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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

PREFACE The significant health impact of deliberate and accidental poisonings resulting from exposures to thousands of drugs, chemicals, and environmental toxins has led to the development of Medical Toxicology as an important medical specialty. In the United States, this development was formalized when the American Board of Medical Specialties recognized Medical Toxicology as a specialty area of practice in 1992. Medical toxicologists provide inpatient and outpatient consultation services in hospitals and clinics, provide direct care for poisoned patients in inpatient toxicology units, and offer clinical expertise to laypeople and health care providers requesting assistance from poison centers. As well, primary care providers and critical care specialists also render care to poisoned patients and thus must have a working knowledge of toxicology. Our goal has been to provide students, residents, and practitioners with an authoritative, affordable textbook of medical toxicology, one whose format allows easy access to clinical information. Nurses, pharmacists, and other health care providers will also find this book to be a helpful training and reference source. The initial chapters examine broad clinical topics, including variations in advanced life support and airway management necessitated by different poisonings. Section II focuses on the evaluation and treatment of patients with specific signs and symptoms, as well as toxicologic problems encountered in specific organ systems. The third section presents information on commonly encountered drugs and toxins in a standardized format. Emphasis has been placed on clinical presentation and treatment, and the standardized format and tables make this information more readily accessible to the busy practitioner. As often occurs with attempts at uniformity, not every chapter could be fitted to a rigid structure, especially those covering multiple drugs or toxins. In these cases, the format was modified appropriately. Concise addenda cover therapeutic drug dosages, laboratory values, pertinent legal issues, and helpful Internet sites. Contributors to this textbook represent a diverse group of practitioners of toxicology with varied expertise. We appreciate their hard work and patience during the writing and editing processes and are grateful for the sharing of their knowledge. I (M.D.F) commend my co-editors, whose labors resulted in a more standardized, readable text. We also thank the staff of W.B. Saunders Company, including Editors Judy Fletcher and Stephanie Donley and Developmental Editors Beth Hatter and Arlene Chappelle. Their constant attention to our editorial needs and timelines got us past many hurdles and to our goal. We are grateful for the work of the many staff assistants, secretaries, and librarians who assisted with secretarial and bibliographic chores. Finally, this project could not have been completed without the support of our families, partners, and friends, who tolerated lost weekends and late evenings—thank you for your understanding. MARSHA D. FORD, KATHLEEN A. DELANEY, L OUIS J. LING , TIMOTHY ERICKSON

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

CLINICAL TOXICOLOGY Marsha D Ford, M.D., FACEP, FACMT Director, Division of Toxicology Assistant Chairman, Department of Emergency Medicine Director, Carolinas Poision Center, Carolinas Medical Center, Charlotte, North Carolina Clinical Associate Professor of Emergency Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina Kathleen A Delaney, M.D., FACP, FACEP, ABMT Professor, Division of Emergency Medicine, University of Texas-Southwestern Medical Center Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas Louis J. Ling, M.D., FACEP, FACMT Professor and Director, Emergency Medicine Program, University of Minnesota Medical School Medical Direcotr, Hennepin Regional Poison Center Associate Medical Director for Medical Education, Hennepin County Medical Center, Minneapolis, Minnesota Timothy Erickson, M.D., FACEP, FACMT Associate Professor of Emergency Medicine Director, Division of Clinical Toxicology Residency Director, Program in Emergency Medicine, University of Illinois, Chicago, Illinois Dedication For our patients, whose lives are entrusted to us and to whom we owe intelligent, informed medical care and In memory of Francis M. “Nick” Nichols, Jr., my revered mentor; for my early teachers at the New York City Poison Center, who nourished my love of toxicology; for my colleagues at Carolinas Medical Center and Carolinas Poison Center, who support, challenge, and continuously teach me; and for my family, friends, and partner, whose love and caring sustain me M. D. FORD To all my students, from whom I continue to learn K. A. DELANEY To the staff of the Hennepin Regional Poison Center, for teaching me toxicology; my parents, Rose and Joseph Ling, for teaching me about caring; and to my family, Amanda, Ali, Eric, and Beth, for teaching me about life. Special thanks to the authors and my fellow editors, who share their wisdom, time, experience, and patience L. J. LING

To Valerie, Camille, Isabelle, Celeste, Julian, and my parents, brothers, and sisters; my mentors, colleagues, and residents in Emergency Medicine; the Toxikon Consortium faculty and fellows, along with special thanks to Paracelsus T. ERICKSON W.B. Saunders Company A Harcourt Health Sciences Company The Curtis Center Independence Square West Philadelphia London New York St. Louis Sydney Toronto Philadelphia, Pennsylvania 19106
Library of Congress Cataloging-in-Publication Data

Clinical Toxicology/Marsha D. Ford.—[et al.]—1st ed. p.cm. ISBN 0–7216–5485–1 1. Poisoning—Treatment.2. Toxicology.3. Toxicological emergencies. I. Ford, Marsha D.[DNLM: 1. Poisoning—therapy.2. Poisons 3. Toxins.QV 601 C641 2001] 00-029712 RA1211.C587 2001515.9—dc21
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Book Interior Designer: Ellen Zanoll CLINICAL TOXICOLOGY ISBN 0-7216-5485-1 Copyright © 2001 by W.B. Saunders Company All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

CONTRIBUTORS Cynthia K. Aaron, M.D., F.A.C.E.P., F.A.C.M.T. Assistant Professor, Emergency Medicine, University of Massachusetts Medical School; Director, Toxicology Services, University of Massachusetts Medical Center, Worcester, Massachusetts Organophosphates and Carbamates Jawaid Akhtar, M.B.B.S. Assistant Professor, Department of Emergency Medicine, University of Pittsburgh School of Medicine; Attending Physician, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Salicylates Timothy E. Albertson, M.D., Ph.D., F.A.C.M.T., F.A.C.E.P. Professor of Medicine, Pharmacology/Toxicology and Anesthesiology, University of California, Davis School of Medicine; Executive Medical Director, California Poison Control System; Chief, Division of Pulmonary and Critical Care Medicine; Chief, Pulmonary Division, Northern California VA Hospital and Clinics, Davis, California Pulmonary Abnormalities Roblee P. Allen, M.D. Associate Professor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Davis, School of Medicine; Medical Director, Laser/Bronchoscopy Lab; Medical Director, Medical Specialties, ICU; Co-Director, Lung Transplant/Volume Reduction Program, UC Davis Medical Center, Sacramento, California Pulmonary Abnormalities Deborah L. Anderson, Pharm.D. Director, Hennepin Regional Poison Center, Hennepin County Medical Center, Minneapolis, Minnesota Camphor and Mothballs Anthony Anker, M.D., F.A.C.E.P. Attending Physician, Emergency Department, Rogue Valley Medical Center, Medford, Oregon Hepatic Failure; Acetaminophen Beth A. Baker, M.D., M.P.H. Director of Occupational and Environmental Medicine, Senior Partner, Medical and Toxicology Consulting, Hennepin County Medical Center, Minneapolis, Minnesota Metal Fume Fever

Theodore Bania, M.D. Assistant Professor of Clinical Medicine, College of Physicians and Surgeons, Columbia University; Director, Division of Toxicology, and Assistant Director of Research, St. Luke's–Roosevelt Hospital Center, New York, New York Thallium and Other Metals Marc J. Bayer, M.D., F.A.C.E.P., A.B.M.T. Medical Director, Connecticut Poison Control Center, Vice Chair, Department of Traumatology and Emergency Medicine; Chief, Division of Toxicology, University of Connecticut School of Medicine, Avon, Connecticut Inhalation: Gases with Immediate Toxicity; Inhalation: Gases with Delayed Toxicity Tareg A. Bey, M.D., F.A.C.E.P. Assistant Professor of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical School; Assistant Director, Medical Toxicology Fellowship, University of Texas Southwestern Medical Center, Dallas, Texas Seizures Kathleen Birnbaum, Pharm.D., C.S.P.I. Poison Specialist II, University of New Mexico, Albuquerque, New Mexico Carbamazepine Robert A. Bitterman, M.D., J.D., F.A.C.E.P. Director of Risk Management and Managed Care, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Appendix B, Patient Refusal of Treatment: Legal Issues; Appendix C, Interhospital Transfer Principles—EMTALA G. Randall Bond, M.D., F.A.C.M.T. Professor, Departments of Pediatrics and Emergency Medicine, University of Cincinnati College of Medicine; Medical Director, Drug and Poison Information Center, Cincinnati, Ohio Black Widow Spider Envenomation Jeffrey Brent, M.D., Ph.D., F.A.C.M.T., F.A.C.E.P. Associate Clinical Professor of Medicine, Surgery, and Pediatrics, University of Colorado School of Medicine; Toxicology Associates, Denver, Colorado Cardiovascular Instability Caused by Drugs or Chemicals; Serotonin Reuptake Inhibitors, Newer Antidepressants, and the Serotonin Syndrome Keith K. Burkhart, M.D., F.A.C.M.T., F.A.C.E.P. Associate Professor of Medicine and Pharmacology, The Pennsylvania State University School of Medicine; Medical Director, Central Pennsylvania Poison Center, The Milton S. Hershey Medical Center, Hershey, Pennsylvania

Anticoagulant Rodenticides E. Martin Caravati, M.D., M.P.H., F.A.C.E.P. Professor, Division of Emergency Medicine, University of Utah School of Medicine; Associate Medical Director, Utah Poison Control Center, Salt Lake City, Utah Insecticides: Pyrethrins, Pyrethroids, Organochlorines; Insecticides: N,N-Diethyl-3-methylbenzamide (DEET) Edward W. Cetaruk, M.D. Attending Faculty, Rocky Mountain Poison Center, Denver; Attending Physician, Department of Emergency Medicine, Swedish Hospital Medical Center, Englewood, Colorado Vitamins Calvin Chiang, M.D. Department of Emergency Medicine, Strong Memorial Hospital, University of Rochester, Rochester, New York Withdrawal Syndromes William K. Chiang, M.D. Assistant Professor of Clinical Surgery/Emergency Medicine, New York University School of Medicine; Assistant Director, Emergency Department, Bellevue Hospital Center, New York; Medical Director, Hudson Valley Poison Control Center, Sleepy Hollow, New York Mercury Rachel L. Chin, M.D., F.A.C.E.P. Assistant Clinical Professor of Surgery, University of California, San Francisco; Attending in Emergency Services, San Francisco General Hospital, San Francisco, California Antivirals Peter A. Chyka, Pharm.D. Professor, Department of Pharmacy Practice and Pharmacoeconomics, and Associate Professor, Department of Physical Therapy, University of Tennessee, College of Medicine; Executive Director, Southern Poison Center, Memphis, Tennessee Androgenic-Anabolic Steroids John J. Cienki, M.D., F.A.C.E.P. Consultant, Florida Poison Information Center–Miami; Attending Emergency Physician, Jackson Memorial Hospital, Miami Beach, Florida Nonanticoagulant Rodenticides James E. Cisek, M.D., F.A.C.M.T., F.A.C.E.D. Associate Professor, Emergency Medicine, Medical College of Virginia School of Medicine; Medical Director, Virginia Poison Center, Richmond, Virginia Polychlorinated Biphenyls and Related Substances

Cathleen Clancy, M.D., F.A.C.E.P. Clinical Assistant Professor, University of Maryland School of Pharmacy, Baltimore, Maryland; Clinical Instructor, Georgetown University Medical Center, Washington, DC; Medical Toxicologist, Adjunct Assistant Professor, George Washington University Medical Center, Washington, DC; Medical Director, Maryland Poison Center, Baltimore, Maryland; Attending Physician, Department of Emergency Medicine, Georgetown University Medical Center, Washington, DC; Medical Toxicologist, National Capital Poison Center, Washington, DC Plants: Central Nervous System Toxicity Richard F. Clark, M.D., F.A.C.M.T., F.A.C.E.P. Associate Professor of Medicine, University of California, San Diego, School of Medicine; Director, UCSD Division of Medical Toxicology; Medical Director, San Diego Division, California Poison Control System, UCSD Medical Center, San Diego, California Nitroprusside; Rattlesnakes and Other Crotalids; Scorpion Envenomation Jack C. Clifton II, M.D. Assistant Professor, Department of Pediatrics, Rush Medical College; Toxicology Fellow, Toxikon Consortium; Cook County Hospital, University of Illinois, Rush-Presbyterian-St. Luke's Medical Center; Attending Physician, Pediatric Emergency Department, Rush Children's Hospital, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois Acid Ingestion David M. Cosentino, M.D., F.A.C.E.P. Clinical Instructor, Department of Emergency Medicine, University of Florida Health Sciences Center, Jacksonville; Attending Physician, Orange Park Medical Center, Orange Park, Florida Inhalation: Gases with Delayed Toxicity Megan C. Cosentino, M.D. Department of Emergency Medicine, University of Florida Health Sciences Center, Jacksonville, Florida Inhalation: Gases with Delayed Toxicity Sandra A. Craig, M.D. Clinical Instructor, Department of Emergency Medicine, University of North Carolina at Chapel Hill, School of Medicine; Associate Residency Director, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Radiology Merilyn J. Crittenden, R.N., C.S.P.I.

Certified Specialist in Poison Information, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North Carolina Appendix F, Internet Resources Barbara Insley Crouch, Pharm.D., M.S.P.H. Associate Professor (Clinical), Department of Pharmacy Practice, College of Pharmacy, University of Utah; Director, Utah Poison Control Center, Salt Lake City, Utah Insecticides: Pyrethrins, Pyrethroids, Organochlorines; Insecticides: N,N-Diethyl-3-methylbenzamide (DEET) Colleen O'Neil Davis, M.D., F.A.A.P. Departments of Emergency Medicine and Pediatrics, Strong Memorial Hospital, University of Rochester, Rochester, New York Focused Physical Examination/Toxidromes Kathleen A. Delaney, M.D., F.A.C.P., F.A.C.E.P., A.B.M.T. Professor, Division of Emergency Medicine, University of Texas Southwestern Medical Center; Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas Initial Approach to the Poisoned Patient; Fluids and Electrolytes; Acid-Base Disturbances in the Poisoned Patient; Central Nervous System Depression; Central Nervous System Agitation; Disorders of Thermoregulation: Hyperthermia and Hypothermia; Anticholinergics and Antihistamines (H1 Antagonists); Cyanide; Antiseptics, Disinfectants, and Sterilizing Agents Francis J. De Roos, M.D., F.A.C.E.P. Assistant Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Attending Physician, Department of Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Neuroleptics; Plants: Gastrointestinal Toxicity J. Ward Donovan, M.D., F.A.C.E.P., F.A.C.M.T. Center for Emergency Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Salicylates Suzanne Doyon, M.D. Medical Director, Maryland Poison Center, School of Pharmacy, Baltimore, Maryland Antimalarials Brent R. Ekins, Pharm.D. Assistant Professor of Clinical Pharmacy, University of the Pacific School of Pharmacy, Stockton; Assistant Clinical Professor of Pharmacy, University of California, San Francisco, School of Pharmacy; Director, California Poison Control System, Fresno Division, Fresno, California Paraquat and Diquat Janet Eng, D.O., F.A.C.O.E.P. Attending Physician, Emergency Medicine, and Medical Toxicologist, Michigan State University Emergency

Medicine Residency, Ingham Regional Medical Center, Lansing, Michigan Arsenic Kristin M. Engebretsen, Pharm.D. Associate Clinical Professor, University of Minnesota College of Pharmacy, Minneapolis; Clinical Toxicologist, Emergency Medicine, Regions Hospital, St. Paul, Minnesota Caffeine and Related Nonprescription Sympathomimetics Timothy Erickson, M.D., F.A.C.E.P., F.A.C.M.T. Associate Professor, Emergency Medicine; Director, Division of Clinical Toxicology; Residency Director, Program in Emergency Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois Anticancer and Other Cytotoxic Drugs Susan E. Farrell, M.D., F.A.A.E.M. Instructor, Department of Medicine, Harvard Medical School; Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts Benzodiazepines Fun H. Fong Jr., M.D., F.A.C.E.P. Assistant Medical Director, Emory Adventist Hospital, Smyrna, Georgia Radiation Show H. Fong, Ph.D. Senior Health Physicist, Atlanta, Georgia Radiation Marsha D. Ford, M.D., F.A.C.E.P., F.A.C.M.T. Director, Division of Toxicology; Assistant Chairman, Department of Emergency Medicine; Director, Carolinas Poison Center, Charlotte; Clinical Associate Professor of Emergency Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina Initial Approach to the Poisoned Patient; Opioids; Ethylene Glycol and Methanol; Isopropanol; Alkali Ingestions Gregory G. Gaar, M.D., F.A.C.E.P. Clinical Associate Professor of Pediatrics, University of South Florida College of Medicine; Co–Medical Director, Florida Poison Information and Toxicology Resource Center; Tampa General Healthcare, Tampa, Florida Valproate and Selected Newer Anticonvulsants; Coral Snakes Richard J. Geller, M.D., M.P.H., F.A.C.M.T. Assistant Clinical Professor, Emergency Medicine, University of California, San Francisco, School of Medicine,

San Francisco; Medical Director, Fresno Division, California Poison Control System; Clinical Director, Emergency Department, Fresno Community Hospital and Medical Center, Fresno, California Paraquat and Diquat Laurie Beth Gesell, M.D. Assistant Professor, Emergency Medicine; Director, Division of Hyperbaric Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio Ethanol Leon M. Gussow, M.D., A.B.M.T. Senior Attending Physician, Department of Emergency Medicine; Toxicology Consultant, Toxikon Consortium, Illinois Poison Center, Cook County Hospital, Chicago, Illinois Inhalants of Abuse; Lacrimating Agents: Tear Gases and Pepper Spray Fred P. Harchelroad Jr., M.D., F.A.C.M.T., F.A.C.E.P. Associate Professor, Emergency Medicine, MCP Hahnemann School of Medicine; Director, Medical Toxicology Treatment Center, Allegheny General Hospital, Pittsburgh, Pennsylvania Ergot Alkaloids Carson R. Harris, M.D., F.A.C.E.P. Assistant Professor of Clinical Emergency Medicine, Senior Staff Physician and Director of Toxicology, University of Minnesota Medical School; Consultant, Hennepin Regional Poison Center, Minneapolis, Minnesota Caffeine and Related Nonprescription Sympathomimetics Sandra Haynes, M.D. Assistant Professor of Surgery and Emergency Medicine, New York Hospital/Bellevue Hospital Center, New York, New York Isoniazid and Other Antituberculous Drugs Fred M. Henretig, M.D., F.A.C.M.T. Professor of Pediatrics and Emergency Medicine, University of Pennsylvania School of Medicine; Director, Section of Clinical Toxicology, Children's Hospital of Philadelphia; Medical Director, Poison Control Center, Philadelphia, Pennsylvania Clonidine and Central-Acting Antihypertensives Glendon C. Henry, M.D. Medical Director, Harlem Hospital, New York, New York Isoniazid and Other Antituberculous Drugs John A. Henry, M.D., R.R.C.P., F.F.A.E.M. Professor of Accident and Emergency Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, England

Amphetamines Robert S. Hoffman, M.D., F.A.C.M.T., F.A.C.E.P. Assistant Professor of Clinical Surgery and Emergency Medicine, New York University School of Medicine; Director, New York City Poison Center, New York, New York Peripheral Neuropathy; Cocaine Judd E. Hollander, M.D., F.A.C.E.P. Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Clinical Research Director, Department of Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Cocaine Rivka S. Horowitz, M.D., Ph.D. Clinical Assistant Professor of Medicine, Brown University School of Medicine, Providence, Rhode Island; Attending Physician, Emergency Department, Lawrence and Memorial Hospital, New London, Connecticut Aromatic Hydrocarbons Susan Hou, M.D. Staff Physician, Loyola University Medical Center, Maywood, Illinois Extracorporeal Removal of Drugs and Toxins Mary Ann Howland, Pharm.D., D.A.B.A.T., F.A.A.C.T. Clinical Professor of Pharmacy, St. John's University College of Pharmacy; Consultant, New York City Poison Control Center, Bellevue Hospital Emergency Department, New York, New York Herbals and Other Dietary Supplements; Theophylline Daniel O. Hryhorczuk, M.D., M.P.H., F.A.C.M.T. Chief, Section of Clinical Toxicology, Cook County Hospital, and the Toxikon Consortium; Professor of Occupational Medicine, University of Illinois; Director, Great Lakes Center for Occupational and Environmental Health and Safety, Chicago, Illinois Arsenic William Kerns II, M.D., F.A.C.E.P., A.C.M.T. Emergency Medicine and Medical Toxicology, Carolinas Medical Center, Charlotte, North Carolina Beta-adrenergic Receptor Antagonists J. Fergus Kerr, M.B.B.S., M.P.H., F.A.C.E.M. Clinical Toxicologist, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia Household Cleaning Products Christopher Keyes, M.D.

Associate Professor, Division of Emergency Medicine, The University of Texas Southwestern Medical Center; Medical Director, North Texas Regional Poison Control Center, Dallas, Texas Psychoactive Drugs Daniel E. Keyler, Pharm.D. Professor, Clinical Pharmacy, University of Minnesota College of Pharmacy; Clinical and Research Toxicologist and Co-Director, Toxicology Research, Hennepin County Medical Center and Minneapolis Medical Research Foundation, Minneapolis, Minnesota Cyclic Antidepressants Mark Kirk, M.D., F.A.C.M.T. Assistant Clinical Professor, Indiana University School of Medicine; Director, Medical Toxicology Fellowship, Medical Advisory, Indianapolis Fire Department Hazardous Materials Team; Indiana Poison Center, Emergency Medicine and Trauma Center, Clarian/Methodist Hospital, Indianapolis, Indiana Managing Patients with Hazardous Chemical Contamination Wendy Klein-Schwartz, Pharm.D., M.P.H. Associate Professor, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy; Coordinator of Research and Education, Maryland Poison Center, Baltimore, Maryland Plants: Central Nervous System Toxicity Kurt C. Kleinschmidt, M.D., F.A.C.E.P. Assistant Professor of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical Center, Associate Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas Fluids and Electrolytes; Opioids Jeffrey A. Kline, M.D. Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Calcium Channel Antagonists Paul Kolecki, M.D. Assistant Professor, Department of Surgery, Division of Emergency Medicine, Jefferson Medical College of Thomas Jefferson University; Consultant, Philadelphia Poison Control Center, Philadelphia, Pennsylvania Central Nervous System Depression Gideon Koren, M.D., F.A.C.M.T. Department of Pediatrics, Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada Special Considerations in the Pregnant Patient

Michael J. Kosnett, M.D., M.P.H., F.A.C.E.P., F.A.C.M.T. Associate Clinical Professor of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado School of Medicine, Denver, Colorado Lead Edward P. Krenzelok, Pharm.D. Professor of Pharmacy and Pediatrics, University of Pittsburgh School of Medicine; Director, Pittsburgh Poison Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania Poison Centers; Household Cleaning Products Ken Kulig, M.D., F.A.C.M.T., F.A.C.E.P. Associate Clinical Professor, Division of Emergency Medicine and Trauma, Department of Surgery, University of Colorado School of Medicine; Director, Porter Regional Toxicology Center; Chairman, Department of Medicine, Porter Adventist Hospital, Denver, Colorado Gastrointestinal Decontamination Jerrold B. Leikin, M.D., F.A.C.P., F.A.C.E.P., D.A.B.M.T., F.A.C.M.T. Professor of Medicine, Rush Medical College; Associate Medical Director, Rush Emergency Services, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois Extracorporeal Removal of Drugs and Toxins; Poison Centers; Hydrogen Sulfide Erica L. Liebelt, M.D., F.A.A.P., F.A.C.M.T. Assistant Professor, Department of Pediatrics, Johns Hopkins University School of Medicine; Attending, Pediatric Emergency Department, and Medical Toxicologist, Johns Hopkins Hospital, Baltimore, Maryland Sedative-Hypnotics Christopher H. Linden, M.D., F.A.C.M.T., F.A.C.E.P. Associate Professor, Department of Emergency Medicine, Division of Medical Toxicology, University of Massachusetts Medical School, Worcester, Massachusetts Digitalis Glycosides Louis J. Ling, M.D., F.A.C.E.P., F.A.C.M.T. Professor and Director, Emergency Medicine Program, University of Minnesota Medical School; Medical Director, Hennepin Regional Poison Center; Associate Medical Director for Medical Education, Hennepin County Medical Center, Minneapolis, Minnesota Pine Oil and Turpentine Toby Litovitz, M.D., F.A.C.M.T., F.A.C.E.P. Clinical Professor, Emergency Medicine, The George Washington University School of Medicine; Director, National Capital Poison Center, Washington, DC Button Batteries

David Malkevich, M.D. Department of Emergency Medicine, Lincoln Medical and Mental Health Center, Bronx, New York Lithium Richard L. Manka, M.D. Assistant Professor of Ophthalmology, University of Minnesota Medical School; Faculty Staff, Hennepin County Medical Center, Minneapolis, Minnesota Ocular Abnormalities Gregory P. Marelich, M.D. Assistant Clinical Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Davis, School of Medicine, Davis, California Pulmonary Abnormalities Thomas G. Martin, M.D., M.P.H., F.A.C.M.T., F.A.A.C.T., F.A.C.E.P. Associate Professor, Department of Medicine, Division of Emergency Medicine, University of Washington; Director, University of Washington Medical Toxicology Service, Seattle, Washington Advanced Life Support in the Poisoned Patient (TOX ACLS) Nancy J. Matyunas, Pharm.D. Adjunct Instructor, Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Managing Director, Kentucky Poison Center, Louisville, Kentucky Nicotine Poisoning Susan M. Maynard, Ph.D. Director of Chemistry and Toxicology Laboratories, Carolinas Medical Center, Charlotte, North Carolina Drugs and Toxins: Therapeutic and Toxic Levels Patrick E. McKinney, M.D., F.A.C.M.T., F.A.C.E.P. Assistant Professor, Department of Emergency Medicine, College of Pharmacy, and Medical Director, New Mexico Poison Center, University of New Mexico, Albuquerque, New Mexico Carbamazepine; Phenytoin Kenneth McMartin, Ph.D. Professor, Department of Pharmacology, Louisiana State University Health Sciences in Shreveport, Shreveport, Louisiana Ethylene Glycol and Methanol William J. Meggs, M.D., F.A.C.E.P. Professor, Department of Emergency Medicine, East Carolina University School of Medicine; Chief of Toxicology, Pitt County Memorial Hospital, Greenville, North Carolina Hypersensitivity Reactions; Hymenoptera

M. John Mendelsohn, M.D. Attending Physician and Toxicologist, Falmouth Hospital, Falmouth, Massachusetts Monoamine Oxidase Inhibitors Timothy J. Meredith, M.D. Professor of Medicine and Pathology, Vanderbilt University School of Medicine; Director, Center for Clinical Toxicology, Vanderbilt University Medical Center, Nashville, Tennessee Hydrofluoric Acid Brent Morgan, M.D. Assistant Professor of Emergency Medicine, Emory University School of Medicine; Assistant Medical Director, Georgia Poison Center, Atlanta, Georgia Renal Failure Michael F. Murphy, M.D., F.R.C.P.C. Associate Professor, Emergency Medicine and Anaesthesia, Dalhousie University; Staff, Emergency Medicine and Anaesthesia, Health Sciences Centre, Halifax, Nova Scotia, Canada Airway Management in the Poisoned Patient Lindsay M. Murray, M.B.B.S., F.A.C.E.M. Senior Lecturer in Emergency Medicine, University of Western Australia; Emergency Physician and Clinical Toxicologist, Sir Charles Gaironer Hospital, Perth, Western Australia, Australia Colchicine Sean Patrick Nordt, Pharm.D. Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine; Assistant Director, San Diego Division, California Poison Control System, UCSD Medical Center, San Diego, California Rattlesnakes and Other Crotalids Sven A. Normann, Pharm.D. Clinical Associate Professor, Pharmacy Practice; Director, Working Professional Pharm.D. Program, College of Pharmacy, University of Florida, Gainesville; Consultant, Florida Poison Information Center, Tampa General Hospital, Tampa, Florida Valproate and Selected Newer Anticonvulsants; Coral Snakes Kent R. Olson, M.D. Clinical Professor of Medicine, Pediatrics and Pharmacy, University of California at San Francisco, School of Medicine, San Francisco, California Smoke Inhalation Janis M. Orlowski, M.D.

Executive Dean and Associate Professor, Rush Medical College; Associate Vice President, Rush Medical Center, Chicago, Illinois Extracorporeal Removal of Drugs and Toxins Harold H. Osborn, M.D., F.A.C.E.P. Emergency Physician, New Rochelle, New York Heparin; Lithium Kevin C. Osterhoudt, M.D. Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine; Consultant Toxicologist, The Poison Control Center and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Methemoglobinemia John D. Osterloh, M.D., M.S., F.A.C.M.T. Professor of Pathology, University of New Mexico School of Medicine; Medical Director of Chemico-Pathology/Toxicology, University of New Mexico Health Sciences Center and Tricore Laboratories, Albuquerque, New Mexico Laboratory Testing in Emergency Toxicology Edward J. Otten, M.D., F.A.C.M.T. Professor, Emergency Medicine and Pediatrics; Director, Division of Toxicology, University of Cincinnati College of Medicine, Cincinnati, Ohio Ethanol Wesley B. Palatnick, M.D., F.R.C.P.C., A.B.E.M., A.B.M.T. Head, Section of Emergency Medicine; Associate Professor, Department of Family Medicine, University of Manitoba Faculty of Medicine; Medical Director, Emergency Program, Health Sciences Centre, Winnipeg Hospital Authority, Winnipeg, Manitoba, Canada Metaldehyde Mary E. Palmer, M.D., F.A.C.E.P. Fellow in Medical Toxicology, New York City Poison Control Center, New York, New York; Emergency Medicine Physician, University of Rykjavik, Iceland; Arlington Hospital, Arlington, Virginia Herbals and Other Dietary Supplements Frank P. Paloucek, Pharm.D., A.B.A.T. Clinical Associate Professor, Department of Pharmacy Practice; Adjunct Assistant Professor, Department of Emergency Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Maria Pelucio, M.D., F.A.C.E.P. Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Appendix E: Drugs and Antidote Dosages Paul R. Pentel, M.D. Professor of Medicine and Pharmacology, University of Minnesota Medical School; Chief, Division of Clinical Pharmacology and Toxicology, Hennepin County Medical Center, Minneapolis, Minnesota Cyclic Antidepressants Jeanmarie Perrone, M.D., F.A.C.E.P. Assistant Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Attending Physician, and Co-Director, Division of Toxicology, Emergency Department, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Selective Beta-Adrenergic Agonists Rebecca Perry, D.O. Assistant Clinical Professor, Department of Emergency Medicine, Wright State University School of Medicine, Dayton, Ohio Insulin Scott D. Phillips, M.D., F.A.C.P., F.A.C.M.T. Associate Clinical Professor, Department of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado School of Medicine; Rocky Mountain Poison and Drug Center, University of Colorado Health Sciences Center; Attending Physician, Porter Adventist Hospital, Littleton Adventist Hospital, Denver Health Medical Center, and University Hospital, Denver, Colorado Drug Testing in the Workplace Michael Policastro, B.A. Senior Medical Student, Wright State University School of Medicine, Dayton, Ohio Oral Hypoglycemic Agents; Insulin Katherine M. Prybys, D.O. Assistant Professor, Emergency Medicine, University of Maryland Medical School, Baltimore, Maryland Ethanol Roy A. Purssell, M.D. Assistant Professor, Department of Surgery, University of British Columbia Faculty of Medicine; Head, Department of Emergency Medicine, and Medical Consultant, Drug and Poison Information Center–British Columbia, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada Antihypertensives Lawrence W. Raymond, M.D., Sc.M.

Clinical Professor of Family Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill; Attending Physician, Carolinas Medical Center, Charlotte, North Carolina Glycol Ethers and Diethylene Glycol David J. Roberts, M.D. Clinical Associate Professor, University of Minnesota Medical School; Senior Consultant, Hennepin Regional Poison Center; Staff Emergency Physician and Toxicology Consultant, North Memorial Medical Center, Minneapolis, Minnesota Plants: Cardiovascular Toxicity George C. Rodgers Jr., M.D., Ph.D., F.A.C.M.T. Professor of Pediatrics and Pharmacology and Toxicology, University of Louisville School of Medicine; Medical Director, Kentucky Poison Center, Louisville, Kentucky Nicotine Poisoning S. Rutherfoord Rose, Pharm.D. Clinical Assistant Professor, Department of Emergency Medicine, University of North Carolina at Chapel Hill School of Medicine; Director, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North Carolina Pharmacokinetics and Toxicokinetics; Appendix A, Acute Nontoxic Exposures Brett Roth, M.D., F.A.C.E.P. Assistant Professor, University of Texas Southwestern Medical Center; Director of Inpatient Toxicology Service, Parkland Memorial Hospital, Dallas, Texas Smoke Inhalation Anna M. Rouse, RPh, C.S.P.I. Assistant Director, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North Carolina Appendix E, Drugs and Antidote Dosages Kevin O. Rynn, Pharm.D., A.B.A.T. Clinical Assistant Professor, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Jay L. Schauben, Pharm.D. Clinical Professor, College of Pharmacy, and Department of Emergency Medicine, College of Medicine, University of Florida; Director, Florida Poison Information Center; Director, Clinical Toxicology Service, Shands Jacksonville, Jacksonville, Florida Muscle Relaxants Nicola Schiebel, M.D. Emergency Medicine, University of Alberta, Edmonton, Alberta, Canada Barbiturates

Robert Schneider, M.D., F.A.C.E.P., F.A.C.S. Associate Director of Clinical Operations, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Airway Management in the Poisoned Patient Sandra M. Schneider, M.D., F.A.C.E.P. Professor and Chair, Department of Emergency Medicine, University of Rochester School of Medicine, Strong Memorial Hospital, Rochester, New York Mushrooms Dirk C. Schrader, M.D. Emergency Department, Athens Regional Medical Center, Athens, Georgia Radiation Charles M. Seamens, M.D., F.A.C.E.P. Assistant Professor, Emergency Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee Hydrofluoric Acid Donna L. Seger, M.D., F.A.C.E.P. Assistant Professor of Medicine and Emergency Medicine, Vanderbilt University School of Medicine; Fellowship Director and Chief, Medical Toxicology Service, Vanderbilt University Medical Center; Medical Director, Middle Tennessee Poison Center, Nashville, Tennessee Hydrofluoric Acid Suzanne M. Shepherd, M.S., M.D., F.A.C.E.P. Associate Professor and Program Director, Residency Training Program in Emergency Medicine, University of Pennsylvania School of Medicine; Education Director, Penn Travel Medicine, and Attending Physician, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Plants: Gastrointestinal Toxicity; Scombroid, Ciguatera, and Other Seafood Intoxications; Plant Poisoning: Berries Kathleen Shilalukey, M.B., Ch.B., B.Sc. Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, the Hospital for Sick Children, Toronto, Ontario, Canada Special Considerations in the Pregnant Patient William H. Shoff, M.D., F.A.C.E.P. Assistant Professor, University of Pennsylvania School of Medicine; Director, Penn Travel Medicine, and Attending Physician, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Scombroid, Ciguatera, and Other Seafood Intoxications; Plant Poisoning: Berries

Marco L.A. Sivilotti, M.D., M.Sc., F.R.C.P.C., F.A.C.E.P. Fellow, Medical Toxicology, Assistant Professor, Emergency Medicine, University of Massachusetts Medical School; Instructor, Emergency Medicine, Harvard Medical School, Worcester, Massachusetts Alkali Ingestions Frank Smeeks, M.D. Attending Emergency Physician, Grace Hospital, Morganton, North Carolina Oral Hypoglycemic Agents Susan C. Smolinske, Pharm.D. Assistant Professor, Department of Pediatrics, Wayne State University College of Medicine; Managing Director, Children's Hospital of Michigan, Regional Poison Control Center, Detroit, Michigan Laxatives Vincent C. Speranza, Pharm.D. Assistant Director, Florida Poison Information and Toxicology Resource Center, Tampa General Hospital, Tampa, Florida Valproate and Selected Newer Anticonvulsants Karl A. Sporer, M.D., F.A.C.E.P., F.A.C.P. Associate Clinical Professor, University of California, San Francisco, School of Medicine; Attending Physician, San Francisco General Hospital, San Francisco, California Antidysrhythmics Christine M. Stork, Pharm.D. Assistant Professor, Department of Emergency Medicine and Department of Medicine, Section of Clinical Pharmacology, Upstate Medical University; Director, Central New York Poison Control Center, University Hospital, Syracuse, New York Theophylline Young-Jin Sue, A.B., M.D. Clinical Assistant Professor of Pediatrics, Albert Einstein College of Medicine; Attending Physician, Pediatric Emergency Services, Montefiore Medical Center, Bronx, New York Antiseptics, Disinfectants, and Sterilizing Agents Milton Tenenbein, M.D., F.A.C.M.T. Professor of Pediatrics, Pharmacology and Medicine, University of Manitoba Faculty of Medicine; Director, Emergency Services, Children's Hospital; Director, Manitoba Poison Control Centre, Children's Hospital, Winnipeg, Manitoba, Canada Iron; Thyroid Hormones Christian Tomaszewski, M.D.

Assistant Clinical Professor, Department of Emergency Medicine, University of North Carolina–Chapel Hill School of Medicine; Director, Hyperbaric Medicine, Division of Medical Toxicology, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina Carbon Monoxide; Aquatic Envenomations Andrew R. Topliff, M.D. Consultant, Hennepin Regional Poison Center, Minneapolis, Minnesota Ergot Alkaloids; Camphor and Mothballs; Pine Oil and Turpentine Richard T. Tovar, M.D., F.A.C.E.P. Assistant Clinical Professor, Medical College of Wisconsin, Milwaukee; Chief of Staff, Oconomowoc Memorial Hospital, Oconomowoc, Wisconsin Halogenated Hydrocarbons John F. Tucker, M.D. Clinical Assistant Professor, Medical College of Wisconsin; Chief of Emergency Medicine, St. Luke's Medical Center, Milwaukee, Wisconsin Aliphatic Hydrocarbons; Halogenated Hydrocarbons Brent van Hoozen, M.D. Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Davis, School of Medicine, Davis, California Pulmonary Abnormalities Susi Vassallo, M.D., F.A.C.E.P., F.A.C.M.T. Clinical Assistant Professor of Emergency Medicine/Surgery, New York Hospital, Bellevue Medical Center; Consultant, New York City Poison Control Center, New York, New York Essential Oils Larissa Velez-Daubon, M.D. Fellow, Medical Toxicology, Clinical Instructor, Division of Emergency Medicine, University of Texas Southwestern Medical School, Dallas, Texas Central Nervous System Agitation Ingrid Vicas, M.D.C.M., F.R.C.P.C., A.B.E.M., D.A.B.M.T. Clinical Associate Professor (Pharmacology and Therapeutics) (Internal Medicine), Family Medicine, University of Calgary Faculty of Medicine; Director, Poison and Drug Information Service–Calgary; Calgary, Alberta, Canada Barbiturates Michael Wahl, M.D., F.A.C.E.P. Clinical Instructor, University of Illinois at Chicago College of Medicine; Attending Physician, Department of Emergency Medicine, Illinois Masonic Medical Center;

Medical Director, Illinois Poison Center, Chicago, Illinois Anticancer and Other Cytotoxic Drugs Michael Wainscott, M.D., F.A.C.E.P. Associate Professor, Division of Emergency Medicine, and Emergency Medicine Residency Director, Southwestern Medical School, Dallas, Texas Opioids Frank G. Walter, M.D., F.A.C.E.P., F.A.C.M.T. Associate Professor of Surgery, Division of Emergency Medicine, Section of Medical Toxicology, University of Arizona College of Medicine; Director, Medical Toxicology Fellowship, and Director of Clinical Toxicology, University Medical Center, Tucson, Arizona Seizures Richard Y. Wang, D.O., F.A.C.M.T., F.A.C.E.P. Assistant Professor, Department of Medicine, Brown University School of Medicine; Director, Division of Medical Toxicology, Rhode Island Hospital, Providence, Rhode Island Hematologic Abnormalities Gary S. Wasserman, D.O., F.A.A.P., F.A.C.M.T., F.A.A.C.T. Professor of Medicine, Department of Pediatrics, University of Missouri–Kansas City School of Medicine; Chief, Section of Medical Toxicology; Director, Poison Control Center, The Children's Mercy Hospital, Kansas City, Missouri Brown Recluse and Other Necrotizing Spiders William A. Watson, Pharm.D. Clinical Professor, Department of Surgery, University of Texas Medical School at San Antonio; Managing Director, South Texas Poison Center, The University of Texas Health Science Center, San Antonio, Texas Pharmacokinetics and Toxicokinetics; Disulfiram Paul M. Wax, M.D., F.A.C.M.T., F.A.C.E.P. Associate Professor, Emergency Medicine, University of Rochester; Associate Medical Director, Fingerlakes Regional Poison Control Center; Attending Physician, Emergency Department, Strong Memorial Hospital, Rochester, New York Focused Physical Examination/Toxidromes; Withdrawal Syndromes Alan L. Weiner, M.D. Medical Toxicologist, Connecticut Poison Control Center, University of Connecticut School of Medicine, Farmington, Connecticut Inhalation: Gases with Immediate Toxicity Suzanne R. White, M.D., F.A.C.E.P.

Associate Professor of Pediatrics and Emergency Medicine, Wayne State University School of Medicine; Medical Director, Regional Poison Control Center, Children's Hospital of Michigan; Detroit, Michigan Laxatives; Botulism; Food Poisoning Lena C. Williams, R.N., B.S.N. Director, North Texas Regional Poison Control Center, Dallas, Texas Psychoactive Drugs Saralyn R. Williams, M.D. Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine, San Diego, California Nitroprusside Leslie R. Wolf, M.D., A.C.M.T. Associate Professor, Toxicology Coordinator, Department of Emergency Medicine, Wright State University School of Medicine, Dayton, Ohio Oral Hypoglycemic Agents; Insulin

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FOREWORD A great textbook appeals to numerous suitors. The pupil, from medical student to pundit, desires an understanding of the fundamentals of the discipline. The clinician appreciates a commonsense-driven approach to patient care. The academician seeks in-depth, state-of-the-art knowledge on the subject, ranging from pathophysiology to management principles. All enjoy an organized, consistent, and scholarly approach to learning. Clinical Toxicology by Ford and colleagues appeals to each. The first 15 chapters are devoted to general management and cover a breadth of topics, each from the perspective of “what's different for the patient with suspected overdose?” To wit, how does one assess and stabilize the generic poison patient? What are the particulars of managing the airway? Are adjustments in advanced life support peculiar to this population? What are the axioms of gastrointestinal decontamination and extracorporeal removal techniques? What are the idiosyncrasies of laboratory and radiologic evaluation? How should the pregnant patient be handled differently? For the pragmatic clinician, there are 13 “approach to” chapters. These provide a cogent thought process for the physician confronted with specific clinical scenarios. Critical care disciplines such as toxicology and emergency medicine often require rapid decision-making based on limited clinical information. Patients are frequently categorized as fitting a particular scenario or toxidrome. Based upon this, the care provider maneuvers through a relevant differential diagnosis and prescribed management schemata, then reacts as the case unfolds. These 13 chapters proceed in precisely this manner, handling presentations such as CNS depression, CNS agitation, seizures, methemoglobinemia, and pulmonary abnormalities. Each chapter gives consideration to initial stabilization, relevant differential entities, examination and laboratory findings, definitive treatment, and patient disposition. The “toxins in depth” chapters, 101 in number, are just that. Within each is discussion of epidemiology, pharmacokinetics, pathophysiology, clinical presentation including specific situations, general and toxinspecific treatment, laboratory analysis, differential considerations, disposition, and sequelae. Of considerable advantage to the reader, all chapters are consistently organized, well tabulated, and fully annotated. Finally, there are six “addenda” chapters intended to serve as easy-to-use resources. These include quick references on therapeutic and toxic levels of drugs and toxins as well as dosages for therapeutic drugs and antidotes. Three give perspective on increasingly germane aspects of care. One reviews toxicology-related Internet resources; two offer clear perspective on the medicolegal aspects common to toxicology patients. In sum, Clinical Toxicology is a carefully formulated text that meets the needs of a wide range of health care providers, teachers, and scientists. Its editors are experienced and expert in the domain of toxicology. And, for the sake of the reader, great care has been taken to consistently arrange and cogently and clearly

describe the information. JOHN M ARX, Chairman, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina, Editor-in-Chief, Rosen's Emergency Medicine, 5th ed.

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Section I – GENERAL MANAGEMENT PRINCIPLES

Chapter 1 – Initial Approach to the Poisoned Patient
Marsha Ford Kathleen A. Delaney

INTRODUCTION
The initial approach to the poisoned patient should focus on six major areas: (1) resuscitation and stabilization; (2) history and physical examination, including evaluation for a specific toxidrome; (3) appropriate decontamination of the gastrointestinal tract, skin, and eyes; (4) judicious use of laboratory tests, electrocardiograms, and radiographic studies; (5) administration of specific antidotes, if indicated; and (6) utilization of enhanced elimination techniques for selected toxins. These topics are covered in detail in selected general management chapters as well as in chapters that deal with specific toxins. This chapter provides a rapid overview of these six areas.

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RESUSCITATION AND STABILIZATION
The first priorities in the management of seriously poisoned patients are the same as with all patients. The patency of the airway must be ensured, followed by assistance of breathing and support of circulation. Cardiac monitoring, pulse oximetry, and intravenous access should be established as indicated by the patient’s clinical condition. Airway management should focus on correcting hypoxia and respiratory acidosis and avoiding pulmonary aspiration. Acidemia due to respiratory depression can exacerbate the toxicity of drugs, such as cyclic antidepressants and salicylates. Certain toxic conditions can pose problems in the performance of standard airway management techniques. For example, severe upper airway injury that occurs following a caustic ingestion may preclude routine endotracheal intubation, necessitating surgical management of the airway. The use of succinylcholine for rapid-sequence intubation can result in prolonged paralysis in patients with organophosphate toxicity.[5] Routine ventilator settings may be grossly inadequate for the patient with severe metabolic acidosis who requires significant respiratory compensation. Similarly, standard advanced cardiac life support (ACLS) protocols may be inadequate or inappropriate for resuscitation of poisoned patients with life-threatening cardiac dysrhythmias or cardiac arrest. Standard ACLS doses of atropine are inadequate for organophosphate-induced cholinergic symptoms. The use of procainamide is contraindicated for ventricular dysrhythmias caused by cyclic antidepressants and other myocardial sodium channel–blocking agents. Intravenous calcium can be lifesaving in a patient poisoned with hydrofluoric acid, a calcium channel–blocking agent, or magnesium. Sodium bicarbonate may be lifesaving in resuscitation of the patient poisoned with cyclic antidepressants or salicylates. Variations in these methods of management are discussed in Chapters 2 and 3 . In patients with altered mental status, administration of naloxone, dextrose, and thiamine should be considered, while flumazenil should be administered cautiously in cases of benzodiazepine overdose with significant respiratory depression. [3]

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HISTORY AND PHYSICAL EXAMINATION
The history provides critical information in the assessment of the patient with suspected overdose. A history of medications potentially available to a patient or a history of chronic medical illnesses in members of the household gives clues to classes of medications available. Accurate identification of ingestants is particularly important in the patient exposed to agents that have delayed onset of toxic effects, such as acetonitrile, which is metabolized to cyanide, or monoamine oxidase inhibitors. The physical examination gives important clues to both the severity and the cause of poisoning. Vital sign and mental status abnormalities are important signs of the severity of toxicity and may also suggest the class of toxin involved. Examples include the respiratory depression of barbiturate or opioid poisoning and the tachycardia and hypertension of poisoning with sympathomimetic agents. Characteristic “toxidromes” indicate the presence of agents with cholinergic, anticholinergic, sympathomimetic, and opioid effects. Less specific findings, such as nystagmus, myoclonus, asterixis, and tremor, also suggest various toxins. Characteristic odors suggest the presence of toxins, such as cyanide (almond odor) or ethchlorvynol (vinyl odor).

