate Dean for Human Subject Research Associate Director Program for the Protection of Human Subjects Icahn School of Medicine at Mount Sinai New York, New York Antidotes in Brief: A23, Lipid Emulsion

Keith J. Boesen, PharmD, FAZPA Instructor, University of Arizona College of Pharmacy Director, Arizona Poison and Drug Information Center Tucson, Arizona Special Considerations: SC9, Exotic Nonnative Snake Envenomations

Fermin Barrueto Jr., MD, MBA, FACEP Volunteer Associate Professor of Emergency Medicine University of Maryland School of Medicine Baltimore, Maryland Senior Vice President Chief Medical Officer University of Maryland Upper Chesapeake Health Bel Air, Maryland Chapter 86, Sodium Monofluoroacetate and Fluoroacetamide

George M. Bosse, MD Professor of Emergency Medicine University of Louisville School of Medicine Medical Director, Kentucky Poison Center Louisville, Kentucky Chapter 20, Antidiabetics and Hypoglycemics/Antiglycemics

James David Barry, MD Clinical Professor of Emergency Medicine University of California, Irvine School of Medicine Irvine, California Associate Director, Emergency Department Long Beach VA Medical Center Long Beach, California Chapter 28, Antimalarials Michael C. Beuhler, MD Professor of Emergency Medicine Carolinas HealthCare System Medical Director, Carolinas Poison Center Charlotte, North Carolina Chapter 85, Phosphorus Steven B. Bird, MD Professor of Emergency Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Chapter 63, Chromium Eike Blohm, MD Assistant Professor of Surgery Division of Emergency Medicine Toxicology Consultant Northern New England Poison Center University of Vermont Larner College of Medicine University of Vermont Medical Center Burlington, Vermont Chapter 89, Marine Envenomations

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Kelly A. Green Boesen, PharmD Clinical Pharmacist Tucson, Arizona Special Considerations: SC9, Exotic Nonnative Snake Envenomations

Nicole C. Bouchard, MD, FACMT, FRCPC Assistant Clinical Professor of Emergency Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Emergency Physician Lenox Health in Greenwich Village, Northwell Health New York, New York Chapter 26, Thyroid and Antithyroid Medications Jeffrey R. Brubacher, MD, MSc, FRCPC Associate Professor of Emergency Medicine University of British Columbia Emergency Physician Vancouver General Hospital Vancouver, British Columbia, Canada Chapter 32, β-Adrenergic Antagonists D. Eric Brush, MD, MHCM Clinical Associate Professor of Emergency Medicine University of Massachusetts Medical School Division of Toxicology Director of Clinical Operations UMass Memorial Medical Center Worcester, Massachusetts Chapter 89, Marine Envenomations Michele M. Burns, MD, MPH Assistant Professor of Pediatrics and Emergency Medicine Harvard Medical School Director, Medical Toxicology Fellowship Medical Director, Regional Center for Poison Control and Prevention Attending Physician, Pediatric Emergency Medicine Boston Children’s Hospital Boston, Massachusetts Chapter 71, Silver

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xii

CONTRIBUTORS

Diane P. Calello, MD Associate Professor of Emergency Medicine Rutgers New Jersey Medical School Executive and Medical Director New Jersey Poison Information and Education System Newark, New Jersey Chapter 66, Lead Chapter 70, Selenium Jennifer L. Carey, MD Assistant Professor of Emergency Medicine Division of Medical Toxicology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Chapter 52, Hallucinogens Gar Ming Chan, MD, FACEM Emergency Medicine Specialist Calvary Health Care, Lenah Valley Tasmania, Australia Chapter 64, Cobalt Yiu-Cheung Chan, MD, MBBS, FRCS (Ed), FHKCEM, FHKAM Consultant, Accident and Emergency Department, United Christian Hospital Hong Kong Poison Information Centre Hong Kong SAR, China Chapter 87, Strychnine Nathan P. Charlton, MD Associate Professor of Emergency Medicine Program Director, Medical Toxicology University of Virginia School of Medicine Charlottesville, Virginia Chapter 93, Smoke Inhalation Betty C. Chen, MD Assistant Professor of Emergency Medicine University of Washington School of Medicine Harborview Medical Center Toxicology Consultant, Washington Poison Center Seattle, Washington Chapter 31, Antithrombotics Antidotes in Brief: A17, Prothrombin Complex Concentrates and Direct Oral Anticoagulant Antidotes Jason Chu, MD Associate Professor of Emergency Medicine Icahn School of Medicine at Mount Sinai Emergency Physician and Medical Toxicologist Mt. Sinai West and Mt. Sinai St. Luke’s Hospitals New York, New York Chapter 25, Antimigraine Medications

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Richard F. Clark, MD Professor of Emergency Medicine Director, Division of Medical Toxicology University of California, San Diego San Diego, California Antidotes in Brief: A37, Antivenom: Spider Antidotes in Brief: A38, Antivenom: Scorpion John A. Curtis, MD Emergency Physician Cheshire Medical Center-Dartmouth Hitchcock Keene Keene, New Hampshire Chapter 69, Nickel Michael A. Darracq, MD, MPH Associate Professor of Clinical Emergency Medicine University of California, San Francisco (UCSF)-Fresno Medical Education Program Department of Emergency Medicine Division of Medical Toxicology Fresno, California Antidotes in Brief: A37, Antivenom: Spider Antidotes in Brief: A38, Antivenom: Scorpion Andrew H. Dawson, MBBS, FRACP, FRCP, FCCP Clinical Professor of Medicine, University of Sydney Clinical Director, NSW Poisons Information Centre Director, Clinical Toxicology Royal Prince Alfred Hospital Sydney, Australia Chapter 80, Barium Francis Jerome DeRoos, MD Associate Professor of Emergency Medicine Perelman School of Medicine at the University of Pennsylvania Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 34, Miscellaneous Antihypertensives and Pharmacologically Related Agents Suzanne Doyon, MD, MPH, ACEP, FACMT, FASAM Assistant Professor of Emergency Medicine Medical Director, Connecticut Poison Control Center University of Connecticut School of Medicine Farmington, Connecticut Chapter 21, Antiepileptics Michael Eddleston, BM, ScD Professor of Clinical Toxicology University of Edinburgh Consultant Clinical Toxicologist Royal Infirmary of Edinburgh and National Poisons Information Service, Edinburgh Edinburgh, United Kingdom Chapter 83, Insecticides: Organic Phosphorus Compounds and Carbamates

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CONTRIBUTORS

Brenna M. Farmer, MD Assistant Professor of Clinical Medicine Weill Cornell Medical College of Cornell University Emergency Physician Assistant Program Director of Emergency Medicine New York-Presbyterian Hospital Director of Patient Safety Weill Cornell Emergency Department New York, New York Chapter 53, g-Hydroxybutyric Acid (g -Hydroxybutyrate) Chapter 57, Aluminum Brandy Ferguson, MD Assistant Professor of Emergency Medicine New York University School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 101, Hazardous Materials Incident Response Denise Fernández, MD Assistant Professor of Emergency Medicine Albert Einstein College of Medicine Medical Toxicologist Emergency Physician Jacobi Medical Center/North Central Bronx Hospital Bronx, New York Chapter 55, Nicotine Laura J. Fil, DO, MS Adjunct Professor Department of Primary Care Touro College of Osteopathic Medicine Middletown, New York Emergency Physician Department of Emergency Medicine Vassar Brothers Medical Center Poughkeepsie, New York Chapter 12, Food Poisoning Lindsay M. Fox, MD Assistant Professor of Emergency Medicine Rutgers New Jersey Medical School University Hospital Toxicology Consultant, New Jersey Poison Information and Education System Newark, New Jersey Chapter 16, Plant- and Animal-Derived Dietary Supplements Jessica A. Fulton, DO Emergency Physician Grandview Hospital Sellersville, Pennsylvania Chapter 76, Caustics

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Howard L. Geyer, MD, PhD Assistant Professor of Neurology Director, Division of Movement Disorders Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York Chapter 11, Botulism Antidotes in Brief: A6, Botulinum Antitoxin Marc Ghannoum, MD, MSc Associate Professor of Medicine University of Montreal Nephrology and Internal Medicine Verdun Hospital Montreal, Québec, Canada Chapter 4, Principles and Techniques Applied to Enhance Elimination Beth Y. Ginsburg, MD Assistant Professor of Emergency Medicine Icahn School of Medicine at Mount Sinai New York, New York Emergency Physician Elmhurst Hospital Center Elmhurst, New York Chapter 17, Vitamins Jeffrey A. Gold, MD Professor of Medicine Chief, Division of Pulmonary and Critical Care (Interim) Associate Director, Adult Cystic Fibrosis Center Oregon Health and Science University Portland, Oregon Chapter 50, Alcohol Withdrawal David S. Goldfarb, MD, FASN Professor of Medicine and Physiology New York University School of Medicine Clinical Chief, Nephrology Division NYU Langone Health Chief, Nephrology Section New York Harbor VA Healthcare System Consultant, New York City Poison Control Center New York, New York Chapter 4, Principles and Techniques Applied to Enhance Elimination Lewis R. Goldfrank, MD, FAAEM, FAACT, FACEP, FACMT, FACP Professor of Emergency Medicine New York University Grossman School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health Medical Director, New York City Poison Control Center New York, New York Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Chapter 90, Mushrooms Chapter 91, Plants

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CONTRIBUTORS

Sophie Gosselin, MD, CSPQ, FRCPC, FACMT, FAACT Emergency Physician and Medical Toxicologist Consultant, Centre antipoison du Québec, Québec, Canada Chief of Department of Emergency Medicine, Centre intégré de santé et services Sociaux de la Montérégie-Centre, Hôpital Charles Lemoyne, Greenfield Park, Québec, Canada. Professor, Department of Family Medicine and Emergency Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada Chapter 22, Antihistamines and Decongestants Antidotes in Brief: A23, Lipid Emulsion Howard A. Greller, MD, FACEP, FACMT Department of Clinical Medicine, Affiliated Medical Professor City University of New York School of Medicine Director of Research and Medical Toxicology SBH Health System Department of Emergency Medicine St. Barnabas Hospital Bronx, New York Chapter 43, Lithium Hallam Melville Gugelmann, MD, MPH Assistant Clinical Professor Division of Clinical Pharmacology and Medical Toxicology, Department of Medicine, University of California, San Francisco Emergency Physician, CPMC St. Luke’s Hospital Emergency Department Assistant Medical Director, California Poison Control System-San Francisco Division San Francisco, California Chapter 34, Miscellaneous Antihypertensives and Pharmacologically Related Agents David D. Gummin, MD, FAACT, FACEP, FACMT Professor of Emergency Medicine, Pediatrics, Pharmacology and Toxicology Section Chief, Medical Toxicology Medical College of Wisconsin Medical Director, Wisconsin Poison Center Milwaukee, Wisconsin Chapter 78, Hydrocarbons Caitlin J. Guo, MD, MBA Assistant Professor of Anesthesiology, Perioperative Care and Pain Medicine New York University School of Medicine Attending Physician Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 38, Inhalational Anesthetics Chapter 39, Neuromuscular Blockers Antidotes in Brief: A24, Dantrolene Sodium

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Amit K. Gupta, MD Assistant Professor of Emergency Medicine Seton Hall Medical School Assistant Residency Director, Department of Emergency Medicine Hackensack University Medical Center Hackensack, New Jersey Chapter 51, Disulfiram and Disulfiramlike Reactions Jason B. Hack, MD Professor of Emergency Medicine Program Director, Division of Medical Toxicology The Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Chapter 35, Cardioactive Steroids In-Hei Hahn, MD, FACEP, FACMT Expedition Medical Officer Research Associate Division of Paleontology American Museum of Natural History New York, New York Chapter 88, Arthropods Stephen A. Harding, MD Assistant Professor of Emergency Medicine Henry J. N. Taub Department of Emergency Medicine Baylor College of Medicine Houston, Texas Chapter 57, Aluminum Rachel Haroz, MD Assistant Professor of Emergency Medicine Cooper University Health Care Camden, New Jersey Chapter 53, g-Hydroxybutyric Acid (g -Hydroxybutyrate) Ashley Haynes, MD, FACEP Assistant Professor of Emergency Medicine Division of Toxicology University of Texas Southwestern Medical School Attending Physician Parkland Hospital Clements University Hospital Children’s Medical Center Dallas, Texas Chapter 74, Antiseptics, Disinfectants, and Sterilants Antidotes in Brief: A5, Sodium Bicarbonate

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CONTRIBUTORS

Robert G. Hendrickson, MD, FACMT, FAACT Professor of Emergency Medicine Program Director, Fellowship in Medical Toxicology Associate Medical Director, Oregon Poison Center Oregon Health and Science University Portland, Oregon Chapter 6, Acetaminophen Antidotes in Brief: A3, N-Acetylcysteine Fred M. Henretig, MD, FAAP, FACMT Professor Emeritus of Pediatrics Perelman School of Medicine, University of Pennsylvania Senior Toxicologist, The Poison Control Center at the Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Chapter 66, Lead Christina H. Hernon, MD Lecturer in Emergency Medicine Harvard Medical School Department of Emergency Medicine Division of Medical Toxicology Cambridge Health Alliance Cambridge, Massachusetts Chapter 29, Antituberculous Medications Elizabeth Quaal Hines, MD Clinical Assistant Professor of Pediatrics Division of Pediatric Emergency Medicine University of Maryland School of Medicine Toxicology Consultant, Maryland Poison Center Baltimore, Maryland Chapter 67, Manganese Lotte C. G. Hoegberg, MS (Pharm), PhD, FEAPCCT Pharmacist, Medical Toxicologist The Danish Poisons Information Centre Department of Anesthesia and Intensive Care Copenhagen University Hospital Bispebjerg Copenhagen, Denmark Chapter 3, Techniques Used to Prevent Gastrointestinal Absorption Robert J. Hoffman, MD, MS, FACMT, FACEP Medical Director, Qatar Poison Center Sidra Medicine Doha, Qatar Chapter 36, Methylxanthines and Selective α-Adrenergic Agonists

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Robert S. Hoffman, MD, FAACT, FRCP Edin, FEAPCCT Professor of Emergency Medicine and Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Emergency Physician Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Chapter 48, Cocaine Chapter 61, Cadmium Chapter 72, Thallium Antidotes in Brief: A26, Benzodiazepines Antidotes in Brief: A27, Thiamine Hydrochloride Antidotes in Brief: A31, Prussian Blue Michael G. Holland, MD, FEAPCCT, FAACT, FACMT, FACOEM, FACEP Clinical Professor of Emergency Medicine SUNY Upstate Medical University Syracuse, New York Medical Toxicologist, Upstate New York Poison Center Syracuse, New York Director of Occupational Medicine, Glens Falls Hospital Center for Occupational Health Glens Falls, New York Senior Medical Toxicologist, Center for Toxicology and Environmental Health North Little Rock, Arkansas Chapter 84, Insecticides: Organic Chlorines, Pyrethrins/Pyrethroids and Insect Repellents Christopher P. Holstege, MD Professor of Emergency Medicine and Pediatrics Chief, Division of Medical Toxicology University of Virginia School of Medicine Medical Director, Blue Ridge Poison Center University of Virginia Health System Charlottesville, Virginia Chapter 96, Cyanide and Hydrogen Sulfide William J. Holubek, MD, MPH, CPE, FACEP, FACMT Vice President of Medical Affairs WellStar Atlanta Medical Center Atlanta, Georgia Chapter 8, Nonsteroidal Antiinflammatory Drugs Fiona Garlich Horner, MD Clinical Assistant Professor of Emergency Medicine Keck School of Medicine of the University of Southern California Los Angeles, California Antidotes in Brief: A26, Benzodiazepines

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xvi

CONTRIBUTORS

Mary Ann Howland, PharmD, DABAT, FAACT Professor of Pharmacy St. John’s University College of Pharmacy and Health Sciences Adjunct Professor of Emergency Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health Senior Consultant in Residence New York City Poison Control Center New York, New York Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Antidotes in Brief: A1, Activated Charcoal Antidotes in Brief: A2, Whole-Bowel Irrigation and Other Intestinal Evacuants Antidotes in Brief: A3, N-Acetylcysteine Antidotes in Brief: A4, Opioid Antagonists Antidotes in Brief: A7, Deferoxamine Antidotes in Brief: A9, Octreotide Antidotes in Brief: A10, l-Carnitine Antidotes in Brief: A11, Physostigmine Salicylate Antidotes in Brief: A12, Folates: Leucovorin (Folinic Acid) and Folic Acid Antidotes in Brief: A15, Pyridoxine Antidotes in Brief: A18, Vitamin K1 Antidotes in Brief: A19, Protamine Antidotes in Brief: A20, Glucagon Antidotes in Brief: A22, Digoxin-Specific Antibody Fragments Antidotes in Brief: A25, Flumazenil Antidotes in Brief: A26, Benzodiazepines Antidotes in Brief: A28, Dimercaprol (British Anti-Lewisite or BAL) Antidotes in Brief: A29, Succimer (2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-1-propanesulfonic acid) Antidotes in Brief: A30, Edetate Calcium Disodium (CaNa2EDTA) Antidotes in Brief: A32, Calcium Antidotes in Brief: A33, Fomepizole Antidotes in Brief: A34, Ethanol Antidotes in Brief: A35, Atropine Antidotes in Brief: A36, Pralidoxime Antidotes in Brief: A41, Hydroxocobalamin Antidotes in Brief: A42, Nitrites (Amyl and Sodium) and Sodium Thiosulfate Antidotes in Brief: A43, Methylene Blue Nicholas B. Hurst, MD, MS, FAAEM Assistant Professor of Emergency Medicine Medical Toxicology Consultant Arizona Poison and Drug Information Center University of Arizona College of Medicine-Tucson Tucson, Arizona Special Considerations: SC9, Exotic Nonnative Snake Envenomations David H. Jang, MD, MSc, FACMT Assistant Professor of Emergency Medicine Divisions of Medical Toxicology and Critical Care Medicine (ResCCU) Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania Chapter 33, Calcium Channel Blockers Chapter 46, Amphetamines

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David N. Juurlink, MD, PhD, FRCPC, FAACT, FACMT Professor of Medicine, Pediatrics and Health Policy, Management and Evaluation Director, Division of Clinical Pharmacology and Toxicology University of Toronto Senior Scientist, Institute for Clinical Evaluative Sciences Medical Toxicologist, Ontario Poison Centre Toronto, Ontario, Canada Chapter 40, Antipsychotics Bradley J. Kaufman, MD, MPH, FACEP, FAEMS Associate Professor of Emergency Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Emergency Physician Long Island Jewish Medical Center New Hyde Park, New York First Deputy Medical Director Fire Department of the City of New York New York, New York Chapter 101, Hazardous Materials Incident Response Brian S. Kaufman, MD Professor of Medicine, Anesthesiology, Neurology and Neurosurgery New York University School of Medicine NYU Langone Health New York, New York Chapter 38, Inhalational Anesthetics William Kerns II, MD, FACEP, FACMT Professor of Emergency Medicine and Medical Toxicology Division of Medical Toxicology Department of Emergency Medicine Carolinas Medical Center Charlotte, North Carolina Antidotes in Brief: A21, High-Dose Insulin Hong K. Kim, MD, MPH Assistant Professor of Emergency Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 75, Camphor and Moth Repellents Mark A. Kirk, MD Associate Professor of Emergency Medicine University of Virginia Charlottesville, Virginia Director, Chemical Defense Countering Weapons of Mass Destruction Department of Homeland Security Washington, District of Columbia Chapter 93, Smoke Inhalation Chapter 96, Cyanide and Hydrogen Sulfide

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CONTRIBUTORS

Cathy A. Kondas, MD, MBS Assistant Professor of Psychiatry New York University School of Medicine Attending Psychiatrist Director, Women’s Mental Health Fellowship Associate Director, Consultation-Liaison Psychiatry Bellevue Hospital Center New York, New York Special Considerations: SC3, Patient Violence Andrea Martinez Kondracke, MD Assistant Professor of Psychiatry and Internal Medicine New York University School of Medicine Division Chief, Department of Medical Psychiatry and Consultation Liaison Psychiatry Bellevue Hospital Center New York, New York Special Considerations: SC3, Patient Violence Jeffrey T. Lai, MD Assistant Professor of Emergency Medicine Department of Emergency Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Chapter 29, Antituberculous Medications Melisa W. Lai-Becker, MD, FACEP, FAAEM Instructor in Emergency Medicine Harvard Medical School Chief, CHA Everett Hospital Emergency Department Director, CHA Division of Medical Toxicology Cambridge Health Alliance Boston, Massachusetts Chapter 71, Silver Jeff M. Lapoint, DO Director, Division of Medical Toxicology Department of Emergency Medicine Southern California Permanente Group San Diego, California Chapter 47, Cannabinoids David C. Lee, MD Professor of Emergency Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Chair, Department of Emergency Medicine WellSpan York Hospital York, Pennsylvania Chapter 45, Sedative-Hypnotics Joshua D. Lee, MD Associate Professor of Population Health New York University School of Medicine New York, New York Special Considerations: SC5, Prevention, Treatment, and Harm Reduction Approaches to Opioid Overdoses

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Justin M. Lewin, MD Assistant Professor of Psychiatry New York University School of Medicine Comprehensive Psychiatric Emergency Program Consultation-Liaison Psychiatry Bellevue Hospital Center New York, New York Special Considerations: SC3, Patient Violence Neal A. Lewin, MD, FACEP, FACMT, FACP Druckenmiller Professor of Emergency Medicine and Professor of Medicine New York University Grossman School of Medicine Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Director, Didactic Education Emergency Medicine Residency Attending Physician, Emergency Medicine and Internal Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Erica L. Liebelt, MD, FACMT Clinical Professor of Pediatrics and Emergency Medicine University of Washington School of Medicine Medical/Executive Director Washington Poison Center Seattle, Washington Chapter 41, Cyclic Antidepressants Zhanna Livshits, MD Assistant Professor of Medicine Weill Cornell Medical College of Cornell University Emergency Physician and Medical Toxicologist New York Presbyterian Weill Cornell Medical Center New York, New York Chapter 62, Cesium Heather Long, MD Associate Professor of Emergency Medicine Director, Medical Toxicology Albany Medical Center Albany, New York Chapter 54, Inhalants Scott Lucyk, MD, FRCPC Clinical Assistant Professor of Emergency Medicine Medical Toxicologist Associate Medical Director, Poison and Drug Information Service (PADIS) Program Director, Clinical Pharmacology and Toxicology Alberta Health Services Calgary, Alberta, Canada Special Considerations: SC1, Decontamination Principles: Prevention of Dermal, Ophthalmic and Inhalational Absorption

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CONTRIBUTORS

Daniel M. Lugassy, MD Assistant Professor of Emergency Medicine Medical Director, New York Simulation Center for the Health Sciences (NYSIM) New York University School of Medicine Division of Medical Toxicology Ronald O. Perelman Department of Emergency Medicine Emergency Physician, Bellevue Hospital Center and NYU Langone Health Toxicology Consultant New York City Poison Control Center New York, New York Chapter 10, Salicylates Nima Majlesi, DO Assistant Professor of Emergency Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Director of Medical Toxicology Staten Island University Hospital Staten Island, New York Chapter 73, Zinc Alex F. Manini, MD, MS, FACMT, FAACT Professor of Emergency Medicine Division of Medical Toxicology Icahn School of Medicine at Mount Sinai Elmhurst Hospital Center New York, New York Chapter 44, Monoamine Oxidase Inhibitors Jeanna M. Marraffa, PharmD, DABAT, FAACT Associate Professor of Emergency Medicine Clinical Toxicologist Assistant Clinical Director, Upstate New York Poison Center Upstate Medical University Syracuse, New York Chapter 13, Dieting Xenobiotics and Regimens Maryann Mazer-Amirshahi, PharmD, MD, MPH Associate Professor of Emergency Medicine Georgetown University School of Medicine Emergency Physician, Department of Emergency Medicine MedStar Washington Hospital Center Washington, District of Columbia Chapter 30, Antidysrhythmics Nathanael J. McKeown, DO, FACMT Assistant Professor of Emergency Medicine Oregon Health & Science University Medical Toxicologist Oregon Poison Center Chief, Emergency Medicine Service VA Portland Health Care System Portland, Oregon Chapter 6, Acetaminophen

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Maria Mercurio-Zappala, RPh, MS Assistant Professor of Emergency Medicine New York University School of Medicine Ronald O. Perelman Department of Emergency Medicine Associate Director New York City Poison Control Center New York, New York Chapter 72, Thallium Stephen W. Munday, MD, MPH, MS Chair, Department of Occupational Medicine and Chief Medical Toxicologist Sharp Rees-Stealy Medical Group San Diego, California Chapter 59, Arsenic Mark J. Neavyn, MD Assistant Professor of Emergency Medicine Program Director, Fellowship in Medical Toxicology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Chapter 52, Hallucinogens Lewis S. Nelson, MD, MBA, FAACT, FACEP, FACMT, FASAM Professor and Chair, Department of Emergency Medicine Professor of Pharmacology, Physiology, and Neuroscience Rutgers New Jersey Medical School Director, Division of Medical Toxicology and Addiction Medicine Chief of Service, Emergency Department, University Hospital of Newark Senior Consultant, New Jersey Poison Information & Education System Newark, New Jersey Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Chapter 9, Opioids Chapter 30, Antidysrhythmics Chapter 50, Alcohol Withdrawal Chapter 65, Copper Chapter 91, Plants Chapter 94, Simple Asphyxiants and Pulmonary Irritants Antidotes in Brief: A4, Opioid Antagonists Antidotes in Brief: A26, Benzodiazepines Special Considerations: SC2, Transdermal Toxicology Vincent Nguyen, MD Assistant Professor of Emergency Medicine Medical Toxicologist Albert Einstein College of Medicine Jacobi Medical Center/North Central Bronx Medical Center The Bronx, New York Antidotes in Brief: A8, Dextrose (d-Glucose)

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CONTRIBUTORS

Sean Patrick Nordt, MD, PharmD, DABAT, FAACT, FAAEM, FACMT Associate Dean, Academic Affairs Gavin Herbert Endowed Professor of Pharmacy Chief Medical Officer Chapman University School of Pharmacy Crean College of Health and Behavioral Sciences Chapman University Adjunct Associate Professor of Emergency Medicine Department of Emergency Medicine University of California, Irvine Irvine, California Chapter 19, Pharmaceutical Additives Ruben E. Olmedo, MD Associate Clinical Professor of Emergency Medicine Icahn School of Medicine at Mount Sinai Director, Division of Toxicology Mount Sinai Hospital New York, New York Chapter 56, Phencyclidine and Ketamine Dean Olsen, DO Assistant Professor of Emergency Medicine and Toxicology NYIT College of Osteopathic Medicine Old Westbury, New York Director, Residency in Emergency Medicine Nassau University Medical Center East Meadow, New York Chapter 9, Opioids Robert B. Palmer, PhD, DABAT, FAACT Assistant Clinical Professor of Emergency Medicine (Medical Toxicology) University of Colorado School of Medicine Attending Toxicologist Medical Toxicology Fellowship Program Rocky Mountain Poison and Drug Center Denver, Colorado Special Considerations: SC10, Assessment of Ethanol-Induced Impairment

Dennis P. Price, MD Assistant Professor of Emergency Medicine New York University School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 97, Methemoglobin Inducers Jane M. Prosser, MD Medical Toxicologist Emergency Physician Department of Emergency Medicine Kaiser Permanente Northern California Kaiser Permanente Vallejo, California Special Considerations: SC4, Internal Concealment of Xenobiotics Rama B. Rao, MD, FACMT Associate Professor of Medicine Weill Cornell Medical College of Cornell University Chief, Division of Medical Toxicology Emergency Physician New York-Presbyterian Hospital New York, New York Chapter 60, Bismuth Special Considerations: SC6, Intrathecal Administration of Xenobiotics Special Considerations: SC11, Organ Procurement from Poisoned Patients Joseph G. Rella, MD Assistant Professor of Medicine Weill Cornell Medical College of Cornell University Emergency Physician New York-Presbyterian Hospital New York, New York Chapter 100, Radiation Antidotes in Brief: A44, Potassium Iodide Antidotes in Brief: A45, Pentetic Acid or Pentetate (Zinc or Calcium) Trisodium (DTPA)

Jeanmarie Perrone, MD, FACMT Professor of Emergency Medicine Director of Medical Toxicology Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania Chapter 18, Iron

Daniel J. Repplinger, MD Assistant Clinical Professor of Emergency Medicine University of California, San Francisco Zuckerberg San Francisco General Hospital San Francisco, California Chapter 88, Arthropods

Anthony F. Pizon, MD Associate Professor of Emergency Medicine University of Pittsburgh School of Medicine Chief, Division of Medical Toxicology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Chapter 92, Native (US) Venomous Snakes and Lizards” Antidotes in Brief: A39, Antivenom for North American Venomous Snakes (Crotaline and Elapid)

Morgan A. A. Riggan, MD, FRCPC Assistant Professor of Emergency Medicine Western University Emergency Physician London Health Sciences Centre London, Ontario, Canada Medical Toxicologist Poison and Drug Information Service (PADIS) Alberta Health Services Calgary, Alberta, Canada Chapter 78, Hydrocarbons

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CONTRIBUTORS

Darren M. Roberts, MBBS, PhD, FRACP Conjoint Associate Professor University of New South Wales Consultant Physician and Clinical Toxicologist St. Vincent’s Hospital and New South Wales Poisons Information Centre Sydney, Australia Chapter 82, Herbicides Anne-Michelle Ruha, MD Professor of Internal Medicine and Emergency Medicine Departments of Internal Medicine and Emergency Medicine University of Arizona College of Medicine—Phoenix Department of Medical Toxicology Banner—University Medical Center Phoenix Phoenix, Arizona Chapter 92, Native (US) Venomous Snakes and Lizards Antidotes in Brief: A39, Antivenom for North American Venomous Snakes (Crotaline and Elapid) Cynthia D. Santos, MD Assistant Professor of Emergency Medicine Emergency Physician University Hospital of Newark Rutgers New Jersey Medical School Toxicology Consultant New Jersey Poison Information and Education System Newark, New Jersey Chapter 7, Colchicine, Podophyllin, and the Vinca Alkaloids Daniel Schatz, MD Addiction Medicine Fellow Department of Medicine New York University School of Medicine Bellevue Hospital Center New York, New York Special Considerations: SC5, Prevention, Treatment, and Harm Reduction Approaches to Opioid Overdoses Capt. Joshua G. Schier, MD, MPH, USPHS Lead, Environmental Toxicology Team Centers for Disease Control and Prevention Assistant Professor of Emergency Medicine Emory University School of Medicine Associate Director, Emory/CDC Medical Toxicology Fellowship Consultant, Georgia Poison Center Atlanta, Georgia Chapter 7, Colchicine, Podophyllin, and the Vinca Alkaloids Special Considerations: SC8, Diethylene Glycol David T. Schwartz, MD Associate Professor of Emergency Medicine New York University School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 5, Principles of Diagnostic Imaging

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Shahin Shadnia, MD, PhD, FACMT Professor of Clinical Toxicology Head of Clinical Toxicology Department School of Medicine Shahid Beheshti University of Medical Sciences Chairman of Loghman Hakim Hospital Poison Center Tehran, Iran Chapter 81, Fumigants Lauren Kornreich Shawn, MD Assistant Professor of Emergency Medicine Icahn School of Medicine at Mount Sinai Mount Sinai St. Luke’s, Mount Sinai West New York, New York Chapter 15, Essential Oils Farshad Mazda Shirazi, MSc, MD, PhD, FACEP, FACMT Associate Professor of Emergency Medicine, Pharmacology and Pharmacy Practice and Science University of Arizona College of Medicine—Tucson Program Director, Medical Toxicology Medical Director, Arizona Poison and Drug Information Center Tucson, Arizona Special Considerations: SC9, Exotic Nonnative Snake Envenomations Silas W. Smith, MD, FACEP, FACMT JoAnn G. and Kenneth Wellner Associate Professor of Emergency Medicine Chief, Division of Quality, Safety, and Practice Innovation Affiliate Faculty, Institute for Innovations in Medical Education Emergency Physician Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 1, Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Chapter 2, Principles of Managing the Acutely Poisoned or Overdosed Patient Antidotes in Brief: A1, Activated Charcoal Antidotes in Brief: A2, Whole-Bowel Irrigation and Other Intestinal Evacuants Antidotes in Brief: A6, Botulinum Antitoxin Antidotes in Brief: A9, Octreotide Antidotes in Brief: A12, Folates: Leucovorin (Folinic Acid) and Folic Acid Antidotes in Brief: A13, Glucarpidase (Carboxypeptidase G2) Antidotes in Brief: A14, Uridine Triacetate Antidotes in Brief: A16, Magnesium Antidotes in Brief: A20, Glucagon Antidotes in Brief: A22, Digoxin-Specific Antibody Fragments Antidotes in Brief: A32, Calcium Craig G. Smollin, MD, FACMT Associate Professor of Emergency Medicine Program Director, Medical Toxicology University of California, San Francisco Medical Director, California Poison Control System–San Francisco Division San Francisco, California Chapter 48, Cocaine

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CONTRIBUTORS

Sari Soghoian, MD, MA Associate Professor of Emergency Medicine New York University School of Medicine New York, New York Clinical Coordinator, Korle Bu Teaching Hospital Department of Emergency Medicine Accra, Ghana Chapter 55, Nicotine Chapter 67, Manganese Kambiz Soltaninejad, PharmD, PhD Associate Professor of Toxicology Department of Forensic Toxicology Legal Medicine Research Center Legal Medicine Organization Tehran, Iran Chapter 81, Fumigants Meghan B. Spyres, MD Assistant Professor of Clinical Emergency Medicine Division of Medical Toxicology University of Southern California, Keck School of Medicine Los Angeles, California Chapter 46, Amphetamines Samuel J. Stellpflug, MD, FAACT, FACMT, FACEP, FAAEM Associate Professor of Emergency Medicine University of Minnesota Medical School Minneapolis, Minnesota Director, Clinical Toxicology Regions Hospital Saint Paul, Minnesota Antidotes in Brief: A21, High-Dose Insulin Christine M. Stork, BS, PharmD, DABAT, FAACT Professor of Emergency Medicine Clinical Director, Upstate NY Poison Center Upstate Medical University Syracuse, New York Chapter 27, Antibacterials, Antifungals, and Antivirals Chapter 42, Serotonin Reuptake Inhibitors and Atypical Antidepressants Mark K. Su, MD, MPH Associate Professor of Emergency Medicine New York University School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health Director, New York City Poison Control Center New York, New York Chapter 31, Antithrombotics Chapter 77, Hydrofluoric Acid and Fluorides Antidotes in Brief: A17, Prothrombin Complex Concentrates and Direct Oral Anticoagulant Antidotes

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Jeffrey R. Suchard, MD Professor of Clinical Emergency Medicine and Pharmacology University of California, Irvine School of Medicine Irvine, California Chapter 98, Chemical Weapons Chapter 99, Biological Weapons Payal Sud, MD, FACEP Assistant Professor of Emergency Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Director of Performance Improvement Department of Emergency Medicine Long Island Jewish Medical Center Assistant Program Director Medical Toxicology Fellowship Northwell Health New Hyde Park, New York Chapter 45, Sedative-Hypnotics Young-Jin Sue, MD Clinical Associate Professor of Pediatrics Albert Einstein College of Medicine Attending Physician, Pediatric Emergency Services The Children’s Hospital at Montefiore Bronx, New York Chapter 68, Mercury Kenneth M. Sutin, MS, MD, FCCP, FCCM Professor of Anesthesiology New York University School of Medicine Attending Physician, Department of Anesthesiology Bellevue Hospital Center New York, New York Chapter 39, Neuromuscular Blockers Antidotes in Brief: A24, Dantrolene Sodium Matthew D. Sztajnkrycer, MD, PhD Professor of Emergency Medicine Mayo Clinic College of Medicine and Science Staff Toxicologist Minnesota Poison Control System Rochester, Minnesota Chapter 37, Local Anesthetics Asim F. Tarabar, MD, MS Assistant Professor of Emergency Medicine Yale University School of Medicine Director, Medical Toxicology Yale New Haven Hospital New Haven, Connecticut Chapter 58, Antimony Stephen R. Thom, MD, PhD Professor of Emergency Medicine Director of Research University of Maryland School of Medicine Baltimore, Maryland Antidotes in Brief: A40, Hyperbaric Oxygen

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CONTRIBUTORS

Christian Tomaszewski, MD, MS, MBA, FACMT, FACEP Professor of Clinical Emergency Medicine University of California, San Diego Health Chief Medical Officer, El Centro Regional Medical Center San Diego, California Chapter 95, Carbon Monoxide Stephen J. Traub, MD Associate Professor of Emergency Medicine Mayo Clinic College of Medicine and Science Chairman, Department of Emergency Medicine Mayo Clinic Arizona Phoenix, Arizona Chapter 61, Cadmium Michael G. Tunik, MD Associate Professor of Emergency Medicine and Pediatrics New York University School of Medicine Director of Research, Division of Pediatric Emergency Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 12, Food Poisoning Matthew Valento, MD Assistant Professor of Emergency Medicine Site Director for Medical Toxicology University of Washington School of Medicine Attending Physician Harborview Medical Center Seattle, Washington Chapter 41, Cyclic Antidepressants Susi U. Vassallo, MD Professor of Emergency Medicine New York University School of Medicine Emergency Physician Ronald O. Perelman Department of Emergency Medicine Bellevue Hospital Center and NYU Langone Health New York, New York Chapter 14, Athletic Performance Enhancers Larissa I. Velez, MD, FACEP Professor of Emergency Medicine University of Texas Southwestern Medical School Vice Chair of Education Program Director of Emergency Medicine Department of Emergency Medicine University of Texas Southwestern Medical Center Staff Toxicologist, North Texas Poison Center Dallas, Texas Antidotes in Brief: A8, Dextrose (d-Glucose) Lisa E. Vivero, PharmD Drug Information Specialist Irvine, California Chapter 19, Pharmaceutical Additives

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Richard Y. Wang, DO Senior Medical Officer National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, Georgia Chapter 23, Chemotherapeutics Chapter 24, Methotrexate, 5-Flourouracil, and Capecitabine Special Considerations: SC7, Extravasation of Xenobiotics Paul M. Wax, MD Clinical Professor of Emergency Medicine University of Texas Southwestern Medical School Dallas, Texas Executive Director American College of Medical Toxicology Phoenix, Arizona Chapter 74, Antiseptics, Disinfectants, and Sterilants Antidotes in Brief: A5, Sodium Bicarbonate Sage W. Wiener, MD Assistant Professor of Emergency Medicine SUNY Downstate Medical Center College of Medicine Director of Medical Toxicology SUNY Downstate Medical Center/Kings County Hospital Brooklyn, New York Chapter 79, Toxic Alcohols Rachel S. Wightman, MD Assistant Professor of Emergency Medicine Division of Medical Toxicology The Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Chapter 76, Caustics Luke Yip, MD Consultant and Attending Staff Medical Toxicologist Denver Health Rocky Mountain Poison and Drug Center Department of Medicine Section of Medical Toxicology Denver, Colorado Senior Medical Toxicologist Centers for Disease Control and Prevention Office of Noncommunicable Diseases, Injury, and Environmental Health National Center for Environmental Health/Agency for Toxic Substances and Disease Registry Atlanta, Georgia Chapter 49, Ethanol Erin A. Zerbo, MD Assistant Professor of Psychiatry Associate Director, Medical Student Education in Psychiatry Rutgers New Jersey Medical School Newark, New Jersey Special Considerations: SC3, Patient Violence

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PREFACE Goldfrank’s Clinical Manual of Toxicologic Emergencies is a distillation of the essential clinical information provided in the 11th edition of Goldfrank’s Toxicologic Emergencies. Designed to stimulate interest in the management of exposed and poisoned patients, this manual is for students and bedside practitioners, including pharmacists, nurses, advanced practice providers, and physicians. It specifically focuses on those healthcare professionals who need the essential information for their daily care of poisoned patients. Ever since the first edition of the Manual was published in 2007 as a companion to the 8th edition of the main textbook, the editors have received many requests for updates. Although our work on the main textbook is relentless, we decided that the time was right to revise this companion book. Although many of the fundamentals of pharmacology and toxicology remain sound, our approach to patients with toxicologic emergencies continues to evolve based on scientific advances and the ever-changing epidemiological landscape of available xenobiotics. Unlike the previous edition of this Manual, we included only the clinical chapters from the main textbook. While this decision may require novice readers to refer to the main textbook for core knowledge, it allowed us to preserve the rigor of

00_Hoffman_FM_pi-pxxiv.indd 23

the clinical chapters while also including critical images and tables from the main textbook, in order to provide a focused approach designed for bedside application. This Manual also serves as a learning tool for others who may prefer a more portable resource. Thus, while the chapters follow the same overall organization as the 11th edition of Goldfrank’s Toxicologic Emergencies, the chapter numbers differ. In the main textbook, chapters are followed by “Antidotes in Depth,” which provide extensive information for more than 40 therapeutic interventions. Here, each “Antidote in Brief ” describes essential clinical toxicological interventions. While this handbook is designed to stand alone, it is truly a companion work to the main textbook, which provides extensive background information and references, and to the Study Guide, which offers self-assessment questions and directed learning. We hope that this updated edition meets your educational needs and allows you to improve the care of your patients. As always, we encourage your comments and thoughtful feedback. We will do our best to incorporate your suggestions into future editions. The Editors

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The General Approach to the Patient

1

INITIAL EVALUATION OF THE PATIENT: VITAL SIGNS AND TOXIC SYNDROMES

For more than 200 years, health care providers have attempted to standardize their approach to the assessment of patients. At the New York Hospital in 1865, pulse rate, respiratory rate, and temperature were incorporated into the bedside chart and called “vital signs.” It was not until the early part of the 20th century that blood pressure determination also became routine. Additional components of the present standard emergency assessment, such as oxygen saturation by pulse oximetry, capillary blood glucose, and pain severity, are sometimes considered vital signs. Although they are essential components of the clinical evaluation and are important considerations throughout this text, they are not discussed in this chapter but can be found in other relevant sections. In the practice of medical toxicology, vital signs play an important role beyond assessing and monitoring the overall status of a patient, because they frequently provide valuable physiologic clues to the toxicologic etiology and severity of an illness. Table 1–1 presents the normal vital signs for various age groups. Published normal values likely have little relevance for an acutely ill or anxious patient in the emergency setting, yet that is precisely the environment in which abnormal vital signs must be identified and addressed. Descriptions of vital signs as “normal” or “stable” are too nonspecific to be meaningful and therefore should never be accepted as TABLE 1–1    Normal Vital Signs by Agea Age

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Pulse (beats/min)

Respirations (breaths/min)

Adult

120

80

50−90

16−24

16 years

≤120

106°F; >41.1°C) from any cause may lead to extensive rhabdomyolysis, myoglobinuric kidney failure, and direct liver and brain injury and must therefore be identified and corrected immediately. Hypothermia is probably less of an immediate threat to life than hyperthermia, but it requires rapid appreciation, accurate diagnosis, and skilled management because it may suggest energy failure. Table  1–6 is a representative list of xenobiotics that affect body temperature.

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2

PRINCIPLES OF MANAGING THE ACUTELY POISONED OR OVERDOSED PATIENT

OVERVIEW For more than 5 decades, medical toxicologists and poison information specialists have used a clinical approach to poisoned or overdosed patients that emphasizes treating the patient rather than treating the poison. Too often in the past, patients were initially ignored while attention was focused on the ingredients listed on the containers of the product(s) to which they presumably were exposed. However, astute clinicians must always be prepared to administer a specific antidote immediately in instances when nothing else will save a patient, such as with cyanide poisoning. Moreover, after resuscitative antidotes are given, all poisoned or overdosed patients benefit from an organized, rapid clinical management plan also known as a toxicological risk assessment. With the widespread availability of accurate rapid bedside testing for capillary blood glucose, pulse oximetry for oxygen saturation, and end-tidal CO2 monitors, clinicians can safely provide rational, individualized approaches to determine the need for, and in some instances more precise amounts of, dextrose, thiamine, naloxone, and oxygen. Likewise, appreciation of the potential for significant adverse effects associated with all types of gastrointestinal (GI) decontamination interventions and recognition of the absence of clear evidence-based support of efficacy have led to abandoning of syrup of ipecac-induced emesis, an almost complete elimination of orogastric lavage, and a significant reduction in the routine use of activated charcoal. The value of whole-bowel irrigation (WBI) with polyethylene glycol electrolyte solution (PEG-ELS) appears to be much more specific and limited than originally thought, and some of the limitations and (uncommon) adverse effects of activated charcoal are now more widely recognized (Chap. 3). However, as with many issues in clinical medicine, properly selected procedures performed in properly selected patients can lead to an acceptable risk-benefit profile. Routine exclusion of GI decontamination procedures is not optimal and can lead to suboptimal care manifested as increased toxic effects and prolonged use of health care resources. Similarly, interventions to eliminate absorbed xenobiotics from the body are now much more narrowly defined or, in some cases, have been abandoned. Multiple-dose activated charcoal (MDAC) is useful for select but not all xenobiotics. Ion trapping in the urine is only beneficial, achievable, and relatively safe when the urine can be maximally alkalinized in a limited number of cases (Antidotes in Brief: A5). Finally, the roles of hemodialysis, hemoperfusion, and other extracorporeal techniques are now much more specifically defined (Chap. 4). Thus, this chapter represents our current efforts to formulate a logical and effective approach to managing a patient with probable or actual toxic exposure.

The management of most patients with toxicologic clinical syndromes cannot be based on specific antidotal therapies but rather relies on the application of directed supportive or pharmacologic care. Table 2–1 provides a recommended stock list of antidotes and therapeutics for the treatment of poisoned or overdosed patients. Consensus antidote stocking guidelines exist as well.

MANAGING ACUTELY POISONED OR OVERDOSED PATIENTS Rarely, if ever, are all of the circumstances involving a poisoned patient known. The history may be incomplete, unreliable, or unobtainable; multiple xenobiotics may be involved; and even when a xenobiotic etiology is identified, it may not be easy to determine whether the problem is an overdose, an allergic or idiosyncratic reaction, or a drug–drug interaction. The patient’s presenting signs and symptoms may force an intervention at a time when there is almost no information available about the etiology of the patient’s condition (Table 2–2).

Initial Management of Patients with a Suspected Exposure The clinical approach to the patient potentially exposed to a xenobiotic begins with the recognition and treatment of life-threatening conditions, including airway compromise, breathing difficulties, and circulatory problems such as hemodynamic instability and serious dysrhythmias. After the “ABCs” (airway, breathing, and circulation) are addressed, the patient’s level of consciousness should be assessed because it helps determine the techniques to be used for further management of the exposure.

Management of Patients with Altered Mental Status Figure 2–1 provides an approach to these patients. Within the first 5 minutes of managing a patient with an altered mental status (AMS), five therapeutic interventions should be administered if indicated and not contraindicated: 1. Supplemental oxygen to treat xenobiotic-induced hypoxia 2. Hypertonic dextrose: 0.5 to 1.0 g/kg of D50W for an adult or a more dilute dextrose solution (D10W or D25W) for a child; the dextrose is administered as an IV bolus as specific or empiric therapy for documented or suspected hypoglycemia when rapid confirmation is unavailable (Antidotes in Brief: A8) 3. Thiamine (100 mg IV for an adult; usually unnecessary for a child) to prevent Wernicke encephalopathy in patients at risk (Antidotes in Brief: A27) 4. Naloxone (0.04 mg IV with upward titration) for an adult or child with opioid-induced respiratory compromise (Antidotes in Brief: A4) 5. Rectal temperature and initiation of appropriate cooling or warming measures if hyperthermia or hypothermia are present

4

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CHAPTER 2 • PRINCIPLES OF MANAGING THE ACUTELY POISONED OR OVERDOSED PATIENT

5

TABLE 2–1    Antidotes and Therapeutics for the Treatment of Poisonings and Overdosesa Therapeuticsb

Indications

Therapeuticsb

Indications

Acetylcysteine (p. 66)

Acetaminophen and other causes of hepatotoxicity

Fomepizole (p. 548)

Ethylene glycol, methanol, diethylene glycol

Activated charcoal (p. 22)

Adsorbent xenobiotics in the GI tract

Glucagon (p. 301)

β-Adrenergic antagonists, CCBs

Antivenom (Centruroides spp) (p. 615)

Scorpion envenomation

Glucarpidase (p. 220)

Methotrexate

Antivenom (Crotalinae) (p. 658)

Crotaline snake envenomations

Hydroxocobalamin (p. 691)

Cyanide

Antivenom (Micrurus fulvius) (p. 658)

Coral snake envenomations

Idarucizumab (p. 285)

Dabigatran

Insulin (p. 331)

Antivenom (Latrodectus mactans) (p. 613)

Black widow spider envenomations

β-Adrenergic antagonists, CCBs, hyperglycemia

Iodide (SSKI) (p. 724)

Radioactive iodine (I131)

Antivenom (Synanceja spp) (p. 624)

Stonefish envenomation

Lipid emulsion (p. 331)

Local anesthetics

Atropine (p. 586)

Bradydysrhythmias, cholinesterase inhibitors (organic phosphorus compounds, physostigmine) muscarinic mushrooms (Clitocybe, Inocybe) ingestions

Magnesium sulfate injection (p. 271)

Cardioactive steroids, hydrofluoric acid, hypomagnesemia, ethanol withdrawal, torsade de pointes

Methylene blue (1% solution) (p. 701)

Methemoglobinemia, ifosfamide, vasoplegic syndrome, shock

Seizures, agitation, stimulants, ethanol and sedative–hypnotic withdrawal, cocaine, chloroquine, organic phosphorus compounds

Naloxone (p. 90)

Opioids, clonidine

Norepinephrine

Hypotension

Botulinum antitoxin (Heptavalent) (p. 114)

Botulism

Octreotide (p. 184)

Insulin secretagogue–induced hypoglycemia

Oxygen (Hyperbaric) (p. 683)

Calcium chloride, calcium gluconate (p. 532)

Fluoride, hydrofluoric acid, ethylene glycol, CCBs, hypermagnesemia, β-adrenergic antagonists, hyperkalemia

Carbon monoxide, cyanide, hydrogen sulfide

d-Penicillamine (p. 473)

Copper

Phenobarbital (p. 418)

Seizures, agitation, stimulants, ethanol and sedative–hypnotic withdrawal

Benzodiazepines (p. 401)

L-Carnitine (p. 195)

Valproic acid: hyperammonemia

Cyanide kit (nitrites, p. 693; sodium thiosulfate, p. 693)

Cyanide

Phentolamine (p. 399)

Vasoconstriction: cocaine, MAOI interactions, epinephrine, and ergot alkaloids

Cyproheptadine (p. 364)

Serotonin toxicity

Physostigmine (p. 206)

Anticholinergics

Dantrolene (p. 346)

Malignant hyperthermia

Decontamination

Deferoxamine (p. 166)

Iron, aluminum

Polyethylene glycol electrolyte lavage solution (p. 25)

Dextrose in water (50% adults; 20% pediatrics; 10% neonates) (p. 181)

Hypoglycemia

Pralidoxime (p. 588)

Acetylcholinesterase inhibitors (organic phosphorus compounds and carbamates)

Protamine (p. 291)

Heparin anticoagulation

Digoxin-specific antibody fragments (p. 319)

Cardioactive steroids

Prussian blue (p. 508)

Thallium, cesium

Dimercaprol (British antiLewisite [BAL]) (p. 457)

Arsenic, mercury, gold, lead

Pyridoxine (vitamin B6) (p. 262)

Isoniazid, ethylene glycol, gyromitrincontaining mushrooms

Diphenhydramine (p. 351)

Dystonic reactions, allergic reactions

Sodium bicarbonate (p. 104)

DTPA (p. 726) (calcium trisodium pentetate)

Radioactive isotopes; americium, curium, plutonium

Edetate calcium disodium (calcium disodium versenate, CaNa2EDTA) (p. 488)

Lead, other selected metals

Ethylene glycol, methanol, salicylates, cyclic antidepressants, methotrexate, phenobarbital, quinidine, chlorpropamide, class I antidysrhythmics, chlorophenoxy herbicides, sodium channel blockers

Starch (p. 516)

Iodine

Succimer (p. 485)

Lead, mercury, arsenic

Ethanol (p. 550)

Ethylene glycol, methanol, diethylene glycol

Thiamine (vitamin B1) (p. 412)

Thiamine deficiency, ethylene glycol, chronic ethanol consumption (“alcoholism”)

Flumazenil (p. 381)

Benzodiazepines

Uridine triacetate (p. 223)

Fluorouracil, capecitabine

Folinic acid (p. 217)

Methotrexate, methanol

Vitamin K1 (p. 289)

Warfarin or rodenticide anticoagulants

Each emergency department should have the vast majority of these antidotes immediately available; some of these antidotes may be stored in the pharmacy, and others may be available from the Centers for Disease Control and Prevention, but the precise mechanism for locating each one must be known by each staff member. b A detailed analysis of each of these antidotes is found in the text in the Antidotes in Brief section on the page cited to the right of each antidote or therapeutic listed. CCB = calcium channel blocker; DTPA = diethylenetriaminepentaacetic acid; EDTA = ethylenediamine tetraacetic acid; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; SSKI = saturated solution of potassium iodide. a

02_Hoffman_Ch02_p0004-0010.indd 5

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6

THE GENERAL APPROACH TO THE PATIENT

TABLE 2–2    Clinical and Laboratory Findings in Poisoning and Overdose Agitation

Anticholinergics,a hypoglycemia, phencyclidine, sympathomimetics,b synthetic cannabinoid receptor agonists, withdrawal from ethanol and sedative–hypnotics

Alopecia

Alkylating agents, radiation, selenium, thallium

Ataxia

Benzodiazepines, carbamazepine, carbon monoxide, ethanol, hypoglycemia, lithium, mercury, nitrous oxide, phenytoin

Blindness or decreased visual acuity

Caustics (direct), cisplatin, cocaine, ethambutol, lead, mercury, methanol, quinine, thallium

Blue skin

Amiodarone, FD&C #1 dye, methemoglobinemia, silver

Constipation

Anticholinergics,a botulism, lead, opioids, thallium (severe)

Deafness, tinnitus

Aminoglycosides, carbon disolfide, cisplatin, loop diuretics, macrolides, metals, quinine, quinolones, salicylates

Diaphoresis

Amphetamines, cholinergics,c hypoglycemia, opioid withdrawal, salicylates, serotonin toxicity, sympathomimetics,b withdrawal from ethanol and sedative–hypnotics

Diarrhea

Arsenic and other metals, boric acid (blue-green), botanical irritants, cathartics, cholinergics,c colchicine, iron, lithium, opioid withdrawal, radiation

Dysesthesias, paresthesias

Acrylamide, arsenic, ciguatera, cocaine, colchicine, thallium

Gum discoloration

Arsenic, bismuth, hypervitaminosis A, lead, mercury

Hallucinations

Anticholinergics,a dopamine agonists, ergot alkaloids, ethanol, ethanol and sedative–hypnotic withdrawal, LSD, phencyclidine, sympathomimetics,b tryptamines

Headache

Carbon monoxide, hypoglycemia, MAOI–food interaction (hypertensive crisis), serotonin toxicity

Metabolic acidosis (elevated anion gap)

Methanol, uremia, ketoacidosis (diabetic, starvation, alcoholic), paraldehyde, metformin, iron, isoniazid, lactic acidosis, cyanide, protease inhibitors, ethylene glycol, salicylates, toluene

Miosis

Cholinergics,c clonidine, opioids, phencyclidine, phenothiazines

Mydriasis

Anticholinergics,a botulism, opioid withdrawal, sympathomimeticsb

Nystagmus

Barbiturates, carbamazepine, carbon monoxide, dextromethorphan, ethanol, lithium, MAOIs, phencyclidine, phenytoin, quinine, synthetic cannabinoid receptor agonists

Purpura

Anticoagulant rodenticides, corticosteroids, heparin, pit viper venom, quinine, salicylates, anticoagulants, levamisole

Radiopaque ingestions

Arsenic, halogenated hydrocarbons, iodinated compounds metals (eg, iron, lead), potassium compounds

Red skin

Anticholinergics,a boric acid, disulfiram, hydroxocobalamin, scombroid, vancomycin

Rhabdomyolysis

Carbon monoxide, doxylamine, HMG-CoA reductase inhibitors, sympathomimetics,b Tricholoma equestre mushrooms

Salivation

Arsenic, caustics, cholinergics,c clozapine, ketamine, mercury, phencyclidine, strychnine

Seizures

Bupropion, camphor, carbon monoxide, cyclic antidepressants, Gyromitra mushrooms, hypoglycemia, isoniazid, methylxanthines, ethanol and sedative–hypnotic withdrawal

Tremor

Antipsychotics, arsenic, carbon monoxide, cholinergics,c ethanol, lithium, mercury, methyl bromide, sympathomimetics,b thyroid hormones

Weakness

Botulism, diuretics, magnesium, paralytic shellfish, steroids, toluene

Yellow skin

APAP (late), pyrrolizidine alkaloids, β carotene, amatoxin mushrooms, dinitrophenol

Anticholinergics, including antihistamines, atropine, cyclic antidepressants, and scopolamine. Sympathomimetics, including adrenergic agonists, amphetamines, cocaine, and ephedrine. c Cholinergics, including muscarinic mushrooms; organic phosphorus compounds and carbamates, including select Alzheimer disease drugs and physostigmine; and pilocarpine and other direct-acting xenobiotics. APAP = acetaminophen; HMG-CoA = 3-hydroxy-3-methyl-glutaryl-CoA; LSD = lysergic acid diethylamide; MAOI = monoamine oxidase inhibitor. a

b

Further Evaluation of All Patients with Suspected Xenobiotic Exposures Vital signs should be obtained serially and a full physical examination should be performed. Toxicologic etiologies of abnormal vital signs and physical findings are summarized in Tables 1–1 to 1–6. Toxic syndromes, sometimes called “toxidromes,” are summarized in Table 1–2. Typically, in the management of patients with toxicologic emergencies, there is both a necessity and an opportunity to

02_Hoffman_Ch02_p0004-0010.indd 6

obtain various diagnostic studies and ancillary tests interspersed with stabilizing the patient’s condition, obtaining the history, and performing the physical examination. For most patients with unintentional exposures or intended self-harm the routine use of laboratory testing is of limited value. Specifically, urine and serum drug screens add little if anything to clinical management and are often misleading or misinterpreted. Rather targeted laboratory testing is preferred as guided by the history and physical examination.

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CHAPTER 2 • PRINCIPLES OF MANAGING THE ACUTELY POISONED OR OVERDOSED PATIENT

Assess airway Clinical evaluation Cervical spine stabilization, if indicated

Assess breathing (oxygenation and ventilation) Clinical evaluation, pulse oximetry, end-tidal CO2

Assess circulation and perfusion Clinical evaluation, cardiac monitor,12-lead ECG Establish IV access and obtain blood for testing

Assess CNS Clinical evaluation Blood glucose determination, rectal temperature

Identify toxidrome History and physical examination Interpret bedside testing Begin discussion with poison control center

Inadequate

Inadequate

Inadequate

Inadequate

Identifiable

7

Airway positioning Airway adjuncts Endotracheal intubation and definitive airway

Supplemental oxygen Bag–valve–mask, assisted respiration Endotracheal intubation and definitive airway Mechanical ventilation

CPR as indicated, ECLS Fluid resuscitation as indicated Antidysrhythmic therapy (eg, atropine, NaHCO3) Vasopressors and inotropes, HDI, etc.

Support oxygenation, ventilation, and perfusion Dextrose, naloxone, thiamine as indicated Special considerations Seizures Benzodiazepines, pyridoxine, barbiturates, propofol Avoid phenytoin Thermal dysregulation Hyperthermia: sedation, cooling, intubation, paralysis, antidotes Hypothermia: rewarming Agitation Sedation

Treat toxidrome

ABG or VBG + lactate, serum electrolytes, BUN, Cr, glucose, CBC, APAP Urine or serum ketones, β-HCG Diagnostic investigation Complete and thorough HPE Specific laboratory analyses, if indicated

Alter toxin pharmacokinetics Perform risk–benefit assessment

Determine disposition Ongoing patient evaluation and treatment

Diagnostic aids

Benefit exceeds risk

Patient status

If suggested by HPE or bedside testing Hepatic or coagulation profile Cardiac or skeletal muscle profile (Tn, CPK) Specific drug concentrations Radiographic studies Studies to exclude nontoxicologic causes

Dermal or ophthalmic decontamination (or both) Gastric emptying (orogastric lavage) Limit absorption (AC, WBI) Enhance elimination (eg, MDAC, alkaline diuresis, HD/HP)

Admission: ICU, telemetry unit, ward bed Continued ED evaluation, or discharge Psychiatric and social evaluation Continue poison control center communications

FIGURE 2–1.  This algorithm is a basic guide to the management of poisoned patients. A more detailed description of the steps in management may be found in the accompanying text. This algorithm is only a guide to actual management, which must, of course, consider the patient’s clinical status. ABG = arterial blood gas; AC = activated charcoal; APAP = acetaminophen; β-HCG = β-human chorionic gonadotropin; CBC = complete blood count; CNS = central nervous system; CPK = creatine phosphokinase; CPR = cardiopulmonary resuscitation; Cr, creatinine; ECG = electrocardiograph; ECLS = extracorporeal life support; HD = hemodialysis; HDI = high-dose insulin; HP = hemoperfusion; HPE = history and physical examination; ICU = intensive care unit; MDAC = multiple-dose activated charcoal; Tn = troponin; VBG = venous blood gas; WBI = whole-bowel irrigation.

02_Hoffman_Ch02_p0004-0010.indd 7

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8

THE GENERAL APPROACH TO THE PATIENT

The Role of Gastrointestinal Decontamination A series of highly individualized treatment decisions regarding limiting the exposure to the xenobiotic follow the initial stabilization and assessment of the patient. As noted previously and as discussed in detail in Chap. 3, evacuation of the GI tract or administration of activated charcoal can no longer be considered standard or routine toxicologic care for most patients.

Eliminating Absorbed Xenobiotics from the Body Discussions of the indications for and techniques of manipulating urinary pH (ion trapping), diuresis, hemodialysis, hemoperfusion, continuous renal replacement therapy, and exchange transfusion are found in Chap. 4. Alkalinization of the urinary pH with sodium bicarbonate is used to enhance salicylate elimination (other xenobiotics are discussed in Chap. 4), and sodium bicarbonate also prevents toxicity from methotrexate (Antidotes in Brief: A5). If extracorporeal elimination is contemplated, hemodialysis is used for patients who overdose with salicylates, methanol, ethylene glycol, lithium, valproic acid, and other xenobiotics that are either dialyzable or cause fluid and electrolyte abnormalities. Plasmapheresis and exchange transfusion are used to eliminate xenobiotics with large molecular weights that are not dialyzable.

AVOIDING PITFALLS

of support that is available if the patient is discharged from the ED. At times, it is essential to initially separate the patient from any relatives or friends to obtain greater cooperation from the patient and avoid violating confidentiality and because the interpersonal anxiety may interfere with therapy.

APPROACHING PATIENTS WITH INTENTIONAL EXPOSURES Initial efforts at establishing rapport with the patient by indicating to the patient concern about the events that led to the ingestion and the availability of help after the xenobiotic is removed (if such procedures are planned) often facilitate management. If GI decontamination is deemed beneficial, the reason for and nature of the procedure should be clearly explained to the patient together with reassurance that after the procedure is completed, there will be ample time to discuss his or her concerns and provide additional care.

SPECIAL CONSIDERATIONS FOR MANAGING PREGNANT PATIENTS In general, a successful outcome for both the mother and fetus depends on optimum management of the mother. Proven effective treatment for a potentially serious toxic exposure to the mother should never be withheld based on theoretical concerns regarding the fetus.

Physiologic Factors

The history alone is not a reliable indicator of which patients require naloxone, hypertonic dextrose, thiamine, and oxygen. Instead, the need for these therapies should be evaluated and performed if indicated (unless specifically contraindicated) only after a clinical assessment for all patients with AMS. Attributing an AMS to alcohol because of an odor on a patient’s breath is potentially misleading. Small amounts of alcohol or alcoholic beverage congeners generally produce the same breath odor as do intoxicating amounts. Conversely, even when an extremely high blood ethanol concentration is confirmed by laboratory analysis, it is dangerous to ignore other possible causes of an AMS. Because some individuals with an alcohol use disorder are alert with ethanol concentrations in excess of 500 mg/dL, a concentration that would result in coma and possibly apnea and death in a nontolerant person, finding a high ethanol concentration does not eliminate the need for further search into the cause of a depressed level of consciousness.

A pregnant woman’s total blood volume and cardiac output are elevated through the second trimester and into the later stages of the third trimester. This means that signs of hypoperfusion and hypotension manifest later than they would in a woman who is not pregnant, and when they do, uterine blood flow may already be compromised. Maintaining the patient in the left-lateral decubitus position helps prevent supine hypotension resulting from impairment of systemic venous return by compression of the inferior vena cava.

ADDITIONAL CONSIDERATIONS IN MANAGING PATIENTS WITH A NORMAL MENTAL STATUS

In all of these cases, the principles of management are as follows:

As in the case of patients with AMS, vital signs must be obtained and recorded. If the patient is alert, talking, and in no respiratory distress, all that remains to document are the respiratory rate and rhythm. Because the patient is alert, additional history should be obtained, keeping in mind that information regarding the number and types of xenobiotics ingested, time elapsed, prior vomiting, and other critical information may be unreliable. Speaking to a friend or relative of the patient may provide an opportunity to learn useful and reliable information regarding the exposure, the patient’s frame of mind, a history of previous exposures, and the type

1. Avoid secondary exposures by wearing protective (rubber or plastic) gowns, gloves, eye protection, and shoe covers. Cases of serious secondary poisoning have occurred in emergency personnel after prolonged skin contact with xenobiotics such as organic phosphorus compounds on the victim’s skin or clothing. 2. Remove the patient’s clothing, place it in plastic bags, and then seal the bags. 3. Wash the patient with soap and copious amounts of water twice regardless of how much time has elapsed since the exposure.

02_Hoffman_Ch02_p0004-0010.indd 8

Use of Antidotes Limited data are available on the use of antidotes in pregnancy. In general, antidotes should not be used if the indications for use are equivocal. On the other hand, antidotes should not be withheld if they have the potential to reduce potential maternal morbidity and mortality as the health of the fetus is directly linked to that of the mother.

MANAGEMENT OF PATIENTS WITH CUTANEOUS EXPOSURE

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CHAPTER 2 • PRINCIPLES OF MANAGING THE ACUTELY POISONED OR OVERDOSED PATIENT

4. Make no attempt to neutralize an acid with a base or a base with an acid. Further tissue damage may result from the heat generated by the exothermic reaction. 5. Avoid using any greases or creams because they will only keep the xenobiotic in close contact with the skin and ultimately make removal more difficult. Special Considerations: SC1 discusses the principles of preventing dermal absorption.

MANAGEMENT OF PATIENTS WITH OPHTHALMIC EXPOSURES The eyes should be irrigated with the eyelids fully retracted for no less than 20 minutes. To facilitate irrigation, an anesthetic should be used, and the eyelids should be kept open with an eyelid retractor. An adequate irrigation stream is obtained by running 1 L of 0.9% sodium chloride through regular IV tubing held a few inches from the eye or by using an irrigating lens. Checking the eyelid fornices with pH paper strips is important to ensure adequate irrigation; the pH should normally be 6.5 to 7.6 if accurately tested, although when using paper test strips, the measurement will often be near 8.0. SC1 describes the management of toxic ophthalmic exposures in more detail.