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DECONTAMINATION
Administration of activated charcoal is the primary method of gastrointestinal decontamination, and it should be administered within 1 hour of toxin ingestion whenever possible. Multiple doses of activated charcoal may be beneficial in patients ingesting life-threatening amounts of carbamazepine, dapsone, phenobarbital, quinine, theophylline, [2] and other toxins. Multiplying digital-to-analog converter (MDAC) may also be beneficial in situations of large acute ingestions of substances such as salicylates, where gastric emptying may be delayed. Limited indications for the use of orogastric lavage, nasogastric suction, and whole-bowel irrigation exist, and these are discussed in Chapter 5 . Syrup of ipecac is used rarely in the prehospital setting, and virtually never in hospitals. The use of cathartics has never been shown to alter clinical outcome. However, their overzealous or inappropriate use has been associated with significant morbidity and mortality, and their routine use is no longer recommended.[1] Dermal decontamination is best accomplished with copious amounts of water. However, the use of water on skin contaminated with metallic sodium, metallic potassium, or phosphorus (white, yellow) may result in further skin injury owing to heat generation and explosive injury. Irrigation of phenol burns with low molecular weight polyethylene glycol is effective. [4] Other therapies, such as topical calcium salts for hydrofluoric acid burns, may be indicated following initial water decontamination. Ocular decontamination can be accomplished with water or normal saline irrigation.

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DIAGNOSTIC TESTING
The results of routine toxicology screens seldom add useful information about the toxins involved that has not already been gleaned from the history, and assessment of signs and symptoms. Additionally, the results of screens may be inaccurate. Many toxic agents are not detected on routine screening, while false-positive results are commonly reported. Unlike broad toxicology screens, serum concentrations of specific drugs are useful in guiding management. A list of the agents in which quantitative serum levels reflect the severity of poisoning and guide management can be found in Table 7–8 . Other tests, such as serum electrolytes, calculated anion gap, glucose, arterial blood gases, serum creatinine, and liver function tests, can assist in the indirect evaluation of the end-organ effects of a toxin. They may also aid in the diagnosis of specific agents. The toxic differential diagnosis of an anion gap acidosis is found in Chapter 11 . Electrocardiograms should be obtained in patients ingesting toxins known to produce cardiac dysrhythmias or conduction delays, or in significantly poisoned patients as an aid to the diagnosis of an unknown toxin. Routine radiographs may be indicated to evaluate potential adverse effects of toxins, such as pulmonary injury due to inhalation of chlorine gas or aspiration of a hydrocarbon. Routine abdominal radiographs may be unreliable for evaluation of toxins thought to be radiopaque. A thoughtful discussion of their utility can be found in Chapter 8 .

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ANTIDOTES
Specific antidotes exist for a few toxins. These are listed in Table 1–1 . Specific indications for antidote use and dosing can be found in the chapters dealing with individual toxins and in Appendix E .

Table 1-1 -- Antidotes and Indications for Use Antidote Antivenom (equine) Crotalid (Crotalidae polyvalent antivenin) Elapid Antivenom (Fab) * Antivenom, latrodectus (equine) Antivenom, loxosceles (rabbit)

Indication for Use

Crotalids: Rattlesnakes (Crotalus spp. and Sistrurus spp.), cottonmouth (Agkistrodon spp.), copperhead (Agkistrodon spp.) Eastern (Micrurus fulvius fulvius) and Texas (Micrurus fulvius tenere) coral snakes Crotalids Black widow spider (Latrodectus spp.) Brown recluse spider (Loxosceles reclusa)

Antivenom, scorpion (goat) Scorpions (Centruroides spp.) Botulinum antitoxin (equine) Clostridium botulinum Calcium channel antagonists Hydrofluoric acid Calcium Hyperkalemia (except cardiac glycosides) Hypermagnesemia Hypocalcemia (e.g., ethylene glycol) Calcium disodium edetate Cyanide antidote kit: Amyl nitrite Sodium nitrite Thiosulfate Deferoxamine Iron Lead Cyanide

Antidote Ackee fruit (hypoglycin) Dextrose Insulin Sulfonylureas

Indication for Use

Other (e.g., salicylates, pentamidine) Digoxin Digoxin-specific antibody fragments (Fab) Digitalis Other cardiac glycosides, e.g., bufodienalides (Bufo toads) Oleander Arsenic Dimercaprol Lead Mercury Diethylene glycol Ethanol Ethylene glycol Methanol Experimental: sodium monofluoroacetate Flumazenil Folic acid/tetrahydrofolic acid (leucovorin) Fomepizole Benzodiazepines Venlafaxine Methanol Methotrexate Ethylene glycol Methanol Glucagon Beta-adrenergic receptor antagonists Calcium channel antagonists Carbon monoxide Hyberbaric oxygen Experimental: carbon tetrachloride Cyanide, hydrogen sulfide Methylene blue N-Acetylcysteine Naloxone, nalmefene, naltrexone Physostigmine Methemoglobin-producing agents Acetaminophen Experimental: carbon tetrachloride, chloroform, pennyroyal oil Opioids Anticholinergic agents, e.g., diphenhydramine, Jimsonweed (Datura spp.), scopalamine

Antidote Pralidoxime Protamine Organophosphates Heparin

Indication for Use

Ethylene glycol (theoretical efficacy) Pyridoxine Isoniazid Monomethylhydrazine mushrooms (Gyrometra esculenta) Myocardial sodium channel blockers, e.g., cyclic antidepressants, cocaine, norpropoxyphene, class Ia and Ic antidysrhythmics, piperidine phenothiazines (thioridazine, mesoridazine) Sodium bicarbonate Altered tissue distribution/enhanced elimination: chlorophenoxy herbicides, chlorpropamide, formic acid (methanol), methotrexate, phenobarbital, salicylates Neutralization: inhaled chlorine gas, hydrogen chloride, phosgene Arsenic Succimer Lead Mercury Vitamin K
* Experimental, not yet approved.

Anticoagulants, e.g., warfarin, long-acting anticoagulant rodenticides

Enhanced Elimination Important methods for enhancing toxin elimination involve manipulations of urine pH, with subsequent increased urinary excretion of certain toxins; and extracorporeal removal via hemodialysis and charcoal hemoperfusion. Urinary alkalinization through parenteral administration of sodium bicarbonate enhances the elimination of weak acids, such as salicylates, phenobarbital, chlorpropamide, chlorophenoxy herbicides, formic acid, and methotrexate. Urinary acidification, previously used for drugs such as phencyclidine and amphetamines, is no longer recommended owing to complications associated with metabolic and urinary acidosis. Hemodialysis is the primary extracorporeal method for increasing the elimination of ethylene glycol, glycolic acid, methanol, lithium, and salicylates. It is used rarely to remove isopropanol, ethanol, metformin, and bromide and to clear theophylline if charcoal hemoperfusion is unavailable. Charcoal hemoperfusion removes theophylline more effectively than hemodialysis and also will enhance the elimination of phenobarbital. A more thorough discussion of these techniques and indications for their use can be found in Chapter 6 .

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REFERENCES
1. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists: Position statement: Cathartics. J Toxicol Clin Toxicol 1997; 35:743. 2. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999; 37:731. 3. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness: Controversies in the use of a ‘coma cocktail.’. JAMA 1995; 274:562. 4. Hunter DM, Timerding BL, Leonard RB, et al: Effects of isopropyl alcohol, ethanol and polyethylene glycol/industrial methylated spirits in the treatment of acute phenol burns. Ann Emerg Med 1992; 21:1303. 5. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med 1987; 16:215.

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Chapter 2 – Airway Management in the Poisoned Patient
Michael F. Murphy Robert Schneider When and how to manage the airway is fundamental to the management of a patient suffering a toxicologic exposure. Little is written specifically addressing airway management in the poisoned patient, aside from highlighting its importance. Issues to be considered in managing the airway of the poisoned patient are, for the most part, no different than those for any other patient requiring intubation. However, the poisoned patient may present unique clinical situations that demand a customized approach. Examples include drug:drug interactions, substances that lead to physical distortion of the airway, and profound physiologic compromise as a result of the exposure.

AIRWAY MANAGEMENT
When and how to manage the airway are challenges that must be individualized on a case-by-case basis. The decision to actively and definitively manage the airway is ordinarily straightforward. The indications generally fall into the following categories: • • • • • Failure to maintain reasonable gas exchange Failure to maintain a patent airway Failure to adequately protect the airway against aspiration (which may be especially problematic in the toxicologic patient prone to vomiting) To provide a route for pulmonary toilette To facilitate patient and symptom control

However, timing the intubation is not quite so straightforward. The pace of change in each clinical situation is an important dimension affecting the timing of the intubation. For instance, it is well recognized that the pace of deterioration in cyclic antidepressant overdose is often rapid, motivating intubation earlier rather than later. Therefore, one must anticipate with some degree of certainty that intubation will ultimately be required and act to secure the airway in an appropriate manner. All things being equal, rapid sequence intubation (RSI) is the preferred method of intubation because it produces the highest success rate coupled with the lowest complication rate. However, before embarking on an RSI course the following points must be addressed: • • • • Am I certain that I can intubate this patient? If intubation fails, will I be able to maintain airway support with a bag and mask? What central nervous system, cardiovascular, and ventilatory reserve does the patient have? What drug:drug interactions and adverse drug reactions need I consider in the RSI sequence?

The ability to successfully intubate any patient is never a certainty. However, it is possible to predict with some accuracy those patients in whom the possibility of failure is significant. If one predicts that failure is a significant possibility the patient should not be paralyzed until an evaluation indicates that success is likely. The Difficult Intubation Anticipating the difficult intubation and selecting the appropriate technique to secure the airway reduces the incidence of failed intubation. Successful application of these principles is predicated on (1) recognizing and predicting the difficult intubation, (2) choosing the most appropriate technique and equipment for the particular situation, and (3) possessing a comprehensive set of pharmacologic and manual skills. The physician may be able to rapidly ascertain a prior history of airway management difficulty from individuals accompanying the patient or from other sources (e.g., a Medic Alert bracelet). Some estimation of degree of difficulty is possible from observation and simple maneuvers during the physical examination, although the clinical situation may impose some limitations. It is important to appreciate that this evaluation will fail to predict all difficult intubations and may predict difficulty when none exists. Physical Examination of the Airway Certain anatomic factors need to be considered in the evaluation of a difficult airway: • C-spine mobility: C-spine immobilization of and by itself adds a dimension of difficulty to the airway management scenario. It also affects the performance of Sellick’s maneuver because the application of cricoid pressure has the potential to cause motion in the case of an unstable C-spine injury. Mouth opening: An adult with normal temporomandibular joint (TMJ) function should be able to open the mouth to accommodate three to four fingers (3–4 cm), incisor to incisor, top to bottom. The physician can check this distance if limited TMJ mobility is a concern and the clinical scenario permits. TMJ involvement in the patient with rheumatoid arthritis may lead to limited mouth opening. Rheumatoid arthritis also has the potential to produce atlantoaxial subluxation and instability. External dimensions: The mandible should be sufficiently large to accommodate a normal-sized tongue. Patients with small mandibles have tongues that obstruct access to the airway during intubation. In the adult, one should expect 3 to 4 fingerbreadths between the symphysis and the hyoid bone. Neck length and larynx position: The larynx descends in the neck from the C3–4 level in infancy to the C5–6 level by the age of 8 or 9. A larynx that is higher may be more difficult to visualize at the time of orotracheal intubation than one that is lower (e.g., in obese individuals or those with “short” necks. Typically, one should be able to get two fingers between the top of the thyroid cartilage and the base of the neck in a normal adult. Teeth: All false teeth, especially full upper or lower plates, should be removed before intubation. Large upper incisors may obstruct visualization of the larynx. Protruding teeth reduce visualization and access because they elongate the anteroposterior axis of the mouth. Jagged teeth may lacerate the balloon on an endotracheal tube. Oral dimension: The airway may be difficult to intubate in patients with narrow facial features and high arched palates. Access to the airway is limited because of the reduced space from side to side in the mouth. In addition, the longer anteroposterior dimension limits the ability to visualize the larynx.

In addition to anatomic features that portend a difficult airway, illnesses and injuries that lead to upper airway distortion may also lead to a failed intubation. Classic disorders include caustic and thermal upper airway injuries ( Fig. 2–1 ); blunt and penetrating neck and facial injuries; upper airway neoplasms; upper airway infections, such as epiglottitis, parapharyngeal and retropharyngeal abscesses, and Ludwig’s angina; and angioedema.

Figure 2-1 This young man has suffered upper airway thermal trauma secondary to freon abuse. He was intubated via the nasotracheal route, awake and in a sitting position. Concerns about swelling in the anterior oropharyngeal airway precluded intubation via the oropharyngeal route.

In the event the intubating physician cannot be assured of success, awake intubation should be undertaken. At some point in this process the physician may visualize sufficient airway structures to be reassured that success is certain and revert to an RSI strategy. Rapid Sequence Intubation Frequently, poisoned patients have a decreased level of consciousness, impaired airway protective reflexes, delayed gastric emptying, and a full stomach. In addition, management usually requires activated charcoal administration and may necessitate gastric lavage, enhancing the risk of aspiration. There is some evidence to suggest that gastric aspiration in the acute phase of the poisoning contributes substantially to a poor outcome.[12]

It is clear that airway protection and the prevention of aspiration in the poisoned patient are primary concerns, and ones for which RSI was specifically designed. A French study of 394 poisoned patients intubated out of hospital found that sedation with any agent followed by neuromuscular blockade facilitated intubation; only 3 of 46 (7 per cent) intubations were difficult. Similar results were obtained with propofol sedation alone (8 per cent [1/12] difficult), whereas etomidate alone resulted in difficulty with 47 per cent (17/36).[1] RSI is the use of medications and techniques to sedate/induce, paralyze, and prevent aspiration in the course of endotracheal intubation. It also is designed to mitigate the adverse physiologic responses to intubation. Patients who are, or are predicted to be, imminently unable to protect the airway, as evidenced by their level of consciousness or the absence of gag and swallowing reflexes, require active airway intervention. Patients who are currently, or who imminently will be, marginally capable of protecting their airway and who are to be given activated charcoal or lavaged should be intubated. The sequence is presented here and is summarized in Table 2–1 .

Table 2-1 -- Simplified Schema for Rapid Sequence Intubation (RSI) 1. Evaluate the airway for degree of difficulty. 2. Attempt to maintain acceptable blood gas tensions: a. Preoxygenate. b. Assist ventilation if necessary. 3. Pretreat 3 minutes before intubation if possible. a. Defasciculate with 10% of the paralyzing dose of a nondepolarizer drug b. Fentanyl, 2–9 µg/kg c. Lidocaine, 1.5 mg/kg 4. Induce and paralyze: a. Etomidate, 0.3 mg/kg b. Succinylcholine, 1.5 mg/kg c. Vecuronium, 0.15 mg/kg 5. Minimize the risk of aspiration (e.g., Sellick’s maneuver)

. Evaluate the Airway Caution is essential with C-spine immobility, limited mouth opening, a big tongue, a high arched palate, buck teeth, a receding chin, a thick neck, or an anatomically disrupted airway (e.g., blunt trauma to face, neck). If there is time and there is concern that intubation may not be possible, the laryngoscope can be used to ensure that the epiglottis can be visualized, indicating that orotracheal intubation is possible. Sedation of the

patient may be necessary to achieve this. In desperate situations this is not an option, but they are not the norm. Caustic ingestions may require visualization to determine the need for intubation, particularly in the patient who is unable to swallow or is hoarse. Furthermore, this visualization may reveal hypopharyngeal burns that may preclude endoscopy. [5][13] Flexible, fiberoptic nasopharyngoscopy may be the most appropriate method of viewing the upper airway in these patients and should be a skill in the armamentarium of the physician managing the airway. Preoxygenate and Avoid Hypercapnea A pulse oximeter is used and the patient is preoxygenated. This replaces the functional residual capacity of the lung (30 mL/kg) with oxygen, providing a buffer when the patient is apneic during the RSI sequence. Preoxygenation is done with three to five vital capacity breaths if the patient is cooperative or, alternatively, with 3 to 5 minutes of tidal respiration of 100 per cent oxygen. In reality, this involves placing 100 per cent oxygen on the patient as soon as it is apparent that intubation is a possibility. The PaCO2 is usually not a significant concern (rises at 3 mm Hg/min when apneic) unless the patient has a head injury, severe ventilatory failure, or poisoning with drugs such as cyclic antidepressants or salicylates, in which worsening of the systemic acidosis could lead to rapid clinical deterioration. In these cases one should (1) assist ventilation in synchrony with natural respirations and (2) gently “bag” the patient after apnea has been induced with cricoid pressure applied (modified RSI). Ordinarily the patient is not “bagged” when apneic to avoid inflating the stomach and increasing the risk of aspiration. Nondepolarizer Pretreatment Nondepolarizer pretreatment to abolish fasciculations secondary to succinylcholine is probably done for cosmetic reasons only. Pretreatment is done 3 minutes before administration of succinylcholine. The dose is 10 per cent of paralyzing dose: Pancuronium, 10 per cent of 0.1 mg/kg
D-Tubocurarine,

10 per cent of 0.5

mg/kg Vecuronium, 10 per cent of 0.1 mg/kg Rocuronium, 10 per cent of 0.6 mg/kg

Pretreatment and priming are not the same. Priming implies that a small (10 per cent) dose of a nondepolarizer (pancuronium, vecuronium), given 3 to 5 minutes before a full paralyzing dose of the same drug leads to a more rapid onset of paralysis (this may or may not be true). Pretreatment refers to the use of a small dose of a nondepolarizer to abolish fasciculations due to the subsequent administration of succinylcholine. Attenuation of Adverse Cardiovascular and Intracranial Pressure Responses

The attenuation of adverse physiologic consequences of intubation, particularly hypertension, tachycardia, and intracranial pressure elevation, may be of concern in the patient poisoned with sympathomimetics or monoamine oxidase inhibitors, or those with cerebral edema from agents such as salicylates, ethylene glycol, and methanol. Drugs ( Table 2–2 ) are given 3 minutes before intubation (like pretreatment) to be optimally effective. This procedure should not be performed in moribund and desperate situations. Medications that are used include (1) the opioids fentanyl, 2 to 9 µg/kg, and alfentanil, 20 to 30 µg/kg; (2) lidocaine, 1.5 mg/kg (probably effective for intracranial pressure, less so for blood pressure); and the ß-adrenergic receptor antagonists esmolol, 1.5 mg/kg over 30 seconds (implies rock stable patient), and labetalol, 0.25 mg/kg over 2 minutes.

Table 2-2 -- Agents That Mitigate Hypertensive Responses to Endotracheal Intubation * Class Drug Dose Comments Thiopentone 1–5 mg/kg Sedativehypnotics Midazolam Propofol Etomidate 0.1–0.35 mg/kg 0.5–2 mg/kg 0.2–0.4 mg/kg Significant decreased blood pressure if compromised cardiovascular reserve. Remember adrenal suppression with etomidate.

Methohexital 0.5–2.5 mg/kg Dissociative agents Beta-adrenergic receptor antagonists Calcium channel antagonists Ketamine 1–1.5 mg/kg 1 mg/kg if compromised hemodynamics.

Esmolol Diltiazem Verapamil Nicardipine Beta-adrenergic antagonists and calcium channel antagonists are rarely, if ever, of use in emergent RSI. Avoid if compromised cardiovascular reserve.

Local anesthetics

Lidocaine Mexilitine

1.5 mg/kg 3 mg/kg

Questionable efficacy. Watch for decreased blood pressure!

Nitrates

Nitroglycerin 1–4 µg/kg

Causes cerebrovasodilatation and increased intracranial pressure.

* Refer to the text for a discussion and dosing guidelines for opioids.

Postintubation surges in blood pressure and heart rate can be managed with the ß-adrenergic receptor antagonists or intermittent bolus doses of thiopental, 1 to 2 mg/kg. This is especially important in the patient with cerebral edema or with a concomitant head injury.

ß-Adrenergic receptor antagonists and thiopental are contraindicated in the poisoned patient who is currently, or anticipated to be, hemodynamically unstable. Examples include patients poisoned with ßadrenergic receptor antagonists, calcium channel antagonists, digoxin, antihypertensives, antidysrhythmic drugs, barbiturates, cyclic antidepressants, iron, and phenothiazines. Small doses of nitrates (sodium nitroprusside and nitroglycerin, 1 µg/kg) have been used with some success immediately before intubation to control the hypertensive response to intubation. However, cerebral vasodilatation leads to increased cerebral blood flow and increased intracranial pressure. Optimize Intubating Conditions Preparations should include suctioning equipment, a selection of tubes, airways, stylets (routinely inserted in an endotracheal tube for emergent intubation), a percutaneous transtracheal ventilator, and a formal cricothyroidostomy kit. Other devices, such as Laryngeal Mask Airways, Combitubes, and Lightwands serve as rescue devices in the event that intubation proves to be impossible. Sedative hypnotics are often used to produce amnesia and obtund sensibilities and adverse physiologic responses to intubation, such as tachycardia, hypertension, bronchospasm, and elevations in intracranial pressure. In each case the need to use such agents must be balanced against the risks of using them. This risk evaluation involves estimating the “reserve” of the cardiovascular and sympathetic nervous systems in accommodating the additional cardiovascular and sympathetic depressant activities of these medications. This is especially apropos in toxicology, in which the toxin may additionally compromise these systems ( Table 2–3 ).

Table 2-3 -- Drugs and Doses Used in the RSI Sequence to Produce Sedation * Drug Midazolam Light Sedation PO: 0.5 mg/kg; max, 10 mg; may repeat 0.25 mg/kg × 1; max total, 15 mg IM: 0.1 mg/kg Thiopentone N/A Methohexital N/A Propofol Etomidate N/A N/A 0.2 mg/kg IV titrated to effect; no 3–5 mg/kg IV maximum 0.1 mg/kg IV titrated to effect; no 1–2 mg/kg IV maximum 0.1 mg/kg IV titrated to effect; no 1–2 mg/kg IV maximum N/A IM: up to 6 mg/kg IV: 0.1–0.5 mg/kg IM: 1–4 mg/kg PO: 4 mg/kg 0.3 mg/kg IV N/A 1–1.5 mg/kg IV Deep Sedation 0.01–0.1 mg/kg IV titrated to effect; no maximum Induction 0.1–0.35 mg/kg IV

Pentobarbital IM: 2 mg/kg N/A Ketamine

* Caution is advised in the poisoned patient when sedative-hypnotic, opioid, neuroleptic, major tranquilizers, and other central nervous system and cardiovascular active medications are already in the patient.

The following sedative hypnotic agents are used: Thiopental, 1 to 5 mg/kg (1 mg/kg potentially unstable; 3 mg/kg probably stable; 5 mg/kg rock stable) Midazolam, 0.1 to 0.3 mg/kg (0.1 mg/kg potentially unstable; 0.2 mg/kg probably stable; 0.3 mg/kg rock stable) Ketamine, 1 to 1.5 mg/kg (1 mg/kg unstable but alert, 1.5 mg/kg asthmatic) Etomidate, 0.3 mg/kg (decrease the dose if hemodynamic instability is possible)

The neuromuscular blocker succinylcholine is given in a dose of 1.5 mg/kg intravenously or 3 mg/kg intramuscularly ( Table 2–4 ). Onset is virtually immediate, with complete paralysis in 30 to 90 seconds. Hyperkalemia may be seen in the presence of neuromuscular disorders, burns, crush injuries, and rhabdomyolysis, although not usually in the acute phase.[9][14][15] It is possible to see as much as a 0.5mEq/L rise in potassium in normal individuals with succinylcholine. This increase may be an issue in poisonings that lead to hyperkalemia, such as toxicity due to cardiac glycosides, hydrofluoric acid, potassium-sparing diuretics, and high doses of penicillin. Atropine, 0.01 mg/kg (minimum, 0.1 mg), should be administered routinely in children younger than the age of 5 years, in children younger than age 8 if bradycardic, and in all patients with symptomatic bradycardia. A second dose of succinylcholine may precipitate profound bradycardia at all ages.

Table 2-4 -- Neuromuscular Blocking Drugs Commonly Used in the Emergency Department Class Drug Dose Comments Contraindications: Hyperkalemia Globe trauma or glaucoma Depolarizer Succinylcholine 1.5 mg/kg Increased intracranial pressure Recent major burns, soft tissue trauma Spinal cord injuries with paraplegia or quadriplegia Muscular dystrophies Rocuronium Vecuronium Nondepolarizers (pretreatment dose is 10% of paralyzing dose given 3 minutes before intubation) Curare (dTc) 0.6 mg/kg 0.2 mg/kg 0.5 mg/kg Rapid onset “Prime” with 0.02 mg/kg 3 minutes before endotracheal intubation Histamine release

intubation)

Class

Drug Atracurium Pancuronium

Dose 0.5 mg/kg 0.1 mg/kg

Comments Elimination neither renal nor hepatic Moderate sympathomimetic effects

dTc = D-tubocurarine.

Vecuronium may be substituted at a dose of 0.15 mg/kg if succinylcholine is contraindicated. Its onset and time to complete paralysis is slower than those of succinylcholine (1 to 2 minutes, depending on circulation time). Rocuronium, 0.6 mg/kg, may have a more rapid onset than vecuronium (comparable to succinylcholine), but like vecuronium it has a duration of paralysis of 20 to 40 minutes before reversal is possible. Minimize the Risk of Aspiration Knowing that the patient has had no recent oral intake (NPO status) is not practical in the emergency department. Sellick’s maneuver (10 lb pressure to the cricoid ring unless there is a potentially unstable C-spine) is applied. Stomach contents are aspirated through a nasogastric tube if one is already in place. Then the tube is removed (a tube left in place may interfere with the function of the gastroesophageal junction, increasing the risk of regurgitation). Some authors, notably Sellick, do not believe that this is necessary. If an acute gastric dilatation exists, some would advocate placing a nasogastric tube before RSI. This depends on how urgently the endotracheal intubation must be performed and on the relative risk of passing a nasogastric tube. An attempt is made to avoid “bagging” the patient throughout the sequence. If it must be done, then Sellick’s maneuver is applied (modified RSI). Adequate suction should be readily available. Cricoid pressure is not released until the tube is in the trachea and the endotracheal tube balloon is inflated. If the esophagus has been intubated and the stomach inflated, the tube is left in place but moved to the left side of the mouth and then the patient is reintubated (similar to the endotracheal obturator airway technique). In the setting of low oxygen saturations, the patient should have the endotracheal tube removed from the esophagus and subsequently should be “bagged.” However, the risk of aspiration can be reduced by the following maneuvers:

1. 2. 3. 4.

Inflate the balloon maximally with the tube in the esophagus. Press on the epigastrium to force gas and gastric contents out through the tube. Deflate the balloon and remove the tube with suction ready. “Bag” the patient.

When using drugs to facilitate intubation, remember the old adage: Don’t take anything away from the patient that you cannot replace.

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AIRWAY MANAGEMENT: SPECIFIC TOXICOLOGIC ISSUES
Adverse Drug Interactions Medications are routinely used to facilitate airway management. These medications have the potential to interact with the pharmacologic or physical effects of a toxin, leading to further patient compromise. The most common interactions to be considered in toxicology include succinylcholine in organophosphate poisoning, succinylcholine in situations in which hyperkalemia may be expected, and the use of medications that compromise cardiovascular or ventilatory performance. Succinylcholine is metabolized rapidly in the liver and plasma by the enzyme butyrylcholinesterase, also known as pseudocholinesterase. Many conditions are associated with a decrease in serum pseudocholinesterase levels, including liver disease, cocaine use,[11] and others. However, this ordinarily is of little clinical significance because even profound decreases in serum activity produce a maximum duration of paralysis in the 20- to 25-minute range.[14] However, the same cannot be said of patients exposed to organophosphate compounds. Cases of paralysis lasting more than 3 hours have been reported.[16] This prolonged paralysis can be problematic if the intubation is difficult or if the clinician wants to observe for seizures. With organophosphate toxicity, consider using short-acting nondepolarizing drugs such as vecuronium or rocuronium instead of succinylcholine. Succinylcholine is known to produce life-threatening elevations in serum potassium in some clinical conditions: • Burned patients may be susceptible to excessive potassium release beginning 24 hours after the injury and persisting for up to 2 years.[15] Although the magnitude of the hyperkalemic response in burn patients does not correlate well with the magnitude of the burn, it is recommended that succinylcholine be avoided in patients suffering burns exceeding 8 per cent body surface area.[15] Patients with extensive neuromuscular disorders, particularly denervation syndromes (spinal cord lesions, progressive muscle wasting disorders), are known to be susceptible to exuberant potassium release with succinylcholine.[9] Patients with severe intra-abdominal infections persisting longer than 1 week have also been reported to have a hyperkalemic response to succinylcholine.[9]

Although succinylcholine produces little elevation of serum potassium levels in normal individuals (up to 0.5 mg/dL), it seems reasonable to avoid succinylcholine in situations in which hyperkalemia may exist, such as cardiac glycoside poisoning or hydrofluoric acid exposure. Muscle cell membrane instability in any clinical setting associated with rhabdomyolysis is likely a setup for hazardous potassium release with succinylcholine. Rhabdomyolysis has been reported with toxicity due to sympathomimetics, phencyclidine, doxylamine, heroin, and envenomation by scorpions, Latrodectus spiders, and crotalids. Lidocaine can be safely used in patients with cocaine toxicity[18]( Table 2–5 ).

Table 2-5 -- Contraindications to RSI in the Poisoned Patient Moribund patient, desperate situation in patient with no muscle tone RSI not needed; can proceed with endotracheal intubation Anatomically abnormal or disrupted airway Caustic injury to the airway Severe swelling Contraindication to individual medications used in the sequence Allergy Lethal electrolyte disturbance Severely compromised hemodynamics Prolonged drug effect Upper Airway Distortion Caustic and thermal injuries to the upper airway are known to lead to complete airway obstruction and are ordinarily managed aggressively in a controlled manner before an uncontrolled, emergency intubation is precipitated by complete airway obstruction.[6][10] Hints that an aggressive approach is indicated in these situations include (1) patient sitting up, leaning forward with the mandible protruded; (2) inability to swallow; (3) “hot potato” voice; (4) stridor; and (5) hoarseness. Although hoarseness may indicate impending upper airway obstruction, it does not possess nearly the strength of association that the previous four signs do. These patients should be intubated using direct visualization; severe burns of the hypopharynx may predispose to perforation during blind intubation attempts.[13] Obstruction can also result from angioedema of the tongue and glottis with use of angiotensin-converting enzyme inhibitors and with angiotensin II receptor antagonist drugs.[17][19] Life-threatening airway obstruction has been reported from the bite of a pet rattlesnake to its owner’s tongue. This patient was nasotracheally intubated for several days until the obstruction subsided.[8] Paralysis to facilitate intubation in these situations should occur only if a high degree of certainty exists that the intubation will be successful. An evaluation of the airway with the patient awake may deliver the required degree of certainty. Alternatively, nasotracheal intubation may be attempted initially and be successful, as in the case of the boy shown in Figure 2–1 . Patient and Symptom Control There are some very specific dilemmas that face the physician from time to time in the management of poisoned patients in whom paralysis and intubation is considered. Examples include, but are clearly not limited to

The patient with violent or combative behavior producing a risk to health care personnel (e.g., from anticholinergics, phencyclidine, sympathomimetics, and abrupt opioid withdrawal secondary to naloxone administration) The patient with intermittent or intractable vomiting (e.g., in organophosphate or theophylline poisoning) to the point that it interferes with management The patient with seizures refractory to pharmacologic management when the cycle of lactic acidosis, hyperthermia, and muscle tissue damage exists (e.g., isoniazid or theophylline toxicity) The patient whose condition is rapidly deteriorating after cyclic antidepressant overdose

• • •

In each of these situations, paralysis and intubation may be a reasonable strategy. In general, the risk of paralysis and intubation must be weighed carefully against the benefit. Material risks include failure to intubate, airway injury attendant with the procedure, and aspiration. These risks are minimized if the principles of airway management articulated earlier are adhered to, including careful airway evaluation, facility with the skill of intubation, and adherence to the details of RSI. Specific risks associated with the pharmacologic management of the intubation must be recognized. Examples include the use of succinylcholine in status seizure patients in whom potassium release is a risk or precipitation of cardiovascular collapse with the use of a sedative hypnotic (e.g., midazolam, etomidate, thiopental) in a hypotensive patient. In a retrospective study of 167 patients poisoned with chloroquine, prehospital cardiac arrest occurred in 25 patients; of the 9 patients not in arrest on arrival of prehospital personnel, 7 had cardiac arrest immediately after administration of thiopental. [4] Administration of intravenous diazepam was followed closely by asystole in two patients with salicylate toxicity.[2] The diazepam may have led to respiratory acidosis, facilitating salicylate entry into the central nervous system.[7] Ventilating the Poisoned Patient The principles dictating how to ventilate the poisoned patient are no different than for any other patient. The most fundamental issue to be addressed in determining minute ventilation is how much carbon dioxide needs to be eliminated. Patients who are hypothermic or anesthetized have low metabolic rates and require less minute ventilation than patients who are actively seizing or acidemic. This latter example is particularly important to appreciate in toxicology, because acid-base status is often a concern. For example, it may be necessary initially to ventilate a salicylate-toxic patient at two to three times the normal rate to compensate for his or her metabolic acidosis. Failure to do this may result in a relative respiratory acidosis with increased shift of salicylate into the central nervous system.[3] Factors guiding the amount of minute ventilation to provide include the patient’s respiratory rate before intubation, knowledge about the particular poison, laboratory investigations, end-tidal carbon dioxide monitoring, and others.

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REFERENCES
1. Adnet F, Borron SW, Finot M-A, et al: Intubation difficulty in poisoned patients: Association with initial Glasgow Coma Scale score. Acad Emerg Med 1998; 5:123. 2. Berk WA, Andersen JC: Salicylate-associated asystole: Report of two cases. Am J Med 1989; 86:505. 3. Chapman BJ, Proudfoot AT: Adult salicylate poisoning: Deaths and outcome in patients with high plasma salicylate concentrations. Q J Med 1989; 72:699. 4. Clemessy JL, Taboulet P, Hoffman JR, et al: Treatment of acute chloroquine poisoning: A 5-year experience. Crit Care Med 1996; 24:1189. 5. di Constanzo J, Noirclerc M, Jouglard J, et al: New therapeutic approach to corrosive burns of the upper gastrointestinal tract. Gut 1980; 21:370. 6. Ferguson MK, Migliore M, Staszak VM, et al: Early evaluation and therapy for caustic esophageal injury. Am J Surg 1989; 157:116. 7. Gabow PA, Anderson RJ, Potts DE, et al: Acid-base disturbances in the salicylate-intoxicated adult. Arch Intern Med 1978; 138:1481. 8. Gerkin R, Sergen KC, Curry SC, et al: Life-threatening airway obstruction from rattlesnake bite to the tongue. Ann Emerg Med 1987; 16:813. 9. Gronert GA, Theye RA: Pathophysiology of hyperkalemia induced by succinylcholine. Anaesthesiology 1975; 43:89. 10. Hawkins DB, Demeter MJ, Barnett TE: Caustic ingestion: Controversies in management: A review of 214 cases. Laryngoscope 1980; 90:98. 11. Hoffman RS, Morasco R, Goldfrank LR: Administration of purified human plasma cholinesterase protects against cocaine toxicity in mice. J Toxicol Clin Toxicol 1996; 34:259. 12. Jay SJ, Johanson WG, Pierce AK: Respiratory complications of overdose with sedative drugs. Am Rev Respir Dis 1975; 112:591. 13. Middelkamp JN, Cone AJ, Ogura JH, et al: Endoscopic diagnosis and steroid and antibiotic therapy of acute lye burns of the esophagus. Laryngoscope 1961; 71:1354. 14. In: Miller RD, ed. Anesthesia, 4th ed. New York: Churchill Livingstone; 1994:427. 15. In: Miller RD, ed. Anesthesia, 4th ed. New York: Churchill Livingstone; 1994:472-473. 16. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med 1987; 16:215. 17. Sharma PK, Yium JJ: Angioedema associated with angiotensin II receptor antagonist losartan. South

Med J 1997; 90:552. 18. Shih RD, Hollander JE, Burstein JL, et al: Clinical safety of lidocaine in patients with cocaine-associated myocardial infarction. Ann Emerg Med 1995; 26:702. 19. Wang PK, Wang HW, Lin JK, et al: Late-onset life-threatening angioedema and upper airway obstruction caused by angiotensin-converting enzyme inhibitor: Report of a case. Ear Nose Throat J 1997; 76:404.

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Chapter 3 – Advanced Life Support in the Poisoned Patient (TOX ACLS)
THOMAS G. MARTIN

INTRODUCTION
A basic tenet of medical toxicology is that most poisonings can be adequately managed with standard supportive care. Standard supportive care for critically ill patients often follows the advanced cardiac life support (ACLS) algorithms published by the American Heart Association (AHA).[20] The fact that most poisonings respond adequately to conventional care may be true only because most poisonings are not very severe. Evidence suggests that standard supportive care may not be adequate for critically ill poisoned patients. The infrequent occurrence of severe life-threatening poisonings is a major obstacle to clinical research in this area. Resuscitation recommendations for severe poisonings are based on data derived primarily from small case series, complex case reports, and animal studies. Many basic questions have not been well studied, and most remain unanswered. The purpose of this chapter is to introduce toxicologyoriented (TOX) ACLS; that is, modifications of or additions to standard ACLS algorithms for critically ill poisoned patients. The topics are discussed using a problem-oriented, rather than a toxin-oriented, approach. When one manages a severe or unusual poisoning, a medical toxicologist or certified regional poison information center should be consulted unless the physician is especially experienced with and knowledgeable about these special cases.

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BASIC LIFE SUPPORT
Airway Management The fundamental principles of airway management also apply to poisoned patients (see Chapter 2 ). Because poisoned patients can deteriorate rapidly, frequent reassessment of airway protection and ventilation is necessary (see Chapter 2 ). Aspiration pneumonia is a common complication that may be avoided with appropriate airway management. Ensuring an adequate airway and ventilation is basic life support and ideally should begin during prehospital care. However, administration of opioid antagonists is indicated prior to intubating patients with suspected drug-induced coma. Reversal of benzodiazepine intoxication is more hazardous than reversal of opioid intoxication; therefore, the routine inclusion of flumazenil in the “coma cocktail,” the protocol used in a comatose patient, is not recommended. When one uses opioid or benzodiazepine antagonists, the recommended endpoint is arousal of the patient to the point where intubation is not required, but not complete arousal. By titrating the dose of antagonist and leaving the patient with some degree of residual sedation, acute withdrawal may be avoided. Successful reversal of heroin-induced respiratory depression almost always occurs with total doses of less than 2 mg of naloxone. Synthetic or semisynthetic opioid poisoning may be more resistant to opioid antagonists. “China white” and other illicit fentanyl analogs are notoriously resistant to opioid antagonists. As much as 10 mg of naloxone has been required for adequate reversal in rare cases. Titration to higher total doses of opioid antagonists is indicated when an opioid overdose is strongly suspected and there has been an inadequate response to the usual doses. In Emergency Medical Service (EMS) systems in which opioidpoisoned patients are not permitted to sign out against medical advice in the field, application of restraints prior to opioid reversal may be prudent. In some EMS systems, naloxone is administered intramuscularly first, then intravenously. The intramuscular dose is more slowly absorbed and so reduces the risk of relapse. Rapid-sequence intubation to prevent aspiration pneumonia is recommended prior to performing gastric lavage on an obtunded or comatose patient. Prolonged Resuscitation In the usual ACLS cases, cardiopulmonary resuscitation (CPR) is terminated within 30 min unless signs of viability of the central nervous system are present. One reason for this is that cerebral blood flow has been shown to drop dramatically with prolonged CPR in animal models of cardiac arrest. However, recovery that includes good neurologic outcome has been reported in cases of severe poisoning requiring prolonged CPR that extended to periods of up to 3 to 5 hours. [88][99][108] One hypothesis is that the marked vasodilation associated with many types of severe poisoning prevents the severe vasoconstriction seen in standard CPR cases. Prolonged CPR is frequently warranted in poisoned patients who have had a witnessed cardiac arrest.

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ADVANCED LIFE SUPPORT
Hyperadrenergic States (Tachycardia and Hypertension) Severe tachycardia may cause hypotension, high-output heart failure, or myocardial ischemia and infarction, especially in susceptible populations. Synchronized cardioversion for hemodynamically significant supraventricular tachycardia may be appropriate for patients with primary cardiac disease, but it should be avoided in severely poisoned patients. Drug-induced, hemodynamically significant tachycardia is very likely to recur after cardioversion, so rate control with pharmaceutical agents (specific antagonists when available) is preferred. For example, physostigmine (Antilirium) is indicated for hemodynamically significant tachycardia associated with pure anticholinergic poisoning.[86] Benzodiazepines such as diazepam or lorazepam are generally safe and effective for chest pain, hypertension, or tachycardia associated with drug-induced hyperadrenergic states. However, deep sedation requiring respiratory assistance must be avoided. In experimental patients undergoing cardiac catheterization, nitroglycerin and phentolamine have been shown to reverse cocaine-induced vasoconstriction, whereas labetalol had no effect and propranolol worsened it.[9][11][68][69] Conventional pharmacologic treatment of hypertension and chest pain may also be effective. In general, short-acting agents are preferred because the hyperadrenergic effects may be short-lived or followed by cardiovascular depression in severe poisonings. The use of ß-adrenergic receptor antagonists for severe sympathomimetic poisonings is controversial. In one case of acute cocaine toxicity, the use of propranolol (a nonselective ß2-adrenergic receptor antagonist) was followed by worsened hypertension. In this case ß2-adrenergic receptor blockade may have led to unopposed a-adrenergic receptor stimulation.[97] Esmolol and metoprolol (ß1- but not ß2-adrenergic receptor antagonists) should not worsen hypertension and may be used to treat drug-induced tachycardia, but not hypertension.[102] Esmolol has the advantage of a very short half-life, which allows its adverse effects to disappear within minutes. Labetalol (a nonselective ß-adrenergic receptor antagonist with weak a-adrenergic receptor antagonist properties and ß2-adrenergic receptor agonistic properties) has been reported to be effective in case reports of cocaine toxicity and other hyperadrenergic states.[22][24][30][78] The ß-adrenergic receptor antagonists must be used cautiously in drug-induced hyperadrenergic states, and a medical toxicology consultation is warranted when one is uncertain of their appropriate indications or utilization. Cardioversion and Defibrillation Electrical cardioversion is appropriate for drug-induced, hemodynamically significant tachycardias and for less severe cases that are refractory to pharmacologic therapy and overdrive pacing. Bradycardias In the ACLS bradycardia algorithm, atropine, pacing, dopamine, epinephrine, and isoproterenol are recommended in sequence for hemodynamically significant or “symptomatic” bradycardia. In bradycardias due to severe poisoning by digoxin, calcium channel antagonists, or ß-adrenergic receptor antagonists,

atropine may be ineffective even in high doses.[50][98][118] In drug-induced, symptomatic bradycardia, many authors have cautioned that isoproterenol (a nonselective ß-adrenergic receptor agonist) may induce or aggravate hypotension (ß2 effect) and ventricular dysrhythmias (ß1 effect). However, such aggravation of hypotension or induction of dysrhythmias has been documented only infrequently.[103] In fact, in massive ß-adrenergic receptor antagonist poisonings, very high-dose isoproterenol therapy has been effective.[1][44][71][113] Isoproterenol appears to be indicated only in acute ßadrenergic receptor antagonist poisonings. Drug-induced, symptomatic bradycardia refractory to atropine is an indication for cardiac pacing (electrical). In some cases, short periods of external cardiac pacing may provide adequate support. When external pacing is poorly tolerated or electrical capture is difficult to maintain, transvenous pacing is indicated. Prophylactic transvenous pacemaker placement is not recommended because the catheter tip may trigger ventricular dysrhythmias when the endocardium is irritable. When the pacemaker fails to capture, repositioning the tip (under fluoroscopy if necessary) may regain capture. In very severe poisonings, the myocardium may fail to capture, even when properly located and with the highest voltage settings. In cases of drug-induced, hemodynamically significant bradycardia resistant to atropine and pacing, vasopressors with greater ß-adrenergic receptor agonist activity are indicated ( Table 3–1 ). In cases refractory to conventional therapy, more heroic measures may be indicated such as high-dose vasopressors or circulatory assist devices (see the later section).

Table 3-1 -- Doses and Properties of Standard Vasopressor Agents Drug Usual Dosage Alpha Beta Dopamine (Intropin) Dobutamine (Dobutrex) Epinephrine (Adrenalin) Norepinephrine (Levophed) Phenylephrine (Neo-Synephrine) 2.5–20 µg/kg/min 2–20 µg/kg/min 2–10 µg/min (0.1 to 1.0 µg/kg/min) 0.5–30 µg/min (0.1 µg/kg/min) Initial: 100–180 µg/min Maintenance: 40–60 µg/min ++ + ++ +++ +++ ++ +++ +++ ++ +

In acute organophosphate or carbamate poisoning, successful management of severe cholinesterase inhibition may require atropine in doses much greater than the maximum parasympatholytic dose of 2–3 mg recommended in ACLS guidelines. The recommended adult starting dose for insecticide poisoning is 2–4 mg. In a case of severe insecticide poisoning, approximately 20 g of atropine over 24 h was required.[33] Atropine cannot reverse the severe nicotinic effects seen with organophosphate insecticides (i.e., muscle paralysis and fasciculations), and pralidoxime will be required. Digoxin-specific Fab antibody fragments have been shown to be extremely effective therapy for severe digoxin and cardiac glycoside poisoning. [2] Digoxin-induced, life-threatening ventricular dysrhythmias and conduction blocks are appropriate indications for Fab antibody fragments. A high potassium level in digoxin

intoxication is a sign of severe potassium sodium ATPase blockade and is an indication for use of Fab antibody fragments when other causes of hyperkalemia (e.g., renal failure) are unlikely.[8] Debatable indications include very high (>10 ng/mL), steady-state (more than 8–10 hr after ingestion) digoxin levels and very large ingested doses (>10 mg in adults). Digoxin levels drawn before a steady state is achieved are not useful predictors of outcome. Patients with digoxin levels as high as 20 ng/mL drawn just hours after an overdose may remain asymptomatic without therapy. Ventricular Dysrhythmias (Tachycardia and Fibrillation) Antidysrhythmics Standard ACLS treatment of unstable, monomorphic ventricular tachycardia involves defibrillation, epinephrine, lidocaine, bretylium, magnesium, procainamide, and sodium bicarbonate. Procainamide (a type Ia antidysrhythmic) may exacerbate cardiovascular toxicity in poisonings by cyclic antidepressants because of its similar antidysrhythmic properties, although there are no studies (in vitro or in vivo) of procainamide use in poisoning by cyclic antidepressants. In some animal models, lidocaine exacerbated the cardiac or central nervous system toxicity of cocaine,[4][21] but in other models lidocaine reduced toxicity.[35][39][72][120] In cocaine users with chest pain, lidocaine was reportedly used frequently, and without adverse effects, to treat ventricular dysrhythmias.[106] Earlier investigators suggested that phenytoin was indicated for ventricular dysrhythmias due to cyclic antidepressant poisonings, but more recent investigators have questioned its efficacy and safety.[13][83] Although bretylium tosylate has been recommended for refractory cases of druginduced ventricular tachycardia or fibrillation, there are few data to support its use. Magnesium has shown conflicting results in a rat model of poisoning by a cyclic antidepressant, but it may also aggravate druginduced hypotension.[56][62] Magnesium was also effective in an animal model of epinephrine-induced dysrhythmias.[82] In most types of drug-induced monomorphic ventricular tachycardia or fibrillation, lidocaine is the antidysrhythmic of choice. Certain acute poisonings are associated with elevated catecholamine levels (e.g., amphetamines, methamphetamines, cocaine, cyclic antidepressants, caffeine, theophylline, monoamine oxidase inhibitors). In poisonings in which high catecholamine levels are suspected, the role of epinephrine in the management of refractory ventricular fibrillation is questionable. The current ACLS recommendation in these cases—to avoid high-dose epinephrine therapy and to increase the interval between doses—seems prudent. Furthermore, in such poisonings, ß-adrenergic receptor blockade may be beneficial for refractory ventricular tachycardia or fibrillation.[7][28][29][111] The current ACLS recommendation of propranolol, 1 mg over 1 min, for refractory ventricular fibrillation associated with hyperadrenergic poisonings may be excessive and may lead to significant hemodynamic deterioration. Torsades de pointes is a type of atypical (polymorphic) ventricular tachycardia characterized by a ventricular axis that gradually swings between positive and negative values ( Fig. 3–1 ). The mechanism of druginduced torsades de pointes is not known with certainty but is believed to be delayed repolarization and associated early after-depolarizations.[18] A prolonged QT interval is a sign of delayed repolarization. Increased QT dispersion is a sign of abnormal repolarization and may be a more reliable indicator than QT prolongation.[43] Torsades de pointes has been associated with both therapeutic and toxic drug exposures. Many drugs have been implicated in torsades de pointes ( Table 3–2 ). Imperfect elimination of these drugs due to renal or hepatic impairment (depending on route of elimination), specific hepatic enzyme inhibition (e.g., imidazole antifungals such as ketoconazole or macrolide antibiotics such as erythromycin), or hypothyroidism may predispose a patient to torsades de pointes. Correctable factors that increase the risk of

torsades de pointes include hypoxemia, hypokalemia, and hypomagnesemia.