IDENTIFYING PATIENTS WITH NONTOXIC EXPOSURES The following general guidelines for determining that an exposure is either nontoxic or minimally toxic will assist clinical decision making: 1. Identification of the product and its ingredients is possible. 2. None of the United States Consumer Product Safety Commission’s “signal words” (CAUTION, WARNING, or DANGER) appear on the product label. 3. The route of exposure is known.

9

4. A reliable approximation of the maximum exposure quantity is able to be made. 5. Based on the available medical literature and clinical experience, the potential effects related to the exposure are expected to be benign or at worst self-limited and not likely to require the patient to access health care. 6. The patient is asymptomatic or has developed the maximal expected self-limited toxicity. 7. Adequate time has occurred to assess the potential for the development of toxicity. For any patient in whom there is a question about the nature of the exposure, it is not appropriate to consider that exposure nontoxic. All such patients, and all patients for whom the health care provider is unsure of the risks associated with a given exposure, should be referred either to the regional poison control center or health care facility for further evaluation.

DISPOSITION OF PATIENTS The poison control center must determine the need for direct medical care in a hospital or whether the patient has had a nontoxic exposure (discussed earlier) and can be managed at home. In the ED, many patients are discharged after their evaluation and treatment and after psychiatric and social services evaluations are obtained as needed. Among clinically ill poisoned patients, the decision is generally simplified based on the relative abilities of the various units within the medical facility. Critical care units expend the highest level of resources to assure both intensive monitoring and the provision of timely care and are necessary for patients who are currently ill or currently stable but likely to decompensate. See Table 2–3 for a description of patients best suited

TABLE 2–3    Define the Indications for Intensive Care Unit Admission Patient Characteristics

Xenobiotic Characteristics

Does the patient have any signs of serious end-organ toxicity? Are the end-organ effects progressing? Are laboratory data suggestive of serious toxicity? Is the patient a high risk for complications requiring ICU intervention?  Seizures   Unresponsive to verbal stimuli  Level of consciousness impaired to the point of potential airway compromise  PCO2 >45 mm Hg   Systolic blood pressure 1,500 mg/L*IU/L). NAC Dose Adjustment.  In rare cases, patients with massive ingestions with or without antimuscarinic coingestants have a highly elevated [APAP] for prolonged periods or secondary elevations of the [APAP]. Several of these patients developed hepatotoxicity despite early (< 6 hours) IV NAC therapy, raising the question of whether the traditional IV NAC infusion (6.25 mg/kg/h) provides enough NAC for these rare patients with a late elevated [APAP] or massive ingestions. In these rare patients, we recommend treating with greater amounts of NAC when prolonged, massive [APAP] is evident. No data exist to determine which, if any, alternative NAC dosing strategy is superior. For a detailed description of increased dosing for massive ingestions, highly elevated [APAP], and prolonged elevations of [APAP], see Antidotes in Brief: A3.

Hepatic Transplantation Hepatic transplantation increases survival for a select group of severely ill patients who have APAP-induced fulminant hepatic failure. Tremendous improvements in transplantation and supportive hepatic care have increased immediate survival rates after hepatic transplantation to 69% to 83% with 3- to 5-year survival rates of 50% to 66%, respectively. Patients who meet criteria for transplant but do not receive an organ have survival rates of 25% to 40%. Concerns that patients who receive transplants for APAP-induced fulminant hepatic failure will have lower survival rates and be unable to maintain posttransplant medication regimens have resulted in the majority of patients not being listed for transplant.

Assessing Prognosis The most commonly used prognosticator of mortality is the King’s College criteria (KCC) (Table 6–1). The survival rate of patients who meet the KCC but are not transplanted is 25% to 40%. Survival rates have significantly increased since the original studies, likely because of the utilization of prolonged NAC therapy and improved supportive care for patients with acute hepatic failure. When determining the KCC, interpretation of PT and INR must include awareness of concurrent NAC therapy as well as therapy with vitamin K, PCCs, factor VII, and FFP. The prognostic importance of monitoring PT

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CHAPTER 6 • ACETAMINOPHEN

65

ELIMINATION TECHNIQUES

TABLE 6–1    King’s College Criteria Either of the following historically predicted a survival rate 3.3 mg/dL (292 µmol/L) b.  Prothrombin time >100 sec (or international normalized ratio >6.5) c. Grade III or IV encephalopathy (somnolence to stupor, responsive to verbal stimuli, confusion, gross disorientation)

Several clinical scenarios benefit from increasing clearance of APAP from the body. Indications early after APAP overdose include patients with an exceedingly high [APAP] who are at high risk of hepatotoxicity despite NAC therapy as well as those with an elevated lactate and a metabolic acidosis. Later in the course of APAP toxicity, elimination techniques are used to remove the remaining [APAP] in patients who are imminently receiving a hepatic transplant or for removal of toxins related to hepatic failure.

Hemodialysis and INR in this setting suggests that FFP should be given only for evidence of bleeding, with risk of bleeding from known concomitant trauma, or before invasive procedures, and not based merely on the PT or INR. A [lactate] above 3.5 mmol/L at a median of 55 hours after APAP ingestion or [lactate] above 3.0 mmol/L after fluid resuscitation is both a sensitive and specific predictor of patient death without transplant. Unfortunately, patients often meet the KCC and lactate criteria quite late in their course of disease, so these criteria are not useful as early predictors or as standards for transfer to a facility that performs hepatic transplant. Additional predictors of severity of hepatic toxicity in patients treated with NAC include a rapid doubling of the [AST] or [ALT] (doubling < 8 hours) and an [AST] or [ALT] reaching 1,000 IU/L within 20 hours of NAC treatment. Table 6–2 summarizes the utility of currently used scoring systems for determining death or the need for transplant.

Score

Sensitivity Specificity (%) (%) PPV

NPV

King’s College Criteria

47

83

0.70

0.65

Acute Physiology and Chronic Health Evaluation II (>12)

67

76

0.69

0.75

Sequential Organ Failure Assessment (>12)

67

80

0.74

0.74

Model for End-Stage Liver Disease (>32) 89

25

0.49

0.77

[Lactate] (>3.3 mmol/L)

52

0.69

0.83

NPV = negative predictive value; PPV = positive predictive value.

11_Hoffman_Ch06_p0057-0065.indd 65

Plasmapheresis and Plasma Exchange Plasmapheresis is useful in patients with ALF to correct coagulopathy, but it does not reliably correct encephalopathy. Exchange transfusion was used in one 1.22-kg neonate who had an [APAP] of 75 µg/mL after maternal oral overdose and subsequent delivery with little reduction in [APAP] and is therefore not routinely recommended.

Liver Dialysis

TABLE 6–2   Prediction of Death or Transplant in 125 Patients With Acetaminophen-Induced Liver Failure

91

The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests hemodialysis for patients with altered mental status, elevated [lactate], or metabolic acidosis with an [APAP] greater than 700 µg/mL (4,630 µmol/L) or for an [APAP] greater than 900 µg/mL (5,960 µmol/L) if the patient is treated with NAC. Furthermore, hemodialysis is recommended for an [APAP] greater than 1,000 µg/mL (6,620 µmol/L) regardless of therapy. Because hemodialysis also removes NAC, we recommend doubling NAC infusion rates during hemodialysis to compensate. No dosing adjustment is likely necessary during continuous venovenous hemofiltration.

Liver dialysis devices such as the molecular adsorbent recirculation system (MARS) or fractionated plasma separation and adsorption, and single-pass albumin dialysis (Prometheus) are used as a bridge to transplantation, for hemodynamic stabilization before hepatic transplant, or as a bridge to spontaneous recovery in patients with APAPinduced hepatic failure. Although some surrogate benefits are reported, a meta-analysis concluded that MARS has no effect on mortality in multiple causes of ALF. We recommend treatment with one of these techniques, if available, in patients with fulminant hepatic failure who meet clinical criteria for transplantation or high mortality (eg, KCC) regardless of whether or not they will be transplanted.

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A3

Antidotes in Brief

N-ACETYLCYSTEINE

INTRODUCTION N-Acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially toxic acetaminophen (APAP) overdoses. If administered early, NAC can prevent APAP-induced hepatotoxicity. If administered after the onset of hepatotoxicity, NAC improves outcomes and decreases mortality. N-Acetylcysteine appears to also limit hepatotoxicity from other xenobiotics that result in glutathione (GSH) depletion and free radical formation, such as cyclopeptide-containing mushrooms, carbon tetrachloride, chloroform, pennyroyal oil, clove oil, and possibly liver failure from chronic valproic acid use.

HISTORY Shortly after the first case of APAP hepatotoxicity was reported, Mitchell described the protective effect of GSH. Prescott first suggested NAC for APAP poisoning in 1974 and by 1977 the first treated patients were reported. Several human investigations were performed with oral (PO) and intravenous (IV) NAC starting in the late 1970s. The US Food and Drug Administration (FDA) approved NAC for PO use in 1985 and for IV use in 2004.

PHARMACOLOGY Chemistry The amino acids cysteine, glycine, and glutamate are used in vivo to synthesize GSH, the primary intracellular antioxidant. N-Acetylcysteine is a thiol containing (R-SH) compound that increases intracellular cysteine concentrations when deacetylated (into cysteine) and causes release of intracellular protein- and membrane-bound cysteine.

Related Xenobiotics Cysteamine, methionine, and NAC, which are all GSH precursors or substitutes, have been used successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than NAC, and methionine is less effective than NAC. Therefore, NAC emerged as the preferred treatment.

Mechanism of Action Early after ingestion when APAP is being metabolized to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI. In this preventive role, NAC acts primarily as a precursor for the synthesis of GSH. The availability of cysteine is the rate-limiting step in the synthesis of GSH, and NAC is effective in replenishing diminished supplies of both cysteine and GSH. Additional minor mechanisms of NAC in preventing hepatotoxicity include acting as a substrate for sulfation, as an intracellular GSH substitute by directly binding to NAPQI, and by enhancing the reduction of NAPQI to APAP.

After hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free radical scavenging, increasing oxygen delivery, increased mitochondrial adenosine triphosphate (ATP) production, antioxidant effects, and alteration of microvascular tone. These nonspecific effects support the use of NAC in nonacetaminophen induced liver injury.

Pharmacokinetics and Pharmacodynamics N-Acetylcysteine has a relatively small volume of distribution (0.5 L/kg), and protein binding is estimated at 83%. N-Acetylcysteine is metabolized to many sulfur-containing compounds such as cysteine, GSH, methionine, cystine, and disulfides, as well as conjugates of electrophilic compounds, that are not routinely measured. Thus, the pharmacodynamic study of NAC is complex. Pharmacokinetics of Oral N-Acetylcysteine.  Oral NAC is rapidly absorbed, but its bioavailability is low (10%–30%) because of significant first-pass liver metabolism. The mean time to peak serum concentration is 1.4 ± 0.7 hours. The mean elimination half-life is 2.5 ± 0.6 hours. Interindividual serum NAC concentrations can vary tenfold. The effervescent NAC formulation (when dissolved in water) has a mean time to peak serum concentration of 1.8 hours with similar peak concentration and area under the plasma drug concentration versus time curve (AUC) as an equivalent dose of the PO NAC solution. Conflicting in vitro and in vivo data regarding the concomitant use of PO NAC and activated charcoal suggest that the resultant bioavailability of NAC is either decreased or unchanged. This interaction is of limited clinical importance, and PO NAC can be initiated without concern for activated charcoal interaction (Chap. 6). Pharmacokinetics of Intravenous N-Acetylcysteine.  Serum concentrations after IV administration of an initial loading dose of 150 mg/kg over 15 minutes reach approximately 500 mg/L (3,075 μmol/L). A steady-state serum concentration of 35 mg/L (range 10–90 mg/L) is reached in approximately 12 hours with the standard IV protocol. Several alternative protocols exist with variable kinetics. In general, slower loading doses lead to lower peak [NAC], and shorter protocols (eg, 12-hour protocol) lead to lower 20-hour [NAC] than longer protocols. Approximately 30% of NAC is eliminated renally. When in the blood, IV and PO NAC have a similar half-life (2–2.5 hours). This halflife is increased in the setting of severe liver failure or end-stage kidney disease because of a reduction in clearance. Intravenous versus Oral Administration.  As in the case of many issues related to APAP toxicity, the choice of PO versus IV NAC is complex. Because no controlled studies have compared IV with PO NAC, conclusions about the relative benefit of each are difficult. With the exception of fulminant hepatic failure,

66

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ANTIDOTES IN BRIEF • N-ACETYLCYSTEINE

for which only the IV route has been investigated, IV and PO NAC administration are essentially equally efficacious in treating patients with APAP toxicity. The route of NAC should not be a factor when considering efficacy. Nausea and vomiting are more frequent in patients treated with PO NAC, whereas anaphylactoid reactions are more common during the rapid initial bolus of the standard IV protocol. Several alternative IV NAC protocols, mainly modifying the initial bolus dose/time, reported lower rates of anaphylactoid reactions requiring medical treatment when compared with the traditional three-bag protocol. Anaphylactoid reactions are severe in approximately 1% of cases, and in rare instances lead to hypotension and death. Intravenous NAC is dosed using a complex three-bag preparation system (see Dosing and Administration section later) that has led to an up to 33% error rate, including 19% of patients having a greater than 1-hour interruption of NAC. Attempts at simplifying this system are described but are not adequately studied for general use (Table A3–1). Additional safety concerns involve dosing for both small children and obese adults. The main disadvantages of the PO NAC formulation are the high rate of vomiting and the concern that vomiting delays therapy. Delays in administration of NAC are correlated with an increased risk of hepatotoxicity. A potential disadvantage of PO NAC is that its systemic absorption takes up to 1 hour compared with the immediate systemic availability of IV NAC. Finally, PO NAC doses are difficult to administer to patients with altered mental status because of aspiration risks; IV NAC offers a distinct advantage in these instances. One theoretical, albeit unproven, advantage of PO NAC early in the course of toxicity is that direct delivery via the portal circulation yields a higher concentration of NAC in the target compartment of toxicity, the liver. However, an elevated serum NAC concentration may be an advantage of

TABLE A3–1   Three-Bag Method Dosage Guide for N-Acetylcysteine by Weight for Patients Weighing ≥ 40 kga

67

IV NAC administration when the liver is not the only target organ of NAC, such as liver failure accompanied by cerebral edema or pregnancy. Several economic analyses conclude that IV NAC is less expensive than PO NAC, but others conclude the opposite. However, the majority of cost is associated with length of hospital stay, and because none of these studies have taken into account that many patients treated with PO NAC now receive shorter courses than 72 hours, the studies do not represent costs of current use. Specific Indications for Intravenous N-Acetylcysteine.  Three situations exist for which the available information suggests IV NAC is preferable to PO NAC: (1) fulminant hepatic failure, (2) inability to tolerate PO NAC, and (3) APAP poisoning in pregnancy. Other common indications for IV NAC include patients with very high [APAP] who are approaching or are more than 6 to 8 hours from the time of ingestion. Use of IV NAC is recommended to prevent further delays and resultant loss of NAC efficacy.

ROLE IN ACETAMINOPHEN TOXICITY In acute overdose, treatment with NAC should be initiated if the serum [APAP] plotted on the Rumack-Matthew nomogram is above the treatment line or the patient’s history suggests an acute APAP ingestion of 150 mg/kg or greater and the results of blood tests will not be available within 8 hours of ingestion. In patients with chronic APAP ingestions, treatment with NAC should be initiated if either aspartate aminotransferase (AST) is above normal or the [APAP] is higher than expected given a pharmacokinetic assessment of the dose and time (Chap. 6).

ROLE IN NONACETAMINOPHEN POISONING The use of NAC has been studied for a number of xenobiotics associated with free radical or reactive metabolite toxicity such as chloroform, carbon tetrachloride, pennyroyal oil, clove oil, and zidovudine. Human data are insufficient for any of these xenobiotics to definitively recommend NAC as a therapeutic intervention. However, the best evidence supports the use of NAC in cases of acute exposures to cyclopeptide containing mushrooms and carbon tetrachloride. N-Acetylcysteine is reasonable in cases of acute pennyroyal oil (ie, pulegone) or clove oil (eg, eugenol) ingestions based on their similarities to APAP-induced hepatoxicity. Both pulegone and eugenol are converted to reactive metabolites that deplete GSH, leading to centrilobular hepatic necrosis. Given the risk–benefit ratio, we recommend the use of NAC for these indications.

Body Weight

Loading Dose (150 mg/kg in 200 mL D5W over 60 minutes)

Second Dose (50 mg/kg in 500 mL D5W over 4 hours)

Third Dose (100 mg/kg in 1000 mL D5W over 16 hours)

(kg)

(lb)

N-Acetylcysteine 20% (mL)b

N-Acetylcysteine 20% (mL)b

N-Acetylcysteine 20% (mL)b

100

220

75

25

50

90

198

67.5

22.5

45

80

176

60

20

40

70

154

52.5

17.5

35

ADVERSE EVENTS AND SAFETY ISSUES Although the IV route ensures delivery, rate-related anaphylactoid reactions occur in 14% to 18% of patients, mainly during the initial bolus. Up to one-third of patients have the infusion completely stopped because of reactions, although it can be restarted in most cases. Most reactions are mild (6%) or moderate (10%) such as cutaneous reactions, nausea, and vomiting; severe reactions such as bronchospasm, hypotension, and angioedema are rare (1%). Anaphylactoid reactions

60

132

45

15

30

50

110

37.5

12.5

25

40

88

30

10

20

The total volume administered should be adjusted for patients weighing < 40 kg and for those requiring fluid restriction. bAcetadote (acetylcysteine) is available in 30-mL (200-mg/mL) single-dose glass vials. D5W = 5% dextrose in water. a

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68

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE A3–2    Three-Bag Method Dosage Guide for N-Acetylcysteine by Weight for Patients Weighing < 40 kga Body Weight

Loading Dose (150 mg/kg over 60 minutes)

Second Dose (50 mg/kg over 4 hours)

Third Dose (100 mg/kg over 16 hours)

(kg)

(lb)

N-Acetylcysteine 20% (mL)

D5W (mL)b

N-Acetylcysteine 20% (mL)b

D5W (mL)

N-Acetylcysteine 20% (mL)b

D5W (mL)

30

66

22.5

100

7.5

250

15

500

25

55

18.75

100

6.25

250

12.5

500

20

44

15

60

5

140

10

280

15

33

11.25

45

3.75

105

7.5

210

10

22

7.5

30

2.5

70

5

140

Acetadote (N-Acetylcysteine ) is hyperosmolar (2,600 mOsm/L) and is compatible with D5W, one-half normal saline (0.45% sodium chloride injection), and water for injection. b Acetadote is available in 30-mL (200-mg/mL) single-dose glass vials. D5W = 5% dextrose in water. a

are more common in patients with lower APAP concentrations because APAP decreases histamine release from mononucleocytes and mast cells in a dose-dependent manner. If hypotension, dyspnea, wheezing, flushing, or erythema occurs, then NAC should be stopped. Adverse reactions, confined to flushing and erythema, are usually transient, and we recommend continuing NAC with meticulous monitoring for systemic symptoms that indicate the need to stop the NAC. Urticaria can be managed with diphenhydramine with the same precautions. After the reaction resolves, we recommend carefully restarting NAC at a slower rate no later than 1 hour after the cessation, assuming NAC is still indicated. If the reaction persists or worsens, IV NAC should be discontinued and a switch to PO NAC is recommended. We recommend against stopping NAC treatment because of mild anaphylactoid reactions because there is evidence of poor outcomes in patients who are undertreated with NAC in these scenarios. Intravenous NAC decreases clotting factors and increases the prothrombin time. International normalized ratio (INR) elevations are typically below 1.5 to 2.0. Iatrogenic overdoses with IV NAC resulted in severe reactions, including hypotension, hemolysis, cerebral edema, seizures, and death.

SAFETY IN PREGNANCY AND NEONATES N-Acetylcysteine is FDA Pregnancy Category B. Untreated APAP toxicity is a far greater threat to fetuses than is NAC treatment. N-Acetylcysteine traverses the human placenta and produces cord blood concentrations comparable to maternal blood concentrations. For treatment of pregnant patients with APAP toxicity, IV NAC (not PO NAC) has the advantage of assuring sufficient fetal delivery of NAC because of reduction of the first-pass metabolism. Limited data exist with regard to the management of neonatal APAP toxicity, although IV and PO NAC have been used safely. When treating neonates, IV administration has the advantage of assuring adequate antidotal delivery and has been administered without adverse effects. Caution regarding NAC preparation is paramount to avoid iatrogenic dilution administration errors.

DOSING AND ADMINISTRATION The standard IV NAC protocol uses 3 consecutive infusions without interruption (as shown in Tables A3–1 and A3–2). The standard 72-hour oral regimen uses a loading dose of 140 mg/kg followed by 17 maintenance doses of 70 mg/kg (as shown in Tables A3–3 and A3–4). If any dose

TABLE A3–3    Calculating the Loading Dose of Oral N-Acetylcysteine Solutiona Body Weight (kg)

(lb)

N-Acetylcysteine (g)

mL of 20% N-Acetylcysteine Oral Solution

Diluent (mL)

5% Solution (Total mL)

100–109

220–240

15

75

225

300

90–99

198–218

14

70

210

280

80–89

176–196

13

65

195

260

70–79

154–174

11

55

165

220

60–69

132–152

10

50

150

200

50–59

110–130

8

40

120

160

40–49

88–108

7

35

105

140

30–39

66–86

6

30

90

120

20–29

44–64

4

20

60

80

If the patient weighs < 20 kg (usually patients younger than 6 years), calculate the dose of N-acetylcysteine. Each milliliter of 20% N-acetylcysteine solution contains 200 mg of N-acetylcysteine. The loading dose is 140 mg per kilogram of body weight. Three milliliters of dilluent is added to each milliliter of 20% N-acetylcysteine solution. Do not decrease the proportion of diluent. a

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ANTIDOTES IN BRIEF • N-ACETYLCYSTEINE

69

TABLE A3–4    Calculating the Mainenance Dose of Oral N-Acetylcysteine Solutiona Body Weight (kg)

(lb)

N-Acetylcysteine (g)

20% N-Acetylcysteine Oral Solution (mL)

Diluent (mL)

5% Solution (Total mL)

100–109

220–240

7.5

37

113

150

90–99

198–218

7

35

105

140

80–89

176–196

6.5

33

97

130

70–79

154–174

5.5

28

82

110

60–69

132–152

5

25

75

100

50–59

110–130

4

20

60

80

40–49

88–108

3.5

18

52

70

30–39

66–86

3

15

45

60

20–29

44–64

2

10

30

40

If the patient weighs < 20 kg (usually patients younger than 6 years), calculate the dose of N-acetylcysteine. Each milliliter of 20% N-acetylcysteine solution contains 200 mg of N-acetylcysteine. The maintenance dose is 70 mg/kg of body weight. Three milliliters of dilluent is added to each milliliter of 20% N-acetylcysteine solution. Do not decrease the proportion of diluent. a

is vomited within 1 hour of administration, then we recommend repeating the dose or using the IV route. Several other regimens, including 48-hour IV, 36-hour IV, 12-hour IV, 36-hour PO, and 20-hour PO protocols, are described; however, none of these has been adequately studied for general use (Chap. 6). Three additional protocols have been developed with the intent of decreasing anaphylactoid reactions. The SNAP protocol infuses an initial 100 mg/kg over 2 hours and then 200  mg/kg over 10 hours. In a randomized controlled trial, this protocol decreased severe anaphylactoid rates from 31% with the traditional IV NAC “three-bag” protocol to 5%. Although the study was not large enough to prove equivalent efficacy, hepatotoxicity rates were similar (2% SNAP protocol versus 3% IV NAC “three-bag” protocol). Another protocol infused 200 mg/kg over 4 hours and then 100 mg/kg over 16 hours and found a lower rate of anaphylactoid reactions (4.3% versus 10%) and no difference in hepatotoxicity. A third group suggested infusing 200 mg/kg at the time of presentation and over a variable time (4–9 h) and then 100 mg/kg over 16 hours but had a high rate of overtreatment. Although these protocols seem to decrease adverse events and severe anaphylactoid reactions, their efficacy has not been studied against the standard protocol. Conceptually, NAC therapy should be started if the patient is at risk of toxicity, continued as long as is necessary, and stopped when the patient is no longer at risk of toxicity. For a detailed description of the indications for treating APAP toxicity with NAC, see Chap. 6. Briefly, in acute overdoses ( from 4–24 h after ingestion), NAC therapy should be initiated if the initial APAP concentration falls above the treatment line of the Rumack-Matthew nomogram. In acute overdoses when the patient arrives more than 24 hours after ingestion, we recommend starting NAC if the APAP concentration is detectable or if the [AST] is greater than the upper limit of normal. In repeated supratherapeutic ingestions, NAC therapy should be initiated if either the APAP concentration is detectable or the AST is elevated (Chap. 6).

12_Hoffman_A3_p0066-0070.indd 69

After the protocol is initiated, an [APAP] and [AST] are evaluated before the end of the NAC infusion ( 25%; independent of signs or symptoms Abnormal cerebellar function Pregnancy with a carboxyhemoglobin ≥ 15% Fetal distress in pregnancy Equivocal cases with age > 35 years and prolonged exposure (≥ 24 h) Patients with these risk factors for cognitive sequelae have the highest potential to benefit from hyperbaric oxygen treatment. a

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681

Delayed Administration of Hyperbaric Oxygen.  The optimal timing and number of HBO treatments for CO poisoning are unclear. Patients treated later than 6 hours after exposure tend to have worse outcomes in terms of delayed sequelae (30% versus 19%) and mortality (30% versus 14%). However, patients benefit even if treated later. In the most recent randomized clinical trial showing beneficial effects of HBO, although all patients were treated within 24 hours of exposure, 38% of patients were treated later than 6 hours after exposure. Improvement in neurologic function was noted in this group. Therefore, it is reasonable to perform HBO, contingent on transport limitations, if the patient can receive HBO within 24 hours of removal from exposure. Repeat Treatment with Hyperbaric Oxygen.  A randomized clinical trial demonstrated that three HBO treatments within the first 24 hours improved cognitive outcome. Unfortunately, there was no group treated with only one or two HBO sessions in that study. Regardless, it is reasonable to give up to three treatments for patients with persistent symptoms, particularly coma, who do not resolve after their first HBO session. With the lack of prospective studies comparing single versus multiple courses of HBO therapy, multiple treatments are not recommended as a routine at this time.

Treatment of Pregnant Patients The management of CO exposure in the pregnant patient is difficult because of the potential adverse effects of both CO and HBO. A literature review of all CO exposures during pregnancy revealed a high incidence of fetal CNS damage and stillbirth after severe maternal poisonings. Traditionally, it was thought that fetal hemoglobin had a high affinity for CO. Pregnant ewe studies show a delayed but substantive increase in COHb levels in fetuses, exceeding the level and duration of those in the mothers. Thus, it appeared that fetuses were a sink for CO and could be poisoned at concentrations lower than mothers. However, such data do not apply to humans because in vitro evidence demonstrates that as opposed to sheep, human fetal hemoglobin actually has less affinity for CO than maternal hemoglobin. The more important issue with maternal CO exposure is the precipitous decrease in fetal arterial oxygen content that occurs following CO poisoning. The approach to treatment of seriously symptomatic CO-poisoned pregnant patients is problematic. All patients should receive 100% oxygen by face mask, at least until the mother is asymptomatic. However, CO absorption and elimination are slower in the fetal circulation than in the maternal circulation. Unfortunately, pregnant patients were excluded from all prospective trials documenting the efficacy of HBO. However, treatment of pregnant patients with HBO is not without theoretical risk. Animal studies show conflicting results on the effects of HBO on fetal development. This is in marked contrast to the extensive Russian experience, in which hundreds of pregnant women were treated with HBO, apparently without significant perinatal complications and with improvement in fetal and maternal status for their underlying conditions of toxemia, anemia, and diabetes. Thus, it appears that HBO should be safe and have the same

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

efficacy for pregnant patients as in nonpregnant patients. There currently is no scientific validation for an absolute level at which to provide HBO therapy for a pregnant patient with CO exposure. Somewhat arbitrarily, we recommend a threshold for HBO in pregnant patients as a COHb level, regardless of symptoms, of greater than or equal to 15%. Pregnant patients should not be treated any differently if they meet the criteria for HBO described above (Table 95–2). Additional criteria include any signs of fetal distress, such as abnormal fetal heart rate.

Treatment of Children It is suggested that children are more sensitive to the effects of CO because of their increased respiratory and metabolic rates. Epidemiologic studies suggest that children become symptomatic at COHb levels lower than commonly expected in adults. The other problem is that these younger patients have unusual presentations. Although most children manifest nausea, headache, or lethargy, an isolated seizure or vomiting is sometimes the only manifestation of CO toxicity in an infant or child. When interpreting COHb levels in infants, clinicians must be aware of two confounding factors. First, many older cooximeters give falsely elevated COHb levels in proportion to the amount of fetal hemoglobin present. Second, CO is produced during breakdown of protoporphyrin to bilirubin. Therefore, infants normally have higher levels of COHb, which are even higher in the presence of kernicterus. There are alternative clinical markers better than COHb for gauging toxicity in children. An elevated lactate concentration was found in 90.1% of 674 pediatric patients admitted for CO poisoning. Many children with elevated troponin concentrations after CO poisoning had normal ECGs or just subtle transitory T-wave changes from repolarization abnormalities. The echocardiogram is abnormal in approximately 50% of patients found to have an elevated troponin concentration, usually showing a temporary decrease in left ventricular function and ejection fraction. Although children are likely more susceptible to acute toxicity with CO, their long-term outcomes appear to be more favorable than for adults. A low incidence of DNS in patients treated only with 100% oxygen at normal pressures is used as an argument to avoid HBO. Often, children exposed to CO under similar circumstances with a parent, although appearing well, are treated simultaneously with the sick parent, especially if a multiplace chamber is available.

Novel Neuroprotective Treatments A variety of neuroprotective therapeutics were tested in animal models. They are targeted primarily at preventing the delayed neurologic sequelae associated with serious CO

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poisoning. One of the simplest treatments tested is insulin. In CO poisoning of rodents, hyperglycemia is associated with worse neurologic outcome. However, insulin, independent of its glucose-lowering effect, is protective after ischemic insults. In rodent studies, improved neurologic outcome, as measured by locomotor activity, occurs in those with CO poisoning treated with insulin. In light of these findings, it is reasonable to treat documented hyperglycemia with insulin in patients with serious CO poisoning. Although there are experimental data in support of dizocilpine, ketamine, dimethyl sulfoxide, disulfiram, 3-N-butylphtalide (a celery seed extract), dexamethasone, allopurinol, and erythropoietin, data are insufficient to recommend their use at this time.

PREVENTION Early diagnosis prevents much of the morbidity and mortality associated with CO poisoning, especially in unintentional exposures. The increased quality of home CO-detecting devices allows personal intervention in the prevention of exposure. If a patient presents complaining that his or her CO alarm sounded, it is important to realize that the threshold limit concentration for the alarm is set roughly to approximate a COHb level of 10% at worst. Alarms are not designed to activate for prolonged low-level exposures to prevent epidemic alarming during winter thermal inversions in large cities. Routine laboratory screening of ED patients during the winter is not very efficacious in diagnosing unsuspected CO poisoning; the yield is less than 1% for patients tested in whom the diagnosis of CO exposure was already excluded by history. Instead, selecting patients with CO-related complaints, such as headache, dizziness, or nausea, increases the yield to 5% to 11%. During the winter, risk factors such as gas heating or symptomatic cohabitants in patients with influenzalike symptoms such as headache, dizziness, or nausea, particularly in the absence of fever, are the most useful method for deciding when to obtain COHb levels for potential patients. The issue of symptomatic cohabitants is especially important from a preventive standpoint. Alerting other cohabitants to this danger and effecting evacuation prevents needless morbidity and mortality. This is especially critical for multifamily domiciles, such as hotels, that have resulted in dramatic collective exposures and even deaths. Most communities have multiple resources for on-site evaluation. Usually the local fire department or utility company can either check home appliances or measure ambient CO concentrations with portable monitoring equipment.

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A40

Antidotes in Brief

HYPERBARIC OXYGEN

INTRODUCTION Hyperbaric oxygen (HBO) is used therapeutically in poisoning by carbon monoxide (CO), methylene chloride, hydrogen sulfide (H2S), and carbon tetrachloride (CCl4). It is also a recognized therapy for air or gas embolism and for functional anemia that arises from oxidants that induce methemoglobinemia.

HISTORY Hyperbaric medicine became established as a clinical discipline in the latter half of the 20th century with a focus on treatment of decompression sickness. The first hyperbaric chamber was built in New York by Corning in 1891. The first case reports of HBO for documented CO poisoning appeared in 1960.

PHARMACOLOGY Chemistry and Preparation Pressures applied while patients are in the hyperbaric chamber usually are 2 to 3 atmospheres absolute (ATA). Treatments generally last for 1.5 to 8 hours and are performed one to three times daily. Monoplace (single-person) chambers usually are compressed with pure oxygen. Multiplace (2–14 patients treated simultaneously) chambers are pressurized with air, and patients breathe pure oxygen through a tight-fitting face mask, a head tent, or an endotracheal tube.

Mechanisms of Action During treatment, the arterial oxygen tension typically exceeds 1,500 mm Hg and achieves tissue oxygen tensions of 200 to 400 mm Hg—more than fivefold higher than when breathing air. The primary effect of HBO is to increase the dissolved oxygen content of plasma. In addition, HBO affects neutrophil adhesion to blood vessels and restores mitochondrial, neutrophil, and immunologic disturbances caused by CO poisoning.

Pharmacokinetics Oxygen inhaled at hyperbaric pressure is rapidly absorbed. Application of each additional atmosphere of pressure while breathing 100% oxygen increases the dissolved oxygen concentration in the plasma by 2.2 mL O2/dL (vol%). Animal models of ischemia suggest that HBO rapidly distributes O2 to target organs to improve penumbral oxygenation.

Pharmacodynamics There are transient benefits from HBO for reducing bubble volume in disorders such as air embolism and oxygenating tissues in conditions in which hemoglobin-based O2 delivery is impaired. These rather straightforward mechanisms form the basis for using HBO for patients with massive ingestions of H2O2 associated with intravascular gas embolism and

for life-threatening poisonings from cyanide (CN), H2S, and exposure to oxidizers causing methemoglobin. Hyperbaric oxygen is also used for CCl4 poisoning, in which acute application of oxygen and pressure inhibit the cytochrome P450 oxidase system responsible for producing hepatotoxic free radicals. Hyperbaric oxygen also has well-described vasoconstriction effects compared with dynamic CO-associated effects on cerebral vasodilation. There are several mechanisms supporting the use of O2 when treating CO poisoning. Elevated COHb results in tissue hypoxia, and exogenous O2 both hastens dissociation of CO from hemoglobin and provides enhanced tissue oxygenation directly through the increased PaO2. Hyperbaric oxygen causes COHb dissociation to occur at a rate greater than that achievable by breathing 100% O2 at sea level pressure. Additionally, HBO accelerates restoration of mitochondrial oxidative processes. Among the earliest events observed in both an animal model and in humans with CO poisoning is platelet–neutrophil interactions that mediate intravascular neutrophil activation. These changes precipitate neutrophil adherence to blood vessel walls that initiate vascular changes, leading to a cascade of localized changes in brain that cause neurologic dysfunction (Fig. A40–1). Rapid intervention with HBO in animal models causes improvement in cardiovascular status, leads to lower mortality rates, reduces platelet–neutrophil activation, and preserves synthesis of nerve growth factors. Exposure to 2.8 to 3.0 ATA O2 for 45 minutes temporarily inhibits neutrophil adherence to endothelium mediated by the activationdependent β2-integrins on the neutrophil membrane in both rodents and humans. The ability of HBO to inhibit function of neutrophil β2-integrin adhesion molecules in animal models forms the basis for amelioration of encephalopathy resulting from CO poisoning. It is important to comment that use of HBO at less than 2.8 ATA, as used in several clinical HBO studies, does not inhibit neutrophil adherence functions.

ROLE IN CARBON MONOXIDE POISONING Survivors of CO poisoning are faced with potential impairments to cardiac and neurologic functions. Events that follow an initial period of symptomatic CO poisoning that occur after a clear or “lucid” interval are termed “subacute” or “delayed” neurologic sequelae. The efficacy of HBO for acute CO poisoning is supported in animal trials, and studies provide a mechanistic basis for treatment. Unfortunately, only one clinical trial of significantly poisoned patients satisfies all items deemed to be necessary for the highest quality of randomized controlled trials. This double-blinded, placebocontrolled clinical trial involved 152 patients who received treatment (initiated within 24 hours of the end of exposure) with either three sessions of HBO therapy or normobaric O2 683

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Carbon monoxide RBC and myocardium

Displaced NO• from platelets NO• – + O2•

COHb and COMb

ONOO– (peroxynitrite) neutrophil activation, Nitric platelet–neutrophil oxide aggregation, and degranulation synthase

Impaired cardiac function

Myeloperoxidasemediated endothelial damage

Altered cerebral blood flow

WBC–endothelial interactions HBO

NMDA neuron NOS-1 activation

β2 Integrin–dependent neutrophil adhesion, protease release, oxidative burst

Endothelium XD

XO –

Hypoxanthine Urate + O 2• + O2 Brain lipid peroxidation Alterations in myelin basic protein

Microglial activation/lymphocyte influx

Brain inflammation and impaired function FIGURE A40–1.  The pathway demonstrating concurrent events leading to vascular injury with carbon monoxide poisoning and the sequence of events leading to neurologic injuries. COHb = carboxyhemoglobin; COMb = carboxymyoglobin; NMDA = N-methyl-d-aspartate neurons; NO• = nitric oxide; NO2 = nitrite (major oxidation product of NO•); NOS-1 = neuronal nitric oxide synthase; O2-• = superoxide radical; ONOO− = peroxynitrite; RBC = erythrocyte; WBC = leukocyte; XD = xanthine dehydrogenase; XO = xanthine oxidase.

with sham pressurization to maintain blinding. The group treated with HBO had a lower incidence of cognitive sequelae than the group treated with NBO. Other clinical trials suffered from a significant loss of patients to follow-up, a lack of blinding, or the use of subtherapeutic pressures. In a trial involving mildly to moderately poisoned patients, 23% of patients (7 of 30) treated with ambient pressure oxygen developed neurologic sequelae, but no patients (0/30; P < 0.05) who were treated with HBO (2.8 ATA) developed sequelae. We recommend that HBO be administered in all cases of serious acute CO poisoning ideally within 6 hours of

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diagnosis but certainly up to 24 hours after the end of the exposure. Normobaric 100% oxygen should be continued until the onset of HBO administration. Risk factors for long-term cognitive impairment in patients not treated with HBO include age older than 36 years, exposure longer than 24 hours, loss of consciousness, COHb greater than 25% on arrival to medical care, and an elevated troponin. Pregnancy poses another special situation in that CO readily crosses the placenta and may cause fetal distress and fetal death. Hyperbaric oxygen has been administered safely to pregnant women, but there are no prospective studies of efficacy. In CO-poisoned pregnant women, HBO is recommended for all of the indications listed above with the exception that a lower COHb threshold (15%) is reasonable as an extra safety measure for the fetus.

ROLE IN METHYLENE CHLORIDE POISONING Methylene chloride (CH2Cl2) is an organic solvent used commercially in aerosol sprays, as a solvent in plastics manufacturing, in photographic film production, in food processing as a degreaser, and as a paint stripper. It is readily absorbed through the skin or by inhalation. Immediate effects of methylene chloride are attributable to the direct depressant actions of this solvent on the central nervous system (CNS) and resulting hypoxia. However, metabolism of methylene chloride produces CO. Production of CO is slow, and peak COHb levels of 10% to 50% are reportedly delayed for 8 hours or more. Hyperbaric oxygen treatment recommendations follow those in patients meeting the aforementioned considerations in CO poisoning. The occurrence of ongoing CO production and persistent or recurring symptoms will likely necessitate additional treatments as the methylene chloride is mobilized from peripheral stores and undergoes metabolism. In patients with contraindications to HBO, prolonged normobaric 100% oxygen therapy is reasonable until COHb levels remain withing normal limits.

ROLE IN COMBINED CARBON MONOXIDE AND CYANIDE POISONING Carbon monoxide and CN poisonings can occur concomitantly from smoke inhalation, and experimental evidence suggests that they can produce synergistic toxicity. Hyperbaric oxygen appears to either have direct effects on reducing CN toxicity or augments the effects of other antidotes, including hydroxycobalamin. However, animal studies have not uniformly found that HBO improves outcome, and clinical experience regarding CN treatment with HBO is sparse. Methemoglobin formation with the standard antidote treatment involving nitrite is not thought to generate high enough methemoglobin concentrations to be of concern, but in the setting of concomitant COHb, the additional reduction of oxygen-carrying capacity poses a potential risk. Hence, there is a special advantage for hydroxycobalamin use in combined poisonings. Hyperbaric oxygen is reasonable in any case of dual (CO and CN) poisoning and in CN poisoning when vital signs and mental status do not improve with antidote treatment, especially in locations that only have the nitrite/thiosulfate antidotes.

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ANTIDOTES IN BRIEF • HYPERBARIC OXYGEN

ROLE IN HYDROGEN SULFIDE POISONING Hydrogen sulfide binds to cytochrome a-a3. This is similar to CN, although it is more readily dissociated by O2. Clinical manifestations of toxicity are also similar to those of CO and CN. Hyperbaric oxygen is more effective than sodium nitrite in preventing death in animals. Several clinical reports indicate that HBO, sometimes in conjunction with supplemental oxygen and blood pressure support, appears to be beneficial. No definitive data regarding use of HBO for H2S poisoning are available, but HBO is reasonable when altered mental status or unstable vital signs persist after standard resuscitation measures.

ROLE IN OXIDANT-INDUCED METHEMOGLOBINEMIA Oxidation of ferrous (2+) heme to the ferric (3+) form renders hemoglobin nonfunctional, and the presence of oxidized hemoglobin varieties causes a left shift of the oxyhemoglobin dissociation curve. Hence, the manifestations of toxicity from acquired methemoglobinemia are usually more severe than those produced by a corresponding degree of anemia. There are numerous anecdotal accounts of clinical improvement with HBO in patients with life-threatening methemoglobinemia. Ongoing exposure to any oxidants and the potential need for methylene blue to treat methemoglobinemia (Antidotes in Brief: A43) should also be addressed.

ROLE IN CARBON TETRACHLORIDE POISONING Experimentally induced CCl4 hepatotoxicity is diminished by HBO. There are also several case reports of patients surviving potentially lethal ingestions with HBO therapy. Because there are no proven antidotes for CCl4 poisoning, we only recommend HBO for patients with confirmed CCl4 exposures. However, because of a delicate balance between oxidative processes that are therapeutic and those that mediate hepatotoxicity, HBO should ideally be instituted before the onset of liver function abnormalities.

ROLE IN HYDROGEN PEROXIDE INGESTION Ingestion of concentrated H2O2 solutions (eg, 35%) can result in venous and arterial gas embolism because of liberation of large volumes of O2. At standard temperature and pressure, ingestion of 1 mL of household 3% H2O2 liberates approximately 10 mL of oxygen gas; by comparison, each milliliter of 35% H2O2 yields 115 mL of oxygen gas. Hyperbaric oxygen is a successful intervention for portal venous gas, and in some cases of impaired consciousness and/or with focal neurologic findings. Hyperbaric oxygen reduces the volume of offending gas and improves solubility of gas into tissues and plasma. We recommend HBO in patients with neurologic symptoms, and it is reasonable in patients with severe abdominal discomfort despite conservative care.

685

initiation of HBO include claustrophobia, sinus congestion, and patients with scarred or noncompliant structures in the middle ear, such as otosclerosis. Middle ear barotrauma is the most common adverse effect of HBO treatment, and it occurs in 1.2% to 7% of patients. Unconscious patients should be evaluated for prophylactic myringotomy prior to HBO. Toxicity resulting from O2 is manifested by injuries to the CNS, lungs, and eyes. Central nervous system O2 toxicity manifests as a generalized seizure and occurs at an incidence of approximately 1 to 4 per 10,000 patient treatments.

PREGNANCY AND LACTATION Hyperbaric oxygen in pregnant patients presents the additional risks of fetal CNS, ocular, pulmonary, and cardiac toxicity. In CO poisoning, these must be weighed against the potentially devastating fetal outcomes such as spontaneous abortion, intrauterine fetal demise, anatomic malformations, CNS injury, respiratory distress, and neonatal jaundice, which occur even in only mildly symptomatic CO-poisoned mothers. For these reasons, COHb thresholds (eg, 15%–20%) for HBO therapy are often set lower for pregnant patients than for other adults in HBO treatment algorithms. The authors of this text recommend treating a pregnant woman with HBO when COHb levels are greater than or equal to 15%. Treatment decisions will ultimately be made on an individual case basis after weighing potential risks and benefits. There are no data regarding the effects of HBO on lactation.

DOSING AND ADMINISTRATION Hyperbaric oxygen efficacy is a time- and pressure-dependent phenomenon. Rodent and human studies demonstrate that exposure to 2.8 to 3.0 ATA O2 for 45 minutes is required to temporarily inhibit neutrophil adherence to endothelium mediated by the activation-dependent β2-integrins on the neutrophil membrane and to ameliorate metabolic insults leading to loss of neuronal growth factors. Clinical trials using HBO at only 2 ATAs have been unable to demonstrate a benefit of HBO, likely because it is an inadequate dose to achieve biochemical effects on cellular responses as discussed earlier. Multiple trials using HBO (2.5 ATA or above) have demonstrated efficacy. One trial using HBO (2.8 ATA) was unable to demonstrate benefit, because of incomplete followup and poor randomization. If undertaken, HBO therapy (2.5–3.0 ATA, weighted toward the latter) should be provided as early as possible because a mortality benefit is demonstrated if HBO is administered within 6 hours of the CO exposure. Clinical trials that have initiated therapy within 24 hours of the end of CO exposure show improvement of neurologic toxicity. The use of more than one treatment is supported by retrospective and prospective analysis, although clinical practice is highly variable in this regard.

ADVERSE EFFECTS AND SAFETY ISSUES

FORMULATION AND ACQUISITION

Many HBO facilities have equipment and treatment protocols and abilities analogous to those found in an intensive care unit. The inherent toxicity of O2 and potential for injury resulting from elevations of ambient pressure must be addressed whenever HBO is used therapeutically. Preexisting conditions that require evaluation for possible management before

Hyperbaric oxygen therapy is provided in monoplace or multiplace chambers, which are considered class II medical devices. For sites not possessing HBO capacity, various online organizational and professional directories may assist in locating hyperbaric facilities in the absence of preexisting HBO transfer protocols.

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96

CYANIDE AND HYDROGEN SULFIDE

Cyanide Normal Whole blood Concentrations  Airborne   Immediately fatal   Life threatening Hydrogen Sulfide Airborne   Odor threshold   Olfactory paralysis   Immediately fatal

< 1 μg/mL < 38.43 μmol/L   = 270 ppm = 110 ppm > 30 minutes   = 0.01–0.3 ppm = 100–150 ppm = 1,000 ppm

CYANIDE POISONING History and Epidemiology Cyanide (CN) exposure is associated with smoke inhalation, laboratory mishaps, industrial incidents, suicide attempts, and criminal activity. Inorganic CNs (also known as CN salts) contain CN in the anion form (CN–) and are used in industries, such as metallurgy, photographic developing, plastic manufacturing, fumigation, and mining. Ingestion of cyanogenic chemicals (ie, acetonitrile, acrylonitrile, and propionitrile) is another source of CN poisoning. Acetonitrile (C2H3N) and acrylonitrile (C3H3N) are themselves nontoxic, but biotransformation via CYP2E1 liberates CN (Fig. 96–1). Many plants, such as the Manihot spp and Prunus spp, contain cyanogenic glycosides such as amygdalin. When ingested, amygdalin is biotransformed to CN (Fig. 96–1). Iatrogenic CN poisoning occurs during prolonged or high-dose nitroprusside therapy for the management of hypertension. Each nitroprusside molecule contains five CN molecules, which are slowly released in vivo. Napoleon III was the first to use hydrogen cyanide (HCN) in chemical warfare, and it was subsequently used on World War I battlefields. During World War II, hydrocyanic acid pellets caused more than one million deaths in Nazi gas chambers. In 1978, KCN was used in a mass suicide led by Jim Jones of the People’s Temple in Guyana, resulting in more than 900 deaths.

the limiting factor in CN detoxification by rhodanese is the availability of adequate quantities of sulfur donors. The endogenous stores of sulfur are rapidly depleted, and CN metabolism slows. Thiocyanate is eliminated in urine. Elimination follows first-order kinetics, although it varies widely in reports (range, 1.2–66 hours). The volume of distribution of the CN anion varies according to species and investigator, with 0.075 L/kg reported in humans.

Pathophysiology Cyanide is an inhibitor of multiple enzymes, including succinic acid dehydrogenase, superoxide dismutase, carbonic anhydrase, and cytochrome oxidase. Cytochrome oxidase is an iron-containing metalloenzyme essential for oxidative phosphorylation and hence aerobic energy production. Cyanide induces cellular hypoxia by inhibiting cytochrome oxidase by binding to the ferric ion on the cytochrome a3 portion of the electron transport chain (Fig. 96–2). Hydrogen ions that normally would have combined with oxygen at the terminal end of the chain are no longer incorporated. Thus, H H

C

C

N

H

C

N + C

H

O

H Hydrogen Formaldehyde cyanide

Acetonitrile A HO O

HO HO

O

OH

Amygdalin

O

HO HO

OH

C O

N

C

β-d-glucosidase

Pharmacology Cyanide is an extremely potent toxin, with even small exposures leading to life-threatening symptoms. The adult oral lethal dose of KCN is approximately 200 mg. Acute toxicity occurs through a variety of routes, including inhalation, ingestion, dermal, and parenteral.

H C N Hydrogen cyanide

HO O

HO

Toxicokinetics Cyanide is eliminated from the body by multiple pathways. The major route for detoxification of CN is the enzymatic conversion to thiocyanate. Two sulfurtransferase enzymes, rhodanese (thiosulfate–CN sulfurtransferase) and β-mercaptopyruvate–CN sulfurtransferase, catalyze this reaction. In acute poisoning,

H CYP2E1

OH OH Glucose (2)

H C

O

HO B

Benzaldehyde

FIGURE 96-1.  Biotransformation of cyanogens acetonitrile (A) and amygdalin (B) to cyanide.

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CHAPTER 96 • CYANIDE AND HYDROGEN SULFIDE

OxyHb Amyl nitrite, sodium nitrite

MetHb

cyt c2+

cyt c3+

cyt a3+

cyt a2+

CN–

OxyHb Amyl nitrite, sodium nitrite

MetHb H2S

2+

CyanoMetHb cyt a3

cyt a33+

SulfMetHb

Sodium Rhodanese thiosulfate 1

Thiocyanate 2 O2 + 2H+ (SCN)

H2O

OxyHb + SOx

FIGURE 96-2.  Pathway of cyanide and hydrogen sulfide toxicity and detoxification. MetHb = methemoglobin; OxyHb = oxyhemoglobin; SulfMetHb = sulfmethemoglobin.

despite sufficient oxygen supply, oxygen cannot be used, and ATP molecules are no longer formed. Unincorporated hydrogen ions accumulate, contributing to acidemia. The lactate concentration increases rapidly following CN poisoning because of failure of aerobic energy metabolism. During aerobic conditions, when the electron transport chain is functional, lactate is converted to pyruvate by mitochondrial lactate dehydrogenase. In this process, lactate donates hydrogen moieties that reduce nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide (NADH). Pyruvate then enters the citric acid cycle, with resulting ATP formation. When cytochrome a3 within the electron transport chain is inhibited by CN, there is a relative paucity of NAD+ and predominance of NADH, favoring the reverse reaction, in which pyruvate is converted to lactate. Cyanide is also a potent neurotoxin. It enhances N-methyld-aspartate (NMDA) receptor activity and directly activates the NMDA receptor, which results in Ca2+ entry into the cytosol of neurons.

Clinical Manifestations

Acute Exposure to Cyanide.  The initial clinical effects of acute CN poisoning are nonspecific, generalized, and nondiagnostic, thereby making the correct diagnosis difficult to obtain. Clinical manifestations reflect rapid dysfunction of oxygensensitive organs, with central nervous system (CNS) and cardiovascular findings predominating. The time to onset of symptoms typically is seconds with inhalation of gaseous HCN or IV injection of a water-soluble CN salt and several minutes after ingestion of inorganic CN. The clinical effects of cyanogenic chemicals often are delayed, and the time course varies among individuals (range, 3–24 hours), depending on their rate of biotransformation. Central nervous system signs and symptoms are typical of progressive hypoxia and include headache, anxiety, agitation, confusion, lethargy, nonreactive dilated pupils, seizures, and coma. A centrally mediated tachypnea occurs initially followed by bradypnea and apnea. Cardiovascular responses to CN are complex. An initial period of tachycardia and hypertension usually occurs followed by hypotension with reflex tachycardia, but the terminal event is consistently bradycardia and hypotension. Gastrointestinal toxicity occurs after ingestion of inorganic CN and cyanogens and includes

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abdominal pain, nausea, and vomiting. These symptoms are caused by hemorrhagic gastritis, which is secondary to the caustic nature of CN salts. Cutaneous manifestations vary. A cherry red skin color is described as a potential finding as a result of increased venous hemoglobin oxygen saturation, which results from decreased utilization of oxygen at the tissue level. Delayed Clinical Manifestations of Acute Exposure.  Survivors of serious, acute poisoning develop delayed neurologic sequelae. Parkinsonian symptoms, including dystonia, dysarthria, rigidity, and bradykinesia, are most common. Response to pharmacotherapy with antiparkinsonian drugs is generally disappointing. Chronic Exposure to Cyanide.  Chronic exposure to CN results in insidious syndromes, including tobacco amblyopia, Konzo, and Leber hereditary optic neuropathy. Chronic exposure to CN is also associated with thyroid disorders. Thiocyanate is a competitive inhibitor of iodide entry into the thyroid, thereby causing the formation of goiters and the development of hypothyroidism (Chap. 26).

Diagnostic Testing Because of nonspecific symptoms and delay in laboratory CN confirmation, the clinician must rely on historical circumstances and some initial findings to raise suspicion of CN poisoning and institute therapy (Table 96–1). Laboratory findings suggestive of CN poisoning reflect an increased anion gap metabolic acidosis and elevated lactate concentration. Elevated venous oxygen saturation results from reduced tissue extraction. The finding of a small arterial– venous oxygen difference is also suggestive of CN toxicity. Hyperlactatemia is found in numerous critical illnesses and typically is a nonspecific finding. However, a significant association exists between blood CN and serum lactate concentrations. A lactate greater than 8 mmol/L following ingestion or greater than 10 mmol/L following smoke inhalation is highly suggested of cyanide toxicity. A determination of the blood CN concentration will confirm toxicity, but this determination is not available in a sufficiently rapid manner to affect initial treatment.

Management First responders should exercise extreme caution when entering potentially hazardous areas such as chemical plants and laboratories where a previously healthy person is “found down.” Because CN poisoning is rare, it is easy to overlook the diagnosis unless there is an obvious history of exposure. Thus, the most critical steps in treatment are considering the diagnosis in high-risk situations (Table 96–1) and initiating empiric therapy with 100% oxygen and either hydroxycobalamin (preferably) or the sodium nitrite and sodium thiosulfate combination. The initial care (Table 96–1) of a CN-poisoned patient begins by directing attention to airway patency, ventilatory support, and oxygenation. Instillation of activated charcoal often is considered by other authors to be ineffective because of low binding of CN (1 g of activated charcoal only adsorbs 35 mg of CN). However, a potentially lethal oral dose of CN (ie, a few hundred

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TABLE 96–1    Cyanide Poisoning: Emergency Management Guidelines When to Suspect Cyanide Sudden collapse of laboratory or industrial worker Fire victim with coma or acidemia Suicide with unexplained rapid coma or acidemia Ingestion of artificial nail remover Ingestion of seeds or pits from Prunus spp Patient with altered mental status, hyperlactatemia, acidemia, and tachyphylaxis to nitroprusside Supportive Care Control airway, ventilate, and give 100% oxygen Crystalloids and vasopressors for hypotension Administer sodium bicarbonate; titrate according to pH and serum [HCO3–] Antidotes 1) Hydroxocobalamin (preferred) Initial adult dose: 5 g IV over 15 min; pediatric dose 70 mg/kg up to 5 g; to be repeated if necessary or 2) Cyanide Antidote Kit Amyl nitrite pearls are included in the kit for prehospital use only. For hospital management, sodium nitrite is the preferred methemoglobin inducer and is given in lieu of the pearls. Give sodium nitrite (NaNO2) as a 3% solution over 2–4 min IV: Adult dose: 10 mL (300 mg) (see Table 96–2 for pediatric dosing) Caution: Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Obtain methemoglobin level 30 min after dose; excess methemoglobin formation will cause deterioration during therapy. Withhold nitrites if COHb is suspected to be present (eg, fires). Give sodium thiosulfate (NaS2O3) as a 25% solution IV: Adult dose: 50 mL (12.5 g) Pediatric dose: 1.65 mL/kg up to 50 mL Decontamination Protect healthcare provider from contamination Cutaneous: Carefully remove all clothing and flush the skin Ingestion: Oro- or nasogastric lavage and instill 1 g/kg activated charcoal Laboratory ABG or VBG Electrolytes and glucose Blood lactate Whole-blood cyanide concentration (for later confirmation only) ABG = arterial blood gas; COHb = carboxyhemoglobin; IV = intravenous; VBG = venous blood gas.

milligrams) is within the adsorptive capacity of a typical 1-g/kg dose of activated charcoal. Although either hydroxocobalamin or sodium nitrite and sodium thiosulfate combination should be administered as soon as CN poisoning is suspected, hydroxocobalamin is preferred. Hydroxocobalamin has few adverse effects, which include rashes and a transient reddish discoloration of the skin, mucous membranes, and urine. No hemodynamic adverse effects other than a potential mild transient rise of blood pressure are observed in those who are not poisoned. Adverse effects of nitrites include excessive methemoglobin formation and, because of potent vasodilation, hypotension and tachycardia. Avoiding rapid infusion, monitoring blood pressure, and adhering to dosing guidelines limit adverse effects. Because of the potential

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TABLE 96–2   Sodium Nitrite Guidelines for Managing Cyanide Poisoning in Children Hemoglobin (g/100 mL)

Sodium Nitrite 3% Solution (mL/kg)

7

0.19

8

0.22

9

0.25

10

0.27

11

0.30

12

0.33

13

0.36

14

0.39

Sodium thiosulfate 25% solution: 1.65 mL/kg IV. Repeat sodium thiosulfate once at half dose (0.825 mL/kg) if symptoms persist. (Reproduced with permission from Tintinalli JE et al. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. New York, NY: McGraw Hill; 2020.)

for excessive methemoglobinemia during nitrite treatment, pediatric dosing guidelines are available (Table 96–2). More detailed discussions of cyanide antidotes can be found in the Antidotes in Brief: A41 and A42.

HYDROGEN SULFIDE POISONING History and Epidemiology Hydrogen sulfide (H2S) exposures are often dramatic and fatal. Most of H2S exposures occur through workplace exposures, but they also occur in environmental disasters and suicides. Bacterial decomposition of proteins generates H2S. Thus, decay of sulfur-containing products such as fish, sewage, and manure produces H2S. Industrial sources include pulp paper mills, heavy-water production, the leather industry, roofing asphalt tanks, vulcanizing of rubber, viscose rayon production, and coke manufacturing from coal. It is a major industrial hazard in oil and gas production, particularly in sour gas fields (natural gas containing sulfur). Natural sources of H2S are volcanoes, caves, sulfur springs, and underground deposits of natural gas. More recently, a large number of suicides called “chemical suicides” or “detergent suicides” were attributed to mixing common household chemicals such as pesticides or fungicides and toilet bowl cleaners to create H2S gas. Up to 25% of fatalities involve rescuers. For example, a leaking food waste pipeline in the propeller room of a cruise ship released H2S, killing three workers attempting to repair the pipe. The emergency response resulted in injury to 18 crew members, including a physician and a nurse rushing into the dangerous environment without personal protective equipment.

Pharmacology and Toxicokinetics Hydrogen sulfide is a colorless gas, more dense than air, with an irritating odor of “rotten eggs.” It is highly lipid soluble, a property that allows easy penetration of biologic membranes. Systemic absorption usually occurs through inhalation, and it is rapidly distributed to tissues. Hydrogen sulfide binds to the ferric (Fe3+) moiety of cytochrome a3 oxidase complex with a higher affinity than does CN. The resulting inhibition of oxidative phosphorylation produces

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CHAPTER 96 • CYANIDE AND HYDROGEN SULFIDE

cellular hypoxia and anaerobic metabolism. Besides producing cellular hypoxia, H2S alters brain neurotransmitter release and neuronal transmission through potassium channel–mediated hyperpolarization of neurons, NMDA receptor potentiation, and other neuronal inhibitory mechanisms. The olfactory nerve is a specific target of great interest. Not only does the toxic gas cause olfactory nerve paralysis, but it also provides a portal of entry into the CNS because of its direct contact with the brain. In addition to systemic effects, H2S reacts with the moisture on the surface of mucous membranes to produce intense irritation and corrosive injury. The eyes and nasal and respiratory mucous membranes are the tissues most susceptible to direct injury. Despite skin irritation, it has little dermal absorption. Inhaled H2S enters the systemic circulation where, at physiologic pH, it dissociates into hydrosulfide ions (HS–). After dissociation, hydrosulfide ions interact with metalloproteins, disulfide-containing enzymes, and thio dimethyl S transferase. Hydrogen sulfide and dissociation products are then metabolized by multiple enzymes, including mitochondrial sulfide quinone oxireductase, sulfur dioxygenase to form sulfate (SO24-), and thiosulfate-CN sulfurtransferase (rhodanese) to form thiosulfate (SSO32-). The most specific marker of H2S metabolism is thiosulfate. Sulfhemoglobin is not found in significant concentrations in the blood of animals or fatally poisoned humans.

CLINICAL MANIFESTATIONS Acute Manifestations.  Hydrogen sulfide poisoning should be suspected whenever a person is found unconscious in an enclosed space, especially if the odor of rotten eggs is noted. The primary target organs of hydrogen sulfide poisoning are those of the CNS, cardiac system, and respiratory system. The clinical findings reported in two large series are listed in Table 96–3. Hydrogen sulfide poisoning has a distinct dose

TABLE 96–3    Hydrogen Sulfide Poisoning When to Suspect Hydrogen Sulfide Poisoning Rapid loss of consciousness (“knocked down”) and abrupt awakening Rapid loss of consciousness (“knocked down”) and apnea Rotten egg odor Rescue from enclosed space, such as sewer or manure pit Multiple victims with sudden death Collapse of a previously healthy worker at work site Clinical Manifestations System

Signs and Symptoms

Cardiovascular

Chest pain, bradycardia, sudden cardiac arrest

Central nervous

Headache, weakness, syncope, convulsions, rapid onset of coma (“knockdown”)

Gastrointestinal

Nausea, vomiting

Ophthalmic

Conjunctivitis

Pulmonary

Dyspnea, cyanosis, crackles, apnea

Metabolic

Metabolic acidosis, elevated serum lactate

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response, and the intensity of exposure likely accounts for the diverse clinical findings in the reports. The odor threshold is between 0.01 and 0.3 ppm, and a strong intense odor is noted at 20 to 30 ppm. Mucous membrane and eye irritation occurs at 20 to 100 ppm. Olfactory nerve paralysis occurs at 100 to 150 ppm, rapidly extinguishing the ability to perceive the gas odor at higher concentrations. Prolonged exposure occurs when the extinction of odor recognition is misinterpreted as dissipation of the gas. Strong irritation of the upper respiratory tract and eyes and acute respiratory distress syndrome (ARDS) occur at 150 to 300 ppm. At greater than 500 ppm, H2S produces systemic effects, including rapid unconsciousness (“knockdown”) and cardiopulmonary arrest. At 1,000 ppm, breathing ceases after one to two breaths. The rapid and deadly onset of clinical effects of H2S are termed the “slaughterhouse sledgehammer” effect. Chronic Manifestations.  Most data about chronic low-level exposures to H2S come from oil and gas industry workers and sewer workers. Mucous membrane irritation seems to be the most prominent problem in patients with low-concentration exposures. The chronic irritating effects of H2S are proposed to be the cause of reduced lung volumes observed in sewer workers. Rapid loss of consciousness from H2S exposure was a well-known and, amazingly, accepted part of the workplace in the gas and oil industry for many years. Single or repeated high-concentration exposures resulting in unconsciousness cause serious cognitive dysfunction. Case series suggest that low-concentration exposures cause subtle changes that are only measured by the most sensitive neuropsychiatric tests.

Diagnostic Testing Diagnostic testing is of limited value for clinical decision making after acute exposures, but can be used for confirmation of acute exposures, occupational monitoring, and forensic analysis after fatal events. Clinicians must base management decisions on history, clinical presentation, and diagnostic tests that infer the presence of H2S because no method is available to rapidly and directly measure the gas or its metabolites (Table 96–3). Specific tests for confirming H2S exposure are not readily available in clinical laboratories. In acute poisoning, readily available diagnostic tests that are biomarkers of H2S poisoning are useful but are nonspecific. Arterial or venous blood gas analysis demonstrating acidemia with an associated elevated serum lactate concentration is expected, and oxygen saturation should be normal unless ARDS is present. Hydrogen sulfide, like CN, decreases oxygen consumption and is reflected as an elevated mixed venous oxygen measurement. Because sulfhemoglobin (Chap. 97) typically is not generated in patients with H2S poisoning, an oxygen saturation gap is not expected.

Management The initial treatment (Table 96–4) is immediate removal of the victim from the contaminated area into a fresh air environment. High-flow oxygen should be administered as soon as possible. Optimal supportive care has the greatest influence on the patient’s outcome. Because death from inhalation of

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TABLE 96–4    Hydrogen Sulfide Poisoning: Emergency Management Supportive care  Prehospital    Attempt rescue only if using appropriate respiratory protection    Move victim to fresh air    Administer 100% oxygen    During extrication, evaluate for traumatic injuries from falls    Apply ACLS protocols as indicated   Emergency department    Maximize ventilation and oxygenation    Utilize PEEP or BiPAP for ARDS   Administer sodium bicarbonate; titrate according to ABG or VBG, and serum [HCO3–]    Administer crystalloid and vasopressors for hypotension Antidote   1)  It is reasonable to administer sodium nitrite (3% NaNO2) IV over 2–4 min    Adult dose: 10 mL (300 mg)    Pediatric dose: Table 96–2; if hemoglobin unknown, presume 7 g/dL for dosing  Caution:    Monitor blood pressure frequently    Obtain methemoglobin level 30 min after dose ABG = arterial blood gas; ACLS = advanced cardiac life support; ARDS = acute respiratory distress syndrome; Hb = hemoglobin; IV = intravenous; PEEP = positive end-expiratory pressure; VBG = venous blood gas.

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H2S is rapid, a limited number of patients reaching the hospital for treatment are reported in the literature. Most patients experience significant delays before receiving treatment. Therefore, specific treatments and antidotal therapies do not show definitive improvement in patient outcome. The affinity of H2S for methemoglobin is greater than that for cytochrome oxidase. Nitrite-induced methemoglobin protects animals from toxicity of H2S poisoning in both preand postexposure treatment models. Because H2S poisoning is rare, no studies have evaluated the clinical outcomes of patients treated with sodium nitrite. However, several human case reports showed rapid return of normal sensorium when nitrites were administered soon after exposure. Sodium nitrite treatment is reasonable to administer to patients with suspected H2S poisoning who have altered mental status, coma, hypotension, or dysrhythmias but should be given cautiously because of the potential for nitrite-induced hypotension during the infusion. Treatment of patients with H2S poisoning requires optimal supportive care. Beyond supportive care, no definitive evidence of significant clinical benefit exists in humans, and additional research is needed to determine efficacy of specific treatments for H2S poisoning.