Figure 3-1 Torsades de pointes. (From Chou T-C: Electrocardiography in Clinical Practice: Adult and Pediatric, 4th ed. Philadelphia, WB Saunders, 1996, p 430.)

Table 3-2 -- Drugs Associated with Torsades de Pointes Antihistamines Astemizole, terfenadine, terodiline Butyrophenones Droperidol, haloperidol Class Ia antidysrhythmics Disopyramide, N-acetyl-procainamide (NAPA), procainamide, quinidine Class III antidysrhythmics Amiodarone, almokalant, sotalol Metals Antimony, arsenic Macrolides Erythromycin, clarithromycin, spiramycin Organophosphates Phenothiazines Chlorpromazine, mesoridazine, thioridazine Other Adenosine, bepridil, cisapride, fluoride, ibutilide, pentamidine, pimozide, propafenone, quinine, vasopressin

Recommended treatments for drug-induced torsades de pointes include correcting risk factors as well as providing electric and pharmacologic therapy. Magnesium has been recommended for polymorphic ventricular tachycardia, even when magnesium levels in the blood are normal.[49][90][114] The AHArecommended loading dose of magnesium sulfate is 1–2 g over 1–2 min with a maintenance dose of 1 g/hr titrated to rhythm suppression. The usual total magnesium dose needed to extinguish this rhythm is 4–6 g. Adverse effects of magnesium include hypotension and respiratory depression. It is not yet known whether these doses of magnesium are either effective or safe in critically poisoned patients. In experimental studies of torsades de pointes, lidocaine has had mixed results.[3][15] Prehospital data suggest that polymorphic ventricular tachycardia and monomorphic ventricular tachycardia respond to lidocaine.[10]
Pacing

Electric and pharmacologic cardiac pacing may be indicated in critically poisoned patients with asystole, hemodynamically significant bradycardias, or torsades de pointes.[16][45][109][112] External electrical pacing is quicker and easier and should be considered first.[48] Because external pacing is often painful for conscious patients, makes it difficult to maintain capture for prolonged periods, and may interfere with patient care, it should be replaced with internal pacing when time permits. Electrical (overdrive) pacing at rates up to 100–120 beats/min is usually effective in terminating torsades de pointes. Pharmacologic overdrive pacing has been recommended with isoproterenol, as well. However, isoproterenol may aggravate the hypotension or ventricular dysrhythmias associated with some acute poisonings.
Hypertonic Saline and Systemic Alkalinization

Type I antidysrhythmics (fast, inward sodium channel antagonists) decrease the influx of sodium during phase 0 of the action potential in nonpacemaker myocytes. Subsequently, poisonings with sodium channel antagonists (membrane stabilizing agents) result in a prolonged action potential and prolonged ventricular conduction (an increased QRS interval), predisposing to monomorphic ventricular tachycardia. Modalities such as hypertonic saline and systemic alkalinization have been shown to reverse these adverse electrophysiologic effects and to prevent or terminate ventricular tachycardia secondary to many types of poisoning caused by sodium channel blocking agents.[12] Hypertonic sodium bicarbonate provides both hypertonic saline and systemic alkalinization and has been shown to be more beneficial than either modality individually in several, though not in all, types of sodium channel antagonist toxicity. Beneficial effects of hypertonic sodium bicarbonate have been reported in serious poisonings with sodium channel antagonists such as cyclic antidepressants,[85][89][104] cocaine,[5][21] propranolol,[51] diphenhydramine,[17][25] type Ia[55] and Ic[54][64] antidysrhythmics, and propoxyphene.[110] When used in severe poisonings, the goal is an arterial pH of 7.50–7.55. Respiratory alkalosis can be used as a temporizing measure until the appropriate degree of metabolic alkalosis can be attained with sodium bicarbonate. Systemic alkalinization can be achieved by means of repetitive administration of 1–2 mEq/kg of sodium bicarbonate as needed to achieve the desired arterial pH. This degree of alkalinization is maintained via a titrated infusion of an alkaline solution (i.e., three ampules of sodium bicarbonate (150 mEq) and potassium chloride (30 mEq) in 850 mL of D5W), although use of this constant infusion is now disputed.
Potassium

Hypokalemia is a risk factor for ventricular dysrhythmias and a well-recognized sequela of both

hyperadrenergic states and alkalinization. Hyperadrenergic states induce hypokalemia as a result of excessive ß2-adrenergic receptor stimulation. Alkalinization induces hydrogen ions to leave the cells in exchange for potassium, which enters the cells, causing an intracellular potassium shift. Potassium should be supplemented during alkalinization to avoid the theoretic increased risk of ventricular dysrhythmias. Accordingly, potassium chloride, 30–40 mEq, may be added to each liter of bicarbonate solution. Excessive potassium administration (rate or amount) may result in significant myocardial depression and must be carefully avoided. Even with normal potassium levels, potassium supplementation has been recommended in torsades de pointes.[36] Shock Vasopressor Agents Shock secondary to critical poisoning commonly results from decreases in intravascular volume, systemic vascular resistance (SVR), myocardial contractility, or a combination of factors ( Table 3–3 ). Initial treatment usually includes correction of clinically suspected hypovolemia and a fluid challenge. Cardiotoxic agents often reduce a patient’s ability to handle aggressive volume loading, especially in those with underlying cardiopulmonary disease. [6] Excess fluid therapy may result in fluid overload and iatrogenic congestive heart failure, even in young and previously healthy patients. When shock persists despite initial volume loading, a vasopressor is indicated. Many prefer to start with dopamine. Some of dopamine’s pressor effects are indirect (it stimulates the release of norepinephrine stores), so it may not be effective when norepinephrine stores are depleted such as in poisoning by a cyclic antidepressant or monoamine oxidase inhibitor. Nonetheless, dopamine has been shown to be effective in mild to moderate poisoning by a cyclic antidepressant.[115] In severe cases of cyclic antidepressant poisoning, dopamine may not be sufficient and more potent vasopressors may be necessary.

Table 3-3 -- Typical Hemodynamic Findings in Shock Type Drug-induced (typical) Distributive ( vasodilation) Cardiogenic ( contractility) Hypovolemic Obstructive Spinal PAOP, pulmonary artery occlusion pressure; CO, cardiac output; SVR, systemic vascular resistance. PAOP CO SVR

Even though many forms of drug-induced shock are caused by decreased contractility and SVR, sometimes increased SVR is encountered. Appropriate treatment varies depending upon whether shock is present with high or low SVR. When drug-induced shock is unresponsive to correction of clinically suspected hypovolemia and moderate-dose vasopressor therapy, Swan-Ganz central hemodynamic monitoring is indicated to help guide more aggressive therapy. Once central hemodynamic monitoring has been established, the first goal is to ensure adequate preload, as indicated by a pulmonary artery occlusion pressure (PAOP) of 15–18 mmHg. When the POAP is < 18 mmHg, further volume therapy is warranted.

Once adequate preload has been attained, appropriate vasopressor selection and use of an inotrope are guided by measured cardiac output (CO) and SVR. When CO is normal or elevated and SVR is decreased (distributive shock), vasopressors with greater a-adrenergic effects are preferred (see Table 3–1 ). Because dobutamine and isoproterenol decrease SVR, these agents may be ineffective or even deleterious when used alone to treat distributive shock. When drug-induced distributive shock is refractory to standard vasopressor therapy, high-dose vasopressor therapy is indicated.[27][42][47] Conventional dose limits for vasopressors do not apply to drug-induced shock. The dose of vasopressor is titrated until the desired blood pressure is attained or adverse effects such as ventricular dysrhythmias are observed. Some poisoned patients can be adequately resuscitated only with doses of vasopressors that are far beyond the usual doses used in nonpoisoned patients. Inotropic Agents In drug-induced shock characterized by a low CO and high SVR (cardiogenic-like shock) or low SVR (typical drug-induced shock), inotropic agents may be required. Calcium, amrinone, glucagon, insulin, and isoproterenol are inotropic agents commonly used in severely poisoned patients ( Table 3–4 ). Sometimes more than one inotropic agent may be required.[75]121 These agents may increase contractility and CO, but they may also decrease SVR. Often a concomitant vasopressor is required, especially in typical druginduced shock.[63]

Table 3-4 -- Inotropic Agents Agents Amrinone Calcium Glucagon GIK Glucose (D50W) Insulin (regular) 1 g/kg 1.5 U/kg Usual Starting Dose 0.75–2.0 mg/kg SIVP 1–3 g SIVP 5–10 mg IVP

Potassium chloride 10 mEq Isoproterenol 2–20 µg/min

SIVP, slow intravenous push.
Intravenous Calcium

Intracellular calcium plays an essential role in the coupling of excitation to mechanical contraction in both the vascular smooth muscle and the heart. Conditions that result in lower cytoplasmic calcium concentrations may impair contraction. Conversely, supplemental extracellular calcium can increase the strength of contraction in these muscles. In cases of acute fluoride poisoning, calcium deficiency occurs due to the binding of calcium with fluoride. Calcium channel antagonists (including magnesium) and ß-adrenergic receptor antagonists impair calcium influx and intracellular calcium release. Although textbooks often state that calcium is contraindicated in digoxin poisoning, there are few published reports to support this statement. Calcium therapy has been shown to be beneficial for acute fluoride and calcium channel and ß-

adrenergic receptor antagonist poisonings. [41][73][80][98][116] However, the optimal dose and rate of administration of intravenous calcium has not been established for these indications. A common practice is to give up to 3 g of calcium chloride by means of slow intravenous (IV) administration. Marked reductions in blood pressure and heart rate may occur with too rapid an administration of calcium intravenously.[14] The treating physician should personally administer calcium at the bedside while monitoring heart rate and blood pressure. The recommended rate of administration is 1 g/min or slower, depending on the cardiovascular response. Calcium chloride is preferred to calcium gluconate because of higher concentrations of ionic calcium in the chloride preparation.[119] Experimental and case report data suggest that total or ionized serum calcium levels may be meaningless when intravenous calcium is administered for these indications. High-dose (>3 g) calcium delivered intravenously should be considered experimental and should be employed only as a last resort in acute poisonings.
Glucagon

Glucagon is a polypeptide hormone produced in the alpha cells of the pancreas. Glucagon’s beneficial cardiac effects include increased contractility and heart rate. These cardiotonic effects result from glucagon’s binding to nonadrenergic receptors, producing increased levels of cyclic adenosine 3',5'monophosphate (cAMP).[77] Increased cAMP levels enhance calcium uptake by the sarcoplasmic reticulum and plasma membrane. Glucagon has been reported to reverse myocardial depression caused by many types of poisonings, including ß-adrenergic receptor antagonists,[65][74] calcium channel antagonists,[23][46] imipramine,[105] ouabain,[95] procainamide,[96] and quinidine.[94] In electrophysiologic studies in human papillary muscle, glucagon has been shown to enhance the membrane responsiveness (increase the Vmax) of phase 0 of the action potential.[92][93] Thus, there is a theoretic rationale for its possible effectiveness in treating toxicity resulting from membrane-stabilizing or sodium-channel–blocking agents such as imipramine, procainamide, and quinidine. The recommended initial adult dose in acute poisonings is a 3–10 mg (0.05–0.15 mg/kg) IV bolus. The duration of effect of glucagon has been estimated to be 20–30 min.[31] If one or more boluses are effective, a glucagon infusion at 5–15 mg/hr is indicated as needed.[87][91] Use of the standard 0.2 per cent phenol diluent may worsen myocardial depression when large amounts of glucagon are utilized.[19] D5W is the recommended diluent when large doses of glucagon are given. Adverse effects of glucagon include vomiting, hyperglycemia, and hypokalemia. Glucagon may be effective in mild to moderate poisonings, but it is not always effective in very severe poisonings.
Type III Phosphodiesterase Inhibitors

Type III phosphodiesterase inhibitors are selective for heart and vascular smooth muscle. These inhibitors increase cytoplasmic cAMP and ionic calcium (as does glucagon) and thereby enhance myocardial contractility and vascular smooth muscle relaxation. Type III phosphodiesterase inhibitors consistently increase cardiac output but inconsistently increase heart rate and blood pressure. Beneficial hemodynamic effects have been reported when phosphodiesterase inhibitors were used in animal models of acute poisoning caused by ß-adrenergic receptor antagonists,[76] calcium channel antagonists,[32] barbiturates, bupivacaine, chloroquine, labetalol, procainamide, and cyclic antidepressants. Amrinone is a type III phosphodiesterase inhibitor with a recommended dose of 0.75–2.0 mg/kg IV over 2–3 min, followed, if effective, by an infusion of 5–15 µg/kg/min. The addition of a- or ß-adrenergic receptor agonists may be required to increase SVR or heart rate, respectively. In very large doses, phosphodiesterase inhibitors may be myocardial depressants and dysrhythmogenic, and the maximum safe and effective dose is not known

for cases of severe poisoning.
Insulin Pump or Glucose-Insulin-Potassium (GIK)

The positive inotropic properties of insulin have been recognized for many years. [101] Glucose was added to prevent hypoglycemia, and potassium to avoid the associated hypokalemia; together, they are known by the acronym GIK. GIK has been reported to counteract the negative inotropic effects of ß-adrenergic receptor antagonists,[53][66][100][101] calcium channel antagonists,[52][57][59][61] ouabain, and halothane. The exact mechanism by which insulin enhances inotropy is uncertain. Verapamil inhibits myocardial fatty acid uptake, induces systemic insulin resistance, and blocks insulin release, which leads to myocardial nutrient deprivation that contributes to clinically relevant negative inotropy.[58][60] In verapamil-poisoned animals, insulin-induced increases in myocardial carbohydrate uptake were associated with positive inotropic effects.[57] Insulin improves systolic and diastolic heart function (increased end-systolic elastance and myocardial mechanical efficiency) during aerobic shock and accelerates in vivo myocardial lactate oxidation without increasing glucose uptake.[59] Thus, insulin-glucose treatment increases myocardial contractile function independent of increased sugar transport. Although insulin or GIK therapy appears to enhance contractility, it may also decrease SVR. Because of its vasodilatory properties, combination with a vasopressor may be necessary in critical poisonings. Sufficient glucose and insulin must be given to stimulate myocardial glucose uptake and glycolysis. The recommended initial dosages are dextrose 50 per cent, 1 g/kg; regular insulin, 1.5 U/kg; and potassium, 10 mEq. The initial dose of insulin is followed by a constant infusion at 0.5–1.0 U/kg/hr with dextrose and potassium supplementation as needed to avoid hypoglycemia and hypokalemia. The use of GIK is promising, but further studies must be performed before it can be recommended as first-line therapy. Circulatory Assist Devices In fatal poisonings, death results from failure to maintain adequate perfusion of vital organs. Intra-aortic balloon pumps (IABPs) and cardiopulmonary bypass circuits are circulatory assist devices that have been used successfully in critical poisonings. Along with providing life support, these devices may enhance tissue perfusion and thereby increase drug distribution and elimination. Circulatory assist devices may permit hemodialysis and perfusion in patients who would otherwise be too hypotensive. Because these techniques are expensive, require a large staff, and have significant associated morbidity, they should be employed only in cases refractory to maximal medical supportive care. To be effective, they must be employed rapidly, before the irreversible effects of severe shock have occurred. Agreement about the initiation criteria and procedures for these techniques must be reached in advance with the appropriate cardiology and cardiothoracic surgery services. The most widely used circulatory assist device is the IABP. The IABP can be inserted in any critical care area of a hospital, including the emergency department. A disadvantage of the IABP is the need for an intrinsic cardiac rhythm for synchronization and optimal augmentation. Successful resuscitation with an IABP has been reported for many types of severe poisonings, such as quinidine,[107] propranolol,[67] and antihistamine[26] poisonings. Emergency cardiopulmonary bypass and extracorporeal life support do not require an intrinsic rhythm to augment perfusion. Recent technologic advancements have made rapid application through peripheral vessels possible in critical care areas of a hospital. Extracorporeal life support has been utilized in successful resuscitations of patients with very severe poisonings, including poisoning by verapamil, [40] propranolol[84] and cyclic antidepressants.[34][70][79][81] In some cases, the patient was

eventually weaned from the circuits and demonstrated good neurologic recovery.

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BRAIN DEATH AND ORGAN DONATION CRITERIA
Electroencephalograms and neurologic examinations do not provide valid criteria for proof of brain death during acute toxic encephalopathy and can be applied only when drug levels are no longer toxic. In the presence of toxic drug levels, the only valid criterion for ascertaining brain death is the absence of cerebral blood flow. Successful transplantation has been reported in cases of organ donation from victims of fatal poisoning caused by acetaminophen, cyanide, methanol, and carbon monoxide.[38] However, failures suspected to be the result of irreversible end-organ damage (direct or indirect) have also been reported. In general, the overall success rate of transplantation from poisoned donors is comparable to that from nonpoisoned donors.[37] Organ transplantation following a fatal poisoning by agents capable of severe endorgan damage (e.g., carbon monoxide, cocaine, iron) is controversial but may be appropriate in donors who are thoroughly evaluated. SUMMARY Utilization of standard AHA ACLS protocols for critically poisoned patients may not result in optimal outcomes. In a small but significant proportion of cases, rapid administration of specific antidotes may result in dramatic improvement. In critical poisonings that do not respond to conventional therapy, a more toxicology-oriented type of ACLS (TOX ACLS) may be effective. Elements of TOX ACLS not usually included in standard ACLS protocols include higher doses of standard drugs, nonstandard drugs (amrinone, calcium, esmolol, glucagon, glucose-insulin-potassium (GIK), metoprolol, phenylephrine, physostigmine, and sodium bicarbonate) and nonstandard techniques such as prolonged CPR and circulatory assist devices. Proper application of TOX ACLS techniques requires basic understanding of the pathophysiology of acute poisonings. In some cases in which resuscitation after a critical poisoning failed, organ donation has been successful. Care of critically poisoned patients can be enhanced through consultation with a medical toxicologist or a regional poison information center.

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68. Lange RA, Cigarroa RG, Clyde WY, et al: Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989; 321:1557-1562. 69. Lange RA, Cigarroa RG, Flores ED, et al: Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990; 112:897-903. 70. Larkin GL, Graeber GM, Hollingsed MJ: Experimental amitriptyline poisoning: Treatment of severe cardiovascular toxicity with cardiopulmonary bypass. Ann Emerg Med 1994; 23:480-486. 71. Lewis M, Kallenbach J, Germond C, et al: Survival following massive overdose of adrenergic blocking agents (acebutolol and labetalol). Eur Heart J 1983; 4:328-332. 72. Liu D, Hariman RJ, Bauman JL: Cocaine concentration-effect relationship in the presence and absence of lidocaine: Evidence of competitive binding between cocaine and lidocaine. J Pharmacol Exp Ther 1996; 276:568-577. 73. Love JN, Hanfling D, Howell JM: Hemodynamic effects of calcium chloride in a canine model of acute propranolol intoxication. Ann Emerg Med 1996; 28:1-6. 74. Love JN, Howell JM: Glucagon therapy in the treatment of symptomatic bradycardia. Ann Emerg Med 1997; 29:181-183. 75. Love JN, Leasure JA, Mundt DJ: A comparison of combined amrinone and glucagon therapy to glucagon alone for cardiovascular depression associated with propranolol toxicity in a canine model. Am J Emerg Med 1993; 11:360-363. 76. Love JN, Leasure JA, Mundt DJ, et al: A comparison of amrinone and glucagon therapy for cardiovascular depression associated with propranolol toxicity in a canine model. J Toxicol Clin Toxicol 1992; 30:399-412. 77. MacLeod KM, Rodgers RL, McNeil JH: Characterization of glucagon-induced changes in rate, contractility and cyclic AMP levels in isolated cardiac preparations of the rat and guinea pig. J Pharmacol Exp Ther 1981; 217:798-804. 78. Mariani PJ: Pseudoephedrine-induced hypertensive emergency: Treatment with labetalol. Am J Emerg Med 1986; 4:141-142. 79. Martin TG, Klain MM, Molner RL, et al: Extracorporeal life support vs thumper after lethal desipramine OD. [Abstract.] Vet Hum Toxicol 1990; 32:349. 80. Martin TG, Menegazzi JJ, Perel HM, et al: Extraordinary medical therapy for severe verapamil overdose. [Abstract]. Ann Emerg Med 1992; 21:627. 81. Martin TG, O’Connell JJ, Pentel P, et al: Resuscitation from severe cyclic antidepressant toxicity using cardiopulmonary bypass. [Abstract.] Vet Hum Toxicol 1988; 30:354. 82. Mayer DB, Miletich DJ, Feld JM, et al: The effects of magnesium salts on the duration of epinephrineinduced ventricular tachyarrhythmias in anesthetized rats. Anesthesiology 1989; 71:923-928. 83. Mayron R, Ruiz E: Phenytoin: does it reverse tricyclic-antidepressant–induced cardiac conduction abnormalities?. Ann Emerg Med 1986; 15:876-880.

84. McVey FK, Corke CF: Extracorporeal circulation in the management of massive propranolol overdose. Anaesthesia 1991; 46:744-746. 85. Nattel S, Mittleman M: Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. J Pharmacol Exp Ther 1984; 231:430-435. 86. Nickalls RW, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning. [Translation.] Anaesthesia 1988; 43:776-779. 87. O’Mahony D, O’Leary P, Molloy MG: Severe oxprenolol poisoning: The importance of glucagon infusion. Hum Exp Toxicol 1990; 9:101-103. 88. Orr DA, Bramble MG: Tricyclic antidepressant poisoning and prolonged external cardiac massage during asystole. Br Med J 1981; 282:1107-1108. 89. Pentel P, Benowitz N: Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. J Pharmacol Exp Ther 1984; 230:12-19. 90. Perticone F, Ceravolo R, De Novara G, et al: New data on the antiarrhythmic value of parenteral magnesium treatment: Magnesium and ventricular arrhythmias. Magnes Res 1992; 5:265-272. 91. Peterson CD, Leeder JS, Sterner S: Glucagon therapy for beta-blocker overdose. Drug Intell Clin Pharm 1984; 18:394-398. 92. Prasad K: Glucagon-induced changes in the action potential, contraction, and Na+-K+-ATPase of cardiac muscle. Cardiovasc Res 1975; 9:355-365. 93. Prasad K: Electrophysiologic effects of glucagon on human cardiac muscle. Clin Pharmacol Ther 1975; 18:22-30. 94. Prasad K: Use of glucagon in the treatment of quinidine toxicity in the heart. Cardiovasc Res 1977; 11:55-63. 95. Prasad K, Desousa HH: Glucagon in the treatment of ouabain-induced cardiac arrhythmias in dogs. Cardiovasc Res 1972; 6:333-343. 96. Prasad K, Weckworth P: Glucagon in procainamide-induced cardiac toxicity. Toxicol Appl Pharmacol 1978; 46:517-528. 97. Ramoska E, Sacchetti AD: Propranolol-induced hypertension in treatment of cocaine intoxication. Ann Emerg Med 1985; 14:1112-1113. 98. Ramoska EA, Spiller HA, Winter M, et al: A one-year evaluation of calcium channel blocker overdoses: Toxicity and treatment. Ann Emerg Med 1993; 22:196-200. 99. Ramsey ID: Survival after imipramine poisoning. Lancet 1967; 2:1308-1309. 100. Reikeras O, Gunnes P, Sorlie D, et al: Metabolic effects of low and high doses of insulin during betareceptor blockade in dogs. Clin Physiol 1985; 5:469-478. 101. Reikeras O, Gunnes P, Sorlie D, et al: Haemodynamic effects of insulin and beta receptor blockade

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Uncited reference Visscher MB, Muller EA: The influence of insulin upon the mammalian heart. J Physiol 1927; 62:341-348.

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

Chapter 4 – Focused Physical Examination/Toxidromes
COLLEEN O’NEIL DAVIS PAUL M. WAX Many toxic exposures cause characteristic physical findings that are detectable by a carefully focused physical examination. This aspect of the evaluation of a poisoned patient is particularly important when a reliable history cannot be obtained. In the case of a patient who is unresponsive or delirious, the physical examination may provide the only clues to the presence of a toxin. This chapter discusses characteristic clinical manifestations of toxins, including effects on vital signs, mental status, pupils, skin, hair, oral cavity, and gastrointestinal tract. It also reviews the five common “toxidromes”—constellations of physical findings that characterize poisoning with anticholinergic, sympathomimetic, opioid, anticholinesterase, and sedative-hypnotic agents.[59] These hallmark physical findings often prove invaluable during the early assessment of an overdosed patient, even when only a few of the features of a specific toxidrome are present.

FOCUSED PHYSICAL EXAMINATION: VITAL SIGNS
The physical examination begins with a full set of vital signs which should be performed immediately upon presentation to the emergency department. Pulse oximetry is a valuable “fifth vital sign” that may provide valuable information. Temperature Exposure to various toxins can result in hyperthermia or hypothermia ( Tables 4–1 and 4–2 ). Accurate measurement of the core temperature is essential in all patients with temperature disturbances. Because the maximal temperature range for standard thermometers is 32°C to 43°C, special high- and low-recording thermometers are needed to measure the core temperature in patients with suspected extreme temperature abnormalities. Once the diagnosis of hyperthermia or hypothermia has been established, the core temperature should be continuously monitored.

Table 4-1 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hyperthermia Increased Heat Production Excessive muscle activity and muscle tone Amphetamines Anticholinergics Cocaine Cyclic antidepressants

Lysergic acid diethylamide (LSD) Methylenedioxymethamphetamine (MDMA), other designer amphetamines Monoamine oxidase inhibitors (MAOIs) Phencyclidine (PCP) Strychnine Withdrawal from ethanol and sedative-hypnotics Uncoupling of oxidative phosphorylation Arsenic Dinitrophenol Pentachlorophenol Salicylates Increased metabolic rate Thyroid hormones Decreased Heat Loss Impaired sweating Anticholinergics Antihistamines Cyclic antidepressants Phenothiazines Vasoconstriction Sympathomimetics Amphetamines Cocaine Ephedrine Phenylephrine Phenylpropanolamine Pseudoephedrine Other Malignant hyperthermia Halothane Succinylcholine Neuroleptic malignant syndrome Haloperidol

Fluphenazine Trifluoperazine Serotonin syndrome Dextromethorphan–MAOI interaction Meperidine–MAOI interaction Selective serotonin reuptake inhibitor (SSRI)–MAOI interaction SSRI overdose Metal fume fever Copper oxide fumes Zinc oxide fumes Hydrocarbon aspiration Gasoline Lamp oil

Table 4-2 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypothermia Vasodilation Cyclic antidepressants Ethanol Phenothiazines Impaired perception of cold Carbon monoxide Ethanol Opioids Sedative-hypnotics Depressed hypothalamic/central nervous system function Barbiturates Ethanol Opioids Phenothiazines Sedative-hypnotics Substrate depletion Ethanol Insulin

Oral hypoglycemics Decreased heat production or metabolic activity Beta-adrenergic receptor antagonists Cyanide Hydrogen sulfide Organophosphates Hyperthermia
Pathophysiology.

The thermoregulatory center in the hypothalamus maintains body temperature at a set-point of 37°C (98.6°F) by regulating sweating, vasodilation, and shivering. [8] Hyperthermia occurs when the body temperature has risen higher than the normal thermal set-point, whereas fever occurs when the thermal setpoint has been increased. Both hyperthermia and fever occur as consequences of drug overdose. Elevation of body temperature in the setting of drug overdose may be due to increased heat production, decreased heat loss, or fever related to the pyrogenic effects of drugs or their diluents. Mechanisms of increased heat production include increased muscle activity or muscle tone, uncoupling of oxidative phosphorylation, and increased metabolic rate. The ability to lose heat is adversely affected by impairment of sweating, extreme vasoconstriction, and impairment of cardiac function. Pyrogens such as drugs, bacteria, viruses, and fungi raise the thermal set-point in the preoptic area of the anterior hypothalamus, causing fever.[46] Pyrogens are also released from endogenous sources by stimulation of neutrophils, monocytes, and Kupffer cells.
Hyperthermia Associated with Drugs and Toxins.

Excessive heat production follows exposure to toxins that cause agitation, muscular hyperactivity, seizures, and increased muscle tone. Common examples of drugs that do this include amphetamines,[27] cocaine,[58] lysergic acid diethylamide (LSD), phencyclidine, cyclic antidepressants, antihistamines, monoamine oxidase inhibitors (MAOIs), and strychnine.[10] Fatal hyperthermia has been associated with methylenedioxymethamphetamine (MDMA) use and dancing at rave parties.[36] Tremors associated with withdrawal from ethanol, barbiturates, and other sedative-hypnotics also increase temperature by this mechanism. Even therapeutic doses of drugs may cause an elevation of body temperature during heavy exercise, infection, or exposure to a warm environment. Heat stress in the setting of therapeutic dosing of aadrenergic receptor agonists, including over-the-counter pseudoephedrine or phenylpropanolamine, has resulted in life-threatening hyperthermia. [6][43] Impaired sweating due to the anticholinergic effects of antihistamines, cyclic antidepressants, phenothiazines, and belladonna alkaloids may also cause significant hyperthermia. Salicylates, dinitrophenol, and pentachlorophenol cause an increase in body heat production by uncoupling oxidative phosphorylation. Overdose of exogenous thyroid hormone raises body temperature by increasing the basal metabolic rate.

“Drug fever” typically occurs 7 to 10 days after initiation of a new drug, although it may have many patterns. It resolves within 48 hours of discontinuing the medication and recurs withing a few hours of re-exposure.[52] Penicillins, sulfonamides, salicylates, antihistamines, barbiturates, procainamide, quinidine, methyldopa, phenytoin, isoniazid, allopurinol, and cimetidine are some of the more common drugs reported to cause drug fever in therapeutic doses. Other drug-induced etiologies of hyperthermia include malignant hyperthermia, neuroleptic malignant syndrome (NMS), and serotonin syndrome. Malignant hyperthermia is a rare autosomal dominant disorder associated with abnormal calcium regulation. It develops as a complication of general anesthesia with inhaled agents such as halothane. Severe, sudden muscle rigidity precipitates extreme hyperthermia, with tachycardia, acidosis, and hyperkalemia. NMS is seen following exposure to antipsychotic drugs that block dopaminergic receptors and after withdrawal of dopaminergic agonists such as amantadine or bromocriptine. The diagnosis of NMS is based on the presence of hyperthermia, increased muscle tone, altered mental status, and autonomic dysfunction. Haloperidol, fluphenazine, and trifluoperazine are common etiologic agents of this syndrome. Acute dystonias may be associated with elevated temperature as well. The serotonin syndrome is most commonly associated with drug interactions between serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) and MAOIs or lithium.[61] The notorious combination of meperidine with an MAOI has resulted in life-threatening hyperthermia attributed to the serotonin syndrome.[11] Metal fume fever following exposure to zinc oxide and copper oxide fumes is postulated to be due to a cytokine response.[9][48] Hyperthermia that occurs during the first 12 to 24 hours following hydrocarbon exposure is due to a chemical pyrogenic response. This is distinguished from the fever caused by bacterial superinfection, which typically develops after 24 to 48 hours.
Differential Diagnosis of Hyperthermia.

The differential diagnosis of hyperthermia includes environmental exposure (heat exhaustion, heatstroke); increased motor activity due to psychosis, status epilepticus, chorea, and parkinsonism; and fever from thyrotoxicosis or infection. . Hypothermia
Pathophysiology.

Hypothermia, defined as a core temperature less than 35°C, has multiple etiologies, particularly when environmental exposure is mild.[19] Defenses against hypothermia include increased heat production by shivering and metabolic activities, vasoconstriction to reduce heat loss to the environment, and behavioral responses that include dressing and seeking shelter. Drugs and toxins induce hypothermia by causing vasodilation, impairing behavioral responses to cold, depressing hypothalamic and central nervous system (CNS) function, depleting substrates, and decreasing metabolic heat production.
Drug-Induced Hypothermia.

Ethanol, a common cause of toxin-related hypothermia, impedes shivering, causes vasodilation, depresses the CNS, can cause hypoglycemia, and is a risk factor for trauma.[66] Drugs with prominent a-adrenergic receptor antagonist properties, such as phenothiazines, potentiate hypothermia by inducing vasodilation. Opioids, sedative-hypnotics, general anesthetics, phenothiazines, and carbon monoxide directly inhibit hypothalamic function. Oral hypoglycemic agents and insulin cause hypothermia by depleting substrates needed for thermogenesis. [42] Beta-adrenergic receptor antagonists interfere with the mobilization of thermogenic substrates and inhibit the ability to maintain euthermia during cold stress.[56]
Differential Diagnosis of Hypothermia.

Infections, hypoglycemia, hypothyroidism, trauma, burns, and cachexia predispose to hypothermia. The very young, very old, unconscious, immobile, and intoxicated are particularly susceptible. The term “urban hypothermia” has been used to describe two different situations: (1) a syndrome of homelessness and substance abuse that leads to exposure-related hypothermia, and (2) mild hypothermia occurring in elderly urban dwellers who are reluctant to heat their homes because of the cost.[60] Hypothermia has been noted as a presenting sign of shaken baby syndrome[54][76] and child abuse.[33] Hypothermia should be suspected in every patient with coma. Pulse The heart rate is the product of competing influences that include the sympathetic and parasympathetic nervous systems, core temperature, and endocrine function. Causes of tachycardia include sinus, supraventricular, or ventricular mechanisms. Bradycardia may be due to direct depression of myocardial pacemakers, reflex mechanisms, decreased central sympathetic outflow, parasympathomimetic effects, CNS depressant effects, and severe membrane depressant effects. Tachycardia
Drug-Induced Tachycardia.

Stimulants associated with an increased heart rate include amphetamines, caffeine, cocaine, ephedrine, and other sympatholytics; phencyclidine; and theophylline ( Table 4–3 ). Withdrawal from ethanol, barbiturates, and other sedative-hypnotic drugs increases the heart rate owing to enhanced noradrenergic stimulation. Anticholinergics and antihistamines decrease parasympathetic tone by blocking muscarinic receptors, inducing tachycardia. Poisoning with anticholinesterase agents such as organophosphate and carbamate pesticides causes tachycardia through acetylcholine stimulation of sympathetic preganglionic nicotinic receptors. Tachycardia may also be a compensatory response to bronchorrhea-induced hypoxemia. Drugs and toxins that decrease peripheral resistance (calcium channel antagonists, ethanol, iron, nitrites, arsenic, and salicylates) are associated with reflex tachycardia, as are agents that cause intravascular volume loss from vomiting, diarrhea, or bleeding (iron, salicylates, colchicine). Agents that increase myocardial sensitization to catecholamines, such as the halogenated hydrocarbons or chloral hydrate, may also precipitate tachycardia. Thyroid hormones cause tachycardia by increasing the metabolic rate.

Table 4-3 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Tachycardia Sympathomimetic–ß1-adrenergic receptor stimulation

Amphetamines Caffeine Cocaine Methylenedioxymethamphetamine (MDMA), other designer amphetamines Phencyclidine (PCP) Theophylline Withdrawal from ethanol, barbiturates, and sedative-hypnotics Acetylcholine excess Carbamates Organophosphates Therapeutic cholinesterase inhibitors (e.g., physostigmine, pyridostigmine, neostigmine) Anticholinergic-muscarinic blockade Antihistamines Belladonna-containing plants Cyclic antidepressants Lomotil (atropine and diphenoxylate) Phenothiazines Vasodilation Arsenic Calcium channel antagonists Cyclic antidepressants Disulfiram reactions Ethanol Iron Nitrites Phenothiazines Volume loss Antibiotics Arsenic (acute) Colchicine Disulfiram-ethanol interaction Iron Mushrooms (e.g., Amanita phalloides)

Opioid withdrawal Thallium Theophylline Increased metabolic rate Thyroid hormones Increased sensitivity to catecholamines Halogenated hydrocarbons Hypoxemia Carbamates Organophosphates Prodysrhythmic Amiodarone Amphetamines Arsenic Caffeine Chloral hydrate Cocaine Cyclic antidepressants Digitalis glycosides Diphenhydramine Flecainide Halogenated hydrocarbons Phenothiazines Procainamide Quinidine Thallium Theophylline Cellular asphyxia Carbon monoxide Cyanide Hydrogen sulfide Oxidizing agents Sodium azide

A number of drugs and toxins can cause ventricular tachycardia or conduction disturbances such as Q-Tc prolongation, which may precipitate atypical ventricular tachycardia, torsades de pointes, and ventricular fibrillation. Excessive doses or drug interactions with certain antidysrhythmics such as quinidine and procainamide may also result in tachycardia.
Differential Diagnosis of Tachycardia.

The nontoxic differential diagnosis of sinus tachycardia includes sympathetic stimulation due to psychiatric disorders, volume depletion, fever or hyperthermia, hyperthyroidism, hypoxemia, vasodilation (in sepsis, for example), and heart failure. In one study, an increase in core temperature of 1°C was associated with a mean increase in heart rate of 8.5 beats per minute.[41] Conduction disturbances in the atria or ventricles may result in supraventricular or ventricular tachycardias. Bradycardia
Drug-Induced Bradycardia.

Sedative-hypnotics such as barbiturates cause bradycardia through their CNS depressant effects ( Table 4–4 ). Opioids and central a2 agonists such as clonidine, guanfacine, and imidazoline-containing eye drops[28][50][55] cause bradycardia by decreasing central noradrenergic outflow from the locus ceruleus. Alpha1-adrenergic receptor agonists such as phenylpropanolamine cause peripheral vasoconstriction and hypertension that secondarily result in bradycardia mediated by baroreceptor reflexes. Group IA antidysrhythmic agents such as procainamide cause bradycardia by blocking the sodium (fast) channels in conduction tissue.

Table 4-4 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Bradycardia Direct myocardial pacemaker depressant effects Calcium channel antagonists Cardiac glycoside-containing plants (e.g., lily of the valley, oleander, foxglove) and toads Digitalis Reflex mechanisms Alpha-adrenergic receptor agonists (phenylpropanolamine) CNS depressants Opioids Sedative-hypnotics Decreased sympathetic outflow Beta-adrenergic receptor antagonists Clonidine Guanabenz

Guanfacine Imidazoline, topical Methyldopa Opioids Cholinomimetic agents Carbamates Mushrooms containing muscarine (Clitocybe and Inocybe spp.) Organophosphates Physostigmine, other medicinal cholinesterase inhibitors Antidysrhythmics—membrane depressant effects Beta-adrenergic receptor antagonists Cyclic antidepressants (severe) Encainide/flecainide (severe) Quinidine/procainamide/disopyramide (severe)

Digoxin and plants that contain cardiac glycosides such as lily of the valley (Convallaria majalis), foxglove (Digitalis purpurea), and oleander (Nerium oleander); ß-adrenergic receptor antagonists; and calcium channel antagonists cause bradycardia by directly affecting myocardial conduction. The muscarinic effects of organophosphates and carbamate insecticides may cause bradycardia. Aphrodisiacs such as “Rock Hard” and “Love Shop,” intended for topical application, contain cardioactive toad venoms (bufadienolides) that cause vomiting, bradycardia, and dysrhythmias when ingested. Significant toxicity has been reported after licking or ingesting Cane and Colorado River toads.[12]
Differential Diagnosis of Bradycardia.

Increased intracranial pressure from mass lesions or cerebral edema may cause bradycardia and hypertension as manifestations of the Cushing reflex. Myocardial depression by ischemia or hypoxia, or myocardial conduction disturbances, may also be associated with bradycardia. Increased vagal tone of any etiology also results in bradycardia. Blood Pressure Measurement of blood pressure should be done with a cuff that covers two thirds of the upper arm or leg. Too small a cuff results in falsely elevated readings, and too large a cuff causes falsely depressed readings. Hypertension The major mechanism of drug- and toxin-induced hypertension is vasoconstriction ( Table 4–5 ). Amphetamines and cocaine increase the availability of norepinephrine at a1-adrenergic receptors, resulting in vasoconstriction and hypertension. Phenylpropanolamine[37][38] and phenylephrine are potent a1-

adrenergic receptor agonists that cause significant vasoconstriction and hypertension. Hypertension also occurs in the early stages of a clonidine overdose owing to nonselective postsynaptic stimulation of peripheral a1-adrenergic receptors. Ergot is also a powerful vasoconstrictor, and ingestion of ergotcontaining compounds sometimes results in hypertension. The MAOIs are among the most notorious agents causing hypertension. MAOIs inhibit the breakdown of catecholamines, increasing the pool of norepinephrine in the presynaptic sympathetic nerve terminal. Indirect-acting sympathomimetic agents and foods that contain tyramine (e.g., Chianti wine, aged cheese, pickled herring, and chicken livers) release this stored pool of norepinephrine, resulting in hypertensive crisis. Overdose of MAOIs or cyclic antidepressants may be associated with hypertension that is followed by hypotension due to “washout” and depletion of catecholamines. Chronic lead exposure has been associated with hypertension due to lead-induced nephropathy or increased catecholamine levels.[14][65][69]

Table 4-5 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypertension Vasoconstriction Amphetamines Clonidine (early intoxication) Cocaine Cyclic antidepressant overdoses (early) Ephedrine Ergot Imidazolines (naphazoline, oxymetazoline, tetrahydrozoline) Monoamine oxidase inhibitors Nicotine Phencyclidine Phenylephrine Phenylpropanolamine Pseudoephedrine Thyroid hormones Withdrawal from ethanol, barbiturates, sedative-hypnotics Nephropathy Chronic lead exposure
Differential Diagnosis of Hypertension.

Nontoxic causes of hypertension, including renal disease, aldosteronism, pheochromocytoma, coarctation of the aorta and thyrotoxicosis should be considered during evaluation of the patient. Hypotension

Drug-induced hypotension is caused by hypovolemia, decreased peripheral vascular resistance, decreased myocardial contractility, and dysrhythmias ( Table 4–6 ). Gastrointestinal fluid losses from vomiting or diarrhea often contribute to hypotension but are seldom the sole cause. Treatment with ipecac and cathartics such as sorbitol can lead to excessive volume losses. Antibiotics, organophosphates, carbamates, iodine, laxatives and cathartics, lithium, and opioid withdrawal are some causes of drug-induced vomiting or diarrhea. The etiology of hypotension due to arsenic and theophylline is multifactorial and includes decreased systemic vascular resistance and hypovolemia. Gastrointestinal tract burns secondary to ingestion of caustic agents such as strong alkalis, strong acids, or mercuric chloride can result in massive fluid shifts that cause hypotension.

Table 4-6 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypotension Decreased peripheral resistance—vasodilation Alpha-adrenergic receptor antagonists (e.g., phenoxybenzamine, phentolamine, tolazoline, prazosin, terazosin, yohimbine, indoramin) Angiotensin-converting enzyme inhibitors Arsenic Caffeine Calcium channel antagonists Clonidine, guanfacine, guanabenz, imidazolines (oral) Cyclic antidepressants Disulfiram-ethanol interaction Ethanol Iron Isopropanol Nitrates/nitrites Nitroprusside Opioids Phenothiazines Salicylates Sedative-hypnotics Theophylline Trimethaphan Decreased myocardial contractility Beta-adrenergic receptor antagonists Calcium channel antagonists Cyclic antidepressants

Iron Hypovolemia or third spacing of intravascular volume Antibiotics Caustic injuries Colchicine, other antimitotics Coprinus-ethanol interaction Disulfiram-ethanol interaction Iron Lead Lithium (diabetes insipidus) Mercury salts Mushrooms Nicotine Organophosphates/carbamates Plants (e.g., pokeweed) Rattlesnake envenomation Theophylline (late) Zinc phosphate Other/unknown Cyanide Monoamine oxidase inhibitors

High doses of CNS depressants such as barbiturates and opioids result in centrally mediated vasodilation, which may lead to vasomotor collapse. Clonidine, guanfacine, and other central a2-adrenergic agonists decrease sympathetic stimulation, which in turn decreases peripheral vascular resistance. A number of antihypertensive agents such as nifedipine, nitroprusside, and prazosin are potent peripheral vasodilators. Nitroglycerin, disulfiram-ethanol reactions, and phenothiazines also cause decreased peripheral resistance. Overdoses of ß-adrenergic receptor antagonists and calcium channel antagonists such as verapamil and diltiazem produce profound hypotension by their negative inotropic effects on cardiac function.[78] Calcium channel antagonists also cause peripheral vasodilation. Cyclic antidepressants cause consequential hypotension through impairment of myocardial contractility, as well as the a-adrenergic receptor antagonist effects. The hypotension associated with severe iron poisoning is also multifactorial, a consequence of hypovolemia, increased capillary permeability, decreased myocardial function, bradycardia, and vasodilation.[75]
Differential Diagnosis of Hypotension.

Traumatic and spontaneous hemorrhage, spinal cord injury, sepsis, and myocardial ischemia are important causes of hypotension that should be considered during the evaluation of a patient with circulatory insufficiency. Respiratory Rate An evaluation of the rate and depth of respirations is a critical aspect of the physical examination. In the past, many deaths due to drug overdose occurred because of untreated hypoventilation and apnea. Although prehospital respiratory arrest is still a significant cause of morbidity and mortality, modern approaches to airway management and ventilation, including judicious use of certain antidotes such as naloxone, should limit the consequences of many cases of respiratory failure.
Tachypnea.

Tachypnea is defined as rapid breathing. Tachypnea is seen with toxins that cause metabolic acidosis, directly stimulate the CNS, produce seizures, are aspirated, or cause noncardiogenic pulmonary edema ( Table 4–7 ). Cases of hydrocarbon aspiration often present with tachypnea. Salicylates, dinitrophenol, pentachlorophenol, and theophylline increase the respiratory rate by directly stimulating the CNS. Agents that cause metabolic acidosis such as ethylene glycol, methanol, phenformin, metformin, and salicylates stimulate respiratory compensatory mechanisms for acidosis. Aspiration, restrictive lung disease, pleuritic chest pain, cardiac tamponade, and congestive heart failure are among the many nontoxic causes of tachypnea.