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A41

Antidotes in Brief

HYDROXOCOBALAMIN

INTRODUCTION Cyanocobalamin, vitamin B12, is formed when hydroxocobalamin combines with cyanide (CN), quickly diminishing CN concentrations and improving hemodynamics. Hydroxocobalamin is now the antidote of choice in fire victims and most other cases of CN toxicity as the previous antidotes based on nitrites therapy have the disadvantage of purposefully inducing methemoglobin.

HISTORY The antidotal actions of cobalt as a chelator of CN were recognized as early as 1894. Development of cobalt-containing cyanide antidotes such as cobalt-EDTA were hampered by poor side effect profiles. Hydroxocobalamin was studied in France as a safer cobalt-containing antidote and became the drug of choice there, first as a sole agent and then in combination with sodium thiosulfate. Hydroxocobalamin was approved for use in the United States (US) by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.

PHARMACOLOGY Chemistry The hydroxocobalamin molecule shares structural similarity with porphyrin, with a cobalt ion at its core. The difference between cyanocobalamin (vitamin B12) and hydroxocobalamin (vitamin B12a) is the replacement of the CN group with an OH group at the active site in the latter.

MECHANISM OF ACTION The cobalt ion in hydroxocobalamin combines with CN in an equimolar fashion to form nontoxic cyanocobalamin—one mole of hydroxocobalamin binds one mole of CN. Thus, given the molecular weights of each, 52 g of hydroxocobalamin is needed to bind 1 g of CN. So, a standard 5 g of hydroxocobalamin would be expected to bind 96 mg of CN, which is on the order of a typical lethal inhaled dose. Hydroxocobalamin also binds the vasodilator nitric oxide (NO), which is structurally similar to CN, causing vasoconstriction both in the presence and in the absence of CN. This property contributes to its beneficial effects by increasing systolic and diastolic blood pressure and improving the hemodynamic status of CN-poisoned patients.

PHARMACOKINETICS AND PHARMACODYNAMICS In human volunteers given a 5-g IV dose, the peak hydroxocobalamin concentrations averaged 813 μg/mL (604 μmol/L), with an average volume of distribution (Vd) of 0.38 L/kg. A mean of 62% of the hydroxocobalamin dose was recovered in the urine in 24 hours. In a pharmacokinetic study of adult victims of smoke inhalation, the elimination halflife of hydroxocobalamin was 26.2 hours and the Vd was

0.45 L/kg. In the one patient who was subsequently determined not to be exposed to CN, the hydroxocobalamin elimination half-life was 13.6 hours, and the Vd was 0.23 L/kg. Renal clearance of hydroxocobalamin was 37% in the CNexposed patients compared with 62% in the unexposed patient.

ROLE IN CYANIDE TOXICITY Animals The ability of hydroxocobalamin to bind CN and produce beneficial effects on mortality and hemodynamics is demonstrated in many animal species, including rabbits, swine, dogs, and baboons.

Humans Many case reports and studies document the efficacy of hydroxocobalamin combined with sodium thiosulfate for treatment of CN toxicity. An observational case series reviewed 69 adult smoke inhalation victims suspected of CN poisoning who were treated with a median dose of 5 g of hydroxocobalamin. Of 42 patients with confirmed CN concentrations greater than 39 μmol/L (1 μg/mL, a potentially fatal concentration), 28 (67%) survived. An 8-year retrospective analysis of the use of hydroxocobalamin in the prehospital setting concluded that the risk-to-benefit ratio favors its use in smoke inhalation victims with suspected CN poisoning. There are currently no studies comparing the nitrite plus sodium thiosulfate regimen with hydroxocobalamin in patients with CN poisoning. There are no studies comparing hydroxocobalamin with or without sodium thiosulfate to sodium thiosulfate alone in smoke inhalation victims presumed to be CN toxic.

ADVERSE EFFECTS AND SAFETY ISSUES Hydroxocobalamin has a wide therapeutic index. Large doses were administered to animals with no adverse effects. The LD50 (median lethal dose in 50% of test subjects) in mice is 2 g/kg. Red discoloration of mucous membranes, serum, and urine is expected and lasts from 12 hours to many days after therapy. Colorimetric assays are adversely affected because both hydroxocobalamin and cyanocobalamin have an intensely red color. Many clinical chemistry laboratory analyses are artificially increased, decreased, or unpredictable. Hematology analyses including hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and basophils are artificially increased. Coagulation tests are unpredictable. Urinalysis analyses are usually artificially increased, but pH can also be artificially low with low doses of hydroxocobalamin. An in vitro study found statistically significant alterations in serum concentrations of aspartate aminotransferase (AST), total 691

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bilirubin, creatinine, magnesium, and iron after hydroxocobalamin administration. Although an in vitro study demonstrated a considerable false increase in carboxyhemoglobin (COHb) levels after hydroxocobalamin administration when measured by cooximetry, other authors suggest that the interference is minimal and results in slight overestimations depending on the instrument and the concentration of hydroxocobalamin. However, more worrisome is the report of two instances in which the COHb levels were falsely low by a factor of 4 to 14 times. An in vitro experiment using human blood confirmed a substantial false decrease in the COHb levels depending on the specific cooximeter tested. Because of the inaccuracies in laboratory determinations, blood should be drawn before hydroxocobalamin administration whenever possible. Because of the deep red color of hydroxocobalamin, hemodialysis machines often sound a false “blood leak” alarm depending on the wavelength of light that the optical emitter detects. Nephrologists should be aware of this possibility.

PREGNANCY AND LACTATION Hydroxocobalamin is US FDA Pregnancy Category C.

DOSING AND ADMINISTRATION Cyanide Toxicity The initial dose of hydroxocobalamin in adults is 5 g IV. A second dose of 5 g should be repeated as clinically necessary. Based on case reports and animal studies, intraosseous administration is anticipated to be of comparable efficacy to IV administration. In children, a dose of 70 mg/kg of hydroxocobalamin up to the adult dose is recommended. Sodium thiosulfate is often administered in addition to

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hydroxocobalamin, but the administration of hydroxocobalamin should always take precedence. However, the two drugs should not be administered simultaneously through the same IV line because the sodium thiosulfate will inactivate the hydroxocobalamin. The adult dose of sodium thiosulfate is 12.5 g (50 mL of 25% solution) and should be administered intravenously as either a bolus injection or infused over 10 to 30 minutes, depending on the severity of the situation. The dose of sodium thiosulfate in children is 1 mL/kg using a 25% solution (250 mg/kg or approximately 30–40 mL/m2 of body surface area) not to exceed 50 mL (12.5 g) total dose.

Nitroprusside-Induced Cyanide Toxicity Nitroprusside-induced CN toxicity should be treated like CN toxicity from any other cause: stop the nitroprusside dosage and administer hydroxocobalamin according to the doses and precautions listed. A dose of hydroxocobalamin of 25 mg/h concurrent with nitroprusside administration (~0.6 mg/kg total dose) was sufficient in one study to decrease the red blood cell and serum CN concentrations and to prevent the development of a metabolic acidosis. We recommend continuing the hydroxocobalamin for 10 hours after the discontinuation of the nitroprusside based on the normal elimination rate of cyanide. However sodium thiosulfate works well for prevention of CN toxicity without producing issues associated with the color changes introduced by hydroxocobalamin.

FORMULATION AND ACQUISITION Cyanokit contains 5 g of lyophilized dark red hydroxocobalamin crystalline powder for injection.

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A42

Antidotes in Brief

NITRITES (AMYL AND SODIUM) AND SODIUM THIOSULFATE

INTRODUCTION Sodium nitrite is an effective cyanide (CN) antidote that acts best when administered in a timely fashion and is followed by sodium thiosulfate. Although there has never been a head-tohead study in humans comparing hydroxocobalamin with the combination for the treatment of CN toxicity, the two main advantages of hydroxocobalamin are that it works quickly and inactivates CN directly by forming non-toxic cyanocobalamin without impairing oxygen-carrying capacity.

HISTORY In 1895, Lang reported the efficacy of sodium thiosulfate in detoxifying hydrocyanic acid. Later, inhaled amyl nitrite was demonstrated to protect canines from up to four minimum lethal doses of sodium CN. Subsequent animal experiments demonstrated improved efficacy of combined nitrite and thiosulfate therapy.

PHARMACOLOGY OF THE NITRITES Mechanism of Action Cyanide quickly and reversibly binds to the ferric iron (Fe3+) in cytochrome oxidase, inhibiting effective energy production throughout the body. Nitrites oxidize the iron in hemoglobin to produce methemoglobin (Fe3+). Methemoglobin preferentially combines with CN, producing cyanomethemoglobin. Because nitrites were accepted antidotes for CN poisoning, for many years, methemoglobin formation was assumed to be their sole mechanism of antidotal action. However, when methylene blue is administered to prevent methemoglobin formation, nitrite remains an effective antidote. This led to the hypothesis that nitrite-induced vasodilation might be part of the mechanism of action. Experimental evidence in hypoxia- or hypotension-induced organ damage suggests that the benefits of nitrites are related to their conversion to nitric oxide (NO), a potent vasodilator. Pretreatment with an NO scavenger negated the effects of the nitrite.

PHARMACOLOGY OF SODIUM THIOSULFATE Mechanism of Action The sulfur atom provided by sodium thiosulfate binds to CN with the help of rhodanese (CN sulfurtransferase) and mercaptopyruvate sulfurtransferase. This produces thiocyanate, which is minimally toxic and renally eliminated. Because sodium thiosulfate does not compromise hemoglobin oxygen saturation, it should be used without nitrites in circumstances when the formation of methemoglobin would be detrimental, as in patients who have elevated levels of carboxyhemoglobin (COHb) from smoke inhalation or preexistent methemoglobinemia congenital dyshemoglobinemias, and when hydroxocobalamin is unavailable.

Sodium thiosulfate is used prophylactically with nitroprusside to prevent CN toxicity. Sodium thiosulfate is also used to treat calcific uremic arteriolopathy (calciphylaxis), by increasing the solubility of calcium deposits, inducing vasodilation, and acting as a free radical scavenger.

PHARMACOKINETICS AND PHARMACODYNAMICS OF NITRITES Inhalation of crushed amyl nitrite ampules in human volunteers produced insignificant amounts of methemoglobin and caused headache, fatigue, dizziness, and hypotension. In one study, 300 mg of IV sodium nitrite produced peak methemoglobin levels of 10% to 18% in healthy adults and values of 7% when 4 mg/kg was administered.

PHARMACOKINETICS AND PHARMACODYNAMICS OF SODIUM THIOSULFATE Animal Studies In canine studies, sodium thiosulfate rapidly distributes into the extracellular space and then slowly into the cell. When administered before CN, thiosulfate converted more than 50% of the CN to thiocyanate within 3 minutes and increased the endogenous conversion rate more than 30 times. Thiosulfate is filtered and secreted in the kidneys.

Human Studies After injection of 150 mg/kg in volunteers, the volume of distribution (Vd) was 0.15 L/kg, the distribution half-life was 23 minutes, and the elimination half-life was 3 hours. Approximately 50% of the drug was eliminated in 18 hours unchanged in the urine, most of that was within the first 3 hours. Oral bioavailability is about 8% and was calculated after 5 g of the IV solution was diluted in 100 mL of water and ingested rapidly. In another study using a population pharmacokinetic model, the Vd was 0.226 L/kg. Total-body clearance in the hemodialysis (HD) patients undergoing HD was double that of the same patients not receiving HD.

ROLE OF NITRITES AND SODIUM THIOSULFATE IN CYANIDE TOXICITY In the few reported cases of CN ingestion treated solely with sodium thiosulfate, the patients had favorable outcomes. However, we recommend administration of sodium nitrite before sodium thiosulfate. As early as 1952, the literature reported 16 CN-poisoned patients who survived after administration of nitrites and sodium thiosulfate. Case reports attest to the ability of amyl nitrite, sodium nitrite, and sodium thiosulfate to jointly reverse the effects of CN if they are administered sequentially in a timely fashion. 693

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ROLE OF SODIUM THIOSULFATE IN NITROPRUSSIDEINDUCED CYANIDE TOXICITY When nitroprusside (which contains five CN ions) infusion rates are less 0.5 mg/kg/h, there is a minimal rise in CN concentrations. Prolonged infusion or doses in excess of the detoxifying capability of the body lead to thiocyanate or CN toxicity. Coadministration of sodium thiosulfate with sodium nitroprusside in a 5:1 molar ratio prevents the rise in CN concentration. Adding 0.5 g of sodium thiosulfate to each 50 mg of nitroprusside is effective in most cases. Although this dose of sodium thiosulfate usually is sufficient to prevent CN toxicity from nitroprusside, thiocyanate can accumulate, especially in critically ill patients and in those with kidney insufficiency. Although thiocyanate is relatively nontoxic compared with CN, it produces dose-dependent tinnitus, miosis, hyperreflexia, and hypothyroidism, especially at serum concentrations greater than 60 μg/mL. Thiocyanate is hemodialyzable. Nitroprusside-induced CN toxicity should be treated by stopping the nitroprusside and administering standard doses of hydroxocobalamin with or without sodium thiosulfate.

ROLE OF SODIUM THIOSULFATE IN CALCIFIC UREMIC ARTERIOLOPATHY (CALCIPHYLAXIS) Calciphylaxis is a rare vascular disease associated with chronic kidney failure that is defined as calcification of the medial layer of arteries, leading to subcutaneous nodules that typically progress to necrotic skin ulcers. Sodium thiosulfate in a typical dose of 5 to 25 g IV in adults during or after HD is used to treat this disease. Thiosulfate likely increases the water solubility of calcium, leading to enhanced excretion of calcium thiosulfate, which induces vasodilation and acts as a free radical scavenger.

ADVERSE EFFECTS AND SAFETY ISSUES: SODIUM THIOSULFATE The toxicity of sodium thiosulfate is low. The LD50 (median lethal dose in 50% of test subjects) for animals is approximately 3 to 4 g/kg, with death attributed to metabolic acidosis, elevated serum sodium concentration, and decreased blood pressure and oxygenation. Sodium thiosulfate is hyperosmolar, delivering a significant sodium load, resulting in an osmotic diuretic effect. Administering the infusion over 10 to 30 minutes limits some of these adverse effects. Adverse effects associated with therapeutic doses include hypotension, nausea, vomiting, and prolonged bleeding time (1–3 days after a single dose) without changes in other hematologic parameters.

ADVERSE EFFECTS AND SAFETY ISSUES: NITRITES Amyl nitrite and sodium nitrite work in part by inducing methemoglobinemia, but excessive methemoglobinemia is potentially lethal. Therefore, nitrite dosages must be carefully calculated to avoid excessive methemoglobinemia, especially in cases in which other coexisting conditions, such as COHb, sulfhemoglobin, and anemia, might compromise hemoglobin oxygen saturation. Children are particularly at risk for medication errors because of dosage miscalculations. Nitrites are potent vasodilators, resulting in transient hypotension. Other common adverse effects include

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headache, tachycardia, palpitations, dysrhythmias, blurred vision, nausea, and vomiting.

PREGNANCY AND LACTATION: NITRITES The nitrites are United States (US) Food and Drug Administration (FDA) Pregnancy Category C. Fetuses are particularly sensitive to methemoglobinemia with the potential for prenatal hypoxia. Hydroxocobalamin is also US FDA Pregnancy Category C; however, even with the limited data available, it likely has a lesser risk than nitrite use for a pregnant woman. It is not known whether nitrites are excreted in breast milk.

PREGNANCY AND LACTATION: SODIUM THIOSULFATE Sodium thiosulfate is US FDA Pregnancy Category C. It is not known whether sodium thiosulfate is excreted in breast milk.

DOSING AND ADMINISTRATION OF NITRITES AND SODIUM THIOSULFATE Adults Amyl nitrite is no longer recommended in medical settings but may have a role as a prehospital antidote in industrial settings. Sodium nitrite 300 mg (10 mL of 3% solution) should be administered intravenously at a rate of 2.5 to 5 mL/min. We recommend repeating sodium nitrite at half the initial dose if manifestations of CN toxicity persist or reappear. Immediately after the completion of the sodium nitrite infusion, 50 mL of 25% solution (12.5 g) sodium thiosulfate should be infused intravenously. The dose of the thiosulfate should be repeated at half the initial dose if manifestations of CN toxicity persist or reappear. In situations in which additional methemoglobin formation would be harmful, as in patients with carbon monoxide poisoning, it is recommended to withhold the nitrite and only administer the IV hydroxocobalamin with or without sodium thiosulfate.

Children Intravenously infuse 0.2 mL/kg (6–8 mL/m2 body surface area {BSA}) or 6 mg/kg of 3% sodium nitrite solution at a rate of 2.5 to 5 mL/min, not to exceed 10 mL or 300 mg. We recommend repeating sodium nitrite at half the initial dose if manifestations of CN toxicity persist or reappear. The dose of sodium thiosulfate in children is 1 mL/kg using a 25% solution (250 mg/kg or ~30–40 mL/m2 of BSA) not to exceed 50 mL (12.5 g) total dose immediately after administration of sodium nitrite. We recommend repeating sodium thiosulfate at half the initial dose if manifestations of CN toxicity persist or reappear. In situations in which additional formation of methemoglobin would be harmful, as in patients with smoke inhalation from a fire in which unknown toxic gases exist, we recommend withholding the nitrite and administering hydroxocobalamin with or without sodium thiosulfate.

FORMULATION AND ACQUISITION Sodium nitrite is available in vials containing 300 mg in 10 mL of water for injection (USP). Sodium thiosulfate is available in 50-mL vials containing 12.5 g in water for injection (USP). In 2011, the FDA approved Nithiodote, a copackaged vial of sodium nitrite (300 mg in 10 mL water for injection) with one vial of sodium thiosulfate (12.5 g in 50 mL of water) for injection.

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97

METHEMOGLOBIN INDUCERS

HISTORY AND EPIDEMIOLOGY Methemoglobinemia is a disorder of the red blood cells (RBCs). Although methemoglobin is always present at low concentrations in the body, methemoglobinemia is defined herein as an abnormal elevation of the methemoglobin level above 1%. The ubiquity of oxidants, both in the environment and xenobiotics prescribed in the hospital, has increased the number of cases of reported methemoglobinemia. Methemoglobin was first described by Felix Hoppe-Seyler in 1864. In the late 1930s, methemoglobinemia was recognized as a predictable adverse effect of sulfanilamide use, and methylene blue was recommended for treatment of the ensuing cyanosis. Methemoglobinemia is either hereditary or acquired, is relatively common, and often produces no clinical findings when present at less than 5%. In hospitalized patients, benzocaine spray accounted for the most seriously poisoned patients, whereas dapsone accounted for the largest number of cases. Of the patients who had elevated methemoglobin levels, 8% had symptomatic methemoglobinemia, and approximately one-third received methylene blue. In a large study of children between the ages of 2 and 5 years old admitted to the hospital for fever, elevated methemoglobin levels were detected in 43% of patients. Vomiting, poor capillary refill, metabolic acidosis with an elevated lactate concentration, severe anemia, and malaria were reported in this population. Acute pesticide poisoning leading to methemoglobinemia is common in many parts of the world. In Sri Lanka, a large, multicenter study followed patients with intentional propanil (a herbicide) ingestions and found a 10.7% mortality rate in those with methemoglobinemia.

HEMOGLOBIN PHYSIOLOGY Hemoglobin consists of four polypeptide chains noncovalently attracted to each other. Each of these subunits carries one heme molecule deeply within the structure. The polypeptide chain protects the iron moiety of the heme molecule from inappropriate oxidation. The iron is held in position by six coordination bonds. Four of these bonds are between iron and the nitrogen atoms of the protoporphyrin ring with the fifth and sixth bond sites lying above and below the protoporphyrin plane. The fifth site is occupied by histidine of the polypeptide chain. The sixth coordination site is where most of the activity within hemoglobin occurs. Oxygen transport occurs here, and this site is involved with the formation of methemoglobin or carboxyhemoglobin (Fig. 97–1). It is at this site that an electron is lost to oxidant xenobiotics, transforming iron from its ferrous (Fe2+) to its ferric (Fe3+) state, which defines methemoglobin.

METHEMOGLOBIN PHYSIOLOGY AND KINETICS Because of the spontaneous and xenobiotic-induced oxidation of iron, the erythrocyte has multiple mechanisms to maintain its normal low concentration of methemoglobin.

Heme Fifth coordination site

Sixth coordination site N N

O2– Oxyhemoglobin

Fe

Histidine

CO Carboxyhemoglobin

N

O N

H H

Methemoglobin

FIGURE 97–1.  Heme molecule depicted with its bonding sites. Oxyhemoglobin, carboxyhemoglobin, and methemoglobin all involve the sixth coordination bonding site of iron.

All these systems donate an electron to the oxidized iron atom. Because of these effective reducing mechanisms, the half-life of methemoglobin acutely formed as a result of exposure to oxidants is between 1 and 3 hours. With continuous exposure to the oxidant, the apparent half-life of methemoglobin is prolonged. Quantitatively, the most important reductive system requires nicotinamide adenine dinucleotide (NADH), which is generated in the Embden-Meyerhof glycolytic pathway (Fig. 97–2). Nicotinamide adenine dinucleotide (NADH) serves as an electron donor, and along with the enzyme NADH methemoglobin reductase, reduces Fe3+ to Fe2+. There are numerous cases of hereditary deficiencies of the enzyme NADH methemoglobin reductase (cytochrome b5 reductase). Individuals who are homozygotes for this enzyme deficiency usually have methemoglobin levels of 10% to 50% under normal conditions without any clinical or xenobiotic stressors. Individuals who are heterozygotes do not ordinarily demonstrate methemoglobinemia except when they are subject to oxidant stress. Additionally, because this enzyme system lacks full activity until approximately 4 months of age, even genetically normal infants are more susceptible than adults to oxidant stress. Within the RBC is another enzyme system for reducing oxidized iron that is dependent on the nicotinamide adenine dinucleotide phosphate (NADPH) generated in the hexose monophosphate shunt pathway. Although this system reduces only a small percentage of methemoglobin under normal circumstances, it plays a more prominent role in maintaining oxidant balance in the cell and is involved in the mechanism of modulating vascular tone during low oxygen delivery to the capillary beds. However, when the NADPH methemoglobin reductase system is provided with an exogenous electron carrier, such as methylene blue, this system is accelerated and greatly assists in the reduction of oxidized hemoglobin (Antidotes in Brief: A43).

XENOBIOTIC-INDUCED METHEMOGLOBINEMIA Nitrates and nitrites are powerful oxidizers that are two of the most common methemoglobin-forming compounds. Sources of nitrates and nitrites include well water, food, industrial compounds, and pharmaceuticals. Nitrogen-based 695

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Glycolysis Glutathione formation

Glucose Hb(Fe2+)

Glyceraldehyde 3-PO4 NAD+

Electron transport chain

NADH 1,3 Biphosphoglycerate

Reduced cytochrome b5

Glucose

Oxidant stress

Glucose 6-PO4

Glucose 6-PO4 NADP+

Hb(Fe3+)

Leukomethylene blue

Glucose 6-phosphate dehydrogenase

NADPH 6-Phosphogluconate

NADPH MetHb reductase

Cytochrome b5 reductase Oxidized cytochrome b5

Hexose monophosphate shunt

Hb(Fe2+)

Methylene blue

FIGURE 97–2.  Role of glycolysis (the Embden-Meyerhof pathway) and the role of methylene blue in the reduction of methemoglobin using nicotinamide adenine dinucleotide phosphate (NADPH) generated by the hexose monophosphate shunt. Hb (Fe3+) is methemoglobin.

fertilizers and nitrogenous waste from animal and human sources may contaminate shallow rural wells. In the past, nitrate-contaminated well water was associated with infant fatalities because of methemoglobinemia. Topical anesthetics continue to be a problem despite numerous case studies and recommendations by authors and manufacturers about safe use standards. Cetacaine spray (14% benzocaine, 2% tetracaine, 2% butylaminobenzoate) and 20% benzocaine sprays commonly produce methemoglobinemia. Dapsone is implicated as a common cause of methemoglobinemia. Cases of prolonged methemoglobinemia from dapsone ingestion are related to the long half-life of dapsone and the slow conversion to its methemoglobin-forming hydroxylamine metabolites. Predispositions for methemoglobinemia are listed in Tables 97–1 and 97–2.

METHEMOGLOBINEMIA AND HEMOLYSIS The enzyme defect responsible for most instances of oxidant-induced hemolysis is glucose-6-phosphate dehydrogenase (G6PD) deficiency. Reviews of hemolysis addressed the confusion regarding the relationship between hemolysis and methemoglobinemia. Both hemolysis and methemoglobinemia are caused by oxidant stress, and hemolysis sometimes occurs after episodes of methemoglobinemia. Another source of confusion concerning hemolysis and methemoglobinemia is that reduced glutathione is required TABLE 97–1   Some Physiologic and Epidemiologic Factors That Predispose Individuals to Methemoglobinemia Acidosis Advanced age Age < 36 mo Anemia Concomitant oxidant use

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Diarrhea Hospitalization Kidney failure Malnutrition Sepsis Xenobiotics

TABLE 97–2    Common Causes of Methemoglobinemia Hereditary Hemoglobin M NADH methemoglobin reductase deficiency (homozygote and heterozygote) Acquired Medications   Amyl nitrite   Local anesthetics (benzocaine, lidocaine, prilocaine)  Dapsone   Nitric oxide  Nitroglycerin  Nitroprusside  Phenazopyridine   Quinones (chloroquine, primaquine)   Sulfonamides (sulfanilamide, sulfathiazide, sulfapyridine, sulfamethoxazole) Other Xenobiotics   Aniline dye derivatives (shoe dyes, marking inks)  Chlorobenzene   Copper sulfate   Fires (heat-induced denaturation)   Organic nitrites (eg, amyl, isobutyl nitrite, butyl nitrite)  Naphthalene   Nitrates (eg, well water)   Nitrites (eg, foods)  Nitrophenol   Nitrogen oxide gases (occupational exposure in arc welders)  Propanil   Silver nitrate  Trinitrotoluene  Zopiclone Pediatric Reduced NADH methemoglobin reductase activity in infants (< 4 mo) Associated with low birth weight, prematurity, dehydration, acidosis, diarrhea, and hyperchloremia NADH = nicotinamide adenine dinucleotide.

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TABLE 97–3   Signs and Symptoms Typically Associated with Methemoglobin Levels in Healthy Patients with Normal Hemoglobin Concentrationsa

FIGURE 97–3.  Heinz bodies are particles of denatured hemoglobin, usually attached to the inner surface of the red blood cell membrane. Xenobiotics that result in the oxidative denaturation of hemoglobin in normal (eg, phenylhydrazine) or glucose-6-phosphate dehydrogenase (G6PD)-deficient (primaquine) individuals and unstable hemoglobin mutants are prone to develop these bodies. The Heinz bodies are identified when blood is mixed with a supravital stain, notably crystal violet. The Heinz bodies appear as purple inclusions. (Reproduced with permission from Lichtman MA. Lichtman’s Atlas of Hematology, 1st ed. New York, NY: McGraw-Hill, Inc; 2007.)

to protect against both toxic manifestations. This co‑ dependence on the reducing power of NADPH links these two disorders. Although it is easier to consider hemolysis and methemoglobin formation as subclasses of disorders of oxidant stress, they are separate clinical entities sharing limited characteristics. Oxidative damage to erythrocytes occurs at different locations in the two disorders. Hemolysis occurs when oxidants damage the hemoglobin chain acting directly as electron acceptors or through the formation of hydrogen peroxide or other oxidizing free radicals. This results in oxidants forming irreversible bonds with the sulfhydryl group of hemoglobin, causing denaturation and precipitation of the globin protein to form Heinz bodies within the erythrocyte (Fig. 97–3). Cells with large numbers of Heinz bodies are removed by the reticuloendothelial system, producing hemolysis. Methemoglobinemia does not necessarily progress to hemolysis even if untreated. Numerous cases describe the occurrence of hemolysis after methemoglobinemia. The combined occurrence is reported with dapsone, phenazopyridine, amyl nitrite, copper sulfate, and aniline. Currently, it is not possible to predict when hemolysis will occur after methemoglobinemia with any degree of certainty, and markers of hemolysis should be followed for several days.

CLINICAL MANIFESTATIONS The clinical manifestations of methemoglobinemia are related to impaired oxygen-carrying capacity and delivery to the tissue (Table 97–3). The clinical manifestations of acquired methemoglobinemia are usually more severe than those produced by a corresponding degree of anemia. This discordance occurs because methemoglobin not only decreases the available oxygen-carrying capacity but also increases the affinity of the unaltered hemoglobin for oxygen. This shifts the oxygen– hemoglobin dissociation curve to the left. Cyanosis typically

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Methemoglobin Level (%)

Signs and Symptoms

1–3 (normal)

None

3–15

Possibly none Pulse oximeter reads low SaO2 Slate gray cutaneous coloration

15–20

Chocolate brown blood Cyanosis

20–50

Dizziness, syncope Dyspnea Exercise intolerance Fatigue Headache Weakness

50–70

Central nervous system depression Coma Dysrhythmias Metabolic acidosis Seizures Tachypnea

> 70

Death Grave hypoxic symptoms

Associated illness and comorbid diseases produce more severe symptoms at lower levels of methemoglobin. a

occurs when just 1.5 g/dL of methemoglobin is present. This represents only 10% conversion of hemoglobin to methemoglobin if the baseline hemoglobin is 15 g/dL. By contrast, 5 g/dL of deoxyhemoglobin (which represents 33% of the total hemoglobin concentration) is needed to produce the same degree of cyanosis from hypoxia. Because the symptoms associated with methemoglobinemia are related to impaired oxygen delivery to the tissues, concurrent diseases such as anemia, congestive heart failure, chronic obstructive pulmonary disease, and pneumonia increase the clinical effects of methemoglobinemia (Fig. 97–4). Predictions of symptoms and recommendations for therapy are based on methemoglobin level in previously healthy individuals with normal total hemoglobin concentrations.

DIAGNOSTIC TESTING Arterial blood gas sampling usually reveals blood with a characteristic chocolate brown color. However, in patients who are clinically stable and not in need of an arterial puncture, a venous blood gas will be accurate in demonstrating the methemoglobin level. The arterial PO2 should be normal, reflecting the adequacy of pulmonary function to deliver dissolved oxygen to the blood. However, arterial PO2 does not directly measure the hemoglobin oxygen saturation (SaO2) or oxygen content of the blood. When the partial pressure of oxygen is known and oxyhemoglobin and deoxyhemoglobin are the only species of hemoglobin, oxygen saturation can be calculated accurately from the arterial blood gas. If, however,

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Functional hemoglobin

14 12 10

A Normal B Hypoxia

8

Hemoglobin (g/dL)

6 4 2

Oxyhemoglobin

0

Deoxyhemoglobin

2

Methemoglobin

4 6 8

Dysfunctional hemoglobin

D Methemoglobinemia and anemia

High-oxygen affinity hemoglobin

Methemoglobinemia C

10

Methemoglobinemia, hypoxia, and anemia E

FIGURE 97–4.  Clinical manifestations of methemoglobinemia depend on the level of methemoglobin and on host factors such as preexisting disease, anemia, and hypoxemia. Five examples of arterial blood gases and cooximeter analyses are presented. (A) Blood gas from a normal individual with 14 g/dL of hemoglobin. Almost all hemoglobin is saturated with oxygen. (B) Blood gas from a patient with cardiopulmonary disease producing cyanosis in which only 9 g/dL of hemoglobin is capable of oxygen transport. (C) Methemoglobin level of 28% in an otherwise normal individual will reduce hemoglobin available for oxygen transport to less than 9 g/dL (~4 g/dL of methemoglobin and 1.3 g/dL of high oxygen affinity hemoglobin because of the left shift of the oxyhemoglobin dissociation curve). (D) Same degree of methemoglobin as in C but in a patient with a hemoglobin of 10 g/dL. Only 6 g/dL of hemoglobin would be capable of oxygen transport. (E) Methemoglobinemia and anemia to the same degree as D but in a patient with hypoxia.

other dyshemoglobins are present, such as methemoglobin, sulfhemoglobin, or carboxyhemoglobin, then the fractional saturation of the different hemoglobin species must be determined by cooximetry. The pulse oximeter applied to a patient’s finger at the bedside was developed to estimate oxygen saturation trends in critically ill patients. Most pulse oximeters in use today use two different wavelengths to determine O2 saturation, and the manufacturers do not provide validation data for situations in which any dyshemoglobin is present. All manufacturers disclaim accuracy under such circumstances. In the dog model, the pulse oximeter oxygen saturation (SpO2) values decrease with increasing methemoglobin levels. This decrease in SpO2 is not exactly proportional to the percentage of methemoglobin. However, the pulse oximeter overestimated the level of actual oxygen saturation at low methemoglobin levels. As the methemoglobin level approached 30%, the pulse oximeter saturation values decreased to about 85% and then leveled off, regardless of how much higher the methemoglobin level became. From our experience and that of others, in humans, much lower levels of oxygen saturation (SpO2) than 85% can be displayed by pulse oximetry when methemoglobin levels increase above 30%. Although the pulse oximeter reading in patients with methemoglobinemia is not as accurate as desired, it remains helpful when it is compared with that of the arterial blood gas: if there is a difference between the measured oxyhemoglobin saturation of the pulse oximeter (SaO2) and the calculated oxyhemoglobin saturation of the arterial blood gas (SpO2), then a “saturation gap” exists. The calculated SaO2

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of the blood gas will be greater than the measured SpO2 if methemoglobin is present (Table 97–4). Several manufacturers developed pulse oximeters that read multiple wavelengths to identify other hemoglobin species such as methemoglobin, carboxyhemoglobin, and total hemoglobin concentration. Validation studies using human volunteers with these new pulse oximeters suggest that the accuracy for detecting methemoglobin is acceptable. While imperfect, these devices can be used for screening in high-risk patients or circumstances. Methemoglobin produces a color change that can be observed when a drop of blood is placed on absorbant white paper. In one study, when various levels of methemoglobin from 10% to 100% were produced in vitro and a drop of each concentration was placed on a white background, a color chart was developed that could reliably be used to predict methemoglobin levels (Fig. 97–5). In situations in which laboratory evaluation is limited, such a bedside test is useful because a determination of the exact methemoglobin level is rarely needed.

MANAGEMENT For most patients with mild methemoglobinemia of approximately 10%, no therapy is necessary other than withdrawal of the offending xenobiotic because reduction of the methemoglobin will occur by normal reconversion mechanisms (NADH methemoglobin reductase). However, in some patients, even small elevations of methemoglobin are problematic because they suggest the individual is at a point at which further oxidant stress will cause methemoglobin levels to increase. Patients should be examined carefully for signs of

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TABLE 97–4    Hemoglobin Oxygenation Analysis Measuring Device

Source

What Is Measured

Blood gas analyzer

Blood

Partial pressure of dissolved oxygen in whole blood

Cooximeter

Blood

Pulse oximeter

Monitor sensor on patient

How Data Are Expressed

Benefits

PO2

Pitfalls

Insight

Also gives information Calculates SaO2 from the about pH and PCO2 partial pressure of oxygen in blood; inaccurate if forms of Hb other than OxyHb and DeoxyHb are present

An abnormal Hb form may exist if a gap exists between ABG and pulse oximeter

Directly measures absorptive SaO2, %MethHb, characteristics of oxyhemoglobin, %COHb, %OxyHb, deoxyhemoglobin, %DeoxyHb methemoglobin, and carboxyhemoglobin and in some cases other hemoglobins (fetal hemoglobin, sulfhemoglobin) at different wavelength bands in whole blood

Directly measures hemoglobin species

Provides data on hemoglobin only; most instruments will not measure sulfhemoglobin, HbM, and some other forms of Hb

Most accurate method of determining the oxygen content of blood

Absorptive characteristics of SpO2 oxyhemoglobin in pulsatile blood assuming the presence of only OxyHb and DeoxyHb in vivo Newer pulse oximeters measure methemoglobin

Moment-to-moment bedside data

Inaccurate data if interfering substances are present (methemoglobin, sulfhemoglobin, carboxyhemoglobin, methylene blue)

Maximum depression, 75%–85% regardless of how much methemoglobin is present

ABG = arterial blood gas; COHB, carboxyhemoglobin; DeoxyHb = deoxygenated hemoglobin; Hb = hemoglobin; HbM = hemoglobin M; MethHb = methemoglobin; OxyHb = oxygenated hemoglobin; SaO2 = hemoglobin oxygen saturation; SpO2 = pulse oximeter oxygen saturation.

physiologic stress related to decreased oxygen delivery to the tissue. Obviously, changes in mental status or ischemic chest pain necessitate immediate treatment, but subtle changes in behavior and inattentiveness are also signs of global hypoxia and should be treated. Patients with abnormal vital signs such as tachycardia and tachypnea or an elevated lactate concentration thought to be caused by tissue hypoxia or the functional anemia of methemoglobinemia should be treated more aggressively. A mildly elevated methemoglobin level alone generally is not an adequate indication of need for therapy, but when levels exceed 30%, treatment is almost always indicated (Fig. 97–4). The most widely accepted treatment of methemoglobinemia is administration of 1 to 2 mg/kg body weight of methylene blue infused intravenously over 5 minutes. The use of a slow 5-minute infusion and flushing the line after administration help prevent painful local responses from rapid infusion. Clinical improvement should be noted within

Normal blood

10%

20%

30%

minutes of methylene blue administration. If cyanosis has not disappeared within 15 to 30 minutes of the infusion, then a second dose is recommended (Fig. 97–6). Methylene blue causes a transient decrease in the pulse oximetry reading because of its blue color. The use of methylene blue in patients with G6PD deficiency is controversial. Glucose-6-phosphate dehydrogenase (G6PD)-deficient patients were once excluded from most treatment protocols because methylene blue is a mild oxidant and case reports suggested the toxicity of methylene blue. However, because of the lack of immediate availability of G6PD testing, most patients who need treatment receive methylene blue therapy before their G6PD status is known. Although many patients with G6PD deficiency undoubtedly have been treated unknowingly, few case reports of toxicity are described. Therefore, we believe that the judicious use of methylene blue is recommended in most patients with G6PD deficiency and symptomatic methemoglobinemia.

40%

50%

60%

70%

80%

Methemoglobin %

FIGURE 97–5.  The relationship between methemoglobin level and blood color. This figure demonstrates the relationship between methemoglobin level and the color of blood. If blood from an anticoagulated tube is placed on a white background, the methemoglobin level can be estimated accurately by comparison with the scale. It is important to note that although normal anticoagulated venous blood oxygenates spontaneously (ie, becomes redder over time), if exposed to room air, methemoglobin is incapable of extracting oxygen from air and will remain dark over time. (Reproduced with permission from Shihana F, Dissanayake DM, Buckley NA, et al. A simple quantitative bedside test to determine methemoglobin. Ann Emerg Med. 2010;55(2):184-189.)

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Cyanosis Supportive care, ABG, airway management Decontamination High-flow O2

Response

Cardiovascular or pulmonary etiology

No response Draw MetHba level < 30% Asxb Observe

> 30%

Symptomatic

Methylene blue 1-2 mg/kg Response

Observe repeat methylene blue PRN

No response Evaluate for: Inadequate dose of methylene blue Hemolysis: eg, chlorates Inadequate decontamination NADPH-dependent MetHba reductase deficiency Hemoglobin M Sulfhemoglobinemia

FIGURE 97–6.  Toxicologic assessment of a cyanotic patient. a = MetHb = methemoglobin; b = Asx = asymptomatic.

If methylene blue treatment fails to significantly reverse methemoglobinemia, other possibilities should be evaluated. Theoretically, exchange transfusion or hyperbaric oxygen (HBO) would be expected to be beneficial when methylene blue is ineffective. Both interventions are time consuming and costly, but HBO allows the dissolved oxygen time to protect the patient while endogenous methemoglobin reduction occurs. Ascorbic acid is not recommended in the management of acquired methemoglobinemia if methylene blue is available because the rate at which ascorbic acid reduces methemoglobin is considerably slower than the rate of normal intrinsic mechanisms. Treatment with dapsone deserves special consideration because of its tendency to produce prolonged methemoglobinemia. N-Hydroxylation of dapsone to its hydroxylamine

148_Hoffman_Ch97_p0695-0700.indd 700

metabolite by CYP2C9 and CYP3A4 is mainly responsible for methemoglobin formation in both therapeutic and overdose situations. Both the parent compound and its metabolites are oxidants with long half-lives. Cimetidine is a competitive inhibitor in the cytochrome P450 metabolic pathway and reduces methemoglobin concentrations during therapeutic dosing because less dapsone will be metabolized by the route. In situations of overdose, cimetidine in therapeutic doses will likely exert some protective effects and is reasonable to use with methylene blue. When dapsone is therapeutically indicated but low levels of methemoglobin are found, cimetidine is a reasonable method for reducing oxidant stress. Additionally, cimetidine is responsible for many drug interactions so dosing of other medications often needs adjustment.

SULFHEMOGLOBIN Sulfhemoglobin is a variant of hemoglobin in which a sulfur atom is incorporated into the heme molecule but is not attached to iron. Sulfhemoglobin is a darker pigment than methemoglobin, producing cyanosis when only 0.5 g/dL of blood is affected. Sulfhemoglobin also reduces the oxygen saturation determined by the pulse oximeter. The diagnosis is often established based on the patient’s failure to improve with methylene blue. Sulfhemoglobin is an extremely stable compound that is eliminated only when RBCs are removed naturally from circulation. Although the oxygen-carrying capacity of hemoglobin is reduced by sulfhemoglobinemia, unlike in methemoglobinemia, the oxyhemoglobin dissociation curve is shifted to the right. This makes oxygen more available to the tissues. This phenomenon reduces the clinical effect of sulfhemoglobin in the tissues. A number of xenobiotics induce sulfhemoglobin in humans, including acetanilid, phenacetin, nitrates, trinitrotoluene, and sulfur compounds. Most of the xenobiotics that produce methemoglobinemia are reported in various degrees to produce sulfhemoglobinemia. Sulfhemoglobinemia usually requires no therapy other than withdrawal of the offending xenobiotic. There is no antidote for sulfhemoglobinemia because it results from an irreversible chemical bond that occurs within the hemoglobin molecule. Exchange transfusion would lower the sulfhemoglobin concentration, but this approach usually is unnecessary.

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Antidotes in Brief

METHYLENE BLUE

INTRODUCTION Methylene blue is an extremely effective antidote for acquired methemoglobinemia. Methylene blue has other actions, including the inhibition of nitric oxide synthase and guanylyl cyclase and the inhibition of the generation of oxygen free radicals.

HISTORY Methylene blue was initially recommended as an intestinal and urinary antiseptic and subsequently recognized as a weak antimalarial. In 1933, Williams and Challis successfully used methylene blue for the treatment of aniline-induced methemoglobinemia.

PHARMACOLOGY Chemistry Methylene blue is a basic thiazine dye that is a deep blue color in the oxidized state but is colorless when reduced to leukomethylene blue.

Mechanisms of Action Methylene blue is an oxidizing agent, which, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and NADPH methemoglobin reductase, is reduced to leukomethylene blue (Fig. 97–2). Leukomethylene blue effectively reduces methemoglobin to hemoglobin. More recent attention has focused on the ability of methylene blue to reverse refractory hypotension from many causes, including drug overdose, vasoplegia, and sepsis. Methylene blue inhibits nitric oxide synthase and guanylyl cyclase in vascular smooth muscle to reduce the amount and effect of vasodilatory nitric oxide.

Pharmacokinetics Methylene blue exhibits complex pharmacokinetics, consistent with extensive distribution into deep compartments, followed by a slower terminal elimination, with a half-life of 5.25 hours. Interindividual variability is significant. Total urinary excretion at 24 hours accounts for 28.6% of the drug after IV administration.

Pharmacodynamics The onset of action of methylene blue for the reversal of methemoglobin is often within minutes. Maximum effects usually occur by 30 minutes.

ROLE IN XENOBIOTIC-INDUCED METHEMOGLOBINEMIA Methylene blue is indicated in patients with symptomatic methemoglobinemia. This usually occurs at methemoglobin levels greater than 20%, but symptoms often occur at lower levels in anemic patients or those with cardiovascular, pulmonary, or central nervous system compromise. The risk-to-benefit ratio of using methylene blue in a patient

for methemoglobinemia must always be weighed as with any other xenobiotic. In almost all cases, the benefit of use for a patient with significant methemoglobinemia will almost always outweigh the risks.

ROLE IN HYPOTENSION Methylene blue has successfully reversed a low systemic vascular resistance in a few case studies and case reports. A recent review of human data suggests that although blood pressure responds to methylene blue in patients with distributive shock, a prospective study is needed to establish whether better oxygen delivery and improved survival occur.

ADVERSE EFFECTS AND SAFETY ISSUES The most common adverse effects reported in healthy volunteers who were administered 2 mg/kg methylene blue were extremity pain at the site of IV administration, chromaturia, dysgeusia, dizziness, feeling hot, diaphoresis, nausea, skin discoloration, headache, and back pain. Reports of the paradoxical induction of methemoglobinemia by methylene blue suggest an equilibrium between the direct oxidization of hemoglobin to methemoglobin by methylene blue and its ability (through the NADPH and NADPH methemoglobin reductase pathway and leukomethylene blue production) to reduce methemoglobin to hemoglobin. Methylene blue does not produce methemoglobin at doses of 1 to 2 mg/kg. Limited studies support the avoidance of doses higher than 7 mg/kg. In these high doses, methylene blue induces acute hemolytic anemia independent of the presence of methemoglobinemia. Because methylene blue is a dye, it will transiently alter pulse oximeter readings. Large doses often interfere with the ability to detect a clinical decrease in cyanosis; therefore, repeat cooximeter measurements and arterial or venous blood gas analysis should be used in conjunction with clinical findings to evaluate for improvement. Methylene blue leads to a bluish-green discoloration of the urine and often causes dysuria. Intravenous methylene blue is often painful, but can be given in any sized catheter. It rarely causes local tissue damage even in the absence of extravasation. Recent reviews reveal an association between an encephalopathy and the use of methylene blue for the staining and localization of parathyroid tumors in women receiving serotonin reuptake inhibitors. Doses of 3 to 7.5 mg/kg were commonly used for this indication. An in vitro study documented the ability of methylene blue to competitively bind to monoamine oxidase A, raising the possibility that methylene blue might interact with serotonergic xenobiotics by acting as a monamine oxidase inhibitor. The United States Food and Drug Administration added a black box warning regarding potential serious or fatal serotonin toxicity when 701

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

methylene blue is given to patients receiving selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or monoamine oxidase inhibitors.

Use in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency Methylene blue is frequently hypothesized to be ineffective in reversing methemoglobinemia in patients with glucose6-phosphate dehydrogenase (G6PD) deficiency because G6PD is essential for generation of NADPH. Without NADPH, methylene blue cannot reduce methemoglobin. However, G6PD deficiency is an X-linked hereditary deficiency with more than 400 variants. The red blood cells containing the more common G6PD A- variant that are found in 11% of African Americans retain 10% residual activity, mostly in young erythrocytes and reticulocytes. By contrast, the enzyme is barely detectable in those of Mediterranean descent who have inherited the defect. Therefore, it is impossible to predict before the use of methylene blue which persons will or will not respond and to what extent. It appears that most individuals have adequate G6PD, and a variable expression of their deficiency allows an effective response to most oxidant stresses. In addition, in theory, normal cells might convert methylene blue to leukomethylene blue, which might diffuse into G6PDdeficient cells and effectively reduce methemoglobin to hemoglobin. However, when therapeutic doses of methylene blue fail to have an impact on the methemoglobin levels, the possibility of G6PD deficiency should be evaluated, and further doses of methylene blue should not be administered because of the risk of methylene blue–induced hemolysis. In these cases, exchange transfusion, vitamin C, and hyperbaric oxygen are potential alternatives for treating methemoglobinemia (Chap. 97).

hemolytic anemia, hyperbilirubinemia, and methemoglobinemia, and should be avoided. Intravenous methylene blue should only be used to treat pregnant women with methemoglobinemia when the benefit outweighs the potential risk to the fetus. There are no data available with regard to use during lactation. However, it is currently recommended to discontinue breastfeeding when methylene blue has been used and not to resume breastfeeding for 8 days after use.

DOSING AND ADMINISTRATION Methemoglobinemia The dose of methylene blue is 1-2 mg/kg given IV over 5 minutes followed immediately by a fluid flush of 15 to 30 mL to minimize local pain. This dose can be repeated in 15 to 30 minutes if necessary, based on clinical signs and symptoms and a consequential methemoglobin level. (A total doses greater than 7 mg/kg is not advised). If there is no effect after two sequential doses of 1 mg/kg, then subsequent dosing should be halted, and the diagnosis reexamined or the possibility of severe G6PD deficiency considered. However, repeated dosing of methylene blue is often required in conjunction with efforts to decontaminate the gastrointestinal tract when there is continued absorption or slow elimination of the xenobiotic producing the methemoglobinemia, such as with dapsone. Intraosseous administration is acceptable if IV access is unavailable.

Vasodilatory Shock The dose of methylene blue for refractory hypotension is not established. Doses of 1 to 3 mg/kg increase systemic vascular resistance and mean arterial pressure and improve tissue oxygenation.

PREGNANCY AND LACTATION

FORMULATION AND ACQUISITION

Methylene blue is listed as a Category X drug in pregnancy. Intraamniotic injection has led to fetal abnormalities, including atresia of the ileum and jejunum, ileal occlusions,

Methylene blue is available in 10-mL vials of a 1% solution for injection, containing 10 mg/mL (100 mg total in 10 mL), and in a 0.5% solution containing 5 mg/mL (50 mg total in 10 mL).

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98

CHEMICAL WEAPONS

HISTORY AND EPIDEMIOLOGY The first well-documented intentional use of chemicals as weapons occurred in 423 B.C. when Spartans besieging Athenian cities burned pitch-soaked wood and brimstone to produce sulfurous clouds. Large-scale chemical warfare began in World War I when the Germans released chlorine near Ypres, Belgium, killing hundreds of people and forcing 15,000 troops to retreat. Both sides rapidly escalated the use of toxic gases released from cylinders or by artillery shells, including various pulmonary irritants, lacrimators, arsenicals, and cyanides. The Germans first used sulfur mustard in 1917, again near Ypres, and caused more than 20,000 deaths or injuries. The Allies soon responded in kind. By the end of the war, chemical weapons caused more than 1.3 million casualties and approximately 90,000 deaths. Germany began producing nerve agents just before World War II. Terrorist groups have also used chemical weapons. Sarin was released twice by the Aum Shinrikyo cult in Japan. Chemical weapons are particularly appealing to terrorist groups because the technology and financial outlay required to produce them is much less than for nuclear weapons, and the potential morbidity, mortality, and societal impact remain high (Table 98–1). Biological weapons share some characteristics with chemical weapons (Table 98–2) and are covered in Chap. 99.

GENERAL CONSIDERATIONS Physical Properties The term war gas is generally a misnomer. Sulfur mustard and nerve agents are liquids at normal temperatures and pressures, and many riot-control agents are solids. These weapons are most efficiently dispersed as aerosols, which probably leads to the confusion with gases. Some chemical weapons such as chlorine, phosgene, and hydrogen cyanide are true gases, and although they are generally considered obsolete for battlefield use, they might still be used as improvisational chemical weapons, especially in terrorist attacks. Liquid chemical weapons have a certain degree of volatility and evaporate into poisonous vapors. Aerosols, gases, and vapors are highly subject to local atmospheric conditions. Except for hydrogen cyanide, chemical weapon (CW) gases and vapors are all denser than air and collect in low-lying areas.

Preparation for Chemical and Biological Weapons (CBW) Incidents A rational medical response to CBW events differs from the common response to isolated toxicologic incidents. Healthcare professionals must learn about these unconventional weapons and the expected “toxidromes” that they produce. In addition, healthcare professionals must protect themselves and their facilities first, or ultimately no one will receive care.

Recommendations for sustained healthcare facility domestic preparedness include improved training to promptly recognize CBW mass casualty events, efforts to protect healthcare professionals, and establishment of decontamination and triage protocols. Table 98–3 lists some specific recommendations. Individual clinicians and hospitals caring for victims of known or suspected CBW incidents should contact their local department of health, which will likely report the incident to outside agencies such as the United States (US) Federal Bureau of Investigation and the Centers for Disease Control and Prevention (Table 98–4).

Decontamination Decontamination serves two functions: (1) to prevent further absorption and spread of a noxious substance on a given casualty and (2) to prevent spread to other persons. Chemical weapons that are exclusively gases at normal temperatures and pressures only require removing the victim from the area of exposure. Isolated aerosol or vapor exposures, as from volatilized nerve agents or sulfur mustard, are also terminated by leaving the area and may require no skin decontamination of the victims. Chemical weapons dispersed as liquids present the greatest need for decontamination. Liquid-contaminated clothing must be removed, and, if able, victims should remove their own clothing to prevent cross-contamination. Decontamination should be done as soon as practicable to prevent progression of disease and should occur outside of healthcare facilities to prevent contamination of the working environment and secondary casualties. Decontamination near the incident scene would be ideal in terms of timeliness, although logistically, this will not be possible in many situations. Field decontamination before transport will also help to avoid loss of vehicles from being contaminated and taken TABLE 98–1    Unconventional Weapons: Definitions and Acronyms Chemical warfare

Intentional use of weapons designed to kill, injure, or incapacitate on the basis of toxic or noxious chemical properties

Biologic warfare

Intentional use of weapons designed to kill, injure, or incapacitate on the basis of microorganisms or xenobiotics derived from living organisms

Terrorism

The unlawful use of force against persons or property to intimidate or coerce a government, the civilian population, or any segment thereof, in furtherance of political or social objectives

CW

Chemical warfare, or chemical weapon

BW

Biological warfare, or biological weapon

CBW

Chemical and/or biological warfare or weapons

NBC

Nuclear, biological, and/or chemical; usually in reference to weapons

CBRNE

Chemical, biological, radiologic, nuclear, and explosive; usually in reference to weapons

WMD

Weapon of mass destruction; nuclear, radiologic, chemical, or biological weapon intended to produce mass casualties 703

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE 98–2   Chemical Versus Biological Weapons: Comparison and Contrast Similarities Xenobiotics most effectively dispersed in aerosol or vapor forms Delivery systems frequently similar Movement of xenobiotics highly subject to wind and weather conditions Appropriate personal protective equipment prevents illness Differences

Chemical Weapons (CWs)

Biological Weapons (BWs)

Rate at which attack results in illness

Rapid, usually minutes to hours

Delayed, usually days to weeks

Identifying release

Relatively easy: Rapid clinical effects Possible chemical odor Commercially available chemical detectors

More difficult: Delayed clinical effects Lack of color, odor, or taste Limited development of real-time detectors

Xenobiotic persistence

Variable Liquids semipersistent to persistent Gases nonpersistent

Generally nonpersistent; most BW xenobiotics are degraded by sunlight, heat, or desiccation (exception: anthrax spores)

Victim distribution

Near and downwind from release point

Victims may be widely dispersed by the time disease is apparent

First responders

EMTs, hazard materials teams, firefighters, law enforcement officers

Emergency physicians and nurses, primary care practitioners, infectious disease physicians, epidemiologists, public health officials (but will likely be same as CW if release is identified immediately)

Decontamination

Critically important in most cases

Not needed in delayed presentations; less important for acute exposures

Medical treatment

Antidotes, supportive care

Vaccines, antibiotics, supportive care

Patient isolation

Unnecessary after adequate decontamination

Crucial for easily communicable diseases (eg, smallpox, pneumonic plague); however, many BW agents are not easily transmissible

EMT = emergency medical technician.

out of service. Evidence supports the likelihood that contaminated victims will present to healthcare facilities on their own or be transported for care without decontamination. The degree of protective gear required by the decontamination personnel cannot be predicted in advance and may be difficult to objectively determine at the time of the incident. Level C personal protective equipment may be sufficient for most hospital settings when the source is defined (eg, receiving and decontamination areas); however, if healthcare professionals begin to develop clinical effects, level B gear TABLE 98–3   Recommendations for Healthcare Facility Response to Chemical and/or Biological Warfare or Weapons Incidents • Immediate access to personal protective equipment for healthcare professionals • Decontamination facilities that can be made operational with minimal delay • Triage of victims into those able to decontaminate themselves (decreasing the workload for healthcare providers) and those requiring assistance • Decontamination facilities permitting simultaneous use by multiple persons and providing some measure of visual privacy • A brief registration process when patients are assigned numbers and given identically numbered plastic bags to contain and identify their clothing and valuables • Provision of food, water, and psychological support for staff, who will likely be required to perform for extended periods • Secondary triage to separate persons requiring immediate medical treatment from those with minor or no apparent injuries who are sent to a holding area for observation • Providing victims with written information regarding the agent involved, potential short- and long-term effects, recommended treatment, stress reactions, and possible avenues for further assistance • Careful handling of information released to the media to prevent conflicting or erroneous reports • Instituting postexposure surveillance

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with supplied air would become necessary (Chap. 101). When the source of the contamination is not yet known, level B gear should be used. Chemically contaminated victims presenting to a healthcare facility should, if possible, be denied entrance until decontaminated. Patients who have already entered a healthcare facility and are only later determined to be a contamination hazard present a more difficult problem. If the situation allows, such patients should be taken outside for decontamination before returning and the previous care area cordoned off until any remaining safety hazard is assessed and eliminated. Although special decontamination solutions are preferable if available, rapid washing is more important than the choice of cleaning solution. Care should be taken to clean the hair, intertriginous areas, axillae, and groin. With small numbers of victims, ocular decontamination after lacrimator exposure is ideally performed with topical anesthesia and TABLE 98–4   Chemical and/or Biological Warfare or Weapons Phone Numbers/Contacts Centers for Disease Control and Prevention (CDC) 800-CDC-INFO (800-232-4636); https://www.cdc.gov CDC Emergency Operations Center: 770-488–7100 CDC Division of Preparedness and Emerging Infections: 404-639–0385 US Army Medical Research Institute of Chemical Defense 410-436-3276 (duty hours), 410-436-3277 (Off Duty Hours) Federal Bureau of Investigation (FBI) Find your local FBI field office at http://www.fbi.gov/contact-us/field/field-offices

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a specially designed contact lens that facilitates irrigation. Decontamination wastewater should ideally be contained and treated, but few facilities have the capability or funds to do this. However, wastewater is a minor issue because with large-scale CWs events, the wastewater represents only a small percentage of the total environmental impact.

Risk of Exposure The actual release of chemical or biologic weapons can be characterized as a low-probability, high-consequence event. Potential sources for civilian exposure include terrorist attacks, inadvertent releases from domestic stockpiles, direct military attacks, and industrial events. The chemicals most likely to be used militarily appear to be sulfur mustard and the nerve agents. A “low-tech” terrorist attack could involve the release of toxic industrial chemicals, such as chlorine, phosgene, or ammonia gas, as chemical “agents of opportunity.”

Psychological Effects Either the threat or the actual use of CBW agents presents unique psychological stressors. Even among trained persons, a CBW-contaminated environment will produce high stress through the necessity of wearing protective gear, potential exposure to weapons, high workload intensity, defensive posture, and interactions with dead and dying patients. The psychological casualties will probably outnumber victims requiring medical treatment. Psychiatrists and other disaster mental health personnel should be enlisted in plans to manage CBW incidents for their expertise in treating anxiety, fear, panic, somatization, and grief. Uncontrolled release of information will compound terror and increase psychological casualties. Examples the influx of patients resulting from a news report suggesting that anyone with dizziness or nausea be checked for cholinesterase inhibitor toxicity or that fever and cough indicate infection with anthrax.

Israeli Experience during the 1990 to 1991 Gulf War Israel is probably one of the best prepared countries for CBW disasters. In late 1990, the civilian population was supplied with rubber gas masks, atropine syringes, and Fuller’s earth decontamination powder. Thirty-nine ballistic missiles with conventional warheads were launched against Israel from Iraq in early 1991, with only six missiles causing direct casualties. Many more injuries resulted from CBW defensive measures and psychological stress than from physical trauma. Of 1,060 injuries reported from emergency departments (EDs) during this time period, 234 persons were directly wounded in explosions, and there were only two fatalities from trauma. More than 200 people presented for medical evaluation after self-injection of atropine, a few requiring admission to the hospital. About 540 people sought care for acute anxiety reactions. Some suffocated from improperly used gas masks, fell and injured themselves when rushing to rooms sealed against CBW agents, or were poisoned by carbon monoxide in these airtight rooms.

Special Populations Pregnancy does not appear to be a significant factor in the treatment of women victims of CWs. Children differ substantially

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from adults with regard to the effects of CWs and decontamination efforts. Children breathe at a lower ground elevation above the ground and at a higher rate than adults. Because nearly all CW gases and vapors are heavier than air, children are exposed to higher concentrations than adults in the same exposure setting and generally exhibit symptoms earlier. Children are also more susceptible to vesicants and nerve agents than adults with equivalent exposures. Children have thinner and more delicate skin, allowing for more systemic absorption and more rapid onset of injury with sulfur mustard. Decontamination of children is another feature that requires an age-adjusted approach. Most children will need assistance and supervision during decontamination procedures; keeping a mother or other adult guardian with a child should help with both decontamination and thermoregulation.

NERVE AGENTS Physical Characteristics and Toxicity Nerve agents are extremely potent organic phosphorus compound cholinesterase inhibitors and are the most toxic of the known CWs. Pure nerve agents are clear and colorless. Tabun has a faint fruity odor, and soman is variably described as smelling sweet, musty, fruity, spicy, nutty, or like camphor. Most subjects exposed to sarin and VX were unable to describe the odor. The G agents tabun (GA), sarin (GB), and soman (GD) are volatile and present a significant vapor hazard. Sarin is the most volatile, only slightly less so than water. VX is an oily liquid with low volatility and higher environmental persistence.

Pathophysiology The pathophysiology of nerve agents is essentially identical to that from organic phosphorus compound insecticides (Chap. 83), differing only in terms of potency, kinetics, and physical characteristics of the xenobiotics.

Clinical Effects Nerve agent vapor exposures produce rapid effects, within seconds to minutes, but the effects from liquid exposure are delayed as the xenobiotic is absorbed through the skin. Aerosol or vapor exposure initially affects the eyes, nose, and respiratory tract. Miosis is common, resulting from direct contact of the xenobiotic with the eye and may persist for several weeks. Ciliary spasm produces ocular pain, headache, nausea, and vomiting, often exacerbated by near-vision accommodation. Rhinorrhea, airway secretions, bronchoconstriction, and dyspnea occur with increasing exposures. With a large vapor exposure, one or two breaths may produce loss of consciousness within seconds followed by seizures, paralysis, and apnea within minutes. Liquid nerve agents permeate ordinary clothing, allowing for percutaneous absorption and rendering the clothing of patients potential hazards to healthcare personnel before proper decontamination. Mild dermal exposure produces localized sweating and muscle fasciculations after an asymptomatic period lasting up to 18 hours. Moderate skin exposure produces systemic effects with nausea, vomiting, diarrhea, and generalized weakness. Substantial dermal contamination will produce earlier and more severe effects,

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often with an abrupt onset. Severe toxicity from any route of exposure causes loss of consciousness, seizures, generalized fasciculations, flaccid paralysis, apnea, and/or incontinence. Cardiovascular effects are less predictable because either bradycardia (muscarinic) or tachycardia (nicotinic) may occur. Long-term effects from nerve agent exposure are mostly limited to psychological sequelae.

Treatment of Nerve Agent Exposure

Decontamination.  In some critically ill patients, antidotal treatment will be necessary before or during the decontamination process; but generally, decontamination should occur before other treatment is instituted. Atropine.  Atropine (Antidotes in Brief: A35) is the standard antidote for the muscarinic effects of nerve agents. Atropine does not reverse nicotinic effects but does have some central effects and will thus assist in halting seizure activity. We recommend an initial minimum dose of 2 mg atropine in adults; dosing in children begins at 0.05 mg/kg for mild to moderate symptoms and 0.1 mg/kg for severe symptoms, up to the adult dose. An initial dose of 5 to 6 mg is given for severely poisoned adult patients. Repeat doses are given every 2 to 5 minutes until resolution of muscarinic signs of toxicity. Neither reversal of miosis nor development of tachycardia is a reliable marker to guide atropine therapy. An autoinjector provides atropine (2.1 mg) plus pralidoxime chloride (600 mg) (Antidotes in Brief: A36). In a mass casualty incident, IV atropine supplies will likely be rapidly depleted from hospital stocks. Alternative sources include atropine from ambulances, ophthalmic and veterinary preparations, or substituting an antimuscarinic such as glycopyrrolate. Facilities expecting large numbers of casualties should store atropine as a bulk powder formulation and rapidly reconstitute it for injection when needed. Oximes.  Oximes are nucleophilic compounds that reactivate organic phosphorus compound–inhibited cholinesterase enzymes by removing the dialkylphosphoryl moiety. The only oxime approved in the US is pralidoxime (2-PAM). Other oximes include trimedoxime (TMB4) and obidoxime (toxogonin) used in some European countries. The Hagedorn (H-series) oximes, particularly HI-6 and HLö-7, are also studied in the context of nerve agent toxicity. Oximes should be given in conjunction with atropine because they are not particularly effective in reversing muscarinic effects when given alone. Oximes are the only antidotes that can reverse the neuromuscular nicotinic effects of fasciculations, weakness, and flaccid paralysis (Antidotes in Brief: A36). Antiepileptics.  Severe human nerve agent toxicity rapidly induces convulsions, which persist for a few minutes until the onset of flaccid paralysis. The US military doctrine is to administer 10 mg of diazepam intramuscularly by autoinjector at the onset of severe toxicity whether seizures are present or not. We recommend midazolam for IM use and any available parenteral benzodiazepine for IV use (Antidotes in Brief: A26). Although diazepam is the most well-studied benzodiazepine in the treatment of nerve agent toxicity, lorazepam and midazolam have similar or improved beneficial effects in animal studies.

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Pyridostigmine Pretreatment.  The first large-scale use of pyridostigmine as a pretreatment for nerve agent toxicity occurred during Operation Desert Storm in 1991. Whereas pyridostigmine is a carbamate acetylcholinesterase inhibitor that is freely and spontaneously reversible, organic phosphorus compound inhibition is permanent after “aging” occurs. Toxicity from rapidly aging weapons such as soman (GD) can probably not be reversed by standard oxime therapy in realistic clinical situations. Almost paradoxically, then, a carbamate can occupy cholinesterase, blocking access of nerve weapons to the active site, and thereby protect the enzyme from permanent inhibition. After nerve agent exposure, pyridostigmine is allowed to rapidly hydrolyze from acetylcholinesterase and can also be easily displaced by oximes, regenerating functional enzyme. Some US troops in the 1990 to 1991 Gulf War took 30 mg pyridostigmine bromide orally every 8 hours when under threat of nerve agent attack because of concern for potential exposure specifically to soman, which has a short aging half-life. Pyridostigmine pretreatment is not recommended in the civilian sector.

VESICANTS Vesicants are historically designated as “blister agents” because they manifest with blistering of skin and mucous membranes.