Table 4-7 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hyperventilation (Tachypnea or Hyperpnea) Stimulation of the central nervous system Dinitrophenol Nicotine (early) Pentachlorophenol Salicylates Metabolic acidosis Arsenic (acute) Cyanide Ethylene glycol Hydrogen sulfide Isoniazid Iron Ketoacidosis (alcoholic) Methanol

Metformin Nonsteroidal anti-inflammatory drugs (propionic acid class) Paraldehyde Phenformin Sodium azide Sodium monofluoroacetate Toluene Hyperadrenergic stimulation Amphetamines Cocaine Aspiration of gastric contents Hydrocarbons Noncardiogenic pulmonary edema Barbiturates Cadmium Carbon monoxide Cocaine Ethchlorvynol Glutethimide Opioids Phosgene Salicylates Hypoxia Carbon monoxide Methemoglobin-producing drugs and toxins Pulmonary edema—multiple drugs/toxins

Hyperpnea, a pattern of deep breathing, occurs with exercise, anxiety, and metabolic acidosis. Increased intracranial pressure, myocardial infarction, hypoxia, and hypoglycemia also cause hyperpnea. At times, salicylate intoxication may cause hyperpnea without tachypnea.
Pulmonary Edema.

Noncardiogenic pulmonary edema has been associated with heroin,[72] meperidine, methadone,[45] barbiturates,[29] ethchlorvynol, cocaine,[17] and salicylates.[32][35] Leakage of pulmonary capillaries is the

postulated mechanism. Pulmonary edema in an otherwise healthy patient should raise the suspicion of an overdose. Toxic gases such as phosgene, carbon monoxide, and the toxic components of smoke may also cause noncardiogenic pulmonary edema.
Bradypnea.

Bradypnea, a decreased respiratory rate, results from CNS depression or ventilatory muscle failure. Exposure to sedative-hypnotics, barbiturates, opioids, clonidine,[31] and alcohol causes respiratory depression. Respiratory failure occurs as a result of muscle weakness following exposure to organophosphates, carbamates,[51] neuromuscular blocking agents, strychnine, tetrodotoxin, venom from elapids and the Mojave rattlesnake (Crotalus scutulatus scutulatus), and botulinum toxin ( Table 4–8 ). Although increased intracranial pressure more commonly causes hyperpnea, it is also associated with bradypnea.

Table 4-8 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Respiratory Depression Depression of central respiratory drive Barbiturates Clonidine Cyclic antidepressants Ethanol and other alcohols Opioids Sedative-hypnotics Zolpidem Respiratory muscle failure Botulinum toxin Coelenterate venom (Physalia, Chironex fleckeri) Elapid venom (e.g., coral snake) Ibuprofen (high doses, especially in children) Mojave rattlesnake (Crotalus scutulatus scutulatus) Neuromuscular blocking agents (e.g., succinylcholine, nondepolarizing drugs) Nicotine (late) Organophosphates/carbamates Phenylbutazone Poison hemlock (conine) Strychnine Tetrodotoxin (toxin found in puffer fish, blue-ringed octopus)

Pulse Oximetry Maintenance of adequate oxygenation is fundamental to the management of poisoned or intoxicated patients.[34][39] Pulse oximetry provides a continuous, noninvasive, painless, and relatively fast measure of arterial hemoglobin oxygen saturation (SaO 2). [47] Most pulse oximeters measure only two forms of hemoglobin (oxygenated and reduced) and do not accurately reflect the presence of abnormal forms of hemoglobin such as carboxyhemoglobin, methemoglobin, and sulfhemoglobin.[80] The detection of abnormal forms of hemoglobin requires the use of co-oximetry. Whereas pulse oximeters may record falsely elevated amounts of oxyhemoglobin in patients with abnormal forms of hemoglobin, falsely decreased levels of oxyhemoglobin are reported with agents that decrease the respiratory rate or cause pulmonary edema. Any condition that reduces the strength of the arterial pulse may interfere with the measurement of the SaO 2. This includes hypotension, hypothermia, vasoconstrictive drugs, or the placement of the oximeter sensor distal to a blood pressure cuff or indwelling arterial line.[47] Patient movement also interferes with the detection of the arterial pulse. This can be a problem with patients who are agitated or who require transport, or with pediatric patients.

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Copyright © 2001 W. B. Saunders Company

FOCUSED PHYSICAL EXAMINATION: NEUROLOGIC MANIFESTATIONS OF TOXINS
Altered Mental Status Drugs and toxins commonly produce alteration of the mental status. Although agitated delirium and coma may appear to be distinct presentations, they are more often manifestations of a continuum of CNS depression, and many drugs cause both conditions. Sedative-hypnotic agents such as ethanol and barbiturates cause an initial period of disinhibition manifested by excitement and agitation. Higher doses lead to sedation and unresponsiveness. Many patients intoxicated with cocaine present with agitation or delirium that is followed by marked lethargy, known as the “washed-out syndrome.” [73] The cyclic antidepressants cause dose-related CNS excitation and depression.
Agitation and Delirium.

Anticholinergic agents, cocaine, amphetamines, ethanol, sedative-hypnotic withdrawal, and hypoglycemic agents are among the most common precipitants of agitation and delirium ( Table 4–9 ). Toxic causes of hypoglycemia include ingestion of akee fruit, ethanol, or sulfonylureas or use of insulin. Carbon monoxide, cyanide, and simple asphyxiants cause hypoxia that leads to agitation and delirium. Acute lead intoxication causes encephalopathy that may present as irritability in children.

Table 4-9 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Agitation and Delirium Direct central nervous system stimulation Amphetamines Anticholinergics Arsenic Carbamazepine Disulfiram reaction Ethanol, sedative-hypnotic, barbiturate withdrawal Lead Lithium Meperidine (normeperidine) Methylphenidate Monoamine oxidase inhibitors Neuroleptic malignant syndrome Nicotine Nonsteroidal anti-inflammatory drugs (phenylbutazone, diclofenac, fenoprofen)

Organochlorines Phenothiazines Propoxyphene (norpropoxyphene) Salicylates Serotonin syndrome Thallium Theophylline Hypoglycemic agents Akee fruit Insulin Sulfonylureas Antidysrhythmic agents Lidocaine Hypoxia-producing agents Carbon monoxide Cyanide Simple asphyxiant hydrocarbons Hallucinogens Ibotenic acid, muscimol-containing mushrooms Khat, methcathinone Lysergic acid diethylamide (LSD) Other psychoactive agents Envenomations Black widow spiders Pit vipers Scorpions Other Mefloquine Quinine (cinchonism)
Sedation and Coma.

Sedation and coma in the setting of a toxic exposure are most commonly caused by global depression of the CNS by drugs, hypoglycemia, or hypoxia ( Table 4–10 ). Agents that directly depress the CNS include

benzodiazepines, sedative-hypnotics, barbiturates, and alcohols. Agents such as ethanol and salicylates induce hypoglycemia, which may contribute to the direct CNS depressant effects. Other toxic causes of CNS depression include agents associated with cellular asphyxia such as cyanide, hydrogen sulfide, carbon monoxide, and sodium azide; methemoglobinemia; anticholinergics; and acetylcholinesterase inhibitors.

Table 4-10 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Sedation and Coma Hypoxia Carbon monoxide Cyanide Hydrogen sulfide Methemoglobin-producing drugs and toxins Oxidants Simple asphyxiants (methane, ethane, butane, propane) Acetylcholinesterase inhibitors Organophosphates Central nervous system depression Alcohols Anticholinergics Anticonvulsants (carbamazepine, phenytoin, valproic acid, ethosuximide) Bromides Clonidine, guanfacine, imidazolines Cyclic antidepressants Lithium Magnesium
Seizures.

Agitation, delirium, or sedation may also result from toxin-induced seizures, resulting in a prolonged postictal state. Some toxins known to cause seizures include camphor,[26] cocaine,[24] cyclic antidepressants,[22] hypoglycemics, isoniazid, lead, lidocaine,[21] lithium,[23] penicillin, phenothiazines, salicylates, and theophylline[3] ( Table 4–11; see Chapter 18 for a more complete discussion). Seizures are the major toxic effect of the potent cicutoxin found in water hemlock (Cicuta spp). Overdoses of anticonvulsants such as carbamazepine are often associated with seizures.[77] Seizures caused by theophylline or isoniazid can be very difficult to control.

Table 4-11 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Seizures Central nervous system—various mechanisms

Amphetamines Anticholinergics Baclofen Camphor Carbamazepine Chloroquine Clonidine, other central a 2 agonists Cocaine Cyclic antidepressants Ethanol, sedative-hypnotic, barbiturate withdrawal Insulin Isoniazid Lead Lidocaine Lindane Lithium Meperidine (normeperidine) Monoamine oxidase inhibitors Organochlorines Penicillin Phencyclidine Phenothiazines Phenylbutazone (especially in children) Propoxyphene (norpropoxyphene) Propranolol Quinine (cinchonism) Quinolones (enoxacin, norfloxacin, ofloxacin) Strychnine Sulfonylureas Theophylline Water hemlock (cicutoxin) Hypoglycemia Akee fruit

Ethanol Insulin Salicylates Sulfonylureas Cerebral edema Arsenic Ethylene glycol Lead Methanol Salicylates Other Cisplatin Pyrimidine analogs (cytarabine, fluorouracil) Vinblastine (intrathecal)
Laboratory Evaluation.

Serum chemistry determination, computed tomography of the head (head CT), and lumbar puncture may be required to exclude metabolic, infectious, or structural etiologies of altered mental status in a poisoned patient. A positive drug screen should not be interpreted as proving causality for a patient’s altered mental status. A positive drug screen only confirms exposure to a particular drug during a recent period.
Differential Diagnosis.

Many patients are brought to the emergency department with altered mental status. Although a past history of drug overdose, alcohol abuse, or psychiatric problems may tempt the physician to attribute the altered mental status to a drug or toxin, other important causes of altered mental status or seizures need to be considered. Differentiating delirium caused by a drug or toxin from other organic etiologies such as encephalitis, head trauma, hypoglycemia, or hypoxemia is critical in order to expeditiously treat the underlying condition. Although some acute psychiatric disorders that present with altered thought and behavior may at times be confused with a drug-precipitated delirium, patients presenting with an altered mental status due to a psychiatric etiology tend to maintain a clear sensorium, are able to attend, and do not have the waxing and waning agitation commonly associated with organic disturbances. A patient whose mental status is altered by drugs or toxins may also have associated traumatic injuries, including diffuse axonal injury, cerebral contusion, or space-occupying lesions such as subdural or epidural hematomas. Physicians should have a high index of suspicion for underlying closed head injuries in patients with altered mental status.[64] Pupils

Pupillary size may be particularly helpful in the evaluation of a toxic patient. Normal pupil size ranges between 2.5 and 5.5 mm in diameter and varies with age.[5] Miosis is defined as a pupillary diameter of 2.5 mm or less. Mydriasis is defined as a pupillary diameter of 6 mm or greater. Actual pupil size results from a balance between sympathetic and parasympathetic innervation. Sympathetic stimulation of a1 receptors causes the radial muscle of the iris to dilate. Blockade of these receptors causes pupillary constriction. Cholinergic stimulation of the iris sphincter muscle via the third cranial nerve also causes pupillary constriction and miosis. Anticholinergic blockade causes mydriasis.
Miosis.

Parasympathetic stimulation of the iris constricts the pupils. Extremely constricted or “pinpoint” pupils are associated with opioid effects. Other causes of miosis include central a2 agonists (clonidine, guanfacine, guanabenz, imidazolines), phenothiazines, organophosphates, carbamates, physostigmine, phencyclidine, and some sedative-hypnotics. Miosis also occurs with topical ophthalmologic miotics such as pilocarpine. Central pontine lesions secondary to trauma, tumor, or vascular insult also cause miosis.
Mydriasis.

Mydriasis is a less specific physical finding than miosis. Sympathomimetics, anticholinergics, antihistamines, and hypoxia cause the pupils to dilate. Amphetamines, cocaine, LSD, and withdrawal from sedativehypnotics and opioids can cause mydriasis due to sympathetic stimulation of pupillary dilator muscles. The topical application of sympathomimetics such as phenylephrine (Neo-Synephrine) to the eye also causes mydriasis. Antihistamines and anticholinergics block iris sphincter muscle contraction. Unilateral mydriasis has been reported in association with scopolamine patches placed behind the ear.[68] This blockade of parasympathetic tone causes nonreactive, fixed, dilated pupils, which may be differentiated from the reactive, dilated pupils associated with sympathomimetic toxicity. This difference, however, is not consistent. Certain opioids and sedative-hypnotics such as meperidine and glutethimide can also cause mydriasis. Botulinum toxin can cause delayed mydriasis. Methanol and quinine cause mydriasis due to the blindness and loss of pupillary light reflex that result from their toxic effects. A useful test to distinguish mydriasis induced by a topical mydriatic agent such as scopolamine from that due to a third nerve palsy involves the administration of pilocarpine eye drops (0.5 or 1 per cent). Topical pilocarpine eye drops will not constrict a pupil blocked by a mydriatic agent but will constrict a pupil dilated secondary to injury to the third cranial nerve.[44] At times, the distinction between drug-induced mydriasis and anoxic brain injury may be difficult.
Nystagmus.

Nystagmus is commonly associated with exposure to anticonvulsants (especially carbamazepine and phenytoin), lithium,[15][16] ethanol, barbiturates, and sedative-hypnotics. MAOIs and isoniazid may also cause nystagmus. Phencyclidine characteristically causes both rotatory and vertical nystagmus.[79]
Retinal Manifestations of Poisoning.

Methanol causes retinal hyperemia. Arteriolization of retinal veins has been reported with cyanide poisoning.[40] Papilledema can occur with methanol, quinine, and vitamin A toxicity and other drug causes of pseudotumor cerebri. Emboli can be seen in the fundi of intravenous drug abusers. Carbon monoxide[53] and methaqualone can cause retinal hemorrhages. Retinal hemorrhages should always suggest the possibility of physical abuse in infants and children. They are also associated with hypertensive encephalopathy, subarachnoid hemorrhage, and endocarditis.
Movement Disorders.

Movement disorders associated with decreased movement are classified as akinesias; those associated with increased movement are classified as dyskinesias. The most common akinesia associated with drugs or toxins is parkinsonism. Dyskinesias include tremors, chorea, dystonia, tardive dyskinesia, myoclonus, and asterixis. Toxin-induced parkinsonism manifests as resting tremor and extrapyramidal rigidity and can be seen following poisoning with carbon disulfide, carbon monoxide, cyanide, manganese, and 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). It is also a common adverse effect of the therapeutic use of neuroleptic drugs. Tremors that increase with movement are called postural tremors. Causes of postural tremors include amiodarone, amphetamines, caffeine, cocaine, cyclic antidepressants, ergotamine, lithium, mercury, phenytoin, theophylline, valproic acid, and withdrawal from ethanol and sedative-hypnotics. Chorea is characterized by rapid, jerky, involuntary movements of the major joints, trunk, and face. Dystonic reactions are involuntary, slow, twisting spasms typically involving proximal muscles of the extremities, trunk, and neck. Neuroleptic drugs, antimalarials, cyclic antidepressants, phenytoin, strychnine, lithium, cocaine, and phencyclidine cause dystonic reactions. Tardive dyskinesia is characterized by choreoathetoid movements of the trunk, limbs, and face that occur after prolonged use of neuroleptic drugs. Myoclonus is a series of forced, alternating contractions and partial relaxations of the same muscle. Toxic causes of myoclonus include lithium and anticholinergic drugs. Myoclonus may occur secondary to fatigue. It is also seen with disorders associated with hyperactive reflexes such as upper motor neuron disease, hyperthyroidism, hypocalcemia, and brain stem tumors. Asterixis is an abnormal flapping tremor characterized by involuntary transient relaxation of muscles that causes a brief loss of posture. Asterixis was originally described in patients with hepatic failure but is also associated with many drug-induced encephalopathies, including anticonvulsants, benzodiazepines, bismuth, cyclic antidepressants, DDT, ethanol, lead, levodopa, mercury, methylbromide, and sedative-hypnotics.

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

FOCUSED PHYSICAL EXAMINATION: DERMATOLOGIC MANIFESTATIONS OF TOXINS
Cyanosis Cyanosis is a dark blue or purple discoloration of the skin and mucous membranes. When cyanosis cannot be explained by cardiac or pulmonary disease, the diagnosis of methemoglobinemia should be considered. Methemoglobin is an abnormal hemoglobin in which the iron molecule is in the oxidized ferric (Fe3+ ) state rather than the normal ferrous (Fe2+ ) state. Methemoglobin is darker than unoxygenated hemoglobin and may cause a marked cyanosis even without other symptoms. Oxygen saturation measured by the bedside pulse oximeter can be falsely estimated in patients with methemoglobinemia. Methemoglobinemia follows exposure to an oxidizing drug or chemical, especially organic nitrates, nitrites, benzocaine, dapsone, phenazopyridine (Pyridium), and aniline dyes.[67] Rare causes of hereditary methemoglobinemia may also occur[18](see Chapter 24 for a complete discussion). Erythema Dry, flushed skin is a hallmark of anticholinergic poisoning. Erythema or flushing is also associated with ethanol, very high levels of carbon monoxide, and nitrites. Niacin ingestion causes sudden marked flushing. Chronic boric acid poisoning is associated with intense erythema and desquamation, resulting in a “boiled lobster appearance.”[70] Rapid intravenous infusion of vancomycin may cause extreme flushing that is sometimes referred to as the “red man syndrome.” Scombroid fish poisoning is associated with intense erythema of the upper torso and face due to a release of histamine. Disulfiram-ethanol interaction and disulfiram-like interactions between ethanol and other agents such as metronidazole, sulfonylureas, cephalosporins, chloral hydrate, griseofulvin, carbon disulfide, trichloroethylene, and Coprinus mushrooms may also manifest by erythematous flushing. Ingestion of monosodium glutamate (MSG) causes the flushing associated with Chinese restaurant syndrome. Examples of medications that induce photosensitivity reactions include tetracyclines, captopril, cyclic antidepressants, furosemide, nonsteroidal anti-inflammatory drugs (NSAIDs; especially piroxicam), phenothiazines, warfarin, antihistamines, griseofulvin, and sulfonamides. Flushing, headache, and hypertension are hallmarks of the tyramine reaction seen in patients on MAOIs who ingest foods that contain tyramine. Ecchymosis Anticoagulant toxicity may inhibit clotting and present with ecchymosis. Icterus Exposure to naphthalene mothballs or arsine gas can cause hemolysis that results in jaundice. Various forms of toxin-induced liver injury result in jaundice, including exposure to acetaminophen, carbon tetrachloride, chloroform, cyclopeptide- and monomethylhydrazine-containing mushrooms, copper, phosphorus, and iron. Bullous Lesions

Barbiturate poisoning is associated with bullous skin lesions. The mechanism of barbiturate-induced skin lesions is controversial. Some authors propose a direct toxic effect that results in sweat gland necrosis[57]; others argue that the lesions are simply due to prolonged recumbency.[1][4][7][20][63] Methadone, meprobamate, carbon monoxide,[53] and glutethimide have also been associated with bullous skin lesions. Track Marks Intravenous drug use results in scarring along veins, or “track marks.” Skin Necrosis The extravasation of certain intravenous medications may result in skin necrosis. These agents include potassium salts, calcium salts, phenytoin, norepinephrine, and chemotherapeutic agents. Diaphoresis Diaphoresis can occur with sympathomimetic agents such as cocaine or amphetamines, as well as with organophosphates, salicylates, and withdrawal from ethanol, sedative-hypnotics, and barbiturates. Hypoglycemia, thyroid storm, and shock can also result in diaphoresis. Alopecia Alopecia (hair loss) can occur as a result of illness, hormonal disturbances, and numerous drugs. Arrested hair growth and hair loss are commonly associated with the use of agents that interfere with rapidly dividing cells, such as chemotherapeutic agents and metals. The combination of rapid, diffuse alopecia and gastrointestinal and neurologic abnormalities is pathognomonic for thallium toxicity. [25] Lithium and valproate have been reported to cause diffuse but rarely total hair loss.[74] Total hair loss has been associated with selenium.[71] Alopecia areata (patchy alopecia) has been described with fluconazole[62] and amiodarone.[2] Delayed alopecia occurs after exposure to arsenic and colchicine. Localized alopecia can occur late after carbon monoxide poisoning.[53] Scarring and nonscarring alopecia has been reported with gold therapy.[13] Fortunately, drug-induced alopecia usually reverses after the drug is withdrawn. Hair Color Copper workers have been reported to have green hair as a result of exogenous deposition of copper.[30][49] Nails Several weeks after poisoning with arsenic and thallium, patients develop horizontal white lines on the finger- and toenails known as Mees lines. Cancer chemotherapeutic agents have been associated with the development of horizontal notches in the nail plate known as Beau lines. Nail staining has been associated with direct exposure to iodine (brown), nicotine (yellow-brown), cupric sulfate (blue), mercury (red), and formaldehyde (gray).

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FOCUSED PHYSICAL EXAMINATION: GASTROINTESTINAL MANIFESTATIONS OF TOXINS
Oral Cavity Salivation or the lack of salivation may be a helpful physical finding. Hypersalivation (sialorrhea) has been associated with cholinesterase inhibitors (organophosphates, carbamates, physostigmine), clozapine, caustic agents, and iodides. Foaming of the mouth may also be a manifestation of drug- or toxin-induced pulmonary edema. Dry mouth (xerostomia) may be caused by anticholinergics and opioids. Angioedema of the lips, mouth, and oropharynx occurs with allergic reactions and may occur secondary to burns from strong acids or alkalis. Captopril and other angiotensin-converting enzyme (ACE) inhibitors may cause significant tongue swelling that can compromise the airway. Ulcerative burns to the lips, mouth, and oropharynx occur after exposure to strong acids and alkalis and other caustic or corrosive agents. Breath Odors The odor of mothballs suggests ingestion of naphthalene or paradichlorobenzene. Acetone smells fruity. Arsine gas, thallium, and organophosphates cause a garlic-like odor. The scent of wintergreen suggests methyl salicylate exposure. Cyanide has a bitter almond odor detectable by 60 to 80 per cent of the population. Vomiting/Hematemesis Causes of vomiting in poisoned patients include direct irritation of the gastric mucosa (alkalis, acids, salicylates, colchicine, mushrooms, fluoride, thallium, iron, mercury, and arsenic) or stimulation of the chemoreceptor trigger zone in the fourth ventricle by substances in the blood or cerebrospinal fluid (opioids, nicotine, cardiac glycosides, theophylline, and carbon monoxide).[53] Vomiting also occurs with excessive acetylcholine activity due to poisoning with acetylcholinesterase inhibitors such as organophosphates. Cocaine, amphetamines, and phenylpropanolamine can cause intracranial hemorrhage that presents with vomiting. Severe lead poisoning can also cause elevated intracranial pressure and vomiting. Increased intracranial pressure due to anoxic brain injury, traumatic hematomas, and other mass lesions must also be considered. Hematemesis results from direct toxic injury to the intestinal mucosa, toxin-induced coagulopathy, or a Mallory-Weiss tear associated with persistent vomiting. Altered Intestinal Activity
Diarrhea.

Causes of diarrhea include intestinal irritation and increased autonomic activity of the bowel. Direct irritation or injury to the bowel mucosa results from chemical burns, mushrooms, solanine-containing plants, cathartics, heavy metals, and colchicine. Cholinesterase inhibitors, nicotine, and opioid withdrawal can cause diarrhea by increasing autonomic activity. Diarrhea also occurs with ingestion of magnesium-

containing compounds and sorbitol and in a variety of marine ingestions (see Chapter 121 ).
Constipation.

Anticholinergic agents, calcium channel antagonists, opioids, and sedative-hypnotics decrease bowel activity, leading to constipation. Bowel sounds may be absent or diminished after exposure to anticholinergic agents. Abdominal Pain Black widow spider envenomation is characterized by spasms of large muscle groups that may present as a rigid abdomen. Urinary Bladder Palpation of the lower abdomen should include assessment of bladder size. Urinary retention occurs with overdose of anticholinergic agents.

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TOXIDROMES
Anticholinergic, sympathomimetic, opioid, anticholinesterase, and sedative-hypnotic or barbiturate poisonings may be recognized by their characteristic toxidromes. In the clinical setting when the patient’s history is limited or nonexistent, characteristic physical findings suggesting a specific drug class may be critical in refining the diagnosis, focusing the management, and directing the antidotal intervention, such as naloxone for opioids or physostigmine for anticholinergic overdoses. Limitations of this approach include the not infrequent occurrence of mixed intoxications and presentations that manifest only a few of the “textbook” signs and symptoms. Failure of the physical findings to be readily categorized as a toxidrome certainly does not exclude a toxic etiology. Anticholinergic Syndrome Drugs and toxins that block acetylcholine at muscarinic receptors cause the anticholinergic toxidrome. Physical findings include elevated temperature; delirium; mumbling speech; tachycardia; dry, flushed skin; dry mucous membranes; urinary retention; decreased to absent bowel sounds; mydriasis; and blurred vision. Seizures and coma may also occur. A simple mnemonic, “hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter, bloated as a bladder,” describes many of the features of the anticholinergic toxidrome. Atropine and atropine-like agents cause this syndrome. Atropine-like agents include a number of commonly used over-the-counter cold medications containing antihistamines, antiparkinson medications such as benztropine and trihexyphenidyl, topical mydriatics, antispasmodics such as Donnatal and dicyclomine, muscle relaxants such as cyclobenzaprine and orphenadrine, and belladonna alkaloids such as scopolamine and hyoscyamine. Cyclic antidepressants also cause anticholinergic symptoms. Plants that contain belladonna alkaloids include jimson weed (Datura stramonium), deadly nightshade (Atropa belladonna), and henbane (Hyoscyamus niger). Sympathomimetic Syndrome Sympathetic agonists such as cocaine and amphetamine produce hypertension, diaphoresis, tachycardia, tachypnea, hyperthermia, and mydriasis. Restlessness, agitation, excessive speech, tremors, and insomnia also occur. Severe cases are associated with dysrhythmias and seizures. Other agents that may cause sympathomimetic effects include over-the-counter decongestants such as phenylpropanolamine, ephedrine, and pseudoephedrine. Theophylline and caffeine may cause many of these findings by enhancing catecholamine release. Overdoses with ß2-adrenergic receptor agonists, methylphenidate, and Ephedra species such as ma huang cause sympathomimetic symptoms. This symptom complex may be difficult to distinguish from the anticholinergic syndrome. Whereas sweating and normal to hyperactive bowel sounds are associated with sympathomimetic overdose, the anticholinergic toxidrome is manifested by dry skin and diminished bowel sounds. Opioid Syndrome

The classic triad of opioid intoxication is mental status depression, respiratory depression, and pinpoint pupils. Bradycardia, hypotension (rare), hypothermia, hyporeflexia, and needle marks may be present. Opioids commonly associated with this toxidrome include morphine, heroin, designer fentanyls, oxycodone, hydromorphone, and propoxyphene. Meperidine, pentazocine, and dextromethorphan may cause CNS and respiratory depression but are often associated with dilated pupils. Central a2-receptor agonists such as clonidine, guanabenz, guanfacine, and imidazoline derivatives that act on the locus ceruleus of the CNS cause many of these same symptoms in the overdose setting. Anticholinesterase Syndrome Organophosphates are commonly available as insecticides. They are readily absorbed through the skin, mucous membranes, and respiratory and gastrointestinal tracts. Organophosphates inactivate cholinesterase enzymes, resulting in accumulation of acetylcholine at receptor sites and overstimulation of muscarinic, nicotinic, and central acetylcholine receptors. Other causes of cholinesterase inhibition include carbamates and therapeutic cholinesterase inhibitors such as physostigmine, pyridostigmine, neostigmine, and edrophonium. Clinical findings suggestive of acute anticholinesterase intoxication include muscarinic effects as well as muscle weakness, fasciculations, altered mental status, seizures, and coma. DUMBELS is a mnemonic used to recall many of the muscarinic effects: defecation, urination, miosis, bronchorrhea, bronchospasm, bradycardia, emesis, lacrimation, and salivation. Sedative-Hypnotic Syndrome Sedative-hypnotic overdoses are associated with hypotension, bradypnea, hypothermia, mental status depression, slurred speech, ataxia, and hyporeflexia. The sedative-hypnotic group includes barbiturates, benzodiazepines, buspirone, paraldehyde, chloral hydrate, meprobamate, methaqualone, ethchlorvynol, glutethimide, and zolpidem. Of course, ethanol intoxication may also present with many of these symptoms. Ingestion of neuroleptics, cyclic antidepressants, and skeletal muscle relaxants may also cause significant sedation. Bullous lesions have been reported in some patients with sedative-hypnotic overdoses. Paradoxical excitement is seen with some of the sedative-hypnotics, especially in very young and elderly patients.

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REFERENCES
1. Ackerman A, Mandy S: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 283:764. 2. Ahmad S: Amidarone and reversible alopecia. Arch Intern Med 1995; 155:1106. 3. Aitken M, Martin T: Life-threatening theophylline toxicity is not predictable by serum levels. Chest 1987; 91:10. 4. Alexander G: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 283:764. 5. Appenzeller O: The normal pupil and some pupillary abnormalities. In: Appenzeller O, ed. The Autonomic Nervous System, 3rd ed. New York: Elsevier; 1982:319. 6. Armstrong LE, Epstein Y, Greenleaf JE, et al: American College of Sports Medicine position stand: Heat and cold illnesses during distance running. Med Sci Sports Exerc 1996; 28:i. 7. Baden M: Bullous skin lesions in barbiturate overdosage and carbon monoxide poisoning [letter]. JAMA 1970; 213:2271. 8. Benzinger T, Pratt A, Kitzinger C: The thermostatic control of human metabolic heat production. Physiology 1961; 47:730. 9. Blanc P, Boushey H, Wong H, et al: Cytokines in metal fume fever. Am Rev Respir Dis 1993; 147:134. 10. Boyd RE, Brennan PT, Deng JF, et al: Strychnine poisoning: Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis. Am J Med 1983; 74:507. 11. Browne B, Linter S: Monoamine oxidase inhibitors and narcotic analgesics: A critical review of the implications for treatment. Br J Psychol 1987; 151:210. 12. Brubacher J, Ravikumar P, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996; 110:1282. 13. Burrows N, Grant J, Crisp A, et al: Scarring alopecia following gold therapy [letter]. Acta Derm Venereol 1994; 74:486. 14. Campbell BC, Meredith PA, Scott JJ: Lead exposure and changes in the renin-angiotensin-aldosterone system in man. Toxicology 1985; 25:25. 15. Chrousos G, Cowdry R, Schuelein M, et al: Two cases of downbeat nystagmus and oscillopsia associated with carbamazepine. Am J Ophthalmol 1987; 103:221. 16. Corbett J, Jacobson D, Thompson H, et al: Downbeating nystagmus and other ocular motor defects caused by lithium toxicity. Neurology 1989; 39:481. 17. Cucco R, Yoo O, Cregler L, et al: Nonfatal pulmonary edema after “freebase” cocaine smoking. Am Rev Respir Dis 1987; 136:179.

18. Curry S: Methemoglobinemia. Ann Emerg Med 1982; 11:214. 19. Danzl D, Pozos R: Multicenter hypothermia survey. Ann Emerg Med 1987; 16:1042. 20. Dunn C, Held J, Spitz J, et al: Coma blisters: Report and review. Cutis 1990; 45:423. 21. Edgren B, Tilelli J, Gehrz R: Intravenous lidocaine overdose in a child. Clin Toxicol 1986; 24:51. 22. Ellison D, Pentel P: Clinical features and consequences of seizures due to cyclic antidepressant overdose. Am J Emerg Med 1989; 7:5. 23. El-Mallakh R, Lee R: Seizures and transient cognitive deterioration as sequelae of acute lithium intoxication. Vet Hum Toxicol 1987; 29:143. 24. Ernst A, Sanders W: Unexpected cocaine intoxication presenting as seizures in children. Ann Emerg Med 1989; 18:774. 25. Feldman J, Levisohn D: Acute alopecia: Clue to thallium toxicity. Pediatr Dermatol 1993; 10:29. 26. Gibson D, Moore G, Pfaff J: Camphor ingestion. Am J Emerg Med 1989; 7:41. 27. Ginsberg MD, Hertzman M, Schmidt-Nowara WV: Amphetamine intoxication with coagulopathy, hyperthermia and reversible renal failure. Ann Intern Med 1970; 73:81. 28. Glazener F, Blake K, Gradman M: Bradycardia, hypotension, and near-syncope associated with Afrin (oxymetazoline) nasal spray. N Engl J Med 1983; 309:731. 29. Goodman J, Bischel M, Wagers P, et al: Barbiturate intoxication morbidity and mortality. West J Med 1976; 124:179. 30. Gould D, Slater D, Durrant T: A case of green hair—a consequence of exogenous copper deposition and permanent waving. Clin Exp Dermatol 1984; 9:545. 31. Grabert B, Conner C, Rumack B, et al: Clonidine-recurrent apnea following overdose. Drug Intelligence Clin Pharmacy 1979; 13:778. 32. Granville-Grossman K, Sergeant H: Pulmonary oedema due to salicylate intoxication. Lancet 1960; 1:575. 33. Gustavson E, Levitt C: Physical abuse with severe hypothermia. Arch Pediatr Adolesc Med 1996; 150:111. 34. Hall C, Hall W, Speers D: Clinical and physiological manifestations of bronchiolitis and pneumonia. Am J Dis Child 1979; 133:798. 35. Heffner J, Sahn S: Salicylate-induced pulmonary edema. Ann Intern Med 1981; 95:405. 36. Henry J, Jeffreys K, Dawling S: Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet 1992; 340:384. 37. Horowitz J, McNeil J, Sweet B, et al: Hypertension and postural hypotension induced by phenylpropanolamine (Trimolets). Med J 1979; 1:175.

38. Howrie D, Wolfson J: Phenylpropanolamine-induced hypertensive seizures. J Pediatr 1983; 102:143. 39. Hurwitz M, Burney R, Howatt W, et al: Clinical scoring does not accurately assess hypoxemia in pediatric asthma patients. Ann Emerg Med 1984; 13:1040. 40. Johnson RP, Mellors JW: Arteriolization of venous blood gases: A clue to the diagnosis of cyanide poisoning. J Emerg Med 1988; 6:401. 41. Karjalainen J, Viitasalo M: Fever and cardiac rhythm. Arch Intern Med 1986; 146:1169. 42. Kedes L, Field J: Hypothermia—a clue to hypoglycemia. N Engl J Med 15:785. 43. Kew M, Hopp M, Rothberg A: Fatal heart-stroke in a child taking appetite-suppressant drugs. S Afr Med J 1982; 62:905. 44. Kiyama S: A simple test for scopolamine mydriasis [letter]. Anesth Analg 1991; 73:824. 45. Kjeldgaard J, Hahn G, Heckenlively J, et al: Methadone-induced pulmonary edema. JAMA 1971; 218:882. 46. Kluger M: Fever. Pediatrics 1980; 66:720. 47. Kulick R: Pulse oximetry. Pediatr Emerg Care 1987; 3:127. 48. Kuschner W, D’Alessandro A, Wintermeyer S, et al: Pulmonary responses to purified zinc oxide fume. J Investig Med 1995; 43:371. 49. Lampe R, Henderson A, Hansen G: Green hair. JAMA 1977; 237:2092. 50. Lev R, Clark R: Visine overdose: Case report of an adult with hemodynamic compromise. J Emerg Med 1995; 13:649. 51. Lifshitz M, Rotenberg M, Sofer S, et al: Carbamate poisoning and oxime treatment in children: A clinical and laboratory study. Pediatrics 1994; 93:652. 52. Lipsky B, Hirschmann J: Drug fever. JAMA 1981; 245:851. 53. Lowe-Ponsford F, Henry J: Clinical aspects of carbon monoxide poisoning. Adverse Drug React Acute Poisoning Rev 1989; 8:217. 54. Ludwig S, Warman M: Shaken baby syndrome: A review of 20 cases. Ann Emerg Med 1984; 13:104. 55. Mahieu L, Rooman R, Goossens E: Imidazoline intoxication in children. Eur J Pediatr 1993; 152:944. 56. Maickel R: Interaction of drugs with autonomic nervous function and thermoregulation. Federation Proceedings 1970; 29:1973. 57. Mandy S, Ackerman A: Characteristic traumatic skin lesions in drug-induced coma. JAMA 1970; 213:253. 58. Merigian K, Roberts J: Cocaine intoxication: Hyperpyrexia, rhabdomyolysis and acute renal failure. Clin Toxicol 1987; 25:135.

59. Mofenson H, Greensher J: The unknown poison. Pediatrics for the Clinician 1974; 54:336. 60. Morgan R, King D: Urban hypothermia. BMJ 1996; 312:124. 61. Muly E, McDonald W, Steffens D, et al: Serotonin syndrome produced by a combination of fluoxetine and lithium [letter]. Am J Psychol 1993; 150:1565. 62. Pappas P, Kauffman C, Perfect J, et al: Alopecia associated with fluconazole therapy. Ann Intern Med 1995; 123:354. 63. Parrish J, Arndt K: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 43:764. 64. Plum F, Posner J: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia: Davis; 1982:87-151. 65. Restek-Samarzija N, Momcilovic B: Delayed effects of lead on the kidney-factor analysis. Arh Hig Rada Toksikol 1993; 44:9. 66. Reuler J: Hypothermia: Pathophysiology, clinical settings, and management. Ann Intern Med 1978; 89:519. 67. Ross J: Deficient activity of DPNH-dependent methemoglobin diaphorase in cord blood erythrocytes. Blood 1963; 21:51. 68. Rubin M, Sadoff R, Cozzi G: Unilateral mydriasis caused by transdermal scopolamine. Oral Surg Oral Med Oral Pathol 1990; 70:569. 69. Sanchez-Fructuoso A, Torralbo A, Arroyo M, et al: Occult lead intoxication as a cause of hypertension and renal failure. Nephrol Dial Transplant 1996; 11:1775. 70. Schillinger B, Berstein M, Goldberg L, et al: Boric acid poisoning. Am Acad Dermatol 1982; 7:667. 71. Srivastava A, Gupta B, Bihari V, et al: Generalized hair loss and selenium exposure. Vet Hum Toxicol 1995; 37:568. 72. Steinberg A, Karliner J: The clinical spectrum of heroin pulmonary edema. Arch Intern Med 1968; 122:122. 73. Trabulsy M: Cocaine washed out syndrome in a patient with acute myocardial infarction. Am J Emerg Med 1995; 13:538. 74. Uehlinger C, Barrelet L, Touabi M, et al: Alopecia and mood stabilizers: Two case reports. Eur Arch Psychiatry Clin Neurosci 1992; 242:85. 75. Vernon D, Banner W, Dean J: Hemodynamic effects of experimental iron poisoning. Ann Emerg Med 1989; 18:863. 76. Wahl N, Woodall B: Hypothermia in shaken infant syndrome. Pediatr Emerg Care 1995; 11:233. 77. Weaver D, Camfield P, Fraser A: Massive carbamazepine overdose: Clinical and pharmacologic observations in five episodes. Neurology 1988; 38:755. 78. Weinstein R: Recognition and management of poisoning with beta-adrenergic blocking agents. Ann

Emerg Med 1984; 13:1123. 79. Welch M, Correa G: PCP intoxication in young children and infants. Clin Pediatr 1980; 19:510. 80. Yelderman M, New W: Evaluation of pulse oximetry. Anesthesiology 1983; 59:349.

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Chapter 5 – Gastrointestinal Decontamination
KEN KULIG “Gastrointestinal decontamination” is a common term in toxicology, but it is not synonymous with “gastric emptying,” with which it is often confused. Such confusion has caused this aspect of patient care to be controversial, when in fact decisions involving the initial management of an overdose patient can be logical and relatively straightforward if the physician has a clear goal in mind—preventing drug absorption in the most effective manner. The typical overdose patient presenting to the emergency department is an adult who has acutely ingested multiple medications in a suicide attempt approximately 3 hours before arrival.[60] Alcohol as a co-ingestant is often involved. The patient is often minimally symptomatic despite the delay in presentation. The history is often inaccurate regarding what was ingested and when, as well as the amounts of medications ingested. This hypothetical typical patient is the focus of the treatment modalities discussed. This chapter discusses methods of gastrointestinal (GI) decontamination—syrup of ipecac gastric lavage, activated charcoal, observation alone, cathartics, whole bowel irrigation ( Table 5–1 )—as well as the initial treatment of the body packer/body stuffer. The objective is to provide a basis for simplified decision making when the goal is to decontaminate the entire GI tract not just the stomach while reducing the risk of iatrogenic harm.

Table 5-1 -- Common Methods of Gastrointestinal (GI) Decontamination Activated charcoal Adult dose: 50 g orally or down nasogastric (NG) tube. May repeat q 2–4 hr if the ingested substance is adsorbed to charcoal, the ingestant is likely to result in significant toxicity, and the patient has bowel sounds and an intact GI tract. Pediatric dose: 25 g orally or down NG tube. May repeat q 2–4 hr if the ingested substance is adsorbed to charcoal, the ingestant is likely to result in significant toxicity, and the patient has bowel sounds and an intact GI tract. Gastric lavage Adult tube size: 32–40 Fr Pediatric tube size: 16–32 Fr Tube placement should be clinically verified in every case. Stomach contents should be aspirated first, then aliquots of water or saline, 50–100 mL in children and 250 mL in adults, should be instilled and then aspirated repeatedly until clear. Airway equipment and suction should be readily available. Instillation of activated charcoal before lavage should be considered. Gastric lavage should not be done routinely. Syrup of ipecac

Adult dose: 30 mL orally; may repeat in 20 min. Pediatric dose: 10 mL orally if between 9 and 12 mo of age; 15 mL orally if older than 1 year of age; may repeat in 20 min. Should not be given to children younger than 9 mo of age. Syrup of ipecac is rarely if ever indicated in the emergency department. Cathartics Sorbitol adult dose: 1 g/kg Sorbitol pediatric dose: 1 g/kg Magnesium sulfate (10%) adult dose: 15 g Magnesium sulfate pediatric dose: 250 mg/kg up to 15 g Magnesium citrate (6%) adult dose: 300 mL Magnesium citrate pediatric dose: 4 mL/kg up to 300 mL Cathartics are commonly used but are of questionable benefit. If used, only one dose should be given with the first dose of activated charcoal. Some commercial charcoal preparations come premixed with sorbitol. Whole bowel irrigation Adult dose: start at 500 mL/hr, increase as tolerated to 2000 mL/hr, continue until rectal effluent clear. Pediatric dose: 20 mL/kg/hr, increase as tolerated to 50 mL/kg/hr to 500 mL/hr maximum, continue until rectal effluent clear.

SYRUP OF IPECAC
Ipecac is rarely if ever indicated in the prehospital or emergency department setting, for a number of reasons. It is a mixture of alkaloids that includes emetine and cephaeline, both of which are potent emetic agents that stimulate the mucosa locally as well as the chemoreceptor trigger zone in the brain. It is available over the counter in syrup form for ease of administration and rapid absorption. Syrup of ipecac initially gained its popularity as a home treatment for pediatric ingestions, where it is still commonly used, although firm data on outcome improvement even in this setting are lacking. One traditional approach to the overdose patient in the emergency department has also been to empty the stomach by using syrup of ipecac. This became popular in the 1960s, when several animal and clinical studies documented that syrup of ipecac was a safe and effective emetic in terms of its ability to induce vomiting in 20 to 30 minutes and to remove a small amount of a marker given shortly before the ipecac.[1][9][12][25][26] Inducing emesis per se became synonymous with efficacy, as opposed to altering clinical outcome. Subsequent studies in human volunteers or patients demonstrated that in many cases, after 30 to 60 minutes, ipecac was not able to decrease absorption of drugs and was inferior to activated charcoal at most time points studied.[28][59][72][79][80][81][82][83][84][85][86][98][110] It gradually became clear that although ipecac administration resulted in vomiting in almost all cases within 20 to 30 minutes, the amount of drug actually removed was small and variable. In addition, serious complications have been reported after ipecac administration, including aspiration pneumonia, gastric rupture, and stroke in an elderly patient.

Contraindications to ipecac include acid or alkali ingestion (if there are no co-ingestants), hydrocarbon ingestion (unless the hydrocarbon is also a systemic toxin such as a halogenated hydrocarbon or is a vehicle for a toxin such as a pesticide), and cases in which the ingested agent is likely to result in rapid onset of central nervous system (CNS) depression (e.g., a tricyclic antidepressant). The administration of ipecac also results in a substantial delay in the administration of activated charcoal.[60][93] Data from the American Association of Poison Control Centers have demonstrated a steady decline in the use of ipecac and a steady increase in the use of activated charcoal over the past several years.

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GASTRIC LAVAGE
Gastric lavage should not be performed routinely in overdose patients. As the name implies, gastric lavage is a procedure that is intended to remove material from the stomach. It is not intended to, nor could it, remove drugs from the small bowel, the primary site of drug absorption. Most lavage tubes or systems in common use today use a large-bore hose (adults, 36–40 French; pediatrics, 16–28 French). Aliquots of about 50–250 mL of water or saline are used to repeatedly rinse the stomach, with the patient usually in the Trendelenburg position on the left side to prevent aspiration.[23] Most clinicians believe that lavage can be performed safely without prior endotracheal intubation if the patient can adequately protect his or her own airway and is monitored carefully and if there is airway equipment and suction on hand if the patient vomits or otherwise rapidly deteriorates. As previously noted, adult drug overdose patients tend to present to the emergency department at least 3 hours after ingestion, making it unlikely that a significant amount of drug is still in the stomach. The holes in even the large-bore lavage tubes are too small to allow many pills to pass through them. Experimental evidence in both animals and humans demonstrates that lavage can remove only a small amount of material from the stomach even when it is performed shortly after administration of a study marker.[1][9][12][26][110] The life-threatening complications of gastric lavage include aspiration pneumonitis, esophageal perforation, endotracheal placement, cardiac arrhythmias, and oxygen desaturation.[3][44][53][60] Clinical studies of overdose patients have not demonstrated a beneficial effect of lavage when compared with the administration of activated charcoal alone.[3][60][75][93] The one exception was in a small subset of patients already obtunded on presentation who seemed to improve if lavage was done within 1 hour of ingestion (not presentation). [60] However, this study did not show that lavage is beneficial within 1 hour of presentation in patients who are minimally symptomatic. Three other studies could not demonstrate a benefit to lavage in any group of patients.[3][75][93] Gastric lavage should be reserved for those patients who have ingested a significant dose of a medication or chemical that is likely to result in morbidity, and only if the procedure can be done very soon after ingestion. If the drugs or chemicals are known to be well adsorbed to charcoal ( Table 5–2 ), the clinician must have an adequate rationale for performing lavage, with its known complications, instead of just administering activated charcoal either orally or down a nasogastric tube. In cases in which lavage is to be performed, administering a dose of charcoal down the lavage tube first, before stomach washes, is theoretically attractive.[18] In cases in which only a liquid (e.g., ethylene glycol or methanol) has been ingested, aspirating stomach contents with a smaller-bore nasogastric tube instead of a large orogastric lavage tube is an alternative treatment. Activated charcoal can then be administered down the tube if the substance is adsorbed to charcoal (see Table 5–2 ).

Table 5-2 -- Charcoal Adsorption of Drugs and Chemicals Commonly Cited as Not Being Adsorbed Not Significantly Adsorbed * Substance Study

Iron Lithium Borates Bromide Potassium Mineral acids and alkalis

Smith et al, 1967[102] Decker 1968[31] Favin 1988[38] Decker 1968[31] Oderda 1987[86] Edwards 1967[34] Welch 1986[115] Cooney 1980[24] Decker 1968[31] Andersen 1948[4] Smith 1967[103] Neuvonen 1984[84]

Ethanol †

Hulton 1985[51] Jackson 1980[52] Minocha 1986[76] Katona 1989[55]

Evidence of Significant Adsorption * Substance Cyanide Study Andersen 1946[5] Lambert 1988[61] Picchioni 1966[91] Malathion Decker 1968[31] Hayden 1975[46] Parathion Diazinon Dichlorvos DDT Carbamates Mercuric chloride Methanol N-Methyl carbamate Ethylene glycol Guven 1994[43] Orisakwe 1993[88] Guven 1994[43] Decker 1968[31] Buck 1986 ‡
[13]

Andersen 1946[5] Decker 1981[32] Decker 1968[31] Decker 1981[32] Szabuniewicz 1975[105]

Kerosene Turpentine Isopropyl alcohol Tolbutamide

Decker 1981[32] Decker 1981[32] Burkhart 1992[16] Neuvonen 1982[81]

* “Significant adsorption” in this context is arbitrarily assumed to exist when 50 g of activated charcoal could adsorb a toxic dose (significant symptoms expected) in adults based on an extrapolation of in vitro data, or when in vivo studies have shown that toxicity or morbidity was decreased by charcoal. † Ethanol appears to be adsorbed in vitro but not in vivo in human studies. ‡ Typographical error in manuscript; 10/10 (not 0/10) animals given activated charcoal after carbaryl survived, versus 0/10 controls.