Sulfur Mustard Sulfur mustard is a vesicant alkylating compound similar to nitrogen mustards used in chemotherapy. Sulfur mustard caused over 1 million casualties in World War I and was later used by the Italians and Japanese in the 1930s, by Egypt in the 1960s, and by Iraq in the 1980s. Nonbattlefield exposures also occurred among Baltic Sea fishermen while recovering corroding shells dumped after World War II and to persons unearthing or handling old chemical warfare ordinance. Physical Characteristics.  Sulfur mustard is a yellow to brown oily liquid with an odor resembling mustard, garlic, or horseradish. Mustard has relatively low volatility and high environmental persistence. Mustard vapor is 5.4 times denser than air. Mustard freezes at 57°F (13.9°C), so it is sometimes mixed with other substances, such as chloropicrin or Lewisite, to lower the freezing point and permit dispersion as a liquid. Pathophysiology.  Sulfur mustard is an alkylating agent, forming bonds with sulfhydryl (–SH) and amino (–NH2) groups. This mechanism is the same as occurs with the nitrogen mustards, first developed as cancer chemotherapy agents in the 1940s. The most important acute manifestation is indirect inhibition of glycolysis. Sulfur mustard rapidly alkylates and crosslinks purine bases in nucleic acids. This activates DNA repair mechanisms, including the activation of the enzyme poly(ADP-ribose) polymerase, depleting nicotinamide adenine dinucleotide (NAD+), which in turn inhibits glycolysis and ultimately leads to cellular necrosis from adenosine triphosphate depletion. Clinical Effects.  The organs most commonly affected by mustard are the eyes, skin, and respiratory tract. Incapacitation is severe in terms of number of lost person-days, time for lesions to heal, and increased risk of infection. In contrast,

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the mortality rate is rather low. Most deaths occur several days after exposure from respiratory failure, secondary bacterial pneumonia, or bone marrow suppression. Dermal exposure produces dose-related injury. After a latent period of 4 to 12 hours, victims develop erythema that progresses to vesicles or bullae formation and skin necrosis. If decontamination is not performed immediately after exposure, injury cannot be prevented. However, later decontamination limits the severity of lesions and further spread of the chemical weapon to develop new lesions. Skin exposure to vapor typically results in first- or second-degree burns, although liquid exposure more commonly results in full-thickness burns. Signs and symptoms of ocular and respiratory tract exposures also occur after a latent period of several hours. Ocular effects include pain, miosis, photophobia, lacrimation, blurred vision, blepharospasm, and corneal damage. Permanent blindness is rare, with recovery generally occurring within a few weeks. Inhalation of mustard results in a chemical tracheobronchitis. Hoarseness, cough, sore throat, and chest pressure are common initial complaints. Bronchospasm and obstruction from sloughed membranes occur in more serious cases, but lung parenchymal damage occurs only in the most severe inhalational exposures. Productive cough associated with fever and leukocytosis is common 12 to 24 hours after exposure and represents a sterile bronchitis or pneumonitis. Nausea and vomiting are common within the first few hours. High-dose exposures also cause bone marrow suppression. Factory workers chronically exposed to mustard have increased risk of respiratory tract carcinomas. Respiratory sequelae include chronic bronchitis, emphysema, tracheobronchomalacia, and bronchiolitis obliterans. Some mustard victims also develop a delayed and often recurrent keratitis. Chronic dermatologic complications include scarring, pigmentation changes, chronic neuropathic pain, and pruritus. Treatment.  Decontamination is essential in treating the sulfur mustard exposures, even among asymptomatic victims. Further treatment is largely supportive and symptomatic. Lewisite.  Lewisite was developed as a less persistent alternative to avoid some shortcomings in the use of sulfur mustard in World War I. Lewisite was never used in combat because the first shipment was en route to Europe when the war ended, and it was intentionally destroyed at sea. British anti-Lewisite (BAL, dimercaprol) was developed as a specific antidote and remains in use for chelation of arsenic and other metals. Pure Lewisite is an oily, colorless liquid. Impure preparations are colored from amber to blue-black to black and have the odor of geraniums. Lewisite is more volatile than mustard and is easily hydrolyzed by water and by alkaline aqueous solutions such as sodium hypochlorite. Lewisite toxicity is similar to that of sulfur mustard, resulting in dermal and mucous membrane damage, with conjunctivitis, airway injury, and vesiculation. An important clinical distinction is that Lewisite is immediately painful, while initial contact with mustard is not. Treatment consists of decontamination with copious water or dilute hypochlorite solution, supportive care,

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and dimercaprol. Dimercaprol is given parenterally for systemic toxicity and is also used topically for dermal or ophthalmic injuries (Antidotes in Brief: A28).

Phosgene Oxime Although classified as a vesicant, phosgene oxime (CX) does not cause vesiculation of the skin. Phosgene oxime is more properly an urticant or “nettle” weapon, in that it produces erythema, wheals, and urticaria likened to stinging nettles. It produces immediate irritation of the skin and mucous membranes. This vesicant has never been used in battle, and little is known about its mechanism or effects on humans.

CYANIDES (CHEMICAL ASPHYXIANTS) Several cyanides have been used as CWs. The clinical effects and treatment of cyanide toxicity are covered elsewhere (Chap. 96) and do not differ significantly if used as a weapon. Hydrocyanic acid gas persists for only a few minutes in the atmosphere because it is lighter than air and rapidly disperses. Cyanogen chloride additionally causes ophthalmic and respiratory tract irritation and with sufficiently high exposures is reported to produce delayed acute respiratory distress syndrome (ARDS) in victims who are not rapidly killed.

PULMONARY IRRITANTS Chlorine, phosgene, and diphosgene were used as war gases in World War I. Chlorine, phosgene, diphosgene, various organohalides, and nitrogen oxides belong to a group of toxic chemicals designated “pulmonary irritants” because they can all induce delayed ARDS from increased alveolar-capillary membrane permeability. Chapter 94 provides clinical details for this class of xenobiotics. When released on the battlefield, chlorine forms a yellowgreen cloud with a distinct pungent odor detectable at concentrations that are not immediately dangerous. Phosgene is either colorless or seen as a white cloud as a result of atmospheric hydrolysis. Phosgene, which is reported to smell like grass, sweet newly mown hay, corn, or moldy hay, accounted for about 85% of all World War I deaths attributed to CWs. Phosgene produces injury by hydrolysis in the lungs to hydrochloric acid and by forming diamides that cross-link cell components. Battlefield exposure triggers cough, chest discomfort, dyspnea, lacrimation, and the peculiar complaint that smoking tobacco produces an objectionable taste. Prolonged observation after phosgene exposure is the rule because some casualties initially appeared well and were discharged, only to return in severe respiratory distress a few hours later.

RIOT CONTROL AGENTS Riot control agents are intentionally nonlethal chemicals that temporarily disable exposed individuals through intense irritation of exposed mucous membranes and skin. These weapons are also known as lacrimators, irritants, harassing agents, human repellents, and tear gas. They are solids at normal temperatures and pressures but are typically dispersed as aerosols or as small solid particles in liquid sprays. Chloroacetophenone (military designation CN) and o-Chlorobenzylidene malononitrile (CS) are the two common

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riot control agents. When used for crowd control, both CN and CS are disseminated as aerosols or as smoke from incendiary devices. Dibenzoxazepine (CR) is a similar weapon with prominent skin irritation. Exposed persons develop burning irritation of the eyes, progressing to conjunctival injection, lacrimation, photophobia, and blepharospasm. Inhalation causes chest tightness, cough, sneezing, and increased secretions. Dermal exposure causes a burning sensation, erythema, or vesiculation, depending on the dose. Victims generally remove themselves from the offensive environment and recover within 15 to 30 minutes. Deaths are rare and typically occur from respiratory tract complications in closed-space exposures where exiting the area is impossible. Law enforcement agencies and private citizens have access to oleoresin capsicum (OC), also known as pepper spray. Oleoresin capsicum is the essential oil derived from pepper plants (Capsicum anuum), which contains capsaicin, a naturally occurring lacrimator. Capsaicin activates the TRPV1 receptor, a heat-dependent nociceptor, explaining why exposures are experienced as “hot.” Severe skin injuries, respiratory tract injuries, and fatalities are occasionally reported from exposures, typically only with prolonged or highly concentrated exposures. Chloropicrin (PS) is another lacrimator that occasionally causes human toxicity through its use as a broad-spectrum fumigant and soil insecticide, as well as a warning agent associated with structural fumigants such as sulfuryl fluoride. 10-Chloro-5,10-dihydrodiphenarsazine (DM) induces vomiting in addition to irritant effects. Because symptoms are delayed, victims remain in the area, and the likelihood of significant absorption is increased. In addition to upper respiratory and ocular irritation, DM causes more prolonged systemic effects with headache, malaise, nausea, and vomiting.

The primary treatment for all riot control agents is removal from exposure. Contaminated clothing should be removed and placed in airtight bags to prevent secondary exposures. Skin irrigation with copious cold water should be used for significant dermal exposures. Symptomatic treatments, such as with topical ophthalmic anesthetics, nebulized bronchodilators, or oral antihistamines and corticosteroids, are indicated for directed therapy in more severely affected victims.

INCAPACITATING AGENTS 3-Quinuclidinyl benzilate (BZ QNB) is an antimuscarinic compound that was developed as an incapacitating CW agent. It is 25-fold more potent centrally than atropine, with an ID50 (dose that incapacitates 50% of those exposed) of about 0.5 mg. Clinical effects are characteristic for anticholinergics, with drowsiness, poor coordination, and slowing of thought processes progressing to delirium. Following exposure there is a delay of at least 1 hour for initial manifestations, which peak at 8 hours, continue to incapacitate for 24 hours, and takes 2 to 3 days to fully resolve. Ultrapotent opioids can be used as incapacitating CWs. In 2002, Russian security forces used a fentanyl derivative (carfentanil and/or remifentanil) to end a 3-day standoff with terrorists in a Moscow theater in which Chechen rebels held more than 800 hostages. Lysergic acid diethylamide (LSD) has also been investigated as an incapacitating weapon. Although effective at very low doses, battlefield use of LSD is impractical because poisoning will not reliably prevent a soldier from participation in combat. Table 98–5 summarizes the various toxic syndromes associated with use of CWs.

TABLE 98–5    Chemical Weapons Toxic Syndromes (Continued) Organ System

Chemical Weapon Nerve Agents  Tabun (GA), Sarin (GB)   Soman (GD), VX  Aerosol/vapor (mild/moderate exposure)

Onset

Eyes

Upper Airways and Mucous Membranes

 

 

 

 

 

 

 

 

  Rapid (seconds–minutes)

  Miosis, eye pain, dim or blurred vision

  Rhinorrhea, ↑secretions

  Dyspnea, cough, wheezing, bronchorrhea

  —

  Headache

  —

—

—

—

Localized sweating

—

  Nausea, vomiting, abdominal cramps —

Miosis

↑Secretions

Apnea

—

Sudden collapse, seizures

Nausea, vomiting, diarrhea, cramping, incontinence

Subjective weakness, local muscle fasciculations, generalized fasciculations, weakness, flaccid paralysis

 Dermal Delayed exposure (mild (minutes–hours) to moderate exposure)  Severe exposure As above (by route) (any route)

Lungs

Skin

CNS

GI Tract

Other

—

(Continued)

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709

TABLE 98–5    Chemical Weapons Toxic Syndromes (Continued) Organ System

Chemical Weapon

Onset

Eyes

Upper Airways and Mucous Membranes

Vesicants  Sulfur mustard (H, HD)

Delayed (hours)

Conjunctivitis, eye pain, blurred vision, blindness (temporary)

Irritation, hoarseness, barky cough, sinus tenderness tracheobronchitis

  Lewisite (L)

Immediate irritation Delayed vesication

 Phosgene oxime (CX)

Immediate irritation Delayed urticaria

Pain, blepharospasm conjunctivitis, eyelid edema Pain, corneal damage

Toxic Inhalants   Phosgene (CG)

Immediate Irritation

  Chlorine (CL)

Lungs

Skin

CNS

GI Tract

Other

Erythema, vesicles, bullae, necrosis

—

Nausea, vomiting

Bone marrow suppression (in severe exposures)

(Same as sulfur mustard)

(More severe exposures) Productive cough, pseudomembrane formation, airway obstruction (Same as sulfur mustard)

Erythema, vesicles

—

—

Shock (in severe exposures)

Irritation

ARDS

Pain, blanching, — erythema, urticaria, necrosis

—

—

Irritation

Irritation

Dyspnea, cough, ARDS

—

—

—

Delayed ARDS

—

Stridor

Dyspnea, cough, ARDS

—

—

—

Chlorine effects more rapid than phosgene  

Cyanides  Hydrogen cyanide (AC)

Rapid (seconds–minutes)

—

—

Hyperpnea and then apnea

—

—

—

 Cyanogen chloride (CK)

Rapid (seconds–minutes)

Irritation

Irritation

Hyperpnea and then apnea

—

Anxiety, agitation, sudden collapse, seizures Anxiety, agitation, sudden collapse, seizures

—

—

Pain, Irritation lacrimation, blepharospasm, conjunctivitis

Cough, chest pain

—

Nausea, retching (may occur with CN or CS)

—

Irritation

Irritation, sneezing

Cough, chest pain

Burning pain, erythema Vesiculation (severe exposures) —

Headache

Nausea, vomiting, abdominal cramps

—

Mydriasis

Dry mouth

—

—

Miosis

—

Hypoventilation

—

Anticholinergic — delirium CNS depression —

Riot Control Agents  Lacrimators Immediate (CN, CS)   Capsaicin (OC)   Adamsite (DM)

Rapid (minutes)

Incapacitating Agents  3-Quinuclidinyl Delayed (hours) benzilate (BZ)  Ultrapotent Rapid opioids (seconds–minutes)

— —

— = not an expected major finding; ARDS = acute respiratory distress syndrome; CN = chloroacetophenone; CNS = central nervous system; CS = o-chlorobenzylidene malononitrile; GI = gastrointestinal.

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99

BIOLOGICAL WEAPONS

Expertise in dealing with biological weapons (BWs) requires specific knowledge from the fields of infectious disease, epidemiology, toxicology, and public health. Biological and chemical weapons share many characteristics in common, including intent of use, some dispersion methods, and initial defense based on adequate personal protective equipment and decontamination (Tables 98–2 and 98–3). However, key differences between biological and chemical weapons involve a greater delay in onset of clinical symptoms after exposure to BWs. Additionally, a few BWs can reproduce in the human host and cause secondary casualties, and disease after exposure to certain BWs can be prevented by the timely administration of prophylactic medications. Biological weapons may be bacteria, fungi, viruses, or toxins derived from microorganisms. Some fungi are listed as potential BWs; however, none are known to have been developed into weapons to date. Because toxin weapons are not living organisms, some authorities classify them as chemical weapons rather than BWs. For the purpose of discussion in this chapter, toxin weapons derived from microorganisms will be considered BWs.

HISTORY Biological warfare has ancient roots. Missile weapons poisoned with natural toxins were used as early as 18,000 years ago. Other uses of biological warfare before the modern era relied mainly on poisoning water supplies with natural toxins or spreading naturally occurring epidemic infections to the enemy by hurling infected corpses over battlements or through the intentional transfer of disease-contaminated goods (eg, smallpox-contaminated blankets). During World War I, Germany was the only combatant nation with an active BW program; however, by World War II, many nations had BW research programs, including Japan, the Soviet Union, Germany, France, Britain, Canada, and the United States (US). In 1979, an outbreak of human anthrax caused at least 66 fatalities in the Russian city of Sverdlovsk. Autopsies revealed that the deaths were from inhalational anthrax, and epidemiologic investigation demonstrated that almost all the cases occurred downwind from a military facility. These data were consistent only with a release of aerosolized anthrax, which has since been confirmed by Russian authorities. In 2001, closely following the September 11, 2001, attack, a bioterrorist attack occurred in the US resulting in several cases of inhalational and cutaneous anthrax, with five fatalities.

GENERAL CONSIDERATIONS Differences Between Biological Weapons Incidents and Naturally Occurring Outbreaks Because the clinical effects of BWs are often delayed for several days after exposure, it may be difficult to differentiate an occult BW release from a naturally occurring disease outbreak. Several epidemiologic criteria are proposed to aid in

such determinations, many of which should be identifiable in a BW incident (Table 99–1).

Preparedness Many BWs initially produce nonspecific symptoms, and diseases that rarely, if ever, occur in clinical practice. Inhalational anthrax and pneumonic plague, for example, could easily be misdiagnosed as influenza or acute bronchitis. Providers in emergency departments and primary care medicine should be educated to recognize the signs, symptoms, and clinical progression of diseases caused by BW. Clear identification, isolation, and aggressive treatment early after exposure within the first 24 to 48 hours are the best and only means of reducing mortality rates and, in the case of smallpox or plague, preventing secondary or tertiary cases.

Decontamination Biological weapons are most effective when dispersed by aerosol and, as such, produce little surface contamination. Simple removal of clothing will eliminate a high proportion of deposited particles, and subsequent showering with soap and water will probably remove 99.99% of any remaining organisms on the skin. Contaminated clothing should be removed and placed in airtight bags or containers to prevent resuspension in the air. After an occult BW release, victims are identified late after exposure; decontamination will obviously not be helpful and may only serve to delay care.

BIOLOGICAL WARFARE AGENTS Bacteria

Anthrax.  Anthrax is caused by Bacillus anthracis, a grampositive spore-forming bacillus found in soil worldwide. B. anthracis causes disease primarily in herbivorous animals. TABLE 99–1    Epidemiologic Clues Suggesting Biological Weapon Release • Large epidemic with unusually high morbidity, mortality, or both • Epidemic curve (number of cases vs time) showing an “explosion” of cases, reflecting a point source in time rather than insidious onset • Tight geographic localization of cases, especially downwind of potential release site • Predominance of respiratory tract symptoms because most BWs are transmitted by aerosol inhalation • Simultaneous outbreaks of multiple unusual diseases • Immunosuppressed and elderly persons more susceptible • Nonendemic infection (“impossible epidemiology”) • Nonseasonal time for endemic infection • Organisms with unusual antimicrobial resistance patterns, reflecting BW genetic engineering • Animal casualties concurrent with disease outbreak • Absence of normal zoonotic disease host • Low attack rates among persons incidentally working in areas with filtered air supplies or closed ventilation systems, using HEPA masks, or remaining indoors during outdoor exposures • Delivery vehicle or munitions discovered • Law enforcement or military intelligence information • Claim of BW release by a belligerent force BW = bioweapon; HEPA = high-efficiency particle absorbing.

710

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Human anthrax cases generally occur in farmers, ranchers, and among workers handling contaminated animal carcasses, hides, wool, hair, and bones.

Pathophysiology.  Inhaled spores are taken up into the lym-

phatic system, where they germinate and the bacteria reproduce. B. anthracis produces three toxins: protective antigen (PA), edema factor, and lethal factor. Protective antigen is so named because antibodies against it protect the individual from the effects of the other two toxins. Protective antigen forms a heptamer that inserts into plasma membranes, facilitating endocytosis of the other two toxins into target cells (Fig. 99–1). Edema factor increases intracellular cyclic adenosine monophosphate (AMP), upsetting water homeostasis, which leads to massive edema and impaired neutrophil function. Lethal factor is a zinc metalloprotease that stimulates macrophages to release tumor necrosis factor α and interleukin-1β, contributing to death in systemic anthrax infections. Treatment.  The primary antibiotics used to treat anthrax

are ciprofloxacin and doxycycline. Although other fluoroquinolones would be expected to have similar activity

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LF

EF PA x7

Clinical Manifestations. A few clinically distinct forms of

anthrax occur, depending on the route of exposure. Cutaneous anthrax results from direct inoculation of spores into the skin via abrasions or other wounds and accounts for about 95% of endemic (naturally occurring) human cases. Patients develop a painless red macule that vesiculates, ulcerates, and forms a 1- to 5-cm brown-black dermatonecrotic eschar surrounded by edema. Most skin lesions heal spontaneously, although 10% to 20% of untreated patients progress to septicemia and death. When treated with antibiotics, cutaneous anthrax rarely results in fatalities. Anthrax is not transmissible among humans. Gastrointestinal (GI) anthrax results from ingesting insufficiently cooked meat from infected animals. Patients develop nausea, vomiting, fever, abdominal pain, and mucosal ulcers, which can cause GI hemorrhage, perforation, and sepsis. The mortality rate from GI anthrax is at least 50%, even with antibiotic treatment. Inhalational anthrax results from exposure to aerosolized B. anthracis spores. Although this form of anthrax is very rare, it is so closely associated with occupational exposures that it is called “wool-sorter’s disease.” Inhalational anthrax is also likely to be the form that occurs in a BW attack because the anthrax spores would be most effectively disseminated by aerosol. After an incubation period of 1 to 6 days, the patient develops fever, malaise, fatigue, nonproductive cough, and mild chest discomfort. The initial symptoms may briefly improve for 2 to 3 days, or the patient may abruptly progress to severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Bacteremia; shock; metastatic infection such as meningitis, which occurs in about 50% of cases; and death may follow within 24 to 36 hours. Before the 2001 bioterrorist outbreak, the mortality rate from inhalational anthrax was expected to be nearly 100%, even with antibiotics, after symptoms develop. With appropriate antibiotic therapy and supportive care, 5 of 11 patients with inhalational anthrax in 2001 died.

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PA heptamer EF cAMP

EF ATPEdema toxin

PK LF Lethal toxin

LF

Inactive PK Active

FIGURE 99–1.  Model of action of anthrax toxins. Edema factor (EF) and lethal factor (LF) are unable to enter cells until they complex with a protective antigen (PA) heptamer, forming edema toxin and lethal toxin, respectively. When intracellular, release from PA allows EF and LF to exert their intracellular effects. Antibodies against PA confer resistance to the toxic effects of anthrax. ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; PK = protein kinase.

against anthrax, ciprofloxacin, levofloxacin, and doxycycline are US Food and Drug Administration (FDA)–approved for use in this infection. In a mass casualty setting or for postexposure prophylaxis, adults should receive ciprofloxacin 500 mg orally (PO) every 12 hours. Alternate therapies are doxycycline 100 mg PO every 12 hours or amoxicillin 500 mg PO every 8 hours if the anthrax strain is proven susceptible. The recommended duration of therapy is 60 days. Children should also be treated with ciprofloxacin (15 mg/kg; maximum, 500 mg/dose) or amoxicillin (80 mg/kg/day divided every 8 hours; maximum, 500 mg/dose). Cutaneous anthrax is treated similarly. Inhalational anthrax should be treated initially with intravenous antibiotics. Adults receive ciprofloxacin 400 mg intravenously (IV) or doxycycline 100 mg IV every 12 hours, along with one or two additional antibiotics with in vitro activity against anthrax (eg, rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, clarithromycin). Children are given ciprofloxacin 10 mg/kg IV (maximum, 400 mg/dose) or doxycycline 2.2 mg/kg IV (maximum, 100 mg/dose) and additional antibiotics, as indicated earlier. Raxibacumab and obiltoxaximab monoclonal antibodies that blocks binding of the anthrax PA to its host cell receptor and are US FDA approved for inhalational anthrax in combination with appropriate antibiotics. Anthrax Vaccine. An effective vaccine against anthrax is

available. In human and animal experiments, the vaccine is highly effective in preventing all forms of anthrax, and the vaccine is recommended for workers in high-risk occupations. Anthrax Immune Globulin Intravenous (Human) is also approved for use. Lessons from the 2001 Anthrax Bioterrorism Event.  Although

the overall number of individuals infected was relatively low, the psychosocioeconomic impact was exceptionally high. Several hundred postal and other facilities were tested for B. anthracis spore contamination, and public health authorities recommended antibiotic prophylaxis be initiated for approximately 32,000 persons. As predicted, the psychological impact far exceeded the actual medical consequences, and events with a modest number of medical patients are probably more likely than true mass casualty BW incidents.

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Published estimates of tens of thousands of deaths from a military-style anthrax attack depend on efficient BW dispersion. Plague.  Yersinia pestis is a gram-negative bacillus responsible for more than 200 million human deaths and three major pandemics in recorded history. Naturally occurring plague is transmitted by flea vectors from rodent hosts or by respiratory droplets from infected animals or humans. Bubonic plague could result from an intentional release of plague-infested fleas. Plague is a particularly frightening BW because it can be released as an aerosol to cause a fulminant communicable form of the disease for which no effective vaccine exists. Antibiotics must be initiated early after exposure because when symptoms develop, mortality rates are reportedly extremely high. Clinical Presentation.  Plague occurs in three clinical forms:

bubonic, septicemic, and pneumonic. Bubonic plague has an incubation period of 2 to 10 days, followed by fever, malaise, and painful, enlarged regional lymph nodes called buboes. Secondary septicemia occurs in 23% of patients presenting with bubonic plague. Distal gangrene occurs from small artery thromboses, explaining why plague pandemics are sometimes called the Black Death. If left untreated, bubonic plague carries a 60% mortality rate. Pneumonic plague is an infection of the lungs that occurs through septicemic spread of the organism or from inhalation of either infected respiratory droplets or an intentionally disseminated BW aerosol. The incubation period of pneumonic plague is 2 to 3 days after inhalation. Patients develop fever, malaise, and cough productive of bloody sputum, rapidly progressing to dyspnea, stridor, cyanosis, and cardiorespiratory collapse. Plague pneumonia is almost always fatal unless treatment is begun with 24 hours of symptom onset. Diagnosis and Treatment.  Plague can be diagnosed by var-

ious staining techniques, immunologic studies, or culturing the organism from blood, sputum, or lymph node aspirates. In a mass casualty setting or for postexposure prophylaxis, treatment should be with doxycycline 100 mg or ciprofloxacin 500 mg PO twice daily for adults. Children should be given doxycycline 2.2 mg/kg or ciprofloxacin 20 mg/kg, up to a maximum of the adult doses. Chloramphenicol 25 mg/kg PO four times daily is an alternative. The durations of treatment are 7 days for postexposure prophylaxis and 10 days for mass casualty incidents. Patients with pneumonic plague need to be isolated to prevent secondary cases. In a containedcasualty setting, patients with pneumonic plague should be treated with parenteral streptomycin or gentamicin; alternative antibiotics include doxycycline, ciprofloxacin, and chloramphenicol. Tularemia.  Francisella tularensis is a small, aerobic, gramnegative coccobacillus weaponized by the US and probably other countries as well. Tularemia occurs naturally as a zoonotic disease spread by blood-sucking arthropods or by direct contact with infected animal material. Tularemia in humans may occur in ulceroglandular or typhoidal forms, depending on the route of exposure. Ulceroglandular tularemia is more common, occurring after skin or mucous membrane exposure to infected animal blood or tissues.

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Patients develop a local ulcer with associated lymphadenopathy, fever, chills, headache, and malaise. Typhoidal tularemia presents with fever, prostration, and weight loss without adenopathy. Diagnosing tularemia is often difficult because the organism is hard to isolate by culture and the symptoms are nonspecific. In mass casualty settings or for postexposure prophylaxis, treatment should be doxycycline 100 mg twice daily or ciprofloxacin 500 mg PO twice daily for 14 days for adults. Pediatric dosing for doxycycline is 2.2 mg/kg or ciprofloxacin 15 mg/kg (maximum, adult dose) twice daily. When dealing with a limited number of casualties, the preferred antibiotics are streptomycin 1 g intramuscularly (IM) twice daily or gentamicin 5 mg/kg IM or IV once daily. Alternatives include parenteral doxycycline, chloramphenicol, and ciprofloxacin. Brucellosis.  Brucellosis could potentially be used as an incapacitating BW because it causes disease with low mortality but significant morbidity. Brucellae (Brucella melitensis, abortus, suis, and canis) are small, aerobic, gram-negative coccobacilli that generally cause disease in ruminant livestock. Humans develop brucellosis by ingesting contaminated meat and dairy products or by aerosol transmission from infected animals. Brucellosis presents with nonspecific symptoms such as fever, chills, and malaise, with either an acute or insidious onset. The diagnosis is established by serologic methods or culture. Patients should be given doxycycline 200 mg/day PO, plus rifampin 600 to 900 mg/day PO for 6 weeks, or doxycycline 200 mg/day PO for 6 weeks, with either streptomycin 15 mg/kg twice daily IM or gentamicin 1.5 mg/kg IM every 8 hours for the first 10 days. Rickettsiae.  Features of rickettsiae favoring their use as BW include environmental stability, aerosol transmission, persistence in infected hosts, low infectious dose, and high associated morbidity and mortality. Rickettsiae that have been weaponized include Coxiella burnetii, the causative organism of Q fever, and Rickettsia prowazekii, the causative organism of louseborne typhus. Q Fever.  Q fever occurs naturally as a self-limited, febrile, zoonotic disease contracted from domestic livestock. Q fever is caused by C. burnetii, a unique rickettsialike organism that can persist on inanimate objects for weeks to months and can cause clinical disease with the inhalation of only a single organism. After a 10- to 40-day incubation period, Q fever manifests as an undifferentiated febrile illness, with headache, fatigue, and myalgias. Patchy pulmonary infiltrates on chest radiography that resemble viral or atypical bacterial pneumonia occur in 50% of cases, although only half of patients have cough, and even fewer have pleuritic chest pain. Uncommon complications include hepatitis, endocarditis, meningitis, encephalitis, and osteomyelitis. Patients are generally not critically ill, and the disease can last as long as 2 weeks. Treatment with antibiotics will shorten the course of acute Q fever and can prevent clinically evident disease when given during the incubation period. Tetracyclines are the mainstay of therapy, and either tetracycline 500 mg PO every 6 hours or doxycycline 100 mg PO every 12 hours should be given for 5 to 7 days.

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CHAPTER 99 • BIOLOGICAL WEAPONS

Viruses

Smallpox.  Smallpox is caused by the variola virus, a large DNA orthopoxvirus with a host range limited to humans. Before global World Health Organization (WHO) efforts to eradicate naturally occurring smallpox by immunization, recurrent epidemics were common, and the disease carried roughly a 30% fatality rate in unvaccinated populations. Smallpox is highly contagious, with 10 to 20 secondary cases per index case. The Soviet Union is known to have weaponized smallpox, and other countries are believed to maintain stocks of variola virus. Pathophysiology.  Transmission of smallpox typically occurs

through inhalation of droplets or aerosols but may also occur through contaminated fomites. After a 12- to 14-day incubation period, the patient develops fever, malaise, and prostration with headache and backache. Oropharyngeal lesions appear, shedding virus into the saliva. Two to 3 days after the onset of fever, a papular rash develops on the face and spreads to the extremities (Fig. 99–2). The fever continues while the rash becomes vesicular and then pustular. Scabs form from the pustules and eventually separate, leaving pitted and hypopigmented scars. Death usually occurs during the second week of the illness. The diseases most likely to be confused with smallpox are chickenpox (varicella) and monkeypox. The lesions of smallpox should all appear at the same stage of development (synchronous), but chickenpox

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lesions occur at varying stages (asynchronous). Smallpox lesions tend to be found in a centrifugal distribution (face and distal extremities), but chickenpox lesions are more centripetal, tend to appear first on the trunk, and are pruritic. Until 2022 outbreaks of monkeypox were uncommon. This self-limited disease resembles smallpox except for the prognosis, which is excellent in immunocompromised individuals. Three antivirals commercially available in the US, cidofovir, tecovirimat, and ribavirin, are effective in vitro against variola. Even a single case of smallpox should be considered a potential international health emergency and immediately reported to the appropriate public health authorities. Smallpox Vaccination.  Rapid postexposure vaccination con-

fers excellent protection against smallpox. The older smallpox vaccine uses a live vaccinia virus (derived from cowpox vaccine) rather than the actual variola virus that causes smallpox. The two most serious reactions are postvaccinal encephalitis and progressive vaccinia. Progressive vaccinia (Fig. 99–3) can occur in immunosuppressed individuals and is treated with vaccinia immune globulin (VIG). The current vaccine contains a live, but replication-incompetent vaccinia virus, that was US FDA-approved in 2019. It is not associated with vaccinia infection. Viral Hemorrhagic Fevers.  Viral hemorrhagic fevers (VHFs) are all highly infectious by the aerosol route, making them candidates for use as BW. These include the viruses causing Lassa fever, dengue, yellow fever, Crimean-Congo hemorrhagic fever, and the Marburg, Ebola, and Hanta viruses. Clinical features, such as the extent of renal, hepatic, and hematologic involvement, vary according to the specific virus, but they all carry the risk of secondary infection through droplet aerosols. Ribavirin is reasonable for some VHFs, but supportive care is the mainstay of therapy. A vaccine for Ebola is now available. Viral Encephalitides.  Three antigenically related α viruses of the Togaviridae family pose risks as BWs: western equine encephalitis (WEE), eastern equine encephalitis (EEE), and Venezuelan equine encephalitis (VEE). Birds are the natural reservoir of these viruses, and natural outbreaks occur among equines and humans by mosquito transmission. Adults infected with VEE usually develop an acute, febrile, incapacitating disease with prolonged recovery.

FIGURE 99–2.  Smallpox rash demonstrating nonpruritic, synchronous tense vesicles.

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FIGURE 99–3.  Progressive vaccinia.

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Venezuelan equine encephalitis is considered the most likely BW threat among the viral encephalitides. After a 1- to 5-day incubation period, victims experience the sudden onset of malaise, myalgias, prostration, spiking fevers, rigors, severe headache, and photophobia. Nausea, vomiting, cough, sore throat, and diarrhea may follow. This acute phase lasts 24 to 72 hours. Between 0.5% and 4% of patients develop encephalitis, with meningismus, seizures, coma, and paralysis, which carries up to a 20% fatality rate. The diagnosis is usually established clinically, although the virus can sometimes be isolated from serum or from throat swabs, and serologic tests are available. The white blood cell count often shows a striking leukopenia and lymphopenia. Treatment is supportive. Person-to-person transmission can theoretically occur from droplet nuclei. Recovery takes 1 to 2 weeks.

Toxins Several toxins derived from bacteria, plants, fungi, and algae could theoretically be used as BWs if produced in sufficient quantities. Because of their high potency, only small amounts would be needed to kill or incapacitate exposed victims. Fortunately, obstacles in manufacturing weaponizable amounts limit the number of toxins that are practical for use as BWs. Discussion here is limited to those toxins known or highly suspected to have been weaponized. Botulinum Toxin.  The US and some other countries developed botulinum toxin as a potential BW. The two most likely means of using botulinum toxin are by food contamination or by aerosol. Either method would result in the clinical syndrome of botulism (Chap. 11). Ricin.  Ricin is derived from the castor bean plant (Ricinus communis) (Chap. 91) and is the only biological toxin to exist naturally in more than microscopic quantities. Its easy accessibility, relative ease of preparation, and low cost may make ricin an attractive BW for terrorists or poor countries. Although ricin has never been used in battle, it has attracted the attention of domestic extremists and terrorists and was used in some politically motivated assassinations. Ricin is a glycoprotein lectin (or toxalbumin) composed of two protein chains linked by a disulfide bond. The B chain facilitates cell binding and entry of the A chain into cells. The A chain inhibits protein synthesis, inactivating eukaryotic ribosomes by removing an adenine residue from ribosomal RNA. Inhalation of aerosolized ricin results in increased alveolar–capillary permeability and airway necrosis after a latent phase of 4 to 8 hours. Ingestion causes GI hemorrhage with necrosis of the liver, spleen, and kidney. Intramuscular administration produces severe local necrosis with extension into the lymphatics. Staphylococcal Enterotoxin B.  Staphylococcal enterotoxin B (SEB) is an enterotoxin produced by Staphylococcus aureus that is

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recognized as a “superantigen” because of its profound activation of the immune system. As a BW, SEB could be ingested through contaminated food or water, resulting in acute gastroenteritis identical to classic staphylococcal food poisoning. If inhaled as an aerosol, SEB produces fever, myalgias, and a pneumonitis after a 3- to 12-hour latent period.

Fungi and Other Fungal Toxins Fungi may at first appear to be ideal BW, given their relative ease of handling, dissemination, and resistance of spores to physical stressors. The only fungi to be included on lists of microbes with potential use as BWs are Coccidioides spp, probably based on the high incidence of symptomatic infection in endemic areas. Nevertheless, the risk of serious disease is low, limiting the utility of Coccidioides spp as an effective weapon. Among the fungal toxins, trichothecene mycotoxins, aflatoxins, and amanita toxins, only trichothecene mycotoxins are noteworthy. Trichothecene Mycotoxins. The trichothecene mycotoxins are produced by filamentous fungi (molds) of various genera, including Fusarium, Myrothecium, Phomopsis, Trichoderma, Tricothecium, and Stachybotrys. Tricothecene mycotoxins are unusual among potential BWs in that toxicity can occur with exposure to intact skin. Naturally occurring trichothecene toxicity results from ingesting contaminated grains or by inhaling toxin aerosolized from contaminated hay or cotton. Outbreaks of ingested trichothecene toxins result in a clinical syndrome called alimentary toxic aleukia, characterized by gastroenteritis, fevers, chills, bone marrow suppression with granulocytopenia, and secondary sepsis—a syndrome clinically similar to acute radiation poisoning. Survival beyond this stage is characterized by the development of GI and upper airway ulceration and intradermal and mucosal hemorrhage. Trichothecene toxins are potent inhibitors of protein synthesis in eukaryotic cells, producing widespread cytotoxicity, particularly in rapidly proliferating tissues. Several reports from the 1970s and 1980s suggested that Soviet-supported forces were using trichothecene mycotoxins as a BW. Aerosol and droplet clouds called Yellow Rain were associated with mass casualty incidents in Southeast Asia. Such incidents would involve multiple routes of exposure, with skin deposition likely being the major site. Early symptoms included nausea, vomiting, weakness, dizziness, and ataxia. Diarrhea would then ensue, at first watery and then becoming bloody. Within 3 to 12 hours, victims would develop dyspnea, cough, chest pain, sore mouths, bleeding gums, epistaxis, and hematemesis. Exposed skin areas would become intensely inflamed, with the appearance of vesicles, bullae, petechiae, ecchymoses, and necrosis. The use of trichothecene mycotoxins was never confirmed.

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100

RADIATION

We use radiation and radionuclides for a vast array of purposes, ranging from mundane household uses such as detecting smoke to powering satellites, treating cancer, and examining the physical properties of individual molecules. Unfortunately, as our knowledge of how to use radiation has expanded, so too has our awareness of radiation as a toxin. The particles of radiation, their sources, and the mechanisms by which they pose a health risk are the subjects of the following discussion.

HISTORICAL EXPOSURES Soon after x-rays were discovered in 1895, a deepening understanding of radiation and radionuclides led to their wider use and resulting injuries. Clarence Dally was the first known radiation-induced death in 1904 after repeated exposures to Thomas Edison’s early fluoroscopes. By 1927, nearly 100 women employed to create illuminated instrument dials became ill or died after exposure to radium-containing paint. After the use of the two atomic bombs in Japan at the end of World War II, estimates of dead and injured for both cities were well over 200,000. Most of the deaths were from the bomb blast, but many thousands died from acute radiation syndrome (ARS) and others subsequently from radiationinduced cancers. In the radioactive cobalt incident beginning in Juarez, Mexico, thousands of tiny metal pellets were spilled in a scrapyard and melted with other metals into table legs later shipped throughout Mexico and the United States (US). In the radioactive cesium incident in Goiânia, Brazil, scavengers were fascinated by the bluish glow of the material. Ultimately, 250 individuals were contaminated, 46 were treated with a chelator, and 4 died. More recently in the post–nuclear testing era, large radiation incidents occurred at the sites of nuclear reactors, such as Chernobyl in 1986 and Fukushima in 2011. Perhaps one of the most notorious deaths from radiation was that of Alexander Litvinenko, a former Soviet KGB operative who was living in London. It was only after a protracted illness and his death that radioactive polonium was discovered to be the cause.

PRINCIPLES OF RADIOACTIVITY Radiation is energy sent out in the form of waves or particles. Despite the strong nuclear force that holds atoms together, many isotopes are unstable. Various influences such as quantum fluctuations and the weak nuclear force can tip the balance toward instability to transform an isotope. This process can be intentional, as with the criticality events in a nuclear reactor or nuclear bomb, but mainly occurs spontaneously in nature as the process called radioactive decay.

Radioactive Decay In 1900, Marie Curie discovered that unstable nuclei decay or transform into more stable nuclei (daughters) via the emission of various particles or energy. Radioactive decay occurs mainly through five nuclear mechanisms: emission of gamma

rays, alpha particles, beta particles, or positrons or by capture of an electron. The emission of these various particles makes radioactive decay dangerous because these particles are ionizing radiation. The half-life (t1/2) is the period of time it takes for a radioisotope to lose half of its radioactivity. In every case, the activities of radioactive isotopes diminish exponentially with time (Table 100–1). Photons are elementary particles that mediate electromagnetic radiation. Depending on their energy, the radiation has different names ranging from extremely long radio waves to high-energy gamma rays. X-rays and gamma rays are high-energy photons and are only distinguishable by their source. Gamma radiation is emitted by unstable atomic nuclei via radioactive decay and has a fixed wavelength depending on the energy that formed it. X-rays come from atomic processes outside the nucleus. Because of their nature, high-energy gamma and x-rays can penetrate several feet of insulating concrete. Beta particles are electrons. Electrons have less penetrating ability than gamma radiation but can still pass several centimeters into human skin. Alpha particles are helium nuclei (two protons and two neutrons) stripped of their electrons. These particles are the most easily shielded of the emitted particles mentioned and can be stopped by a piece of paper, skin, or clothing. Neutrons are primarily released from nuclear processes. The natural decay of radionuclides does not include emission of neutrons, which is mainly a health hazard for workers in a nuclear power facility or victims of a nuclear explosion. Unique among the particles of radioactivity, when neutrons are stopped or captured,

TABLE 100–1    Physical Properties of Radioisotopes Isotope

Half-Life

Mode of Decay

Decay Energy (MeV)

Medicine and Research Radioisotopes 2 H Stable   131 I 8 days β– 201 Tl 73 hours EC 99m Tc 6 hours IT 133 Xe 5.27 days β– 67 Ga 78 hours EC 137 Cs 30.17 years β– 18 F 109 months β–, EC

  0.97 0.41 0.14 0.43 1.00 1.17 1.65

Military Radioisotopes 3 H 12.26 years 90 Sr 28.79 years 235 U 7.1 × 108 years 238 U 4.51 × 109 years 210 Po 138 days 239 Pu 24,400 years 241 Am 470 years

0.02 0.55 4.68 4.27 5.307 5.24 5.14/0.02

β– β– α, SF α, SF α α, SF α, γ

EC = electron capture; IT = isomeric transition from upper to lower isomeric state; MeV = megaelectron volts; SF = spontaneous fission. 715

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

they can cause a previously stable atom to become radioactive in a process known as neutron activation. Cosmic rays are streams of electrons, protons, and alpha particles thought to emanate from stars and supernovas. Isotopes and nuclides are very closely related terms, and most experts in the field use them interchangeably. Isotopes are two or more species or variants of a particular chemical element (same number of protons) that have different amounts of neutrons (eg, 123I, 125I, 127I, 131I). Nuclide is a more general term that may or may not be isotopes of a given element, such as fissile nuclides or primordial nuclides. Radioisotopes are isotopes that are radioactive, that is, they spontaneously decay and emit energy. Finally, radionuclides are simply nuclides that are radioactive.

Ionizing Radiation Versus Nonionizing Radiation Ionizing radiation refers to any radiation with sufficient energy to disrupt an atom or molecule with which it impacts. Hydroxyl free radicals, formed by ionizing water, are responsible for biochemical lesions that are the foundation of radiation toxicity. The space between collisions of ionizing radiation and their target molecules varies with the particle type and its energy. A charged particle, such as an alpha particle, loses kinetic energy through a series of small energy transfers to other atomic electrons in the target medium, such as tissues. Because of its large size, collisions along the path of an alpha particle are clustered together, impeding its ability to penetrate tissue. By comparison, collisions along the path of gamma rays are spread out, increasing their ability to penetrate tissue. This ability to penetrate tissue and transfer

Bq/Ci

Roentgens

energy accounts for the relative dangers of the forms of radiation and tissue susceptibility. For a source of radiation to pose a threat to tissue, the ionizing particle must be placed in close proximity to vital components of tissue to inflict damage. High-energy photons penetrate deeply, so they pose a similar risk whether they come from an external source or from an incorporated source. Because alpha particles have much more limited tissue penetration, alpha emitters, radionuclides that radiate these particles, must first be incorporated to pose a threat to tissue. Generally, nonionizing radiation consists of relatively low-energy photons and is used safely in cell phone and television signal transmission, radar, microwaves, and magnetic fields that emanate from high-voltage electricity and metal detectors. These photons lack the necessary energy required to cause ionization and cellular damage.

Radiation Units of Measure The units used to measure radiation are shown in Figure 100–1.

Protection from Radiation Shielding refers to the process by which one limits the amount of unwanted ionizing radiation in a given setting. Placing a specific material between a radiation source and a target will limit the amount of ionizing radiation that will interact with the target. Distance is an important safety factor in limiting radiation exposure. Because of their mass and electric charge, alpha and beta particles have a high probability of interacting with matter, such as the atmosphere. The result is that these particles do not travel more than a few centimeters through air and, in general, moving a few feet from the source of this

Gy/rad

Sv/rem

α β γ or Χ γ or Χ

The amount of radioactivity in a radionuclide can be described by the number of disintegrations per second, the becquerel (Bq), or by comparing the number of disintegrations to that of roughly 1g of 226radium, the curie (Ci). 1 Ci = 3.7 × 1010 Bq

Particles released during radioactive decay travel in all directions. Surrounding air is then ionized, producing an electrostatic charge, quantified by the roentgen (R).

Most of these particles pass through tissue without being absorbed. Only the fraction that is absorbed by tissue can cause cellular damage. This absorbed dose is measured in grays (Gy) and radiation absorbed doses (rad).

100 rad = 1 Gy

Different kinds of radiation produce different degrees of effect for the same absorbed dose. This dose equivalent, given in sieverts (Sv) or roentgen equivalents man (rem) is equal to the dose multiplied by a quality factor for the type of radiation. 100 rem = 1 Sv

FIGURE 100–1.  The definitions associated with radiation. Both curies and becquerels describe a quantity of radionuclide in terms of the number of disintegrations rather than mass. Roentgens describes the amount of charge per volume of air ionized by either γ- or x-rays, which indirectly quantifies the amount of radiation in the air around a source. Rads and grays (Gy) describe the fraction of radiation that actually interacts with cellular material and potentially causes injury. Roentgen equivalents man (rem) and sieverts (Sv) calculate the effective dose, taking into account the different particles. For example, a 100-keV alpha particle causes more damage to cellular material than a 100-keV beta particle.

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CHAPTER 100 • RADIATION

kind of radiation is enough protection by distance. However, x-rays and gamma rays are uncharged and have no rest mass, greatly reducing their probability of interacting with matter, resulting in an unlimited range in space. Photon radiation that is emitted from a point source diverges from that source to cover an increasingly wider area. For example, if the intensity of radiation 1 m from a source is 1 Gy, its intensity would be 0.11 Gy at 3 m from the source. Time of exposure is another important safety factor in limiting radiation exposure. Obviously, the longer a person is exposed to radiation, the greater the exposure.

Irradiation, Contamination, and Incorporation An object is irradiated when it is exposed to ionizing radiation. The risk of tissue damage depends on the total amount of radiation and the tissue type because each tissue type has its own intrinsic resistance to radiation damage. An irradiated object does not become radioactive itself unless exposed to neutrons, and therefore, irradiated individuals pose no risk to others. Contamination occurs when a radioactive substance covers an object completely or in part. In these similar cases, the source of radiation is the nuclide undergoing its normal decay process, and the individual is exposed to particles such as those mentioned in Table 100–1. The risk of tissue damage from the radiation particles is usually quite low, assuming that the contamination is detected and appropriate measures for decontamination are instituted. Incorporation occurs when a radionuclide is taken up by tissue via some route that permits the radionuclide to enter the body. This principle is used in many diagnostic and therapeutic procedures such as a thallium stress test, gallium scan, or thyroid ablation therapy. Depending on the dose and type of radionuclide, incorporation may lead to tissue damage. TABLE 100–2   Annual Estimated Average Effective Dose Equivalent in the United States Dosea Source

mSv/year

mrem/year

% of Total Dose

Natural  Cosmic  Internal  Radonb  Terrestrial   Subtotal

0.27 0.31 2.29 0.19 3.10

27 31 233 19 310

5 5 37 3 50

Human-Made   Consumer products   Nuclear medicine  Occupational   Medical procedures   Subtotal Total

0.12 0.74 < 0.01 2.23 3.10 6.20

12.4 74.4 0.62 223.2 310 620

2 12 0.1 36 50 100

All doses are averages and contain some variability within the measurement. Average effective dose to bronchial epithelium. mSv = millisieverts; mrem = millirem. Data from Mettler FA, Bhargavan M, Faulkner K, et al. Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources—1950-2007. Radiology. 2009;253(2):520-531. a

b

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EPIDEMIOLOGY Everyone is exposed to radiation in one form or another each day (Table 100–2). In the US, the estimated annual dose equivalent of radiation is now considered to be 6.2 mSv, a number revised sharply upward by the National Council on Radiation Protection and Measurement (NCRP) in 2009.

Natural Sources of Radiation A wide variety of natural sources expose humans on a daily basis to ionizing radiation. Terrestrial sources of radiation originate from radionuclides in the Earth’s crust that move into the air and water. Radon, a radioactive noble gas, accounts for most of the human exposure to radiation from natural sources. This gas, a natural decay product of uranium and thorium, enters homes and other buildings from the building materials themselves or through microscopic cracks in the building’s structures. With a relatively short half-life of 3.82 days, 222 Rn poses a health risk if decay occurs while in the respiratory space and one of its solid daughter isotopes deposits on respiratory tissue. These radon daughters emit alpha particles as they decay and are the principal causes in the associated increased incidence of lung cancer in those exposed to radon. The second largest natural source of radiation originates from ingested radionuclides, of which 40K, a naturally occurring isotope, is the most abundant. The lifetime cancer mortality risk calculated for 40K is 4 in 100,000 from external exposure.

Human-Made Sources The estimated annual dose of radiation exposure from humanmade sources of radiation is increasing, largely from the steeply rising use of computed tomography (CT) (Table 100–3). One retrospective study found an increased relative risk of these cancers resulting from accumulated doses of just a few CT scans. Perhaps influenced by data like these, accompanied by increased availability of other alternative imaging modalities, such as magnetic resonance imaging, several studies report trends of decreasing use of CT for children. Nuclear Occupational Exposure.  Estimates of the annual number of workers occupationally exposed to radiation worldwide are several million. On average, the occupations with the highest exposures (about 4 mSv/year) are uranium miners and millers. Despite the many factors that play a role in occupational exposure at more than 1,200 nuclear reactors worldwide, the estimated effective dose to measurably exposed workers fell to 2.7 mSv/year. Medical occupational exposure principally includes physicians, nurses, radiology technologists, and laboratory workers who receive an additional effective dose of about 0.5 mSv/year. Fluoroscopy constitutes less than 10% of all examinations in the US but remains the largest source of occupational exposure in medicine. Worldwide, nearly 500,000 workers are monitored for exposures during dental radiography, but the annual effective dose averaged over 5 years has declined to 0.05 mSv. Depleted uranium (DU) is used by the US military and by several other governments. Uranium ore mined from the earth is about 99% 238U and 1% 235U. Enrichment involves separating the isotopes so that 235U can be used as nuclear fuel

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TABLE 100–3   Diagnostic Imaging Procedures: Type and Amount of Radionuclide or Radiation Amount Test

Radionuclide

Thyroid scan

123

Cardiac stress-rest test

201

Lung perfusion

99m

Lung ventilation

133

Bone scan

99m

Gallium scan

67

Tumor (PET)

18

Effective Dose

MBq

mCi

mSv

mrem

I

25

0.68

1.9

191

Tl

185

5

40.7

4,070

Tc

185

5

2.0

200

Xe

740

20

0.5

50

Tc

1,110

30

6.3

630

Ga

150

4.05

15

1,500

F

740

20

14.1

1,410

Radiographs Posteroanterior and lateral study of the chest Abdomen Pelvis Lumbar spine ERCP

0.1 0.7 0.6 1.5 4.0

10 70 60 150 400

Computed Tomography Head Cervical spine Chest Chest for pulmonary embolism Abdomen Pelvis Coronary angiography

2 3 7 15 8 6 16

200 300 700 1,500 800 600 1,600

ERCP = endoscopic retrograde cholangiopancreatography; MBq = megabequerel; mCi = millicuries; mSv = millisievert; mrem = millirem; PET = positron emission tomography.

and the leftover 238U can be used in munitions. Consequently, although DU is radioactive, it is 40% less so than naturally occurring uranium. The Depleted Uranium Follow-Up Program that has surveyed exposed veterans since 1994 has not discovered any consistent, clinically significant illness.

EXPOSURE LIMITS The Nuclear Regulatory Commission (NRC) established the “Standards for Protection against Radiation,” which regulates radiation exposures using a twofold system of dose limitation: doses to individuals shall not exceed limits established by the NRC, and all exposures shall be kept as low as reasonably achievable (ALARA). The total effective dose equivalent may not exceed 50 mSv/year to reduce the risk of stochastic effects (see Stochastic Versus Deterministic Effects of Radiation). The dose to the fetus of a pregnant radiation worker may not exceed 5 mSv over 9 months and should not substantially exceed 0.5 mSv in any 1 month.

Ionizing Radiation (BEIR) Committee, the International Commission on Radiological Units and Measurements (ICRU), the Radiation Effects Research Foundation (RERF), and the International Radiation Protection Association (IRPA). National regulatory agencies include the NRC, Environmental Protection Agency (EPA), Occupational Safety and Health Administration (OSHA), and Food and Drug Administration (FDA). The Oak Ridge Institute for Science and Education (ORISE) supports the NRC by maintaining the NRC website for Radiation Exposure Information and Reporting System (REIRS) and the database of radiation exposure from NRC licensees (http://www.reirs.com). The Oak Ridge Institute for Science and Education’s Radiation Emergency Assistance Center/Training Site (REAC/TS) and the International Atomic Energy Agency (IAEA) both maintain radiation incident registries that track US and foreign radiation incidents.

PATHOPHYSIOLOGY Ionizing radiation causes damage to tissue by several mechanisms called direct or indirect effects. Direct effects are when particles physically damage the DNA in a cell. When this kind of damage occurs, a mutation can arise, which may then result in alteration of a germline, development of a neoplasm, or cell death. The risk of these consequences overall, however, is low because of the relative paucity of DNA within a cell, the even smaller percentage of active DNA within a given cell, and the ability of DNA to repair itself. Although DNA represents a low-probability target for radiation, the rest of the cell media represents a higher probability target. Indirect effects are when radiation impacts a molecule and creates a reactive species, which then chemically reacts with organic molecules in cells altering their structure or function. Water, which is in great abundance within cells, can transform into a hydroxyl radical (OH·) after interaction with incident radiation. The bystander effect refers to cellular damage in unirradiated cells proximate to irradiated cells. Studies demonstrate the bystander effect for proton beams, x-rays, and low energy transfer radiation. Genomic instability is a single mutation followed by a cascade of further mutations altering the fidelity of genomic replication. Although any molecule can be damaged in a variety of ways that may lead to cell injury of varying severity, double-stranded breaks in DNA are the type of damage most likely to cause chromosomal aberrations or cell death. Dose–response relationships for mutation are approximately linear down to about 25 mGy, the statistical limit of these studies. Although repair mechanisms reduce substantially the radiation risk of mutation, there is no evidence yet that these mechanisms eliminate those risks at low doses, although some question this conclusion.

REGULATION AND REPORTING

STOCHASTIC VERSUS DETERMINISTIC EFFECTS OF RADIATION

The use of ionizing radiation, radiation sources, and the by-products of nuclear energy are among the most heavily regulated processes worldwide. Among the international groups are the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the International Commission on Radiological Protection (ICRP), the Biological Effects of

The radiation damage just described has two consequential results: it kills cells, or it alters cells and causes cancer. Injuries that do not require a threshold limit to be exceeded include mutagenic and carcinogenic changes to individual cells in which DNA is the critical and ultimate target. This is the stochastic effect of radiation. Theoretically, there is no dose

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of radiation too small to have the potential of causing cancer in an exposed individual. Whereas the stochastic effects of radiation can follow less severe exposures, the deterministic effects of radiation usually follow a large whole-body exposure. In terms of cell death, a relatively large number of cells of an organ system must be killed before an effect becomes clinically evident. This number of killed cells constitutes a threshold limit that must be exceeded, and this is what is known as the deterministic or nonstochastic effects of radiation.

ACUTE RADIATION SYNDROME Acute radiation syndrome (ARS) involves a sequence of events that varies with the severity of the exposure. Generally, more extensive exposures lead to more rapid onset of symptoms and more severe clinical features. Four classic clinical stages are described, which begin with the early prodromal stage of nausea and vomiting. Although the time to onset postexposure is inversely proportional to the dose received, the duration of the prodromal phase is directly proportional to the dose. That is, the greater the dose received, the more rapid the onset of symptoms, and the longer their duration, except in cases in which death follows rapidly. The latent period follows next as an apparent improvement of symptoms, during which time the patient appears to have recovered and has no clinically apparent difficulties. The duration of this stage is inversely related to dose and can last from several days to several weeks. The third stage usually begins in the third to fifth week after exposure and consists of manifest illness described in subsequent paragraphs. If the patient survives this stage, recovery, the fourth stage, is likely but can take weeks to months before it is completed. Those exposed to supralethal amounts of radiation can experience all the phases in a few hours before a rapid death. The cerebrovascular syndrome describes the manifestations of injury to the central nervous system after massive irradiation. This syndrome, after exposure to doses of about 15 to 20 Gy or greater, is characterized by rapid or immediate onset of hyperthermia, ataxia, loss of motor control, apathy, lethargy, cardiovascular shock, and seizures. The mechanism of this injury may be a combination of radiation-induced vascular lesions and free radical–induced neuronal death and cerebral edema. The pulmonary system is not spared injury from irradiation. Pneumonitis can occur within 1 to 3 months after a dose of 6 to 10 Gy. This can lead to respiratory failure, pulmonary fibrosis, or cor pulmonale months to years later. The gastrointestinal (GI) syndrome begins after an exposure to about 6 Gy or more when GI mucosal cell injury and death occur. Findings and effects include anorexia, nausea, vomiting, and diarrhea. As the mucosal lining is sloughed, there is persistent bloody diarrhea, hypersecretion of cellular fluids into the lumen, and a loss of peristalsis, which can progress to abdominal distension and dehydration. Destruction of the mucosal lining allows for colonization by enteric organisms with ensuing sepsis. The hematologic changes that occur after an exposure to about 1 Gy or greater are called the hematopoietic syndrome. Hematopoietic stem cells are highly radiosensitive, in contrast to the more mature erythrocytes and platelets.

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Lymphocytes are also radiosensitive and can die quickly from cell lysis after an exposure. The main effect of radiation-induced hematopoietic syndrome is pancytopenia, leading to death from sepsis complicated by hemorrhage. The lymphocyte nadir typically occurs 8 to 30 days postexposure, with higher doses achieving earlier nadir. The cutaneous syndrome, a local radiation injury, can develop shortly after exposure or can take years to manifest fully. Target cells include all layers, including the epidermis, hair follicle canals, and subcutaneous tissue. Signs and symptoms include bullae, blisters, hair loss, pruritus, ulceration, and onycholysis. Skin injury ranges from epilation beginning at doses of 3 Gy to moist desquamation at about 15 Gy, to necrosis at greater than 50 Gy.

DOSE ESTIMATION Determining an accurate dose of radiation exposure is critical to providing the best care for the irradiated patient because increasing radiation exposure will affect different organ systems, call for different therapies, require different levels of monitoring, and assign different prognoses. Biodosimetry is the use of physiological, chemical, or biological markers to reconstruct radiation doses to individuals or populations and assess the probability of developing ARS. Key elements of dose estimation include time to onset of vomiting, lymphocyte depletion kinetics, and chromosomal assays. Today, there are numerous tools available on the Internet to assist with dosimetry, including the Biological Assessment Tool available at the Armed Forces Radio-biology Research Institute’s website (https://www.usuhs.edu/afrri/ biodosimetrytools), guidelines from the International Atomic Energy Agency, the Radiation Emergency Medical Management website (https://www.remm.nlm.gov), and the CDC guidance (https://www.cdc.gov/nceh/radiation/emergencies/ clinicians.htm).

CARCINOGENESIS Radiation was recognized as a carcinogen soon after it was initially discovered in 1895. After decades of research, including animal models, epidemiologic studies, and the lifespan studies of Japanese nuclear bomb survivors, radiation was shown to be a “universal carcinogen” able to induce tumors in nearly every tissue type in nearly every species at all ages.

COMMONLY ENCOUNTERED RADIONUCLIDES Americium (symbol Am, atomic number 95, and atomic weight 243) was discovered in 1944 in Chicago during the Manhattan Project. Its most stable nuclide, 243Am, has a halflife of more than 7,500 years, although 241Am, with a half-life of 470 years, decays by alpha and gamma emission and will accumulate in bone if incorporated. It is used to test machinery integrity, glass thickness, and in smoke detectors (about 0.26 μg per detector). Cesium (symbol Cs, atomic number 55, and atomic weight 132) was discovered by Bunsen in 1860. It decays by beta and gamma emissions and is used as a radiation source in radiation therapy and as a radionuclide source for atomic clocks.

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Iodine (symbol I, atomic number 53, and atomic weight 126.9) was discovered by Courtois in 1811. Of the 23 isotopes of iodine, 127I is the only one that is stable. 129I and 131I are fission products that are released into the environment during an event. These isotopes will accumulate in thyroid tissue if incorporated and can cause local damage to thyroid tissue. Polonium (symbol Po, atomic number 84, and atomic weights range from 192 to 218) was discovered by Marie Curie. Polonium has 27 isotopes, the most isotopes of all the elements, and all are radioactive. The short half-life of 210Po, 138 days, and high specific activity of 4,490 Ci/g means it emits a great deal of high-energy alpha particles (5.3 MeV) that produce 140 W/g. For example, a capsule containing 500 mg of 210Po reaches a temperature of 932°F (500°C). Radon (symbol Rn, atomic number 86, and atomic weights range from 204 to 224) was discovered in 1900 by Dorn and is the heaviest noble gas. 222Radon decays by alpha and gamma emissions. Exposure of radon gas to the pulmonary epithelium is associated with an increased incidence of lung cancer in both uranium miners and in those who dwell in residences with increased concentrations of radon. Damage to bronchial epithelium results from the alpha emissions of radon and radiation from radon daughters that precipitate as solids and remain in the lungs. Technetium (symbol Tc, atomic number 43, and atomic weight 98.9) was discovered in 1937 and was the first element to be produced artificially. Unusual among the lighter elements, Tc has no stable isotopes and is therefore found on earth as a product of spontaneous uranium fission. Most human contact with Tc is in medical scans in which Tc has a biological half-life of about 1 day. Thallium (symbol Tl, atomic number 81, and atomic weight 204) was discovered by Crookes in 1861. 201Tl is used for cardiac imaging, has a half-life of 73 hours, and decays by electron capture and gamma emission. Tritium is an isotope of hydrogen whose nucleus contains one proton and two neutrons, and its symbol is 3H. Tritium decays by beta activity and is used in basic science research as a radioactive label, for luminous dials, and for self-powered exit signs, which can contain as much as 9.3 × 1011 Bq (25 Ci). Tritium has a half-life of 12.3 years. Tritium emits very weak radiation in the form of 18.6 KeV beta particles, which are easily stopped by thin layers of material, and is safe for glowin-the-dark watches. When absorbed as tritiated water, tritium tends to follow the water cycle in humans, providing a whole-body dose if incorporated.

MANAGEMENT Initial Assessment and Early Triage The initial management of patients exposed to radiation will depend on a number of factors, including the amount of radiation in the exposure and the number of casualties in the event. Small-scale exposures to radiation still require at least a brief evaluation for burns and trauma, depending on the circumstances surrounding the nature of the exposure. Calls to the poison center from a residence require referral to emergency services for an expert evaluation of the extent of the contamination of the site and appropriate decontamination

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measures. Exposures in the laboratory or nuclear medicine suites require referral to the radiation safety officer (RSO) in the building for a similar evaluation. When considering a local incident involving nuclear material, first responders will likely include a hazardous materials team (HAZMAT) and local police and fire departments. Hospitals should involve their RSO, and public officials will involve a state agency such as the State Department of Environmental Protection. As part of its primary mission for the US Department of Energy, REAC/TS offers consultation with anyone on a 24/7 basis on questions regarding radiation exposure. Its emergency phone number is 865-576-1005 (ask for REAC/TS). For large incidents, other federal agencies will be involved led by the Federal Emergency Management Agency. Additional radiation expertise can be provided via the Department of Energy, and if applicable, the Federal Bureau of Investigation will be called to protect against further threats. In a mass casualty event, established prehospital plans should be followed to provide the best management for the large numbers of variably injured given that an explosion of potentially catastrophic size also accompanies the radiation exposure. First responders must use universal precautions and should assume that all victims are contaminated; most events will only require C- or D-level protection (Chap. 101). Field triage protocols tailored to the kind of event in question will designate patients as minor, delayed, immediate, or deceased and should not be altered because of radiation exposure. Preliminary decontamination, including removal of clothing and washing the victim, should be performed before transportation to a medical facility, taking care not to contaminate prehospital providers or equipment. Uninjured patients who are contaminated should be relocated upwind of the incident site for further care.

Initial Emergency Department Management It is not considered a medical emergency to have been irradiated or contaminated; even highly irradiated patients take days to die, which is why standard protocols regarding trauma and other medical complaints continue to be followed even in mass casualty events. In the event of a radiation incident, there will likely be little warning of these patients arriving, and information will be incomplete. Ideally, the emergency department (ED) is divided into clean and dirty areas where the floor of the dirty area is covered by plastic or butcher’s paper. Staff should don surgical scrubs, gowns, surgical caps, masks, booties, and face shields. Two sets of gloves should be worn, with the inner set taped to the gown. Dosimeters should be worn at the neck for easy access by the RSO, and staff should be reminded that medical personnel have never received a medically significant acute radiation dose when caring for an exposed patient. When patients arrive to the ED, it is essential to follow an algorithm that takes into account issues of irradiation or contamination and includes data collection specific to biodosimetry. One such algorithm is the REAC/TS patient treatment algorithm at https://orise.orau.gov/reacts/infographics/ radiation-patient-treatment-algorithm.pdf. Physical examination, in addition to airway, breathing, and circulation, should

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CHAPTER 100 • RADIATION

focus on vital signs, skin (erythema, blisters, desquamation), GI symptoms (abdominal pain and cramping), neurologic findings (ataxia, headache, motor or sensory deficits), and hematologic signs (ecchymoses or petechiae). Vomiting very early after exposure is considered a sign of the central nervous system subsyndrome and is a poor prognostic indicator. Recommended initial laboratory testing includes baseline complete blood count (CBC) with differential (including an extra sample in a heparinized tube for cytogenetics), serum amylase (increased from specific salivary gland inflammation and degeneration), urinalysis, baseline radiologic assessment of urine, and starting a 24-hour urine collection. Nasal swabs, emesis, and stool should be collected for radiologic monitoring. For patients with persistent vomiting, erythema, or fever, a repeat CBC with differential is recommended every 4 to 6 hours. If a patient requires surgery, we recommendation that surgery proceed immediately because of the delayed and impaired wound healing expected as a result of decreases in leukocytes and platelets.

Decontamination When a patient is medically stable, decontamination should proceed. Patients who were not decontaminated in the prehospital setting but who are grossly contaminated should be fairly easily detected as such by a quick evaluation with an appropriate instrument. As a first step, all clothing should be removed gently by cutting and not tearing as is typically done for trauma patients. Rolling supine patients allows contaminated clothes to be carefully gathered and bagged and marked. Bagged clothes and other contaminated articles should be removed from the ED to a site designated by the RSO so as not to present another source of radiation. A portable dosimeter should assist in external decontamination. After clothing removal, remonitor the patient for contamination, paying attention to exposed areas such as hair. Contaminated hair should be washed with soap and water before washing the body to avoid trickle-down contamination. For patients with contaminated wounds, decontamination should prioritize the wound first, then body orifices around the face, and then intact skin. Always wipe gently away from the wound. Irrigate gently to reduce splashing. Care must be taken not to abrade skin by excessively vigorous scrubbing or shaving of hair. For patients with smaller exposures to radionuclides, such as laboratory workers, decontamination is often the only management technique required to limit injury. Portable dosimeters will identify contaminated areas, which should be sealed off to limit spread of exposure, especially if the radionuclide is in gaseous form. As with larger exposures, contaminated clothing must be removed and collected. Contaminated skin must be washed with lukewarm soap and water, repeatedly if needed.

Medical Decision Making Exposure to radiation can lead to a complex spectrum of organ damage that can be difficult and confusing for physicians when creating a treatment plan. Establishment of guidance in the form of a response category (RC) helps clarify a medical plan and disposition (Table 100–4). (For specific suggestions, refer to the interactive version of this assessment tool at the REMM’s website at http://www.remm.nlm.gov.)

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Medical Management Supportive care quality will determine the extent of the morbidity and mortality. The majority of patients with ARS who succumb usually do so from fluid loss, infection, or bleeding. Irradiated patients require treatment for nausea and vomiting, diarrhea, pain, and fluid and electrolyte losses. Vomiting is thought to occur as a result of serotonin release from damaged gut tissue. The 5-HT3 antagonists are the most effective medications to control vomiting. Loperamide, anticholinergics, and aluminum hydroxide are reasonable to treat diarrhea. Mild pain should be managed with acetaminophen, but we recommend against the use of aspirin and nonsteroidal drugs because they exacerbate gastric bleeding. An opioid is recommended for the management of more severe pain. Probiotic use introduces selective nonpathogenic strains of Lactobacillus and Bifidobacteria into the GI tract to suppress the number of pathogens. Based on the existing data, it would be reasonable to treat patients who develop diarrhea with probiotics. Intravenous access should be established and maintained with care because these patients are prone to infection. Fluid replacement begins with crystalloid solution with the goal of replacing GI losses. Cutaneous injuries are cared for depending on the nature, location, and extent of the wounds. Surgical consultation or referral to a burn center should be offered early in the clinical course. Prevention of infection includes attention to several aspects of care. Maintain the patient in a clean environment and institute reverse isolation for patients with at least moderate exposure or when neutrophil counts decline below 1,000/µL. Prophylactic antibiotics and antifungals are recommended for neutropenic patients, as well as acyclovir or a similar antiviral for herpes simplex virus–positive patients. If neutropenic patients become febrile, we recommend following the Infectious Diseases Society of America guidelines for antibiotic choices. It is reasonable to administer broad-spectrum prophylactic antibiotic coverage, including anaerobic coverage, for patients with burns. Cytokine therapy (colony-stimulating factor {CSF}) use in radiation-exposed patients is based on demonstrated enhancement of neutrophil recovery in patients with cancer, a perceived benefit in a small number of radiation-incident victims, and several prospective trials using different animal models involving radiation exposure. Colon stimulating factors such as filgrastim should be started as soon as possible for patients exposed to a survivable dose of radiation who are at risk for hematopoietic syndrome, that is, more than 3 Gy. Use of blood products is required for patients with significant blood loss or for those experiencing radiation-induced aplasia. Use of leukoreduced and (ironically) irradiated blood products should be the rule to prevent transfusion-associated graft-versus-host disease. Stem cell transplantation (SCT) can be used to treat patients with severe bone marrow injury, but the decision to use this therapy is very complicated. If conditions are favorable and resources are available, it would be reasonable to attempt SCT in patients with a severe radiation exposure who have an otherwise grave prognosis.

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TABLE 100–4    Grading System for Organ System Dysfunction and Response Category for Disposition Symptom

Degree 1

Degree 2

Degree 3

Degree 4

Neurovascular System Anorexia Nausea Vomiting Fatigue Fever Headache Hypotension (BP, mm Hg) (Adult) Cognitive deficits Neurological deficits

Able to eat Mild 1/day Able to work (< 38°C) Minimal > 100/70 Minor Barely detectable

Decreased Moderate 2–5/day Impaired (38°–40°C) Moderate < 100/70 Moderate Easily detectable

Minimal Severe 6–10/day Assisted ADLs (> 40°C) < 24 hours Severe < 90/60 Major Prominent

Parenteral Excruciating > 10/day No ADL (> 40°C) > 24 hours Excruciating < 80 systolic Complete Life threatening

Hematopoietic System (all counts × 109/L) Lymphocytes Granulocytes Platelets

1.5–3.5 4–9 150–350

0.5–1.5 < 1a 50–100

0.25–1 < 0.5a 0–50

0.1–0.25 0–0.5 Very lowb

Gastrointestinal System Diarrhea   Frequency (/day)  Consistency  Bleeding Abdominal cramps/pain

2–3 Bulky Occult Minimal

4–6 Loose Intermittent Moderate

7–9 Loose Persistent Severe

≥ 10 Watery Large, persistent Excruciating

Cutaneous System Erythema Edema Blistering Desquamation Ulceration or necrosis Hair loss

Minimal Asymptomatic Rare, sterile Absent Epidermal Absent

< 10% BSA Symptomatic Rare, bloody Patchy, dry Dermal Partial

10%–40% BSA Secondary dysfunction Bullae, sterile Patchy, moist Subcutaneous Partial

> 40% BSA Total dysfunction Bullae, bloody Confluent, moist Muscle or bone Complete

Response Category

1

2

3

4

Triage and Monitoring

Ambulatory

Ambulatory vs. hospitalized

Hospitalized ICU

Hospitalized Specialized hospitalsc

 

 

Supportive care Blood products

Blood products CSFs

Blood products CSFs or SCT

An abortive rise in cell counts begins between days 5 and 10, which lasts about 8 to 12 days. Afterward, cell counts decline slowly, reaching a nadir around day 20. bCell counts decline faster, reaching lower nadir for more severe exposures at about days 22, 16, and 10 for grades 2 to 4. c”Specialized hospitals” refers to those with experience in all areas of intensive care medicine, particularly allogenic stem cell transplantation (SCT). ADL = activity of daily living; BP = blood pressure; BSA = body surface area; CSF = colony-stimulating factor; ICU = intensive care unit. a

Management of Internal Contamination

PROGNOSIS

Internal contamination cases are assessed differently from external doses in that they are not measured but rather are calculated. These calculations are performed by a health physicist on samples such as nasal swabs, urine, or stool to estimate how much activity entered the body. Doses are termed committed doses, defined as the doses received that last more than 50 years because of the internal deposit of the radionuclide. That is, the radionuclide dose is protracted and remains until it decays or is eliminated via normal kinetic processes. These doses are compared with the annual limits on intake (ALIs) provided by the EPA as a benchmark for medical decision making. Interpretation of committed doses from contaminated wounds requires special conversion factors provided by the NCRP. Management of internal contamination is isotope dependent (Antidotes in Brief: A44 and A45).

Survival is inversely proportional to the radiation dose absorbed. Historically, the mean lethal dose required to kill 50% of humans at 60 days was about 3.5 Gy without supportive care. The addition of antibiotics and blood products increases that mean to 6 to 7 Gy. This dose is likely to be even higher for those treated early with CSFs in a specialized hospital. An acute dose of 20 Gy or more is considered supralethal. During a catastrophic radiation incident, resources will likely become depleted to the extent that not all patients who require certain medical treatments to survive will be able to receive them. The REMM Scarce Resources Triage Tool is available online for assistance in evaluating a patient’s prognosis, in which a patient’s injury extent may indicate an expectant prognosis, assisting clinicians to help those who may survive instead.

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CONSIDERATION OF THE DECEASED Contaminated bodies should be placed in a temporary morgue that is refrigerated. Use of the hospital morgue will lead to contamination there. These bodies should not be cremated because this will only redistribute the nuclear material, which is not destroyed by fire.

PREGNANCY AND RADIATION In general, radiation effects to an embryo or fetus are dependent on its stage of development and the dose received. The medical decision to perform imaging or a diagnostic procedure that exposes any patient to radiation is always based on a risk-to-benefit analysis with a given patient’s situation. Very early in a pregnancy before implantation, the embryo is in an “all-or-none” period of development in which the greatest risk from radiation is miscarriage but not greater than baseline risk. Older than this, the fetus is next at greatest risk between 8 and 15 weeks of gestation, during which major neuronal migration takes place. The NCRP considers risk to fetuses to be negligible compared with other risks of pregnancy when the dose to a fetus is less than 50 mGy (5 rad), which corresponds to 50 mSv from x-ray examination, compared with about 6 mSv effective dose from a CT examination of the pelvis. The risk of malformation is increased only at doses above 150 mSv. The vast majority of routine diagnostic imaging procedures impart

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less than 5 mSv to a fetus, increasing baseline risk by about 0.17%. Shared decision making should always balance the potential maternal benefit of the radiologic procedure and the potential risk to the fetus.

PEDIATRICS AND RADIATION The use of CT scanning in children has markedly increased over the past 30 years. Estimates calculate an increased risk of lifetime mortality rate in the range of 0.04% for a head CT for a young female patient (1 in 2,500) compared with a normal lifetime cancer mortality risk of 20% (1 in 5). This excess relative risk was supported by a large retrospective study of a pediatric population that found increased incidence of certain leukemias and certain brain tumors attributed to CT scans over a 23-year period. Radiographic studies should continue to be ordered in the best interest of the patient, although it is likely that the number of scans performed could safely be diminished without compromising care. Reports on this topic commonly include problems with ordering unnecessary multiple CTs, follow-up CT scans, and CT scans that occur simply because of a lack of communication among the patient, healthcare professional, and technician. These problems, compounded by inappropriate CT protocol for pediatric patients, suggest that the medical community must be more proactive in reducing the health risk of those in our charge.

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A44

Antidotes in Brief

POTASSIUM IODIDE

INTRODUCTION

Pharmacokinetics

Potassium iodide (KI) is the antidote to radioactive iodine that is released into the atmosphere after a nuclear incident. It functions as a competitive inhibitor of thyroid uptake of radioiodine to reduce the risk of thyroid cancer.

Dietary iodide distributes selectively into the thyroid gland but also to a lesser extent into salivary glands, choroid plexus, and gastric mucosa with a volume of distribution of 0.3 L/kg. During pregnancy and lactation, iodide distribution to the mammary glands and ovaries increases. Iodide that is not concentrated in the thyroid is excreted 80% in urine and 20% in feces.

HISTORY Following the study of thyroid cancers in Pacific Islanders who were subjected to fallout from nuclear testing, scientists concluded in 1957 that KI could effectively protect the thyroid from radioactive iodine. The National Council on Radiation Protection and Measurements reported in 1977 that the sudden release of radionuclides, including radioiodine, could affect large numbers of people after a nuclear incident (Fig. A44–1). The following year, the United States (US) Food and Drug Administration (FDA) requested the production and storage of KI for the purpose of blocking the effects of radioiodine on the thyroid gland when needed.

PHARMACOLOGY Chemistry Iodine (I), atomic number 53, derives from the Greek iodes meaning violet, owing to the violet color of elemental iodine vapor. Similar to other halogens, iodine occurs mainly as a diatomic molecule I2. The term iodide refers to the ion I–, which forms inorganic compounds with iodine that is in the oxidation state –1, such as KI. Only 127I is stable.

Mechanism of Action Neonates, children, and adolescents are particularly susceptible to developing thyroid cancer following radioactive iodine exposure because during rapid developmental periods, the thyroid gland grows and accumulates a larger percentage of exogenously ingested iodide as it increases thyroglobulin and iodothyronine stores. Similarly, during pregnancy, the maternal thyroid gland is stimulated and takes up more iodide compared with other adults. Exposure to radioactive iodine occurs via inhalation or via ingestion of contaminated food. After being incorporated into the thyroid gland, radioiodine exposes thyroid tissue to β and γ emissions, potentially leading to cancer. Because the chemical properties of radioactive iodine are unchanged from stable iodine, prophylaxis with KI is effective through isotopic dilution. That is, KI competes with radioactive iodine for the active iodide transport system to reduce the concentration of radioiodine in the serum, making the uptake of radioiodine much less likely. 235U

+ 1n

131In

0.28 s

131Sn

56 s

Pharmacodynamics Iodide (I–), an essential nutrient present in minute total-body amounts of 15 to 25 mg, is required for the synthesis of the thyroid hormones l-thyroxine (T4) and l-triiodothyronine (T3). Iodide is actively transported into thyroid follicular cells and concentrated 20- to 40-fold compared with the serum. It is then transported into the follicular lumen, where it iodinates thyroglobulin to form T4 and T3 (Chap. 26).

ROLE IN RADIOACTIVE IODINE EXPOSURE Radioactive iodine uptake is effectively blocked by KI supplementation. The 1986 Chernobyl incident remains the largest experience of KI distribution following a nuclear incident from which data and recommendations are derived. After Chernobyl, the Polish government distributed nearly 18 million doses of KI in its most affected provinces, but none was distributed in Ukraine and Belarus. Studies demonstrated not only a dose–response relationship between radiation dose and the relative risk of thyroid cancer, but also a threefold reduction of this risk through use of KI supplementation.

ADVERSE EFFECTS AND SAFETY ISSUES Thyroidal Effects Extensive experience with treating goiter and the use of iodized salt demonstrates that both hyper- and hypothyroidism result from supplementation with KI. Both the prevalence of goiter and subclinical hypothyroidism increase when iodine intake is chronically high. A large study in Poland after the Chernobyl incident investigated the risks and benefits of KI prophylaxis. Of the thousands of men, women, and children who were studied, the vast majority of whom received a single dose of KI, no statistical differences were found between treated and untreated groups when thyroid-stimulating hormone (TSH) concentrations were measured among all populations.

Extrathyroidal Effects “Iodide mumps,” is an inflammation of the salivary glands and appears to be unpredictable. Iododerma is a rare and 131Sb

23 m

131Te

25 m

131I

8.02 d

131Xe

FIGURE A44–1.  The decay pathway that describes how 131I is derived from nuclear fuel (whether in a bomb or a reactor) and ultimately decays to stable xenon. s = seconds; m = months; d = days. U = uranium; In = indium; Sn = tin; Sb = antimony; Te = tellurium; Xe = xenon; N = neutron. 724

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ANTIDOTES IN BRIEF • POTASSIUM IODIDE

725

TABLE A44–1    Threshold Radiation Exposure Doses and Recommended KI Doses for Different Risk Groups Predicted Thyroid Exposure (Gy, rad)  

Gy

rad

KI Dose (mg)

No. of 130-mg Tablets

Milliliters of Oral Solution, 65 mg/mL

Adults > 40 yr

≥5

≥ 500

130

1

2

Adults 18–40 yr

≥ 0.1

≥ 10

130

1

2

Pregnant or lactating women

≥ 0.05

≥5

130

1

2

Children and adolescents 3–18 yr

≥ 0.05

≥5

65

1/2a

Children 1 mo to 3 yr

≥ 0.05

≥5

32

Use KI oral solution

0.5

Birth to 1 mo

≥ 0.05

≥5

16

Use KI oral solutionb

0.25

1 b

Adolescents approaching adult size (70 kg) should receive a full dose of 130 mg. For smaller, more precise dosing, a potassium iodide (KI) oral solution is available with a dropper marked for 1-mL, 0.5-mL, and 0.25-mL dosing. Gy = Gray = 100 rads. Modified from Food and Drug Administration. Guidance. Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm080542.pdf. a

b

reversible acneiform eruption related to iodine ingestion that may result from nonspecific immune stimulation, which is similar to bromoderma. Other reactions reported in association with KI use include gastrointestinal disturbances, fever, and shortness of breath. “Allergy” to radiocontrast media is actually an anaphylactoid (nonimmune hypersensitivity) response to the high osmolarity of these xenobiotics. Although seafood contains iodide, allergy to fish or shellfish is caused by specific marine proteins and not sensitivity to iodide. Patients manifesting allergic contact dermatitis resulting from iodine-containing cleaning preparations such as povidone–iodine do not react to patch testing with KI. Therefore, the decision to administer KI dosing in the event of radioactive iodine exposure should not be based on a history of reactions to radiocontrast media, seafood, and povidone–iodine.

PREGNANCY AND LACTATION Potassium iodide is listed as Pregnancy Category D and readily crosses the placenta and distributes into milk. Both the US FDA and World Health Organization (WHO) support the use of KI for pregnant women when the risk is declared substantial by public health authorities.

DOSING AND ADMINISTRATION Based on data from Chernobyl regarding estimated doses and cancer risks in exposed children, the WHO in 1999 and the US FDA in 2001 provided recommendations for KI supplementation for various populations, depending on their relative risks (Table A44–1).

Timing of Administration For full blocking effect, KI should be administered shortly before exposure or immediatly afterward. Some models describe the blockade of only 50% of iodide uptake when there

153_Hoffman_A44_p0724-0725.indd 725

is a delay of several hours after an exposure. Depending on the duration and type of risk, administration of KI months after an exposure may also partially reduce thyroid cancer risk.

Daily Versus Single Dosing The protective effect of KI lasts for about 24 hours, so it should be dosed daily depending on the dosing estimates for exposure in children aged 1 month to 18 years in whom an ongoing risk is perceived. Groups in whom only a single dose is recommended include pregnant women and neonates, in whom there is a significant risk of iodine causing harm to the fetus related to impaired cognitive development. For lactating women, stable iodide will be delivered to the nursing newborn and may cause functional blocking of iodide uptake by an overload of iodine. Therefore, the US FDA recommends that lactating mothers not receive repeated doses except during continuing, severe contamination, which would generally be defined by health officials.

Monitoring All neonates who are treated with KI should be monitored for changes in TSH and total T3 and free T4. Likewise, when a lactating mother requires repeat doses of KI, the nursing infant should be monitored for the development of hypothyroidism.

FORMULATION AND ACQUISITION Several manufacturers formulate KI and market them as nonprescription, US FDA-approved products with a shelf life of 7 years. Tablets are available in both 130-mg and 65-mg doses, as well as an oral solution in a concentration of 65 mg/mL. Iodide-containing products not considered useful as radioiodine protective treatments include iodized salt, seaweed, and tincture of iodine.

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A45

Antidotes in Brief

PENTETIC ACID OR PENTETATE (ZINC OR CALCIUM) TRISODIUM (DTPA)

INTRODUCTION

Pharmacodynamics

Pentetate zinc trisodium and pentetate calcium trisodium (zinc or calcium diethylenetriaminepentaacetate; Zn-DTPA and Ca-DTPA, respectively) are chelators recommended for the treatment of internal contamination with plutonium (Pu), americium (Am), and curium (Cm).

DTPA increases the urinary elimination rate of chelated metals. In animals, treatment with Ca-DTPA within 1 hour of internal contamination resulted in 10-fold greater rate of urinary elimination of plutonium compared with Zn-DTPA. The greatest chelating capacity occurred immediately and for the first 24 hours after contamination while the metal was still circulating and available for chelation. Similarly, inhalation of Ca-DTPA followed by a month-long regimen of Zn-DTPA reduced lung deposits of aerosolized plutonium to 2% of control animals.

HISTORY First synthesized in 1954, these chelators were used as investigational therapies to enhance elimination of transuranic elements. Over the past decades, hundreds of human exposures to radionuclides as well as numerous animal studies helped to define the best practices for the use of these chelators, culminating in their approval by the United States (US) Food and Drug Administration (FDA) in 2004.

PHARMACOLOGY Chemistry Pentetic acid is a synthetic polyaminopolycarboxylic acid that bonds stoichiometrically with a central metal ion through the formal donation of one or more of its electrons. The calcium trisodium salt and the zinc trisodium pentetic acid are used therapeutically.

Related Xenobiotics Several metal chelators in clinical practice include deferoxamine, dimercaprol, dimercaptopropane sulfonate, edetate calcium disodium, penicillamine, Prussian blue, succimer, and trientine hydrochloride. However, none of these are effective for transuranic metals (elements with atomic numbers greater than 92).

Mechanism of Action Pentetic acid wraps itself around the metal, forming up to eight bonds, exchanging its calcium or zinc ions for a metal with greater binding capacity (Fig. A45–1). The chelated complex is then excreted by glomerular filtration into the urine.

ROLE IN RADIONUCLIDE CONTAMINATION DTPA is recommended and US FDA approved for contamination from plutonium, americium, and curium. For inhaled metals, such as might be experienced after an explosion, treatment with nebulized DTPA is recommended. While chelation is reasonable to increase elimination of the radionuclide and decrease cancer risk, this risk reduction has only been demonstrated in animals. Increased urinary excretion of transuranic elements is a clinically meaningful endpoint for efficacy of DTPA. We recommend against chelation after ingestion of americium, curium, or plutonium, because increased GI absorption will result. Although data are limited, we agree with the Radiation Emergency Assistance Center/Training Site (REAC/TS) recommendation of DTPA for chelating berkelium, californium, cobalt, einsteinium, europium, indium, iridium, manganese, niobium, promethium, ruthenium, scandium, thorium, and yttrium. Pentetic acid salts are not effective in removing antimony, beryllium, bismuth, gallium, lead, mercury, neptunium, platinum, or uranium.

DTPA is rapidly absorbed via intramuscular, intraperitoneal, and intravenous (IV) routes, but animal studies indicate that DTPA is poorly (< 5%) absorbed by the gastrointestinal (GI) tract. Absorption via the lungs approximates 20% to 30%. Its volume of distribution is small (0.14 L/kg in humans), and it is distributed mainly throughout the extracellular space. The plasma half-life is 20 to 60 minutes, although a small fraction is bound to plasma proteins with a half-life of more than 20 hours. DTPA undergoes minimal, if any, metabolism. Elimination is via glomerular filtration, with more than 95% excreted within 12 hours and 99% by 24 hours. There are no specific data regarding dosing or clearance changes when chelating patients with kidney disease. However, hemodialysis increases elimination. Fecal excretion is less than 3%.

O

O

Pharmacokinetics

O

N O Zn O

N

N O

O

3Na+ O

O O FIGURE A45–1.  Trisodium zinc diethylenetriaminepentaacetate, in which a transuranic element (Am, Pu, Cm) is substituted for Zn, forming a stable chelate.

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ANTIDOTES IN BRIEF • PENTETIC ACID OR PENTETATE (ZINC OR CALCIUM) TRISODIUM (DTPA)

DTPA is neither recommended nor approved for treating patients contaminated with uranium or neptunium for several reasons. DTPA mobilizes uranium from tissue stores but does not increase urinary elimination. Chelating incorporated neptunium is problematic because it forms extremely stable complexes with transferrin, making it very difficult to decorporate.

ADVERSE EFFECTS AND SAFETY ISSUES No serious toxicity is reported among humans after more than 4,500 Ca-DTPA administrations at recommended doses. Common adverse reactions include nausea, vomiting, diarrhea, chills, cramps, fever, pruritus, and muscle. Doses of 4 g of Ca-DTPA per day in hemochromatosis patients are associated with lethargy, obtundation, oral mucosal ulceration, stomatitis, dermatitis, loss of lower extremity sensation, and three deaths. The nonfatal reactions resolved upon cessation of Ca-DTPA. Injury was attributed to zinc depletion. In animals, Zn-DTPA is approximately 30-fold less toxic than Ca-DTPA.

Safety Because of the renal excretion of the radioactive chelate, the kidneys are exposed to potentially higher doses of radiation than other organs, which theoretically increases the risk of malignancy. Additionally, because urine is radioactive during chelation, there are recommendations to use toilets instead of urinals and to flush several times. Any spilled urine or feces should be cleaned promptly and completely, accompanied by thorough hand washing. Patients being chelated should take special care to dispose of any expectorant or breast milk carefully. After nebulization treatments, patients should be cautioned not to swallow any expectorant. Radiologically contaminated patients do not generally pose a danger to healthcare personnel. Universal precautions, including a gown, a mask, gloves, a head cover, and booties, effectively protect workers from contaminated material. Ambulances, operating rooms, and dialysis machines may become contaminated after providing care to contaminated patients and should be evaluated for decontamination before providing care for the next patient.

DOSING AND ADMINISTRATION If the contamination route is mixed (defined as anything in addition to inhalation) or unknown, then intravenous Ca-DTPA is recommended at a dose of 1 g in adults and 14 mg/kg up to the adult dose as a maximum in children younger than 12 years. This dose is administered either undiluted over 3 to 4 minutes or diluted in 100 to 250 mL D5W, lactated Ringer, or 0.9% sodium chloride administered over 30 minutes daily up to 5 days per week for the first week. If subsequent chelation is indicated, a twice-a-week regimen is recommended until the excretion rate of the contaminant does not increase with Zn-DTPA administration. If contamination was solely by inhalation, then we recommend diluting Zn-DTPA 1:1 with sterile water or 0.9% sodium chloride and administering via nebulization. Although Ca-DTPA is recommended as the initial chelator, Zn-DTPA should be used after the first 24 hours, given daily at the same dose because it has less adverse effects on essential metals.

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727

Timing of Administration and Duration of Therapy Administration of DTPA should be initiated as soon as possible but remains effective as long as radiocontaminants persist prior to their sequestration in bone and liver. Historically, about 55% of all patients treated with DTPA received only one dose. The decision to continue therapy should be based on radioassay data. This assessment should include collection of 24-hour urine samples, whole-body or chest counting, and close consultation with the hospital radiation safety officer or REAC/TS (865-576–1005). Current recommendations are to continue chelation until the deposition of contaminant is less than 5% of the maximum permissible body burden for each specific contaminant.

Monitoring A complete blood count with differential, blood urea nitrogen, serum electrolytes, and urinalysis, as well as blood and urine radioassays should be obtained before initiating treatment. Daily zinc, manganese, and magnesium monitoring should be performed. During treatment, repeated blood, urine, and fecal radioassays should be used to monitor elimination. Zinc supplementation is recommended during therapy. A standard oral multivitamin that contains zinc is considered sufficient.

Patients with Chronic Kidney Disease No dose adjustment is needed for patients with chronic kidney disease.

PREGNANCY AND LACTATION Calcium-DTPA is listed as US FDA Pregnancy Category C based on animal data. Zinc-DTPA is listed as US FDA Pregnancy Category B, also based on animal data. There are no human pregnancy outcome data from which to draw conclusions regarding the risk of DTPA. Contaminated pregnant women should begin any treatment with Zn-DTPA as opposed to Ca-DTPA because of perceived risks of the latter chelator for adverse reproductive outcome. However, in pregnant women with severe internal contamination in which the risk to the mother and fetus is considered to be high, that is, greater than an expected dose of 200 mSv, it would be reasonable to give Ca-DTPA for a first dose in conjunction with mineral supplements that contain zinc. These chelators do not cross the placental barrier. There are no studies regarding DTPA excretion in breast milk. However, radiocontaminants are excreted in breast milk. Thus, women with known or suspected contamination should not breastfeed until contamination risk is reduced. Likewise, there are no data regarding safety in lactating women, and data regarding the use in children are extrapolated.

FORMULATION AND ACQUISITION DTPA is available as Ca-DTPA or Zn-DTPA as a sterile solution in 5-mL ampules containing 200 mg/mL (1 g per ampule) for IV use. It should be stored in a cool, dry place with an ambient temperature of between 59°F (15°C) and 86°F (30°C) away from sunlight. Several manufacturers formulate DTPA for IV administration. Both chelators are maintained in the US Strategic National Stockpile.

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101

HAZARDOUS MATERIALS INCIDENT RESPONSE

This chapter focuses on the identification, management, and response to hazardous materials incidents. According to the United States (US) Department of Transportation, a hazardous material is any item or agent that has the potential to cause harm to humans, animals, or the environment, either by itself or through interaction with other agents. These can be chemical, radiologic, or biological. A hazmat incident is the result of an unplanned or uncontrolled release of or exposure to a hazardous material. Although there are no specific requirements for an event to be considered a hazardous materials incident, typically, there must be the potential for many people or a large area to be affected. Each incident and the associated response are unique. Emergency managers and healthcare professionals must consider all possibilities and adjust the incident response based on the specific xenobiotics involved, the route of the exposure, and other variables (eg, time, location, and weather conditions). This chapter discusses the basic principles used for a confined and quickly identifiable hazardous materials incident. In general, a hazardous materials incident response focuses on the care of patients exposed to xenobiotics in the prehospital setting, prepares for multiple casualties, and emphasizes patient decontamination while at the same time trying to prevent exposure and contamination of first responders and healthcare professionals.

DISASTER MANAGEMENT AND RESPONSE Local resources and agencies such as police, fire, and emergency medical services (EMS) provide initial disaster management preparedness and response. If necessary, local agencies can escalate response to the county, state, or federal level. The US Federal Emergency Management Agency (FEMA) within the US Department of Homeland Security is the lead federal agency for emergency management in the US. According to FEMA, disaster management contains four phases: (1) mitigation, (2) preparedness, (3) response, and (4) recovery. Mitigation measures are plans and efforts that attempt to prevent and reduce or eliminate the effects of a potential hazard from becoming a disaster. Preparedness involves creating action plans to be initiated when a disaster occurs, as well as testing plans with mock exercises and runthroughs. The response phase includes the mobilization of appropriate resources and the coordinated management of the incident. A hazardous materials incident response must include the containment of the xenobiotic followed by neutralization, removal, or both. The recovery phase occurs after the immediate needs and threats to human life are addressed in the response phase and entails the restoration of property, infrastructure, and the environment. Limiting the loss of life is dependent on all responding agencies and personnel working efficiently and effectively together. The coordination of federal, state, and local governments is mandated by the National Incident Management

System (NIMS), which uses a systematic approach designed to allow agencies to work together and manage incident response. The National Incident Management System provides for an incident command system (ICS) to be used during a disaster response. The ICS is a standardized, on-scene, all-hazards approach to incident management. The goal of the ICS is to enable a coordinated response among agencies and jurisdictions. It provides a common organizational structure and integrates equipment personnel, facilities, procedures, and communication. During a response, an incident commander (IC) is responsible for managing the incident, establishing objectives, and implementing tactics. Four subsections report to the IC: operations, planning, logistics, and finance and administration. The planning section supports the incident action planning process, collects and analyzes information, and tracks resources. The logistics section arranges for resources and services, and the finance and administration section monitors costs related to the incident. Medical professionals are a necessary part of all hazardous materials incident responses because patient assessment and treatment are typically the highest priority. Unsolicited medical personnel at the scene of a hazardous materials incident, although well intentioned, may actually harm the coordinated response and interfere with operational efforts. The plan for mobilization, management, and use of volunteer medical personnel at the scene of a disaster should be created in advance, especially for events that might reasonably be expected to require resources. Disaster plans incorporate the use of local medical assets such as hospitals and clinics. Therefore, communities are best served if medical providers respond to their respective institutions during an incident.

RESPONSE COMPONENTS After the identification of a release of a hazardous material, there must be a notification to emergency response personnel. Typically, an individual activates the emergency response system by calling 9-1-1. Initially, first responders are often not aware that an incident involves hazardous materials. For instance, a responder to an unconscious patient may be unaware that the cause of the medical emergency was a chemical exposure. First responders must consider that every incident may have a hazardous materials etiology. Extensive knowledge, training, and judgment are requirements for all emergency personnel, especially those responding to a hazardous material incident. They must follow basic response paradigms. Personnel should approach the scene from uphill and upwind if possible. Personnel should not immediately rush to the scene because the rescuer may become an additional victim. Establishment of a perimeter is essential to scene security to prevent uncontaminated individuals from becoming exposed. First responders and prehospital personnel must also consider other aspects of incident response, including the need for escalation to other

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CHAPTER 101 • HAZARDOUS MATERIALS INCIDENT RESPONSE

emergency response agencies, weather and wind conditions, terrain, confinement of the release, intentionality, and the need for rapid rescue and evacuation of casualties.

Identification of Hazardous Materials Identification of the specific xenobiotic(s) involved is of the highest priority because many of the response components depend on the properties and potential health effects of the xenobiotic itself. This information can be gleaned from placards, container labels, shipping documents, material safety data sheets (MSDSs), detector devices, personnel at the scene, patients’ signs and symptoms, and odors at the scene (eg, the rotten egg smell of hydrogen sulfide). In the US, first responders are required to be familiar with the use of the Emergency Response Guidebook, which is an aid for quickly identifying the hazards of the material(s) involved in a transportation incident. Hazardous materials may be classified as radioactive, flammable, explosive, asphyxiating, pathogenic, and biohazardous. Although most hazardous materials incidents involve only one hazardous material, more than one xenobiotic may be encountered at an incident. For consequential hazardous materials, the vast majority are caused by gases, vapors, or aerosols. Inhalation is the most common route of exposure at hazardous materials incidents. Because the number of hazardous materials is large, it is efficient to group hazardous materials according to their toxicologic characteristics. The International Hazard Classification System (IHCS) is the most commonly used system (Table 101–1). Chemical Names and Numbers.  Chemical compounds may be known by several names, including the chemical, common, generic, or brand (proprietary) name. The Chemical Abstracts Service (CAS) of the American Chemical Society assigns a unique CAS registry number (CAS#) to chemicals in order to overcome the confusion regarding multiple names for a single chemical. Identifying a chemical by name and CAS# is critical because one must be as specific as possible about the hazardous material in question. CHEMTREC provides essential chemical information and is available at 800-424-9300 or at http://www.chemtrec.org. A regional poison center is also a valuable source of medically relevant information. Other information sources include local and state health departments, the American Conference of Governmental and Industrial Hygienists, the Occupational Safety and Health Administration (OSHA), the National Institutes of Occupational Safety and Health (NIOSH), the Agency for Toxic Substances and Disease Registry, and the Centers for Disease Control and Prevention. Vehicular Placarding: United Nations Numbers, North American Numbers, and Product Identification Numbers.  Xenobiotics in each hazard class of the IHCS (Table 101–1) are assigned four-digit identification numbers, which are known as United Nations, North American, or Product Identification Numbers, and are displayed on characteristic vehicular placards. This system is used by the US Department of Transportation in the Emergency Response Guidebook. Unfortunately, this system provides very little guidance in treating poisonings caused by hazardous materials.

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729

TABLE 101–1    International Hazard Classification System Class 1: Explosives Division 1.1: Mass explosion hazard Division 1.2: Projection hazard Division 1.3: Predominantly a fire hazard Division 1.4: No significant blast hazard Division 1.5: Very insensitive explosives Division 1.6: Extremely insensitive detonating articles Class 2: Gases Division 2.1: Flammable gases Division 2.2: Nonflammable compressed gases Division 2.3: Poisonous gases Division 2.4: Corrosive gases (Canada) Class 3: Flammable or Combustible Liquids Class 4: Flammable Solids Division 4.1: Flammable solid Division 4.2: Spontaneously combustible materials Division 4.3: Dangerous when wet materials Class 5: Oxidizers and Organic Peroxides Division 5.1: Oxidizers Division 5.2: Organic peroxides Class 6: Poisonous Materials and Infectious Substances Division 6.1: Poison materials Division 6.2: Infectious substances Class 7: Radioactive Substances Class 8: Corrosive Materials Class 9: Miscellaneous Hazardous Materials

National Fire Protection Association 704 System for Fixed Facility Placarding.  Fixed facilities, such as hospitals and laboratories, use a placarding system that is different from the vehicular placarding system. The National Fire Protection Association (NFPA) 704 system is used at most fixed facilities. The NFPA system uses a diamond-shaped sign that is divided into four color-coded quadrants: red, yellow, white, and blue. The red quadrant on top indicates flammability; the blue quadrant on the left indicates health hazard; the yellow quadrant on the right indicates reactivity; and the white quadrant on the bottom is for other information, such as OXY for an oxidizing product, W for a xenobiotic that has unusual reactivity with water, and the standard radioactive symbol for radioactive substances. Numbers in the red, blue, and yellow quadrants indicate the degree of hazard: numbers range from 0, which is minimal, to 4, which is severe, and indicate specific levels of hazard. Similar to all placarding systems, this one also has limitations. It does not name the specific hazardous substances in the facility and gives no information about the quantities or locations of the materials. United Nations.  Recognizing that the transport of chemicals often occurs across international boundaries, the United Nations developed a chemical classification system in an attempt to harmonize an approach to classification and labeling. The Globally Harmonized System of Classification and Labelling of Chemicals classifies substances and mixtures by their health, environmental, and physical hazards.

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730

THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Exposure and Contamination Primary contamination is contamination of people or equipment caused by direct contact with the initial release of a hazardous material by direct contact at its source of release. Primary contamination occurs whether the hazardous material is a solid, a liquid, or a gas. Secondary contamination is contamination of healthcare personnel or equipment caused by direct contact with a patient or equipment covered with adherent solids or liquids removed from the source of the hazardous material spill. For instance, if a patient arrives at a healthcare facility and is not decontaminated, the hospital and healthcare providers are at risk for secondary contamination. Secondary contamination generally occurs only with solids or liquids, but as noted later, some “gaseous” xenobiotics are actually suspended liquids or solids. Aerosols are airborne xenobiotics, not gases. Aerosols are suspensions of solids or liquids in air, such as solid dusts or liquid mists, that can cover victims with these adherent solids or liquids, which cause secondary contamination.

Hazardous Materials Site Operations Limiting dispersion of the hazardous material is critical to prevent further consequences. The physical state of a material determines how it will spread through the environment and gives clues to the potential route(s) of exposure. Unless moved by physical means such as wind, ventilation systems, or people, solids usually stay in one area. Solids can cause exposures by inhalation of dusts, by ingestion, or rarely by absorption through skin and mucous membranes. A vapor

TABLE 101–2    Nomenclatures of the Hazardous Materials Control Zones Temperature Terminology Systema

Color Terminology System

Explanatory Terminology System

Hot zone

Red zone

Exclusion or restricted zone

Warm zone

Yellow zone

Decontamination or contamination reduction zone

Cold zone

Green zone

Support zone

Data from the National Institutes of Occupational Safety and Health and the Environmental Protection Agency. a

is defined as a gaseous dispersion of the molecules of a substance that is normally a liquid or a solid at standard temperature and pressure. Uncontained liquids will spread over surfaces and flow downhill. Liquids that evaporate create a vapor hazard. The vapor pressure (VP) is useful to estimate whether enough of a solid or liquid will be released in the gaseous state to pose an inhalation risk. The lower the VP, the less likely the xenobiotics will volatilize and generate a respirable gas. Standard references (eg, NIOSH Pocket Guide to Chemical Hazards and the Merck Index) list VPs for commonly encountered chemicals.

Hazardous Materials Scene Control Zones Scene management is a fundamental feature of hazardous materials incident response. Three control zones are established around a scene and are described by “temperature,” “color,” or “explanatory terminology” (Table 101–2 and Fig. 101–1). Crowd control line Decontamination line Hot line

Staging area

Drainage

Staging area

Access control points

Exclusion (hot) zone

Access corridor Command post

Contamination reduction (warm) zone Support (cold) zone

Wind FIGURE 101–1.  National Institutes of Occupational Safety and Health/Occupational Safety and Health Administration recommended hazardous materials control zones.

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CHAPTER 101 • HAZARDOUS MATERIALS INCIDENT RESPONSE

731

TABLE 101–3    Personal Protective Equipment

Protects Skin and Eyes From

Protects Respiratory System From

Select Vapors and Gases, Vapors, Oxygen-Deficient Aerosols and Aerosols Atmospheres

Liquids Gases and and Solids Vapors

D

 

 

 

 

 

C

+

 

 

+

 

B

+

 

+

+

+

A

+

+

+

+

+

Level

a

Level A is a self-contained breathing apparatus (SCBA) worn under a vapor-protective, fully encapsulated, airtight, chemical-resistant suit. Level B is a positive-pressure supplied-air respirator with an escape SCBA worn under a hooded, splash-protective, chemical-resistant suit. Level C is an air-purifying respirator worn with a hooded, splash-protective, chemical-resistant suit. Level D is regular work clothing (offers no protection). a

Personal Protective Equipment A critical goal of hazardous materials emergency responders is protecting themselves and the public. Safeguarding hazardous materials responders includes wearing appropriate PPE to prevent exposure to the hazard and prevent injury to the wearer from incorrect use of or malfunction of the PPE equipment. Donning PPE poses significant health hazards for the provider, including loss of cooling by evaporation, heat stress, physical stress, psychological stress, impaired vision, impaired mobility, and impaired communication. Because of these risks, individuals involved in hazardous materials emergency response must be properly trained regarding the appropriate use, decontamination, maintenance, and storage of PPE. Levels of Protection.  The US EPA defines four levels of protection for PPE: levels A (greatest protection) through D (least protection) (Table 101–3). Level A provides the highest level of protection and is airtight and fully encapsulating. A breathing apparatus must be worn under the suit. Level B uses chemicalresistant clothing. Level C protection should be used when the type of airborne xenobiotic is known, its concentration can be measured, the criteria for using air-purifying respirators (APRs) are met, and skin and eye exposures are unlikely. Level D is basically a regular work uniform. Personal Protective Equipment Respiratory Protection.  Level A PPE mandates the use of a self-contained breathing apparatus (SCBA) composed of a face piece connected by a hose to a compressed air source. Disadvantages of the SCBA include its bulkiness and heaviness and a limited time period of respiratory protection because of the limited amount of air in the tank. A supplied-air respirator (SAR) may be used in level B PPE and differs from SCBA in that air is supplied through a line that is connected to a source located away from the contaminated area (Fig. 101–2). One major advantage of SARs over SCBA is that they allow an individual to work for a longer period. However, a hazardous materials worker must stay connected to the SAR and cannot leave the contaminated area by a different exit. An APR may be used in level C PPE

155_Hoffman_Ch101_p0728-0733.indd 731

FIGURE 101–2.  Individuals wearing level A PPE. (Used with permission from Chris McLoughlin/Alamy Stock Photo.)

and allows breathing of ambient air after inhalation through a specific purifying canister or filter. Powered devices reduce the work of breathing, which can significantly limit an individual’s performance while wearing PPE.

Decontamination One of the most important and essential aspects of hazardous materials response is decontamination of patients. Not only does decontamination reduce the health consequences for the patient (by reducing absorption or exposure time), but it also prevents secondary contamination. Decontamination of equipment, the environment, and the entire area (ie, hot zone) is necessary but is secondary in priority to the decontamination of victims. An estimated 75% to 90% of contaminants can be removed simply by removing clothing and garments. Subsequent decontamination is most commonly accomplished by using water to copiously irrigate the skin of a patient, thereby physically washing off, diluting, or hydrolyzing the xenobiotic. All exposed skin, including the skin folds, axillae, genital area, and feet, should be decontaminated. Lukewarm water should be used with gentle water pressure to reduce the risk of hypothermia. Water should be applied systematically from head to toe while the airway is protected if necessary. Exposed, symptomatic eyes should be continuously irrigated with water throughout the patient contact, including transport, if possible. Remember to check for and remove contact lenses. Providers should use care with chemical contaminants because some solid contaminants react with water and create an increased hazard. Some xenobiotics are better removed mechanically by physically wiping them from the skin while avoiding smearing the xenobiotic or abrading the skin. Some contaminants may be chemically “inactivated” by applying another chemical, such as a 0.5% hypochlorite solution (see extensive discussion in Special Considerations: SC1). Scene Triage.  Victim decontamination and movement from a scene require an organized methodology for categorization of medical severity. The most common triage method used is the Simple Triage and Rapid Treatment (START) system, although many others exist. This system follows a simple algorithm that allows for a color categorization based upon respiration, perfusion, and mental status: immediate

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

(red), delayed (yellow), walking wounded or minor (green), and deceased or expectant (black). Victims may be initially triaged in the contaminated zone and then retriaged after decontamination.

HAZARDOUS MATERIALS INCIDENT RESPONSE RULES AND STANDARDS Occupational Safety and Health Administration and the NFPA have developed rules and guidelines, respectively, regarding hazardous materials incident response. Occupational Safety and Health Administration rules are mandated as law and must be followed. Meeting NFPA guidelines will ensure OSHA compliance. The Superfund Amendments and Reauthorization Act of 1986 (SARA) required OSHA to develop and implement standards to protect employees responding to hazardous materials emergencies. This resulted in the Hazardous Waste Operations and Emergency Response standard, 29 CFR 1910.120, or HAZWOPER. NFPA 471, Recommended Practice for Responding to Hazardous Materials Incidents, outlines the following tactical objectives: incident response planning, communication procedures, response levels, site safety, control zones, PPE, incident mitigation, decontamination, and medical monitoring. NFPA 472, Standard on Professional Competence of Responders to Hazardous Materials Incidents, helps define the minimum skills, knowledge, and standards for training outlined in HAZWOPER for three types of responders.

Prehospital Hazardous Materials Emergency Response Team Composition, Organization, and Responsibilities

First Responder at the Awareness Level.  First responders at the awareness level are expected to recognize the presence of hazardous materials, protect themselves, secure the area, and call for better-trained personnel. They must take a safe position and keep other people from entering the area. First Responder at the Operational Level.  These individuals are additionally trained to protect nearby persons, the environment, and exposed property from the effects of hazardous materials releases. They are expected to assume a defensive posture, control the release from a safe distance, and keep the hazardous material from spreading. Operational level individuals are trained on the following aspects of material containment: absorption of liquids, containment of the spill, vapor suppression, and vapor dispersion. They do not operate within the hot zone. Hazardous Materials Technician.  Hazardous materials technicians are trained in the use of chemical-resistant suits, air-monitoring equipment, mitigation techniques, and the interpretation of physical properties of hazardous materials. Technicians are capable of containing an incident, making safe entry into a hazardous environment, determining the appropriate course of action, victim rescue, and cleaning up or neutralizing the incident to return property to a safe and usable status, if possible. These individuals are trained to operate within the hot zone to mitigate the incident.

Advanced Hazardous Materials Components

Advanced Hazardous Materials Providers.  Paramedics are trained in the recognition of signs and symptoms caused by exposure

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to hazardous materials and the delivery of antidotal therapy to victims of hazardous materials poisonings. Ideally, entry into hazardous atmospheres should not be performed until appropriately trained paramedics are on the scene with resuscitative equipment in place, including a drug box containing essential antidotes for specific hazardous materials. Patient Care Responsibilities of the Prehospital Decontamination Team and the Hazardous Materials Entry Team.  Hazardous material incident responders should identify the entry and exit areas by controlling points for the access corridor (decontamination corridor) from the hot zone, through the warm zone, to the cold zone (Fig. 101–1). This corridor should be upwind, uphill, and upstream from the hot zone, if possible. Hazardous materials technician entry team members should remove victims from the contaminated hot zone and deliver patients to the inner control point of the access (decontamination) corridor. Hazardous materials decontamination team members decontaminate patients in the decontamination (access) corridor of the contamination reduction (warm zone). The primary responsibility of the prehospital hazardous materials sector is the protection of the hazardous materials entry team personnel. In some systems, the hazardous materials entry team may include specialized providers who have the ability to provide lifesaving patient care within the hot zone. The ability to perform triage or cardiopulmonary resuscitation or to provide any medical care is greatly limited by the PPE being worn. Therefore, only immediately lifesaving procedures should be considered, such as intubation or antidote administration. Patient Care Responsibilities of Emergency Medical Services Providers at Hazardous Materials Incidents.  Emergency medical services providers who are not part of the hazardous materials team should report to the incident staging area and await direction from the IC. They should approach the site from upwind, uphill, and upstream, if possible. Emergency medical services providers should remain in the cold zone until properly protected hazardous materials incident responders arrive, decontaminate, and deliver patients to them for further triage and treatment. Ideally, EMS response for an event will involve direct communication with the EMS medical director or medical control; this physician will assist with coordination of appropriate care with the hospital, regional poison centers, and toxicologists. Patients with skin contamination should not be transported from the hazardous materials site without being properly decontaminated. Before transportation, EMS should notify the receiving hospital of the number of victims being transported and their toxicologic history, patient assessments, and treatment rendered. Hospital Responsibilities for Hazardous Materials Victims.  Ideally, local or regional emergency department (ED) physicians and personnel will receive prompt advanced notification about a hazardous materials incident before any victims arrive at the hospital. The notification should include, if known, information regarding the event, hazardous materials involved, number and condition of casualties to be transported to the hospital, and estimated time of arrival, as well as information

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CHAPTER 101 • HAZARDOUS MATERIALS INCIDENT RESPONSE

regarding the decontamination completed. The mnemonic ETHANE (exact location; type of incident; hazards, access route; numbers of casualties; emergency services on site) is one way to remember these required elements. Assistance of a poison control center and a medical toxicologist is generally recommended. Victims may leave an incident scene and subsequently present to a hospital. The hospital must have a preestablished

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protocol by which hospital response teams will decontaminate patients who arrive at the hospital if not previously decontaminated or if field decontamination is believed to be insufficient. Patients who require skin decontamination should be denied entry to the ED until they are decontaminated by an appropriately trained and equipped hazardous materials response team. Treatment should not be initiated until the patient is in the cold zone.

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SC10

Special Considerations

ASSESSMENT OF ETHANOL-INDUCED IMPAIRMENT

INTRODUCTION This discussion describes the history and use of assessments of ethanol-induced impairment, primarily in a legal context. Throughout this chapter, the terms ethanol and alcohol are used interchangeably and words such as drunk and punishable are used to preserve the specific language from early studies and legal writings.

HISTORY Although the intoxicating effects of ethanol have been known for centuries, the advent of mechanized transportation spawned increased public and legal scrutiny. Although railroads had regulations against the operation of equipment while intoxicated dating back to at least the 1850s, the first arrest for drunk driving in an automobile was a London taxicab driver in 1897. In 1910, New York was the first state in the United States (US) to enact a “drunken driving” law. Prior to the landmark work by Widmark in Sweden and by Heise in the US, evaluations of driver impairment were predominantly based on the “expert” testimony of an evaluating physician and the arresting police officer, as well as behaviors reported by witnesses. The development of analytical technology capable of measuring the concentration of alcohol in blood gave rise to the idea that diagnosis of intoxication might be assisted by an objective chemical test result. The greater the blood alcohol concentration (BAC), the more drinks the individual must have consumed and, therefore, the greater the degree of impairment. Although the assignment of a specific clinical effect to a given BAC is not rigorously applicable to evaluation of an individual case, the general trends when examined across a population formed the foundation of many modern driving while intoxicated (DWI) laws. Despite centuries’ worth of knowledge of the effects of alcohol and decades of efforts to articulate drunk driving standards, a single universal definition of “alcohol intoxication” does not exist.

PER SE LIMITS The first US states to incorporate BAC into drunk-driving statutes were Indiana and Maine, which did so in 1939. The approach taken by the Indiana legislature resulted in a threetiered statute, which stated that a BAC of less than 50 mg/dL (10.9 mmol/L) was considered presumptive evidence of no intoxication, a BAC between 50 and 100 mg/dL was considered supportive evidence of intoxicated driving, and a BAC of greater than 150 mg/dL (32.6 mmol/L) was considered prima facie (ie, obvious and evident without proof) evidence of guilt. From a legal perspective, prima facie evidence shifts the burden of proof from the accuser having to substantiate the charge to the defense to rebut the allegation. It is this

legal perspective from which the so-called per se standards are derived—that is, an individual whose BAC exceeds a predetermined concentration is deemed guilty of driving while impaired by alcohol, even without any other evidence of intoxication or impairment. However, by 1960, as data regarding alcohol-related motor vehicle crashes became available, most states adopted a more rigorous per se BAC driving standard of 100 mg/dL (21.7 mmol/L). Epidemiologic assessments demonstrate that the probability of causing an alcohol-related motor vehicle crash increases slightly at a breath alcohol concentration (BrAC) of 50 mg/dL. The risk of causing a crash is increased by roughly 4-fold at a BrAC of 80 mg/dL, 7-fold at a BrAC of 100 mg/dL, and 25-fold at a BrAC of 150 mg/dL. In 1994, all states in the US lowered the BAC used to define per se intoxicated driving to 80 mg/dL (17.4 mmol/L). Lower per se BACs are applied to interstate commercial drivers (40 mg/dL) (8.7 mmol/L) and pilots of aircraft (40 mg/dL, with no alcohol consumed within 8 hours prior to acting as pilot in command), as well as minors (10–20 mg/dL, depending on the state, and 20–50 mg/dL (5.4-10.9 mmol/L) in some European countries). Laws addressing per se driving under the influence (DUI) limits are based on ethanol concentrations measured in whole blood. BrAC limits (which are arithmetically linked to BAC) are also frequently specified in per se statutes. It is, however, imperative to understand that per se BACs do not define drunkenness or alcohol intoxication in nondriving situations, and their use in circumstances not involving motor vehicle operation is generally inappropriate. The legal significance of a per se limit is that there is no requirement for behavioral evidence of intoxication, as long as the measured BAC exceeds that established by the legislature.

ANALYTICAL CONSIDERATIONS Accurate measurement of ethanol concentration in various biological matrices can be done using a number of analytical techniques. Enzymatic ethanol assays based on alcohol dehydrogenase (ADH) are commonly used, especially in high-throughput laboratories. The greater selectivity for ethanol of gas chromatographic (GC) methods makes these techniques the mainstay for quantitative analysis in most forensic laboratories. As ethanol distributes based on total body water, the water content of the matrix will affect the amount of ethanol present in a given volume or mass of biological sample. A common circumstance in which this is observed is in the difference between a whole blood ethanol determination and a plasma or serum ethanol determination. The water content of serum and plasma is 10% to 12% higher than whole blood, meaning that serum or plasma ethanol concentrations will

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SPECIAL CONSIDERATIONS • ASSESSMENT OF ETHANOL-INDUCED IMPAIRMENT

be correspondingly higher than whole blood concentrations. Clinical laboratories most often use serum and plasma for analysis, whereas per se driving under the influence (DUI) statutes are written in terms of whole blood. Therefore, if a comparison is to be made between a serum or plasma analytical result and a legal standard, the result must be converted to an approximated whole blood ethanol concentration. Typically, a ratio of 1.16 is used for this conversion, and no significant difference appears to exist between the serum-to-whole blood and plasma-to-whole blood ratios. Breath testing is commonly performed to assess BAC because of its relative simplicity and less invasive collection compared to urine or blood. The analytical basis for sampling exhaled breath is that, at equilibrium, alcohol in expired air is present at a predictable ratio with blood. In the US, a blood-to-breath alcohol ratio of 2,100:1 is commonly used in the calibration of breath alcohol testing devices, although experimental evidence suggests that the actual ratio is closer to 2,300:1. As such, a systematic underestimation of BAC is expected when breath alcohol results are converted to whole blood alcohol results. Several studies document this underestimation with data from suspected impaired drivers and evidential breath alcohol testing instruments. In 1983, Britain adopted a legal limit in breath of 35 μg/100 mL, which corresponds to a blood alcohol of 80 mg/dL, using a 2,300:1 blood-to-breath ratio. Legal statutes that include in their offense definition breath alcohol results expressed in units of grams/210 L of exhaled air eliminate the need to convert breath alcohol to blood alcohol, largely mitigating arguments based on the breath-to-blood ratio.

BREATH-TESTING DEVICES Breath-testing instruments are generally divided into four broad categories: passive alcohol sensors (PASs), screening devices (preliminary breath testers {PBTs}), breath alcohol ignition interlock devices (BAIIDs), and evidential breath testers (EBTs). A PAS device may be concealed in a device such as a modified police flashlight and is used to detect alcohol on or in the immediate vicinity of a subject through passive means (ie, with no requirement for subject cooperation). Breath alcohol ignition interlock devices are used to prevent drinking and driving by requiring the driver to blow into a sensor in order to start the ignition of the vehicle. The PBT and EBT devices are the most common breath alcohol–testing devices encountered in cases of DUI arrest. In this setting, PBT results are used in conjunction with observation and field sobriety tests to establish probable cause for DUI arrest. In contrast to PBT results, measurements from an EBT device are admissible in court and administrative proceedings and can be used as the basis for establishment of per se DUI cases without the necessity of blood collection and analysis. Although mobile EBT devices are available, most often the EBT is maintained in a fixed location such as a police station. Required procedures for the use of EBT devices exist for the subject as well as the instrument. The subject must have a period of alcohol deprivation of at least 15 to 20 minutes during which trained personnel observe him or her to ensure not only that

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no additional ethanol is consumed but also that no regurgitation, emesis, or eructation occurs, which could result in residual ethanol in the mouth prior to breath alcohol analysis.

STANDARDIZED FIELD SOBRIETY TESTS A driver whose BAC exceeds the established legal standard is considered per se intoxicated and often convicted without behavioral evidence of intoxication. However, some objective findings of impairment assist in establishing probable cause to demand chemical testing, initiate a DUI arrest, or prosecute a charge of impairment, without invoking per se limits. In these settings, results of a specific group of behavioral tests are of value in discriminating and prosecuting or refuting an impaired driving charge, although submitting to these behavioral tests is typically voluntary. The three tests comprising the standardized field sobriety tests are the oneleg stand (OLS), walk-and-turn (WAT), and horizontal gaze nystagmus (HGN). Descriptions of these tests are provided in Table SC10–1.

ESTIMATING THE AMOUNT OF ALCOHOL INGESTED The kinetic profile of ethanol in the blood has been extensively studied. In general, it is known that when blood ethanol concentration is greater than 20 mg/dL (4.3 mmol/L), it follows a zero-order elimination profile and then converts to first-order elimination when the concentration drops below this threshold. In the zero-order portion of the curve, typical elimination rates range from 10 to 20 mg/dL/h in social drinkers, whereas in chronic users, the rate is higher. The estimation of the TABLE SC10–1    Standardized Field Sobriety Tests Test

Test Description

Test Scoring (“clues”)

One-leg stand (OLS)

With the arms at sides, 4-point scale raise one foot at least 1. Putting foot down 6 inches off the ground 2. Hopping and stand on the other foot 3. Swaying for at least 30 seconds. 4. Raising arms Any 2 “clues” is failure.

Walk-and-turn (WAT)

Balance with feet heelto-toe and listen to test instructions. Walk 9 steps heel-to-toe in a straight line, turn 180 degrees, and walk 9 more steps heel-to-toe, while counting steps, watching feet, and keeping hands at sides.

8-point scale 1. Inability to maintain balance in the starting position 2. Starting too soon (eg, prior to completion of instructions) 3. Stepping off the line 4. Not touching toe to heel 5. Raising arms 6. Improper turn 7. Stopping 8. Wrong number of steps Any 2 “clues” is failure.

Horizontal gaze nystagmus (HGN)

Angle of onset of nystagmus is determined for each eye.

6-point scale (3 points for each eye) 1. Lack of smooth pursuit 2. Distinct nystagmus at maximum deviation 3. Onset of nystagmus before 45 degrees Cutoff is 4 “clues.”

Reproduced with permission from Rubenzer SJ. The standardized field sobriety tests: a review of scientific and legal issues. Law Hum Behav. 2008;32(4):293-313.

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THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

number of drinks ingested to achieve a given BAC or back calculation from a current concentration to a previous moment in time has been extensively studied, but the results are too imprecise for and individual legal argument. Some legal arguments have quite incorrectly suggested that ethanol is odorless. Ethanol has a characteristic pleasant smell, with an odor threshold of approximately 50 ppm. The presence or absence of breath alcohol odor is often used by police officers in the decision to proceed further with sobriety testing. In one study, 20 experienced police officers assessed alcohol odor on 14 subjects with BACs ranging from 0 to 130 mg/dL (28.2 mmol/L) after drinking beer, wine, bourbon, or vodka. Assessments were initiated 30 minutes after cessation of drinking. The strength of breath alcohol odor was determined to be an unreliable indicator of BAC. Correct detection of the presence of alcohol was 85% for BACs at or above 80 mg/dL but declined with decreasing BAC or the presence of food.

DRAM SHOP Liquor liability or “dram shop” laws hold the server of alcoholic beverages liable for damages or injuries caused by an individual who was provided alcohol when such service should have been refused. In the 19th century, laws were enacted to punish tavern owners who contributed to the downfall of patrons. By contrast, current application of the laws is typically as a means to compensate innocent victims injured by an intoxicated patron. This action on behalf of the innocent victim is why liquor liability law is sometimes referred to as “third party” liability. Direct comparison of the efficacy of dram shop liability laws between states is difficult as liability laws and insurance vary widely. One study concluded that dram shop liability and responsible beverage service (RBS) laws were associated with significant reduction in per capita beer consumption and fatal crash ratios in drivers under age 21.

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INTOXICATION AND ESTIMATION OF BLOOD ALCOHOL CONCENTRATION The ability of an individual to accurately estimate his or her own BAC is poor. Drivers who underestimate their own BAC are more impulsive and riskier drivers than those who overestimate their BAC. A lack of accuracy in estimating BAC is also observed in trained medical providers and police officers. A large confounding factor in these observations is tolerance. Greater tolerance, as occurs in people with alcohol use disorder, imparts greater difficulty in detecting the clinical effects associated with a given alcohol concentration. However, tolerance has no bearing on the potential prosecution of a DUI case on a per se BAC or BrAC basis. The central nervous system effects of alcohol intoxication are typically more pronounced on the ascending portion of the blood alcohol kinetic curve than on the descending side due to the development of acute tolerance. In other words, the clinical effect of intoxication is greater during the absorptive arm of the kinetic curve than on the elimination arm, even though the same blood alcohol concentration is measured in both kinetic phases. This principle is known as acute tolerance, or the Mellanby effect. Multiple studies have examined the likelihood of alcohol sales to obviously intoxicated individuals (typically, paid professional actors pretending to be drunk) by various commercial entities for consumption on-premise (bars, restaurants, outdoor events like festivals) and off-premise (liquor stores, grocery stores, and convenience stores). The results are fairly uniform in that the majority of the time the alcohol was sold or served to the “intoxicated” individual. Additionally, it was noted that male servers/clerks who appeared younger than age 31 were reportedly more likely to make such sales and the sales were more likely to occur in off-premise establishments.

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SC11

Special Considerations

ORGAN PROCUREMENT FROM POISONED PATIENTS

Xenobiotic poisonings can cause brain death. However, with supportive care, poisoned patients may be suitable candidates for organ donation depending on the xenobiotic and the target organ involved. Early identification of donors is critical as the viability of transplantable tissue diminishes as duration of brain death progresses and may be further complicated by the presence of xenobiotics that mimic brain death (Table SC11–1). Published brain death protocols require exclusion of poisoning, but obtaining and interpreting xenobiotic concentrations is complex and, in many circumstances, not feasible in a clinically meaningful timeframe. Although other methods of establishing brain death such as cerebral blood flow are utilized, the effects of xenobiotics on these studies are not well described. Once brain death is established, organ procurement personnel assist in obtaining familial consent, deciding which organs are most suitable for transplant, and maximizing physiological support and perfusion until organ procurement occurs. Successful transplantation of organs is reported from poisoned donors associated with a variety of xenobiotics (Tables SC11–2 and SC11–3). The 1-year survival in recipients from poisoned donors approximates that from nonpoisoned donors and was reported as 75% in one series. Additionally, in most transplant failures from poisoned donors, the causes are rejection, sepsis, or technical reasons, not the initial xenobiotic. Waitlists for organs are far greater than the number of available organs. Finding consensus on the ethics of

TABLE SC11–2    Organs Transplanted After Donor Poisonings

TABLE SC11–1    Xenobiotic Mimicsa of Clinical Brain Death

TABLE SC11–3    Xenobiotic-Related Deaths With Successful Organ Donation

Amitriptyline Baclofen Barbiturates Bupropion Lidocaine Phorate Snake envenomationb Valproic acid Vecuronium a

Based on reported cases. bCase from India, species not identified.

Organ

Xenobiotics Identified in Donors

Cornea

Brodifacoum, cyanide

Heart

Acetaminophen, β-adrenergic antagonists, alkylphosphate, benzodiazepines, brodifacoum, carbamazepine, carbon monoxide, chlormethiazole, cyanide, digitalis, digoxin, ethanol, glibenclamide, insulin, meprobamate, methanol, propoxyphene, thiocyanate

Kidney

Acetaminophen, brodifacoum, carbon monoxide, Conium maculatum, cyanide, ethylene glycol, insulin, malathion, methanol, cyclic antidepressants

Liver

Brodifacoum, carbon monoxide, Conium maculatum, cyanide, ethylene glycol, insulin, malathion, methanol, methaqualone, cyclic antidepressants

Lung

Brodifacoum, carbon monoxide, methanol

Pancreas

Acetaminophen, brodifacoum, carbon monoxide, Conium maculatum, cyanide, ethylene glycol, methanol, cyclic antidepressants

Skin

Cyanide, methanol

a

a

a

Can be cadaveric procurement.

procuring organs from poisoning fatalities is challenging. Patients who suffer brain death from poisoning are potentially suitable donors, and exclusion of this population for organ procurement should not be defined or limited by the xenobiotic.