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ACTIVATED CHARCOAL ALONE
Administering charcoal to the typical overdose patient without gastric emptying has become a common treatment modality. There is significant literature support for this approach. Charcoal has been used for medicinal purposes since antiquity; the first recorded use was by the ancient Egyptians circa 1550 B.C. [24] The first recorded scientific studies of charcoal being used to treat human poisoning were from France, England, and America in the 1800s. Medical use of charcoal has greatly increased since those earliest studies alluded to its effectiveness.[20][21][22][23][24][33][42][50][55][90][102][113] Modern activated charcoal is a far more efficient product than that used in initial studies. It is manufactured by the pyrolysis of wood or other carbonaceous material, which is then oxidized at high temperatures using steam, air, carbon dioxide, or oxygen. Metallic chlorides may be used to enhance pore development and removed later with a dilute acid. The final product has a surface area of 950 to 2000 m2/g. A superactivated charcoal with a surface area of 3150 m2/g was previously marketed[29] but is not currently available. There are several advantages to the use of activated charcoal not seen with other methods of GI decontamination: 1. It can be administered very quickly. If the patient is awake and cooperative, the patient may drink a dose immediately after presentation. If the patient is comatose or uncooperative, the dose can be quickly administered down a nasogastric tube. Drugs or chemicals can continue to be absorbed during more time-consuming procedures such as ipecac-induced emesis or gastric lavage. Charcoal is effective even if the history is inaccurate. Even if the substances in question and the time of ingestion are unknown, charcoal can still be effective, as it adsorbs most commonly ingested drugs and chemicals (see Table 5–2 ). Unlike induced vomiting and lavage, which under the best of circumstances might remove some of the ingested material still in the stomach, a charcoal slurry can easily pass through the pylorus to the primary site of drug absorption—the small intestine.

2.

3.

There are no contraindications to the use of activated charcoal in overdose patients if the GI tract is intact (i.e., without perforation) and there is no bowel obstruction or ileus to impede passage through the gut. Because acids and alkalis are not well adsorbed to charcoal, and because charcoal may obscure the view of an endoscopist, it should not be given in cases of isolated acid or alkali ingestion. However, if charcoal is administered for other ingested agents that are systemic toxins, the corrosive is not a contraindication. There are no published cases of anaphylaxis from charcoal. There are several disadvantages to and complications from activated charcoal:

1.

Charcoal may induce vomiting in some patients.[77] Whether this is due to the gritty texture of the charcoal, the volume administered, additives such as sorbitol, or a combination of factors is unclear. Volunteers who drink charcoal have a low incidence of vomiting.[79] Some options for antiemetics in patients vomiting from either the charcoal or the ingested drugs are shown in Table 5–3 . Table 5-3 -- Parenteral Antiemetics of Possible Utility in Poisoned Patients with Severe Vomiting Generic Name Trade Name Adult IV Dose Pediatric IV Dose * Prochlorperazine Compazine Promethazine Metoclopramide Droperidol Ondansetron Granisetron Dolasetron Phenergan Reglan Inapsine Zofran Kytril Anzemet 2.5–10 mg q 4 hr 12.5–25 mg q 4 hr 10 mg 0.06 mg/lb IM † 0.50 mg/lb IM † 0.25 mg/kg

1.25–5 mg q 4 hr prn 0.05 mg/kg/dose ‡ 4–32 mg qd 10 µg/kg qd 12.5 mg qd 0.1 mg/kg qd 10 µg/kg qd 0.35 mg/kg qd up to 12.5 mg qd

* For children 2 years of age and older. Doses may be based on those used during chemotherapy; the package insert may not have a recommended pediatric dose. † Children are very susceptible to the dystonic effects of these agents, and they should be used only if essential for treatment. Based on the package insert, intramuscular (IM) and not intravenous (IV) use is recommended. ‡ May cause significant sedation or dysphoria.

2.

Although charcoal itself is inert, aspiration into the lungs can result in a mechanical obstruction of the airways, particularly if the slurry is inadequately diluted. This may result in respiratory failure and other pulmonary complications.[35][44][53][74][92][94] In most cases, aspiration of the acidic stomach contents is the likely cause of the pneumonitis seen, and the presence of charcoal in the aspirate is incidental. Charcoal may cause constipation and mechanical bowel obstruction when used in a multiple-dose manner.[10][41][69][114] This is not seen after a single dose. Charcoal may not be readily accepted by children, which might necessitate a nasogastric tube for administration. Charcoal might theoretically adsorb oral antidotes such as N-acetylcysteine, D-penicillamine, and DMSA (dimercaptosuccinic acid; Chemet). Usual adult doses of charcoal have not been shown to significantly alter absorption of N-acetylcysteine. Charcoal is generally unpleasant for health care personnel to use, as it stains clothing, walls, floors, ceilings, and so forth.

3. 4. 5.

6.

The evidence for the efficacy of activated charcoal in the treatment of poisoning comes primarily from in vitro binding studies, in vivo mortality studies, volunteer studies, and comparison studies in overdose patients. The combined knowledge gathered from these studies demonstrates that charcoal effectively binds the vast majority of drugs and chemicals likely to be acutely ingested (see Table 5–2 ). There have been some differences of opinion regarding what constitutes “significant adsorption,” resulting in numerous review

articles claiming that, for example, cyanide, DDT, N-methyl carbamate, and others are not adsorbed. If the goal of charcoal therapy is to bind an amount of toxin that could result in major toxicologic effects (for example, as defined by the Amercian Association of Poison Control Centers), then by extrapolating these data to humans or by examining the in vivo data, these chemicals are adsorbed by charcoal. Using the same criteria, substances more clearly shown not to be adsorbed are also listed in Table 5–2 . Cyanide is an example of the importance of the principles just outlined. The original research[6] demonstrated that 1 g of charcoal could bind 35 mg of potassium cyanide in vitro. This was claimed in multiple review articles to demonstrate lack of adsorption, which seems to overlook that as little as 200 mg of potassium cyanide is a potentially lethal dose in humans, while 50 g of charcoal is a typical charcoal dose. If this stoichiometry holds at higher doses, 50 g of charcoal might bind up to 1750 mg of cyanide, which would be multiple potential lethal doses. Adsorption was clearly demonstrated by in vivo research,[61] whereby the mortality rate in rats given 35 mg/kg of cyanide was reduced from 93 per cent to 33 per cent when charcoal was administered immediately afterward, and from 100 per cent to 27 per cent when a dose of 40 mg/kg of cyanide was used. It is disturbing that clinicians relying on inaccurate information over the years might have withheld charcoal therapy in patients known to be poisoned by cyanide. Another approach to the issue of adsorbability is demonstrated for boric acid. In this case, the original research[31] showed that 5 g of charcoal could bind 30–45 mg of borate. Another in vitro study[86] demonstrated that 30 g of charcoal bound 38.6 per cent of 1 g of boric acid. Extrapolating the latter data, 100 g of charcoal would likely be unable to bind a significant amount of a toxic adult dose of borate (approximately 15 g). The advantage of in vitro work is that many different substances can be tested at the same time, and the research is relatively less expensive and less time intensive than other types of charcoal research. Historically, in vitro studies[4][5][6][22][31][32][65] have provided important background that has driven the enthusiasm for the use of charcoal in patients and for additional charcoal research. In vivo studies of charcoal are commonly performed in small animals in which the median lethal dose (LD50) or LD100 of the substance in question is administered, with and without activated charcoal, and the decrease in mortality is evaluated. Assuming that the doses of drug and charcoal are, by extrapolation, analogous to what might be seen in overdose patients, this type of study provides some evidence for the efficacy of charcoal in humans. However, because of the higher metabolic rates of small animals, charcoal is usually administered very soon after the toxin. This technique has been employed, for example, for cyanide [61] and carbamates.[13] A different in vivo approach in dogs was used to evaluate lavage versus charcoal versus a charcoal-lavagecharcoal approach in which the 6-hour level of salicylate was measured and used to compare efficacy.[18] In this study, charcoal was superior to lavage, and the combined approach tended toward even more efficacy but did not achieve statistical significance. This type of charcoal study can be very valuable, as toxic doses of drugs can be administered, but it has the disadvantage of requiring anesthesia and a large budget. Volunteer studies in general have attempted to compare activated charcoal with ipecac or lavage when volunteers are given a therapeutic or slightly supratherapeutic dose of medications. By examining the area under the serum concentration time curve, or the total amount of drug excreted (by implication, the amount

absorbed), a comparison of the efficacy of charcoal versus lavage versus ipecac can be attempted. This technique has been used to evaluate many drugs, including acetaminophen, ampicillin, aspirin, chlorpropamide, theophylline, and numerous others.[63][72][79][80][81][82][83][84][85][98][110] In most cases, charcoal alone proved superior to ipecac and lavage either alone or with charcoal. The obvious disadvantage to volunteer studies is the inability to administer an overdose of medications and chemicals, the kinetics and the binding ability of charcoal not necessarily being similar to what is seen after overdose. Charcoal studies in actual overdose patients are few in number and may be the hardest to interpret because of the heterogeneous nature of overdose patients and the difficulty in determining whether it was the charcoal that altered the outcome. The first of these compared charcoal alone versus ipecac plus charcoal and found no difference in clinical outcomes.[60] The same study also compared charcoal by nasogastric tube alone versus lavage plus charcoal and detected a difference only if lavage was performed within 1 hour of ingestion in patients who were already obtunded from the overdose. It was clear from these data that charcoal alone was a viable treatment option to gastric emptying. A similar study[3] examined ipecac plus charcoal versus charcoal alone in overdose patients. Outcomes were similar, but the group that received ipecac had a higher incidence of iatrogenic complications (5.4 per cent vs. 0.9 per cent; p < .05), which included four cases of aspiration pneumonitis after ipecac-induced vomiting. One must be cautious in ascribing certain complications to “charcoal,” as if they occurred from a single dose and not from multiple doses. The two main published complications have been pulmonary aspiration with sequelae[35][44][45][53][74][92][94] and GI obstruction.[10][69][95][114] The pulmonary complications are more commonly seen after multiple-dose rather than single-dose charcoal, and it is not clear whether they are from the charcoal or the accompanying acidic gastric contents in the aspirate. Likewise, inspissated charcoal causing obstruction is not seen from single-dose charcoal and should not be considered a complication of “charcoal” but of repeated use in patients with decreased GI motility. There have been reports of corneal abrasions from charcoal getting into the eyes of overdose patients during vomiting.[71] This complication should be avoidable or easily treatable if it occurs. Not infrequently, it is desirable to administer charcoal to a patient who is vomiting and therefore unlikely to retain charcoal or an oral antidote in the GI tract. Antiemetics can be effectively used in this setting (see Table 5–3 ). Serotonin 5-HT3 antagonists appear particularly effective in this regard but are very expensive. The less expensive agents may be used first, with the more expensive agents used only if the former are ineffective.

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CATHARTICS
It is recommended that one dose of a cathartic, preferably sorbitol 1 g/kg, be administered with the first dose of activated charcoal. However, it has never been shown in clinical studies that the use of cathartics makes a difference in clinical outcome. When given, cathartics are commonly co-administered with activated charcoal on the theory that they may cause the drug-charcoal complex to be excreted more quickly, thereby resulting in less risk of desorption (de-binding of the charcoal-drug complex) or charcoal inspissation. Some experimental evidence suggests that cathartics do not interfere with charcoal adsorption of drugs and may actually enhance it. Sorbitol may also make the charcoal more palatable. Cathartics in common use include magnesium sulfate, magnesium citrate, and sorbitol. Some commercial charcoal preparations come premixed with sorbitol. Several case reports have demonstrated the dangers of multiple doses of magnesium-containing cathartics resulting in life-threatening hypermagnesemia. Excessive sorbitol use in children may result in severe dehydration. The use of multiple doses of cathartics is not recommended, as their theoretic benefit is outweighed by the potential for harm.

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OBSERVATION ALONE
An innovative approach was taken in one study of overdose patients in which one group of asymptomatic or minimally symptomatic patients received neither gastric emptying nor charcoal, but observation only.[75] This study demonstrated a higher incidence of aspiration pneumonitis in patients in whom gastric emptying was performed (8.5 per cent vs. 0 per cent; p = .001) but failed to demonstrate a beneficial effect of activated charcoal use. The authors concluded that in asymptomatic overdose patients presenting to the emergency department, observation only is an option. Although this may be a safe approach in some patients with trivial ingestion, if the patient has not provided an accurate history and has really ingested something very dangerous, the absence of any initial decontamination measures may be of clinical and medicolegal significance.

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WHOLE BOWEL IRRIGATION
Whole bowel irrigation entails flushing the entire GI tract with a nonabsorbable isotonic electrolyte solution containing polyethylene glycol (PEG).[30][36][57][100][106][108][109][110] This can be done by having the patient drink the solution or by infusing it down a nasogastric tube. Typical doses in adults are 500 mL/hr of Colyte or GoLYTELY initially down a nasogastric tube, which can be increased to 1000–2000 mL/hr in patients who are not vomiting. Pediatric doses are generally 100–200 mL/hr by nasogastric tube. This is generally administered until the rectal effluent is clear or, in cases in which the ingested substance is radiopaque, such as iron, until the abdominal films are clear. A dose of activated charcoal can be administered first if the ingested material is adsorbed to it to both prevent absorption and act as a marker for the procedure. Some studies have shown a slightly decreased efficacy of charcoal in the presence of PEG.[47][58][99] Much of the evidence for the effectiveness of the procedure is anecdotal. It has been used for a variety of drugs, including sustained-release preparations.[7][8][14][15][17][37][57][73][78][87] Whole bowel irrigation seems to be, from both a practical and an effectiveness standpoint, useful primarily when the ingested drugs are not adsorbed to charcoal or when bags of illicit drugs have been ingested that need to be removed as quickly as possible before rupture occurs (see discussion later). Drugs or chemicals not well adsorbed to charcoal for which this procedure might be particularly beneficial include iron,[37][54][66][106][108][109] lead,[96] other metals,[62] lithium,[103][106][108] and borates (see Table 5–2 ).

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THE BODY PACKER/BODY STUFFER PATIENT
Body packers and stuffers may be therapeutic dilemmas in GI decontamination, because the packets containing the illicit drugs are large and not easily removed, and a life-threatening situation can occur if a packet ruptures (iatrogenically or spontaneously).[19][39][68][70][116] Drugs can also leak from intact packets.[2] Body packers are smugglers who swallow tightly sealed packets of cocaine, amphetamines, tetrahydrocannabinol (THC), or heroin.[70] Body stuffers are usually drug sellers on the street who are suddenly confronted by the police and swallow the evidence, which is often not tightly or efficiently packaged.[97] Crack vials may also be ingested.[48] Radiographic evidence of packets in the GI tract may be seen, with the larger, denser packets in body packers being far more likely to be visible than those in body stuffers.[11][19] Abdominal computed tomography (CT),[27] plain films with contrast,[40][67] or ultrasonography may also be useful in visualizing packets. If packets are not clearly seen despite a good history of ingestion, consultation with the radiologist is recommended to determine which of these procedures is preferable. Screening ultrasonography can often be performed by the emergency department physician, although its value in the detection of drug packets is currently unknown. The drugs involved (cocaine,[111] heroin, amphetamines, or THC) are adsorbed to charcoal, but if rupture occurs, there must be a large amount of charcoal in the immediate vicinity of the packets to be effective. Surgery is an option but is unnecessary if the packets can be removed by less invasive maneuvers. If packets rupture, however, surgery may be lifesaving. Endoscopy may be useful to visualize packets, but packets may rupture if the endoscopist attempts to snare and remove them. Ipecac has been used successfully to remove packets from the stomach,[64] but doing so is theoretically dangerous and seldom recommended. Whole bowel irrigation is often useful in body packers and stuffers.[48][49] The solution may act as a lubricating surface in addition to a mechanical force to push packets along and out the GI tract. At least one dose of activated charcoal should be administered first, although the PEG solution will decrease its efficacy somewhat.[65] If the drug involved is heroin, naloxone or naltrexone should be kept at the bedside and administered at the first sign of opioid toxicity. Whenever packet rupture is suspected on the basis of patient deterioration, emergent surgery to remove packets should remain an option.[104][112] Whole bowel irrigation after one dose of charcoal, without ipecac, lavage, or endoscopy, is the current treatment recommendation for both body packers and body stuffers. Because of the potential for catastrophic deterioration, patients should be kept in a closely monitored setting with frequent observation and measurement of vital signs. It is prudent to maintain the patient in that setting for at least 12 hours after it is thought that the last packet has been removed, based on radiographic studies, clinical appearance, vital signs, and, in some cases, the number of packets ingested by history, if known. Patients on a police hold should be monitored as closely as patients who are not.

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CONCLUSION
Which methods of GI decontamination to use in a specific overdose patient can be determined largely by common sense. For the typical adult overdose patient who has ingested several different drugs several hours ago and is minimally symptomatic, the most sensible as well as the easiest approach is to simply administer a dose of activated charcoal. If the history turns out to be inaccurate, the clinician has still addressed the other drugs or chemicals ingested, except in the rare case of ingestion of drugs not adsorbed to charcoal. There is little reason to perform lavage in these patients, and no reason to administer ipecac. One dose of a cathartic is commonly used but is of unproven benefit. Multiple dose of cathartics should be avoided. Whole bowel irrigation should be reserved for patients who have ingested iron, other metals and radiopaque material, and substances not adsorbed to charcoal or for body packers or body stuffers.

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REFERENCES
1. Abdallah AH, Tye A: A comparison of the efficacy of emetic drugs and stomach lavage. Am J Dis Child 1967; 113:571. 2. Aks SE, Vander Hoek TL, Hryhorczuk DO, et al: Cocaine liberation from body packets in an in vitro model. Ann Emerg Med 1992; 21:1321. 3. Albertson TE, Derlet RW, Foulke GE, et al: Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989; 18:56. 4. Andersen AH: Experimental studies on the pharmacology of activated charcoal. III. Adsorption from gastro-intestinal contents. Acta Pharmacol 1948; 4:275. 5. Andersen AH: Experimental studies on the pharmacology of activated charcoal. II. The effect of pH on the adsorption by charcoal from aqueous solutions. Acta Pharmacol 1946; 3:199. 6. Andersen AH: Experimental studies on the pharmacology of activated charcoal. I. Adsorption power of charcoal in aqueous solutions. Acta Pharmacol 1946; 2:69. 7. Arimori K, Deshimaru M, Furukawa E, Nakano M: Adsorption of mexiletine onto activated charcoal in macrogol-electrolyte solution. Chem Pharm Bull 1993; 41:766. 8. Arimori K, Furukawa E, Nakano M: Adsorption of imipramine onto activated charcoal and a cation exchange resin in macrogol-electrolyte solution. Chem Pharm Bull 1992; 40:3105. 9. Arnold FJ, Hodges JB, Barta PA, et al: Evaluation of the efficacy of lavage and emesis in the treatment of salicylate poisoning. Pediatrics 1959; 23:286. 10. Atkinson SW, Young Y, Trotter GA: Treatment with activated charcoal complicated by gastrointestinal obstruction requiring surgery. BMJ 1992; 305:563. 11. Beerman R, Nunez Jr D, Wetli CV: Radiographic evaluation of the cocaine smuggler. Gastrointest Radiol 1986; 11:351. 12. Boxer L, Anderson FP, Rowe DS: Comparison of ipecac-induced emesis with gastric lavage in the treatment of acute salicylate ingestion. J Pediatr 1969; 74:800. 13. Buck WB, Bratich PM: Activated charcoal: Preventing unnecessary death by poisoning. Vet Med 1986; 73(Jan): 14. Buckley N, Dawson AH, Howarth D, Whyte IM: Slow-release verapamil poisoning: Use of polyethylene glycol whole-bowel irrigation lavage and high-dose calcium. Med J Aust 1993; 158:202. 15. Burkhart KK, Kulig KK, Rumack B: Whole-bowel irrigation as treatment for zinc sulfate overdose. Ann Emerg Med 1990; 19:1167. 16. Burkhart KK, Martinez MA: The adsorption of isopropanol and acetone by activated charcoal. Clin

Toxicol 1992; 30:371. 17. Burkhart KK, Wuerz RC, Donovan JW: Whole-bowel irrigation as adjunctive treatment for sustainedrelease theophylline overdose. Ann Emerg Med 1992; 21:1316. 18. Burton BT, Bayer MJ, Barron L, et al: Comparison of activated charcoal and gastric lavage in the prevention of aspirin absorption. J Emerg Med 1984; 1:411. 19. Caruana DS, Weinbach B, Goerg D, et al: Cocaine-packet ingestion. Ann Intern Med 1984; 100:73. 20. Chin L, Picchioni AL, Bourn WM, et al: Optimal antidotal dose of activated charcoal. Toxicol Appl Pharmacol 1973; 26:103. 21. Chin L, Picchioni AL, Duplisse BR: The action of activated charcoal on poisons in the digestive tract. Toxicol Appl Pharmacol 1970; 16:786. 22. Chin L, Picchioni AL, Duplisse BR: Comparative antidotal effectiveness of activated charcoal, Arizona montmorillonite, and evaporated milk. J Pharm Sci 1968; 58:1353. 23. Comstock EG, Boisaubin EV, Comstock BS, et al: Assessment of the efficacy of activated charcoal following gastric lavage in acute drug emergencies. Clin Toxicol 1982; 19:149. 24. Cooney DO: Activated Charcoal: Antidotal and Other Medical Uses, New York, Marcel Dekker, 1980. 25. Corby DC, Decker W: Clinical comparison of pharmacologic emetics in children. Pediatrics 1968; 42:361. 26. Corby DC, Lisiandro RC, Lehman RH, et al: The efficacy of methods used to evacuate the stomach after acute ingestions. Pediatrics 1967; 40:871. 27. Cranston PE, Pollack Jr CV, Harrison RB: CT of crack cocaine ingestion. J Comput Assist Tomogr 1992; 16:560. 28. Curtis RA, Barone J, Giacona N: Efficacy of ipecac and activated charcoal/cathartic: Prevention of salicylate absorption in a simulated overdose. Arch Intern Med 1984; 144:48. 29. Curt-Sneed CD, Parks KS, Bordelon JG, et al: In vitro adsorption of sodium pentobarbital by superchar, USP and Darco G-60 activated charcoals. Clin Toxicol 1987; 25:1. 30. Davis GR, Santa Ana CA, Morawski SG, et al: Development of a lavage solution associated with minimal water and electrolyte absorption or secretion. Gastroenterology 1980; 78:991. 31. Decker WJ, Combs HF, Corby DG: Adsorption of drugs and poisons by activated charcoal. Toxicol Appl Pharmacol 1968; 13:454. 32. Decker WJ, Corby DG, Hilburn RE, et al: Adsorption of solvents by activated charcoal, polymers, and mineral sorbents. Vet Hum Toxicol 1981; 23(suppl 1):44. 33. Derlet RW, Albertson RE: Activated charcoal—past, present, and future. West J Med 1986; 145:493. 34. Edwards DG, McCredie M: Binding properties of acidic, basic, and neutral drugs to anion and cation exchange resins and charcoal in vitro. Med J Aust 1967; 1:535.

35. Elliot CG, Colby TV, Kelly TM, et al: Charcoal lung: Brochiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672. 36. Ernstoff JJ, Howard DA, Marshall JB, et al: A randomized blinded clinical trial of a rapid colonic lavage solution (GoLYTELY) compared with standard preparation for colonoscopy and barium enema. Gastroenterology 1983; 84:1512. 37. Everson GW, Bertaccini EJ, O’Leary J: Use of whole bowel irrigation in an infant following iron overdose. Am J Emerg Med 1991; 9:366. 38. Favin FD, Klein-Schwartz W, Oderda GM, Rose SR: In vitro study of lithium carbonate adsorption by activated charcoal. J Toxicol Clin Toxicol 1988; 26:443. 39. Fishbain DA, Wetli CV: Cocaine intoxication, delirium, death in a body packer. Ann Emerg Med 1981; 10:531. 40. Gherardi R, Marc B, Alberti X, et al: A cocaine body packer with normal abdominal plain radiograms: Value of drug detection in urine and contrast study of the bowel. Am J Forensic Med Pathol 1990; 11:154. 41. Gomez HF, Brent JA, Munoz DC, et al: Charcoal stercolith with intestinal perforation in a patient treated for amitriptyline ingestion. J Emerg Med 1994; 12:57. 42. Greensher J, Mofenson HC, Picchioni AL, et al: Activated charcoal updated. J Am Coll Emerg Phys 1979; 8:261. 43. Guven H, Tuncok Y, Gidener S, et al: In vitro adsorption of dichlorvos and parathion by activated charcoal. Clin Toxicol 1994; 32:157. 44. Harris CR, Filandrinos D: Accidental administration of activated charcoal into the lung: Aspiration by proxy. Ann Emerg Med 1993; 22:1470. 45. Harsch HH: Aspiration of activated charcoal. N Engl J Med 1986; 314:318. 46. Hayden JW, Comstock EG: Use of activated charcoal in acute poisoning. Clin Toxicol 1975; 8:515. 47. Hoffman RS, Chiang WK, Howland MA, et al: Theophylline desorption from activated charcoal caused by whole bowel irrigation solution. J Clin Toxicol 1991; 29:191. 48. Hoffman RS, Chiang WK, Weisman RS, et al: Prospective evaluation of “crack-vial” ingestions. Vet Hum Toxicol 1990; 32:164. 49. Hoffman RS, Smilkstein MJ, Goldfrank LR: Whole bowel irrigation and the cocaine “body-packer”: A new approach to a common problem. Am J Emerg Med 1990; 8:523. 50. Holt LE, Holz PH: The black bottle. Pediatrics 1963; 63:306. 51. Hulton BA, Heath A, Mellstrand T, et al: Does alcohol adsorb to activated charcoal?. Hum Toxicol 1985; 5:211. 52. Jackson JE, Picchioni AL, Chin L: Contraindications for activated charcoal use. Ann Emerg Med 1980; 9:599.

53. Justiani FR, Hippalgaonkar R, Martinez LO: Charcoal containing empyema complicating treatment for overdose. Chest 1985; 87:404. 54. Kaczorowski JM, Wax PM: Five days of whole-bowel irrigation in a case of pediatric iron ingestion. Ann Emerg Med 1996; 27:258. 55. Katona BG, Siegel EG, Cluxton RJ, et al: The new black magic: Activated charcoal and new therapeutic uses. J Emerg Med 1987; 5:9. 57. Kirshenbaum LA, Mathews SC, Sitar DS, et al: Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals. Clin Pharmacol Ther 1989; 46:264. 58. Kirshenbaum LA, Sitar DS, Tenenbein M: Interaction between whole-bowel irrigation solution and activated charcoal: Implications for the treatment of toxic ingestion. Ann Emerg Med 1990; 19:1129. 59. Kornberg AE, Dolgin J: Pediatric ingestions: Charcoal alone versus ipecac and charcoal. Ann Emerg Med 1991; 20:648. 60. Kulig K, Bar-Or D, Cantrill SV, et al: Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985; 14:562. 61. Lambert RJ, Kindler BL, Schaeffer DJ: The efficacy of superactivated charcoal in treating rats exposed to a lethal oral dose of potassium cyanide. Ann Emerg Med 1988; 17:595. 62. Lee DC, Roberts JR, Kelly JJ, Fishman SM: Whole-bowel irrigation as an adjunct in the treatment of radiopaque arsenic. Am J Emerg Med 1995; 13:244. 63. Levy G, Tsuchiya T: Effect of activated charcoal on aspirin absorption in man. Clin Pharmacol Ther 1972; 13:317. 64. Linden CH: Ipecac for ingested drug packets [abstract A-29]. Vet Hum Toxicol 1984; 26:404. 65. Makosiej FJ, Hoffman RS, Howland MA, et al: An in vitro evaluation of cocaine hydrochloride adsorption by activated charcoal and desorption upon addition of polyethylene glycol electrolyte lavage solution. J Toxicol Clin Toxicol 1993; 31:381. 66. Mann KV, Picciotti MA, Spevack TA, Durbin DR: Management of acute iron overdose. Clin Pharm 1989; 8:428. 67. Marc B, Baud FJ, Aelion MJ, et al: The cocaine body-packer syndrome: Evaluation of a method of contrast study of the bowel. J Forensic Sci 1990; 35:345. 68. Marc B, Gherardi RK, Baud FJ, et al: Managing drug dealers who swallow the evidence. BMJ 1989; 299:1082. 69. Mariani PJ, Pool N: Gastrointestinal tract perforation with charcoal peritoneum complicating orogastric intubation and lavage. Ann Emerg Med 1993; 132:606. 70. McCarron MM, Wood JD: The cocaine bodypacker syndrome. JAMA 1983; 250:1417. 71. McKinney PE, Phillips S, Gomez HF, et al: Corneal abrasions secondary to activated charcoal. Am J Emerg Med 1993; 11:562.

72. McNamara RM, Aaron CK, Gemborys M, et al: Efficacy of charcoal and cathartic versus ipecac in reducing serum acetaminophen in a simulated overdose. Ann Emerg Med 1989; 18:934. 73. Melandri R, Re G, Morigi A, et al: Whole bowel irrigation after delayed release fenfluramine overdose. J Toxicol Clin Toxicol 1995; 33:161. 74. Menzies DG, Busuttil A, Prescott LF: Fatal pulmonary aspiration of oral activated charcoal. BMJ 1988; 297:459. 75. Merigian KS, Woodard M, Hedges JR, et al: Prospective evaluation of gastric emptying in the self poisoned patient. Am J Emerg Med 1990; 8:479. 76. Minocha A, Herold DA, Barth JT, et al: Activated charcoal in oral ethanol absorption: Lack of effect in humans. J Toxicol Clin Toxicol 1986; 24:225. 77. Minocha A, Krenzolek EP, Spyker DA: Dosage recommendations for activated charcoal-sorbitol treatment. J Toxicol Clin Toxicol 1985; 23:579. 78. Mizutani T, Yamashita M, Okubo N, et al: Efficacy of whole bowel irrigation using solutions with or without adsorbent in the removal of paraquat in dogs. Hum Exp Toxicol 1992; 11:495. 79. Neuvonen PJ: Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin Pharmacokinet 1982; 7:465. 80. Neuvonen PJ, Elonen E: Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine, and phenylbutazone in man. Eur J Pharmacol 1980; 17:51. 81. Neuvonen PJ, Kannisto H, Alanen T et al. Effect of activated charcoal on the absorption of tolbutamide and valproate in man [abstract]. Joint meeting of the British and Scandinavian Pharmacological Societies, July 4–6, 1982. 82. Neuvonen PJ, Karkkainen S: Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics. Clin Pharmacol Ther 1983; 33:386. 83. Neuvonen PJ, Olkkola KT: Oral activated charcoal in the treatment of intoxications: Role of single and repeated doses. Med Toxicol 1988; 3:33. 84. Neuvonen PJ, Olkkola KT: Activated charcoal and syrup of ipecac in prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as an antiemetic agent. Clin Toxicol 1984; 22:103. 85. Neuvonen PJ, Variainen M, Tokola O: Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J Clin Pharmacol 1983; 24:557. 86. Oderda GM, Klein-Schwartz W, Insley BM: In vitro study of boric acid and activated charcoal. Clin Toxicol 1987; 25:13. 87. Olsen KM, Ma FH, Ackerman BH, Stall RE: Low-volume whole bowel irrigation and salicylate absorption: A comparison with ipecac charcoal. Pharmacotherapy 1993; 13:229. 88. Orisakwe OE, Obi N: In vitro and in vivo adsorption studies of diazinon. Hum Exp

Toxicol 1993; 12:301. 90. Picchioni AL, Chin L, Laird HE: Activated charcoal preparations— relative antidotal efficacy. Clin Toxicol 1974; 7:97. 91. Picchioni AL, Chin L, Verhulst HL, et al: Activated charcoal vs. universal antidote as an antidote for poisons. Toxicol Appl Pharmacol 1966; 8:447. 92. Pollack MM, Dunbar BS, Holbrook PR, et al: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528. 93. Pond SM, Lewis-Driver DJ, Williams GM, et al: Gastric emptying in acute overdose: A prospective randomised controlled trial. Med J Aust 1995; 163:345. 94. Rau NR, Nagara MV, Prakesh PS, et al: Fatal pulmonary aspiration of activated charcoal. BMJ 1988; 297:918. 95. Ray MJ, Padin R, Condie JD, et al: Charcoal bezoar: Small bowel obstruction secondary to amitriptyline overdose therapy. Dig Dis Sci 1988; 33:106. 96. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg Med 1992; 10:577. 97. Roberts JR, Price D, Goldfrank L, et al: The bodystuffer syndrome: A clandestine form of drug overdose. Am J Emerg Med 1986; 4:24. 98. Rose SR, Gorman RL, Oderda GM, et al: Simulated acetaminophen overdose: Pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064. 99. Rosenberg PJ, Livingstone DJ, McLellan BA: Effect of whole-bowel irrigation on the antidotal efficacy of oral activated charcoal. Ann Emerg Med 1988; 17:681. 100. Scharman EJ, Lembarsky R, Krenzelok EP: Efficacy of whole bowel irrigation with and without metoclopramide pretreatment. Am J Emerg Med 1994; 12:302. 102. Smith RP, Gosselin RE, Henderson JA, et al: Comparison of the adsorptive properties of activated charcoal and Alaskan montmorillonite for some common poisons. Toxicol Appl Pharmacol 1967; 10:95. 103. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991; 20:536. 104. Suarez CA, Arango A, Lester III JL: Cocaine-condom ingestion: Surgical treatment. JAMA 1977; 238:1391. 105. Szabuniewicz M, Bailey EM, Wiersig DO: A new regimen for the treatment of ethylene glycol poisoning. IRCS Medical Science 1975; 3:102. 106. Tenenbein M: Whole bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Med Toxicol 1988; 3:77. 108. Tenenbein M: Whole bowel irrigation for toxic ingestions. Clin Toxicol 1985; 23:177.

109. Tenenbein M, Cohen S, Sitar DS: Whole bowel irrigation as a decontamination procedure after acute drug overdose. Arch Intern Med 1987; 147:905. 110. Tenenbein M, Cohen S, Sitar DS: Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute overdose. Ann Emerg Med 1987; 16:838. 111. Tomaszewski C, McKinney P, Phillips S, et al: Prevention of toxicity from oral cocaine by activated charcoal in mice. Ann Emerg Med 1993; 22:1804. 112. Trent MS, Kim U: Cocaine packet ingestion. Arch Surg 1987; 122:1179. 113. Vale JA, Proudfoot AT: How useful is activated charcoal?. BMJ 1993; 306:78. 114. Watson WA, Cremer KF, Chapman JA: Gastrointestinal obstruction associated with multiple dose activated charcoal. J Emerg Med 1986; 4:401. 115. Welch DW, Johnson PN, Driscoll JL, et al: In vitro potassium binding: A comparison, of activated charcoal and sodium polystyrene sulfonate. Vet Hum Toxicol 1986; 28:495. 116. Wetli CV, Mittleman RE: The “body packer syndrome”—toxicity following ingestion of illicit drugs packaged for transportation. J Forensic Sci 1981; 26:492.

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Uncited references Katona BG, Siegel EG, Roberts JR, et al: The effect of “superactive” charcoal and magnesium citrate solution on blood ethanol concentration and area under the curve in humans. J Toxicol Clin Toxicol 1989; 27:129. Palatnick W, Tenenbein M: Activated charcoal in the treament of drug overdose. Drug Safety 1992; 7:3. Schneider SM, Michelson EA: Enhanced activated charcoal delivery through small-bore tubing. Vet Hum Toxicol 1993; 35:503. Tenenbein M: Whole bowel irrigation in iron poisoning. J Pediatr 1987; 111:142.

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Chapter 6 – Extracorporeal Removal of Drugs and Toxins
JANIS M. ORLOWSKI SUSAN HOU JERROLD B. LEIKIN Although very few toxic exposures require, or are effectively treated by, extracorporeal techniques, these techniques are essential modalities that may be lifesaving in the treatment of selected poisoned patients. The extracorporeal techniques most commonly employed for the removal of toxins are hemodialysis and charcoal hemoperfusion, although plasmapheresis, exchange transfusion, and continuous ultrafiltration techniques may also be used. According to the 1998 American Association of Poison Control Centers (AAPCC) data, extracorporeal procedures were utilized in fewer than 0.05 per cent of cases, with hemodialysis accounting for 93 per cent. [33] Implementation of these invasive techniques requires the 24hour availability of nephrologists and other critical care specialists, dialysis equipment, technicians, and reference laboratory personnel who monitor the efficacy of treatment. Employing extracorporeal techniques to remove toxins should be considered if, in so doing, total body elimination of the toxin can be increased by 30 per cent or more.[45] Specific criteria related to physical characteristics of the toxin, the efficacy of alternative therapies, the presence of renal failure, and the severity of poisoning guide decisions regarding the utilization of these techniques ( Table 6–1 ). Certain agents that predictably cause severe toxicity are routinely dialyzed, based on an assessment of blood levels or clinical manifestations of toxicity. These include lithium, ethylene glycol, methanol, salicylates, and theophylline ( Table 6–2 ). Extracorporeal techniques may also be beneficial in the treatment of severe poisoning with other agents ( Tables 6–3 and 6–4 ). Physical characteristics that predict the successful removal of an agent by dialysis or charcoal hemoperfusion include low volume of distribution (<1 L/kg), the presence of the toxin in the central compartment, and low endogenous clearance (< 4 mL/min per kilogram). Additionally, for hemodialysis, a low molecular weight (<500 daltons), low protein binding, and water solubility of the toxin are necessary, whereas for hemoperfusion, adsorption of the toxin to activated charcoal is important ( Table 6–5 ). For some toxins, extracorporeal removal is instituted in an effort to prevent delayed toxicity. Early removal of toxic alcohols prevents toxicity from their conversion to toxic metabolites, which are also removed by hemodialysis. [23] For some drugs, hemodialysis results in not only removal of the drug but also correction of the metabolic consequences of the poisoning; for example, the metabolic acidosis associated with salicylates, ethylene glycol, methanol, or metformin.[7] Although the great majority of patients poisoned with barbiturates and sedative-hypnotic agents, such as phenobarbital, chloral hydrate, ethanol, or isopropyl alcohol, do well with supportive care, extracorporeal removal may be indicated for unstable patients. Patients with renal or cardiac insufficiency may not tolerate the alkaline load required for treating salicylism, and may benefit from the earlier institution of dialysis or initiation at lower serum levels of the toxin.[14] In addition to removal of a toxin, the treatment of renal failure and the correction of the metabolic abnormalities associated with poisoning, hemodialysis increases the temperature of the blood in poisonings complicated by hypothermia.[15]

Table 6-1 -- Indications for Extracorporeal Removal of Extractable Drugs and Toxins

Intoxication with a drug or poison whose removal is enhanced 30 per cent or more by extracorporeal techniques AND ONE OR MORE OF THE FOLLOWING: Blood level or ingested quantity that is generally associated with severe or lethal toxicity Natural removal mechanism impaired Clinical condition deteriorating with supportive care Clinical evidence exists of severe toxicity, including hypotension, coma, metabolic acidosis, respiratory depression, dysrhythmias, or cardiac decomposition Ingestion of a toxin with serious delayed effects

Table 6-2 -- Toxins for Which Extracorporeal Removal Is Indicated Molecular Weight (Daltons) 62 Volume of Distribution (L/kg) 0.6–0.7 0.8 32 232 138 0.6–0.7 0.50–0.88

Toxin Ethylene glycol Lithium Methanol

Serum Level 50 mg/dL Clinical 50 mg/dL

Protein Binding Negligible Negligible Negligible 50%

Modality HD HD HD HP/HD HD

Phenobarbital Clinical Salicylates Acute: =100 mg/dL Chronic: Clinical Theophylline Acute: 90 µg/mL Chronic: 40 µg/mL and poorly responsive to therapy

0.15–>0.3 (increases 50–90% (binding with increasing decreases with levels) increasing levels) 0.5 56%

180

HP/HD

Table 6-3 -- Toxins and Drugs Removed by Hemodialysis/Hemoperfusion Common Uncommon * Barbiturates Aminoglycosides

Ethylene glycol Atenolol Lithium Methanol Salicylates Theophylline Boric acid Bromide Carbamazepine Chloral hydrate (trichloroethanol)

Common

Uncommon * Diethylene glycol Ethanol Isopropanol Magnesium Metformin Methotrexate (high flux) Paraquat (very early) Procainamide/N-acetylprocainamide Sotalol Thallium Valproic acid

* Extracorporeal removal uncommonly performed or use based on one or more case reports and not well established.

Table 6-4 -- Therapeutic Agents Removed by Hemodialysis or Hemoperfusion Aminoglycosides ß-Adrenergic receptor antagonists (atenolol, sotalol) Carbamazepine Glutethimide Isoniazid Methaqualone Methyldopa Metronidazole Penicillins Procainamide Pyrazinamide Quinidine Sulfonamides Thyroid hormone Valproic acid Vidarabine

Table 6-5 -- Characteristics of Toxin Removed by Extracorporeal Therapy

Hemodialysis Hemoperfusion Distribution time Short Short

Low endogenous clearance <4 mL/min/kg <4 mL/min/kg Volume of distribution Protein binding Solubility Molecular weight =1 L/kg Low Water =500 daltons =1 L/kg Low or high Water or lipid =40,000 daltons

TYPES OF EXTRACORPOREAL THERAPY
Intermittent Hemodialysis Hemodialysis is accomplished by actively pumping blood past a semipermeable membrane, most commonly configured as a bundle of hollow fibers that has a nonsterile solution on the opposite side of the membrane. The diffusion of dialyzable substances across the membrane, from an area of high concentration to an area of low concentration, allows their removal. Solutes dissolved in fluid are also removed by convection, which has a more prominent role in some of the continuous forms of dialysis therapy. Most of the hemodialysis systems currently in use are single-pass systems; that is, the dialysate comes in contact with the blood only one time. Single-pass systems use 30 to 40 L/hr of nonsterile treated water, which dilutes a concentrated solution of electrolytes. The maximum gradient between the serum and the dialysate is maintained throughout the treatment. In the acute setting, the REDY sorbent system, which regenerates dialysate and requires only 6 L of water per treatment, is sometimes used in place of a single-pass system.[46] Dialysate is regenerated by passage through a five-layered sorbent cartridge that uses urease to convert urea to ammonium carbonate and binds other toxins at other levels of the cartridge. A disadvantage of this system is that the toxin may be incompletely bound by the cartridge, so that over time the concentration of the toxin in the dialysate increases, thereby decreasing the gradient of toxin from blood to dialysate and markedly decreasing the efficiency of toxin removal. This system is less efficient for poison removal and should be used only if standard hemodialysis is not available. Effect of the Dialysis Membrane on Toxin Removal Many characteristics of the dialysis system influence the efficacy of dialysis, including membrane surface area, pore size, and rate of blood flow through the dialyzer. The ability of a substance to cross the membrane depends on membrane thickness and on pore size and shape. There is significant variation in the characteristics of dialysis membranes. They are divided into three basic categories based on permeability to solutes and ease of ultrafiltration of fluid: standard, high-efficiency, and high-flux. High-flux membranes can be used only with specialized dialysis machines that continuously adjust ultrafiltration, based on computerized measurements. Dialysis machines require recalibration to switch from standard to high-flux membranes. For the treatment of acute poisoning, time constraints and availability of personnel usually make it necessary to use the more readily available standard hemodialysis systems. There is little

advantage to a more efficient dialyser for small molecules such as lithium (atomic weight = 6.94), which are almost completely removed by the passage of blood through any dialyzer.[18] Larger molecules, such as methotrexate (molecular weight = 454.45 daltons) are poorly removed by standard dialyzers but may be removed by high-flux dialyzers and highly permeable filters used for continuous therapies. [38] The permeability of the membrane is usually expressed in terms of the clearance of urea. Most manufacturers also specify the clearance of vitamin B12 as a representative of molecules of middle molecular weight. A knowledge of the permeability characteristics of the dialyzers that are available in a specific setting allows the nephrologist to better predict the efficacy of dialysis for the removal of a given substance. Effects of Characteristics of the Toxin on Efficacy of Removal by Dialysis There are several characteristics of toxins that determine the efficacy of dialysis in the treatment of poisoning or overdose.
Size and Charge

The rate at which molecules travel down a concentration gradient and across the dialysis membrane is inversely proportional to molecular weight. Simply put, large molecules move more slowly than small molecules. From the example noted earlier, a molecule of vitamin B12 (molecular weight = 1355 daltons) would be dialyzed more slowly than a molecule of urea (molecular weight = 60 daltons), and a molecule of lithium would be dialyzed more rapidly than a molecule of methotrexate.
Protein Binding.

The dialysis membrane is designed to prevent the movement of large quantities of plasma proteins into the dialysate. For this reason, only drugs that are not protein bound are removed by dialysis. Protein binding may vary with the concentration of a drug. Although both salicylates and valproic acid are highly protein bound at therapeutic levels, the fraction of protein binding is decreased at toxic levels, allowing for their removal by hemodialysis.[28][53]
Volume of Distribution

The volume of distribution is the theoretical space over which a substance is distributed. Substances that are widely distributed in tissues have a higher calculated volume of distribution than substances that are confined to the intravascular space. For example, the administration of a given amount of a toxin that is confined to the intravascular space results in a higher serum concentration and a lower volume of distribution than the same amount of a substance that is distributed into the intravascular space plus fat and muscle. Hemodialysis removes only the toxins that are in the intravascular space. Substances that can be effectively removed by dialysis have a volume of distribution that is less than 1 L/kg. Although widely distributed substances may be efficiently extracted from the blood by hemodialysis or hemoperfusion, they are still not effectively removed because only a small percentage of the toxin is in the intravascular space. An example is cyclic antidepressants, which have a volume of distribution of more than 10 L/kg. Although easily removed from the intravascular space by dialysis, they are so widely distributed in tissue that their removal has little impact on total body burden and toxicity. For some of these substances, there is a critical time period between ingestion of the toxin and the concentration of toxin in tissues, when removal is feasible.