β-Adrenergic antagonists Alkylphosphate Barbiturates Benzodiazepines Brodifacoum Carbamazepine Carbon monoxide Cardioactive steroids Chlormethiazole Conium maculatum Cyanide Cyclic antidepressants

Ethanol Ethylene glycol Glibenclamide Ibuprofen Insulin Malathion Methaqualone Meprobamate Methanol Nicotine Opioids Propoxyphene

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INDEX Note: Page numbers followed by f indicate figures; and page numbers followed by t indicate tables. A AAS (anabolic-androgenic steroids), 131–132, 132t Abacavir, 245 Abciximab, 284 Abdominal imaging, 44–46, 46f, 47f Abrin, 638t, 646, 646f Abrus precatorius (jequirity pea, rosary pea), 638t, 646f, 647 Absinthism, 152. See also Wormwood (Artemisia absinthium, absinthe) Abuse of alcohol. See Alcoholism (alcohol use disorder) of cannabinoids, 392 of cathartics/emetics, 130 of halogenated hydrocarbons, 337–338 of inhalants. See Inhalants of inhalational anesthetics, 337–338 of opioids, 80, 82t Acacia confusa, 372 Acanthaster planci (crown-of-thorns sea star), 623 Acanthoscurria. See Tarantulas Acarbose, 173–174, 175t Acebutolol, 294t, 295–296, 297, 300 ACEIs (angiotensin-converting enzyme inhibitors), 312–313, 312f Acetaminophen, 57–65 clinical manifestations of, 59 diagnostic testing in, 63 elimination techniques for, 65 history and epidemiology of, 57 isometheptene and, 232 management of, 63–64. See also N-acetylcysteine (NAC) metabolism of, 57, 58f pathophysiology of, 57–59 pharmacokinetics of, 57 pharmacology of, 57 prognosis of, 64–65, 65t properties of, 33t risk determination in after acute overdose, 59–61, 60f after chronic overdose, 61–62 biomarkers and, 63 in children, 62 CYP inducers and, 62 ethanol and, 62 with extended-release formulations, 61 with intravenous administration, 61 in pregnancy, 62 principles of, 59

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in uncertain diagnosis, 62 with unknown time of ingestion, 61 toxicokinetics of, 57 Acetanilid, 700 Acetic acids, 76t, 523t Acetohexamide, 175t Acetone, inhaled, 432t Acetonitrile, 686, 686f Acetylcholine (ACh), 577, 578f Acetylcholinesterase (AChE), 577, 578f Acetylcholinesterase (AChE) inhibitors, 341t, 344, 344t, 588. See also Physostigmine salicylate Acetylsalicylic acid (aspirin, ASA), 98, 283, 283f. See also Salicylates Acids, 524. See also Caustics; specific acids Ackee (Blighia sapida), 638t, 647 Aconite, 144t, 151–152 Aconitine, 638t, 648 Aconitum spp, 638t, 648 Acorus calamus, 638t Acromelic acid–containing mushrooms, 629t Acrylonitrile, 686 Actinia equina, 618t Actinodendron plumosum, 618t Activated charcoal (AC), 22–24 adverse effects of, 23 with cathartics or evacuants, 22 complications of, 16 contraindications to, 16t dosing and administration of, 15–16, 23–24 effects on oral therapeutics, 16 efficacy of, 14 formulation and acquisition of, 24 history, 22 indications for, 16t mechanism of, 14, 15f multiple-dose, 16–17, 17t, 23, 24 pharmacology of, 22 in pregnancy and lactation, 16 prehospital use of, 15, 23–24 safety issues with, 23 single-dose, 15–16, 16f, 23 vs. whole-bowel irrigation, 26 Activated prothrombin complex concentrates (aPCCs), 286–287 Acute coronary syndrome, cocaineassociated, 399 Acute promyelocytic leukemia differentiation syndrome (APL DS), 158

Acute radiation syndrome (ARS), 719 Acute respiratory distress syndrome (ARDS), 83, 91, 433, 461, 667 Adam (3,4-methylenedioxy‑ methamphetamine), 385t, 387 Adamsite (10-Chloro-5,10dihydrodiphenarsazine, DM), 708 Adamsite (DM), 709t Adenosine, 267t, 270 Adenosine diphosphate receptor inhibitors, 283–284 Adenosine reuptake inhibitors, 283 Adenosine triphosphate (ATP), 173, 174f Adhesives, inhaled, 431t Adrenergic antagonists (blockers) α1, 311 β-. See β-adrenergic antagonists Adulterants, in cocaine, 399–400 Aesculus hippocastanum (horse chestnut), 147t, 638t Agave lecheguilla, 638t Agent Orange, 574 Aggressive patient. See Violent patient Agitation, 6t Agkistrodon contortrix (copperhead), 651t, 652f. See also Pit viper bites Agkistrodon piscivorus (cottonmouth), 651t, 652f, 658, 658t. See also Pit viper bites Agkistrodon spp, 664t Air freshener, inhaled, 431t Airspace filling, 41–42, 44f, 44t Akathisia, 351–352, 352t Alachlor, 564t, 568–569 ALARA (as low as reasonably achievable), 718 Albendazole, 244t Albiglutide, 126t, 173, 174, 175t Alcohol. See Ethanol Alcohol dehydrogenase (ADH), 546. See also Ethanol Alcohol Use Disorders Identification Test (AUDIT-C), 411, 411t Alcohol withdrawal, 416–419 clinical manifestations of, 416–417, 416t diagnostic testing for, 417 history and epidemiology of, 416 management of, 91, 272, 417–419 pathophysiology of, 416 resistant, 418 risk factors for, 417 toxic syndrome, 2t

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740

INDEX

Alcoholic hallucinosis, 416 Alcoholic ketoacidosis (AKA), 182, 409–410 Alcoholism (alcohol use disorder), 410–411, 410t, 411t, 412t Alcohols, toxic, 542–547 chemistry of, 542 diagnostic testing for, 544–545, 545f history and epidemiology of, 542 management of, 545–547, 546t ethanol in, 546, 550–552, 551t folate and leucovorin in, 547 fomepizole in, 546, 548–549 formate in, 547 hemodialysis in, 546, 546t sodium bicarbonate in, 106 pathophysiology and clinical manifestations of, 542–544 poisoning epidemics of, 547 risk assessment for, 545 toxicokinetics and toxicodynamics of, 543f Aldrin, 591t Alfalfa, 144t Aliphatic hydrocarbons, 535, 535t, 536t, 671–672 Alkalis, 523–524. See also Caustics Alkalization, of urine, 30 Alkaloids anticholinergic, 342, 637 antimitotic, 649 central nervous system stimulants and depressants, 644 cholinergic, 644 history of, 637 isoquinoline, 644 nicotine and nicotinelike, 643–644 pharmacology of, 143, 637 psychotropic, 644 pyrrolizidine, 644 Alkyl nitrites, volatile, 431t, 432, 434, 434t Alkylating agents, 209t, 211f Allenic norleucine-containing mushrooms, 628t, 634–635, 635f Allergic dermatitis, 650 Allium porrum (leeks), 648 All-trans-retinoic acid (ATRA, tretinoin), 155, 158, 211f Almotriptan, 231t Aloe spp, 127t, 144t, 638t Alogliptin, 174, 175t Alopecia, 6t α particles, 715 α1-adrenergic antagonists, peripheral, 311 α-methyltryptamine (AMT, IT-290), 424 Alprazolam, 377t. See also Sedative-hypnotics Alteplase (t-PA), 281 Altered mental status, 4, 7f Alum, 445

158_Hoffman_Index_p0739-0776.indd 740

Aluminum, 445 Aluminum hydroxide, 234t, 236, 445 Aluminum phosphide, 558 Aluminum toxicity clinical manifestations of, 446 diagnostic testing for, 446 history and epidemiology of, 445 management of, 167, 446–447 pathophysiology of, 446 Amanita spp allenic norleucine–containing, 628t, 634–635, 635f 2R-amino-4,5-hydroxy-5-hexynoic acid–containing, 629t cyclopeptide-containing, 627–631, 628t, 629f, 630f muscimol-containing, 633, 633f Amantadine syrup, 172t Amatoxins, 33t, 627–629, 628t Amblyomma americanum (Lone Star tick), 609 American dog tick (Dermacentor variabilis), 609 American mistletoe (Phoradendron spp), 148t, 641t, 647 Americium, 719 Amide herbicides, 568–569, 568t Amiloride, 312 Amines, biogenic, 370 Amino alcohols, 248–251, 248t 2R-Amino-4,5-hydroxy-5-hexynoic acid–containing mushrooms, 629t Aminocaproic acid, 282 Aminoglutethimide, 132, 234t Aminoglycosides, 109t, 238t, 239, 239t, 341t 4-Aminoquinolones, 248t, 251–252 8-Aminoquinolones, 248t, 252 Amiodarone antithyroid effects of, 234t, 235t, 269–270 benzyl alcohol in, 169t clinical manifestations of, 266t, 269 imaging findings, 36t pharmacology of, 266t, 269 Amisulpride, 349t, 350, 350t. See also Antipsychotics Amitriptyline, 331, 356, 356f. See also Antidepressants, cyclic (CAs) Amlodipine, 303t. See also Calcium channel blockers (CCBs) Ammonia, 523t, 673–674, 673t Ammonium compounds, quaternary, 515t, 517–518 Ammonium sulfamate, 565t Amnestic shellfish poisoning, 118t, 119 Amobarbital, 377t. See also Sedative-hypnotics Amodiaquine, 248t, 252 Amoxapine, 356f. See also Antidepressants, cyclic (CAs) Amoxicillin-clavulanic acid, 240

Amphetamines, 383–388 as athletic performance enhancer, 135 bromo-dragonFLY (BDF), 387–388 cathinones, 387 clinical manifestations of, 368t, 383–384 2C-series, 388 diagnostic testing for, 384 2,5-dimethoxy-4-iodoamphetamine (DOI), 388 2,5-dimethoxy-4-methylamphetamine (DOM), 388 history and epidemiology of, 383 management of, 385–386, 387t methamphetamine, 386 N-2-methoxybenzylphenyethylamines, 388 3,4-methyelenedioxymethamphetamine (MDMA), 385t, 387 pathophysiology of, 383 pharmacokinetics and toxicokinetics of, 383 pharmacology of, 383, 384f, 385t, 386t phenylethylamines, 424–425. See also Hallucinogens for weight loss, 125, 127t Amphotericin B, 169t, 238t, 242–243, 244t Amrinone, 299, 303 AMT (α-methyltryptamine), 424 Amygdalin, 144t, 151, 642t, 645 Amyl nitrite, 431t, 434, 434t, 693–694 Amylin, 174 Amylin analog, 175t Anabaena spp (blue-green algae), 638t, 647 Anabolic xenobiotics. See Athletic performance enhancers, anabolic xenobiotics Anabolic-androgenic steroids (AAS), 131–132, 132t Anacardium occidentale (cashew), 638t, 650 Anaphylaxis in food poisoning, 122, 123t penicillin-related, 239–240, 240t Anastrozole, 132 Andexanet alfa, 276t, 281, 287–288 Androctonus spp, 616t Androgens, 234t Anemones, 618t, 619 Anemonia sulcata, 618t Anesthetics, inhalational, 335–338 abuse of, 337–338 halogenated hydrocarbons. See Halogenated hydrocarbons history and epidemiology of, 335 nitrous oxide. See Nitrous oxide pharmacokinetics of, 335 pharmacology of, 335 response to NMBs after, 341t

22/09/23 5:47 PM

INDEX

Anesthetics, local, 327–330 clinical manifestations of, 328–329, 328t, 329f, 329t diagnostic testing for, 329 history and epidemiology of, 327 pharmacokinetics of, 328 pharmacology of, 327, 327t treatment of, 329–330 Angioedema, 312–313 Angiography, 46, 47f Angiotensin II receptor blockers (ARBs), 312f, 313 Angiotensin-converting enzyme inhibitors (ACEIs), 312–313, 312f Anilide herbicides, 564t, 568–569 Anion inhibitors, 235t Anisakiasis, 120t, 122 Anisatin, 646 Annelida, 623 Anthoxanthum odoratum, 638t Anthozoa, 618, 618t, 619 Anthracyclines, 208, 209t, 212t, 227t Anthraquinone glycosides, 645 Anthrax, 710–711, 711f Antiandrogens, 132 Antibacterials aminoglycosides, 109t, 238t, 239, 239t, 341t β-lactam antibiotics, 238t, 240 cephalosporins, 238t, 239–240, 406t chloramphenicol, 238t, 241 fluoroquinolones, 238t, 241 linezolid, 238t, 372 macrolides, lincosamides, and ketolides, 238t, 241–242 nitrofurantoin, 36t, 238t, 406t penicillins, 238t, 239–240, 240t sulfonamides, 238t, 242, 248t tetracyclines, 238t, 242, 712 vancomycin, 238t, 242 Anticholinergic syndrome, 2t, 201, 203, 206, 427 Anticholinergics differential diagnosis of, 109t herbal, 153 physostigmine for, 206 in plants, 637, 643 toxic syndrome, 2t Anticholinesterases. See Acetylcholinesterase (AChE) inhibitors Anticoagulants. See Antithrombotics Antidandruff shampoos, 500, 500t Antidepressants, atypical, 365–366 drug discontinuation syndrome with, 366 norepinephrine/dopamine reuptake inhibitor, 362t, 363t, 366 presynaptic serotonin and norepinephrine releaser, 362t, 363t, 366

158_Hoffman_Index_p0739-0776.indd 741

receptor activity of, 363t seizure potential of, 363t serotonin antagonist/partial agonist/ reuptake inhibitors, 362t, 363t, 365 serotonin reuptake inhibitors/partial receptor agonists, 362t, 363t, 365 serotonin/norepinephrine reuptake inhibitors, 362t, 363t, 365 Antidepressants, cyclic (CAs), 356–360 classification of, 356, 356f clinical manifestations of, 357–358 diagnostic testing for, 358–359, 358f–359f history and epidemiology of, 356 interaction with ethanol, 406t management of, 104, 359–360 pathophysiology of, 356–357 pharmacokinetics and toxicokinetics of, 356 pharmacology of, 356, 356f response to NMBs after, 342t Antidepressants, tricyclic (TCAs), 358 Antidiabetics, 173–174, 175t. See also Hypoglycemia, drug-induced Antidotes. See also specific antidotes overview of, 5t in pregnancy, 8 Antidysrhythmics, 264–270. See also specific drugs adenosine, 267t, 270 class I, 264, 264f, 267, 268 class IA, 265t, 267–268 class IB, 265t, 268–269 class IC, 265t–266t, 269 class III, 266t, 269–270 class IV, 266t classification of, 264 digoxin. See Digoxin magnesium. See Magnesium Antiepileptics, 186–194. See also specific drugs for alcohol withdrawal, 418 history and epidemiology of, 186 hypersensitivity syndrome with, 193–194 mechanism of action of, 186t metabolism of, 188t for nerve agents, 706 pharmacokinetics of, 188t pharmacology of, 186, 187f Antiestrogens, 132 Antifolates, 248t, 253 Antifreeze. See Ethylene glycol Antifungals amphotericin B, 238t, 242–243, 244t clinical manifestations of, 238t, 243t triazoles and imidazoles, 238t, 243 Antihistamines, 197–203 atypical, 200

741

clinical manifestations of, 200–202 epidemiology of, 197 H1 clinical manifestations of, 200–201 interactions with ethanol, 406t mechanism of action of, 198f, 199 pathophysiology of, 201t pharmacokinetics and toxicokinetics of, 200, 200t H2 clinical manifestations of, 201–202 mechanism of action of, 199, 199f pharmacokinetics and toxicokinetics of, 200, 200t history of, 197 management of, 202–203 pharmacology of, 197–198 Antihypertensives angiotensin II receptor blockers, 313 angiotensin-converting enzyme (ACE) inhibitors, 312 β-adrenergic antagonists. See β-adrenergic antagonists calcium channel blockers. See Calcium channel blockers (CCBs) central imidazoline agonists, 310–311 classification of, 309t clonidine and other centrally acting agents, 309–311 direct renin inhibitors, 313 direct vasodilators, 311–312 diuretics, 312 sympatholytics, 310–311 Antimalarials, 247–254 amino alcohols, 248–251, 248t 4-aminoquinolones, 248t, 251–252 8-aminoquinolones, 248t, 252 antifolates and antibiotics, 248t, 253 endoperoxides, 248t, 252–253 history of, 247–248 naphthoquinones, 248t, 253 new directions in, 253–254 pharmacokinetics of, 249t Antimetabolites, 209t Antimicrobials (antibiotics). See also specific drugs adverse effects of, 238, 238t antibacterials. See Antibacterials antifungals. See Antifungals antineoplastic, 209t antiparasitics, 243 antivirals, 243. See also HIV therapeutics history and epidemiology of, 238 for malaria. See Antimalarials pharmacology of, 238t Antimigraine medications, 229–232. See also specific agents abortive, 229t calcitonin gene–related peptide (CGRP) antagonists, 232

22/09/23 5:47 PM

742

INDEX

Antimigraine medications (Cont.): 5-hydroxytrypamine1F receptor agonists, 232 isometheptene, 232 prophylactic, 229t triptans, 231–232, 231f, 231t Antimitotic agents, 71–74, 72t, 74t, 209t. See also Chemotherapeutics Antimony, 448–452 chemistry of, 448 clinical manifestations of, 449–451, 450t compounds of, 450t diagnostic testing for, 451 history and epidemiology of, 448 normal concentrations of, 448 pathophysiology of, 449 pentavalent, 244t pharmacology of, 448 stibine, 451 toxicokinetics of, 448–449 treatment of, 451–452 Antimuscarinic syndrome, central, 355 Antimuscarinics, 206, 344t Antineoplastics. See Chemotherapeutics Antioxidants, 160 Antiparasitics, 243 Antiplatelet agents, 276t, 282–284, 282f, 283f Antipsychotics, 348–355 acute overdose of, 354 adverse effects of acute dystonia, 351 akathisia, 351–352 extrapyramidal syndromes, 351, 352t neuroleptic malignant syndrome, 352–353, 353t parkinsonism, 352 tardive dyskinesias, 352 atypical, 348, 349t classification of, 349t diagnostic tests for, 354 history and epidemiology of, 348 management of, 354–355 pathophysiology and clinical manifestations of, 351–354, 351t pharmacokinetics and toxicokinetics of, 350t, 351 pharmacology of, 348–350, 350t typical, 348, 349t for violent behavior, 55–56 Antiseptics, disinfectants, and sterilants, 513–519 boric acid, 514t, 518–519 chlorates, 514t, 519 chlorhexidine, 513, 514t chlorine and chlorophors, 514t, 516 definitions of, 513 ethanol, 514t. See also Ethanol

158_Hoffman_Index_p0739-0776.indd 742

ethylene oxide, 514t, 518 formaldehyde, 514t, 516–517 glutaraldehyde, 514t, 518 hexachlorophene, 515t, 517 history and epidemiology of, 513 hydrogen peroxide, 513, 514t, 515 iodine and iodophors, 514t, 515–516 isopropanol, 514t. See also Isopropanol mercurials, 514t, 516 phenol, 515t, 517 potassium permanganate, 514t, 516 quaternary ammonium compounds, 515t, 517–518 substituted phenols, 515t, 517 Antithrombin agonists, 276t, 277–278 Antithrombotics, 273–284 antiplatelet agents, 276t, 282–284, 282f, 283f antithrombin agonists, 276t, 277–278 direct thrombin inhibitors, 276t, 278–280 factor Xa inhibitors, 276t, 280–281 fibrinolytic agents, 276t, 281–282 history and epidemiology of, 273 management of, 273 pentasaccharides, 276t, 281 physiology of, 273, 274f vitamin K antagonists. See Vitamin K antagonists Antithyroid medications, 234t, 236–237 Antituberculous medications bedaquiline, 260–261 capreomycin, 257t, 260 cycloserine, 257t, 259–260 delamanid, 261 ethambutol, 244t, 257t, 259 ethionamide, 257t, 260 history and epidemiology of, 255 isoniazid. See Isoniazid (INH) para-aminosalicylic acid, 257t, 260 pyrazinamide, 257t, 259 rifamycins, 257t, 258–259 Antivenom phenol concentration in, 170t scorpion, 615–617 adverse effects of, 615 for Centruroides spp, 615, 616t dosing and administration of, 615 formulation and acquisition of, 615, 616t history of, 615 pharmacology of, 615 in pregnancy and lactation, 615 for species not native to North America, 616t, 617 sea snake, 624, 624t snake, 654t, 655, 662 Crotalidae immune F(ab′)2 (equine). See Crotalidae immune F(ab′)2 (equine)

Crotalidae polyvalent immune Fab antivenom (ovine). See Crotalidae polyvalent immune Fab antivenom (ovine) experimental cross-reactivity of, 663, 664–665t hospital use of, 663 North American Coral Snake Antivenin (equine). See North American Coral Snake Antivenin (equine) zoological and exotic, 663 spider adverse effects of, 614 availability of, 613t dosing and administration of, 614 formulation and acquisition of, 614 funnel web spp, 614 history of, 613 Lactrodectus spp, 614 Loxosceles spp, 614 pharmacology of, 613–614 in pregnancy and lactation, 614 thimerosal concentration in, 172t Antivenom Index, 662 Antivirals, 243. See also HIV therapeutics Ants. See Fire ants (Hymenoptera) Anxiolytics, 376. See also Sedative-hypnotics Aortic dissection, 42, 45f APAP. See Acetaminophen Aphanizomenon, 638t Apidae (bees), 609–610, 609f, 610t Apixaban, 276t, 279t, 280–281 APL DS (acute promyelocytic leukemia differentiation syndrome), 158 Apocynum cannabinum (dogbane), 314, 320 Apraclonidine, 168t Apricot pits, 144t, 642t, 645 Arachidonic acid (AA), 77f ARBs (angiotensin II receptor blockers), 312f, 313 ARDS (acute respiratory distress syndrome), 83, 91, 433, 461 Areca catechu (betel nut), 144t, 152, 638t, 644 Arecoline, 638t, 644 Argatroban, 276t, 279–280, 279f Argemone mexicana (Mexican pricklepoppy), 638t, 644 Argyreia nervosa (Hawaiian baby woodrose), 423, 425t Argyreia spp, 638t. See also Morning glory Argyria, 503–504, 504f Aripiprazole, 349t, 350, 350t. See also Antipsychotics Aristocholia, 144t, 152 Aristocholic acid, in plants, 648 Aristolochia spp (Texan or Red River snake root), 638t, 648 Aromatase inhibitors, 132 Aromatic acid herbicides, 564t

22/09/23 5:47 PM

INDEX

Aromatic hydrocarbons, 535t, 536t Arsenic, 453–456 chemistry of, 453 clinical manifestations of, 454–455, 455f diagnostic testing for, 455–456 history and epidemiology of, 453 management of, 456 dimercaprol in, 456, 457 succimer in, 456, 486 normal concentrations of, 453 pharmacokinetics and toxicokinetics of, 454 pharmacology/physiology of, 453 toxicology/pathophysiology of, 453–454, 453f, 454f Arsenic contamination, 217–219 Arsenic trioxide, 208, 211f, 212t, 455 Arteether, 248t, 252–253 Artemether, 248t, 252–253 Artemisia absinthium. See Wormwood (Artemisia absinthium, absinthe) Artemisinin, 249t, 252–253 Artemisone, 248t Artesunate, 248t, 252–253 Arthropod repellents, 595, 595t Arthropods, 603–612. See also specific types antivenom for, 613–617 descriptions of, 603t history and epidemiology of, 603, 603t North American, of medical importance, 603t taxonomy of, 603, 603f, 603t Arthroprosthetic cobaltism, 469, 470 Artificial tears, 168t Arylcyclohexylamines. See Ketamine; Phencyclidine (PCP) Asbestos, 36t, 44f Asclepias syriaca (milkweed), 314, 638t Ascorbic acid (vitamin C), 156t, 160–161 Asenapine, 349t, 350, 350t, 351. See also Antipsychotics l-Asparaginase, 209t, 211f Aspart, 176t Asphalt injury, 540 Asphyxiants chemical, 666, 666t simple. See Simple asphyxiants toxic thermal degradation products in, 666t Aspirin (acetylsalicylic acid, ASA), 98, 283, 283f, 406t. See also Salicylates Asthma, 677, 677t Astoria tokesii (Stokes’ sea snake), 624 Astragalus (Astragalus membranaceus), 144t Astragalus spp (locoweed), 638t, 644 Astrovirus, 117t Ataxia, 6t Atenolol, 33t, 294t, 295–296, 297 Athlete’s biological passport, 136

158_Hoffman_Index_p0739-0776.indd 743

Athletic performance enhancers, 131–135. See also specific substances anabolic xenobiotics, 131–133 administration of, 132 anabolic androgenic steroids, 131–132, 132t antiestrogens and antiandrogens, 132 clinical manifestations of, 132–133 metabolic pathway of, 132–133 banned, 131, 131t diuretics, 135 history and epidemiology of, 131 laboratory detection of, 135–136 masking xenobiotics for, 135–136 for neurocognitive enhancement, 136 for oxygen transport, 134–135 peptides and glycoprotein hormones, 133–134 principles of, 131 stimulants, 135 sudden death in athletes and, 136 Atovaquone, 244t, 248t, 249t, 253 ATRA (All-trans-retinoic acid, tretinoin), 155, 158 Atractylis gummifera (thistle, atractylis), 144t, 638t Atractyloside, 638t, 645–646 Atracurium, 169t, 340t. See also Neuromuscular blockers (NMBs) Atrax spp ( funnel web spider), 607–608, 613t, 614 Atrazine, 576 Atropa belladonna, 638t Atrophy, brain, 48, 48t Atropine, 586–587 adverse effects and safety issues for, 586 for calcium channel blocker toxicity, 305 for chemical weapons nerve agents, 587 for decongestant overdose, 205 dosage and administration of, 586–587 formulation and acquisition of, 587 history of, 586 for nerve agents, 706 for NMB reversal, 344t for organic phosphorus and carbamate insecticides, 586 pharmacology of, 586 in pregnancy, 586 Atypical antidepressants. See Antidepressants, atypical AUDIT-C (Alcohol Use Disorders Identification Test), 411, 411t Australian estuarine stonefish, 625t Australian marsupial tick (Ixodes holocyclus), 609 Autumn crocus (Colchicum autumnale), 144t, 639t, 649 Avascular necrosis, femoral head, 43f Ayahuasca, 150, 153, 153t, 424

743

Ayurvedic remedies, 150–151 Azalea spp (azalea), 638t, 649 Azelastine, 200 Azithromycin, 244t, 248t Azole antifungals, 243 Aztreonam, 240 B BabyBIG (botulism immune globulin), 113, 114, 116 Bacillus anthracis, 710–711 Bacillus cereus food poisoning, 117t, 120t, 121 Bacitracin, 243t Baclofen, 418–419, 430 Bacteriostatic saline/water, 169t Bagging, 431. See also Inhalants BAL (British anti-Lewisite). See Dimercaprol (British anti-Lewisite, BAL) Banisteriopsis caapi (caapi), 145t, 153, 153t, 371–372, 424 Barbiturates, 376, 377t, 378. See also Sedative-hypnotics Barium, 556–557, 556t Bark scorpion (Centruroides exilicauda), 608, 608t, 616t Batrachotoxin (poison dart frog), 109t 1,4-BD (1,4-butanediol), 428, 429t BDF (bromo-dragonFLY), 387–388 Beaded lizard (Heloderma horridum), 652, 652f Beaked sea snake (Enhydrina schistosa), 624, 624t Becquerel (Bq), 716f Bedaquiline, 260–261 Bee pollen, 144t Bee venom, 144t “Beer drinkers’ cardiomyopathy,” 468 Bees (Apidae), 609–610, 609f, 610t Belladonna alkaloids, 425, 637, 638t, 643 Benzalkonium chloride, 168, 168t, 515t, 518, 523t Benzene, 535t, 536t, 539 Benzocaine, topical, 327, 328. See also Anesthetics, local Benzodiazepine receptors, 381, 401–402, 401f, 402f Benzodiazepines, 401–404. See also Sedative-hypnotics adverse effects and safety issues for, 404 for alcohol withdrawal, 417–418 for cannabinoid hyperemesis syndrome, 392 chemistry of, 401 for chloroquine overdose, 403–404 for cocaine-associated chest pain, 404 dosing and administration of, 402t, 404 flumazenil for reversal of. See Flumazenil formulation and acquisition of, 402t, 404

22/09/23 5:47 PM

744

INDEX

Benzodiazepines (Cont.): for GHB withdrawal, 430 for hallucinogen toxicity, 427 history of, 401 mechanism of action of, 378 for neuroleptic malignant syndrome, 353 for nicotine-induced seizures, 439 for organic phosphorus insecticides, 585 for PCP-associated agitation, 444 pharmacokinetics and pharmacodynamics of, 377t, 402–403, 402t in pregnancy and lactation, 404 for psychomotor agitation, 403 for sedative-hypnotic withdrawal, 403 for violent behavior, 55 for xenobiotic-induced seizures, 403 Benzoylecgonine, 395, 395f Benzphetamine, 127t Benztropine, 351 Benzyl alcohol (benzene methanol), 168–169, 169t, 547 Berberine, 638t, 639t, 640t, 644 Berberis spp, 638t Bergamottin, 639t, 648 Beriberi, 414 Beryllium, 36t, 42 Beta blockers. See β-adrenergic antagonists (blockers) β-adrenergic agonists history and epidemiology of, 323 management of, 324–325 pharmacokinetics and toxicokinetics of, 324 pharmacology of, 324 toxicity spectrum of, 323 β-adrenergic antagonists (blockers), 293–300 for alcohol withdrawal, 418 clinical manifestations of, 266t, 296–297 in combination products, 297 contraindications to, 374 diagnostic testing for, 297 epidemiology of, 293 history of, 293 hypoglycemia and, 174–175 management of, 297–300, 298f calcium in, 298–299, 533 catecholamines in, 299 extracorporeal removal in, 299 glucagon in, 298, 301–302 insulin and glucose in, 299 lipid emulsion in, 299 mechanical life support in, 300 for membrane stabilizing effects, 300 observation in, 300 for peripheral vasodilating effects in, 300

158_Hoffman_Index_p0739-0776.indd 744

phosphodiesterase inhibitors in, 299 sotalol in, 300 ventricular pacing in, 299 ophthalmic, 294t, 296, 297 pathophysiology of, 296 pharmacokinetics of, 266t, 295–296, 295f pharmacology of, 293–295, 294t response to NMBs after, 341t sustained release, 297 for thyroxine overdose, 236 β-adrenergic receptors in heart, 293 noncardiac effects of activation of, 293 Betadine, 514t β-lactam antibiotics, 238t, 240 β particles, 715 Betaxolol, 168t, 294t, 295–296, 297, 300 Betel nut (Areca catechu), 144t, 152, 638t, 644 Betrixaban, 280–281 Bialaphos, 565t Biguanides, 175t. See also Metformin Biodosimetry, radiation, 719 Biogenic amines, 370 Biological weapons, 710–714 anthrax, 710–711, 711f botulinum toxin, 714 brucellosis, 712 vs. chemical weapons, 704t decontamination for, 710 definitions and acronyms, 703t fungi and fungal toxins, 714 history of, 710 vs. naturally occurring outbreaks, 710, 710t plague, 712 preparation for, 710 Q fever, 712 ricin, 714 rickettsiae, 712 smallpox, 713, 713f staphylococcal enterotoxin b, 714 trichothecen mycotoxins, 714 tularemia, 712 viral encephalitides, 713–714 viral hemorrhagic fevers, 713 Bioterrorism, food poisoning in, 123 BioUD, 595t Bipyridyl herbicides. See Paraquat Birgus latro L. (Coconut crab), 320 Bismuth, 459–460, 459t, 460t Bismuth subsalicylate, 98–99. See also Salicylates Bisoprolol, 294t, 295, 297 Bispyribac, 564t Bitter orange extract (Citrus aurantium) adverse effects of, 144t as decongestant, 203 primary toxicity of, 639t

stimulant effects of, 644 for weight loss, 125–126, 126t Bivalirudin, 276t, 279f Black cohosh, 144t Black locust (Robinia pseudoacacia), 642t, 647 Black phosphorus, 597. See also Phosphorus Black widow spider (Latrodectus mactans, hourglass spider), 603–605, 604f, 613t, 614 Blackfoot disease, 455 Bleach, 516 Bleomycin, 209t Blighia sapida (ackee), 638t, 647 Blindness, 6t Blister beetles, 611–612 Blood alcohol concentration (BAC), 734 Blood doping, 136 Blood pressure normal, by age, 1t in toxic syndromes, 2t xenobiotics affecting, 2t Blue cohosh (Caulophyllum thalictroides), 144t, 639t, 643 Blue skin, 6t Bluebottle (Physalia utriculus), 618, 618t, 620 Blue-green algae (Anabaena spp), 638t, 647 Blue-ringed octopus (Hapalochlaena maculosa), 622–623, 622f Body packers bioavailability and, 93 clinical manifestations of, 93 imaging findings, 36t, 37–38, 40f, 46t, 93, 94f laboratory evaluation of, 93, 398 legal principles and, 95 management of, 88, 93–95, 94f package composition, 93 Body stuffers, 36t, 38, 95 Body temperature, 2–3, 2t, 3t Boletus spp, 628t, 629t Boneset, 144t Borage (Borago officinalis), 144t, 638t Boric acid, 514t, 518–519, 523t Bothriechis spp, 664t Bothrops spp, 664t Botulinum antitoxin, 114–116 for adult botulism, 113, 114 adverse effects and safety issues for, 115 dosing and administration of, 115–116, 116t formulation and acquisition of, 116 history of, 114 for infant botulism, 113, 114–115 pharmacology of, 114, 115t in pregnancy and lactation, 115 Botulinum toxins, 108, 109f, 341t, 714 Botulism, 108–113 adult intestinal colonization, 111 bacteriology of, 108

22/09/23 5:47 PM

INDEX

clinical manifestations of, 109–111, 118t diagnosis of, 111–112, 112f, 112t differential diagnosis of vs. Guillain-Barré syndrome, 110t nontoxicologic, 110t toxicologic, 109t epidemiologic and therapeutic assistance for, 113 foodborne, 109, 112t history and epidemiology of, 108, 117t iatrogenic, 111 infant. See Infant botulism inhalational, 111 pathophysiology of, 108, 109f pharmacokinetics of, 108 in pregnancy, 113 prognosis of, 113 toxicokinetics of, 108 treatment of, 112–113 wound, 111 Botulism immune globulin (BabyBIG), 113, 114, 116 Bowel obstruction, 40f, 45, 46t Box jellyfish, 618t, 621, 624t Bq (becquerel), 716f Brachypelma. See Tarantulas Bradycardia, 2t Bradypnea, 3t Brain death clinical diagnosis of, 737 organ procurement after, in poisoning, 737, 737t xenobiotic mimics of, 737t Brassaia spp, 638t Brassica nigra, 638t Brassica oleracea var. capitata, 638t Brazilian scorpion (Tityus serrulatus), 608f Breath-testing devices, for alcohol, 735 Brevetoxin, 118t, 119 Bridging, in AAS use, 132 Brimonidine/timolol, 168t Bristle worms, 623 British anti-Lewisite (BAL). See Dimercaprol (British anti-Lewisite, BAL) Brittle stars, 623 Brodifacoum, 289 Bromides, 379. See also Sedative-hypnotics 4-Bromo-2,5-dimethoxy-amphetamine (DOB), 385t. See also Amphetamines 4-Bromo-2,5-methoxyphenyl-ethylamine (2CB, MFT), 385t. See also Amphetamines Bromocriptine, 230t, 353 Bromo-dragonFLY (BDF), 387–388 Bronchospasm, cocaine-associated, 396 Broom (Cytisus scoparius), 144t, 153t, 639t, 643

158_Hoffman_Index_p0739-0776.indd 745

Brown recluse spider (Loxosceles reclusa, violin or fiddleback spider), 605–606, 605f, 606t, 613t, 614 Brucellosis, 712 Brucine, 643t, 644 Bubonic plague, 712 Buchu, 144t Bucindolol, 294t, 296, 297, 300. See also β-adrenergic agonists Buckthorn (Karwinskia humboldtiana) clinical manifestations of, 109t, 640t, 648 differential diagnosis of, 109t usages of, 109t for weight loss, 127t Bufadienolides, 145t, 152, 314 Bufo spp toad, 314, 320, 424 Bufotenine, 423, 424f Bullrout (Notesthes robusta), 625t Bumetanide, 169t, 312 Bungarotoxin, 109t Bupivacaine. See also Anesthetics, local clinical manifestations of, 328–329 injection, parabens in, 170t lipid formulations of, 169t pharmacology of, 327t toxic intravenous dose of, 328t treatment of, 329–330. See also Intravenous lipid emulsion (ILE) Buprenorphine, 84t, 86, 92, 97 Bupropion, 351, 362t, 363t, 366. See also Antidepressants, atypical Bupropion/naltrexone, 126t, 129 Burdock root, 144t Busulphan, 209t Butabarbital, 377t. See also Sedative-hypnotics Butachlor, 564t, 568–569 Butane, 431t, 432t, 672 1,4-Butanediol (1,4-BD), 428, 429t Buthus spp, 616t, 617 Butorphanol, 84t Butoxyethanol, 549 Butterflies, 610–611 Butyl nitrite, 431t Bystander effect, radiation, 718 BZ (3-quinuclidinyl benzilate, QNB), 708, 709t C Caapi (Banisteriopsis caapi), 145t, 153, 153t Cachectic (disuse) myopathy, 344t Cactus spp, 638t Cadmium, 461–462, 461t Cadmium oxide fumes, 673t Caffeine, 323–326 as athletic performance enhancer, 135 in commonly used products, 323, 323t

745

diagnostic testing for, 325 management of, 325–326, 326t medical uses of, 323 pathophysiology of, 324–325 pharmacokinetics and toxicokinetics of, 324 properties of, 33t therapeutic concentration of, 323 for weight loss, 125, 127t withdrawal from, 323 Caffeinism, 323 CAGE questions, 411t Calabar bean (Physostigma venenosum), 641t, 644 Caladium spp, 638t Calcified pleural plaques, 42f, 44 Calcitonin, 159 Calcitonin gene–related peptide (CGRP) antagonists, 232 Calcium, 532. See also Calcium (therapeutic) Calcium carbonate suspension, 172t Calcium channel blockers (CCBs), 303–306 classification of, 303, 303t clinical manifestations of, 266t, 304 diagnostic testing for, 304 disposition in, 306 history and epidemiology of, 303 management of, 304–306, 305f, 532–533, 533t pharmacokinetics and toxicokinetics of, 303, 303t pharmacology of, 303 physiology and pathophysiology of, 303–304, 304f response to NMBs after, 341t for vasoconstriction, 231 Calcium channels in cardiac cycle, 293, 295f, 296f, 304f voltage-gated, 303, 303t Calcium chloride, 533t. See also Calcium (therapeutic) Calcium diethylenetriaminepentaacetic acid. See Pentetic acid/pentetate (zinc or calcium) trisodium (DTPA) Calcium edetate disodium. See Edetate calcium disodium (CaNa2EDTA) Calcium edetate disodium (CaNa2EDTA) for lead, 482, 483t succimer with, 486 Calcium gluconate. See also Calcium (therapeutic) for calcium channel blocker toxicity, 533t for hydrofluoric acid, 502, 531 for selenium hexafluoride gas, 502 Calcium preparations, 234t Calcium (therapeutic) adverse effects and safety issues for, 534 for β-adrenergic antagonists, 298–299, 533

22/09/23 5:47 PM

746

INDEX

Calcium (therapeutic) (Cont.): for calcium channel blockers, 305, 532–533, 532t for citrates, 534 dosing and administration of, 533t, 534 for ethylene glycol, 533 formulation and acquisition of, 534 for hydrofluoric acid, 533 for hyperkalemia, 533–534 for hypermagnesemia, 533 for phosphates, 533 in pregnancy and lactation, 534 California poppy, 153t California sculpin, 625t Calotropis spp, 638t Camellia sinensis, 638t Camphor clinical manifestations of, 137–138, 520 diagnostic testing for, 520 history and epidemiology of, 137, 142, 520 management of, 520 pathophysiology of, 137, 138f, 139f, 520 pharmacokinetics and toxicokinetics of, 520 pharmacology of, 137, 520 Camphorated oil, 520 Camptothecins, 209t, 211f Campylobacter jejuni food poisoning, 117t, 120t, 121–122 CaNa2EDTA. See Edetate calcium disodium (CaNa2EDTA) Canagliflozin, 174, 175t Cangrelor, 284 Cannabinoids, 389–394 acute toxicity, 390–392 adverse reactions to, 392–393 clinical manifestations of, 390 diagnostic testing for, 393–394, 393t driving ability and, 393 history and epidemiology of, 389 management of, 394 medical uses of, 389 pharmacokinetics and toxicokinetics of, 390, 392f pharmacology and pathophysiology of, 389–390, 391f Cannabis spp, 389, 639t Cantharidin, 611–612 Capecitabine clinical manifestations of, 209t, 215 management of, 216, 216f, 223–224 mechanism of action of, 211f pathophysiology of, 215 pharmacology of, 215, 215f Capillary glass chromatography–mass spectrometry, 135 Capreomycin, 257t, 260 Capsaicin (Capsicum annuum), 639t, 647, 675, 708

158_Hoffman_Index_p0739-0776.indd 746

Capsicum (Capsicum spp), 639t Capulincillo (Karwinskia humboldtiana ), 640t, 648 Carbamate insecticides, 577–585 clinical manifestations of, 582 diagnostic testing for, 583 differential diagnosis of, 109t history and epidemiology of, 577 management of, 585 pathophysiology of, 579–580, 580f pharmacokinetics and toxicokinetics of, 579 pharmacology of, 577–578, 579f Carbamazepine antithyroid effects of, 234t clinical manifestations of, 186–187, 193t diagnostic testing for, 187 drug interactions of, 189t mechanism of action of, 186t metabolism of, 188t pharmacokinetics and toxicokinetics of, 186, 188t properties of, 33t response to NMBs after, 341t syrup, sorbitol in, 172t Carbanilate herbicides, 564t Carbimazole, 236–237 Carbol-fuchsin solution, 243t Carbon dioxide, 672 Carbon monoxide (CO), 678 Carbon monoxide (CO) poisoning, 678–682 cascade of events in, 684f clinical manifestations of, 679 diagnostic testing for, 679–680 history and epidemiology of, 678, 678t imaging findings, 36t, 48, 50f, 679f, 680 inhalational anesthetic-related, 337 management of, 680–682 airway management and monitoring in, 680 in children, 682 hyperbaric oxygen in, 680–681, 681t, 683–684 initial, 670 in pregnancy, 681–682 prevention of, 682 pathophysiology of, 678–679 smoke inhalation and, 670 sources of, 678t toxicokinetics of, 678 Carbon tetrachloride (CCl4) clinical manifestations of, 53 hyperbaric oxygen for, 685 inhaled, 432t, 433. See also Inhalants toxicokinetics of, 536t uses and viscosity of, 535t Carboplatin, 209t Carboxyhemoglobin (COHb), 679–681 Carboxylic acids, in plants, 648

Carboxypeptidase G2 (CPDG2). See Glucarpidase (carboxypeptidase G2, CPDG2) Carburetor cleaners, inhaled, 431t, 434t Cardenolides, 314, 314f Cardiac cycle, 293, 295f Cardioactive steroids (CASs), 314–318 chemistry of, 314, 314f clinical manifestations of, 316–317, 316t diagnostic testing for, 317 endogenous digoxinlike immunoreactive substance, 317 history and epidemiology of, 314 management of, 317–318, 317t mechanisms of action and pathophysiology of, 315–316, 315f, 315t, 316f pharmacokinetics of, 314–315, 314t from plants, 645–646 response to NMBs after, 341t Cardiomyopathy, dilated, 42 Cardiovascular abnormalities, 42, 45f Carisoprodol, 379. See also Sedative-hypnotics Carmustine, 209t l-Carnitine (levocarnitine), 195–196 Carp bile, 145t Carteolol, 168t, 294t, 296, 297, 300. See also β-adrenergic agonists Carvedilol, 294t, 295–296, 297, 300. See also β-adrenergic agonists Carybdea spp, 618t, 620 Cascara (Cascara sagrada), 130, 145t, 639t Cashew (Anacardium occidentale), 638t, 650 Caspofungin, 244t Cassava (Manihot esculenta), 641t, 645 Cassia spp (senna), 127t, 130, 149t, 639t Castor bean (Ricinus communis), 642t, 646–647, 646f Cat, 385t, 387 Catecholamines for β-adrenergic antagonist toxicity, 299 for calcium channel blocker toxicity, 306 in hypoglycemia, 176 Caterpillars, 610–611 Catha edulis (khat), 147t, 385t, 387, 639t, 644. See also Amphetamines Catharanthus roseus (catharanthus, vinca, Madagascar periwinkle), 639t, 649 Cathartics, 17 abuse of, for dieting, 130 Cathinones, 387, 644 Catnip, 145t, 153t Caulophyllum thalictroides (blue cohosh), 144t, 639t, 643 Caustics, 523–528 classification and progression of injury with, 524, 525t clinical presentation of, 524–525, 524f

22/09/23 5:47 PM

INDEX

decontamination for, 20 definition of, 523 diagnostic testing for, 525–526 history and epidemiology of, 523 imaging findings, 36t, 525, 526f management of, 527–528 ophthalmic exposures to, 20, 528 pathophysiology of, 523–524 predictors of injury with, 525 sources of, 523t 2C-B (4-bromo-2,5-methoxyphenylethylamine), 385t, 424f, 425, 425t. See also Hallucinogens CCA-treated lumber, 465 Cefazolin, 240 Cefotetan, 240 Celecoxib, 75, 76t Celiprolol, 294t, 295–296, 297, 300. See also β-adrenergic agonists Cellular chemokine receptor (CCR5) antagonists, 246 Central antimuscarinic syndrome, 355 Centruroides exilicauda (bark scorpion), 608, 608t, 616t Cephaelis ipecacuanha (syrup of ipecac), 130, 639t, 644 Cephaelis spp. See Ipecac, syrup of (Cephaelis ipecacuanha) Cephaline, 644 Cephalopoda, 621–622 Cephalosporins, 238t, 240, 406t Cerbera manghas (sea mango), 314, 320 Ceruloplasmin, 471 Cesium, 463–464, 509, 719 Cetirizine, 200, 200t CGRP (calcitonin gene–related peptide) antagonists, 232 Chacruna (Psychotria viridis), 145t, 153, 154t Chamomile, 145t Ch’an Su, 145t, 152, 153t Chaparral, 145t Chelation. See also specific chelating agents for arsenic, 456, 457 for bismuth, 460 for cobalt, 470 for copper, 473 for lead, 458, 482–483, 483t for mercury, 457, 496 for nickel, 499 for thallium, 507 Chemical asphyxiants, 666t, 667 Chemical weapons, 703–709 vs. biological weapons, 704t in children, 705 cyanides, 707, 709t decontamination for, 703–705 definitions and acronyms, 703t exposure risk, 705 history and epidemiology of, 703

158_Hoffman_Index_p0739-0776.indd 747

incapacitating agents in, 708 Israeli experience with during Gulf War, 705 nerve agents, 705–706, 708t physical properties of, 703 preparation for incidents with, 703, 704t psychological effects of, 705 pulmonary irritants, 707, 709t riot control agents, 707–708, 709t vesicants, 706–707, 709t Chemotherapeutics, 208–212. See also specific substances classification and effects of, 208, 209t–210t extravasational injury from, 227–228, 227t intrathecal administration of, 225–226 mechanism of action of, 208, 210t, 211f toxicity of clinical manifestations of, 208–210, 209t–210t, 212t diagnostic testing for, 210 imaging findings, 36t management of, 210–211 patient-specific factors in, 208 workplace safety issues for, 211–212 Chernobyl incident, 724 Chest pain, after cocaine use, 42, 45f, 404 Chest radiography, 44t Chinese herb nephropathy, 130 CHIPES mnemonic, 35 Chirodropidae, 618 Chironex fleckeri (sea wasp), 618–621, 618t Chiropsalmus spp, 618t, 620 Chitosan, 126t Chloral hydrate, 377f, 377t, 379. See also Sedative-hypnotics Chlorambucil, 209t Chloramines, 673t, 674, 674f Chloramphenicol, 238t, 241 Chlorates, 514t, 519 Chlordane, 591t. See also Organic chlorine pesticides Chlordecone, 591t, 593. See also Organic chlorine pesticides Chlordiazepoxide, 377t. See also Sedative-hypnotics Chlorfenapyr, 593 Chlorhexidine, 513, 514t Chlorine, 514, 514t, 516 Chlorine (gas) characteristics of, 673t, 674, 674f as chemical weapon, 707, 709t sodium bicarbonate for, 106–107 4-Chloro-2-methylphenoxyacetic acid (MCPA), 566t, 574–575 10-Chloro-5,10-dihydrodiphenarsazine (Adamsite, DM), 708 Chloroacetophenone (CN), 675, 707–708 Chlorobenzilate, 591t

747

Chlorobenzylidene malononitrile (CS), 675, 707–708 Chlorobutanol, 169, 169t Chlorophenoxy herbicides, 106 Chlorophors, 514, 516 Chlorophyllum spp, 628t, 633–634 Chlorophytum comosum, 639t Chloropicrin (PS), 708 Chloroprocaine, 328t, 329t. See also Anesthetics, local Chloroquine, 248t, 249t, 251–252 Chlorpheniramine, 200, 200t Chlorproguanil, 248t Chlorpromazine, 349t, 350t. See also Antipsychotics Chlorpropamide, 175t, 176 Chlorprothixene, 349t. See also Antipsychotics Chlorthalidone, 312 Cholecalciferol. See Vitamin D Cholestyramine, 234t, 236 Cholinergic syndrome, 2t, 36t, 580–581, 580f Cholinergics, in plants, 644 Cholinesterase inhibitors. See Acetylcholinesterase (AChE) inhibitors Chondrodendron spp (curare), 339, 639t, 644 Chromium, 465–467 clinical manifestations of, 466 common forms of, 465t diagnostic testing for, 466 history and epidemiology of, 465 management of, 466–467 normal concentrations of, 465 pathophysiology of, 456 pharmacokinetics and toxicokinetics of, 465–466 pharmacology, 465 Chromium picolinate, 126t, 465, 465t, 466 Chrysanthemum (Chrysanthemum spp), 593, 639t Chrysaora quinquecirrha (sea nettle), 618t, 619, 620 Chuen-Lin, 145t Ci (curie), 716f Cicuta douglasii (western water hemlock), 648 Cicuta maculata (water hemlock), 639t, 648 Cicutoxin, 639t, 648 Cigarettes, 436, 436t. See also Nicotine Cigars, 436, 436t. See also Nicotine Ciguatera poisoning, 117–119, 118t Cilostazol, 283 Cimetidine for dapsone overdose, 253, 700 drug interactions of, 289t, 406t history of, 197 pharmacokinetics of, 200, 200t syrup, 172t

22/09/23 5:47 PM

748

INDEX

Cinchona (Cinchona spp), 145t, 639t “Cinchonism,” 250 Cinnamon, 153t Ciprofloxacin for anthrax, 711 ophthalmic, benzalkonium chloride in, 168t for plague, 712 for tularemia, 712 Cisatracurium, 340t. See also Neuromuscular blockers (NMBs) Cisplatin, 209t Citalopram, 362–363, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Citrates, 534 Citronella oil, 595t Citrus aurantium. See Bitter orange extract (Citrus aurantium) Citrus paradisi (grapefruit), 639t, 648 Clarithromycin, 244t Claviceps paspali, 639t Claviceps purpurea, 229, 423, 639t Clearance (Cl), 31 Clenbuterol adverse effects of, 127t as athletic performance enhancer, 133, 323 as heroin contaminant, 84 as illegal food additive, 123 mechanism of action of, 128f Clevidipine, 303t. See also Calcium channel blockers (CCBs) Clindamycin, 242, 243t, 244t, 248t Clitocybe acromelalga, 629t Clitocybe dealbata, 628t, 632, 632f Clofarabine, 211f Clomiphene, 132 Clomipramine, 356f. See also Antidepressants, cyclic (CAs) Clonazepam, 376, 377t. See also Sedative-hypnotics Clonidine for alcohol withdrawal, 418 clinical manifestations of, 310 diagnostic testing for, 310 management of, 310 pathophysiology of, 310 pharmacokinetics of, 309–310 pharmacology of, 309 withdrawal from, 310 Clopidogrel, 283–284 Clorazepate, 377t. See also Sedative-hypnotics Clorgyline, 364t, 371 Clostridium spp, 108, 117t, 120. See also Botulism Clove, 145t, 154t Clove oil, 138, 142

158_Hoffman_Index_p0739-0776.indd 748

Clozapine, 349, 349t, 350t, 351. See also Antipsychotics “Club drugs,” 423, 428. See also γ-hydroxybutyric acid (GHB); Hallucinogens Cnidaria, 618–621 Anthozoa class, 618t, 619 characteristics of, 618, 618t, 619f clinical manifestations of cardiotoxicity, 620–621 dermatitis, 619–620, 619f Irukandji syndrome, 621 seabather’s eruption, 621 Cubozoa class, 618, 618t Hydrozoa class, 618–619, 618t Scyphozoa class, 618t, 619 Coagulation factors, 273, 274f Coagulation pathway, 273, 274f Coagulopathy, 273, 274f Coal dust, 36t Cobalt, 468–470 chemistry of, 468 clinical manifestations of, 468–469 for cyanide, 691 diagnostic testing for, 469–470 history and epidemiology of, 468 normal concentrations of, 468, 470 pathophysiology of, 468 toxicity of, 468 toxicokinetics of, 468 treatment of, 470 Cobbler (Gymnapistes marmoratus), 625t Coca, 395, 640t. See also Cocaine Cocaine, 395–400. See also Anesthetics, local adulterants in, 399–400 cessation of use, 398 clinical manifestations of, 42, 48, 396–397 diagnostic testing for, 397–398 disposition in, 400 history and epidemiology of, 327, 395 imaging findings, 36t, 45f, 48f–49f interaction with ethanol, 395–396 as local anesthetic, 327, 327t management of, 398–399, 404 pathophysiology of, 396, 396f pharmacology of, 395–396, 395f, 395t Coconut crab (Birgus latro L.), 320 Codeine, 83, 84t, 85f. See also Opioids Coffea arabica (coffee), 639t Cola spp (Kola nut), 147t, 639t Colchicine, 71–72, 72t, 74t, 649 Colchicum autumnale (autumn crocus), 639t, 649 Colestipol, 234t, 236 Colistimethate, 243t Colloidal silver protein (CSP), 503 Coltsfoot, 145t Comfrey (Symphytum spp), 145t, 153, 643t Compound Q, 145t

Cone snails, 622–623, 622t Conium maculata (poison hemlock), 639t, 643–644 Conocybe, 424 Conotoxin (cone snails), 109t Constipation, 6t Contact dermatitis, 650 Contamination, 717 Continine, 436, 436t Continuous renal replacement therapy (CRRT), 31f, 32–33 Contrast agents extravasation of, 39 iodinated, 234t, 235t Control zones, hazard materials scene, 730, 730f, 730t Conus spp, 622–623, 622t Convallaria majalis (Lily of the valley), 314, 320, 639t Copper, 471–473 chemical principles of, 471 clinical manifestations of, 472 compounds of, 471t deficiency of, 511 diagnostic testing for, 472 history and epidemiology of, 471 management of, 472 normal concentrations of, 471 pharmacology of, 471–472 toxicology and pathophysiology of, 472 Copper oxide fumes, 673t Copper sulfate, 598 Copperhead (Agkistrodon contortrix), 651, 651t, 652f. See also Pit viper bites Coprine-containing mushrooms, 628t, 632–633, 632f Coprinus atramentarius, 628t, 632, 632f Coprinus comatus, 632, 632f Coptis spp, 639t Coral snake bites clinical manifestations of, 653–654 differential diagnosis of, 109t management of, 656. See also North American Coral Snake Antivenin (equine) pathophysiology of, 653 Coral snakes, 651–652, 652f Corticosteroids antithyroid effects of, 234t, 235t for caustic-induced inflammation, 527–528 imaging findings, 36t response to NMBs after, 341t Cortinarius spp, 628t, 634, 634f Cosmic rays, 716 Cottonmouth (Agkistrodon piscivorus), 651t, 658, 658t. See also Pit viper bites Coxiella burnetti, 712 Coyotillo (Karwinskia humboldtiana ), 640t, 648

22/09/23 5:47 PM

INDEX

Crack, 395. See also Cocaine Crassula spp, 639t Creatine, as performance enhancer, 133 Critical illness myopathy, 344t Critical illness polyneuropathy, 344t Crotalaria (heliotrope), 147t, 153 Crotalaria spp (rattlebox), 639t Crotalidae immune F(ab′)2 (equine) adverse effects and safety issues for, 660 clinical use of, 659 dosing and administration of, 661, 665 formulation and acquisition of, 661 pharmacology of, 658–659 in pregnancy and lactation, 660 Crotalidae polyvalent immune Fab antivenom (ovine) adverse effects and safety issues for, 660 clinical use of, 659 dosing and administration of, 655, 658t, 660–661, 661f history of, 658, 658t pharmacology of, 658, 659f in pregnancy and lactation, 660 source of, 658t Crotalus spp. See also Pit viper bites native (US), 651, 651f, 651t nonnative, 664–665t Croton (Croton tiglium, Croton spp), 639t Crown-of-thorns sea star (Acanthaster planci), 623 Cryptosporidium spp, 117t CS (chlorobenzylidene malononitrile), 675, 707–708 2C-series, 388 2C-T-7, 424f, 425 Cubozoa, 618, 618t Curare (Chondrodendron spp), 339, 639t, 644. See also Neuromuscular blockers (NMBs) Curie (Ci), 716f Cyanea capillata (lion’s mane or hair jellyfish), 618t, 619 Cyanide, 686–688 with carbon monoxide, 684 as chemical weapon, 707, 709t clinical manifestations of, 687 diagnostic testing for, 687 herbal sources of, 144, 151 history and epidemiology of, 686 management of, 687–688, 688t, 692 from nitroprusside, 311, 692 normal concentrations of, 686 pathophysiology of, 686–687, 687f pharmacology of, 686, 686f prevention of, 311 smoke inhalation and, 670 toxicokinetics of, 686 Cyanogen chloride (CK), 707, 709t Cyanogenic glycosides, 645, 686 Cyanosis, 697, 700, 700f

158_Hoffman_Index_p0739-0776.indd 749

Cycas circinalis, 639t Cyclic adenosine monophosphate modulators, 283 Cyclic antidepressants (CAs). See Antidepressants, cyclic (CAs) Cyclic hydrocarbons, 535 Cyclodienes, 591t. See also Organic chlorine pesticides Cycloguanil, 248t Cyclohexane oxime herbicides, 564t Cyclohexyl nitrite, 431t Cyclooxygenase-1 (COX-1), 75, 76t, 77f Cyclooxygenase-1 (COX-1) inhibitor (aspirin), 98, 283, 283f Cyclooxygenase-2 (COX-2), 75, 76t, 77f Cyclopentolate, 168t Cyclopeptide-containing mushrooms, 627, 628t, 629–631, 629f, 630f Cyclophosphamide, 209t, 212t Cycloprop-2-enecarboxylic acid–containing mushrooms, 628t, 635 Cycloserine, 257t, 259–260 Cyclosporine, 50–51f CYP2E1, 61, 433 CYPE21, 406 Cyproheptadine, 200t, 202, 375 Cystine, 641t, 643 Cystitis, ketamine-induced, 444 Cytarabine, 169t, 209t, 211f Cytisine, 437 Cytisus scoparius (broom), 144t, 153t, 639t, 643 D 2,4-D, 566t, 574–576 Dabigatran, 276t, 279–280, 279f, 279t Dacarbazine, 209t Dactinomycin, 209t Dakin solution, 514t, 516 Damiana, 154t Danshen, 151t Dantrolene sodium, 346–347 adverse effects and safety issues for, 346 dosing of, 347 formulation of, 346–347 history of, 346 in malignant hyperthermia, 342, 343t, 346 for neuroleptic malignant syndrome, 353 pharmacology of, 346 in pregnancy and lactation, 346 response to NMBs after, 341t Dapagliflozin, 175t Dapsone adverse effects of, 244t, 253 antimalarial mechanism of, 253 management of, 253 mechanism of action of, 248t methemoglobinemia from, 700

749

for opportunistic infections, 244t pharmacokinetics of, 249t, 253 Darbepoetin, 134 Datura stramonium (Jimson weed), 147t, 425, 425t, 639t Daunorubicin, 209t, 211f DBH (dopamine β-hydroxylose), 420 DDC (diethyldithiocarbamate), 420, 420f DDT (dichlorodiphenyltrichloroethane), 590–591, 591t, 593 Deadly nightshade (Atropa belladonna), 425 Deafness, 6t Decongestants, 203–205 clinical manifestations of, 204–205, 204t diagnostic testing for, 205 history and epidemiology of, 203 management of, 205 pathophysiology of, 204 pharmacokinetics and toxicokinetics of, 204 pharmacology of, 203–204, 203f Decontamination for biologic weapons, 710 for caustics, 20 for chemical weapons, 702–704 for dermal exposure, 19–20 gastrointestinal. See Gastrointestinal decontamination for hazardous materials, 19 for hazardous materials incident, 731–732 hydrofluoric acid, 20–21 for inhalation exposures, 20 for nerve agents, 706 for ophthalmic exposures, 20 phenol, 21 for radiation, 721 unknown xenobiotics, 21 DEET (N,N-Diethyl-3-methylbenzamide), 595–596, 595t Deferasirox, 166 Deferiprone, 166 Deferoxamine, 166–167 adverse effects of, 167 in aluminum toxicity, 167, 446–447 chemistry of, 166 dosing and administration of, 167 formulation and acquisition of, 167 in iron toxicity, 166–167 mechanism of action of, 166 pharmacokinetics of, 166 in pregnancy and lactation, 165, 167 urinary color change with, 167 Degreasers, inhaled, 431t Dehydroepiandrosterone (DHEA), 133, 133f Delamanid, 261 Delirium tremens, 416, 417 Delphinium spp, 640t, 648 Delta (δ) receptor, 79, 80, 80t

22/09/23 5:47 PM

750

INDEX

Demeclocycline, 242 Deodorants, inhaled, 431t Depleted uranium, 717 Dermacentor andersoni (Rocky Mountain wood tick), 609 Dermacentor variabilis (American dog tick), 609 Dermatitis nickel, 497–498, 498t plant-induced, 649–650 Desflurane, 337. See also Anesthetics, inhalational Desipramine, 356, 356f. See also Antidepressants, cyclic (CAs) Desirudin, 278, 279f Desloratadine, 200, 200t Desmopressin, 284 Desvenlafaxine, 362t, 363t, 365. See also Antidepressants, atypical Detemir, 176t Deterministic effects, radiation, 719 Dexamethasone, 168t Dexfenfluramine, 127t Dexmedetomidine, 311, 377t, 380, 418. See also Sedative-hypnotics Dexrazoxane adverse effects of, 228 for anthracycline extravasation, 211, 227t, 228 for doxorubicin overdose, 209t mechanism of action of, 228 Dextromethorphan, 84t, 87, 379 Dextrose (d-glucose), 181–183 adverse effects and safety issues for, 182 for alcoholic ketoacidosis, 182 chemistry and physiology of, 181 dosing and administration of, 183, 183t formulation and acquisition of, 183 for GHB toxicity, 430 with high-dose insulin treatment, 182, 306, 308 in hyperkalemia, 182 for hypoglycemia, 181–182 pharmacodynamics of, 181 pharmacokinetics of, 181 in pregnancy and lactation, 182–183 for salicylate poisoning, 102, 182 Diabetes insipidus, lithium-induced, 368, 369 Diacetylmorphine, 88 Dialysis, peritoneal, 30 Diaphoresis, 6t Diarrhea, 6t Diazepam. See also Benzodiazepines for alcohol withdrawal syndrome, 417 benzyl alcohol in, 169t for chloroquine toxicity, 252, 403–404 dosing and administration of, 402t, 404 formulation and acquisition of, 402t

158_Hoffman_Index_p0739-0776.indd 750

injection benzyl alcohol in, 169t, 402t propylene glycol in, 171t, 402t for PCP-associated agitation, 444 pharmacokinetics and pharmacodynamics of, 377t, 402–403, 402t, 403t for psychomotor agitation, 403 for sedative-hypnotic withdrawal, 403 Diazoxide, 311 Dicamba, 564t Dichapetalum cymosum (gifblaar), 600 Dichloralphenazone, in isometheptene, 232 Dichloramine, 674, 674f Dichlorodiphenyltrichloroethane (DDT), 590–591, 591t, 593 Dichloropropene, 558t, 559t, 561 Diclofenac, 75, 76t Dicofol, 591t Didanosine (ddI), 245 Dieffenbachia spp, 640t, 649–650, 650f Dieldrin, 591t. See also Organic chlorine pesticides Dienochlor, 591t. See also Organic chlorine pesticides Dietary fibers, for weight loss, 126t, 129 Dietary supplements, 143–154. See also specific substances adulteration of, 150 contamination with metals and minerals, 150–151 definition of, 143 history and epidemiology of, 143 pathophysiology and clinical manifestations of, 151–153 pharmacokinetics and toxicokinetics of, 143, 150 pharmacologic interactions of, 150, 151t, 152f pharmacologic synergies of, 150 pharmacological principles of, 143 psychoactive xenobiotics in, 153t–154t regulation of, 143 Dieter’s teas, 127t, 130 N,N-Diethyl-3-methylbenzamide (DEET), 595, 595t Diethyldithiocarbamate (DDC) for nickel poisoning, 499 pharmacology and pharmacokinetics of, 420, 420f Diethylene glycol clinical manifestations of, 554 diagnostic testing for, 554 extracorporeal elimination of, 33t fomepizole for, 548–549 history and epidemiology of, 553 pathophysiology of, 554 as pharmaceutical additive, 168 pharmacokinetics and toxicokinetics of, 553, 553f

toxic dose of, 554 treatment of, 554–555 Diethylenetriaminepentaacetic acid. See Pentetic acid/pentetate (zinc or calcium) trisodium (DTPA) Diethylpropion, 126t Dieting xenobiotics and regimens, 125–130 alternative approaches, 130 approved, 126t cathartic/emetic abuse, 130 dietary fibers, 126t, 129 dinitrophenol, 127t, 129 endocannabinoid receptor agonists and inverse agonists, 129 fat absorption blockers, 129 gastrointestinal agents, 126t GLP-1 agonists, 126t history of, 125 hypocaloric diets, 130 liraglutide, 129–130 mechanisms of action of, 128f naltrexone/bupropion, 129 nonpharmacologic interventions, 130 pharmacology of, 125, 128f regulation of, 125 serotonergics, 126t, 129 sympathomimetics, 125–127, 126t unapproved, 125, 127t Diffuse airspace filling, 39, 41, 44f, 44t Difluoroethane, 431t, 432t, 434t DigiFab. See Digoxin-specific antibody fragments (DSFab) Digitalis effect, 314, 314f Digitalis spp ( foxglove), 130, 146t, 314, 640t, 645 Digitoxin, 314t Digoxin. See also Cardioactive steroids (CASs) diagnostic testing for, 317 elixir, sorbitol in, 172t injection, propylene glycol in, 171t magnesium for, 271–272 pharmacology of, 314, 314t treatment of, 317–318, 317t Digoxin-specific antibody fragments (DSFab), 319–322 adverse effects and safety issues for, 320–321 for CAS poisoning, 317, 317t, 320 dosing and administration of, 321–322, 321t formulation and acquisition of, 322 history of, 319 indications for, 320 measurement of serum digoxin concentration after administration of, 322 pharmacology of, 319–320 in pregnancy and lactation, 321

22/09/23 5:47 PM

INDEX

DIHS (drug-induced hypersensitivity syndrome), 193–194 Dihydroartemisinin, 248t, 249t, 252–253 Dihydroergotamine, 229, 230t Dihydrofolic acid reductase (DHFR), 217 Dihydropyridines, 303, 303t. See also Calcium channel blockers (CCBs) N,N-Diisopropyl-5-methoxytryptamine (5-Meo-DiPT), 424 Dilated cardiomyopathy, 42 Diltiazem, 303, 303t. See also Calcium channel blockers (CCBs) Dimenhydrinate, 197, 202 Dimercaprol (British anti-Lewisite, BAL), 457–458 adverse effects and safety issues with, 107, 458 for antimony, 452 for arsenic, 457 for bismuth, 460 for copper, 473 dosing and administration of, 458 formulation and acquisition of, 458 history of, 457 for lead, 458, 482, 483t for mercury, 457, 496 pharmacology of, 457 in pregnancy and lactation, 458 Dimercaptopropane sulfonate (DMPS), 452, 460, 485 2,5-Dimethoxy-4-iodoamphetamine (DOI), 388 2,5-Dimethoxy-4-methylamphetamine (DOM), 388 Dimethyl sulfoxide (DMSO), 227t Dimethylprimaquine, 248t N,N-Dimethyltryptamine (DMT), 423–424, 424f, 425t Dinitroaniline herbicides, 565t Dinitrophenol, 127t, 128f, 129 Dinitrophenol herbicides, 565t Dinoflagellates, 119 Dipeptidyl peptidase-4 (DPP-4) inhibitors, 174, 175t Diphenhydramine clinical manifestations of, 201 diagnostic testing for, 202 for dystonia, 351 history of, 197 management of, 202 pharmacology of, 199, 200t Diphenoxylate, 84t, 86–87 Diphenylether herbicides, 565t Diphosgene, 707 Diphtheria, 109t Diphtheria and tetanus toxoids, 172t Diphyllobothrium food poisoning, 122 Dipteryx spp (Tonka bean), 149t, 640t Dipyridamole, 283 Diquat, 569. See also Paraquat