Water Solubility

In order to be removed by hemodialysis, a substance must be soluble in the aqueous phase of plasma. Lipid-soluble drugs are poorly removed. Lipid-soluble drugs also frequently have a large volume of distribution.
Rate of Transfer from Tissues

As a substance is removed from the intravascular space, a portion of the drug distributed in tissue (including red blood cells) and in interstitial water diffuses into the serum. This movement accounts for the postdialysis rebound in the blood level of some drugs that occurs independent of continued gastrointestinal absorption. The rate of transfer during the treatment affects the efficiency of removal. This rebound effect is prominent following the removal of lithium by hemodialysis.[18] Hemoperfusion Hemoperfusion is similar to hemodialysis except that blood passes through a cartridge containing either charcoal or a resin that adsorbs the toxin directly, rather than passing through a hollow fiber. Hemoperfusion efficiently removes toxins that adsorb to activated charcoal or resin, including substances that are lipid soluble or have a higher molecular weight than those able to pass a hollow-fiber hemodialyzer.[19] It is also more effective in removing substances that are protein bound. Hemoperfusion is very efficient in removing toxin located within the intravascular space, including the lipid portion of plasma as well as red blood cells. It does not overcome the problem of removing a toxin that has a large volume of distribution. Although the same machine used for hemodialysis can be used for hemoperfusion, hemoperfusion is not as readily available as hemodialysis. Cartridges are not available in many hospitals, and familiarity with hemoperfusion, even by nephrologists, is limited owing to its low frequency of utilization. Certain complications occur frequently, including hypotension, thrombocytopenia, leukopenia, and electrolyte disturbances. The causes of hypotension are multifactorial. It may be caused by the toxin itself, the blood volume used to prime the filter, or a pyrogen reaction to the filter itself. Leukopenia and thrombocytopenia are frequently seen, although with newer hemoperfusion cartridges, thrombocytopenia is usually limited to approximately a 30 per cent drop in platelet count.[19] Nonselective binding of important molecules, such as calcium, phosphate, and glucose, to the charcoal or the resin in the hemofiltration cartridge requires close monitoring for hypocalcemia, hypophosphatemia, and hypoglycemia. Systemic anticoagulation, which is necessary to prevent clotting of the filter, may lead to bleeding problems. Charcoal embolization has been reported but is uncommon with the newer hemofiltration cartridges. The efficiency of hemoperfusion may be increased by using a standard hemodialyzer and hemoperfusion cartridges in series. The removal of small molecules, such as urea, by hemodialysis decreases their concentration in the blood reaching the hemoperfusion cartridge, thus decreasing their binding to the charcoal or resin. This leaves a greater portion of the cartridge surface area available for binding the targeted toxin, increasing the time before the cartridge is saturated and must be replaced. As with any extracorporeal system for toxin removal, repeated treatments may be necessary, as plasma levels of the toxin rebound. While hemoperfusion has been used in the treatment of numerous poisonings, there are few studies comparing the long-term outcomes of patients treated with hemoperfusion versus those treated with conservative therapy.[52]

Continuous Therapies Continuous renal replacement therapies, introduced for the treatment of acute renal failure in hemodynamically unstable patients, allow ongoing removal of small volumes of fluid and toxins at low blood flow rates.[35] Blood is pumped continuously through a very permeable hollow-fiber membrane, either from an artery to a vein, relying on the patient’s own blood pressure, or by a blood pump from a large vein with a double-lumen catheter. The permeable membrane allows for an ultrafiltration rate as high as 1 to 1.5 L/hr. When continuous arteriovenous hemofiltration (CAVH) is done without the use of a blood pump, the ultrafiltration rate is determined by the positive pressure caused by venous resistance on the blood side of the filter and the negative pressure generated by gravity as determined by the height of the drain bag on the ultrafiltrate side. When the rate of ultrafiltration exceeds the desired rate of fluid removal, replacement fluid is given. A wide range of sophisticated ultrafiltration controls are available for continuous venovenous hemofiltration (CVVH) or CAVH, with new refinements being introduced regularly. For all continuous therapies, toxins are removed by convection in concentrations approximately equal to the unbound blood level, but the serum concentration does not change until replacement solution is given. Continuous therapies are relatively inefficient for solute (and thus toxin) removal. The efficiency can be increased by circulating dialysate on the outside of the hollow fibers. Because the membrane is permeable enough to allow the passage of larger molecules, including inflammatory mediators, the dialysate solution must be sterile. One of a number of specifically formulated dialysis fluids, including peritoneal dialysate, can be used. Many of the fluids designed for continuous systems use lactate as the base precursor, which needs to be changed to a bicarbonate-containing solution in patients with lactic acidosis. The dialysate flow rate with continuous therapies is usually no more than 4 L/hr (more commonly 1 or 2 L/hr), rather than the 30 L/hr used in hemodialysis. Continuous methods have several advantages. The larger pore size allows removal of molecules up to 50,000 daltons. These methods are better tolerated in hemodynamically unstable patients. For conditions in which there is endogenous production of a toxic substance, such as lactate or ongoing absorption from an inadequately decontaminated gastrointestinal tract, continuous therapies provide ongoing removal. Finally, they avoid the problem of rebound toxicity by removing the toxin continuously as it reenters the intravascular space. Peritoneal Dialysis Peritoneal dialysis involves instillation of a dialysate of electrolytes, glucose, calcium, and magnesium into the peritoneal space through a percutaneously placed catheter. Toxins from the splanchnic circulation diffuse across the abdominal mesentery into the dialysate, which is then drained from the body. The efficiency of dialysis depends largely on dialysate flow rate. When acute dialysis is done, the fluid is usually changed hourly. Peritoneal dialysis is much less efficient than hemodialysis in the removal of toxins, and it is generally used only when hemodialysis is not available.[51] Peritoneal dialysis is more efficient in children than in adults because the peritoneal surface area in children is larger than that in adults relative to body surface area.[10] The base precursor in most peritoneal dialysis solutions is lactate, which precludes its use in intoxications associated with lactic acidosis. When dialysis is instituted for the treatment of toxin-induced renal failure, rather than for toxin removal, peritoneal dialysis is an acceptable alternative in all but the most catabolic patients. Plasmapheresis

Plasmapheresis is the removal of plasma in exchange for albumin or fresh frozen plasma from another donor. It removes toxins only from the intravascular space. The plasma concentration of toxins is lowered by the plasma volume exchanged. Double-lumen central access is required, as well as a centrifugal separator to remove the plasma. Specifically trained technicians are required for monitoring plasma removal, with appropriate physician directed replacement. Complications include hypotension, bleeding, hypocalcemia, alkalosis secondary to the citrate preservative in the blood products, and complications of central venous access. Bleeding complications are exacerbated when albumin is used for replacement because the patient’s clotting factors are removed, along with plasma and the toxin. Plasmapheresis is most useful for removing protein-bound toxins, such as phenytoin, that are not removed by hemodialysis and are inefficiently removed by hemoperfusion.[30] Exchange Transfusion Exchange transfusion is the technique of removing blood from a patient, followed by transfusions of the similar quantity of blood from a donor. The process is usually repeated several times, in order to remove a sufficient quantity of the toxin. This technique is theoretically helpful in situations of hemoglobin toxicity, such as methemoglobinemia, or in cases of severe hemolysis.[42] This technique is rarely used except in neonates. The complications are those associated with the risk of transfusions. Chelation Therapy Combined with Extracorporeal Removal Occasionally, metals such as iron and aluminum accumulate in the body in quantities sufficient to cause neurologic and hematologic toxicity, severe bone disease, or liver disease. Patients with renal failure are at particular risk for the accumulation of metals. The neurologic complications of aluminum accumulation include myoclonus, dementia, and coma. Aluminum can also cause a microcytic anemia and osteomalacia. Iron accumulates in patients receiving frequent blood transfusions. Patients with renal failure who receive frequent transfusions or intravenous infusions of iron as part of treatment with erythropoietin are at particular risk for iron accumulation, with its associated liver and heart disease. Removal from the body is achieved only after combination of these metals with chelating agents. Chelation therapy may be effective in patients with normal renal function, but in patients with renal failure chelation of some metals must be combined with hemodialysis in order to have effective removal.[34][50] Caution must be taken when one uses chelating agents to avoid precipitating acute toxicity because of an increase in serum levels due to mobilization from tissues. This therapy is also associated with anaphylactic reactions and severe hypotension. Long-term therapy with deferoxamine can predispose to fungal infections. [34][49]

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DRUGS AND TOXINS COMMONLY REMOVED BY EXTRACORPOREAL THERAPY
Because of the characteristics required for effective removal of a drug or toxin by extracorporeal techniques, the number of drugs for which hemodialysis is useful is relatively small. For the drugs that are removed well by both hemoperfusion and hemodialysis, hemodialysis is usually preferred because of the greater experience with its use and because it simultaneously corrects associated electrolyte abnormalities. For drugs and toxins for which hemoperfusion is superior, hemodialysis should be used only when hemoperfusion is not available. Barbiturates Most patients with barbiturate overdose do well with supportive care. Chronic users of these drugs may tolerate very high levels with minimal symptoms, so that a decision to dialyze a patient with barbiturate overdose should be based on evidence of severe toxicity unresponsive to conservative management, rather than on blood levels. Phenobarbital can be removed by hemoperfusion or hemodialysis because of its low volume of distribution, its adsorbency to activated charcoal, and its slow intrinsic elimination rate. It is the barbiturate most frequently considered for extracorporeal removal. Hemoperfusion (more effective) or hemodialysis should be considered for toxicity associated with hypotension, respiratory depression, or deep and prolonged coma. [26][32] When extracorporeal removal is instituted for barbiturate overdose, the treatment may precipitate a state of acute withdrawal manifested by seizures or delirium tremens in the chronic user. Ethylene Glycol Ethylene glycol is converted by multiple enzymatic reactions to metabolites that cause metabolic acidosis, renal failure, pulmonary edema, and central nervous system damage, including cerebral edema. The treatment for ethylene glycol poisoning consists of inhibiting alcohol dehydrogenase, the initial enzyme in the metabolic pathway, and instituting hemodialysis to remove the parent compound and its metabolites, to treat the metabolic acidosis and to treat the renal failure. The indications for dialysis include an ethylene glycol level of at least 50 mg/dl or evidence of ongoing metabolic acidosis with end-organ failure; for example, rising serum creatinine, decreased urine output, pulmonary edema, and cerebral edema, regardless of the serum level.[11] Hemodialysis clearance rates of 156 mL/min and 210 mL/min have been achieved for ethylene glycol. These clearances are significantly greater than the normal renal clearance rate reported at 27.5±4.1 mL/min.[43][47] Glycolate, the metabolite responsible for the acidosis, is also cleared by hemodialysis. In 10 patients studied as part of a multicenter, prospective trial[5] the hemodialysis clearance of glycolate was 170±23mL/min (flow rates 250 to 400 mL/min) with an elimination half-time of 155±42 minutes. This compared favorably to a nonhemodialysis elimination rate of 1.08±0.67 mmol/L per hour with an elimination half-time of 626±474 minutes.[39] Lithium Lithium is ideally suited to removal by hemodialysis. With a weight of 74 daltons, it passes readily across virtually all dialysis membranes. It has a volume of distribution of 0.8 L/kg of body weight and is not protein bound. Extraction by dialysis is 90 per cent. In a series of 14 patients, hemodialysis clearances in three

patients ranged from 63.2 to 114.4 mL/min.[20] Because 70 to 80 per cent of lithium filtered by the kidney is reabsorbed in the proximal tubule, removal by dialysis is more efficient than removal by the kidney. In the study of 14 patients discussed earlier, mean renal clearance was 17.2±5.4 mL/min. In patients in whom renal function is preserved, dialysis and renal excretion are additive. Hemodialysis should be instituted regardless of serum levels if moderate to severe central nervous system abnormalities such as confusion, stupor, coma, or seizures are present. The serum lithium level is effectively lowered by hemodialysis. However, a rebound in serum lithium levels that peaks at 6 to 8 hours after a treatment occurs as lithium enters the blood from the interstitial and intracellular spaces. This rebound often necessitates repeated treatments until the serum lithium level remains below 1.0 mEq/L.[20] Lithium is also removed via continuous hemofiltration. In 7 patients treated with CAVH or CVVH for 18 to 44 hours, mean lithium clearances were 41.4±4.6 mL/min (CAVH, flow rate 4 L/hr) and 48.4±1.4 to 61.9±2.3 mL/min (CVVH, flow rate 1 to 2 L/hr). No significant rebound in the serum lithium levels occurred.[31] This technique may also be employed after initial hemodialysis.[4] Methanol Methanol toxicity causes blindness, severe metabolic acidosis, central nervous system toxicity, and death. Formic acid is responsible for the toxic manifestations and acidosis. It is produced when methanol is metabolized to formaldehyde by alcohol dehydrogenase and then to formic acid by aldehyde dehydrogenase. Like ethylene glycol, methanol poisoning is treated by infusion of an alcohol dehydrogenase inhibitor to block metabolism, followed by hemodialysis. Hemodialysis indications mirror those for ethylene glycol listed earlier and include a plasma level of 50 mg/dL or greater or evidence of ongoing metabolic acidosis with end-organ failure; for example, visual disturbances, metabolic acidosis, cerebral edema, and seizures. Hemodialysis clearance rates of 142 to 286 mL/min have been reported for methanol, while formic acid clearances range 148 to 203 mL/min.[9][22][24][25][48] However, the hemodialysis elimination half-time of formic acid does not vary appreciably from the nonhemodialysis half-time. In a prospective multicenter trial involving 11 patients poisoned with methanol, seven of whom underwent hemodialysis, the nonhemodialysis half-time of formic acid was 205±25 minutes, while the hemodialysis half-time was 185±62.7 minutes. Overall, the hemodialysis clearance for formic acid was 223±24.5 mL/min.[29] When hemodialysis is used to treat methanol or ethylene glycol intoxication, the dose of fomepizole or ethanol should be increased during dialysis to offset the removal of these alcohol dehydrogenase inhibitors (see Chapter 93 ). Salicylates Salicylates are poorly removed by dialysis at therapeutic levels because protein binding exceeds 90 per cent. However, at toxic levels, protein binding saturates and decreases to 50 to 75 per cent, leaving a large free fraction that can be readily removed.[1] Hemodialysis should be instituted when the serum level is 100 mg/dL or greater or when altered mental status (cerebral edema), noncardiogenic pulmonary edema, noncorrectable severe acid-base disturbances, renal failure, or a deteriorating clinical condition occur at lower levels.[53] Hemoperfusion removes salicylates more effectively; however, hemodialysis facilitates correction of the associated acid-base disturbances while also removing the toxin. Theophylline

Hemoperfusion is the preferred method for removal of theophylline, which is more than 50 per cent protein bound, but hemodialysis is also effective.[52] Theophylline avidly binds to the activated charcoal cartridges. The level at which extracorporeal removal should be instituted depends on whether the poisoning results from acute ingestion or chronic toxicity. With acute ingestion, extracorporeal removal is usually instituted if the serum level is 90 µg/mL or more. In the setting of chronic ingestion, hemoperfusion or hemodialysis is instituted if serum levels are more than 40 µg/mL and the patient manifests serious toxicity.[13] Extracorporeal removal should be used in the presence of ventricular dysrhythmias, metabolic acidosis, refractory hypotension, or seizures. See Chapter 48 for a more extensive discussion of the indications for extracorporeal therapy and extracorporeal elimination rates in theophylline toxicity.

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COMPLICATIONS AND LIMITATIONS OF EXTRACORPOREAL REMOVAL OF TOXINS
Although in the United States only 900 to 1000 poisoned patients are treated with hemodialysis yearly, the total number of hemodialysis treatments performed annually has reached the tens of millions. Extensive experience has made it a relatively safe procedure, particularly when only a few treatments are needed. Although it is rational to use extracorporeal techniques in cases of severe poisoning when these techniques can remove significant amounts of toxin, there are few data that clearly demonstrate decreases in mortality and long-term disability produced by these interventions. Vascular Access With the exception of peritoneal dialysis, all the aforementioned therapies require access to the intravascular space with a large-bore catheter. For hemodialysis or CVVH, a large-bore catheter is placed in either the femoral, subclavian, or jugular vein. For poisoned patients who do not have renal failure, treatment is limited to one or two treatments and the problems of long- or intermediate-term vascular access are usually not of concern. If short-term treatment is anticipated, placement of the catheter in the femoral vein carries the lowest risk of complications. Perforation of an artery or of the opposite side of the vein is a risk associated with placement of a line in any of these vessels, but control of bleeding is easiest with the femoral placement. Placement in the subclavian vein also carries the risk of pneumothorax, hemothorax, hemopericardium, and laceration of the thoracic duct. A later complication of subclavian lines is stenosis of the subclavian vein. CAVH requires the placement of a catheter in a large artery, and the patient must be monitored for signs of arterial occlusion distal to the catheter. As with any intravenous access, catheters placed for hemodialysis or hemoperfusion can introduce infection. The risk increases with the length of time the catheter is in place. Hypotension Hypotension, the most common complication of dialysis, is most often precipitated by fluid removal. The extracorporeal circuit itself contains 70 to 175 mL in the dialyzer and 100 to 150 mL in the blood lines. The blood flow is usually 200 to 400 mL/min. In an otherwise stable patient, dialysis without the removal of fluid causes hemodynamic demands that are easily met. In the patient with a drug overdose, dialysis may exacerbate hypotension in a patient with hemodynamic instability from the effects of the drug. If the intoxication involves a drug that causes renal failure, the patient may have received large quantities of fluid during an attempt at conservative treatment that must now be removed by dialysis. When hemodynamic instability is a limiting factor, a continuous therapy such as CVVH may be used, although the efficacy of these modalities is unknown. Hypotension may also be caused by sepsis, bleeding, or pericardial tamponade or by toxin-induced sympathetic blockade, acidosis, myocardial depression, or dysrhythmia. Bleeding The performance of hemodialysis, CAVH and CVVH are facilitated by the use of heparin or other anticoagulants, although hemodialysis can be performed without anticoagulation in patients at high risk for bleeding. When heparin is not used, there is an increased risk of clotting of the extracorporeal circuit, but the

risk of late bleeding is minimal. Hemoperfusion cannot be done without full anticoagulation. The bleeding tendency increases during hemoperfusion if thrombocytopenia develops owing to platelet adherence to the cartridge. Bleeding may occur at any site, and severe bleeding into the retroperitoneum may occur without clinical manifestations until hypotension develops. Citrate has been used as an anticoagulant in continuous therapies that combine diffusive and convective clearance.[37] It is associated with fewer bleeding complications, but with a higher risk of disturbances of calcium metabolism and metabolic alkalosis. Accidental disconnection of blood lines in any of these therapies can result in death from exsanguination. The risk is higher with continuous therapies in which the caretaker generally has other responsibilities in addition to tending the renal replacement therapy. Hemodialysis machines are equipped with alarms that will detect a change in pressure associated with disconnection and stop the blood pump and clamp the blood lines. The most sophisticated machines will not run if the alarms are disarmed. Most pumps for CVVH are similarly equipped with pressure monitors and air detectors. CAVH, which does not employ a blood pump, requires that the connections always be exposed so that accidental disconnection is immediately detected. The use of Luer lock connections minimizes this risk. Other Complications The use of intermittent hemodialysis on a widespread basis for acute and chronic renal failure has led to technology that minimizes many of the risks. Several of the most feared complications of dialysis have become uncommon. Virtually all dialysis machines are equipped with air detectors that shut off the blood pump and prevent air emboli. Many machines will not function unless the air detector is armed. On the outflow path of the dialysate, there is a colorimetric blood leak detector that will detect small quantities of blood in the dialysate exiting the dialyzer. If small quantities of blood are detected, the blood pump is shut off, preventing the return of blood contaminated by nonsterile dialysate to the patient. The amount of blood loss with rupture of the membrane in a hollow fiber kidney is trivial. There are monitoring systems that detect changes in the osmolality of dialysate and shunt blood away from the dialysate to prevent exposure to very hypotonic or hypertonic solution. A temperature monitor prevents exposure to overheated dialysate that may result in hemolysis. Some dialyzers, particularly with membranes made of cuprophane, have occasionally been associated with anaphylactic reactions. These membranes have been replaced largely by more biocompatible synthetic membranes, particularly in the hospital setting, which have been associated with a more rapid recovery from acute renal failure. Removal of Therapeutic Agents During dialysis it should be remembered that some drugs will be removed and must be supplemented. Categories of drugs removed by extracorporeal therapy are listed in Table 6–4 .[3] Not every drug in a category is removed equally well. As new drugs in each category are introduced, the need for replacement during or after extracorporeal therapy should be checked. For some drugs, removal with extracorporeal therapy may be sufficient to interfere with therapeutic levels, but such therapy may not be good enough to

reliably treat overdose. When dialysis is used in the absence of renal failure, the loss of some solutes that are generally present in excess in renal failure may become a problem. These include phosphorus and magnesium. Toxic Injuries Caused by Exposure to Dialysis During Treatment of Chronic Renal Failure Chronic dialysis patients have received significant toxic exposures via contaminated dialysis equipment. The primary vehicle of toxic exposure is contaminated water used in the dialysis process. Elevated water levels of calcium,[12] copper,[36] fluoride,[2] chloramines,[8] hydrogen peroxide,[16] sodium,[40] formaldehyde,[41] sodium azide,[17] sodium hypochlorite,[21] aluminum,[6] and zinc[44] all have been reported to cause toxicity in dialysis patients. Recently, 50 deaths occurred in Brazil when microcystins produced by Cyanobacteria in the public water system caused acute hepatic failure in dialysis patients at one dialysis center.[27] SUMMARY Extracorporeal removal of drugs and toxins is an essential though infrequently utilized tool in the management of the poisoned patient. Specific criteria related to the physical characteristics of the toxin, the efficacy of alternative therapies, and the severity of poisoning guide decisions regarding the utilization of these techniques. These are not “last ditch” heroic maneuvers, but essential modalities for toxin removal that have an important role in the treatment of selected poisoned patients.

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REFERENCES
1. Alvan G, Bergman U, Gustafsson LL: High unbound fraction of salicylate in plasma during intoxication. Br J Clin Pharmacol 1981; 11:625. 2. Arnow PM, Bland LA, Garcia-Houchins S, et al: An outbreak of fatal fluoride intoxication in a long-term hemodialysis unit. Ann Intern Med 1994; 121:339. 3. Aronoff GR, Berns JS, Brier ME, et al: Drug Prescribing in Renal Failure, Philadelphia: American College of Physicians; 1999. 4. Bellomo R, Kearly Y, Parkin G, et al: Treatment of life-threatening lithium toxicity with continuous arteriovenous hemodiafiltration. Critical Care Med 1991; 19:836. 5. Brent J, McMartin K, Phillips S, et al: Fomepizole treatment of ethylene glycol poisoning. N Engl J Med 1999; 340:832. 6. Burwen DR, Olsen SM, Bland LA, et al: Epidemic aluminum intoxication in hemodialysis patients traced to use of an aluminum pump. Kidney Int 1995; 48:469. 7. Cutler RE, Forland SC, John St, Hammond PG, Evans JR: Extracorporeal removal of drugs and poisons by hemodialysis and hemoperfusion. Annu Rev Pharmacol Toxicol 1987; 27:169. 8. Eaton JW, Kolpin CF, Swofford HS, et al: Chlorinated urban water: A cause of dialysis-induced hemolytic anemia. Science 1973; 181:463. 9. Ekins BR, Rollins DE, Duffy DP, et al: Standardized treatment of severe methanol poisoning with ethanol and hemodialysis. West J Med 1985; 142:337. 10. Fine RN, Tejani A: Dialysis in infants and children. In: Daugirdas JT, Ing TS, ed. Handbook of Dialysis, Boston: Little, Brown; 1994:553-568. 11. Ford MD, Sivilotti MLA: Alcohols and glycols. In: Irwin RS, Cerra FB, Rippe JM, ed. Irwin and Rippe’s Intensive Care Medicine, 4th ed. Philadelphia: Lippincott-Raven; 1999:1478-1493. 12. Freeman RM, Lawton RL, Chamberlain MA: Hard-water syndrome. N Engl J Med 1967; 276:1113. 13. Garella S: Extracorporeal techniques in the treatment of exogenous intoxications. Kidney Int 1988; 33:735. 14. Garrettson LK, Geller RJ: Acid and alkaline diuresis: When are they of value in the treatment of poisoning. Drug Safety 1990; 5:220. 15. Gentilello LM, Cobean RA, Offner PJ, et al: Continuous arteriovenous rewarming: Rapid reversal of hypothermia in critically ill patients. J Trauma 1992; 32:316. 16. Gordon SM, Bland LA, Alexander SR, et al: Hemolysis associated with hydrogen peroxide at a pediatric dialysis center. Am J Nephrol 1990; 10:123.

17. Gordon SM, Drachman J, Bland LA, et al: Epidemic hypotension in a dialysis center caused by sodium azide. Kidney Int 1990; 37:110. 18. Groleau G: Lithium toxicity. Emerg Med Clin North Am 1994; 12:511. 19. Gurland H, Samtleben W, Lysaght MJ, Winchester JF: Extracorporeal blood purification techniques: Plasmapheresis and hemoperfusion. In: Jacob C, Kjellstrand CM, Kock KM, Winchester JF, ed. Replacement of Renal Function by Dialysis, Dordrecht: Kluwer Academic; 1996. 20. Hansen HE, Amdisen A: Lithium intoxication: Report of 23 cases and review of 100 cases from the literature. Q J Med 1978; 186:123. 21. Hoy RH: Accidental systemic exposure to sodium hypochlorite (Chlorox) during hemodialysis. Am J Hosp Pharm 1981; 38:1512. 22. Jacobsen D, Jansen H, Wilk-Larsen E, et al: Studies on methanol poisoning. Acta Med Scand 1982; 212:5. 23. Jacobsen D, McMartin KE: Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol 1997; 35:127. 24. Jacobsen D, Ovrebo S, Sejersted OM: Toxicokinetics of formate during hemodialysis. Acta Med Scand 1983; 214:409. 25. Jacobsen D, Webb R, Collins TD, et al: Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol 1988; 3:418. 26. Jacobsen D, Wilk-Larsen E, Dahl T, et al: Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning. Eur J Clin Pharm 1984; 26:109. 27. Jochimsen EM, Carmichael WW, An JS, et al: Liver Failure and Death after Exposure to Microcystins at a Hemodialysis Center in Brazil. N Engl J Med 1998; 338:873. 28. Johnson LZ, Martinez I, Fernández MC, et al: Successful treatment of valproic acid overdose with hemodialysis. Am J Kidney Dis 1999; 33:786. 29. Kerns W, Tomaszewski C, McMartin K, et al: Formate kinetics in methanol poisoning [abstract]. J Toxicol Clin Toxicol 1999; 37:669. 30. Larsen LS, Sterrett JR, Whitehead B, Marcus SM: Adjunctive therapy of phenytoin overdose: A case report using plasmapheresis. J Toxicol Clin Toxicol 1986; 24:37. 31. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996; 27:365. 32. Lim PS, Lim JL: Continuous arteriovenous hemoperfusion in acute poisoning. Ann Emerg Med 1995; 26:725. 33. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 Annual Report of the American Association of Poison Control Centers. Am J Emerg Med 1999; 17:435.

34. Malluche HH, Smith AJ, Abreo K, Faugere MC: The use of desferoxamine in the management of aluminum accumulation in bone in patients with renal failure. N Engl J Med 1984; 311:140. 35. Manns M, Sigler MH, Teehan BP: Continuous renal replacement therapies: An update. Am J Kidney Dis 1998; 32:185. 36. Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia: A new complication of hemodialysis. Ann Intern Med 1970; 73:409. 37. Mehta RL, Dobos GJ, Ward DM: Anticoagulation in continuous renal replacement therapy. Semin Dial 1992; 5:61. 38. Molina R, Fabian C, Cowley B: Use of charcoal hemoperfusion with sequential hemodialysis to reduce serum methotrexate levels in a patient with acute renal insufficiency. Am J Med 1987; 82:350. 39. Moreau CL, Kerns W, Tomaszewski CA, et al: Glycolate kinetics and hemodialysis clearance in ethylene glycol poisoning. J Toxicol Clin Toxicol 1998; 36:659. 40. Nickey WA, Chinitz VL, Kim DE, et al: Hypernatremia from water softener malfunction during home dialysis. JAMA 1970; 214:915. 41. Orringer EP, Mattern WD: Formaldehyde-induced hemolysis during chronic hemodialysis. N Engl J Med 1976; 294:1416. 42. Osborn HH, Henry G, Wax P, et al: Theophylline toxicity in a premature neonate: Elimination kinetics of exchange transfusion. J Toxicol Clin Toxicol 1993; 31:639. 43. Peterson CD, Collins AJ, Himes JM, et al: Ethylene glycol poisoning: Pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981; 304:21. 44. Petrie JJB, Row PG: Dialysis anaemia caused by subacute zinc toxicity. Lancet 1977; 1:1178. 45. Pond SM: Extracorporeal techniques in the treatment of poisoned patients. Med J Aust 1991; 154:617. 46. Roberts M, Daugirdas JT: REDY sorbent hemodialysis. In: Daugirdas JT, Ing TS, ed. Handbook of Dialysis, Boston: Little, Brown; 1994. 47. Sabeel AI, Kurkus J, Lindholm T: Intensified dialysis treatment of ethylene glycol intoxication. Scand J Urol Nephrol 1995; 29:125. 48. Swartz RD, Millman RP, Billi JE, et al: Epidemic methanol poisoning: Clinical and biochemical analysis of a recent episode. Medicine 1981; 60:373. 49. US Department of Health and Human Services: Hemoperfusion in Conjunction with Desferoxamine for the Treatment of Aluminum Toxicity and Iron Overload in Patients with End-Stage Renal Disease, Rockville, MD, USDHHS, 1986. 50. Vaziri ND, Upham T, Barton CH: Hemodialysis clearance of arsenic. J Toxicol Clin Toxicol 1980; 17:451. 51. Winchester JF: Use of dialysis and hemoperfusion in treatment of poisoning. In: Daugirdas JT, Ing TS, ed. Handbook of Dialysis, Boston: Little, Brown; 1994.

52. Woo OF, Pond SM, Benowitz NL, Olson KR: Benefit of hemoperfusion in acute theophylline intoxication. J Toxicol Clin Toxicol 1984; 22:411. 53. Yip L, Dart RC, Gabow PA: Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994; 12:351.

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Chapter 7 – Laboratory Testing in Emergency Toxicology
JOHN D. OSTERLOH

INTRODUCTION
The majority of toxicologic diagnoses and therapeutic decisions are made on a clinical basis, even though technology has provided the ability to measure many toxins. The applications of these laboratory measurements are limited by practical considerations. Analytic turnaround time is often longer than the critical time course of an overdose, and laboratories cannot support the cost of maintaining the procedures, instruments, training, and specialized labor that would be needed to analyze every toxin.[34] In addition, most hospital laboratories do not have discrete toxicology sections; many of the laboratory tests used by toxicologists are distributed throughout the laboratory. This trend will continue with the use of more automated analyzers that incorporate a diverse selection of tests and with ongoing workforce reductions. This can mean more rapid turnaround time for some tests but will tend to dilute expertise in a specialty area such as toxicology and preclude time-consuming searches for unusual or less prevalent toxins. The initial workup of a poisoned patient always starts with a history and physical examination, during which a preliminary toxicologic diagnosis can usually be made based on the constellation of signs and symptoms.[12][26][33] General laboratory tests help identify and confirm the presence of a pathologic process or a nonhomeostatic state on which a suspected diagnosis can be postulated. The use of arterial blood gases, electrolytes, anion gaps, osmol gaps, metabolic substrates and products (e.g., glucose, ketones), and markers of organ damage (e.g., creatine kinase, creatinine, alanine aminotransferase, amylase) are discussed in other chapters. Some tests for drugs can aid in the diagnosis and treatment of an intoxicated patient. The interpretation of such measurements requires that the relationship between the presence or concentration of a toxin and its pharmacologic or toxicologic effects be known. Sometimes the drug concentration and its concentrationrelated toxic effects can provide a better indicator of clinical condition or prognosis than the clinical signs (e.g., with acetaminophen toxicity). Unfortunately, our knowledge of such relationships is limited for most toxins. Even when toxins have been well studied, there may be no clear relationship. For example, a toxin at an effector site may not be in rapid equilibrium with the sampled fluid (e.g., lithium in the serum is not representative of lithium in the brain during acute overdose), or the measured toxin may be metabolized to an unknown, unmeasured, and active metabolite (e.g., organophosphate toxicity). In addition, predictions based on pharmacokinetics or pharmacodynamics in the therapeutic range do not always extrapolate to overdose (e.g., theophylline elimination is first order at therapeutic doses and zero order in overdose). The prior probability (prevalence) strongly influences the reliability of any test (predictive value of a positive or negative test) at any given sensitivity and specificity. For example, in employee drug screening (low prior probability of drugs being present), toxicologic methods are adapted to improve sensitivity and specificity for finding low concentrations of a few drugs in unselected populations.[18][41] Without such adaptations, the false positives would be too high in this low-prevalence setting. In emergency toxicology, procedures are

geared toward rapidly finding a large number of drugs at a high concentration in populations clinically suspected of overdose (i.e., high prior probability, diagnostic situations). In brief, for any test to serve its function, it must be (1) analytically valid (defined and tested for detection limits, calibration-response relationship, precision, referenced accuracy, dynamic range, interferents); (2) clinically reliable (investigated for clinical sensitivity, specificity, and predictive value in the actual clinical setting); (3) applied correctly to monitor (measure change), diagnose (categorize or sort), or screen (find without preselection); and (4) useful (i.e., the test result will assist in making a diagnosis or change the course of therapy or disposition of the patient). The following discussion is limited to currently available drug tests used in the emergency evaluation of acutely overdosed patients. Methadone testing programs, employee (surveillance) drug testing, forensic (cause-of-death) testing, therapeutic drug monitoring, and mechanisms or methodologies of tests are not discussed here.

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

TOXICOLOGY SCREENS
Toxicology (tox) screens have limited utility and should be applied when the diagnosis (drug vs. disease) is not known. Use of history and clinical signs and symptoms precludes the need for screens on most occasions. When a tox screen in necessary: • Write the suspected diagnoses and suspected drugs on the requisition form. • Know which drugs are included and not included on the screen to avoid interpretive false positives and negatives. • Do not order emergency screens for surveillance purposes.

The techniques for detecting the presence of drugs include a variety of chromatographic methods, immunoassays, and chemical and spectrometric techniques. Each of these general techniques can be adapted to detect a wide number of drugs and chemicals, or focused to detect and quantitate certain drugs. The analysis of drugs, chemicals, or toxins requires matching the properties (e.g., chemical, chromatographic, light absorption) of a substance with those of a reference compound. For each drug, a laboratory must possess that particular reference compound. Because the blood or urine sample may contain components that can interfere in the detection of a drug, isolation of the drug from the sample is often necessary before applying characterization procedures. Immunoassays are most widely used for discrete analysis, and gas chromatographic techniques are used for broad screens. A comparison of the common toxicologic methods is given in Table 7–1 . Most broad screening methods are limited by the range of drugs detectable or by sensitivity. Methods that can detect many drugs simultaneously can vary considerably in their sensitivity to individual drugs.[14 ] For example, ease of detection for morphine would be ranked in order of sensitivity as follows: immunoassay (IA), thinlayer chromatography (TLC), gas chromatography (GC); for fluoxetine, the order is reversed. Tables 7–2 and 7–3 show the types of discrete tests applied to urine and serum and some common interferents.

Table 7-1 -- Comparison of Generic Toxicologic Methods for Drugs Chemical spot + + No No <0.5 + 0 500

Spectrometric † + + No Some <2–4 ++ ++ 10,000 Immunoassay † ++ ++ Some Some ‡ <1 + + 15,000 Thin-layer chromatography ++ + Yes No 2–4 +++ +++ 1500 Gas chromatography ++ ++ Yes Yes ‡ <4 ++ ++ 15,000 High-performance liquid chromatography ++ ++ Yes Yes ‡ <4 ++ ++ 20,000 Gas chromatography–mass spectrometry +++ +++ Yes

Yes ‡ <8 +++ ++++ 60,000 Specificity Sensitivity Method * * Multidrug Detection Possible Initial Quantitative Turnaround Labor Technical Capital Ability Time (hr) Intensive Expertise Costs ($)

* Relative comparison for a specific analyte. † Can be performed on analyzers widely used in clinical laboratory. ‡ Adaptable.

Table 7-2 -- Qualitative Toxicologic Methods Used in Urine Salicylate Trinder’s Spot, SC TD (<1 d), OD Salicylamide, diflunisal, ketonuria, phenylketonuria, proteinuria, sulfonamides, hippuric acids (from toluene, xylene ‡ ) Acetaminophen (p -aminophenol detected) Orthocresol Spot, SC TD (<1 d), OD N -acetylcysteine, phenols from throat lozenges and mouthwashes ‡ , proteinuria Phenothiazines (metabolites) Forrest or ferric-perchlorate-nitric (FPN) Spot TD for some (<3 d), OD Salicylates, ketonuria ‡ , proteinuria Ethchlorvynol Diphenylamine Spot, SC OD (<3 d) Phencyclidine-methadone-tricyclics Tetrabromophenophthalein ethyl ester Spot OD Other opiates, antihistamines, antipsychotics ‡ Chloral hydrate (trichloroethanol) Fujiwara Spot OD (<2 d) Chlorinated hydrocarbons ‡ Opiates (morphine, codeine)

EMIT, FPIA, KIMS, CEDIA, RIA, CMI IA RD (<3 d), OD Other opiates (hydrocodone, hydromorphone, oxycodone, dihydrocodeine), morphine from poppy seeds, adulterants § , rifampin, ofloxacin Barbiturates EMIT, FPIA, KIMS, CEDIA, RIA, CMI IA RD (<4 d), OD Other less used barbiturates, NSAIDs # ¤ , adulterants § Benzodiazepine (metabolites) EMIT, FPIA, KIMS, CEDIA, CMI IA TD for some, OD (days to weeks) Other less used benzodiazepines, NSAIDs # ¤ , less sensitive to triazolam, lorazepam, and alprazolam (diazepam, nordiazepam, chlordiazepoxide, temazepam, midazolam, oxazepam are typically detected) Amphetamines (amphetamine/methamphetamine) EMIT, FPIA, KIMS, CEDIA, RIA, CMI IA RD (<2 d), OD Newer-generation assays react with MDA, MDMA, STP, and L -methamphetamine (in Vicks inhaler); older assays cross-reacted with many adrenergic amines ¥ , chlorpromazine ‡ Marijuana (11-nor-9-carboxy-tetrahydrocannabinol) EMIT, FPIA, KIMS, CEDIA, CMI IA RD (<2 wk, <2 mo (if chronic), OD Adulterants § Cocaine (benzoylecgonine) EMIT, FPIA, KIMS, CEDIA, CMI IA RD (<2 d), OD Few; teas made from coca leaf, adulterants § Phencyclidine EMIT, FPIA, KIMS, CEDIA, CMI IA RD (<1 wk), OD PCP analogs, chlorpromazine, diphenhydramine, dextromethorphan Ethanol Enzymatic SC RD (<1 d), OD Microbiologic production of ethanol in poorly stored urine CEDIA, cloned enzyme donor immunoassay; CMI, colloidal cold microparticle immunoassay; EMIT, enzyme multiplied immunoassay technique; FPIA, fluorescent polarization immunoassay; IA, immunoassay; KIMS, kinetic interaction of microparticle spheres; MDA, methylenedioxyamphetamine; MDMA, methylenedioxymethamphetamine; RIA, radioimmunoassay; SC, spectrochemical; STP, 2,5-dimethoxy-4methylamphetamine.

* Method sensitive to overdose dosage (OD), therapeutic dosage (TD), or recreational dosage (RD) for window of time detectable in parentheses. †

Drug/Group

Reagent/Method Name

Type of Method

Sensitivity * (Detection Interval)

Interferences, Nonspecificity †

* Method sensitive to overdose dosage (OD), therapeutic dosage (TD), or recreational dosage (RD) for window of time detectable in parentheses. † Immunoassays vary in cross-reactivity. ‡ Requires extremely large amounts. Amitriptyline and similar tertiary amine tricyclic antidepressants. § Adulterants intended to cause false negatives. # Not all reagents/methods cross-react to the same extent. ¤ Negative interference. ¥ Adrenergic amines such as phenylpropanolamine, ephedrine, pseudoephedrine, fenfluramine, phentermine, isometheptene, propylhexedrine. Also ranitidine, ritodrine, labetalol, and others in the past.

Table 7-3 -- Potential Interferences in Quantitative Serum Drug and Chemistry Tests Used in Emergency Toxicology Acetaminophen SC * Salicylate, salicylamide, methyl salicylate (each will increase acetaminophen level by 10% of salicylate level using mg/L for salicylate); bilirubin; phenols; renal failure (each 1 mg/dL increase in creatinine = 30 mg/L acetaminophen) HPLC * Cephalosporins; sulfonamides Amitriptyline HPLC, GC Cyclobenzaprine Carboxyhemoglobin SC Fetal hemoglobin Chloride SC, EL Bromide (0.8 mEq Cl = 1 mEq Br) Creatinine SC * Ketoacidosis (may increase creatinine up to 2–3 mg/dL); cephalosporins; creatine (e.g., with rhabdomyolysis), isopropanol ENZ Lidocaine metabolite, 5-fluorouracil Digoxin IA Endogenous digoxin-like immunoreactive substances (up to 1 ng/mL) in newborns, renal failure, pregnancy, liver failure; oleander and toad toxin ingestion (cardiac glycosides identified as digoxin); after digoxin antibody (Fab)

administration Ethylene glycol SC * Other glycols; elevated triglycerides GC Propylene glycol Iron SC Deferoxamine causes 15% lowering of total iron-binding capacity (TIBC); Lavender-top Vacutainer tube contains EDTA, which lowers total iron Isopropanol GC Skin disinfectant containing isopropyl alcohol used before venipuncture (highly variable, usually trivial, but up to 40 mg/dL) Lithium F, EL Green-top Vacutainer specimen tube (contains lithium heparin) may cause marked elevation (up to 6–8 mEq/L) SC Quinidine, procainamide Methemoglobin SC Sulfhemoglobin (cross-positive 10% by oximeter); methylene blue (2 mg/kg dose gives transient false positive as high as 15% methemoglobin); hyperlipidemia (triglyceride, 6000 mg/dL, may give false methemoglobin up to 28.6%) Falsely decreased level with in vitro spontaneous reduction to hemoglobin in Vacutainer tube (~10%/hr); analyze within 1 hr Osmolality Osm Lavender-top (EDTA) Vacutainer Specimen tube (15 mOsm/L); gray-top (fluoride-oxalate) tube (150 mOsm/L); blue-top (citrate) tube (10 mOsm/L); green-top (lithium heparin) tube (theoretically, up to 6–8 mOsm/L). Falsely normal if vapor pressure method used (alcohols are volatilized) Salicylate SC Diflunisal > ketosis, salicylamide; accumulated salicylate metabolites in patients with renal failure (~10% increase) IA Diflunisal SC Decreased or altered salicylate level with bilirubin; phenylketones Theophylline SC * Diazepam; caffeine; accumulated theophylline metabolite HPLC * Acetazolamide; cephalosporins; endogenous xanthines; theophylline metabolites in renal failure (minor effect) IA Caffeine; accumulated theophylline metabolites in renal failure EL, electrochemical; F, flame emission; GC, gas chromatography (interferences primarily with older methods); HPLC, high-pressure liquid chromatography; IA, immunoassay; SC, spectrochemical; TLC, thin-layer chromatography; ENZ, enzymatic; Osm, osmometer.
* Method rarely used today.

Drug or Toxin Method Causes of Falsely Increased Blood Level
* Method rarely used today.

Components A toxicology screen is a combination of procedures aimed at identifying common drugs in emergency toxicology and is often adapted to reflect regional differences in drug prevalence.[27 ] Also, screens can be tailored to suit particular diagnostic categories (e.g., panels for coma drugs, seizure drugs, illicit drugs, or comprehensive screens). Most laboratories do not report a drug unless it has been confirmed by two procedures or by a single method that is known to be highly specific for a highly prevalent intoxicant (e.g., ethanol by GC). Initial identification of a drug by one method (e.g., codeine-morphine by IA) is only presumptive. Subsequent confirmation (e.g., by TLC or GC-MS [gas chromatography–mass spectrometry]) would make the result reportable, and lack of confirmation would be reported as not detected. Confirmation is not always a requirement in clinical testing; it depends on the prevalence of the drug, the specificity of the initial test, and the implications of a positive result. For illicit drugs, confirmation should always be used, because the consequences of recording this event in the medical chart may extend beyond the patient’s care. Some highly prevalent drugs, such as benzodiazepines, may not require confirmation or individual identification, as these drugs often are present in hospital populations (high prior probability) and may contribute little to the clinical picture. Communication between the treating physician and the laboratory reduces the likelihood of false positives or false negatives, speeds up analysis time, and helps the laboratory better use its resources. A comprehensive urine toxicology screen is a labor-intensive approach intended to detect as many drugs as reasonably possible using common techniques. A comprehensive screen may include the following methods: two spot tests (salicylate and phenothiazines); eight IAs (for codeine-morphine, benzodiazepine metabolite, amphetamine-methamphetamine, methadone, phencyclidine, ethanol, cocaine metabolite, and barbiturates); TLC for 30 to 60 drugs; and GC (or GC-MS) by two columns using nitrogen-phosphorus and flame ionization detectors, which detect about 60 to 80 drugs. The drugs screened by this combination of methods are listed in Table 7–4 . Toxins not usually detectable in such a comprehensive toxicology screen are listed in Table 7–5 . Many of these unscreened drugs have low prevalence or low toxicity, but many important intoxicants are not detected in comprehensive screening procedures (e.g., ethylene glycol, isoniazid, cyanide). Drugs not detectable on the tox screen can often be requested separately for screening or sent out for quantitation. Because the composition of tox screens varies from laboratory to laboratory, the clinician should know which drugs or toxins are not included on the tox screens at their hospitals (see Tables 7–4 and 7–5 , for example).

Table 7-4 -- Common Drugs Included on a Comprehensive Toxicology Screen * Alcohols: ethanol, methanol, isopropanol, acetone Barbiturates/sedatives: amobarbital, secobarbital, pentobarbital, butalbital, butabarbital, phenobarbital, glutethimide, ethychlorvynol, methaqualone Antiepileptics: phenytoin, carbamazepine, primidone, phenobarbital Benzodiazepines: chlordiazepoxide, diazepam, alprazolam, temazepam Antihistamines: diphenhydramine, chlorpheniramine, brompheniramine, tripelennamine, trihexyphenidyl, doxylamine, pyrilamine, methapyrilene Antidepressants: amitriptyline, nortriptyline, doxepin, imipramine, desipramine, trazodone, amoxapine, maprotiline, fluoxetine, paroxetine

Antipsychotics: trifluoperazine, perphenazine, prochlorperazine, chlorpromazine Stimulants: amphetamine, methamphetamine, phenylpropanolamine, ephedrine, MDA, MDMA (other phenylethylamines) cocaine, phencyclidine Opioid analgesics: heroin, morphine, codeine, oxycodone, hydrocodone, hydromorphone, meperidine, pentazocine, propoxyphene Other analgesics: salicylates, acetaminophen Cardiovascular drugs: lidocaine, propranolol, metoprolol, quinidine, procainamide, verapamil Others: theophylline, caffeine, nicotine, oral hypoglycemics, strychnine MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine.

* Comprehensive screens vary considerably in content, and the physician should be familiar with the drugs tested at a particular hospital. Tailored screens, such as “drugs of abuse screens,” usually focus on illicit drugs using 4–8 immunoassays in the initial screening process.

Table 7-5 -- Toxins Not Detectable by Emergency Toxicology Screens Classified by Area of Difficulty Too polar: antibiotics, diuretics, isoniazid, ethylene glycol, lithium, lead, iron Too nonpolar: steroids, tetrahydrocannabinol (THC), digoxin, polychlorinated biphenyls, organochlorine pesticides Too nonvolatile: plant and fungal alkaloids, some phenothiazines Too volatile: aromatic and halogenated hydrocarbon solvents, anesthetic gases, noxious gases (hydrogen sulfide, nitrogen dioxide, carbon monoxide) Concentration too low (potent drugs or drugs with large volume of distribution): clonidine, fentanyl, colchicine, ergot alkaloids, lysergic acid diethylamide (LSD), dioxin, digoxin, THC, polychlorinated biphenyls Toxic anions (too polar): thiocyanate, cyanide, fluoride, bromide, borate, nitrite New drugs: buspirone

Because the turnaround time for comprehensive screens is often several hours to several days, their utility and impact are limited. A focused screen , most commonly for illicit drugs or drugs of abuse, is composed of the four to eight IAs with confirmation procedures as needed, and results can be available in minutes. This screen is used mostly by emergency and psychiatric services, where cases of drug overdose and abuse constitute the largest proportion of screening requests. Such limited screens detect many of the prevalent drugs in emergency departments, but the limitations of sensitivity and specificity must be realized (see Table 7–2 ). For example, an illicit drug panel may include an IA for benzodiazepines but not detect a potent benzodiazepine such as triazolam. Also, many laboratories do not screen for marijuana metabolite in emergency situations because it is present in many overdoses among the drug-using population, is rarely considered responsible for serious toxicologic effects, is excreted in urine for a long time after use, and may not be related to the acute clinical picture. Rationale and Use of Toxicology Screens In the emergency setting, specimens should be obtained as soon as a toxicologic diagnosis is considered in a seriously ill patient. Although comprehensive screening is unlikely to affect emergency management (see under Clinical Utility later), the results may assist the admitting physicians in evaluating the patient if the diagnosis remains unclear.