158_Hoffman_Index_p0739-0776.indd 751

Direct renin inhibitors, 312f, 313 Direct thrombin inhibitors, 276t, 278–280, 279f Direct vasodilators, 309t, 311–312 Disinfectants. See Antiseptics, disinfectants, and sterilants Disopyramide, 33t, 265t, 267–268 Disulfiram, 406t, 420–422 chronic therapy with, 421–422 ethanol reaction with, 420–421, 420f, 421t fomepizole for, 548 history and epidemiology of, 420 as nickel antidote, 499 pharmacology and pharmacokinetics of, 420, 420f in pregnancy and lactation, 421 toxicity of, 421–422 Disulfiramlike reaction with ethanol, xenobiotics causing, 421, 421t Disuse (cachectic) myopathy, 344t Diuresis, forced, 29–30 Diuretics as antihypertensives, 309t, 312 as athletic performance enhancer, 135 clinical manifestations of, 312 DMPS (dimercaptopropane sulfonate), 452, 460, 485 DMT (N,N-dimethyltryptamine), 423–424, 424f, 425t DOB (4-bromo-2,5-dimethoxyamphetamine), 385t. See also Amphetamines Docetaxel, 209t Dofetilide, 266t, 270 Dogbane (Apocynum cannabinum), 314, 320 DOI (2,5-dimethoxy-4-iodoamphetamine), 388. See also Amphetamines DOM (2,5-dimethoxy-4methylamphetamine), 388. See also Amphetamines Domoic acid, 118t, 119 DOM/STP (4-methyl-2,5dimethoxyamphetamine), 385t Dong Quai, 145t Dopamine (DA), 234t, 306 Dopamine β-hydroxylose (DBH), 420 Dopamine hypothesis, 348 Doping, 131. See also Athletic performance enhancers Dorzolamide/timolol, 168t Doxazosin, 311 Doxepin, 356f. See also Antidepressants, cyclic (CAs) Doxorubicin, 169t, 209t, 211f Doxycycline, 248t for anthrax, 711 for brucellosis, 712 for plague, 712

751

for Q fever, 712 for tularemia, 712 Doxylamine, 200t, 202 DPP-4 (dipeptidyl peptidase-4) inhibitors, 174, 175t Dronedarone, 266t, 269 Droperidol, 55, 349. See also Antipsychotics Drug discontinuation syndrome, 366, 373 Drug packets. See Body packers Drug-induced hypersensitivity syndrome (DIHS), 193–194 Dry beriberi, 414 Dry cleaning agents, inhaled, 431t Dry ice, 672 DSFab. See Digoxin-specific antibody fragments (DSFab) DTPA. See Pentetic acid/pentetate (zinc or calcium) trisodium (DTPA) Dulaglutide, 126t, 173, 174, 175t Duloxetine, 362t, 363t, 365. See also Antidepressants, atypical Dusting, 431. See also Inhalants Dusts, 675 DVD player head cleaner, inhaled, 431t Dysesthesias, 6t Dysrhythmias cocaine-associated, 396, 399 definition of, 264 ethanol-associated, 408 in hypoglycemia, 176 inhalant-associated, 435 treatment of. See Antidysrhythmics Dystonia, acute, 351, 352t E E. coli O157:H7, 117t, 121 Echinacea, 145t Echinodermata, 120, 622 Ecstasy, herbal, 203 Ecstasy (3,4-methylenedioxy‑ methamphetamine), 385t, 387. See also Amphetamines Edetate calcium disodium (CaNa2EDTA), 488–489 adverse effects and safety issues with, 488 for cobalt, 470 with dimercaprol, 457 dosing and administration of, 489 formulation and acquisition of, 489 history of, 488 for lead, 482, 483t, 488 pharmacokinetics of, 488 pharmacology of, 488 in pregnancy and lactation, 488–489 succimer with, 489 for zinc, 512 EDLIS (endogenous digoxinlike immunoreactive substance), 317 Edoxaban, 276t, 279t, 280–281

22/09/23 5:47 PM

752

INDEX

Edrophonium, 111, 344t Edwardsiella lineata, 621 Eels, 119 Eggerthella lenta, 314 Elapid envenomation. See Coral snake bites Elapidae. See Coral snakes Elder, 145t Electrolyte abnormalities differential diagnosis of, 110t magnesium, 110t, 533 phosphate, 533 potassium. See Hyperkalemia Electronic cigarettes, 437 Electrophysiologic testing, for botulism, 111–112, 112f Electroporation, 53t Eletriptan, 231t Elimination, enhanced clinical approach to, 34f effectiveness of, 28 indications for, 28 methods of, 28, 28t continuous renal replacement therapy, 31f, 32–33 forced diuresis, 29–30 hemodialysis, 30–31, 31f, 31t hemofiltration, 31f, 32 hemoperfusion, 31, 31t manipulation of urinary pH, 30 multiple-dose activated charcoal, 29. See also Activated charcoal peritoneal dialysis, 30 plasmapheresis and exchange transfusion, 33–34 resins, 29 xenobiotics appropriate for, 28–29, 29t, 33t Embden-Meyerhof pathway, 695, 696f Emergence reaction, 443 Emetics, abuse of, 130 Emetine, 130, 644 Empagliflozin, 175t Enalaprilat, 169t, 312 Endocannabinoid receptor agonists and inverse agonists, 128f, 129 Endogenous digoxinlike immunoreactive substance (EDLIS), 317 Endoperoxides, 248t, 252–253 Endorphins, 79 Endoscopy, 18, 95 Endosulfan, 591t. See also Organic chlorine pesticides Endrin, 591t. See also Organic chlorine pesticides Enflurane, 337. See also Anesthetics, inhalational Enhydrina schistosa (beaked sea snake), 624, 624t Enolic acids, 76t Enoximone, 299

158_Hoffman_Index_p0739-0776.indd 752

Entactogens, 387, 423. See also Hallucinogens Entheogens, 423. See also Hallucinogens Ephedra spp (ma-huang) clinical manifestations of, 145t, 152–153 as decongestant, 203 toxicity of, 640t, 644 usages of, 145t for weight loss, 125, 127t Ephedrine clinical manifestations of, 204–205, 204t epidemiology of, 203 pharmacology of, 203, 203f Epinephrine injection, 169t Epipodophyllotoxins, 210t, 227t Epipremnum aureus, 640t Epirubicin, 209t Epothilones, 211f Eptifibatide, 284 Erenumab, 232 Erethism, 494 Ergocalciferol. See Vitamin D Ergonovine, 229, 230t Ergot alkaloids, 229–231 clinical manifestations of, 229–230, 230t history and epidemiology of, 229 pharmacology and pharmacokinetics of, 229, 230t treatment of, 230–231 Ergotamine, 230t Ergotism, 229–230, 230t, 423 Erlotinib, 209t Erythrocyte protoporphyrin (EP) concentration, 479 Erythromycin, 241 Erythropoiesis-stimulating proteins, 134 Erythropoietin (EPO), 134–135 Erythroxylum coca, 395, 640t. See also Cocaine Escherichia coli food poisoning, 120t, 121 Escitalopram, 362–363, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Eslicarbazepine, 186t, 188t, 189t, 193t Esmolol, 294t, 295, 297, 341t Esophageal perforation, 45 Esophageal strictures, 528 Essential (volatile) oils, 137–142 definition of, 137 diagnostic testing for, 141 eucalyptus oil, 138–139 history and epidemiology of, 137 lavender oil, 139 nutmeg oil, 139–140 oil of wintergreen, 141 pennyroyal oil, 140, 141, 142, 148t pine oil, 140 tea tree oil, 140–141 treatment of, 141–142

Estazolam, 377, 377t. See also Sedative-hypnotics Estramustine, 211f Estrogens, 234t Eszopiclone, 377t, 379. See also Sedative-hypnotics Ethacrynic acid, 312 Ethambutol, 244t, 257t, 259 Ethane, 672 Ethanol, 405–411 alcohol dehydrogenase affinity of, 550 for alcohol dehydrogenase-metabolized xenobiotics, 550–552 adverse effects and safety issues for, 550 dosing and administration of, 550, 551t vs. fomepizole, 549, 552 formulation and acquisition of, 551 pharmacokinetics of, 550 pharmacology of, 550 in pregnancy and lactation, 550 for alcohol withdrawal, 418 as antiseptic and disinfectant, 514t assessment of impairment from analytical considerations in, 734–735 breath-testing devices for, 735 estimating amount ingested in, 735–736 history of, 734 intoxication and self-estimate of, 736 per se limits in, 734 standardized field sobriety tests for, 735, 735t third-party liability laws and, 736 clinical manifestations of, 48, 407–408 diagnostic tests for, 408–409 disulfiram reaction with. See Disulfiram disulfiramlike reaction with, 421, 421t history and epidemiology of, 405, 416 hospitalization indications in, 409–410 imaging findings, 36t management of, 409 metabolism of, 377f pathophysiology of, 407, 407t, 408f pharmacokinetics and toxicokinetics of, 405–406, 405t, 406f for sodium monofluoroacetate, 600 toxic syndrome, 2t withdrawal from. See Alcohol withdrawal xenobiotic interactions of, 395–396, 406–407, 406t Ethchlorvynol, 377t. See also Sedative-hypnotics Ethionamide, 257t, 260 Ethylene glycol. See also Alcohols, toxic calcium for, 533 chemistry of, 542 history and epidemiology of, 542 management of, 545–547

22/09/23 5:47 PM

INDEX

properties of, 33t sodium bicarbonate for, 106 toxicokinetics and toxicodynamics of, 542, 543f Ethylene oxide, 514t, 518, 673t Etidocaine, 327t, 328, 328t, 329. See also Anesthetics, local Etodolac, 76t Etomidate, 171t, 371t, 377t, 380. See also Sedative-hypnotics Etoposide, 169t, 170t, 209t, 211f Eucalyptus (Eucalyptus spp), 138–139, 640t Eugenol, 138 Euphorbia spp, 640t European mistletoe (Viscum album), 148t, 643t, 647 Eustrongyloides anisakis food poisoning, 122 Eve (3,4-methylenedioxyethamphetamine), 385t. See also Amphetamines Evening primrose, 145t Exchange transfusion, 33–34 Exenatide, 126t, 173, 174, 175t Extended-release formulations, 12, 12f, 13f Extracorporeal therapy, 28–29, 29t, 32t, 34f Extrapyramidal syndromes (EPS), 351–353, 352t, 353t Extravasation injuries, 227–228, 227t Ezogabine, 186t, 188t, 189t, 193t F Factor VIII inhibitor bypassing activity (FEIBA), 275, 285t, 286 Factor Xa inhibitors, 276t, 280–281 Famotidine, 200, 200t Fat absorption blockers, 129 Fat overload syndrome, 333 Fava beans (Vicia faba), 646 Favism, 646 Felbamate, 189t Felodipine, 303t. See also Calcium channel blockers (CCBs) Fenamic acids, 76t Fenfluramine, 127t Fennel, 146t Fenoprofen, 76t Fentanyl, 84t, 85. See also Opioids Fentanyl analogs, 84t. See also Opioids Fenugreek, 146t Ferrioxamine, 166, 166f. See also Deferoxamine Ferrous sulfate, 234t Ferrous sulfate drops, 172t Fetal solvent syndrome (FSS), 434 Feverfew, 146t Fexofenadine, 197, 200t Fibers, dietary, 126t for weight loss, 129 Fibrinolytic agents, 276t, 281–282 Fibrinolytic pathway, 274f

158_Hoffman_Index_p0739-0776.indd 753

Fibrinolytic system, 273 Fiddleback spider (brown recluse spider), 605–606, 605f, 606t Field sobriety tests, 735, 735t Fire ants (Hymenoptera), 610, 610t Fire coral (Millepora alcicornis), 618t, 619, 620 Fire sponge (Tedania ignis), 623 Fireflies (Photinus spp), 314 Fish envenomations, 624–626, 625f, 625t, 626f Fish tapeworms, 122 Fixed oils, 143 Flashbacks, with LSD, 427 Flecainide, 265t, 269 Fluconazole, 244t Flucytosine, 244t Fludarabine, 209t, 211f Flumazenil, 381–382 adverse effects and safety issues for, 382 in benzodiazepine overdose, 378–379, 381–382, 382t in conscious sedation, 381 contraindications to, 382t dosing and administration of, 382 in ethanol intoxication, 382 formulation of, 382 in hepatic encephalopathy, 382 injection, parabens in, 170t in paradoxical reactions, 381 pharmacokinetics and pharmacodynamics of, 381t pharmacology of, 381 in pregnancy and lactation, 382 Flunitrazepam, 377t. See also Sedative-hypnotics Fluorides, 33t, 529. See also Hydrofluoric acid (HF) Fluoroacetamide, 600 Fluoropyrimidines. See Capecitabine; 5-Fluorouracil Fluoroquinolones, 238t, 241 Fluorosis, skeletal, 36t, 42f, 433, 433f 5-Fluorouracil antidotes for, 209t, 216 clinical manifestations of, 209t, 212t, 215 diagnostic testing for, 216 management of, 216, 223–224 pathophysiology of, 215 patient-specific factors in toxicity of, 208 pharmacology of, 211f, 215, 215f Fluoxetine, 351, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Flupentixol, 349t. See also Antipsychotics Fluphenazine, 349t, 350t. See also Antipsychotics

753

Flurazepam, 377t. See also Sedative-hypnotics Flurbiprofen, 76t Flurbiprofen ophthalmic solution, 172t Fluvoxamine, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Focal airspace filling, 41, 44t Focal degenerative lesions, of brain, 48, 50f Folate, 547 Folic acid, 217, 219 Folinic acid. See Leucovorin ( folinic acid) Fomepizole, 548–549 adverse effects and safety issues for, 549 for diethylene glycol, 534–535 dosing and administration of, 549 vs. ethanol, 549, 552 for ethanol-disulfiram reaction, 548 formulation and acquisition of, 549 history of, 548 pharmacokinetics of, 548 pharmacology of, 548 in pregnancy and lactation, 549 for toxic alcohols, 548–549 Fondaparinux, 276t, 281 Food additives, 123 Food poisoning, 117–124 with anaphylaxis and anaphylactic presentations, 122–123, 123t in bioterrorism, 123 vs. botulism, 110t with gastrointestinal presentation, 120–121 epidemiology of, 121, 121t Salmonella species, 117t, 121 timing of onset and primary presenting symptom, 120t history and epidemiology of, 117, 117t with multiorgan system dysfunction Bacillus cereus, 117t, 120t, 121 Campylobacter jejuni, 117t, 120t, 121–122 E. coli, 120t, 121 intestinal parasitic infections, 122 Listeria monocytogenes, 117t, 122 Staphylococcus species, 117t, 120t, 121 Yersinia spp, 117t, 120t, 122 with neurologic symptoms botulism, 109, 118t. See also Botulism ciguatera poisoning, 117–119, 118t ciguateralike poisoning, 119 differential diagnosis of, 117t shellfish poisoning, 118t, 119 tetrodotoxin poisoning, 118t, 119–120 prevention of, 123–124 xenobiotic-induced, 122 Forced diuresis, 29–30 Foreign-body ingestion, 46t Formaldehyde, 514t, 516–517, 523t, 673t

22/09/23 5:47 PM

754

INDEX

Formate, 547 Foscarnet, 244t Fosphenytoin, 186t, 190–191. See also Phenytoin Fo-Ti, 146t Foxglove (Digitalis spp), 130, 146t, 314, 640t, 645 Foxy methoxy, 424, 425t Free-base, 395. See also Cocaine Freon, inhaled, 431t Fresh-frozen plasma (FFP) for ACEI angioedema, 313 for direct thrombin inhibitor–induced coagulopathy, 280 vs. four-factor prothrombin complex concentrates, 286 in pregnancy and lactation, 285 for vitamin K antagonist–induced coagulopathy, 275 Frovatriptan, 231t FSS ( fetal solvent syndrome), 434 Fumagillin, 244t Fumigants, 558–562 clinical effects of, 559t dichloropropene, 561 history and epidemiology of, 558 metal phosphides and phosphine, 558–559 methyl bromide, 559–561 methyl iodide, 562 properties and uses of, 558t sulfuryl fluoride, 561 Funnel web spider (Atrax, Hadronyche spp), 607–608, 613t, 614 Furazolidone, 372 Furosemide as antihypertensive, 312 response to NMBs after, 341t solution, sorbitol in, 172t thyroid hormones and, 234t Fusion inhibitors, 246 G G6PD deficiency, 699 GA (Tabun), 705, 709t Gabapentin adverse effects of, 193t for alcohol dependence, 418 clinical manifestations of, 188 diagnostic testing for, 188 drug interactions of 4, 189t management of, 189 mechanism of action of, 186t metabolism of, 188t pharmacokinetics and toxicokinetics of, 188, 188t Galerina spp, 627, 628t Galium triflorum, 640t γ-aminobutyric acid type A (GABAA) receptors, 401

158_Hoffman_Index_p0739-0776.indd 754

γ-butyrolactone (GBL), 428, 429t γ-hydroxybutyric acid (GHB), 428–430 clinical manifestations of, 429–430 diagnostic testing for, 430 endogenous, 428, 429f exogenous, 428 history and epidemiology of, 428 management of, 430 pharmacokinetics and toxicokinetics of, 428 pharmacology of, 428, 429f synonyms and analogs of, 428, 429t withdrawal from, 430 γ-hydroxyvaleric acid (GHV), 429t γ-rays, 715 γ-valerolactone (GVL), 429t Ganciclovir, 244t Ganglionic blockers, 311 Garcinia, 126t, 146t Garlic, 146t, 151t Gases, irritant. See Pulmonary irritants Gasoline antiknock agent as source of manganese, 490 classification and viscosity of, 535t imaging findings, 39, 41f inhaled, 431t Gastric emptying. See Gastrointestinal decontamination Gastrointestinal absorption drug delivery systems and, 12, 12f, 13f prevention of. See Gastrointestinal decontamination rates of, 11–12 Gastrointestinal decontamination activated charcoal for, 14–16, 16f, 16t, 17f. See also Activated charcoal adjunctive methods for, 18 for body packers, 94 cathartics for, 17 general guidance for, 18 multiple-dose activated charcoal for, 16–17, 17t orogastric lavage for, 12–14, 14f in post–bariatric surgery patients, 18 surgery and endoscopy for, 18 trends in use of, 11 whole-bowel irrigation for, 17, 17t Gastrointestinal perforation, 44, 46f Gastrointestinal toxin–containing mushrooms, 628t, 633–634, 634t Gastropoda, 622–623 GB (Sarin), 705, 709t GD (Soman), 705, 709t Gefitinib, 209t Gemcitabine, 211f Gemtuzumab, 209t Gene doping, 136

General anesthesia, 335. See also Anesthetics, inhalational Genomic instability, 718 Gentamicin for brucellosis, 712 ophthalmic, benzalkonium chloride in, 168t for plague, 712 Gentian violet, 243t Gentiana lutea (gentian), 648 Germander, 130, 146t GHB. See γ-hydroxybutyric acid (GHB) GHV (γ-hydroxyvaleric acid), 429t Giardia intestinalis, 117t Gifblaar (Dichapetalum cymosum), 600 Gila monster (Heloderma suspectum), 652, 652f Ginger, 146t Ginkgo (Ginkgo biloba), 146t, 151t, 640t, 646, 650 Ginseng, 146t, 151t Glargine, 176t Glimepiride, 175t Glipizide, 175t, 176 Gloriosa superba, 640t Glucagon, 301–302 adverse effects and safety issues with, 302 for β-adrenergic antagonist toxicity, 298, 301–302 for calcium channel blocker toxicity, 302, 305–306 dosing and administration of, 302 formulation and acquisition of, 302 history of, 301 for hypoglycemia, 302 pharmacology of, 301 in pregnancy and lactation, 302 Glucagon-like peptide-1 (GLP-1) agonists/ analogs, 126t, 128f, 129–130, 174f, 175t Glucarpidase (carboxypeptidase G2, CPDG2), 220–222 adverse effects and safety issues for, 220–221 dosing and administration of, 222 formulation and acquisition of, 222 history of, 220 for methotrexate toxicity, 214, 220 pharmacology of, 220, 221f in pregnancy and lactation, 222 Glucocorticoids. See Corticosteroids Glucomannan, 126t, 129, 146t Glucosamine, 146t Glucose. See also Dextrose (d-glucose) for β-adrenergic antagonist toxicity, 299 blood, 177, 182 chemistry and physiology of, 181 on insulin release, 173, 174f Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 699

22/09/23 5:47 PM

INDEX

α-Glucosidase inhibitors, 173–174, 175t Glues, inhaled, 431t Glufosinate, 565t, 572–573, 573f Glulisine, 176t Glutaraldehyde, 514t, 518 Glutethimide, 377t. See also Sedative-hypnotics Glyburide, 175t, 176t Glycemic threshold, 176 Glycerol monoacetate, for sodium monofluoroacetate, 600 Glycolysis, 181, 695, 696f Glycoprotein IIb/IIIa inhibitors, 284 Glycopyrrolate, 169t, 344t Glycosides, 143, 637, 644–646, 645f Glycyrrhiza glabra (licorice), 147t, 151t, 153, 640t, 645 Glycyrrhizin, 645 Glyphosate, 565t, 573–574 Goat’s rue, 146t Goji, 146t Golden chain, 641t, 643 Goldenseal (Hydrastis canadensis), 146t, 640t Gordoloba yerba, 146t Gossypium spp, 640t Gotu kola, 147t Grammostola. See Tarantulas Granulocyte-macrophage colonystimulating factor (GM-CSF), 210 Grapefruit (Citrus paradisi), 639t, 648 Grass pea (Lathyrus sativus), 641t, 647 “Gray baby” syndrome, 241 Gray (Gy), 716f Grayanotoxins, 649 Green leaf tobacco sickness (GTS), 437, 438 Green tea, 147t, 638t Griseofulvin, 243t, 406t Growth hormone (GH), 132 Guanabenz, 309 Guanfacine, 309 Guar gum, 127t Guarana (Paullinia cupana), 125, 126t, 323, 641t Guillain-Barré syndrome, vs. botulism, 110t Gum discoloration, 6t Gun-bluing solution, 500, 501t GVL (γ-valerolactone), 429t Gy (gray), 716f Gymnapistes marmoratus (cobbler), 625t Gymnopilus spectabilis, 628t, 633 Gyromitra spp, 626, 628t, 631–632, 631f Gyromitrin-containing mushrooms, 628t, 631–632, 631f H Hadronyche spp ( funnel web spider), 607–608, 613t, 614 Haff disease, 120

158_Hoffman_Index_p0739-0776.indd 755

Hair jellyfish (Cyanea capillata), 618t, 619 Hair spray, inhaled, 431t Hair testing, for arsenic, 456 Haldane ratio, 678 Hallucinations, 6t, 416, 423 Hallucinogen-persisting perception disorder (HPPD), 427 Hallucinogens, 423–427. See also specific substances belladonna alkaloids, 425 classification of, 423t clinical effects of, 426 epidemiology of, 423 in herbal dietary supplements, 154t–155t history of, 423 indolealkylamines (tryptamines), 423–424, 424f kratom. See Kratom (Mitragyna speciosa) laboratory testing for, 426 long-term effects of, 426 lysergamides, 423, 424f nutmeg oil. See Nutmeg oil (Myristica fragrans, mace) pharmacology of, 425–426 phenylethylamines (amphetamines), 424–425, 424f Salvia divinorum. See Salvia divinorum (salvinorin A) toxicokinetics of, 425, 425t treatment of, 425–426 Halofantrine, 248t, 249t, 251 Halogenated hydrocarbons, 336–338. See also specific substances abuse of, 337–338, 433 carbon monoxide poisoning from, 337 chronic exposure to waste, 337 classification of, 535t clinical manifestations of, 336–337, 433 imaging findings, 38–39 long-term use of, 337 toxicokinetics of, 337, 536t Haloperidol, 55, 349t, 350t, 351. See also Antipsychotics Halothane, 336–337. See also Anesthetics, inhalational Hamburger thyrotoxicosis, 233 Hapalochlaena lunulata, 622 Hapalochlaena maculosa (blue-ringed octopus), 622–623, 622f Hapalopilus rutilans, 629t Hard-metal disease, 469 Harmala alkaloids, 153 Hashish, 389–390, 639t. See also Cannabinoids “Hatters’ shakes,” 493 Hawaiian baby woodrose (Argyreia nervosa), 423, 425t Hawthorn, 147t Hazardous materials incident response, 728–733

755

advanced components of, 732–733 components of, 728–729 control zones in, 730, 730f, 730t decontamination in, 19, 731–732 disaster management in, 728 identification and classification of materials in, 729, 729t personal protective equipment in, 731, 731f, 731t prehospital emergency response team in, 732 primary and secondary contamination with, 730 rules and standards in, 732–733 site operations for, 730 Headache, 6t Heart rate, 293, 295f Heavy fuel oil, 535t Hedeoma pulegioides (pennyroyal), 140, 141, 142, 148t, 640t Hedera helix, 640t Hedysarium alpinum, 640t Heliotrope (Crotalaria, Heliotropium), 147t, 153 Heliotropium spp (ragwort), 640t Helleborus niger, 640t Heloderma horridum (beaded lizard), 652, 652f Heloderma suspectum (Gila monster), 652, 652f Hemlock water dropwort (Oenanthe crocata), 648 Hemodialysis, 30–31, 31f, 31t, 32t for acetaminophen toxicity, 65 for barbiturate poisoning, 378 for lithium poisoning, 369, 369t for methotrexate toxicity, 214–215 for methylxanthine poisoning, 326, 326t NAC elimination by, 70 for salicylate poisoning, 102–103, 102t toxicology of, 34 Hemofiltration, 31f, 31t, 32 Hemoglobin, 695, 695f Hemoglobin oxygenation analysis, 698, 699t Hemolysis, 696–697, 697f Hemolytic uremic syndrome (HUS), 121 Hemoperfusion, 31f, 31t, 32, 32t Hemorrhagic fevers, viral, 713 Henbane (Hyoscyamus niger), 147t, 640t Heparin, 276t, 277–278, 291, 292 Heparin-induced thrombocytopenia (HIT/HITT), 278 Hepatitis A, 117t Hepatotoxic xenobiotics acetaminophen. See Acetaminophen amoxicillin-clavulanic acid, 240 halothane, 336–337 herbal, 153 isoniazid, 257–258

22/09/23 5:47 PM

756

INDEX

Hepatotoxic xenobiotics (Cont.): niacin, 162 rifampin, 258 valproic acid, 192, 195 vitamin A, 157, 157f Heptachlor, 591t. See also Organic chlorine pesticides “Herbal ecstasy,” 203 Herbal supplements. See Dietary supplements Herbicides, 563–576 amide compounds, 564t, 568–569 bipyridyl compounds. See Paraquat chemical classes of, 564–567t coformulations of, 563 diagnosis of, 563 epidemiology of, 563 glufosinate, 572–573, 573f glyphosate, 573–574 history of, 563 management of, 563, 568 occupational and secondary exposures, 568 phenoxy compounds. See Phenoxy herbicides regulation of, 563 triazine compounds, 576 WHO hazard classification of, 563, 564–567t Heroin, 83–84, 84t, 97, 234t. See also Opioids Hexachlorocyclohexanes, 591t Hexachlorophene, 515t, 517 n-Hexane inhaled, 431t, 432t, 434. See also Inhalants toxicokinetics of, 536t, 539, 539f Hexavalent chromium, 466. See also Chromium hGH (human growth hormone), 134 High-dose insulin (HDI), 307–308 adverse effects and safety issues for, 307–308 for calcium channel blocker toxicity, 306, 307 dextrose administration with, 182, 306, 308 dosing and administration of, 308 pharmacology of, 307 Hippuric acid, 433 Hirudin, 278–279, 279f Histamine receptors inverse agonists vs. antagonists, 198–199, 198f. See also Antihistamines physiology of, 197–198 Histone deacetylase inhibitors, 211f HIT/HITT (heparin-induced thrombocytopenia), 278 HIV therapeutics, 243–246 cellular chemokine receptor (CCR5) antagonists, 246

158_Hoffman_Index_p0739-0776.indd 756

fusion inhibitors, 246 integrase inhibitors, 246 nonnucleoside reverse transcriptase inhibitors, 245 nucleoside analog reverse transcriptase inhibitors, 244–245 for opportunistic infections, 244t–245t protease inhibitors, 246 Hobo spider (Eratigena agrestis), 606 Hoigne syndrome, 240 Holly (Ilex spp), 147t, 640t, 645 Hops, 154t Hormone antagonists, 211f Hornets (Vespidae), 609–610, 609f, 610t Horse chestnut (Aesculus hippocastanum), 147t, 638t Hourglass spider (black widow spider), 603–605, 604f HPPD (hallucinogen-persisting perception disorder), 427 Huffing, 42f, 431. See also Inhalants β-Human chorionic gonadotrophin (hCG), 127t, 134 Human growth hormone (hGH), 134 HUS (hemolytic uremic syndrome), 121 Hyaluronidase, 227–228, 227t Hydralazine, 36t, 311 Hydrangea, 147t, 154t Hydrastine, 640t Hydrastis canadensis (goldenseal), 146t, 640t Hydrazide, 262 Hydrazine, 262 Hydrocarbons, 535–541. See also specific hydrocarbons aromatic, 535t, 536t chemistry of, 535 classification of, 535t clinical manifestations of, 537–539, 538f common uses of, 535t diagnostic testing for, 540 halogenated. See Halogenated hydrocarbons history and epidemiology of, 535 management of, 540–541 n-hexane. See n-Hexane pathophysiology of, 537–539 pharmacology of, 535–536 toxicokinetics of, 536, 536t volatile, 433–434. See also Inhalants Hydrochloric acid, 523t Hydrochlorothiazide, 312 Hydrocodone, 84t, 85. See also Opioids Hydrofluoric acid (HF), 529–531 chemistry of, 529 clinical manifestations of, 529–530, 529f diagnostic testing for, 530 history and epidemiology of, 529 magnesium for, 272 management of, 502, 530–531, 533t

pathophysiology of, 529 sources of, 523t Hydrofluorocarbons, 431t Hydrogen chloride (HCl), 673t, 674 Hydrogen cyanide (HCN), 707, 709t Hydrogen fluoride (HF), 673t, 674 Hydrogen peroxide (H2O2), 47f, 513, 514t, 515, 685 Hydrogen sulfide (H2S), 688–689 clinical manifestations of, 689, 689t diagnostic testing for, 689 history and epidemiology of, 688 management of, 689–690, 690t hyperbaric oxygen in, 685 nitrites and sodium thiosulfate in, 693 pharmacology and toxicokinetics of, 673t, 674, 688–689 Hydromorphone, 84t, 85. See also Opioids Hydroxocobalamin (vitamin B12A), 312, 691–692 Hydroxychloroquine, 248t, 251–252 Hydroxyl (OH) group, 542 5-Hydroxytrypamine1F receptor agonists, 232 Hydroxyurea, 211f Hydroxyzine, 200, 200t, 202 Hydrozoa, 618–619, 618t Hymenoptera, 609–610, 609f, 610t Hyoscyamus niger (hyoscyamus, henbane), 146t, 640t Hyperadrenergic crisis, 372t, 373 Hyperalgesia, 80 Hyperammonemia, 192, 195 Hyperbaric oxygen (HBO), 683–685 adverse effects of, 685 for carbon monoxide, 680–681, 681t, 683–684 for carbon monoxide and cyanide, combined, 684 for carbon tetrachloride, 685 delayed administration of, 681 dosing and administration of, 683, 685 formulation and acquisition of, 685 history of, 683 for hydrogen peroxide, 685 indications for, 681, 681t for methylene chloride, 684 for oxidant-induced methemoglobinemia, 685 pharmacology of, 683, 684f in pregnancy and lactation, 685 repeat treatment with, 681 Hypercalcemia, 157, 159–160 Hypercarotenemia, 157 Hypericum perforatum. See St. John’s wort (Hypericum perforatum) Hyperkalemia, 110t, 182, 533–534 Hypermagnesemia, 110t, 533 Hyperphosphatemia, 533

22/09/23 5:47 PM

INDEX

Hypersensitivity pneumonitis, 42, 676–677 Hypertension, 2t, 205 Hyperthermia, 3t, 202 Hyperthermia, malignant. See Malignant hyperthermia (MH) Hyperthyroidism, 233, 237 Hyperventilation, 2 Hypoglycemia causes of, 173t clinical manifestations of, 181 definition of, 175 drug-induced, 173–178 clinical manifestations of, 174–177 diagnostic testing for, 177, 177t history and epidemiology of, 173 malicious, surreptitious, or unintentional insulin overdose in, 177, 177t, 178 management of, 177–179 pathophysiology of, 174–175 pharmacokinetics and toxicokinetics of, 174, 175t, 176t pharmacology of, 173–174, 174f ethanol-associated, 409 management of dextrose for, 181–183, 183t glucagon for, 302 octreotide for, 184–185 Hypoglycemic agents, 173–174, 175t, 176t, 406t. See also Hypoglycemia, drug-induced Hypoglycin, 638t, 647 Hypokalemia, 110t Hypokalemic periodic paralysis, 110t Hypomagnesemia, 271 Hypotension, 1, 2t, 202 Hypothermia, 3t Hypothyroidism, 233 Hypoventilation, 2 I Iboga/ibogaine, 147t, 154t Ibotenic acid–containing mushrooms, 628t, 633, 633f Ibuprofen, 75, 76t Ibutilide, 266t, 270 Idarubicin, 209t Idarucizumab, 280, 287 Ifosfamide, 209t IGF-1 (insulinlike growth factor 1), 134 ILE. See Intravenous lipid emulsion (ILE) Ileus, 45, 46t Ilex paraguayensis (mate), 148t, 154t, 640t Ilex spp berries, 417t, 640t, 645 Illicium anisatum (Japanese star anise), 640t, 646 Illicium verum (Chinese star anise), 640t, 646 Iloperidone, 349t, 350t. See also Antipsychotics

158_Hoffman_Index_p0739-0776.indd 757

Imaging, diagnostic, 35–51 extravasation of contrast material in, 39 radiation exposure from, 717, 718t xenobiotic effects visualization in, 39 abdominal, 44–46 neurologic, 46–51 pulmonary and thoracic, 39–44 skeletal, 39 xenobiotic visualization in, 35, 36t in containers, 37–38 halogenated hydrocarbons, 38–39 iron tablets, 35, 37f metals, 35–36 moth repellents, 39 radiolucent, 39 radiopaque, 35 on ultrasound, 35 with unknown xenobiotic, 35, 36f Imidazoles, 238t, 243 Imidazoline decongestants, 204–205, 204f, 204t Imidazoline herbicides, 565t Imipenem, 240 Imipramine, 356, 356f. See also Antidepressants, cyclic (CAs) Immune checkpoint inhibitors, 211f Impila, 147t Implants, metal-on-metal, 465, 469, 470 Incapacitating agents, 708, 709t Incorporation, 717 Indian marking nut (Semecarpus anacardium), 650 Indian stonefish (Synanceja horrida), 625t Indobufen, 76t Indolealkylamines (tryptamines), 423–424, 424f. See also Hallucinogens Indomethacin, 75, 76t Infant botulism. See also Botulism clinical manifestations of, 109–111 laboratory assessment of, 112t prevention of, 113 toxicokinetics of, 108 treatment of, 113 Influenza vaccine, 172t INH. See Isoniazid (INH) Inhalants, 431–435 clinical manifestations of, 432–434, 434t commonly used, 431, 431t history and epidemiology of, 431 imaging findings, 36t laboratory and diagnostic testing for, 434–435 management of, 435 pharmacology and pharmacokinetics of, 431–432, 432t teratogenicity of, 434 withdrawal from, 434, 435 Inhalational anesthetics. See Anesthetics, inhalational

757

Injection drug users imaging findings in, 36t, 43f, 46, 47f interventions for, 96–97 Inky cap mushrooms, 632 Inocybe mushrooms, 628t, 632 Inorganic dusts, 676 Insecticides arthropod repellents, 595, 595t carbamates. See Carbamate insecticides DEET, 595–596, 595t EPA toxicity classification of, 596, 596t history and epidemiology of, 577 organic chlorine pesticides. See Organic chlorine pesticides organic phosphorus compounds. See Organic phosphorus insecticides pyrethrins and pyrethroids, 593–595, 594t pyrroles (chlorfenapyr), 593 WHO toxicity classifications of, 577, 577t Insulin as athletic performance enhancer, 134 for β-adrenergic antagonist toxicity, 299 forms of, 176t high-dose. See High-dose insulin (HDI) history of, 173 laboratory detection of, 135 malicious, surreptitious or unintentional overdose of, 177, 177t, 178. See also Hypoglycemia, drug-induced Insulinlike growth factor 1 (IGF-1), 134 Integrase inhibitors, 246 Intensive care unit (ICU), indications for, 9–10, 9t Interleukin-2, 234t Interleukin-α, 234t Interstitial lung diseases, 42, 44t Intracranial hypertension, 158, 158t Intrathecal administration, 225–226 Intravenous lipid emulsion (ILE), 331–334 adverse effects and safety issues for, 333 in calcium channel blocker toxicity, 306 dosing and administration of, 333 formulation and acquisition of, 334 history of, 331 in local anesthetic toxicity, 330, 332 in non–local anesthetic toxicity, 332–333 pharmacology of, 331–332 in pregnancy and lactation, 334 Involutin-containing mushrooms, 629t Iodides (iodide salts), 234t, 237 Iodinated contrast agents, 234t, 235t Iodine as antiseptic, 514t, 515, 523t deficiency of, 233 radioactive, 235t, 720, 724, 724f thyroid function and, 235t Iodism, 237 Iodophors, 514t, 515–516 Ionizing radiation, 716

22/09/23 5:47 PM

758

INDEX

Iontophoresis, 53t Iopanoic acid, 234t Ipecac, syrup of (Cephaelis ipecacuanha), 130, 639t, 644 Ipodate, 234t Ipomoea spp (morning glory), 148t, 154t, 423, 640t, 644 IR3535, 595t Irinotecan, 208, 209t Iron, 163 Iron formulations, 163t Iron toxicity, 163–165 clinical manifestations of, 164 diagnostic testing for, 164 history and epidemiology of, 163 imaging findings in, 35, 36t, 37f management of, 164–165, 165f. See also Deferoxamine pathophysiology of, 163–164 pharmacology, pharmacokinetics, and toxicokinetics of, 163 in pregnancy, 165, 167 Irradiation, 717 Irritant gases. See Pulmonary irritants Irukandji jellyfish (Carukia barnesi), 618, 618t, 621 Irukandji syndrome, 621 Isobenzan, 591t. See also Organic chlorine pesticides Isobutyl nitrite, 431t Isocarboxazid, 364t. See also Monoamine oxidase inhibitors (MAOIs) Isoflurane, 337, 341t. See also Anesthetics, inhalational Isometheptene, 232 Isoniazid (INH), 255–258 clinical manifestations of, 255–258, 257t diagnostic testing for, 258 drug and food interactions of, 255, 257t, 406t imaging findings, 36t injection, chlorobutanol in, 169t management of, 258. See also Pyridoxine pathophysiology of, 255, 256f pharmacokinetics of, 255, 256f pharmacology of, 55 in pregnancy, 255 Isopropanol. See also Alcohols, toxic clinical manifestations of, 542–543 diagnostic testing for, 544 management of, 546 properties of, 33t toxicokinetics and toxicodynamics of, 542, 543f uses of, 514t, 542 Isoquinoline alkaloids, 644 Isotope ratio mass spectometry, 135 Isotretinoin, 155 Isradipine, 303t. See also Calcium channel blockers (CCBs)

158_Hoffman_Index_p0739-0776.indd 758

IT-290 (α-methyltryptamine), 424 Itai-itai, 461 Itraconazole, 245t Ixodes holocyclus (Australian marsupial tick), 609 J Jalap, 147t Jamaican vomiting sickness, 647 Japanese star anise (Illicium anisatum), 640t, 646 Jarisch–Herxheimer reaction, 240 Jatropha spp, 640t, 647 “Jeff,” 385t, 387 Jellyfish. See Cnidaria Jequirity pea (Abrus precatorius), 638t, 647 Jewelry workers cadmium exposure in, 461 nickel exposure in, 497 Jimson weed (Datura stramonium), 147t, 425, 425t, 639t Juniper, 154t Jurema, 154t K Kalmia (mountain laurel), 649 Kappa (κ) receptor, 79, 80, 80t Karwinskia humboldtiana (buckthorn, wild cherry, tullidora, coyotillo, capulincillo), 640t, 648 Karwinskia toxins, 648 Kava kava (Piper methysticum), 147t, 151t, 154t, 641t, 646 Kerosene, 535t Keshan disease, 500 Ketamine, 440–444 for alcohol withdrawal, 419 analogs of, 440t clinical manifestations of, 442–443, 443f diagnostic testing for, 444 emergence reaction, 443 forms of, 441 history and epidemiology of, 440 management of, 444 pathophysiology of, 441–442 pharmacology of, 440–441, 440t tolerance and withdrawal, 443–444 for violent behavior, 55 Ketolides, 238t, 241–242 Ketoprofen, 76t Ketorolac, 76t, 168t Keyboard dust remover, inhaled, 431t Khat (Catha edulis), 147t, 385t, 387, 639t, 644. See also Amphetamines KI. See Potassium iodide (KI) Kinematic viscosity, 535t, 537 King’s College Criteria, 64, 65t Kola nut (Cola spp), 147t, 639t Kombucha, 147t Korsakoff psychosis, 414

Kratom (Mitragyna speciosa) adverse effects of, 147t, 153 pharmacology of, 153, 425, 425t popular usages of, 147t, 153, 154t, 425 L Labetalol, 170t, 294t, 296, 297, 300 Laburnum anagyroides (laburnum), 641t, 643 Lacosamide, 186t, 188t, 189, 193t Lactarius spp, 628t, 633 Lactation. See Pregnancy and lactation Lactrodectus spp (widow spiders), 603–605, 604f, 613t, 614 Laetrile, 645 Lambert-Eaton myasthenic syndrome, vs. botulism, 110t Lamotrigine, 186t, 188t, 189–190, 189t, 193t Lanoteplase, 281 Lanreotide, 184 Lantana camara, 641t Lasiodora. See Tarantulas Lasmiditan, 232 Lathyrins, 647 Lathyrus sativus (grass pea), 641t, 647 Latrodectus spp (black widow spider), 614 Laudanosine, 343 Lavender oil, 139 Laxatives, herbal, 130 Lead, 474–484 chemical principles of, 474 clinical manifestations of, 476–478, 477t diagnosis of clinical, in symptomatic patients, 478–479 imaging findings, 36t, 37 abdominal, 37f, 479, 479f, 480f brain, 477, 478f joints, 39f, 41f, 476, 476f laboratory evaluation in, 476, 476f environmental exposure to, 474, 474t history and epidemiology of, 474 management of, 480–484 in adults, 482 chelation therapy in, 480, 482, 483t. See also Dimercaprol (British anti-Lewisite, BAL); Edetate calcium disodium (CaNa2EDTA); Succimer (2,3,-dimercaptosuccinic acid, DMSA) in children, 481–482 in neonates, 483 overview of, 480, 482t in pregnancy and lactation, 482–483, 484t normal concentrations of, 474 occupational exposure to, 474, 475t pathophysiology of, 475–476, 476f

22/09/23 5:47 PM

INDEX

pharmacology of, 474–475 screening for, 480, 481t Lectins, in plants, 637, 646–647, 646f Leiurus spp, 616t, 617 Lente, 176t Lepiota spp, 627, 628t Lepirudin, 278 Leucothoe, 649 Leucovorin ( folinic acid), 217–219 adverse effects and safety issues with, 218 for arsenic toxicity, 217–218 formulation and acquisition of, 219 for methanol and formate toxicity, 217, 219, 546 for methotrexate toxicity, 215, 217, 218–219, 218t, 219f for pemetrexed toxicity, 219 pharmacology of, 217, 221f in pregnancy and lactation, 218 for proguanil toxicity, 253 for pyrimethamine toxicity, 218, 253 Leukotrienes, 77f Levetiracetam, 186t, 188t, 189t, 190, 193t Levobunolol, 168t, 294t Levocabastine, 200 Levocarnitine (l-carnitine), 195–196 Levocetirizine, 200t Levodopa, 234t Levomilnacipran, 362t, 363t, 365. See also Antidepressants, atypical Levorphanol, 84t. See also Opioids Levothyroxine, 233 Lewisite, 707, 709t Licorice (Glycyrrhiza glabra), 147t, 151t, 153, 640t, 645 Lidocaine. See also Anesthetics, local as antidysrhythmic clinical manifestations of, 265t, 268 management of, 268–269 pharmacology of, 265t, 268 diagnostic testing for, 329 history and epidemiology of, 327 intravenous injection parabens in, 170t toxic dose of, 328t as local anesthetic. See also Anesthetics, local clinical manifestations of, 328–329, 329f, 329t management of, 329–330 pharmacology of, 327t response to NMBs after, 341t Lighter fluid, inhaled, 431t Lily of the valley (Convallaria majalis), 314, 320, 639t Linagliptin, 174, 175t Lincosamides, 238t Lindane, 591t Linezolid, 238t, 372

158_Hoffman_Index_p0739-0776.indd 759

Linuche unguiculata (thimble jellyfish), 618t, 619, 621 Lionfish (Pterois spp), 624, 625t, 626f Lion’s mane jellyfish (Cyanea capillata), 618t, 619 Lipid emulsion. See Intravenous lipid emulsion (ILE) Lipids, as pharmaceutical additives, 169–170, 169t Lipoic acid, 147t Lipoid pneumonia, 539–540 LipoKinetix, 127t Liraglutide, 126t, 129–130, 173, 174, 175t Lispro, 176t Listeria monocytogenes food poisoning, 117t, 122 Lithium, 367–369 antithyroid effects of, 234t, 235t clinical manifestations of, 367–368 diagnostic testing for, 368–369 history and epidemiology of, 367 management of, 369, 369t pharmacokinetics and toxicokinetics of, 367 pharmacology of, 367, 368f, 369f properties of, 33t response to NMBs after, 341t therapeutic concentration of, 367 Liver support devices, 32, 65 Liver transplantation, for acetaminopheninduced liver failure, 64 Lizard bites clinical manifestations of, 654 diagnostic testing for, 654 management of, 656–657 pharmacology of venom in, 653 Lizards, 652, 652f Lobelia, 147t, 154t Lobelia inflata, 641t, 643 Lobeline, 641t, 643 Local anesthetics. See Anesthetics, local Locoweed Astragalus spp, 638t, 644 Datura stramonium, 639t Oxytropis spp, 641t, 644 Sida carpinifolia, 642t Swainsonia spp, 643t, 644 Lomustine, 209t Lone Star tick (Amblyomma americanum), 609 Lonomia spp, 611 Loop diuretics, 309t, 312 Loperamide, 84t, 87 Lophophora williamsii (peyote), 424, 425t, 641t, 644 Loratadine, 200t Lorazepam. See also Benzodiazepines for alcohol withdrawal, 417 dosing and administration of, 402t, 404 formulation and acquisition of, 402t

759

injection benzyl alcohol in, 169t, 402t PEG in, 170t, 402t propylene glycol in, 171t pharmacokinetics and pharmacodynamics of, 377t, 402–403, 402t, 403t Lorcaserin, 126t, 129 Love drug (3,4-methylenedioxy‑ amphetamine), 385t Lower urinary tract syndrome (LUTS), ketamine-associated, 443, 443f Low-molecular-weight heparins (LMWHs), 276t, 277–278, 291, 292 Loxapine, 349t, 350t. See also Antipsychotics Loxosceles reclusa (brown recluse spider), 605–606, 605f, 606t, 613t, 614 LSD. See also Hallucinogens clinical effects of, 426 diagnostic testing for, 426 epidemiology of, 423 history of, 423 long-term effects of, 427 pharmacology of, 423, 424f treatment of, 426–427 Lucibufagin, 314 Lugol solution, 514t Lumber, chromium and arsenate in, 465 Lumefantrine, 248t, 249t, 251 Lupinus spp, 641t Lurasidone, 349t, 350t. See also Antipsychotics Lycoperdon spp, 629t Lycopersicon spp, 641t Lye. See Sodium hydroxide (lye) Lymphadenopathy, 42 Lysergamides, 423, 424f. See also Hallucinogens Lysergic acid diethylamide. See LSD M Macadamia integrifolia, 650 Mace, 139, 148t Macrolides, 238t, 241–242 Madagascar periwinkle (Catharanthus roseus), 639t, 649 Magnesium, 271–272 adverse effects and safety issues for, 272 in alcohol disorders and thiamine deficiency, 272, 418 for cardiac toxin poisoning, 271–272 dosing and administration of, 272 formulation and acquisition of, 272 history of, 271 for hydrofluoric acid and fluoridereleasing xenobiotics, 272 for hypomagnesemia, 271 in pesticide poisoning, 272 pharmacology of, 271

22/09/23 5:47 PM

760

INDEX

Magnesium (Cont.): in pregnancy and lactation, 272 response to NMBs after, 341t Mahonia spp, 641t Ma-huang. See Ephedra spp (ma-huang) Malaria, 247, 247f, 248t. See also Antimalarials Malaria vaccine, 254 Malignant hyperthermia (MH) clinical manifestations of, 342 dantrolene sodium for, 342, 343t, 346 treatment of, 342, 343t xenobiotics causing, 342 Mandrake (Mandragora officinarum), 148t, 154t, 641t Manganese, 490–492 chemistry of, 490 clinical manifestations of, 491, 491t diagnostic testing for, 491–492 history and epidemiology of, 490 imaging findings, 36t, 492 normal concentrations of, 490 pathophysiology of, 490–491 pharmacology and physiology of, 490 sources of, 491 treatment of, 492 Mango (Mangifera indica), 650 Manihot (Manihot esculenta), 641t, 645 MAOIs. See Monoamine oxidase inhibitors (MAOIs) Maprotiline, 356f. See also Antidepressants, cyclic (CAs) Maqianzie, 153 Maraviroc, 246 Marijuana, 389, 639t. See also Cannabinoids Marine envenomations, 618–626 invertebrates, 618–623 Cnidaria. See Cnidaria Mollusca, 621–623, 622f, 622t vertebrates, 623–626 fish, 624–626, 625f, 625t, 626f snakes, 109t, 623–624, 624t Mark I Nerve Agent Antidote Kit (NAAK), 587 Masking xenobiotics, 135–136 Mate (Ilex paraguayensis), 148t, 154t, 640t Mauve stinger (Pelagia noctiluca), 618t, 619 Mayapple (Podophyllum peltatum), 148t, 642t, 649, 649f Mazindol, 126t MCPA (4chloro-2-methylphenoxyacetic acid), 566t, 574–575 MDA (3,4-methylenedioxyamphetamine), 385t. See also Amphetamines MDEA (3,4-methylenedioxyamphetamine), 385t. See also Amphetamines MDMA (3,4-methylenedioxy‑ methamphetamine), 385t, 387. See also Amphetamines

158_Hoffman_Index_p0739-0776.indd 760

Mechanical ventilation, 103 Mechlorethamine, 209t, 227t Meclofenamate, 76t Mecoprop, 574 Medroxyprogesterone depot injection, 170t Mees lines, 455, 455f Mefenamic acid, 76t, 234t Mefloquine, 248t, 249t, 250–251 Meglitinides, 174f, 175t, 178, 179 Meglumine antimoniate, 449, 450t, 451. See also Antimony Melamine, 123 Melarsoprol, 453 Melatonin, 377t, 380. See also Sedative-hypnotics Meldonium, 134 Melilotus spp, 641t Meloxicam, 75, 76t Melphalan, 209t Meningococcal vaccine, 172t Mentha pulegium, 641t Menthol (peppermint oil), 140 5-Meo-DiPT, 424, 425t 5-Meo-DMT, 424, 425t Meperidine, 84t, 87 Mephedrone (methcathinone), 385t, 387. See also Amphetamines Mephobarbital, 377t. See also Sedative-hypnotics Mepivacaine, 327t, 328t. See also Anesthetics, local Meprobamate, 377t, 379. See also Sedative-hypnotics Merbromin, 514t, 516 6-Mercaptopurine, 209t, 211f Mercurials, 514t, 516 Mercuric chloride, 523t Mercurochrome, 514t, 516 Mercury, 493–496 clinical syndromes with, 494–495, 494f diagnostic testing for, 495, 495t forms and kinetics of, 493–494, 493t history and epidemiology of, 493 imaging findings, 36–37, 36t, 38f, 494f management of, 495–496 chelation in, 496 dimercaprol in, 457, 496 succimer in, 486, 496 normal concentrations of, 493 pathophysiology of, 494 in thimerosal, 172 Mercury vapor, 673t Merthiolates, 514t, 516 Mescaline, 424, 424f, 425t Mesenteric ischemia, 45 Mesobuthus spp, 616t, 617 Mesoridazine, 349t, 350t. See also Antipsychotics

Metabisulfites, 123t Metabolic acidosis, 6t, 106 Metabolic acidosis with elevated lactate concentration (MALA), 179–180, 179f Metachlor, 564t, 568–569 Metal fume fever, 512, 677 Metal phosphides, 558–559, 558t, 559t Metal pneumonitis, 675–676 Metal-on-metal implants, 465, 469 Metals. See also specific metals in herbal dietary supplements, 150–151 imaging findings, 35, 36t, 37f Metalworking, cadmium exposure in, 461 Metformin history of, 173 lactic acidosis from, 130, 179–180 mechanism of action of, 173, 179f pharmacokinetics and toxicokinetics of, 175t properties of, 33t Methadone. See also Opioids classification, potency, and characteristics of, 84t injection, chlorobutanol in, 169t interaction with ethanol, 406t in medication-assisted therapy, 85–86, 97 solution, sorbitol in, 172t thyroid hormones and, 234t Methamphetamine, 386. See also Amphetamines Methane, 671–672, 673t Methanol. See also Alcohols, toxic chemistry of, 542 diagnostic testing for, 544 history and epidemiology of, 542 inhaled, 431t, 434t. See also Inhalants management of, 106, 217, 545–547, 546t pathophysiology and clinical manifestations of, 542–544 properties of, 33t toxicokinetics and toxicodynamics of, 542, 543f Methcathinone, 385t, 387. See also Amphetamines Methemoglobin, 695, 695f, 696f Methemoglobinemia clinical manifestations of, 697, 697t, 698f definition of, 695 diagnostic testing for, 697–698 etiologies of, 695–696, 696t hemolysis and, 696–697, 697f history and epidemiology of, 695 management of, 698–700, 699f, 699t, 700f in dapsone-induced disease, 253, 702 hyperbaric oxygen for, 685, 700 methylene blue in, 699, 702

22/09/23 5:47 PM

INDEX

Methimazole, 234t, 236–237 Methohexital, 377t. See also Sedative-hypnotics Methotrexate, 213–215 benzyl alcohol in, 169t clinical manifestations of, 208, 209t, 210, 213–214 management of extracorporeal elimination for, 214–215 glucarpidase for, 214, 220 leucovorin for, 214, 217, 218–219, 218t, 219f sodium bicarbonate for, 105–106 mechanism of action of, 211f pathophysiology of, 213 pharmacology of, 213, 213f properties of, 33t Methotrimeprazine, 349t. See also Antipsychotics Methoxetamine, 440, 440t, 441. See also Ketamine N-2-Methoxybenzylphenyethylamines, 388 Methoxychlor, 591t 5-Methoxydimethyltryptamine (5-Meo-DMT), 424 Methoxyflurane, 337 Methyl bromide, 558–561, 558t, 559t, 673t Methyl iodide, 562 Methyl isocyanate, 675 Methyl salicylate (oil of wintergreen), 98, 141. See also Salicylates 4-Methyl-2,5-dimethoxyamphetamine (DOM/STP), 385t N-Methylcytisine, 639t, 643 Methyldopa, 170t, 309–310 Methylene blue, 701–702 for ACEI or ARB overdose, 313 adverse effects and safety issues for, 701–702 for dapsone overdose, 253 dosing and administration of, 702 formulation and acquisition of, 702 in G6PD deficiency, 702 history of, 701 for hypotension, 701, 702 for ifosfamide-induced encephalopathy, 210 for methemoglobinemia, 699–700, 701 pharmacology of, 701 in pregnancy and lactation, 702 Methylene chloride (CH2Cl2) classification and viscosity of, 535t hyperbaric oxygen for, 684 inhaled, 431t, 433–434, 434t. See also Inhalants toxicokinetics of, 536t, 539 3,4-Methylenedioxyamphetamine (MDA, love drug), 385t

158_Hoffman_Index_p0739-0776.indd 761

3,4-Methylenedioxyethamphetamine (MDEA, Eve), 385t 3,4-Methylenedioxymethamphetamine (MDMA), 385t, 387. See also Amphetamines Methylenedioxypyrovalerone (MDPV), 387 Methylergonovine, 229, 230t Methylethyl ketone peroxide, 523t Methylnaltrexone, 84t, 90–92 Methylxanthines, 323–326 chronic use of, 325 diagnostic testing for, 325 history and epidemiology of, 323t management of, 325–326, 326t pathophysiology of, 324–325 pharmacokinetics and toxicokinetics of, 324 pharmacology of, 323–324 toxicity spectrum of, 323 Methysergide, 229, 230t Metipranolol, 294t Metoprolol, 294t, 295, 297 Metronidazole, 243t, 406t Mexican pricklepoppy (Argemone mexicana), 638t, 644 Mexiletine, 265t, 268 Meyer-Overton lipid-solubility theory, 335 MFT (4-bromo-2,5-methoxyphenylethylamine), 385t. See also Amphetamines Microcystins, 641t, 647 Microcystis spp, 641t, 647 Microneedle-based devices, 53t Micruroides spp. See Coral snakes Micrurus spp. See Coral snakes Midazolam. See also Benzodiazepines dosing and administration of, 402t, 404 formulation and acquisition of, 169t, 402t pharmacokinetics and pharmacodynamics of, 377t, 402–403, 402t, 403t for xenobiotic-induced seizures, 403 Miglitol, 173–174, 175t Migraine medications. See Antimigraine medications Milkweed (Asclepias syriaca), 314, 638t Millepora alcicornis ( fire coral), 618t, 619, 620 Milnacipran, 362t, 363t, 365. See also Antidepressants, atypical Milrinone, 299 Mineral seal oil, 535t Mineral spirits, 535t Minoxidil, 311 Miosis, 6t, 80–81 Mirex, 591t Mirtazapine, 362t, 363t, 366. See also Antidepressants, atypical Mistletoe (Phoradendron spp, Viscum album), 148t, 641t, 643t, 647

761

Mitomycin C, 209t, 211f, 227t Mitotane, 234t Mitoxantrone, 209t Mitragyna speciosa (Kratom), 147t, 153, 154t Mivacurium, 341t. See also Neuromuscular blockers (NMBs) Moclobemide. See Monoamine oxidase inhibitors (MAOIs) Molinate, 566t Mollusca, 621–622 Mollusks, 119 Molly (3,4-methylenedioxy‑ methamphetamine), 385t, 387. See also Amphetamines Monoacetin, for sodium monofluoroacetate, 600 Monoamine oxidase inhibitors (MAOIs), 370–375 clinical manifestations of, 372–373, 372t diagnostic testing for, 374 dietary restrictions with, 373, 373t drug discontinuation syndrome with, 373 drug interactions of, 373, 373t history and epidemiology of, 372t management of, 374–375 miscellaneous and experimental, 372 naturally occurring, 371–372. See also Banisteriopsis caapi (caapi); St. John’s wort (Hypericum perforatum); Syrian rue (Peganum harmala) nonselective and irreversible, 370 pathophysiology of, 372 pharmacokinetics and toxicokinetics of, 372 pharmacology of, 370–372, 370t, 371f, 372f selective and irreversible, 371 selective and reversible, 371 serotonin toxicity from, 364t treatment of, 374–375 Monoamines, 370 Monochloramine, 674, 674f Monoclonal antibodies, 209t Monosodium glutamate (MSG), 122 Monteplase, 281 Morel (Morchella esculenta), 631, 631f Moricizine, 266t, 268 Mormon tea, 154t Morning glory (Rivea corymbosa, Ipomoea spp, Argyreia spp) adverse effects of, 148t common usages of, 148t, 154t primary toxicity of, 638t, 640t psychotropic effects of, 423, 644 Morphine. See also Opioids classification, potency, and characteristics of, 83, 84t lipid formulations of, 169t metabolism of, 85f

22/09/23 5:47 PM

762

INDEX

Moth repellents, 520–522 camphor. See Camphor imaging findings, 39 laboratory differentiation of, 522, 522t naphthalene, 520–521 paradichlorobenzene, 521–522 Moths, 610–611 Mountain laurel (Kalmia), 649, 649f Movement disorders, manganeseassociated, 491, 492 Moxonidine, 310–311 Mu (μ) receptor, 79, 80, 80t Mugwort, 148t Multifocal airspace filling, 42, 44t Multivitamin injection, propylene glycol in, 171t Mupirocin ointment, 170t Muscarine-containing mushrooms, 628t, 632, 632f Muscarinic receptors, 584 Muscimol-containing mushrooms, 628t, 633, 633f Mushrooms, 627–636 acromelic acid–containing, 629t allenic norleucine-containing, 628t, 634–635, 635f 2R-amino-4,5-hydroxy-5-hexynoic acid–containing, 629t classification of, 627 coprine-containing, 628t, 632–633, 632f cyclopeptide-containing, 627, 628t, 629–631, 629f, 630f cycloprop-2-enecarboxylic acid–containing, 628t, 635 epidemiology of, 627 GI toxin–containing, 628t, 633–634, 634t gyromitrin-containing, 628t, 631–632, 631f ibotenic acid– and muscimol-containing, 628t, 633, 633f identification of, 636 involutin-containing, 629t management of, 627, 635–636 muscarine-containing, 628t, 632, 632f orellanine– and orellinine-containing, 628t, 634 polyporic acid–containing, 629t psilocybin-containing, 628t, 633, 633f unknown, general approach to ingestion of, 626 Mussels, 118t, 119 Myasthenia gravis, vs. botulism, 110t Mycotoxins, 714. See also Mushrooms Mydriasis, 6t Myelopathy, 110t Myocyte, calcium flow and contractility of, 293, 295f Myristica fragrans, 641t

158_Hoffman_Index_p0739-0776.indd 762

N NAAK (Mark I Nerve Agent Antidote Kit), 587 Nabumetone, 76t N-acetylcysteine (NAC), 66–70 for acetaminophen poisoning adverse effects and safety issues with, 67–68 assessing hepatoxicity risk in, 64 chemistry of, 66 dosing and administration of, 64, 68–70, 68t, 69t duration of treatment with, 64 formulation of, 70 history of, 66 indications for, 67 IV vs. oral administration of, 64, 66–67, 67t mechanism of action of, 64, 66 in neonates, 68 pharmacokinetics of, 66–67 in pregnancy, 68 for cobalt, 470 metabolism of, 58f, 64 for non-acetaminophen poisoning, 67 Nadolol, 294t Nail polish remover, inhaled, 431t Nail testing, for arsenic, 456 Nalbuphine, 84t Naloxegol, 84t, 90–92 Naloxone, 90–92 adverse effects and safety issues of, 91 classification, potency, and characteristics of, 84t controversies regarding, 96 dosing and administration of, 91–92 in ethanol abstinence, 91 formulation and acquisition of, 92 for GHB toxicity, 430 injection, parabens in, 170t in maintenance of opioid abstinence, 91 in opioid overdoses, 96–97 in opioid poisoning/toxicity, 88, 88t, 90–91 pharmacokinetics and pharmacodynamics of, 90 pharmacology of, 90 public policy regarding, 96–97 Naltrexone, 84t, 89, 90–92, 97 Naltrexone/bupropion, 126t, 128f, 129 Naphazoline, 168t, 204f, 204t Naphtha, 535t Naphthalene, 520–521 Naphthoquinones, 248t, 253 NAPQI, 57, 66 Naproxen, 75, 76t Naratriptan, 231t Narcissus spp (narcissus), 641t, 649 Naringenin, 648 Naringin, 648

Nateglinide, 173, 175t, 177 National Fire Protection Association (NFPA) 704 system, 729 NDRI (norepinephrine/dopamine reuptake inhibitor), 362t, 363t, 366 Nebivolol, 294t, 295–296, 297, 300 Needleless injection, 53t Nefazodone, 362t, 363t, 365. See also Antidepressants, atypical Nematocysts, 618–620, 619f Neofibularia nolitangere (poison-bun sponge), 623 Neonatal (serotonin) abstinence syndrome (NSAS), 366 Neosaxitoxin (paralytic shellfish poisoning), 109t Neosporin ophthalmic solution, 172t Neostigmine, 344t Neostigmine methylsulfate injection, 170t Nephrocalcinosis, 46t Nephrotoxic xenobiotics aminoglycosides, 239, 239t amphotericin B, 243 lithium, 368 methoxyflurane, 337 Nerium oleander (oleander), 148t, 314, 320, 641t, 645 Nerve agents, 705–706 clinical effects of, 705–706, 708t pathophysiology of, 705 physical characteristics and toxicity of, 705 treatment of, 587, 706 Neurodegenerative disorders, xenobioticmediated, 48–51 Neurolathyrism, 647 Neuroleptic malignant syndrome (NMS) causes of, 352–353 clinical manifestations of, 352t, 353 diagnosis of, 353t vs. serotonin toxicity, 365, 365t treatment of, 353 Neurological imaging, diagnostic, 46, 48, 48f, 48t Neuromuscular blockers (NMBs), 339–345 complications of, 109t, 339–340 depolarizing. See Succinylcholine diagnostic testing for, 345 history and epidemiology of, 339 mechanism of action of, 339, 339f nondepolarizing drug interactions of, 341t–342t persistent weakness associated with, 343, 344t pharmacology of, 340t toxicity of, 343 pharmacokinetics of, 339 pharmacology of, 340t reversal drugs for, 344–345, 344t

22/09/23 5:47 PM

INDEX

Neuromuscular transmission, 339 Neurotoxic shellfish poisoning, 118t, 119 Neutrons, 715 Niacin (nicotinic acid) deficiency of, 162 as masking agent, 135–136 pharmacology of, 162 RDA for, 156t toxicity of, 162 Nicardipine, 303t. See also Calcium channel blockers (CCBs) Nickel, 497–499 clinical manifestations of, 497–498, 498t diagnostic testing for, 498–499 history and epidemiology of, 497 normal concentrations of, 497 sources of, 497 toxicokinetics of, 497 treatment of, 499 Nickel carbonyl, 497, 673t Nickel-cadmium batteries, 461 Nicotiana spp, 641t, 643. See also Tobacco Nicotine, 436–439 clinical manifestations of, 438, 438t diagnostic testing for, 438–439 history and epidemiology of, 436 management of, 439 pathophysiology of, 437–438 pharmacology and pharmacokinetics of, 436, 436t in plants, 643 sources and uses of, 436–437, 436t Nicotine receptor agonists, 437 Nicotinelike alkaloids, in plants, 643 Nicotinic agents, herbal, 152 Nifedipine, 231, 303t. See also Calcium channel blockers (CCBs) Night blindness (nyctalopia), 144 Nimesulide, 76t Nimodipine, 303t. See also Calcium channel blockers (CCBs) Nisoldipine, 303t. See also Calcium channel blockers (CCBs) Nitazoxanide, 245t Nitrates, 695 Nitrile herbicides, 565t Nitrofurantoin, 36t, 243t, 406t Nitrogen dioxide, 673t Nitrogen gas, 672, 673t Nitrogen mustards, 208, 209t Nitrogen oxides, 673t, 675 Nitroglycerin injection, 171t Nitroprusside, 311–312, 692, 694 Nitrosoureas, 208, 209t Nitrous oxide abuse of, 431t, 434, 435 as inhaled anesthetic, 335–336, 366f pharmacology of, 432, 432t Nizatidine, 200t N-methylthiotetrazole (nMTT), 240

158_Hoffman_Index_p0739-0776.indd 763

NMS (neuroleptic malignant syndrome), 352–353, 352t, 353t Noble gases, 671–672 Nociceptin/orphanin FQ (ORL1) receptor, 79–80, 80t Nodularia spp, 647 Nondepolarizing neuromuscular blockers. See Neuromuscular blockers (NMBs) Nonionizing radiation, 716 Nonnucleoside reverse transcriptase inhibitors, 245 Nonsteroidal antiinflammatory drugs (NSAIDs), 75–78 classes of, 76t clinical manifestations of, 75–78, 78t diagnostic testing for, 78 history and epidemiology of, 75 management of, 78 pathophysiology of, 75 pharmacokinetics and toxicokinetics of, 75 pharmacology of, 75, 76t Norepinephrine/dopamine reuptake inhibitor (NDRI), 362t, 363t, 366 Norovirus, 117t North American Coral Snake Antivenin (equine) adverse effects and safety issues for, 660 clinical use of, 659 dosing and administration of, 658t, 661 formulation and acquisition of, 661 history of, 658 pharmacology of, 659 in pregnancy and lactation, 660 source of, 658t Northwestern brown spider (Eratigena agrestis), 606 Nortriptyline, 356, 356f. See also Antidepressants, cyclic (CAs) Nostoc spp, 647 Notesthes robusta (bullrout), 625t NPH insulin, 176t NSAIDs. See Nonsteroidal antiinflammatory drugs (NSAIDs) Nuclear scintigraphy, 49 Nucleoside analog reverse transcriptase inhibitors, 244–245 Nuclides, 716 Nutmeg oil (Myristica fragrans, mace) adverse effects of, 148t clinical manifestations of, 140 common usages of, 139, 148t, 154t, 425 history of, 139 pathophysiology of, 139–140 pharmacology of, 139, 154t, 425t, 426f primary toxicity of, 641t Nyctalopia (night blindness), 144 Nystagmus, 6t Nystatin, 243t

763

O Obesity. See Dieting xenobiotics and regimens Obidoxime, 584, 588 Occupational asthma, 677, 677t Octopamine, 125 Octreotide, 174f, 184–185 Odontobuthus doriae, 616t Oenanthe crocata (hemlock water dropwort), 648 Ofloxacin, 168t Oil of lemon eucalyptus, 595t Oil of wintergreen, 141, 142 Olanzapine, 349t, 350, 350t. See also Antipsychotics Oleander (Nerium oleander), 148t, 314, 320, 641t, 645 Oleoresin capsicum (pepper spray), 675, 708 Omphalotus olearius, 628t, 632, 632f Ondansetron, 170t OP4 receptor, 80, 80t Ophryacus spp, 665t Ophthalmic exposures, 9, 20, 528 Ophthalmic medications, 168t Opiates, 79. See also Opioids Opioid antagonists, 90–92 adverse effects and safety issues of, 91–92 dosing and administration of, 91–92 in ethanol abstinence, 91 history of, 90 in maintenance of opioid abstinence, 91 mechanism of action of, 90 for nonopioid overdoses, 91 in opioid poisoning/toxicity, 88, 88t, 90–91 pharmacokinetics and pharmacodynamics of, 90–334 pharmacology of, 90 in pregnancy and lactation, 91 in rapid opioid detoxification, 89 Opioid detoxification, 89 Opioid receptors, 79–80, 80t, 81f Opioid use disorder, 80, 82t, 96–97 Opioid withdrawal (syndrome), 2t, 91 Opioids, 79–89 acute poisoning with, 88–89, 89t. See also Opioid antagonists classification, potency, and characteristics of, 84t clinical effects of, 80, 82t diagnostic testing for, 87–88 history and epidemiology of, 79 imaging findings, 36t as incapacitating agents, 708, 709t interaction with ethanol, 406t metabolism of, 83, 85f nontherapeutic and adverse effects of, 80–82

22/09/23 5:47 PM

764

INDEX

Opioids (Cont.): overdoses of, 96–97 pharmacology of, 79–80, 80t, 81f policies and practice reforms, 97 semisynthetic, 79 synthetic, 79 therapeutic effects, 80 toxic and life-threatening effects of, 2t, 82–83 Opportunistic infections, 244t–245t Ordeal bean (Tanghinia venenifera), 320 Orellanine- and orellinine-containing mushrooms, 628t, 634 Organ procurement, from poisoned patients, 737, 737t Organic chlorine pesticides, 590–593 classification of, 591t clinical manifestations of, 591–593 diagnostic testing for, 593 drug interactions of, 591 history and epidemiology of, 590 management of, 593 mechanisms of toxicity of, 590–591, 592f toxicokinetics of, 590 Organic dusts, 676 Organic phosphorus herbicides. See also Glufosinate; Glyphosate applications and uses, 565t WHO hazard classification of, 565t Organic phosphorus insecticides clinical manifestations of, 580–583, 581f, 582f diagnostic testing for, 583, 584t differential diagnosis of, 109t, 584t history and epidemiology of, 577 management of, 584–585 atropine in, 584, 586. See also Atropine benzodiazepines in, 585 magnesium for, 272 oximes in, 584–585, 589. See also Pralidoxime pathophysiology of, 579–580, 580f pharmacokinetics and toxicokinetics of, 578–579 pharmacology of, 577, 577f, 578f, 578t, 579f response to NMBs after, 341t ORL1 (Nociceptin/orphanin FQ) receptor, 79–80, 80t Orlistat, 126t, 128f, 129 Orogastric lavage, 12–14, 14t Oscillatoria spp, 647 Osteolathyrism, 647 Osteomalacia, 159, 446, 462 Osteomyelitis, 39, 43f Ostrich fern, 148t Ototoxic xenobiotics, 239, 249 Overdoses. See Poisonings and overdoses Oxalate raphides, in plants, 648 Oxalic acid, 523t, 648

158_Hoffman_Index_p0739-0776.indd 764

Oxaliplatin, 209t Oxaprozin, 76t Oxazepam, 377t. See also Sedative-hypnotics Oxcarbazepine, 186t, 188t, 189t, 190, 193t Oximes, 584–585, 588, 706. See also Pralidoxime Oxprenolol, 294t, 295–296, 297, 300 Oxycodone, 84t, 85. See also Opioids Oxygen, 675 Oxymetazoline, 204, 204f, 204t Oxymorphone, 84t, 85. See also Opioids Oxytropis spp, 641t Ozone (O3), 673t, 675 P Pacemaker cells, 295f Pacific urchin (Tripneustes), 623 Paclitaxel, 209t Paint thinner, inhaled, 431t Paints, inhaled, 431t Palamnaeus spp, 616t Paliperidone, 349t, 350t. See also Antipsychotics 2-PAM. See Pralidoxime Pamidronate, 159 Panaelous, 424 Pancuronium, 340t, 341t. See also Neuromuscular blockers (NMBs) Papaver spp (poppy), 641t, 644 Para-aminobenzoic acid (PABA), 328 Para-aminosalicylic acid (PAS), 257t, 260 Parabens, 170, 170t Parabuthus spp, 616t, 617 Paradichlorobenzene, 521–522 Paraffin, 535, 536t Paralytic shellfish poisoning (saxitoxin), 109t, 118t, 119 Para-methoxyamphetamine (PMA), 385t, 387. See also Amphetamines Para-methoxyamphetamine-monomethoxy (PMMA), 387. See also Amphetamines Paraquat, 569–572 clinical manifestations of, 570–571 diagnostic testing for, 571 history and epidemiology of, 569 management of, 571–572 pathophysiology of, 570 pharmacokinetics and toxicokinetics of, 569–570 pharmacology of, 569, 570f prognosis in, 571, 571f properties of, 33t, 564t Parasites, intestinal, 117t, 122 Paregoric, 84t Paresthesias, 6t Pargyline. See Monoamine oxidase inhibitors (MAOIs) Parkinsonism, 325, 352t

Paromomycin, 245t Paroxetine, 351, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Parsley, 148t Particulates, 42 Pasireotide, 184 Passion flower, 148t, 154t Patch formulations, 52–53, 52t Patient violence. See Violent patient Pau d’Arco, 148t Paullinia cupana (guarana), 125, 126t, 323, 641t Pausinystalia yohimbe (yohimbe), 149t, 154t, 641t Paxillus involutus, 628t, 629t PCCs. See Prothrombin complex concentrates (PCCs) Peganum harmala (Syrian rue), 149t, 153, 154t Peginterferon α-2a, 170t Pelagia noctiluca (mauve stinger), 618t, 619 Pelamis platurus (yellow-bellied sea snake), 623 Pellagra, 162 Penbutolol, 294t, 296, 297 Pendimethalin, 565t D-Penicillamine, 473 Penicillins, 238t, 239–240, 240t Pennyroyal (Hedeoma pulegioides), 140, 141, 142, 148t, 640t Pentamidine, 245t Pentasaccharides, 276t, 281 Pentazocine, 80, 83, 84t, 170t Pentetic acid/pentetate (zinc or calcium) trisodium (DTPA), 726–727 adverse effects and safety issues for, 727 for cobalt, 469 dosing and administration of, 727 formulation and acquisition of, 727 history of, 726 pharmacology of, 726, 726f in pregnancy and lactation, 727 in radionuclide contamination, 726–727 Pentobarbital, 377t. See also Sedative-hypnotics Pentostatin, 209t Pepper spray (oleoresin capsicum), 675, 708 Peppermint oil (menthol), 140 Peptides, in plants, 637, 646–647, 646f Per se limits, blood alcohol level, 734 Perampanel, 186t, 188t, 189t, 193t Performance enhancers, athletic. See Athletic performance enhancers Periostitis deformans, 42f Peripheral benzodiazepine receptor, 401–402, 402f Peripheral α1-adrenergic antagonists, 311 Peritoneal dialysis, 30

22/09/23 5:47 PM

INDEX

Periwinkle, 148t, 154t Permanganates, 490 Perphenazine, 349t, 350t, 351. See also Antipsychotics Personal protective equipment (PPE), 731, 731f, 731t Pesticides. See Insecticides Pethidine, 84t Peyote (Lophophora williamsii), 424, 425t, 641t, 644 Pharmaceutical additives, 168–172 benzalkonium chloride, 168, 168t benzyl alcohol (benzene methanol), 168–169, 169t chlorobutanol, 169, 169t lipids, 169–170, 169t parabens, 170, 170t phenol, 170, 170t polyethylene glycol, 170–171, 170t propylene glycol, 171, 171t sorbitol, 171–172, 172t thimerosal, 172, 172t toxicity of, by organ system, 168t Pharmacobezoar, 12, 13f Phenacetin, 700 Phencyclidine (PCP), 440–444 analogs of, 440t clinical manifestations of, 442–443 diagnostic testing for, 444 emergence reaction, 443 forms of, 441 history and epidemiology of, 440 management of, 444 pathophysiology of, 441–442 pharmacology of, 440–441, 440t tolerance and withdrawal, 443–444 Phendimetrazine, 127t Phenelzine, 341t, 364t. See also Monoamine oxidase inhibitors (MAOIs) Phenformin, 173, 175t Phenobarbital. See also Sedative-hypnotics for alcohol withdrawal, 418 antithyroid effects of, 234t diagnostic testing for, 378 injection, propylene glycol in, 171t management of, 378 metabolism of, 188t pharmacokinetics of, 188t, 377t, 378 properties of, 33t sodium bicarbonate for, 105 Phenols chemistry of, 637 decontamination for, 21 as disinfectant, 515t as pharmaceutical additive, 170, 170t in plants, 647–648 sources of, 523t toxicity of, 517 Phenoxy herbicides, 574–576 applications of, 566t

158_Hoffman_Index_p0739-0776.indd 765

clinical manifestations of, 575 diagnostic testing for, 575 management of, 575–576 pathophysiology of, 575 pharmacokinetics and toxicokinetics of, 575 pharmacology of, 575 WHO hazard classification of, 566t Phentermine, 126t, 127 Phentermine/topiramate, 126t, 127–128, 186t Phentolamine, 374 Phenylbutazone, 76t Phenylephrine, 168t, 203, 204t Phenylethylamines, 424–425, 424f. See also Amphetamines Phenylpropanoids, 637, 647–648 Phenylpropanolamine, 127t, 203, 203f, 205 Phenytoin antithyroid effects of, 234t clinical manifestations of, 190–191, 193t, 265t diagnostic testing for, 191 drug interactions of, 189t, 257t, 406t imaging findings, 36t, 42 injection, propylene glycol in, 171t management of, 191 mechanism of action of, 186t metabolism of, 188t pharmacokinetics and toxicokinetics of, 188t, 190, 265t properties of, 33t response to NMBs after, 342t Philodendron spp (philodendron), 641t, 649 Phoradendron spp (American mistletoe), 641t, 647 Phorbol esters, 650 Phosgene, 673t, 674–675, 707, 709t Phosgene oxime, 707, 709t Phosphates, calcium for, 533 Phosphine, 558–559, 558t, 559t Phosphodiesterase inhibitors, 283, 299 Phosphoric acid, 523t, 524f Phosphorus, 597–599 chemistry and pharmacology of, 597 clinical manifestations of, 597–598 diagnostic testing for, 598 history and epidemiology of, 597 management of, 598–599 normal concentrations of, 597 pathophysiology of, 597 pharmacokinetics and toxicokinetics of, 597 sources of, 523t Phossy jaw, 597 Photinus spp ( fireflies), 314 Photons, 715 Photosensitivity dermatitis, 650 Physalia physalis (Portuguese man-of-war), 618, 618t, 619f, 620

765

Physalia utriculus (bluebottle), 618, 618t, 619 Physical restraints, 56 Physostigma venenosum (calabar bean), 641t, 644 Physostigmine salicylate, 206–207 adverse effects and safety issues for, 206–207 for antimuscarinic/anticholinergic toxicity, 203, 206, 427 for central antimuscarinic syndrome, 355 dosing and availability of, 207 formulation and acquisition of, 207 history of, 206 pharmacokinetics and pharmacodynamics of, 206 pharmacology of, 206 in pregnancy and lactation, 207 Phytolacca americana (pokeweed), 641t, 646f, 647 Phytonadione. See Vitamin K1 (phytonadione) Picaridin, 595t Pilocarpus jaborandi (pilocarpus), 641t, 644 Pilocarpus pinnatifolius, 641t Pimozide, 349t, 350t. See also Antipsychotics Pindolol, 294t, 296, 297 Pine mushroom matsutake (Tricholoma magnivelare), 634, 635f Pine oil, 140, 539 “Pink disease,” 493, 495 Pioglitazone, 175t, 177 Piper methysticum (kava kava), 147t, 151t, 154t, 641t, 646 Piperaquine, 248t, 249t, 252 Piperine, 151t Pipotiazine, 349t. See also Antipsychotics Piroxicam, 76t Pistachio (Pistacia vera), 650 Pit viper bites clinical manifestations of, 653, 654f, 654t management of, 654t, 655–656. See also Antivenom, snake pathophysiology of, 653, 653t Pit vipers native (US), 651, 651f, 651t nonnative, 664–665t Plague, 712 Plantago spp, 641t Plants, 637–650. See also specific plants approach to the patient, 637 identification of, 637 toxic constituents and taxonomic associations alcohols, 648 alkaloids. See Alkaloids carboxylic acids, 648 glycosides, 143, 637, 644–646, 645f phenols and phenylpropanoids, 647–648

22/09/23 5:47 PM

766

INDEX

Plants, toxic constituents and taxonomic associations (Cont.): proteins, peptides, and lectins, 646–647 terpenoids and resins, 646 xenobiotics from, classification of, 637 xenobiotics interactions with, 648 Plasmapheresis, 33–34, 65 Plasminogen, 281 Plasmodium spp, 247, 247f, 248t. See also Antimalarials Plateauing, with AASs, 132 Platelet activation pathway, 274f, 282f Platinum-based complexes, 209t, 211f Pleural disorders, diagnostic imaging of, 42, 44f, 45f Pleurocybella porrigens, 629t PLP (pyridoxal-5′-phosphate), 262 Plumbism. See Lead PMA (para-methoxyamphetamine), 385t, 387. See also Amphetamines Pneumococcal vaccine, 170t Pneumomediastinum, 42, 46f Pneumonic plague, 712 Pneumonitis cadmium, 461 hypersensitivity, 42, 676–677 metal, 675–676 Pneumoperitoneum, 44–45, 46t Pneumothorax, 42 Podophyllum emodi, 641t Podophyllum peltatum (mayapple), 148t, 642t, 649, 649f Podophyllum resin (podophyllin), 72–73, 74t Poison hemlock (Conium maculatum), 639t, 643–644 Poison ivy (Toxicodendron radicans), 643t, 650 Poison oak (Toxicodendron diversilobum), 643t, 650 Poison oak (Toxicodendron toxicarium), 643t, 650 Poison sumac (Toxicodendron vernix), 50, 643t Poison-bun sponge (Neofibularia nolitangere), 623 Poisonings and overdoses antidotes and therapeutics for, 5t clinical and laboratory findings in, 6t organ procurement following, 737, 737t patient management with altered mental status, 4 with cutaneous exposure, 8–9 further evaluation in, 6–8 indications for critical care unit admission, 9–10, 9t intentional, 8 nontoxic, 9 with normal mental status, 8

158_Hoffman_Index_p0739-0776.indd 766

with ophthalmic exposure, 9 overview of, 4, 6, 7f pitfalls in, 8 in pregnancy and lactation, 8 Pokeweed (Phytolacca americana), 148t, 641t, 646f, 647 Poliomyelitis, vs. botulism, 110t Polonium, 720 Polychaetae, 623 Polyethylene glycol 3350 (PEG), 25 Polyethylene glycol 3350 with electrolyte solution (PEG-ELS), 25, 170t Polyethylene glycols (PEGs), 170–171, 170t Polymer fume fever, 677 Polymyositis, vs. botulism, 110t Polymyxin, 342t Polymyxin B sulfate/trimethoprim, 168t, 243t Polyporic acid–containing mushrooms, 629t “Poppers,” 431t, 434 Poppy (Papaver spp), 641t, 644 Poppy seeds, 87–88 Populus spp, 642t Porifera, 623 Porthidium spp, 665t Portuguese man-of-war (Physalia physalis), 618, 618t, 619f, 620 Positrons, 715 Posterior reversible encephalopathy syndrome, 48–49, 50–51f Potassium, for thallium elimination, 507 Potassium channel blockers, 296, 297 Potassium chlorate, 514t, 519 Potassium chloride solution, 172t Potassium hydroxide, 523t Potassium iodide (KI), 724–725 adverse effects of, 724–725 dosing and administration of, 725, 725t formulation and acquisition of, 725 history of, 724, 724f pharmacology of, 724 in pregnancy and lactation, 725 for radioactive iodine exposure, 237, 724 Potassium permanganate, 514t, 516, 523t Potassium-sparing diuretics, 309t, 312 Potrooms, 445, 446 Povidone-iodine (iodophor), 514t, 515–516 Pralidoxime, 588–589 adverse effects and safety issues for, 589 for carbamate insecticides, 589 dosing and administration of, 589 duration of treatment with, 589 formulation and acquisition of, 589 history of, 588 for nerve agents, 706 for organic phosphorus insecticides, 588–589 pharmacokinetics and pharmacodynamics of, 588

pharmacology of, 588 in pregnancy and lactation, 589 Pramlintide, 174, 175t Prasugrel, 284 Prazosin, 311 Pregabalin, 186t, 188t, 189t, 191, 193t Pregnancy and lactation activated charcoal use in, 23 management of poisonings and overdoses in, 8. See also specific antidotes; specific xenobiotics whole-bowel irrigation in, 27 Presynaptic adrenergic neuron antagonists, 311 Presynaptic serotonin and norepinephrine releaser (PSNR), 362t, 363t, 366 Prickly poppy, 154t Prilocaine, 327t. See also Anesthetics, local Primaquine, 245t, 248t, 249t, 252 Primidone, 377t. See also Sedative-hypnotics Primula obconica, 642t Procainamide, 36t, 265t, 267 Procaine, 327, 327t, 328t. See also Anesthetics, local Procarbazine, 209t, 372 Prochlorperazine, 169t, 349t. See also Antipsychotics Proguanil, 248t, 249t, 253 Promazine, 349t. See also Antipsychotics Promethazine, 200t, 349t. See also Antipsychotics Propafenone, 266t, 269 Propane, 431t, 672, 673t Propanil, 564t, 568 Propionic acids, 76t Propofol, 169t, 376, 377t, 379–380. See also Sedative-hypnotics Propoxyphene, 81 Propranolol clinical manifestations of, 297 effect on thyroid hormones, 234t management of, 300 mechanism of action of, 331 pharmacokinetics of, 295–296 pharmacology of, 294t response to NMBs after, 341t Propylene glycol (PG), 33t, 171, 171t, 547 Propylthiouracil (PTU), 234t, 235t, 236–237 Prostacyclins, 77f Prostaglandins, 75, 77f Protamine, 291–292 adverse effects and safety issues for, 291 availability of, 292 dosing and administration of, 292 for heparin reversal, 278, 291, 292 history of, 291 pharmacokinetics and pharmacodynamics of, 291 pharmacology of, 291 in pregnancy and lactation, 291

22/09/23 5:47 PM

INDEX

Protease inhibitors, 246 Proteases, 136 Protein C, 274f, 277 Protein kinase inhibitors, 209t, 211f Protein S, 274f, 277 Proteins, in plants, 637, 646–647, 646f Prothrombin complex concentrates (PCCs), 285–287 activated (aPCCs), 286–287 adverse effects and safety issues for, 285 availability of, 285t, 286 for direct oral anticoagulant reversal, 281, 286 dosing and administration of, 285, 286t four-factor vs. fresh frozen plasma, 286 four-factor vs. three-factor, 286 history of, 285 in liver disease, 286 pharmacokinetics of, 285, 286t pharmacology of, 285, 285t in pregnancy and lactation, 285 in trauma, 286 for vitamin K–induced coagulopathy, 275 Protriptyline, 356f. See also Antidepressants, cyclic (CAs) Prunus spp, 642t, 645 Prussian blue adverse effects and safety issues for, 509–510 for cesium, 464, 509 formulation and acquisition of, 510 history of, 508 pharmacology of, 508 in pregnancy and lactation, 510 for thallium, 507, 508–509 Psathyrella foenisecii, 628t, 633 Pseudoephedrine, 203–205, 203t Pseudoephedrine syrup, 172t Psilocin, 424f, 425t Psilocybin, 424f, 633 Psilocybin-containing mushrooms, 425t, 628t, 633, 633f PSNR (presynaptic serotonin and norepinephrine releaser), 362t, 363t, 366 Psychedelic, 423. See also Hallucinogens Psychoactive xenobiotics in herbal dietary supplements, 153, 153t–154t psychotropic alkaloids, 644 Psychotria viridis (chacruna), 145t, 153, 154t, 424 Pteridium spp, 642t Pterois spp (lionfish), 624, 625t, 626f Puffer fish, 119 Pulmonary irritants, 672–677 ammonia, 673–674, 673t asthma and reactive airways dysfunction syndrome and, 677, 677t characteristics of, 673t

158_Hoffman_Index_p0739-0776.indd 767

as chemical weapons, 707, 709t chloramines, 673t, 674 chlorine gas, 673t, 674, 709t clinical manifestations of, 672–673 hydrogen chloride, 673t, 674 hydrogen fluoride, 673t, 674 hydrogen sulfide, 673t, 674 hypersensitivity pneumonitis and, 676–677 imaging findings, 36t inorganic dust, 676 management of, 676 metal fume fever and, 677 metal pneumonitis, 675–676 methyl isocyanate, 675 nitrogen oxides, 673t, 675 organic dust, 676 oxygen, 675 ozone, 673t, 675 pathophysiology of, 672 phosgene, 673t, 709t polymer fume fever and, 677 riot control agents, 675 in smoke inhalation, 666–667 sulfur dioxide, 673t, 674 in thermal degradation products, 666–667, 666t Pulmonary problems, xenobiotic causes of, 39, 41–42 Pulsatilla spp, 642t Pulse rate, 2, 2t Purine analogs, 209t Purpura, 6t Pyramiding, with AASs, 132 Pyrazinamide (PZA), 257t, 259 Pyrazole herbicides, 566t Pyrethrins and pyrethroids, 593–595, 594t Pyridazinone herbicides, 566t Pyridine herbicides, 566t Pyridostigmine, 344t Pyridoxal-5′-phosphate (PLP), 262 Pyridoxine (vitamin B6), 262–263 adverse effects and safety issues for, 262 dosing and administration of, 263 for ethylene glycol toxicity, 262 formulation of, 263 history of, 262 for hydrazide- and hydrazine-induced seizures, 262 injection, chlorobutanol in, 169t for isoniazid toxicity, 258 for mushroom poisoning, 262 for nerve agent pretreatment, 706 overdose of, 161 pharmacology of, 262 in pregnancy and lactation, 262–263 RDA for, 156t Pyrimethamine adverse effects of, 245t, 253 antimalarial mechanism of, 253

767

leucovorin for toxicity of, 218 management of, 253 mechanism of action of, 248t for opportunistic infections, 245t pharmacokinetics of, 249t Pyrimidine analogs, 209t Pyrroles (chlorfenapyr), 593 Pyrrolizidine alkaloids, 153, 644 Q Q fever, 712 Qinghaosu, 248 QNB (3-quinuclidinyl benzilate, BZ), 708, 709t Quaternary ammonium compounds, 515t, 517–518 Quercus spp, 642t Quetiapine, 349t, 350t. See also Antipsychotics Quinidine, 170t, 248–249, 265t, 267 Quinine, 248–250 clinical manifestations of, 250 diagnostic testing for, 250 as heroin adulterant, 83 management of, 250 mechanism of action of, 248t pathophysiology of, 248–249 pharmacokinetics and toxicokinetics of, 248, 249t R Raclopride, 349t. See also Antipsychotics Rad (radiation absorbed doses), 716f Radiation, 715–723 acute radiation syndrome from, 719 average effective doses of, 717t as carcinogen, 719 in children, 723 commonly encountered sources of, 719–720 consideration of the deceased, 723 from diagnostic imaging, 717–718, 718t dose estimation for, 719 epidemiology of, 717–718, 718t exposure limits for, 718 historical exposures to, 715 ionizing vs. nonionizing, 716 irradiation, contamination, and incorporation of, 717, 717t management of, 720–722 decision making in, 721, 722t decontamination in, 721 initial assessment in, 720 initial emergency department, 720–721 medical, 721–722 potassium iodide in. See Potassium iodide (KI) triage in, 720 occupational exposure to, 717 pathophysiology of, 718

22/09/23 5:47 PM

768

INDEX

Radiation (Cont.): in pregnancy, 723 principles of, 715–717 prognosis with, 722 protection from, 716–717 regulation and reported processes, 718 stochastic vs. deterministic effects of, 718–719 units of measure in, 716f Radioactive decay, 715–716 Radioactive iodine, 235t Radioactivity, 715–717, 715t, 716f Radiocesium, 464 Radioisotopes, 715t Radiolucent ingestions, 39, 41f Radiopaque ingestions, 6t, 35 Radon, 717, 717t, 720 Ragwort (Heliotropium spp), 640t Raloxifene, 132 Ramaria rufescens, 629t Ramelteon, 376, 377t. See also Sedative-hypnotics Ramipril, 312 Ranitidine, 200, 200t, 202, 406t Ranunculus spp, 642t Rasagiline. See Monoamine oxidase inhibitors (MAOIs) Raspberry ketone, 126, 126t Rattlebox (Crotalaria spp), 639t Rattlesnake bites. See Pit viper bites Rattlesnakes. See Pit vipers Rauwolfia serpentina, 642t Reactive airways dysfunction syndrome (RADS), 677 Reactive oxygen species (ROS), 675 Recombinant factor VII (rFVIIa), 275, 287 “Red man” syndrome, 242 Red phosphorus, 597. See also Phosphorus Red River snake root (Aristolochia spp), 638t, 648 Red skin, 6t Red squill (Urginea spp), 149t, 314, 320, 643t Red-moss sponge, 623 Reef stonefish (Synanceja verrucosa), 625t Refrigerants, inhaled, 431t Rem (roentgen equivalent man), 716f Remijia pedunculata, 642t Remoxipride, 349t, 350t. See also Antipsychotics Renal tubular acidosis, 433 Repaglinide, 173, 175t, 177 Reptiles. See Lizards; Snakes Reserpine, 311 Resins, 29, 143, 637, 646, 649 Respirators, 731, 731t Respiratory rate, 1t, 2, 3t Reteplase, 281 Retinol, 155–156 Retinol activity equivalents (RAEs), 155 Rhabdomyolysis, 6t, 201, 202, 342

158_Hoffman_Index_p0739-0776.indd 768

Rhamnus frangula, 642t Rheum spp, 642t Rhododendron (rhododendron), 642t, 649 Ricin, 642t, 646–647, 714 Ricinus communis (castor bean), 642t, 646–647, 646f Rickettsiae, 712 Rifabutin, 234t, 245t, 258–259 Rifampin, 234t, 257t, 258–259, 712 Rilmenidine, 310–311 Rimonabant, 127t, 129 Riot control agents, 675, 707–708, 709t Risperidone, 349t, 350, 350t, 351. See also Antipsychotics Rivaroxaban, 276t, 279t, 280–281 Rivea corymbosa (morning glory), 148t, 154t, 423, 640t, 644 Rizatriptan, 231t Robinia pseudoacacia (black locust), 642t, 647 Rocky Mountain wood tick (Dermacentor andersoni), 609 Rocuronium, 340t, 341t. See also Neuromuscular blockers (NMBs) Rodenticides barium in, 556, 556t strychnine in, 601 thallium in, 505 warfarin in, 275 Roentgen equivalent man (rem), 716f Roentgens, 716f Rofecoxib, 75 Ropivacaine, 327t. See also Anesthetics, local Rosary pea (Abrus precatorius), 638t, 646f, 647 Rosiglitazone, 175t, 177 Rotavirus, 117t Roundworms, in food, 122 Royal jelly, 144t Rue, 148t Rufinamide, 186t, 188t, 193t Rumack-Matthew nomogram, 59, 60f Rumex spp, 642t S Safe injection sites, 97 Sage, 148t St. Ignatius bean, 643t St. John’s wort (Hypericum perforatum) adverse effects of, 371 common usages of, 148t drug interactions of, 150, 151t, 152f, 648 primary toxicity of, 640t Salicin, 645 Salicylates, 98–103 clinical effects of, 99–100 clinical manifestations of, 100, 100t, 101t diagnostic testing for, 101, 101f forms of, 98–99

history and epidemiology, 98 imaging findings, 36t management of, 101–103 in children, 103 fluid replacement in, 102 gastric decontamination and activated charcoal in, 101–102 glucose supplementation in, 102, 182 hemodialysis in, 102–103, 102t monitoring in, 103 in pregnancy, 103 sedation, intubation, and mechanical ventilation in, 103 serum and urine alkalinization in, 102, 102f sodium bicarbonate in, 104–105 pathophysiology of, 99 pharmacokinetics of, 98 pharmacology of, 98, 283, 283f properties of, 33t therapeutic concentration of, 98, 101 thyroid hormones and, 234t toxicokinetics of, 98, 99f Salicylic acid, 98, 243t. See also Salicylates Salivation, 6t Salix spp, 642t Salmonella spp food poisoning, 117t, 120t, 121 Salvia divinorum (salvinorin A) adverse effects of, 149t history of, 425 pharmacology of, 425–426, 425t popular usages of, 149t, 154t Sambucus spp, 642t Sand dollars, 623 Sanguinaria canadensis, 642t Sanguinarine, 638t, 644 Saponin glycosides, 644–645, 645f Sarin (GB), 705, 709t SARIs (serotonin antagonist/partial agonist/reuptake inhibitors), 362t, 363t, 365 Sassafras, 149t Saw palmetto, 149t Saxagliptin, 174, 175t Saxitoxin (paralytic shellfish poisoning), 109t, 118t, 119 Schefflera spp, 642t Schlumbergera bridgesii, 642t Scombroid poisoning, 122–123, 123t Scopolamine, 83–84 Scorpaena spp, 625t Scorpaenidae, 624–625 Scorpio maurus, 616t Scorpionfish, 625t Scorpions, 608, 608f, 608t, 615–617, 616t Scotch broom. See Broom (Cytisus scoparius) Scurvy, 160–161 Scyphozoa, 618t, 619

22/09/23 5:47 PM

INDEX

Sea cucumbers, 623 Sea mango (Cerbera manghas), 314, 320 Sea nettle (Chrysaora quinquecirrha), 618t, 619, 620 Sea snakes, 109t, 623–624, 624t Sea sponges, 623 Sea stars, 623 Sea urchins, 120, 623 Sea wasp (Chironex fleckeri), 618–621, 618t Seabather’s eruption, 621 Secobarbital, 377t. See also Sedative-hypnotics Sedative-hypnotics, 376–380 barbiturates, 376, 377t, 378 benzodiazepines. See Benzodiazepines bromides, 379 carisoprodol and meprobamate, 377t, 379 chloral hydrate, 377f, 377t, 379 clinical manifestations of, 377–378, 377f dexmedetomidine, 311, 377t, 380, 418 diagnostic testing for, 378 etomidate, 171t, 371t, 377t, 380 flumazenil for reversal of. See Flumazenil history and epidemiology of, 376 interaction with ethanol, 406t management of, 378 melatonin, ramelteon, and tasimelteon, 377t, 380 pharmacodynamics and toxicodynamics of, 376 pharmacokinetics and toxicokinetics of, 372t, 376 propofol, 169t, 376, 377t, 379–380 suvorexant, 377t, 380 tolerance and withdrawal, 377 zolpidem, zaleplon, zopiclone, eszopiclone, 377t, 379 Seizures, 6t in alcohol withdrawal, 417 from antidepressants, 362, 363t from antihistamines, 202 from antipsychotics, 355 from ethanol, 408 from hydrazide and hydrazine, 262 from nicotine, 439 Selective androgen receptor modulators (SARMs), 132 Selective estrogen receptor modulators (SERMs), 132 Selective serotonin reuptake inhibitors (SSRIs), 361–365 adverse effects after therapeutic doses of, 363–364. See also Serotonin toxicity clinical manifestations of, 362–363, 363t drug discontinuation syndrome with, 366 history and epidemiology of, 361 management of, 363

158_Hoffman_Index_p0739-0776.indd 769

mechanism of action of, 361, 361f pathophysiology of, 361–362, 363t pharmacokinetics and toxicokinetics of, 361, 362t receptor activity of, 362, 362t seizure potential of, 362, 363t Selegiline. See Monoamine oxidase inhibitors (MAOIs) Selenious acid, 500, 500t, 523t Selenium, 500–502 chemistry of, 500 clinical manifestations of, 501 compounds and uses of, 500t diagnostic testing for, 502 history and epidemiology of, 500 management of, 502 normal concentrations of, 500 pathophysiology of, 501 pharmacokinetics and toxicokinetics of, 500–501, 501f pharmacology of, 500 RDA for, 500 sources of, 500 Selenium hexafluoride gas, 500t, 501, 502 Selenium sulfide, 243t, 500, 500t Selenosis, 500 Self-contained breathing apparatus (SCBA), 731, 731t Semecarpus anacardium (Indian marking nut), 650 Semustine, 209t, 210 Senecio spp, 642t Senna (Cassia spp), 127t, 130, 149t, 639t Sennosides, 639t, 645 Serotonergics, for weight loss, 126t, 128f, 129 Serotonin antagonist/partial agonist/ reuptake inhibitors (SARIs), 362t, 363t, 365 Serotonin reuptake inhibitors/partial receptor agonists (SPARIs), 362t, 363t, 365 Serotonin toxicity clinical manifestations of, 2t, 364, 372t diagnosis of, 364, 365t, 373 from hallucinogens, 427 management of, 364–365 vs. neuroleptic malignant syndrome, 365, 365t pathophysiology of, 364 xenobiotics causing, 364t Serotonin/norepinephrine reuptake inhibitors (SNRIs), 362t, 363t, 365 Sertindole, 349t, 350, 350t, 351. See also Antipsychotics Sertraline, 362t, 363t. See also Selective serotonin reuptake inhibitors (SSRIs) Sevoflurane, 337

769

SGLT2 (sodium glucose co-transporter 2) inhibitors, 173, 174, 175t, 177, 179 Shellfish poisoning, 109t, 118t, 119 Shielding, 716 Shigella spp food poisoning, 117t, 120t, 121 Sibutramine, 127t Sida carpinifolia, 642t Sida cordifolia, 642t Sievert (Sv), 716f SILENT (syndrome of irreversible lithiumeffectuated neurotoxicity), 368 Silica, 36t Silver clinical manifestations of, 503–504, 504f, 504t diagnostic testing for, 504 history and epidemiology of, 503, 503t normal concentrations of, 503 pharmacology of, 503 treatment of, 504 Silver acetate, 503t Silver nitrate, 503t Silver salts, 503 Silver sulfadiazine, 243t, 503, 503t Simple asphyxiants aliphatic hydrocarbon gases, 671–672 carbon dioxide, 672 clinical manifestations of, 671, 671t history and epidemiology of, 671 management of, 672 nitrogen gas, 672 noble gases, 671 pathophysiology of, 671 in thermal degradation products, 666, 666t Sinoatrial (SA) node, 293, 295f, 303 Sistrurus spp, 651t, 665t. See also Pit viper bites Sitagliptin, 174, 175t Skates, 624 Skeletal changes, xenobiotic causes of, 39, 41f–43f, 41t, 433, 433f Slippery elm, 149t Smallpox, in warfare, 713 Smoke inhalation, 666–670 clinical manifestations of, 667 diagnostic testing for, 667, 668f history and epidemiology of, 666, 666t management of, 668–670, 669f pathophysiology of, 666–667, 666t, 669f Smoking cessation products, 436, 436t. See also Nicotine Snakebites antivenom for, 654t, 655. See also Crotalidae immune F(ab′)2 (equine); Crotalidae polyvalent immune Fab antivenom (ovine); North American Coral Snake Antivenin (equine) coral snake. See Coral snake bites exotic nonnative, 662–663, 662t, 663t, 664–665t

22/09/23 5:47 PM

770

INDEX

Snakebites (Cont.): history and epidemiology of, 662 management of, 653–655, 654t, 662t, 663–665 pit viper. See Pit viper bites Snakeroot, 154t Snakes coral, 651–652, 652f epidemiology of, 651–652, 651t identification of, 651–652, 651f, 652f pit vipers, 651, 651f sea, 109t, 623–624, 624t taxonomy of, 662, 662t venom toxicity of, 662 Sniffing, 431. See also Inhalants SNRIs (serotonin/norepinephrine reuptake inhibitors), 362t, 363t, 365 Soapwort, 149t Sodium bicarbonate, 104–107 adverse effects and safety issues for, 107 as athletic performance enhancer, 135 for chlorophenoxy herbicides, 106 dosing and administration of, 107 formulations of, 107 indications for chlorine gas, 106–107 metabolic acidosis, 106 metformin, 106 methotrexate, 105–106 phenobarbital, 105 salicylates, 104–105 sodium channel blockers, 104 toxic alcohols, 106 tricyclic antidepressants, 104 mechanism of action of, 104, 105t pharmacology of, 104 in pregnancy and lactation, 107 Sodium borates, 523t Sodium carbonates, 523t Sodium channel blockers class I antidysrhythmics, 264, 264f, 265t–266t, 267–269 sodium bicarbonate for, 104 Sodium channels, plants affecting, 648–649 Sodium chlorate (NaClO3), 514t, 519, 565t Sodium glucose co-transporter 2 (SGLT2) inhibitors, 173, 174, 175t, 177, 179 Sodium hydroxide (lye) barium swallow imaging of, 47f, 526f burns from, 524f endoscopy of, 524f sources of, 523t Sodium hypochlorite, 514t, 516, 523t Sodium monofluoroacetate (SMFA), 600 Sodium nitrite, 693–694 Sodium nitroprusside, 311–312, 692, 694 Sodium phosphates, 523t Sodium polystyrene sulfonate (SPS), 369

158_Hoffman_Index_p0739-0776.indd 770

Sodium silicates, 523t Sodium stibogluconate, 449, 450t, 451. See also Antimony Sodium thiosulfate, 693–694 adverse effects and safety issues for, 694 in calciphylaxis, 694 for cyanide toxicity, 693–694 for cyanide toxicity prevention, 311 formulation and acquisition of, 694 history of, 693 for mechlorethamine extravasation, 227t, 339 pharmacokinetics and pharmacodynamics of, 693 pharmacology of, 693 with sodium nitrite, 693–694 Solanum americanum, 642t Solanum dulcamara, 642t Solanum nigrum, 642t Solanum tuberosum, 642t Solderers, cadmium exposure in, 461 Solenopsis spp ( fire ants), 610, 610t Solvents hydrocarbon. See Hydrocarbons inhaled. See Inhalants Soman (GD), 705, 709t Somatostatin, 184–185, 234t Soot, 667 Sorafenib, 209t Sorbitol, 171–172, 172t Sotalol, 294t, 296, 297, 300 Soy formula, infant, 234t Soy isoflavone, 149t Spanish fly, 612 SPARIs (serotonin reuptake inhibitors/ partial receptor agonists), 362t, 363t, 365 Sparteine, 639t, 643 Spathiphyllum spp, 642t Spiders. See Arthropods Spinacia oleracea, 642t Spiny fish, 624–625, 625t Spironolactone, 312 Sponges, 623 Spongiform leukoencephalopathy, in heroin users, 84 Spores, mushroom, 629t Spot removers, inhaled, 431t Spray paint, inhaled, 431t Squill (Urginea spp), 149t, 314, 320, 643t SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) Stacking, of AASs, 132 Staphylococcal enterotoxin B (SEB), 714 Staphylococcus spp food poisoning, 117t, 120t, 121 Star anise (Illicium anisatum), 640t, 646 Stavudine (d4T), 245 Sterilants. See Antiseptics, disinfectants, and sterilants

Steroids anabolic-androgenic (AAS), 131–132, 132t cardioactive. See Cardioactive steroids (CASs) Stibine, 450t, 451. See also Antimony Stingrays, 624–626 Stiripentol, 186t Stochastic effects, radiation, 718–719 Stokes’ sea snake (Astoria tokesii), 624 Stomolophus spp, 618t, 620 Stonefish (Synanceja spp), 624–626, 625f, 625tf Streptococcus group A, 117t Streptokinase, 281 Streptomycin, 712 Streptozocin, 209t Stroke, cocaine-related, 48, 49f, 399 Stroke, vs. botulism, 110t Strychnine, 601–602 in Chinese herbal medicine, 153 clinical manifestations of, 153, 601 diagnostic testing for, 602 differential diagnosis of, 601 history and epidemiology of, 601 management of, 602 pathophysiology of, 601 toxicokinetics of, 601 Strychnos spp, 153, 601, 643t, 644. See also Strychnine Subarachnoid hemorrhage, 48, 48f Succimer (2,3,-dimercaptosuccinic acid, DMSA), 485–487 adverse effects and safety issues with, 486 for antimony, 452 for arsenic, 456, 486 for bismuth, 460 CaNa2EDTA with, 486, 489 for copper, 473 dosing and administration of, 486–487 formulation and acquisition of, 487 history of, 485 for lead, 482, 483t, 485–486 for mercury, 486, 496 pharmacokinetics of, 485 pharmacology of, 485, 485f in pregnancy and lactation, 486 Succinylcholine. See also Neuromuscular blockers (NMBs) clinical manifestations of, 340, 342–343 hyperkalemia, 340, 342 malignant hyperthermia. See Malignant hyperthermia muscle spasms, 342–343 prolonged effect, 340 rhabdomyolysis, 342 drug interactions of, 341t–342t mechanism of action of, 339, 339f pharmacology of, 340, 340t

22/09/23 5:47 PM

INDEX

Sucralfate, 234t, 236, 445 Sudden death, in athletes, 136 Sudden sniffing death, 431, 433 Sugammadex, 344–345 Sulfacetamide, 170t Sulfadiazine, 245t Sulfadoxine, 248t, 258 Sulfanilamide, 168 Sulfhemoglobin, 700 Sulfhemoglobinemia, 700 Sulfonamides, 238t, 242, 248t Sulfonylureas in children, 179 history of, 173 hypoglycemia from, 176, 177t, 178 pharmacokinetics and toxicokinetics of, 174, 174f, 175t Sulfur dioxide, 673t, 674 Sulfur mustard, 706–707, 709t Sulfuric acid, 523t, 674 Sulfuryl fluoride, 558t, 559t, 561 Sulindac, 76t Sulpiride, 349t. See also Antipsychotics Sumatriptan, 231t Superwarfarins, 275 Surface tension, 537 Suvorexant, 377t, 380. See also Sedative-hypnotics Sv/rem, 716f Swainsonia spp (locoweed), 643t, 644 Swainsonine, 640–643t, 644 Sydney funnel web spider, 607 Sympatholytics, 309t, 311 Sympathomimetics as decongestants, 203–205, 204t as dieting xenobiotics, 125–126, 126t mechanism of action of, 128f pharmacology of, 203, 203f toxic syndrome, 2t Symphytum spp (comfrey), 145t, 153, 643t Synanceja spp (stonefish), 624–626, 625f, 625t Syndrome of irreversible lithiumeffectuated neurotoxicity (SILENT), 368 Synephrine, 644. See also Bitter orange extract (Citrus aurantium) p-Synephrine, 125 Synthetic erythropoiesis protein, 134 Syrian rue (Peganum harmala), 149t, 153, 154t, 372 T T3 (triiodothyronine), 233, 233f, 235, 236t T4 (tetraiodothyronine), 233, 233f, 235, 236t Tabun (GA), 705, 709t Tachycardia, 2t Tachypnea, 3t Tafenoquine, 253–254

158_Hoffman_Index_p0739-0776.indd 771

Tamoxifen, 132, 234t Tanacetum vulgare (tansy), 643t, 646 Tanghinia venenifera (Ordeal bean), 320 Tapentadol, 84t, 86 Tapeworms, 122 Tar injury, 540 Tarantulas, 606–607, 606f Taraxacum officinale, 639t Tardive dyskinesia, 352, 352t Tartrazine, 123t Tasimelteon, 376, 377t. See also Sedative-hypnotics Taxanes, 209t, 211f Taxine, 648 Taxus spp (yew), 149t, 643t, 648–649, 649f Tea tree oil, 140–141 Tear gas, 675, 707 Technetium, 720 Tedania ignis ( fire sponge), 623 Temazepam, 377t. See also Sedative-hypnotics Temozolomide, 209t, 211f Temperature, 2–3, 2t, 3t Tenecteplase, 281 Teniposide, 209t, 211f Terazosin, 311 Terpenes/terpenoids, 539, 637, 646 Testosterone, 132t Testosterone-to-epitestosterone ratio, 135 Tetanus, vs. botulism, 110t Tetracaine, 327, 327t, 328, 328t. See also Anesthetics, local Tetrachloroethylene, 535t, 536t Tetracyclines, 238t, 242, 248t, 712 Tetrafluoroethane, 431t, 434t Tetrahydrocannabinol (THC), 389, 393, 393t. See also Cannabinoids Tetrahydrofuran (THF), 429t Tetrahydrozoline, 168t, 204f, 204t Tetraiodothyronine (T4), 233, 233f, 235, 236t Tetrodotoxin (TTX), 109t, 118t, 119–120, 622 Texan snake root (Aristolochia spp), 638t, 648 Thallium, 505–507 clinical manifestations of, 505–506, 506t diagnostic testing for, 506 differential diagnosis of, 109t, 506 history and epidemiology of, 505, 720 management of, 507. See also Prussian blue normal concentrations of, 505 pathophysiology of, 505 teratogenicity of, 505–506 toxicokinetics of, 505 Theobroma cacao, 643t Theobromine management of, 325–326, 326t pathophysiology of, 324–325 pharmacokinetics and toxicokinetics of, 324

771

Theophylline diagnostic testing for, 325 history and epidemiology of, 323 management of, 325–326, 326t pathophysiology of, 324–325 pharmacokinetics and toxicokinetics of, 324 properties of, 33t response to NMBs after, 342t therapeutic concentration of, 323 Thermal degradation products, 666–667, 666t. See also Smoke inhalation Thermo-transient receptor (TRP) channels, 137, 138f, 139f, 140 Thevetia peruviana (yellow oleander), 314, 320, 643t, 645 THF (tetrahydrofuran), 429t Thiamine hydrochloride (vitamin B1), 412–415 adverse events of, 415 for cobalt toxicity, 470 daily requirements for, 412 deficiency of, 272, 413–414, 413f dosing and administration of, 415 formulation and acquisition of, 415 for GHB toxicity, 430 history of, 412 indications for, 414–415, 417 injection, chlorobutanol in, 169t pharmacology of, 412–413, 412f, 413f in pregnancy and lactation, 415 Thiazide diuretics, 309t, 312 Thiazolidinedione derivatives, 175t, 177, 179 Thimble jellyfish (Linuche unguiculata), 618t, 619, 621 Thimerosal as antiseptic, 516 concentration in common medications, 172t toxicity of, 168, 172t, 495, 514t Thioamides, 234t, 236–237 Thiocarbamate herbicides, 566t Thiocyanate, 311–312 6-Thioguanine, 209t, 211f Thioridazine, 349t, 350t, 351. See also Antipsychotics Thiothixene, 349t. See also Antipsychotics Thistle (Atractylis gummifera), 638t Thorium dioxide, 36t Thorn apple, 154t Thromboxanes, 77f Thujones, 137, 152, 638t, 646. See also Wormwood (Artemisia absinthium, absinthe) Thyroid gland, 233, 233f Thyroid medications (thyroid hormones), 233–236 clinical manifestations of, 234–235 diagnostic testing for, 235, 236t history and epidemiology of, 233

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772

INDEX

Thyroid medications (thyroid hormones) (Cont.): management of, 235–236 pathophysiology of, 234 pharmacology of, 234, 234t physiology of, 233, 233f xenobiotic effects on, 235t xenobiotic interactions with, 234t Thyroid peroxidase, 234t, 235t, 236 Thyroid storm, 237 Thyroid-releasing hormone (TRH), 233f, 234t Thyroid-stimulating hormone (TSH), 233f, 235, 236t Thyrotoxicosis, 235, 235t Tiagabine, 186t, 188t, 191, 193t Ticagrelor, 284 Tick paralysis, 110t Ticks, 608–609 Ticlopidine, 283 Timolol, 168t, 294t Tinnitus, 6t Tirofiban, 284 Tissue plasminogen activator (t-PA), 281 Tityus serrulatus (Brazilian scorpion), 608f Tityus spp, 616t, 617 Tobacco (Nicotiana spp). See also Nicotine in herbal dietary supplements, 154t preparations of, 436, 436t primary toxicity of, 641t, 643–644 Tobramycin, ophthalmic, 168t, 169t Tocainide, 265t, 268 Tocopherols, 160 Tolazamide, 175t Tolbutamide, 175t Tolmetin, 76t Toluene classification and viscosity of, 535t inhaled, 431t, 433, 434t. See also Inhalants pharmacology of, 432t toxicokinetics of, 536t Tonka bean (Dipteryx spp), 149t, 640t Topiramate, 186t, 188t, 191, 193t. See also Phentermine/topiramate Topoisomerase inhibitors, 208, 210t Topotecan, 209t Toxalbumins, 646–647 Toxaphene, 591t. See also Organic chlorine pesticides Toxic alcohols. See Alcohols, toxic Toxic syndromes, 2, 2t. See also specific xenobiotics Toxicodendron diversilobum (poison oak), 643t, 650 Toxicodendron radicans (poison ivy), 643t, 650 Toxicodendron toxicarium (poison oak), 643t, 650 Toxicodendron vernix (poison sumac), 50, 643t

158_Hoffman_Index_p0739-0776.indd 772

Trace of burning, 136 Trachinus spp (weeverfish), 624, 625t Tramadol, 84t, 86 Tranexamic acid, 282 Tranquilizers. See Sedative-hypnotics Transdermal drug delivery, 52–53, 52t, 53t Tranylcypromine. See Monoamine oxidase inhibitors (MAOIs) Trastuzumab, 209t Trazodone, 362t, 363t, 365. See also Antidepressants, atypical Tremor, 6t Tretinoin (all-trans-retinoic acid, ATRA), 155, 158 TRH (thyroid-releasing hormone), 233f, 234t Triamterene, 312 Triazine herbicides, 566t, 576 Triazinone herbicides, 566t Triazolam, 377t Triazoles, 238t, 566t Triazolopyrimidine herbicides, 567t Tribulus terrestris, 643t Trichinella, 117t Trichloramine, 674 Trichloroethane, 431t, 432t, 434t Trichloroethanol, 376, 377f, 379 Trichloroethylene (TCE) chemistry of, 535t clinical manifestations of, 434t, 539 in inhalants, 431t pharmacokinetics of, 432t, 536t Tricholoma equestre (T. flavovirens), 628t, 635 Tricholoma magnivelare (pine mushroom matsutake), 634, 635f Trichosanthes spp, 647 Trichothecene mycotoxins, 714 Trifluoperazine, 349t, 350t. See also Antipsychotics Trifluralin, 565t Trifolium pratense, 643t Triiodothyronine (T3), 233, 233f, 235, 236t Trimethoprim, 248t Trimethoprim-sulfamethoxazole, 171t, 240–241, 245t 2,4,5-Trimethoxyamphetamine, 385t. See also Amphetamines Trimetrexate, 245t Trimipramine, 356f. See also Antidepressants, cyclic (CAs) Trinitrotoluene, 700 Tripneustes (Pacific urchin), 623 Triptans, 231–232, 231f, 231t Tritium, 720 Tritoqualine, 200 Trivalent chromium, 466. See also Chromium Trogia venenata, 628t Tropane alkaloids, 153

Tropicamide, 168t TRP (thermo-transient receptor) channels, 137, 138f, 139f Tryptamines (indolealkylamines), 423–424, 424f. See also Hallucinogens Tryptophan-rich sensory protein (TSPO), 401–402, 402f TSH (thyroid-stimulating hormone), 233f, 235, 236t TTX (tetrodotoxin), 109t, 118t, 119–120, 622 Tubocurarine, 339, 340. See also Neuromuscular blockers (NMBs) Tularemia, 712 Tullidora (Karwinskia humboldtiana), 640t, 648 Tung seed, 149t Turpentine, 535t T’u-san-chi, 149t Tussilago farfara, 643t Typewriter correction fluid, inhaled, 431t Typhoid Vi vaccine, 170t Tyramine, 123t, 372t, 373, 373t Tyrosine kinase inhibitors, 208 U Ultralente, 176t Ultrasound for transcutaneous drug delivery, 53 xenobiotic visualization on, 35 Unconventional weapons, 703t. See also Biological weapons; Chemical weapons Undecylenic acid/salt, 243t Unfractionated heparin (UFH), 276t, 277–278 Uracil herbicides, 567t Urea herbicides, 567t Urginea spp (squill), 149t, 314, 320, 643t Uridine triacetate, 215f, 223–224 Urine alkalinization of, 102, 102f, 104, 107 manipulation of pH, 30 Urokinase, 281 Urushiol oleoresins, 650 V Valdecoxib, 75 Valerian, 149t, 154t Valganciclovir, 245t Valproic acid clinical manifestations of, 192, 193t diagnostic testing for, 192 drug interactions of, 189t management of, 192, 195 mechanism of action of, 186t metabolism of, 188t, 192, 192f pathophysiology of, 192 pharmacokinetics and toxicokinetics of, 188t, 192 properties of, 33t

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INDEX

Vancomycin, 238t, 242 Vapreotide, 184 Varenicline, 437 Vasodilators, direct, 311–312, 406t Vasopressin, 169t Vasopressors, 306 Vasospasm, cocaine-associated, 396, 397 Vecuronium, 340t, 341t. See also Neuromuscular blockers (NMBs) Vehicle placarding, for hazardous materials, 729 Venlafaxine, 362t, 363t, 365. See also Antidepressants, atypical Verapamil, 303, 303t, 331. See also Calcium channel blockers (CCBs) Veratridine, 643t, 648 Veratrum spp, 643t, 648 Verbal de-escalation, 55 Vesicants Lewisite, 707, 709t phosgene oxime, 707, 709t sulfur mustard, 706–707, 709t Vespidae, 609–610, 609f, 610t Vetch seeds (Vicia sativa), 646 Vibrio spp food poisoning, 117t, 120, 120t Vicia faba ( fava beans), 643t, 646 Vicia sativa (vetch seeds), 643t, 646 Video cassette player head cleaner, inhaled, 431t Vigabatrin, 186t, 188t, 189t, 192–193, 193t Vilazodone, 362t, 363t, 365. See also Antidepressants, atypical Vinca alkaloids (vinblastine, vincristine, vindesine) clinical manifestations of, 73, 74t, 208, 209t, 210 drug interactions of, 73 extravasation of, 227t, 337 history of, 73 management of, 74, 74t mechanism of action of, 211f pathophysiology of, 73 pharmacokinetics of, 73 plant sources of, 649 toxic dose of, 73 Vinca (Catharanthus roseus), 639t, 649 “Vineyard sprayer’s lung,” 472 Violent patient approach to, 56t assessment of, 55 differential diagnosis of, 54 mental illness and, 54 substance use and, 54 treatment of, 55–56 warning signs, 56t Violin spider (brown recluse spider), 605–606, 605f, 606t Viral encephalitides, 713 Viral hemorrhagic fevers, 713 Virola calophylla (Yakee plant), 424

158_Hoffman_Index_p0739-0776.indd 773

Viscosity, 537 Viscum album (European mistletoe), 643t, 647 Vital signs, 1–3, 1t, 2t, 3t Vitamin A chemistry of, 155 deficiency of, 155 history and epidemiology of, 155 injection, chlorobutanol in, 169t RDA for, 156t toxicity of, 155–158 clinical manifestations of, 157–158, 158t diagnostic testing for, 158 pathophysiology of, 156–157, 157f pharmacology, pharmacokinetics, and toxicokinetics of, 155–156 treatment of, 158 Vitamin B1. See Thiamine hydrochloride (vitamin B1) Vitamin B6 (pyridoxine). See Pyridoxine (vitamin B6) Vitamin B12A (hydroxocobalamin), 312, 691–692 Vitamin C (ascorbic acid), 156t, 160–161 Vitamin D clinical manifestations of, 159 deficiency of, 158, 159 diagnostic testing for, 159 history and epidemiology of, 158 pharmacology, pharmacokinetics, and toxicokinetics of, 158–159, 159f RDA for, 156t treatment of, 159–160 Vitamin E, 156t, 160 Vitamin K. See also Vitamin K1 (phytonadione) daily requirement for, 289 deficiency of, 276, 289–290 history of, 289 interactions of, 155 pharmacokinetics and pharmacology of, 274, 275f, 289 Vitamin K antagonists clinical manifestations of, 275, 277 diagnostic testing for, 275, 276t management of, 275, 276t, 277, 277t nonbleeding complications of, 277 pharmacology of, 274–275 Vitamin K1 (phytonadione), 289–290 adverse effects and safety issues for, 290 dosing and administration of, 290 formulation and acquisition of, 290 mechanism of action of, 289 pharmacodynamics of, 289 pharmacokinetics of, 289 pharmacology of, 289 in pregnancy and lactation, 290 for vitamin K antagonist–induced coagulopathy, 275–277, 277t

773

Vitamin K3 (menadione), 289 Vitamin K4 (menadiol sodium diphosphate), 289 Vitamins, 155, 156t. See also specific vitamins Volatile oils. See Essential (volatile) oils Volatility, 537 Vomit button, 643t Vomiting, chemotherapeutic-related, 210–211 Voriconazole, 243, 245t Vortioxetine, 362t, 363t, 365. See also Antidepressants, atypical VX, 705, 708t W Walckenaer spider (Eratigena agrestis), 606 Warfarin, 276t, 279t. See also Vitamin K antagonists Wasps (Vespidae), 609–610, 609f, 610t Water hemlock (Cicuta maculata), 639t, 648 Waterpipes, 436–437 Weakness, 6t Weapons biological. See Biological weapons chemical. See Chemical weapons Weeverfish (Trachinus spp), 624, 625t Welders cadmium exposure in, 461 manganese exposure in, 490 zinc exposure in, 511 Wernicke encephalopathy, 413–414, 413f Wernicke-Korsakoff syndrome, 414 Western water hemlock (Cicuta douglasii), 648 Wet beriberi, 414 Whipped cream dispensers, 431t White cohosh, 149t White phosphorus, 597. See also Phosphorus White willow bark, 149t WHO (World Health Organization), pesticide toxicity/hazard classifications, 563, 564–567t, 577t Whole-bowel irrigation, 25–27 vs. activated charcoal, 26 adverse effects of, 26 for body packers, 94 complications of, 26 contraindications to, 17t, 26 dosing and administration of, 27 formulation and acquisition of, 27 for gastrointestinal decontamination, 17, 165 history, 25 indications for, 17t, 26 interactions of, 26–27, 406t

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774

INDEX

Whole-bowel irrigation (Cont.): pharmacology of, 25–26 in pregnancy and lactation, 27 safety issues with, 26 Widow spiders (Lactrodectus spp), 603–605, 604f, 613t Wild cherry (Karwinskia humboldtiana ), 640t, 648 Wild lettuce, 149t, 154t Willow bark, 125, 127t Wilson disease, from copper, 473 Wintergreen, oil of, 141, 142 Wisteria spp (wisteria), 643t, 647 Withdrawal from alcohol. See Alcohol withdrawal from caffeine, 323 from cannabinoids, 392–393 from central antihypertensives, 310 from GHB, 430 from inhalants, 435 from opioids, 2t, 91 from sedative-hypnotics, 376 Woodrose (Argyreia nervosa), 423, 425t Woodruff, 149t Workplace violence, 54. See also Violent patient World Anti-Doping Agency (WADA), 131, 131t World Health Organization (WHO), pesticide toxicity/hazard classifications, 563, 564–567t, 577t Wormwood (Artemisia absinthium, absinthe) clinical manifestations of, 137, 149t, 152, 154t, 646 diagnostic testing for, 141 history of, 137, 152 pathophysiology of, 137 pharmacology of, 137, 154t, 638t

158_Hoffman_Index_p0739-0776.indd 774

treatment of, 142 usages of, 149t, 154t Wound botulism, 111, 112t. See also Botulism X Xenobiotics. See also specific xenobiotics internal concealment of. See Body packers; Body stuffers intrathecal administration of, 225–226 vesicant, extravasation of, 227–228, 227t Xenon, 671 Xerophthalmia, 144 X-rays, 715 XTC (3,4-methylenedioxy‑ methamphetamine), 385t, 387. See also Amphetamines Xylene, 535t, 536t Xylometazoline, 204t Y Yakee plant (Virola calophylla), 424 Yarrow, 149t Yellow jackets (Vespidae), 609–610, 609f, 610t Yellow oleander (Thevetia peruviana), 314, 320, 643t, 645 Yellow phosphorus, 597 Yellow skin, 6t Yellow-bellied sea snake (Pelamis platurus), 623 Yersinia pestis, 712 Yersinia spp food poisoning, 117t, 120t, 122 Yew (Taxus spp), 149t, 643t, 648, 649f Yohimbe (Pausinystalia yohimbe), 149t, 154t, 641t Z Zaleplon, 376, 377t, 379. See also Sedative-hypnotics Zephiran, 515t

Zigadenus spp, 648 Zinc, 511–512 chemistry of, 511 clinical manifestations of, 511–512 diagnostic testing for, 512 history and epidemiology of, 511 management of, 512 normal concentrations of, 511 pharmacology and physiology of, 511 RDA for, 511 toxicokinetics and pathophysiology of, 511 Zinc acetate, 511 Zinc chloride, 511, 523t, 673t Zinc diethylenetriaminepentaacetic acid. See Pentetic acid/pentetate (zinc or calcium) trisodium (DTPA) Zinc gluconate, 511 Zinc oxide, 511, 673t Zinc phosphide, 558 Ziprasidone, 349t, 350, 350t. See also Antipsychotics Zoledronic acid, 160 Zolmitriptan, 231t Zolpidem, 376, 377t, 379. See also Sedative-hypnotics Zonisamide adverse effects of, 193t clinical manifestations of, 130, 193 diagnostic testing for, 193 drug interactions of, 189t management of, 193 mechanism of action of, 186t metabolism of, 188t pharmacokinetics of, 188t, 193 Zopiclone, 376, 379. See also Sedative-hypnotics Zuclopenthixol, 349t. See also Antipsychotics Zygacine, 648

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  Common Toxicology Laboratory Concentrations (serum unless otherwise noted)  

Conventional

SI

 

Conventional

SI

Acetaminophen* Arsenic (blood) Arsenic (urine) Caffeine• Carbamazepine• Carboxyhemoglobin (blood) Cyanide (blood) Digoxina,• Ethanolb Ethlyene glycolc Iron• Lead (blood) Lidocaine•

10–30 mg/mL < 5 mg/L < 50 mg/L 1–10 mg/mL 4–12 mg/L < 2% < 1 mg/mL 0.8–2 ng/mL 80 mg/dL < 25 mg/dL 80–180 mg/dL < 10 mg/dL 1.5–5 mg/mL

66–199 µmol/L < 0.0665 µmol/L < 0.665 µmol/L 5.2–51 µmol/L 17–51 µmol/L < 2% < 38.5 µmol/L 1.1–2.6 nmol/L 17.4 mmol/L < 4 mmol/L 14–32 µmol/L < 0.48 µmol/L 6.4–21.4 µmol/L

Lithium• Mercury (blood) Mercury (urine) Methanolc Methemoglobin Phenobarbital• Phenytoin• Salicylatesc, • Thallium (blood) Thallium (urine) Theophylline• Thiocyanate Valproic acid•

0.6–1.2 mEq/L < 10 mg/L < 20 mg/L < 25 mg/dL < 3% 15–40 mg/L 10–20 mg/L 15–30 mg/dL < 2.0 mg/L < 5.0 mg/L 5–15 mg/mL < 30 mg/mL 50–120 mg/L

0.6–1.2 mmol/L < 50 nmol/L < 100 nmol/L < 7.8 mmol/L < 3% 65–172 µmol/L 40–79 µmol/L 1.1–2.2 mmol/L < 9.78 nmol/L < 24.5 nmol/L 27.8–83 µmol/L < 100 µmol/L 347–832 µmol/L

Therapeutic, generally accepted normal or nonaction concentrations are listed. Please see the appropriate chapter for details regarding specific situations. Normal ranges vary by laboratory. a The therapeutic concentration of digoxin for heart failure is 0.5 to 0.9 ng/mL, but toxicity is usually present only when the concentration is > 2 ng/mL. bThis value is the “per se” concentration for ethanol above which motor vehicle operators are considered legally impaired in the United States. cConcentration must be interpreted with respect to the serum pH and clinical status. * See acetaminophen nomogram (page 60). •

Hoffman_IBC.indd 715

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  Normal Vital Signs by Agea Age

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Pulse (beats/min)

Respirations (breaths/min)b

Adult

120

80

50−90

16−24

16 years

120

< 80

80

16−30

12 years

119

76

85

16−30

10 years

115

74

90

16−30

6 years

107

69

100

20−30

4 years

104

65

110

20−30

2 years

102

58

120

25−30

1 year

100

55

120

25−30

6 months

90

55

120

30

4 months

90

50

145

30−35

2 months

85

50

145

30−35

Newborn

65

50

145

35−40

The normal rectal temperature is defined as 96.8° to 100.4°F (35°−38°C) for all ages. For children ≤ 1 year, these values are the mean values for the 50th percentile. For children > 1 year, these values represent the 90th percentile at a specific age for the 50th percentile of weight in that age group. bThese respiration values were determined in the emergency department and are likely environment and situation dependent. a

Hoffman_IFC.indd 715

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