Urine is the best specimen for finding the greatest number of drugs and produces the highest rate of positive findings when compared with serum or gastric aspirates.[20 ] [23 ] [34 ] The earlier the urine collection, the greater the chance of finding a drug, because many have short intervals of detection (see Table 7–2 for detection intervals of common illicit drugs). Rarely has a drug gone undetected because the urine collection was too soon after a single acute ingestion. Adding a blood sample to a urine specimen produces a slightly greater overall yield of positives when extraordinary screening techniques are available. However, because of lower concentrations in serum or blood, smaller sample size, and incompatibility with some methodologies, serum or blood testing cannot identify as many drugs as urine screening. Gastric specimens often contain high concentrations of the parent drugs, which can help in identification when the drug is extensively metabolized and is not identifiable on the basis of urinary metabolites, although this is rarely necessary. In one study, patients who had received gastric lavage for initial management showed the following percentage of the positive results in their specimens: urine 93 per cent, serum 54 per cent (only sedative-hypnotics screened), and gastric aspirate or lavage 38 per cent.[1 ] Tox screens should be applied as diagnostic tests and not screening tests. These “screens” are intended to aid the physician in considering whether a set of signs and symptoms is drug induced or has some other cause. When ordering a tox screen, suspected drugs or drug classes, key symptoms, or the working diagnosis should be written on the requisition. This will facilitate testing as well as communication back to the ordering physician. For instance, if a tox screen is ordered with “clonidine” as the suspected drug causing “pinpoint pupils,” the laboratory can call the physician and indicate that the screening methods would be unlikely to detect clonidine but could rule out opiates. In another case, a physician may order only a test for “amphetamine” in urine because of a “bizarrely acting” patient. Because antihistamines are common and produce anticholinergic delirium with similarities to both functional and amphetamine psychoses, a tox screen or limited screen may be better. Fligner and Robertson indicated that the best method of communication is with adequate prompting and space on requisition forms, but only 48 per cent of forms surveyed had space to list suspected drugs.[15 ] Drug Overdose and Drugs Found The drug categories responsible for the most deaths reported by poison control centers are analgesics (opioid and nonopioid), antidepressants, stimulants (including amphetamines, cocaine, phencyclidine), sedative-hypnotics, cardiovascular drugs, and alcohol.[28 ] All these classes of drugs are detectable by comprehensive toxicology screening. Comprehensive toxicology screening is positive for 50 to 80 per cent of the cases in which testing is requested (varies by center and composition of the screen), and the top five drug classes account for 70 to 90 per cent of all drugs found.[20 ] [34 ] The most common second drug group detected is benzodiazepines, regardless of the primary drug abused.[39 ] From the 1970s through the 1980s, there was a decrease in the incidence of barbiturates and ethanol and an increase in benzodiazepines, tricyclic antidepressants, sympathomimetic amines, and cocaine. Bailey[2 ] reported that the incidence of cocaine-positive tox screens rose from 1 per cent in 1978 to 10 per cent in 1986. In larger centers dealing with emergency drug testing, cocaine may be positive in a quarter or more of all submitted specimens. In contrast to tox screens and poison control center reports, medical examiners report a slightly different spectrum of drug involvement, including carbon monoxide (includes fire deaths), ethanol, sedativehypnotics, opioids, cyclic antidepresssants, and propoxyphene as the more common causes of drug-related deaths.[9 ] [32 ] In pediatric overdose, suicide and drug abuse are less likely. Drugs are responsible for only a minority of all exposures in children (40 per cent) but account for a large portion of intoxications, hospital admissions, and deaths, particularly in the teenage group.[13 ] [21 ] [28 ] [44 ] Drug exposures in patients younger than 6 years old are usually due to single agents, whereas 27 to 66 per cent of adults ingested multiple drugs.[34 ]

Analytic Accuracy of Toxicology Screens Clinicians should realize that not all drugs are detectable with the technologies used in toxicologic testing. For the average laboratory today, false negatives occur at a rate of 10 to 30 per cent (when considering all drugs) and false positives at a rate of 0 to 10 per cent. The most common reason for an analytic false negative is that the laboratory has not validated or quality controlled its detection limits. The most common reason for a clinical false negative is ordering a screen in which the suspected drug is not included. Many false positives and some false negatives are due to misidentification within a class (e.g., pentobarbital for amobarbital), so the impact on the clinical diagnosis would be small. Hospital laboratories can be assessed by participation in proficiency testing programs from the American Association of Clinical Chemists and College of American Pathologists. A random sample of proficiency test results for a single quarter demonstrated that, in a set of four specimens, false negatives for a rare drug such as carisoprodol were as high as 60 per cent, versus about 10 per cent for a common drug such as codeine.[10 ] False positives are low partly because of high concentrations and confirmatory techniques. A more difficult challenge was presented to 26 specialty toxicology laboratories in the West.[7 ] A case history was presented along with a urine sample containing four drugs. Only two laboratories were able to identify all four drugs present. Sixty-five per cent identified dihydrocodeine, 54 per cent identified MDEA (3,4methylenedioxymethamphetamine), 23 per cent identified naloxone, and 23 per cent identified aminoflunitrazepam (metabolite of Rohypnol). False negative identification may also be due to interferences from adulterants. These are more likely in surveillance programs (probational, employee, methadone) and are unusual in emergency toxicologic screening. Common adulterations include dilution (by ingestion or direct addition of water), substitution (with purchased urine or the urine of a second person or animal), ingestion of weak acids and bases (vinegar, bicarbonate) to influence the excretion of acidic or basic drugs, the use of interfering substances to alter test results (e.g., benzalkonium chloride), and the addition of strong chemicals to impair biologically based IAs (soap, bleach, glutaraldehyde).[17 ] [30 ] [40 ] [46 ] The aim of adulterant use is to interfere with the initial test by IA. Because there is a wide variety of IA methodologies, not every adulterant will have the same effect in each assay. Accuracy of the Clinical Diagnosis Rygnestad and Berg[37 ] showed that in 265 self-poisoned overdoses, the correct drug or class of drug could be identified in 85 per cent of the cases using patient history, physical examination, and basic laboratory tests, including acetaminophen, salicylate, barbiturates, and lithium. Diagnosis was incorrect or unknown in 14 per cent when compared with extensive follow-up and other toxicologic testing. Toxicologic screening was needed to identify drugs in only 5 per cent of cases and was most useful in identifying ethanol and benzodiazepines. Nice and colleagues[31 ] assessed the use of “toxidromes” for the identification of drugintoxicated patients and showed that nurses, physicians, and clinical pharmacists could identify the drug or class causing intoxication in over 80 per cent of cases. In contrast, Bury and Mashford[6 ] indicated that information on drug intake was unreliable or unavailable in 75 per cent of 167 drug overdose cases, confirming earlier suspicions of Teitelbaum and associates.[43 ] Complete concordance of clinical predictions with toxicology results (all drugs named vs. all drugs found) is estimated at only 20 to 32 per cent, because additional drugs are often found by screening (20 to 48 per cent of the time). The clinically predicted drug is not found in 9 to 25 per cent of cases.[34 ]

Clinical Reliability of Toxicology Screens Overall clinical reliability depends on analytic sensitivity and specificity, whether the laboratory will test for the drugs that are expected in the screen, and the prevalence of drug-positive cases and intoxications in the clinical setting. The prevalence of drug-positive screens in past surveys of overdoses is about 50 to 80 per cent,[34 ] but it varies by situation and by region. If the prior probability of drugs being present in a patient is 50 per cent and the tox screen has an average sensitivity of 70 to 90 per cent (based on proficiency testing data given earlier), the predictive value of a negative test is 63 to 83 per cent. With a specificity of 90 to 100 per cent, the predictive value of a positive test is 83 to 100 per cent. Thus the “rule-in” value of the tox screen is better than the “rule-out” ( Fig. 7–1 ). Kellermann and colleagues[24 ] indicated that most physicians tend to use tox screens to rule out drug toxicity as a diagnosis and are less likely to use tox screens for rule-in purposes. This is disconcerting if tox screens have a higher positive than negative predictive value in high-prevalence settings. In contrast, when diagnostic choices are few and the working diagnosis is less likely to be drug intoxication, rule-out testing makes some sense (see Fig. 7–1 ). For example, if a patient was strongly believed to have a non–druginduced coma, the prior probability of detectable drugs might be considered very low (e.g., 5 per cent). With this prior probability and the same specificity and sensitivity of the tox screen, the predictive value of a negative test is 76 to 90 per cent, and the predictive value of a positive test is 33 per cent; hence there is a better rule-out value.

Figure 7-1 Posterior probability of finding any common drug in the toxicology screen at various prevalences (prior probabilities) given a

screen that is 70 per cent sensitive (on average to any of the drugs detectable) and a specificity of 95 per cent. PV+ is posterior probability of a positive test and PV- is posterior probability of a negative test.

Clinical Utility of Toxicology Screens Tox screens are reliable for limited clinical use, but do the results make a diagnosis or change a plan of management? Tox screens may be suspected of having little usefulness because (1) diagnostic and management decisions are made before results are returned; (2) benign and diagnostic intervention may preclude the need for these tests (e.g., response to naloxone for opioids); (3) there are only a few specific interventions or antidotes in toxicologic management that could possibly hinge on toxicologic test outcomes[5 ] ; (4) the incidence of morbidity is less than 1 per cent[21 ] [28 ] ; and (5) toxicity is often apparent on presentation. Clinical features not only identify a toxic syndrome but also are prognostic for outcome. In 209 overdose patients, Brett demonstrated that they could be categorized as low or high risk with respect to developing complications or requiring intensive care interventions based on initial clinical, blood gas, or electrocardiogram findings.[4 ] Although comprehensive screens can detect most of the drugs causing toxicologic deaths as well as many drugs unsuspected by the physician, their impact is limited. Most studies in Table 7–6 indicate that the impact of screening on clinical diagnosis and management is low (<15 per cent). In prospective evaluations of diagnostic certainty before and after the return of toxicologic screen results, Kellermann and colleagues[24 ] showed that the use of toxicologic screening increased diagnostic certainty by 16.5 per cent (the prior probability of drug toxicity was 75.5 per cent and increased to an after-test probability of 92.0 per cent), and that these changes in diagnostic certainty occurred in 66 per cent of the 183 cases evaluated. Such estimates of utility validate the impression of most toxicologists. However, many of the studies in Table 7–6 focused only on positive tox screen results. The impact of a negative test is difficult to assess. No intervention as a result of a negative test can also be considered contributory to the diagnostic and treatment process. For example, when considering the differential diagnosis of drug-induced or functional psychosis, the negative toxicology screen is considered by some as a predictor of the need for greater psychiatric care.[38 ] However, thorough study of this hypothesis is needed.

Table 7-6 -- Impact of Toxicology Screening on Clinical Diagnosis and Management Wiltbank (1974)[45 ] 148 <7 R, chart review ED Helliwell (1979)[19 ] 108 15 P, verbal, chart ED coma Bury (1981)[6 ] 167 66 R, chart review OD * Mahoney (1987)[29 ]

176 8 R,? OD Kellermann (1987)[24 ] 183 4.4 (66.3) † P, questionnaire before/after ED-OD Brett (1988)[4 ] 198 1.5 R, records review Intentional OD ED, emergency department patients suspected of drug toxicity; OD, overdosed patients; P, prospective; R, retrospective. Reference No. of Patients % of Cases in Which Diagnosis or Study Type of (Year) Studied Management Altered Due to Tox Screen Methods Patient
* Self-poisoning excluded. † 4.4% altered management; 66.3% had slightly improved diagnostic certainty.

Copyright © 2007 Elsevier Inc . All rights reserved. - www.mdconsult.com

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

SERUM QUANTITATION OF OVERDOSED DRUGS
For serum concentrations of a drug to be useful, there must be a relationship between the drug concentration and the toxic effects or therapeutic decision points. The underlying clinical condition of the patient may alter the concentration-effect relationship or its interpretation. Serum concentrations have proved useful in only a limited number of emergency situations. Rationale and Uses Quantitative drug levels in overdose can monitor the course of the patient, predict whether toxicity is occurring but not yet clinically apparent, or predict that toxicity will occur in the future. In the emergency setting, there are relatively few quantitative measurements that meet these goals. These measurements include quantitation for acetaminophen, salicylates, theophylline, methanol, ethanol, ethylene glycol, iron, carboxyhemoglobin, and lithium. Quantitation is also useful when hazardous therapy is being considered or in evaluating the efficacy of such therapy. Two criteria need to be satisfied for blood levels to be useful. First, there should be an absence of reliable clinical indicators that reveal the status or condition of the patient. If a toxin is suspected and toxicity is apparent (clinical effects), a drug level will yield little additional information, except for the drugs listed earlier. For most drug intoxications, the clinical indicators of toxicity are better indicators than are drug concentrations. For example, the clinical manifestations of a cyclic antidepresssant overdose indicate the course and severity of the ingestion better than drug concentrations.[3][8] The second criterion for the use of drug concentrations is the existence of a concentration-effect relationship. In therapeutic drug monitoring, these relationships are well described for the endpoints of efficacy or toxicity, but these cannot be extrapolated to the overdose setting. For instance, carbamazepine is an anticonvulsant at therapeutic concentrations of 5–10 mg/L but may cause seizures in overdose (see under Altered Pharmacokinetic and Pharmacodynamic Relationships in Overdosage). Prescott[35] considered the most important role for the toxicology laboratory to be the quantitation of drug concentrations to determine the need for dangerous or expensive treatment. These drugs may require hemoperfusion (e.g., theophylline, phenobarbital) or hemodialysis (e.g., salicylate, methanol, lithium) to avoid life-threatening concentrations, to shorten coma, and to evaluate the efficacy of extracorporeal elimination. Drug concentrations are required for similar reasons when deciding to treat a digoxin overdose with Fab fragments (Digibind) and for the appropriate use of chelators in metal poisoning. Table 7–7 presents commonly used criteria for evaluating when to use these hazardous interventions.

Table 7-7 -- Examples of the Utility of Drug Concentrations in the Use and Evaluation of Hazardous Therapies

Drug/Toxin Acetaminophen

Clinical Presentation * History or none Hypotension, seizures, dysrhythmias Altered mental status, rigidity, renal insufficiency AG metabolic acidosis ± osmol gap, visual changes AG metabolic acidosis ± osmol gap AG metabolic acidosis, confusion, pulmonary or cerebral edema, seizures

Concentration Criteria >150 µg/mL @ 4 hr >90–100 µg/mL (acute OD only) >1.5 mEq/L ‡ (chronic OD) >50 mg/dL >50 mg/dL

Therapy † NAC

Rationale for Intervention Prevent hepatotoxicity Avoid seizures, dysrhythmias, fatality Reduce CNS effects, avoid seizures Avoid blindness, fatality Avoid renal failure, fatality Avoid fatality

Theophylline Lithium Methanol Ethylene glycol

HP/HD HD § HD HD

Salicylates

>100 mg/dL (acute HD OD only)

Digoxin

AV block, hyperkalemia, >4 ng/mL § (acute symptomatic bradycardia or OD) ventricular ectopy History, nausea, vomiting Stupor, coma, acidosis, ischemic chest pain >350–500 µg/dL

Fab

Avoid cardiovascular failure, fatality

Iron

Avoid cardiovascular Deferoxamine collapse, acidosis, hepatic failure Oxygen, HBO Avoid CNS injury

Carboxyhemoglobin

>15%

AG, anion gap; AV, atrioventricular; CNS, central nervous system; HBO, hyperbaric oxygen; HD, hemodialysis; HP, hemoperfusion; NAC, N-acetylcysteine, OD, overdose.
* Important signs or symptoms that suggest the need for the listed therapy. All diagnostic symptoms are not listed.

† Only concentration-related therapies listed; other therapies may be instituted at earlier stages. In some cases, the clinical condition may indicate the need for the listed therapy at lower than listed concentrations. ‡ Upper limit of therapeutic range, varies by locale. § Therapeutic decision weighted more heavily on clinical signs and symptoms than on drug levels. Consider contribution of digoxin metabolites with renal insufficiency and digoxin-like immunoreactive substances to the measured digoxin concentration.

Availability and Reliability Measurements should be available on an immediate, 24-hour basis and should be precise (not semiquantitative) in order to discern real change in the concentration within a given patient. With the increasing use of quantitative IAs on rapid chemistry analyzers, most large hospital laboratories have assays available for therapeutic drug monitoring (TDM). However, of all hospitals capable of routine chemistry tests, only 63 per cent performed iron tests, 38 per cent lithium, 79 per cent theophylline, 51 per cent salicylate,

and 51 per cent acetaminophen.[10] Although serum quantitations require adequate precision to recognize change from time point to time point, they should also be accurate so that management decisions can be made correctly. The accuracy and interlaboratory variability of quantitative concentrations may be assessed from proficiency testing programs.[10] In general, accuracy (defined as nearness to target concentrations) and agreement between laboratories are most apparent for drugs measured commonly and by uniform techniques, such as antiepileptic drugs. For drugs that are measured infrequently and by more diverse methods, the results are more diverse. Today, most TDM-type drugs demonstrate interlaboratory variation of less than 8 per cent and biases of less than 15 per cent.[10] Altered Pharmacokinetic and Pharmacodynamic Relationships in Overdosage Serum drug quantitations must be evaluated with respect to each patient’s clinical condition. The variation in pharmacology from person to person, the interactions of diseases and medications, the altered pharmacodynamics and pharmacokinetics with overdose, and potential interferences in assays (see Table 7–3 ) may change how a drug concentration is interpreted.[36] For example, salicylate overdose is more toxic than linear extrapolation of therapeutic concentrations would predict. This is due to increased free (unbound) concentrations at increasing serum concentrations, increased central nervous system (CNS) penetration at acidic blood pH, and slower (saturated) metabolism at higher concentrations. Also important in interpreting concentration–toxic effect relationships are the conditions under which these relationships were established. Therapeutic concentrations and concentrations associated with lithium toxicity are based on chronic dose regimens in which there is equilibrium between serum and CNS concentrations. Early in an acute lithium overdose (without chronic use), serum levels appear high but do not yet reflect CNS concentrations, and the patient can be asymptomatic. Many other drugs have different clinical presentations in acute versus chronic overdose (e.g., salicylate, theophylline, digoxin). Interpretation of drug levels may be altered by multiple factors simultaneously. For instance, a patient with renal failure on digoxin may have no digoxin-related symptoms with a level of 4 ng/mL while taking normal doses. Falsely measured digoxin-like immunoreactive substances in renal failure may raise the patient’s measured “digoxin” level by 1 ng/mL, and cross-reaction of accumulated metabolites due to poor renal clearance may falsely raise the measured level an additional 2 ng/mL. In contrast, another patient with a level of 2 ng/mL may exhibit digoxin-related toxicity due to exacerbation from hypokalemia. Therefore, each drug concentration must be interpreted relative to the condition of the patient and less by the use of rigid therapeutic windows.

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TESTING FOR OTHER TOXINS
Toxins from plants, animals, microorganisms, and chemical sources are numerous, but exposure to them is relatively infrequent compared to drug ingestions. Although there are many potent and deadly toxins in those categories, most exposures tend to be insufficient in quantity, short-lived, or benign in toxicity. Therefore, few tests have been developed or studied or have any commercial potential. Certain plant toxins such as nicotine, strychnine, and atropine can be recognized on comprehensive toxicology screens. Specific tests for digoxin (and oleander), cyanide (from cyanogenic glycoside-containing plants, fires, or chemical ingestion), and carbon monoxide (as carboxyhemoglobin) can be ordered from larger hospitals laboratories. Many specific plant and fungal toxins cannot be measured, and the clinician must use the history and physical examination as a guide. However, most regional poison centers have contacts with a wide variety of agencies that may help in identifying specimens from plants, mushrooms, or chemicals used in agriculture. In hazardous chemical exposure (e.g., metals, hydrocarbons), guidelines for interpreting concentrations are usually based on timed or chronic exposures. These guidelines and cutoffs are often used to discern excessive but not necessarily toxic exposure rather than amounts associated with ill effects. Guidelines and laboratory methods are available for a narrow variety of commonly encountered chemicals (e.g., lead, mercury, cadmium, arsenic, trichloroethylene, benzene, toluene, hexane, polychlorinated biphenyls).[25][42] SUMMARY Emergency physicians using toxicologic testing should learn the capabilities of their laboratories: What is detectable? What is not? What is the expected turnaround time? Do pharmacologic relationships exist? The laboratory should allow the physician to order limited test combinations, and the physician can assist the laboratory in the search for unknowns by indicating the possible diagnosis and suspected drugs. Only a few drugs require quantitation in serum in order to assist in therapeutic decisions ( Table 7–8 ). Comprehensive urine drug screening is useful in documenting intoxications due to drugs and in demonstrating other drugs not clinically expected. The impact of comprehensive drug screening on diagnosis and therapy in emergency patients appears to be low. However, focused screens based on IAs that can be turned around quickly are widely used. Generally, drug screening in the emergency setting has a better positive predictive value (rule in) than negative predictive value. Drug testing on patients in hospital settings may prove to have other benefits affecting patient disposition.

Table 7-8 -- Situations in Which Toxicology Testing Is Useful

Overdoses and toxic conditions requiring serum drug concentration to diagnose severity, monitor course, assess need or effectiveness of therapy Acetaminophen Salicylates Theophylline Lithium Digoxin Ethanol Carboxyhemoglobin Methemoglobin Iron Methanol Ethylene glycol Lead, mercury, arsenic Organophosphates (cholinesterases) Anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine, valproate) Situations in which qualitative toxicology tests or screens have utility When the differential diagnosis is sufficiently narrowed to a drug cause vs. a disease cause (e.g., psychosis—functional vs. amphetamines) Documentation that the working diagnosis was correct (post facto) After admission if the diagnosis is still unclear

Future directions include new IAs that can be used directly within the emergency department. Also, with improvements in technology, screening of serum drugs will become more common, including the discovery of more quantitative relationships between serum concentration and toxic effects.

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REFERENCES
1. Auerbach PS, Osterloh J, Braun O, et al: Efficacy of gastric emptying: Gastric lavage vs. emesis induced with ipecac. Ann Emerg Med 1986; 15:692. 2. Bailey DN: Changing trends in drug abuse [abstract]. California Association of Toxicologists Newsletter, winter 1990, p 20. 3. Boehnert MT, Lovejoy FH: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985; 313:474. 4. Brett AS: Implications of discordance between clinical impression and toxicology analysis in drug overdose. Arch Intern Med 1988; 148:437. 5. Brett AS, Rothschild N, Gray R, et al: Predicting the clinical course in intentional drug overdose: Implications for use of the intensive care unit. Arch Intern Med 1987; 147:133. 6. Bury RW, Mashford ML: Use of a drug-screening service in an inner-city teaching hospital. Med J Aust 1981; 1:132. 7. California Association of Toxicologists Newsletter, summer 1995, pp 13–16. 8. Callahan M: Tricyclic antidepressant overdose. JACEP 1979; 8:413. 9. Caplan YH, Ottinger WE, Park J, et al: Drug and chemical related deaths: Incidence in the state of Maryland—1975 to 1980. J Forensic Sci 1985; 30:1012. 10. College of American Pathologists—CAP Surveys; Urine Toxicology Survey 1995 Set UT-B; Therapeutic Drug Monitoring Survey 1995 Set Z-B; Chemistry Survey 1995 Set C4–B., Northfield, College of American Pathologists, 1995. 12. Ellenhorn MJ, Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, New York, Elsevier, 1988. 13. Fazen LE, Lovejoy FH, Crone RK, et al: Acute poisoning in a children’s hospital: A 2-year experience. Pediatrics 1986; 77:144. 14. Ferrara SD, Tedeschi L, Frison G, et al: Drugs-of-abuse testing in urine: Statistical approach and experimental comparison of immunochemical and chromatographic techniques. J Anal Toxicol 1994; 18:278. 15. Fligner CL, Robertson WO: Request and report forms in toxicology screening [abstract]. Vet Hum Toxicol 1985; 28:306. 17. Goldberger BA, Kaplan YH: Effect of glutaraldehyde (UrinAid) on detection of abused drugs in urine by immunoassay. Clin Chem 1994; 40:1606.

18. Griner PF, Glaser RJ: Misuse of laboratory tests and diagnostic procedures. N Engl J Med 1982; 307:1336. 19. Helliwell M, Hampel G, Sinclair E: Value of emergency toxicological investigations in differential diagnosis of coma. BMJ 1979; 2:819. 20. Hepler BR, Sutheimer CA, Sunshine I: The role of the toxicology laboratory in emergency medicine. II. Study of an integrated approach. J Toxicol Clin Toxicol 1984–1985; 22:503. 21. Jacobsen D, Fredericksen PS, Knutsen KM, et al: A prospective study of 1212 cases of acute poisoning: General epidemiology. Hum Toxicol 1984; 3:93. 23. Kellerman AL, Fihn SD, Logerfro JP, et al: Utilization and yield of drug screening in the emergency department. Am J Emerg Med 1988; 6:14. 24. Kellermann AL, Fihn SD, Logerfro JP, et al: Impact of drug screening in suspected overdose. Ann Emerg Med 1987; 16:1206. 25. Kneip TJ, Crable JV: Methods for Biologic Monitoring: A Manual for Assessing Human Exposure to Hazardous Substances, Washington, DC, American Public Health Association, 1988. 26. Kulig K: Utilization of emergency toxicology screens. Am J Emerg Med 1985; 6:573. 27. Lasky FD, Wesley JF, Marx AJ: Changes in the pattern of drugs detected in a toxicology screen in an upstate New York hospital. Pathol Annu 1985; 20:161. 28. Litovitz TL, Felberg L, White S, Klein-Schwartz W: 1995 annual report of the American Association of Poison Control Centers: Toxic Exposure Surveillance System. Am J Emerg Med 1996; 14:487. 29. Mahoney JD, Gross PL, Stern TA: The use of the toxic screen in the management of overdosed patients [abstract]. Vet Hum Toxicol 1987; 29:474. 30. Mikkelsen SL, Ash KO: Adulterants causing false negatives in illicit drug testing. Clin Chem 1988; 34:2333. 31. Nice A, Leikin JB, Maturen A, et al: Toxidrome recognition to improve efficiency of emergency urine drug screens. Ann Emerg Med 1988; 17:676. 32. Norton LE, Garriott JC, Di Maio VJM: Drug detection at autopsy: A prospective study of 247 cases. J Forensic Sci 1982; 27:61. 33. Olson KR: Comprehensive evaluation and treatment of poisoning and overdose. In: Olson KR, et al ed. Poisoning and Drug Overdose, 2nd ed. Norwalk, CT: Appleton and Lange; 1994:1-58. 34. Osterloh JD: Utility and reliability of emergency toxicologic testing. Emerg Med Clin North Am 1990; 8:693. 35. Prescott LF: Limitations of hemodialysis and forced diuresis. In: Curry AS, ed. Symposium on the Poisoned Patient—Role of the Laboratory. CIBA Foundation Symposium, New York: Elsevier; 1974:278282. 36. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin

Pharmacokinet 1981; 6:161. 37. Rygnestad T, Berg KJ: Evaluation of benefits of drug analysis in the routine clinical management of acute self-poisoning. J Toxicol Clin Toxicol 1984; 22:51. 38. Sanguineti VR, Samuel SE: Comorbid substance abuse and recovery from acute psychiatric relapse. Hosp Community Psych 1993; 44:1073. 39. Schwartz JG, Stuckey JH, Prihoda TJ, et al: Hospital-based toxicology: Patterns of use and abuse. Tex Med 1990; 86:44. 40. Schwarzhoff R, Cody JT: The effects of adulterating agents on FPIA analysis of urine for drugs of abuse. J Anal Toxicol 1993; 17:14. 41. Spiehler VR, O’Donnell CM, Gokhale DV: Confirmation and certainty in toxicologic screening. Clin Chem 1988; 34:1535. 42. Tarcher AB: Principles and Practice of Environmental Medicine, New York, Plenum Medical Book Company, 1992. 43. Teitelbaum DT, Morgan J, Gray G: Nonconcordance between clinical impression and laboratory findings in clinical toxicology. Clin Tox 1977; 10:417. 44. Trinkoff AM, Baker SP: Poisoning hospitalizations and deaths from solids and liquids among children and teenagers. Am J Public Health 1986; 76:657. 45. Wiltbank TB, Sine HE, Brody BB: Are emergency toxicology measurements really used?. Clin Chem 1974; 20:116. 46. Wu AH, Forte E, Casella G, et al: CEDIA for screening drugs of abuse in urine and the effect of adulterants. J Forensic Sci 1995; 40:614.

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Uncited references Dalrymple RW, Sterns FM: Diflunisal interferes with determination of salicylate by Trinder, Abbott TDx and Dupont aca methods. Clin Chem 1986; 32:230. Frings CS, Battaglia DJ, White RM: Status of drug-of-abuse testing in urine under blind conditions: An AACC study. Clin Chem 1989; 35:891. Jacobsen D, Halvorsen K, Marstrander J, et al: Acute poisonings of children in Oslo. Acta Paediatr Scand 1983; 72:553.

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Chapter 8 – Radiology
SANDRA A. CRAIG Poisoned patients present to the clinician in a number of ways. Some are known to be victims of a toxin at the outset, and for these patients diagnostic radiology can be a valuable tool in documenting the presence of the toxin or assessing its impact on the patient. Other patients present with symptoms not recognized as being related to a poison, and the physician must always consider the possibility that a clinical or radiologic finding might be related to an unrecognized toxin.

THE ABDOMEN
Direct Visualization of Toxins Solid Medications Much has been written about the use of plain abdominal radiography in the assessment of patients suspected of ingesting solid medications ( Table 8–1 ). Early studies by Handy [25] and O’Brien and associates[44] evaluated the radiopacity of common solid medications using a 20-cm water bath to simulate the radiodensity of the human abdomen. A variety of medications were found to be visible using this technique, leading to the often-quoted mnemonic “CHIPES” for solid medications likely to be visible on abdominal films. This mnemonic, first coined by Handy and later revised by others, stands for Chloral hydrate, calcium carbonate, Heavy metals, Iron, iodides, Psychotropics, potassium preparations, and Enteric-coated and Slow-release formulations.[53]

Table 8-1 -- Toxins Known to Cause Abnormalities on Abdominal Imaging Studies Kidney-Ureter-Bladder Views Direct Visualization of Toxin Solids Iron tablets (except chewable vitamins with iron) Contraband drug packets Lead-containing products Zinc sulfate tablets Thallium-tainted foods Elemental mercury Arsenic Button batteries

Paradichlorobenzene deodorizers/moth repellents Liquids Carbon tetrachloride Methylchloroform Methylene iodide Kerosene Indirect Clues Colonic Ileus Amphetamine Cyclic antidepressants Heroin Methadone Morphine Antiparkinsonian drugs Anticholinesterase insecticides Diltiazem Clonidine Multiple-dose activated charcoal Phenothiazines Verapamil Small Bowel Obstruction Activated charcoal Aluminum hydroxide antacids Pneumoperitoneum Cocaine Pneumatosis Intestinalis Intravenous drug use Nifedipine overdose Phenobarbital overdose Abdominal Computed Tomography Aluminum hydroxide antacid bezoar Brodifacoum rodenticide-induced hemoperitoneum Upper Gastrointestinal Series

Enteric-coated aspirin concretions

Use of the CHIPES mnemonic in clinical practice is limited by several factors. One is the failure of the water bath model to accurately simulate the heterogeneous radiodensity of the human abdomen. Savitt and coworkers[52] demonstrated that, of 312 medications tested, the only ones consistently radiopaque when placed inside a human cadaver were chloral hydrate, calcium carbonate, iron preparations, iodinated compounds, acetazolamide, busulfan, and potassium preparations. Second, neither a water bath nor a human cadaver model accounts for the time-dependent process of dissolution of these solid medications in gastric secretions. Dissolution data collected by Handy in 1971 suggest that medications that are radiopaque in the human cadaver and likely to remain undissolved at least 90 minutes after ingestion include iron preparations, potassium iodide, and potassium chloride. In actual clinical practice abdominal films have been reported helpful only in the case of iron ingestion, both for documenting the presence of medication in the gastrointestinal tract and tracking its elimination during decontamination procedures.[43] In summary, the literature supports the following conclusions with respect to the use of plain abdominal radiography in patients with known or suspected ingestion of solid medications: 1. 2. 3. The majority of solid medications are not radiopaque on abdominal films, and nonvisualization of a medication should never be the sole criterion used to eliminate the possibility of a toxic ingestion. Specific medications will not be identifiable based on their radiographic appearance; hence, routine abdominal radiography is of little benefit in the patient who has ingested an unknown medication. Of the medications included in the mnemonic CHIPES, those that have been visualized on radiographs of the human cadaver and have a measured dissolution time of at least 90 minutes in gastric secretions are limited to iron preparations, potassium chloride, and potassium iodide. The abdominal radiograph has been reported clinically useful only in ingestions of iron tablet preparations and not in the subgroup of chewable multivitamins with iron.[21] Serial radiographic examinations can be useful to document successful gastrointestinal decontamination in a patient with significant iron tablet ingestion whose initial abdominal radiograph demonstrates presence of iron pills in the gastrointestinal tract ( Fig. 8–1 ).

4.

Figure 8-1 Iron tablets (arrow) visualized on abdominal radiograph.

Liquid Toxins Visualization of ingested liquid poisons on plain abdominal radiographs is rarer still but has been documented in several cases of chlorinated hydrocarbon ingestion. Chlorinated hydrocarbons are immiscible in water and have a radiopacity that is proportional to the number of chlorine atoms in the molecule, so that their presence in the upright stomach can create a triple layer sign in which the ingested hydrocarbon is seen as a layer of increased radiopacity below gastric gas and above gastric secretions. Halogenated hydrocarbons that have been visualized on upright abdominal films include carbon tetrachloride (CCl4), methylchloroform (CH 3CHCl3), and methylene iodide (CH2I2). [4][18][59] A similar gastric layering phenomenon has also been noted in cases of kerosene ingestion.[17] Kerosene is less dense and less radiopaque than are gastric secretions and, therefore, will form a layer of intermediate radiodensity overlying the gastric contents on upright films. Some authorities suggest that the patient be given a glass of water to drink before obtaining the film to ensure the presence of water density within the stomach.[2] An unusually sharp demarcation between gastric fluid and gaseous layers has also been noted in these cases.

Body Packers and Body Stuffers Plain abdominal radiography can help in the evaluation of patients who ingest illegal drugs. These patients can be divided into two groups with distinctive characteristics in terms of radiographic evaluation and clinical outcome: body packers and body stuffers. Drug smugglers, known as “body packers,” ingest drug-filled packets to avoid detection of drug contraband by customs officials. Typically, they administer a laxative on arrival at their destination so that these packets can be expelled from the gastrointestinal tract and retrieved for trafficking. These drug packets are carefully assembled and typically composed of two to seven layers of latex, each tied at one end.[13] These packets are swallowed in groups of 50 to 200 at a time, and a coingested constipating agent facilitates packet retention in the gastrointestinal tract during smuggling.[30] Body packers typically present to the emergency department after being apprehended at an airport. Although they may initially deny ingestion of drug contraband, they know precisely the number of packets ingested.[13] Plain abdominal radiography is positive in 75 to 90 per cent of these patients, typically showing numerous smooth, oval foreign bodies, often with a rosette-type pattern at one end representing the tied free end of the outermost layer of latex ( Fig. 8–2 ).[6][15][38] These densities are most easily seen in the stomach and ascending colon, where gas provides a radiovisible interface with the homogeneous drug packet.[54]

Figure 8-2 Abdominal radiograph, body packer.

“Body stuffers,” on the other hand, ingest drug contraband in an urgent attempt to eliminate evidence when they are confronted with the possibility of capture. These patients typically present in custody of police who witnessed these ingestions during drug arrests, or they are brought from jail having been found unresponsive shortly after incarceration. The hastily ingested drugs are typically unwrapped or contained within a sandwich bag or single layer of aluminum foil or latex. Polypharmacy ingestion is common, and the

quantity of ingested contraband is smaller than that of the body packer.[50] Anecdotal experience suggests these hastily assembled drug packets are less likely to be seen on plain abdominal radiograph than are the professionally wrapped packages of the body packer.[50] Case reports imply that use of oral contrast or abdominal computed tomography (CT) may be helpful in documenting the presence of gastrointestinal tract contraband in this group, but formal studies are lacking.[46] Other Ingestants Plain abdominal radiography has been useful in documenting acute ingestions of lead-containing products ( Fig. 8–3 ), zinc sulfate tablets, thallium-tainted candies and foods, elemental mercury, arsenic, and button batteries.[10][35][49] In addition, abdominal films can be useful in patients who ingest household deodorizers and moth repellents of uncertain composition. These products typically contain either paradichlorobenzene or naphthalene mixed with essential oils and fragrances and compressed into a solid ball. Differentiating the two can be important because naphthalene causes significantly more toxicity than does paradichlorobenzene. Paradichlorobenzene is radiopaque in anecdotal human reports and in one in vitro study.[60] In contrast, naphthalene was radiolucent in this same study[60] ( Fig. 8–4 ).

Figure 8-3 Abdominal radiograph, lead in intestines.

Figure 8-4 Abdominal radiograph, radiopaque mothball.

Clinical Clues Aside from direct visualization of ingested toxins, abnormalities on abdominal films can provide clues to the presence of a specific class of toxin. Intestinal pseudo-obstruction, also known as colonic ileus, has been documented after morphine overdose, chronic methadone use, heroin addiction; the ingestion of amphetamines, phenothiazines, cyclic antidepressants, antiparkinsonian drugs, diltiazem, verapamil, clonidine, and multiple dose-activated charcoal; and exposure to anticholinesterase insecticides.[5][45] Plain films show gaseous distention of the small bowel and colon, with or without large amounts of retained fecal material. Mechanical obstruction of the small bowel, with typical findings of dilated loops of small intestine with air fluid levels on flat and upright abdominal films, has been associated with concretions of activated charcoal and aluminum hydroxide antacids.[23] Intestinal perforation with free intra-abdominal air is a welldocumented consequence of cocaine use ( Fig. 8–5 ).[34] Pneumatosis intestinalis and gas in the portal system have developed in association with necrotizing enteritis due to intravenous drug use with nonsterile needles and after overdoses of phenobarbital and nifedipine.[5] Finally, metallic densities found in the gluteal soft tissues of an elderly patient may indicate a course of antisyphilis therapy in the distant past, typically with bismuth or arsenicals.[24]

Figure 8-5 Pneumoperitoneum secondary to cocaine use.

Special Studies Ultrasound can detect solid medications within the stomach,[1] but clinical usefulness will likely be limited by the dissolution phenomenon. Only enteric-coated and sustained-release preparations are formulated to remain intact in the human stomach for as long as 2 hours. Further studies are needed to determine whether ultrasound can alter the clinical management of patients who ingest solid medications. Upper gastrointestinal series using barium contrast have been used to visualize concretions of enteric-coated aspirin in the stomach,[55] and in one case an antacid concretion was diagnosed by CT of the abdomen.[57] Medication concretions have also been reported after ingestion of verapamil and of theophylline and after heavy use of aluminum hydroxide gel antacids. Abdominal CT documented the presence of hemoperitoneum in a case of brodifacoum rodenticide poisoning. [42]

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THE CHEST
Chest radiography, first used widely in the 1920s to detect pulmonary tuberculosis, now plays a major role in the diagnosis and treatment of a wide variety of cardiovascular and pulmonary conditions. Toxins can be responsible for radiographic findings of pulmonary edema or infiltrates, cardiomegaly, obstructive airway disease, pleural effusion or thickening, pneumothorax, pneumomediastinum, and aortic dissection. Noncardiogenic Pulmonary Edema Noncardiogenic pulmonary edema (NCPE) is defined in radiologic terms as pulmonary edema in the absence of cardiomegaly or signs of pulmonary venous distention. Mild cases may demonstrate only interstitial edema, with interstitial markings persisting into the peripheral lung fields, Kerley A and B lines, and fluid in the interlobar fissures. More severe cases will manifest diffuse ill-defined alveolar infiltrates in which edema fluid leaves the interstitium and collects in the alveoli. These infiltrates are typically most visible centrally and fade out peripherally, producing a “butterfly” or “bat wing” pattern on the chest film. Alveolar edema may be impossible to distinguish from diffuse inflammatory alveolar infiltrates based on radiography alone. Rapid onset over several hours is more typical of noncardiogenic pulmonary edema, whereas gradual progression over one to several days suggests inflammatory alveolar infiltrates. A considerable number of toxins have been reported to cause noncardiogenic pulmonary edema. The most common offenders are salicylates and opioids. In one series, NCPE was noted in up to 35 per cent of patients older than the age of 30 who overdosed on salicylate ( Fig. 8–6 ).[58] Opioids associated with NCPE include heroin, propoxyphene, and methadone. Edema may occur up to 24 hours after overdose, and after reversal of opioid toxicity with naloxone. Cholinergic excess due to organophosphate insecticides may give rise to patchy areas of pulmonary edema, typically associated with clinical signs of excessive salivation, lacrimation, urination, defecation, and emesis. Other drugs reported to cause NCPE include ethchlorvynol, ritodrine, isoxsuprine, salbutamol, terbutaline, hydrochlorothiazide, protamine, recombinant interleukin 2, cyclosporine, cyclic antidepressants, amiodarone, Vinca alkaloids, mitomycin, bleomycin, iodinated contrast agents, and cytarabine. [47]

Figure 8-6 Chest radiograph, noncardiogenic pulmonary edema secondary to salicylate use.

Alveolar Infiltrates Alveolar infiltrates are most commonly caused by infectious agents but can also result from exposure to a variety of toxins. This exposure can occur through inhalation of toxins, by aspiration during ingestion of liquid toxins, or indirectly as part of a systemic reaction to the offending agent. In contrast to the homogenous “butterfly” distribution of opacities seen with noncardiogenic pulmonary edema, the radiographic distribution of infiltrates is patchy and often asymmetric. Several inhaled gases, vapors, or aerosols are capable of producing pulmonary infiltrates, and the ability to do so is to a great degree dependent on their water insolubility. Inhalants that are highly water soluble tend to dissolve in the upper airway mucosa, causing irritant symptoms and alerting the victim to escape the environment. Thus, these agents tend to cause fewer pulmonary effects. Representative water-soluble inhalants include ammonia, chlorine, bromine, fluorine, sulfur dioxide, and sulfuric, hydrochloric, and

hydrofluoric acids. In contrast, water-insoluble inhalants produce few to no irritant symptoms in the upper respiratory tract. Longer exposure times engender more severe effects on the lower respiratory tract and the development of patchy infiltrates. Examples include isocyanates, methyl bromide, nitrogen dioxide (silo filler’s disease), and phosgene (COCl2). Alveolar infiltrates have also developed with acute exposure to metal fumes and after subcutaneous injection of polydimethylsiloxane (Dimethicone) fluid used in cosmetic procedures. [15] Hydrocarbons aspirated into the tracheobronchial tree during ingestion or subsequent emesis are another well-known cause ( Fig. 8–7 ).

Figure 8-7 Chest radiograph, patchy infiltrates due to hydrocarbon aspiration.

Hypersensitivity pneumonitis may manifest days to months after initiation of drug therapy and gives rise to illdefined patchy opacities or an interstitial pattern in the lung fields that may or may not be accompanied by fever and blood eosinophilia. Radiographic findings typically resolve on discontinuation of the offending medication. The bipyridyl herbicide paraquat found in commercial weed killers such as Gramoxone, Weedol, and Pathclear can cause extensive pulmonary opacities after ingestion of less than one mouthful of a 20 per cent commercial solution. These opacities are often followed by progressive pulmonary fibrosis and death. A more complete list of the numerous agents known to cause pulmonary infiltrates is found in Table 8–2 .

Table 8-2 -- Toxins Reported to Cause Pulmonary Infiltrates on a Chest Radiograph Inhaled Gases, Vapors, or Aerosols Water Soluble Ammonia Bromine

Chlorine Fluorine Hydrochloric acid Hydrofluoric acid Sulfur dioxide Sulfuric acid Water Insoluble Isocyanates Methyl bromide Nitrogen dioxide Phosgene Hydrocarbons Carbon tetrachloride Chloroform Freon 11 (fluorocarbon 11) Gasoline Mineral seal oil Toluene Trichloroethane Trichloroethylene Turpentine Hypersensitivity Nitrofurantoin Penicillin Sulfonamides Tetracycline Isoniazid Phenytoin Propranolol Gold salts Penicillamine Tolbutamide Chlorpropamide

Tolazamide Carbamazepine Methotrexate Procarbazine Azathioprine Bleomycin Cromolyn sodium Metal Fumes Aluminum Antimony Arsenic Beryllium Brass Cadmium Chromium Cobalt Copper Iron Lead Magnesium Manganese Mercury Nickel carbonyl Selenium Silver Tin Zinc Miscellaneous Paraquat Polydimethylsiloxane (silicone) Radiation therapy Organophosphates Amiodarone

Nonsteroidal anti-inflammatory drugs Scorpion envenomation Interstitial Lung Disease Interstitial lung diseases featuring reticular, nodular, or mixed reticulonodular patterns are most often seen in patients with sarcoidosis, collagen vascular disorders, or idiopathic pulmonary fibrosis, but approximately one third of cases are toxin induced.[16] Over 135 agents have been associated with interstitial lung disease. The most common offenders include inhaled inorganic dusts of silica, asbestos, and coal, which produce the pneumoconioses. Also commonly implicated are the organic dusts of various living species, which give rise to extrinsic allergic alveolitis. The third major group is the drug-induced form of interstitial lung disease caused by an ever-expanding list of medications. The patient with evidence of interstitial infiltrates on chest radiography should be questioned closely regarding occupational exposures and medication use and the medication list examined for agents known to be associated with interstitial lung disease ( Fig. 8–8 ). A history of intravenous drug use raises the possibility of granulomatous interstitial lung disease due to talc particles that commonly contaminate injected heroin.

Figure 8-8 Chest radiograph, interstitial lung disease.

Obstructive Airway Disease Radiographic signs of obstructive airway disease have been associated with toxins and can easily be mistaken for asthma or chronic obstructive pulmonary disease due to cigarette smoking. Toxin-mediated small airway disease, also known as bronchiolitis obliterans, may appear on chest radiograph as hyperinflation, focal atelectasis, interstitial prominence, or even restrictive lung disease. It has developed after exposure to nitrogen dioxide, sulfur dioxide, ammonia, chlorine, phosgene, chloropicrin,

trichloroethylene, ozone, cadmium, methyl sulfate, hydrogen sulfide, hydrogen fluoride, zinc chloride, talcum powder, high-dose oxygen therapy, and free base cocaine ( Fig. 8–9 ).[33]

Figure 8-9 Chest radiograph, bronchiolitis obliterans.

. Pleural Disease Pleural fibrosis and plaques have primarily been associated with long-term exposure to asbestos ( Fig. 8–10 ), but other substances are causative. Long-term use of methysergide, ergotamine, and bromocriptine have also been reported to cause pleural fibrosis. [11] Pleural plaques have been noted in workers exposed to mineral wool fibers. Pleural effusions may be seen after single or multiple dose methotrexate therapy, as a hypersensitivity reaction to nitrofurantoin, or as part of a drug-induced lupus syndrome secondary to hydralazine, procainamide, quinidine, isoniazid, phenytoin, or chlorpromazine.[11]

Figure 8-10 Chest radiograph, pleural plaques secondary to asbestosis.

Pneumothorax has been reported repeatedly in intravenous drug users who attempt to use neck veins for injection. In one series from Detroit Receiving Hospital this injection technique accounted for approximately 20 per cent of pneumothoraces diagnosed during a 2-year interval.[20] This complication is especially likely in those engaged in “pocket shooting” into the supraclavicular fossa. The chest radiograph may also demonstrate retained needle fragments broken off during injection attempts. Pneumothorax and pneumomediastinum have also occurred in those who perform a forceful Valsalva maneuver while smoking marijuana or crack cocaine and after recreational sniffing of trichloroethane or nitrous oxide cartridges used in commercial whipped cream dispensers. Cardiovascular Abnormalities On a chest radiograph, cardiovascular abnormalities will occasionally be related to toxic exposure. Cardiomegaly with dilated cardiomyopathy occurs with chronic exposure to ethanol, cocaine, and emetine, the active ingredient in ipecac. The chemotherapeutic agents daunorubicin and doxorubicin cause cardiomegaly, congestive heart failure, and pericardial effusion up to 6 months after exposure and in a doserelated fashion. In rare cases, carbon monoxide has caused an ischemic cardiomyopathy with cardiomegaly. Chest radiograph has occasionally assisted in the diagnosis of acute aortic dissection in patients who present with chest pain after a cocaine binge.[22] Findings include clear lung fields with a widened mediastinum. The diagnosis is confirmed by transesophageal echocardiogram, helical CT scan of the chest, or aortography ( Fig. 8–11 ).

Figure 8-11 A, Chest radiograph, aortic dissection after cocaine use. B, Chest CT scan, aortic dissection after cocaine use.

.

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BONES AND SOFT TISSUES
Toxins that alter the radiographic characteristics of the musculoskeletal system generally do so by either increasing or decreasing the density of bone or by causing ectopic calcific densities in the soft tissues. Effects may be localized or diffuse and in most cases resolve on withdrawal of the offending agent, when and if it is identified. Lead Perhaps the best known finding in this category is the “lead line” associated with subacute or chronic lead toxicity. Lead and calcium are used interchangeably by bone. In adults, lead deposition is relatively homogeneous throughout the skeleton and discrete hyperdense lead lines are not seen. In children, however, lead deposited at centers of rapid bone growth, especially at the metaphyses of the femur and tibia, interferes with bone remodeling during the growth process. It is this growth disturbance, and not visualization of skeletal lead itself, that gives rise to transverse bands of increased density best seen at the distal femur, distal radius ( Fig. 8–12 ), and the proximal tibia and fibula. Similar markings have been noted along the margin of the iliac crest and within vertebral bodies, reflecting the regions of active growth of the pediatric skeleton. Lead lines have been seen in a group of children whose average serum lead level was as low as 50 µg/dL.[7] They have been noted in infants as young as 23 days after in utero contact with lead and may be multiple in cases of repeated exposure.[48] Similar bands of increased metaphyseal bone density may be seen in children with bismuth or metallic (yellow) phosphorus poisoning and in association with healed rickets.[48] Normal infants younger than age 3 will sometimes have increased metaphyseal density, which is prominent enough to be mistaken for lead lines. One study by Blickman and associates,[7] in 1986, suggested that presence of the radiodense band in the proximal fibula is more specific for plumbism and can be used as an adjunct to distinguish true lead lines from physiologic metaphyseal sclerosis. In all cases, suspicion of lead toxicity should be confirmed by determination of serum lead levels.

Figure 8-12 Lead lines in the distal radius.

Retained Lead Ammunition Unfortunately, humans frequently choose to bestow on each other another potential source of lead toxicity in the form of a bullet. Despite the occurrence of thousands of incidents of retained missiles in the human body over the centuries, fewer than 40 cases of lead toxicity related to retained ammunition have been clearly documented in the literature.[19] In general, lead projectiles that come to rest in human soft tissues become encased in fibrous tissue, which isolates the missile from the systemic vascular supply. This foreign body reaction and the relatively small surface area of lead exposed to potential dissolution seem to protect the victim from lead toxicity in the vast majority of cases. Dillman and colleagues[19] reviewed symptomatic lead poisoning resulting from retained lead missiles and noted common features. Nine of 18 cases involved retention of numerous particles of buckshot or shrapnel, with a greater surface area of exposed dissolvable lead. In 15 of 18 cases the lead missile was retained within a joint or bone. Eight of these 15 cases involved contact of the missile with synovial fluid, and in 6 of the 15 an associated arthritis was documented. This information suggests that the incidence of symptomatic lead toxicity is related to surface area of the retained fragments, presence of fragments within bone, and contact with a synovium-lined cavity ( Fig. 8–13 ). Time from gunshot wound to onset of symptoms varied from 2 days to 40 years. Scattered case reports suggest that plumbism may appear in a previously asymptomatic patient during periods of increased bone metabolism such as fever, hyperthyroidism, or limb immobilization. [12] More recently, lead toxicity has been attributed to bullets lying in contact with a pancreatic pseudocyst, the pleural space, and the cranium.[39][32] Treatment may require surgical removal of missile fragments and synovial stripping in addition to chelation therapy.[56]

Figure 8-13 Lead bullet arthrogram.

Skeletal Sclerosis Increased bone density throughout the skeleton is more closely associated with Paget’s disease or osteoblastic metastases of prostate or breast carcinoma, but a number of toxins should be included in the differential diagnosis as well.[31] Skeletal fluorosis is characterized by roughening of the bones of the pelvis and spine, with thickening and merging of bony trabeculae. Ultimately, diffuse sclerosis of the axial skeleton occurs with periosteal thickening and ligamentous calcification.[9] Chronic vitamin A poisoning in children is also associated with hyperostosis, primarily involving the ulna and metatarsals. Hypervitaminosis D causes osteoporosis in adults but in children produces diffuse skeletal sclerosis, with periarticular soft tissue calcifications. Periostitis involving the ribs, scapulae, humeri, femora, tibiae, and fibulae has also been noted after long-term therapy with prostaglandins E 1 and E2. Milk alkali syndrome, resulting from prolonged intake of large volumes of alkali and milk, is mainly associated with soft tissue calcification, but sclerosis of the skull and long bones has been noted as well.[2] Osteopenia Decreased bone density is a more common radiographic finding than osteosclerosis, in large part due to the frequent occurrence of osteoporosis in postmenopausal women. Here again, the possibility of bone rarefaction due to toxic agents should not be overlooked. Chronic cadmium exposure, endemic in parts of Japan and occasionally seen after prolonged occupational contact, presents as bone pain and severe osteomalacia with pseudofractures and biconcave deformation of the vertebrae. In addition, several medications have been associated with osteopenia ( Table 8–3 ).

Table 8-3 -- Medications Associated with Radiographic Signs of Osteopenia Aluminum (antacids) Methotrexate Barbiturates Corticosteroids Cyclosporine Heparin (long term) Phenytoin Primidone Etidronate disodium Vitamin D (adults)

From Hart RG, Boop BS, Anderson DC: Oral anticoagulants and intracranial hemorrhage: Facts and hypotheses. Stroke 1995; 8:1471–1477.

Finally, local rarefaction of bone may develop after long-term exposure to a variety of medications and toxins. Avascular necrosis, typically of the femoral head, is a prime example ( Fig. 8–14 ). Agents linked to avascular necrosis include cyclophosphamide, ethanol, glucocorticosteroids, radiation, and the combination of bleomycin and vinblastine. Slipped capital femoral epiphyses have been reported after use of growth hormone supplements and after pelvic radiation therapy. Polyvinyl chloride exposure produces a distinctive pattern of transverse bandlike bone rarefaction in the phalanges known as acro-osteolysis. Silastic implants in the joints of patients with rheumatoid arthritis can lead to cystic degeneration in adjacent carpal bones. Local bony degeneration has also been noted after hydrofluoric acid injury.

Figure 8-14 Avascular necrosis due to long-term corticosteroid use.

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CENTRAL NERVOUS SYSTEM
The development of cranial CT and magnetic resonance imaging (MRI) and their inclusion in routine clinical practice facilitated recognition of toxin-associated central nervous system radiographic abnormalities ( Table 8–4 ). Cerebral atrophy, intracranial hemorrhage, cerebral edema, ischemia, and infarction have all been precipitated by toxins, and recognition of a toxic cause is critical in preventing further morbidity in these cases.

Table 8-4 -- Toxins Causing Radiographic CNS Abnormalities Atrophy Ethanol Phenytoin intoxication Phenytoin therapy Lithium therapy Toluene Methyl mercury Podophyllin Radiation therapy Glucocorticosteroids Adrenocorticotropic hormone (ACTH) Amphetamine Cerebral Ischemia Amphetamine Cocaine Ergot derivatives High-dose oral contraceptives Sympathomimetic nasal decongestants Carbon monoxide Cyanide Methanol Subarachnoid Hemorrhage Amphetamine Cocaine

Phencyclidine Cerebral Edema Carbon monoxide Ethylene glycol Pentachlorophenol insecticides Sodium valproate Pseudotumor Cerebri Vitamin A Glucocorticosteroids Tetracycline Oral contraceptive agents Nalidixic acid Levothyroxine Lithium Mestranol/norethisterone Intracranial Hemorrhage Phenylpropanolamine Amphetamine Cocaine Anticoagulant drugs Rodenticides Scorpion envenomation Subdural Hematoma Anticoagulants Cerebral Atrophy To some degree this condition is an expected consequence of the aging process, but it can be accelerated by some toxins. Chronic exposure to ethanol is a familiar example, initially documented with pneumoencephalography in the 1960s and better delineated in recent years with CT and MRI. The characteristic pattern is one of cerebellar degeneration, which may be confined to the vermis or may involve both the vermis and the cerebellar hemispheres. Milder degrees of cerebral atrophy are typically noted as well. These radiographic abnormalities are found in up to 40 per cent of chronic alcoholics studied and were noted in 29 per cent of alcoholics younger than the age of 35 in one series.[28] Clinical signs of cerebellar dysfunction are not evident in over half of those with CT findings of alcoholic cerebellar degeneration; hence, radiographic recognition of this syndrome may allow for intervention before clinical signs manifest.[29] Cerebellar atrophy has also been associated with acute phenytoin intoxication,[36] chronic therapy with

phenytoin or lithium, and chronic toluene exposure.[51] MRI in chronic toluene abuse typically shows mild to marked cerebral and cerebellar atrophy and ventriculomegaly. There is increased periventricular white matter signal intensity and loss of gray-white differentiation on T2weighted sequences where gray-white contrast is normally best demonstrated.[51] Focal cerebral atrophy has also been noted on CT after chronic exposure to methyl mercury. A cluster of cases occurred near Minamata Bay, Japan, after ingestion of fish and shellfish contaminated with methyl mercury from a nearby chemical factory.[37] Cranial CT in these patients revealed atrophic changes of the calcarine gyrus of the occipital lobe and the cerebellar vermis and hemispheres. These findings corresponded to clinical symptoms of constricted visual fields, dysarthria, and ataxia. Diffuse cerebral atrophy has also been noted on CT and MRI 1 year after podophyllin exposure in a patient with disabling long-term neurologic sequelae, as a consequence of radiation therapy, and after exposure to glucocorticosteroids, adrenocorticotrophic hormone (ACTH), amphetamines, and toluene.[14][51] Cerebral Edema Cranial CT manifestations of cerebral edema include narrowing of the sulci and diminution of the lateral and midline ventricles. Nontoxicologic causes include anoxic insult to the brain, closed-head injury, altitude or heat exposure, and idiopathic pseudotumor cerebri, but a number of toxins should also be considered. Cerebral edema has been noted after acute exposure to carbon monoxide, ethylene glycol, and pentachlorophenol insecticides, and with both acute exposure to and therapy with sodium valproate. Patients with pseudotumor cerebri have abnormally small ventricles in 5 per cent of cases. This syndrome of benign intracranial hypertension has been induced by a variety of agents including vitamin A, glucocorticosteroids (use and withdrawal), tetracycline, oral contraceptives, nalidixic acid, thyroid supplements, lithium, and mestranol/norethisterone supplements in postmenopausal women.[2] Focal Cerebral Ischemia This is a manifestation of atherosclerotic cardiovascular disease in a majority of cases, and for that reason the possibility of toxic etiology is rarely entertained. In younger patients presenting with cerebral infarction, a history of exposure to cocaine, amphetamine, ergot derivatives, high-dose oral contraceptives, or excessive sympathomimetic nasal decongestants should be sought. Venous infarction due to thrombosis of an intracranial venous sinus is another well-described complication of oral contraceptive agents.[8] Distinctive patterns of focal cerebral ischemia have been observed on cranial CT and MRI in patients with carbon monoxide and cyanide poisoning and after toxic ingestion of methanol. In one series of 60 patients who presented comatose after carbon monoxide exposure, 23 had abnormalities on cranial CT scan.[41] In 21 of the 23 patients, symmetric and diffuse low density abnormalities were seen in the cerebral white matter and the severity of these white matter changes correlated with prognosis. In 18 of the 23 patients, bilateral low density changes were seen in the globus pallidus as well, although these findings did not correlate with clinical outcome ( Fig. 8–15 ). Focal ischemia of the putamen and globus pallidi have been visualized on CT and MRI in several cases of cyanide toxicity.[40] These lesions were sometimes absent on cranial CT scans obtained in the initial weeks after exposure. Methanol ingestion has produced symmetric areas of low attenuation in the putamen that correlated to areas of necrosis noted on subsequent autopsy ( Fig. 8–16 ).[3] In anecdotal reports extension of pathologic changes into the white matter and hemorrhagic transformation

portended a bad prognosis, whereas regression of putaminal lesions on follow-up MRI correlated with neurologic recovery and absence of extrapyramidal disturbance.[3][26]

Figure 8-15 CT scan of head, ischemia of bilateral globus pallidus due to carbon monoxide exposure.

Figure 8-16 CT scan of head, focal ischemia after methanol ingestion.

Intracerebral Hemorrhage These are associated with nontoxic causes such as hypertension and cerebral aneurysm. However, toxic causes should be considered, especially in younger patients. Phenylpropanolamine, scorpion evenomation, amphetamines, cocaine, anticoagulant drugs, and rodenticides have been implicated ( Fig. 8–17 ). Anticoagulants have also been associated with an increased incidence of subdural hematoma.[27] Bleeding in the abdomen and other sites may also occur ( Fig. 8–18 ). Subarachnoid hemorrhage has followed use of amphetamines, phencyclidine, and cocaine. An underlying cerebral aneurysm may or may not be found.

Figure 8-17 CT scan of head, intracerebral hemorrhage after cocaine.

Figure 8-18 CT scan of abdomen, spontaneous hemoperitoneum due to long-acting anticoagulant rodenticide toxicity.

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REFERENCES
1. Amitai Y, Silver B, Leikin JB, et al: Visualization of ingested medications in the stomach by ultrasound. Am J Emerg Med 1992; 10:18-23. 2. Ansell G: Radiology of Adverse Reactions to Drugs and Toxic Hazards, Rockville, MD, Aspen Systems Corporation, 1985. 3. Aquilonius SM, Bergstrom K, Enoksson P, et al: Cerebral computed tomography in methanol intoxication. J Comput Assist Tomogr 1980; 4:425-428. 4. Bagnasco FM, Stringer B, Muslim AM: Carbon tetrachloride poisoning—radiographic findings. NY State J Med 1978; 78:646-647. 5. Balthazar EJ, Lefleur R: Abdominal complications of drug addiction: Radiologic features. Semin Roentgenol 1983; 18:213-220. 6. Beerman R, Nunez D, Wetli CV: Radiographic evaluation of the cocaine smuggler. Gastrointest Radiol 1986; 11:351-354. 7. Blickman JG, Wilkinson RH, Graef JW: The radiologic “lead band” revisited. AJR 1986; 146:245-247. 8. Brown JI, Coyne TJ, Hurlbert RJ, et al: Deep cerebral venous system thrombosis: Case report. Neurosurg 1993; 33:911-913. 9. Bruns BR, Tytle T: Skeletal fluorosis: A report of two cases. Orthopedics 1988; 11:1083-1087. 10. Burkhart KK, Kulig KW, Rumack B: Whole-bowel irrigation as treatment for zinc sulfate overdose. Ann Emerg Med 1990; 19:1167-1170. 11. Byrd RP, Morris CJ, Roy TM: Drug-induced pleural effusions. Kans Med Assoc J 1991; 89:71-73. 12. Cagin CR, Diloy-Puray M, Westerman MP: Bullets, lead poisoning, and thyrotoxicosis. Ann Intern Med 1978; 89:509-511. 13. Caruana DS, Weinback B, Goerg D, et al: Cocaine-packet ingestion: Diagnosis, management, and natural history. Ann Intern Med 1984; 100:73-74. 14. Chan YW: Magnetic resonance imaging in toxic encephalopathy due to podophyllin poisoning. Neuroradiology 1991; 33:372-373. 15. Chastre J, Basset F, Viau F, et al: Acute pneumonitis after subcutaneous injection of silicone in transexual men. N Engl J Med 1983; 30:764-767. 16. Crystal RG: Interstitial lung disease. In: Wyngaardern JB, Smith Jr LH, ed. Cecil Textbook of Medicine, 18th ed. Philadelphia: WB Saunders; 1988:432. 17. Daffner RH, Jimenez JP: The double gastric fluid level in kerosene poisoning.

Radiology 1973; 106:383-384. 18. Dally S, Garnier R, Bismuth C: Diagnosis of chlorinated hydrocarbon poisoning by xray examination. Br J Indust Med 1987; 44:424-425. 19. Dillman RO, Crumb CK, Lidsky MJ: Lead poisoning from a gunshot wound: Report of a case and review of the literature. Am J Med 1979; 66:509-514. 20. Douglass RE, Levison MA: Pneumothorax in drug abusers: An urban epidemic?. Am Surg 1986; 52:377-380. 21. Everson GW, Oudjhane K, Young LW, et al: Effectiveness of abdominal radiographs in visualizing chewable iron supplements following overdose. Am J Emerg Med 1989; 7:459-463. 22. Gadaleta D, Hall MH, Nelson RL: Cocaine-induced acute aortic dissection. Chest 1989; 96:12031205. 23. Goulbourne KB, Cisek JE: Small bowel obstruction secondary to activated charcoal and adhesions. Ann Emerg Med 1994; 24:108-110. 24. Graham JB: Doctor’s diplomacy. NC Med J 1992; 53:33-40. 25. Handy CA: Radiopacity of oral nonliquid medications. Radiology 1971; 98:525-533. 26. Hantsen P, Duprez T, Mahieu P: Neurotoxicity to the basal ganglia shown by magnetic resonance imaging (MRI) following poisoning by methanol and other substances. Clin Toxicol 1997; 35:151-161. 27. Hart RG, Boop BS, Anderson DC: Oral anticoagulants and intracranial hemorrhage: Facts and hypotheses. Stroke 1995; 26:1471-1477. 28. Haubek A, Lee K: Computed tomography in alcoholic cerebellar atrophy. Neuroradiology 1979; 18:7779. 29. Hillbom M, Muuronen A, Holm L, et al: The clinical versus radiological diagnosis of alcoholic cerebellar degeneration. J Neurol Sci 1986; 73:45-53. 30. Hoffman RS, Smilkstein MJ, Goldfrank LR: Whole bowel irrigation and the cocaine body-packer: A new approach to a common problem. Am J Emerg Med 1990; 8:523-527. 31. Jones G, Sambrook PN: Drug-induced disorders of bone metabolism: Incidence, management and avoidance. Drug Safety 1994; 10:480-489. 32. Kikano GE, Stange KC: Lead poisoning in a child after a gunshot injury. J Fam Practitioner 1992; 34:498-500. 33. King TE: Bronchiolitis obliterans. Lung 1989; 167:69-93. 34. Kram HB, Hardin E, Clark SR, et al: Perforated ulcers related to smoking “crack” cocaine. Am Surgeon 1992; 58:293-294. 35. Litovitz TL: Button battery ingestions: A review of 56 cases. JAMA 1983; 249:2495-2500.

36. Masur H, Fahrendorf G, Oberwittler C, et al: Cerebellar atrophy following acute intoxication with phenytoin. Neurology 1990; 40:1800-1801. 37. Matsumoto SC, Okajima T, Inayoshi S, et al: Minamata disease demonstrated by computed tomography. Neuroradiology 1988; 30:42-46. 38. McCarron MM, Wood JD: The cocaine body packer syndrome: Diagnosis and treatment. JAMA 1983; 250:1417-1420. 39. Meggs WJ, Gerr F, Aly MH, et al: The treatment of lead poisoning from gunshot wounds with succimer (DMSA). Clin Toxicol 1994; 32:377-385. 40. Messing B, Storch B: Computer tomography and magnetic resonance imaging in cyanide poisoning. Eur Arch Psychiatr Neurol Sci 1988; 237:139-143. 41. Miura T, Mitomo M, Kawai R, et al: CT of the brain in acute carbon monoxide intoxication: Characteristic features and prognosis. AJNR 1985; 6:739-742. 42. Morgan BW, Tomaszewski CA, Rotker I: Spontaneous hemoperitoneum from Brodifacoum overdose. Am J Emerg Med 1996; 14:656-659. 43. Ng RC, Perry K, Martin DJ: Iron poisoning: Assessment of radiography in diagnosis and management. Clin Pediatr 1979; 18:614-646. 44. O’Brien RP, McGeehan PA, Helmeczi AW, et al: Detectability of drug tablets and capsules by plain radiography. Am J Emerg Med 1986; 4:302-312. 45. Ohri SK, Patel T, Desa L, et al: Drug-induced colonic pseudo-obstruction. Report of a case. Dis Colon Rectum 1991; 34:347-351. 46. Pollack CV, Biggers DW, Carlton FB, et al: Two crack cocaine body stuffers. Ann Emerg Med 1992; 21:1370-1380. 47. Reed CR, Glauser FL: Drug-induced noncardiogenic pulmonary edema. Chest 1991; 100:1120-1124. 48. Resnick D: Heavy metal poisoning and deficiency. In: Resnick D, Niwayama G, ed. Diagnosis of Bone and Joint Disorders, 2nd ed. Philadelphia: WB Saunders; 1988:3102-3114. 49. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg Med 1992; 10:577-583. 50. Roberts JR, Price D, Goldfrank L, et al: The bodystuffer syndrome: A clandestine form of drug overdose. Am J Emerg Med 1986; 4:24-27. 51. Rosenberg NL, Kleinschmidt-DeMasters BK, Kavis KA, et al: Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol 1988; 23:611-614. 52. Savitt DL, Hawkins HH, Roberts JR: The radiopacity of ingested medications. Ann Emerg Med 1987; 16:331-339. 53. Schwartz DT, Goldfrank L: Toxicologic imaging. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al ed. Toxicologic Emergencies, 5th ed. Norwalk, CT: Appleton & Lange; 1994:110.

54. Sinner WN: The gastrointestinal tract as a vehicle for drug smuggling. Gastrointest Radiol 1981; 6:319-323. 55. Sogge MR, Griffith JL, Sinar DR, et al: Lavage to remove enteric-coated aspirin and gastric outlet obstruction. Ann Intern Med 1977; 87:721-722. 56. Stromberg BV: Symptomatic lead toxicity secondary to retained shotgun pellets: Case report. J Trauma 1990; 30:356-357. 57. Sussman S, Goldberg RP, Glotzer DJ: Aluminum hydroxide gel bezoar—CT diagnosis. J Can Assoc Radiol 1985; 36:148-149. 58. Walters JS, Woodring JH, Stelling CB, et al: Salicylate induced pulmonary edema. Radiology 1983; 146:289-293. 59. Weimerskirch PJ, Burkhart KK, Bono MJ, et al: Methylene iodide poisoning. Ann Emerg Med 1990; 19(10):1171-1176. 60. Woolf AD, Saperstein A, Zawin J, et al: Radiopacity of household deodorizers, air fresheners, and moth repellents. Clin Toxicol 1993; 31:415-428.

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Chapter 9 – Pharmacokinetics and Toxicokinetics
WILLIAM A. WATSON S. RUTHERFOORD ROSE Pharmacokinetics is the science of drug movement through the body. The movement of a drug or substance in the body can be described in terms of its absorption, distribution, and elimination.[6] Pharmacokinetics describes the concepts that govern these processes, the impact of patient and disease variables, and the mathematical description of the processes. This chapter provides an overview of “just what you need to know” to understand pharmacokinetic concepts. These concepts are the basis for applying pharmacokinetic information to toxicokinetics. Toxicokinetics is used to describe the absorption, distribution, and elimination of drugs and other substances at doses that produce clinical toxicity. Pharmacokinetics improves our understanding of the relationship between the dose of a drug and its effect over time ( Fig. 9–1 ). The relationship between dose and effect would be best defined by measuring the amount of drug at the site of action. Because we cannot collect samples from patients to measure the amount of drug at the site of action, kinetics is useful in predicting the relationship based on drug concentration in samples such as plasma that can be collected. Samples should be obtained from a site that can be related to drug at the site of action. In this chapter plasma is used as the fluid for teaching purposes. Other samples such as whole blood, breath, urine, arterial blood, cerebrospinal fluid, and tissue are less useful and infrequently used.

Figure 9-1 The role of pharmacokinetics.

The application of pharmacokinetics to patient care is directed toward individualizing the use of therapeutic agents such as aminoglycosides, digoxin, lidocaine, and theophylline. In this setting the patient receives a known drug dose and clinical effects can be observed. A plasma drug concentration, usually a trough

concentration at steady state, is measured during a known dosing regimen. Application of the drug’s pharmacokinetic parameters allows the drug dosing regimen to be adjusted to either increase or decrease the plasma drug concentration and increase drug efficacy or decrease toxicity. The information and clinical conditions when pharmacokinetics and toxicokinetics are used are generally much different ( Table 9–1 ). The trough plasma drug concentration is the lowest value during the repeated dosing of a drug. The trough occurs immediately before the next dose of drug is administered. There is no trough drug concentration after an acute, single dose poisoning episode. Additionally, there is no intent to adjust the dose of an ingested drug that is producing clinical toxicity.

Table 9-1 -- Comparison of Kinetics in Therapeutic and Toxic Situations Therapeutic Dose Time of administration Controlled research describing: Kinetics Concentration effect Plasma concentrations measured at steady state Drug effects alter kinetics Yes Yes Yes No No No No Yes Well identified, low dose Well identified Toxic Often unknown, may be altered by therapy, high dose Often unknown

In overdose and poisoned patients toxicokinetic concepts are most often used in the interpretation of drug concentrations in plasma or urine drug testing results. Toxicokinetics may also be used to predict the onset of symptoms and duration of toxicity. Kinetic parameters such as area under the plasma concentration–time curve (AUC), half-life, and clearance are used to evaluate the efficacy of gastrointestinal decontamination and methods of increasing drug removal from the body. These parameters are used as outcomes in volunteer or animal studies where the dose administered and time intervals are defined.[1][8][15]

BASIC PRINCIPLES
Kinetics is based on the mathematical description of changes in drug concentrations over time. For the equations and mathematical background necessary to do pharmacokinetic calculations, the reader should use kinetic consultants and reference texts.[4][7]

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ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
Absorption, distribution, and elimination are the processes that substances undergo after administration by all routes except direct injection into blood, which foregoes the absorption process. Elimination is the combination of metabolism and renal excretion ( Fig. 9–2 ). The peak plasma concentration is achieved at the point in time when the combination of distribution and elimination are occurring at the same rate as drug absorption. The shape of the concentration-time curve depends on the relative rates of these processes.

Figure 9-2 Drug absorption, distribution, and elimination for a drug with first-order absorption and elimination.

Absorption Absorption is usually a first-order process. This indicates that it is the passive, concentration gradient dependent movement of drug into the body. A half-life can be calculated to describe the absorption rate. Half-life is the amount of time required for absorption of 50 per cent of drug in the gastrointestinal tract. Halflife is more commonly used to describe the elimination rate when it is a first-order process. The elimination half-life is the length of time it takes for the plasma concentration to decrease by 50 per cent, after distribution is complete. With a first-order process the half-life will be the same when the plasma

concentration decreases from 100 to 50 units, 50 to 25 units, and 25 to 12.5 units. In addition to the concentration gradients, the physical state of the molecule is important in determining the absorption rate. The drug must be in solution, and nonionized molecules cross membranes more easily than ionized molecules. The pKa of the substance, pH of the environment around the drug (gastrointestinal fluid), and molecular size are important in determining the rate of absorption. Because most ingested substances are solids, disintegration and dissolution of the solid tablet are required before absorption can occur.[21] The primary site of absorption is the small intestine, which has greater surface area than the stomach. This suggests that the physiologic process of emptying stomach contents through the pylorus into the small intestine should be an important variable controlling the rate of absorption. Ingestion of a drug dose does not mean that all the dose will be absorbed and end up in the systemic circulation. Bioavailability is the term used to define the fraction of a dose that is absorbed and available for systemic activity. Drug may be degraded or metabolized in the gastrointestinal tract before absorption. Most commonly, a drug will be metabolized or degraded in the gastrointestinal tract or as it passes through the liver on the way to the systemic circulation. For some drugs, this “first-pass effect” will significantly decrease the amount of parent drug that is available for distribution to the site of action, and the bioavailability will be less than 1.0. Cocaine and ethanol are examples of drugs that can have their bioavailability decreased both in the gastrointestinal tract and in the liver. Cocaine is hydrolyzed by water and ethanol is metabolized by alcohol dehydrogenase in the gastrointestinal tract. Both drugs are extensively metabolized by hepatic enzymes. The bioavailability of ethanol (from beer) is approximately 0.80. The bioavailability of an oral dose is determined by comparison with an intravenous dose, which does not require absorption. The area under the AUC is used to compare the bioavailability of an oral dose of drug to an equal intravenous dose. Using AUC as a measure of bioavailability without an intravenous control can be misleading. The best example of this problem occurred when acetylcysteine and activated charcoal were studied (see Fig. 9–2 ).[20] Data about drug absorption rates are usually more difficult to obtain than other kinetic parameters. The number and timing of sample collection is very important. An adequate number of samples is usually not collected. As an example, Figure 9–3 demonstrates plasma acetaminophen concentrations after the administration of 5.0 g of acetaminophen solution to a healthy volunteer. As can be seen, if the 2-hour sample were not collected, the peak plasma concentration achieved with the dose would be significantly underestimated.[15]

Figure 9-3 The usefulness of getting as many serum concentrations as possible. (Redrawn from Rose SR, Gorman RL, Oderda GM, et al: Simulated acetaminophen overdose: Pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064.)

Distribution Distribution is the process of drug movement throughout the body. Drugs distribute into various tissues to different extents. The distribution phase can often be seen on a concentration-time curve after intravenous drug administration because it results in a rapid decline in plasma concentrations immediately after administration, until equilibrium is reached ( Fig. 9–4 ). Plasma and other organs into which drugs rapidly

distribute are called the central compartment, and areas into which the drug distributes more slowly are called peripheral compartments. Distribution is important because it is during this process that the drug reaches its site of action. During distribution there is binding of drug to plasma proteins such as albumin. This decreases the amount of free drug that will be available to produce an effect at the site of action.

Figure 9-4 Log plasma drug concentration versus time curve after intravenous bolus of a drug with first-order elimination kinetics. During the distribution phase plasma drug concentrations decrease more rapidly, because distribution into body tissue and elimination are both occurring.

Distribution is also a concentration-gradient dependent process, and the distribution half-life into central and peripheral compartments can be calculated. If the site of action is in the peripheral compartment and distribution is relatively slow, there may be a time delay before the onset of toxicity. This could explain the delay in onset of seizures with high initial plasma theophylline concentrations, compared with the lower concentrations associated with seizures with chronic theophylline therapy. [12] In a very elegant series of experiments with rats, Ramzan and Levy demonstrated that the dose of theophylline that resulted in seizures was dependent on the rate of intravenous infusion.[14] The dose that caused seizures increased as theophylline was more rapidly infused. They also demonstrated that cerebrospinal fluid theophylline concentrations were not predictive of the concentration of theophylline at the site of central nervous system action.

The calculated term volume of distribution is a measure of the apparent space that a dose of drug would distribute into if the concentration of drug was equal throughout that volume. Distribution varies depending on how water or fat soluble the drug is and on how much it binds to proteins and other tissues. The volume of distribution is usually “apparent,” because it may not be a physiologically real number. The volume of distribution does not identify the specific anatomic areas where the drug will be found but can provide general information about where the drug is. The volume of distribution for some drugs is approximately equal to the intravascular volume (gentamicin) or to total body water (ethanol). For very lipid soluble drugs and those highly bound to tissue it will exceed 1000 mL/kg (1.0 L/kg), a value that is physiologically impossible. A very large volume of distribution indicates that most of the drug is not in plasma but rather is in other tissue. The volume of distribution can be calculated under different conditions, such as after a single intravenous dose or at steady state. Metabolism and Elimination The elimination of a drug is primarily the combination of metabolism via different pathways and the renal excretion of unchanged drug in urine. Some drug is also eliminated by other routes, including the gastrointestinal tract (fecal), and volatile gases may be exhaled via the lungs. Additional routes that usually contribute a small amount to drug elimination include sweat, hair, and tears. Metabolism is that portion of elimination that involves enzyme activity, usually hepatic. When hepatic metabolism is the predominate means of drug elimination, the amount of drug metabolized per unit time will usually have a maximum rate that is equivalent to that achieved when enzyme saturation occurs. Renal elimination of drugs can be concentration dependent or enzyme mediated, depending on the drug. Other pathways for both metabolism and elimination are usually less important than the liver and the kidneys. When the liver and kidneys do not function normally (e.g., renal failure), these secondary pathways become more important. Clearance is the removal of drug from plasma per time. Clearance may be described as total body clearance or clearance by the kidneys or liver. The use of extracorporeal methods to clear drug, such as hemoperfusion or hemodialysis, can also be described with a calculated clearance term. The extraction ratio of an organ or of an extracorporeal method of drug removal describes how efficiently the drug is removed. For example, if the kidneys are presented with 100 mL of blood per minute and the drug in that blood is completely removed, then the extraction ratio would be 100 per cent. This points out the importance of blood flow in determining the clearance rate. The combination of clearance rate and volume of distribution determine the half-life of the drug.

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MATHEMATICAL DESCRIPTIONS
When a known amount of drug is administered and serial plasma concentrations are measured, various equations can be used to determine kinetic parameters, including the drug’s absorption half-life (with oral administration), distribution half-life, elimination rate (half-life, or Km and Vmax), clearance, volume of distribution, and area under the AUC. The units for these terms are presented in Table 9–2 . The calculation of these parameters allows for a standardized method of mathematically describing the drug’s movement through the body. The kinetics of a drug are usually presented visually as a graph of plasma concentration (y axis) plotted over time (x axis). Before the equations are selected to describe a drug’s kinetic parameters, the plasma concentrations should be graphed and visually inspected. This will provide information about what processes are most likely occurring, using the shape of the line and whether concentrations are graphed as raw or log data ( Fig. 9–5 ; see Figs. 9–2 and 9–4 ).

Table 9-2 -- Units and Abbreviations for Kinetic Parameters Half-life (t½): time (often hours-1). Volume of distribution (Vd): volume per weight (usually mL/kg, can be L/kg). Area under the plasma concentration/time curve (AUC): concentration per time, usually in the form (amount) (volume-1) (time). Clearance (CL): volume per time (e.g., mL/min). Km: the Michaelis constant, which is the drug concentration at which the elimination rate is equal to 50% of its maximum. Vmax: the maximum rate of metabolism for a drug that undergoes Michaelis-Menton metabolism kinetics.

Figure 9-5 Comparison of linear and log concentrations.

The concentration-time curve is a mathematically best-fit line that describes measured plasma drug concentrations at known times. To accurately define a given portion of the curve it is generally stated that a minimum of 3 to 5 points is necessary. In addition, in order to accurately describe the elimination phase of the concentration-time curve, the measured points should be spread out over a time period that is expected to be at least two or three half-lives long. Although the large number of points necessary to describe a line is often impractical, obtaining fewer

samples may not accurately reflect the drug’s true movement through the body (see Fig. 9–3 ). Linear kinetics are also called first-order kinetics. The parameter calculated is half-life, which indicates the length of time required for half of the dose to be eliminated. For example, if there was 100 mg of drug in the body at time zero after absorption and distribution and the half-life of elimination was 2 hours, then the amount of drug in the body would be 50 mg at 2 hours, 25 mg at 4 hours, 12.5 mg at 6 hours, 6.25 mg at 8 hours, and 3.125 mg at 10 hours (one, two, three, four, and five half-lives, respectively). This demonstrates that the rate of drug elimination from the body is not a constant amount per hour but a constant fraction of drug remaining. The general rule is that all first-order processes will be nearly complete after five half-lives. A graph of this process using the plasma concentration–time curve is curved when the concentration is plotted on the y axis and time on the x axis and linear when the natural log of concentration is used (see Fig. 9–5 ). The presence of a first-order process suggests that the process does not rely on an enzyme system that is saturated. Half-lives can also be calculated for absorption and distribution when they are linear. Nonlinear processes are described by the Michaelis-Menten function. The Michaelis-Menten function is used when there is limited enzyme activity relative to the amount of drug present. In this case, the rate of drug elimination changes as the amount of drug changes, and the rate is described by an equation using the terms Vmax and Km. Km is the concentration of drug that is 50 per cent of the maximum elimination rate, and Vmax is the maximum rate of elimination. Drugs with Michaelis-Menten elimination do not have a constant elimination half-life. The elimination rate of some drugs with Michaelis-Menten kinetics may appear linear when the log concentration is plotted over time. In this case a half-life can be calculated.[10] It is acceptable to think of elimination in this manner as long as results are not extrapolated to concentrations outside the studied range. Zero-order processes occur at a constant rate independent of the amount of drug present. There is usually a range of drug concentrations in which zero-order processes occur. An example would be ethanol. Over the blood ethanol concentration range of 50 to 200 mg/dL, the decline in blood ethanol concentrations is an average of approximately 20 mg/dL/hr.[5]

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PHARMACOKINETICS IN CLINICAL TOXICOLOGY
Pharmacokinetics Versus Toxicokinetics: Does Dose Change Kinetics? Whether a drug’s absorption, distribution, and elimination differs between therapeutic and toxic doses is an important consideration. In general, it is believed that differences in kinetics will be seen as the dose is significantly increased. If this concept is correct, then the pharmacokinetic parameters that describe absorption, distribution, and elimination at therapeutic doses may not be applicable with the toxic doses involved in poisonings and overdoses. In general, if the ingestion of a large dose of drug alters kinetics, the following changes may occur: (1) the absorption rate may slow down; (2) the volume of distribution may increase; (3) the rate of hepatic metabolism may be saturated, and secondary elimination pathways become important; and (4) the elimination rate of the drug may be slowed.[13][18][19] Evidence supporting the changes in absorption, distribution, and elimination is not available for most drugs at toxic doses, because controlled trials are extremely difficult to perform. Examples that are available include phenytoin and aspirin. The absorption rate of phenytoin is slowed significantly as the oral dose is increased, and aspirin’s elimination rate is lengthened as the amount of drug in the body increases.[19] Kinetics and Interpreting Toxicology Laboratory Results The kinetics of a drug should be considered before interpreting toxicology laboratory results or recommending collection of a biologic sample (blood, serum, plasma, urine, breath) to determine the concentration of a drug or its presence. Interpretation of plasma concentrations requires at least an estimate of the time between dosing and the collection of the biologic sample. To imply a concentration-effect relationship, at a minimum the drug’s absorption and distribution must be complete. This requires knowledge of the rate of absorption and distribution of the drug and characteristics that may alter these parameters. As previously discussed, most concentration-effect relationships are developed with steady-state trough plasma concentrations, which occur immediately before the next dose of drug in therapeutic dosing. The trough concentration is the most constant relationship between the drug concentration in plasma and the site of action. Because there is no trough concentration with poisoned and overdosed patients, this concept cannot be used. Because steady-state trough concentrations are not available, ensuring that drug absorption and distribution are complete before making a correlation between plasma concentration and clinical toxicity is very important. An example of the application of absorption kinetics to plasma concentration interpretation is the Matthews-Rumack nomogram for prediction of acetaminophen-induced hepatotoxicity.[17] Plasma concentrations collected within the 4-hour period after ingestion cannot be interpreted, because absorption may still be occurring. There is generally more disagreement about interpreting plasma iron concentrations. The relationship between plasma iron concentrations at various times after ingestion and the risk of severe toxicity has not been well defined, possibly because the time from ingestion to sample collection has not been well documented.[9][11] Toxicokinetics and Drug Metabolites

Kinetics and evaluation of plasma drug concentrations are generally considered more important for drugs that have toxic metabolites because the development of toxicity is delayed until metabolite formation. For these agents, knowledge about the relationship between the parent drug and the toxic metabolite must be well defined before the kinetics of the parent drug can be useful for predicting toxicity. If factors impacting the toxicity of the metabolite are not reflected by the kinetics of the parent drug, then useful interpretation of plasma concentrations is difficult. An example would be the amount of glutathione in the liver and interpretation of a plasma acetaminophen concentration. Patients with dramatic depletion of hepatic glutathione would be expected to develop liver toxicity at lower plasma acetaminophen concentrations than might be expected based on the Matthews-Rumack nomogram. Kinetics and Prediction of Drug Effects Onset of Effect Because most drug poisonings and overdoses involve the oral ingestion of substances, an understanding of absorption and distribution could be useful in predicting the onset of toxicity. These kinetic predictions should be considered as general rather than precise. Unfortunately, there are generally less data available regarding the absorption rate for oral overdoses than is available for elimination rates. Case reports suggest that the ingestion of large numbers of tablets may slow tablet dissolution and result in delayed, erratic absorption. This is supported by animal models; however, there is little information that is useful for predicting how rapidly absorption will occur after the ingestion of a toxic oral dose. [2][3][16] Duration of Effect The duration of toxicity for drugs that produce their toxicity by reversibly binding to a receptor may be predictable by the elimination rate. The duration of effect will be less predictable when acute tolerance (often of the central nervous system) develops, when toxicity is secondary to a metabolite, or when receptor binding is irreversible and the offset of toxicity is based on another process, such as the generation of new enzymes. An example is the duration of untreated organophosphate toxicity that depends on the formation of new acetylcholinesterase.

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KINETICS IN TOXICOLOGY RESEARCH
In studies designed to measure the effects of treatment on drug toxicity, kinetic parameters are often used as a surrogate for clinical outcome. To be useful, the change in kinetics should be related to a reasonably expected change in toxicity. Establishing this relationship is difficult because volunteer studies must use nontoxic doses. In these models kinetics may not reflect what will happen with toxic doses. Kinetic outcomes are commonly used to evaluate the impact of gastrointestinal decontamination on drug absorption. The most important consideration is whether the kinetic parameter accurately reflects the percentage of the dose that is absorbed. Most commonly the area under the plasma concentration versus time curve is used to define the amount of drug absorbed. Using this endpoint requires prior knowledge about the relationship between intravenous and oral AUCs. This ensures that using the AUC after an oral dose will adequately reflect the total dose absorbed. With some drugs, such as acetylcysteine, the AUC may not adequately reflect the absorbed dose.[20] The calculated AUC should use plasma concentration points sufficient to accurately reflect the true AUC, and it works best under conditions of first-order elimination. Comparison of the AUC of the control group compared with that achieved with treatment will give a reasonable indication of the efficacy of decontamination. A more valid method of evaluating the efficacy of gastrointestinal decontamination would be to quantitate the amount of drug actually recovered in emesis, gastric lavage effluent, or feces. These methods are infrequently used. An indirect method useful for drugs with zero-order or Michaelis-Menten elimination kinetics may be measurement of drug and metabolite recovered in urine. With drugs in which the total amount administered can be recovered in urine over a reasonable period of time, subtraction of the amount recovered from the dose administered provides a measure of the amount that was not absorbed secondary to gastrointestinal decontamination. This method has been used for salicylate and provides a much more accurate estimate of the efficacy of gastrointestinal decontamination than AUC.[1] Calculation of half-life and drug clearance can be used to determine the efficacy of treatments such as multiple-dose activated charcoal, hemoperfusion, or modification of urinary pH used to enhance drug elimination. Because determination of clearance requires knowledge of the dose ingested, these calculations may not be appropriate for many overdose patient observations, unless the dose ingested can be verified and was not altered by some method of gastrointestinal decontamination. In addition, it is important to determine the increase in clearance rate necessary to produce a clinically useful treatment effect. Calculation of clearance evaluates the efficacy of extracorporeal methods of drug removal, such as hemoperfusion and hemodialysis.

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REFERENCES
1. Dillon ED, Wilton JH, Barlow JC, et al: Large surface area activated charcoal and the inhibition of aspirin absorption. Ann Emerg Med 1989; 18:547-552. 2. Dupuis RE, Cooper AA, Rosamond LJ, et al: Multiple delayed peak lithium concentrations following acute intoxication with an extended-release product. Ann Pharmacother 1996; 30:356-360. 3. Eppler J, Johnson D, Verjee Z, et al: Measurement of serum acetylsalicylic acid in a porcine model of aspirin overdose. Vet Hum Toxicol 1996; 6:409-412. 4. In: Evans WE, Schentag JJ, Jusko WJ, ed. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd ed. Vancouver, WA: Applied Therapeutics; 1986. 5. Garriott JC: Forensic aspects of ethyl alcohol. Clin Lab Med 1983; 3:385-395. 6. Gibaldi M, Levy G: Pharmacokinetics in Clinical Practice: I. Concepts. JAMA 1976; 235:1864-1876. 7. Gibaldi M, Perrier D: Pharmacokinetics, New York, Marcel Dekker, 1975. 8. Johnson D, Eppler J, Giesbrecht E, et al: Effect of multiple-dose activated charcoal on the clearance of high-dose intravenous aspirin in a porcine model. Ann Emerg Med 1995; 26:569-574. 9. Ling LJ, Hornfeldt CS, Winter JP: Absorption of iron after experimental overdose of chewable vitamins. Am J Emerg Med 1991; 9:24-26. 10. Mauro LS, Mauro VF, Brown DL, et al: Enhancement of phenytoin elimination by multiple-dose activated charcoal. Ann Emerg Med 1987; 16:1132-1135. 11. Mills KC, Curry SC: Acute iron poisoning. Emerg Med Clin North Am 1994; 12:397-413. 12. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose: Acute single ingestion vs. chronic repeated overmedication. Am J Emerg Med 1985; 3:386. 13. Platt D: Pharmacokinetics of drug overdose. Clin Lab Med 1990; 10:261-269. 14. Ramzan IM, Levy G: Kinetics of drug action in disease states: XVI. pharmacodynamics of theophyllineinduced seizures in rats. J Pharmacol Exp Ther 1986; 236:708-713. 15. Rose SR, Gorman RL, Oderda GM, et al: Simulated acetaminophen overdose: Pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064-1068. 16. Schwartz HS: Acute meprobamate poisoning with gastrotomy and removal of a drug-containing mass. N Engl J Med 1976; 295:1177-1178. 17. Smilkstein MJ, Knapp GL, Kulig KW, et al: Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 391:1557-1562.

18. Sue YJ, Shannon M: Pharmacokinetics of drugs in overdose. Clin Pharmacokinet 1979; 23:93-105. 19. Watson WA: Toxicokinetics and management of the poisoned patient. US Pharm 1990; 15:H1-H15. 20. Watson WA, McKinney PE: Activated charcoal and acetylcysteine absorption: Issues in interpreting pharmacokinetic data. DICP Ann Pharmacother 1991; 25:1081-1084. 21. Watson WA, Vraa EP, Neau SH: Acetaminophen tablet dissolution [letter]. Ann Pharmacother 1997; 31:1262-1263.

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Chapter 10 – Fluids and Electrolytes
KURT C. KLEINSCHMIDT KATHLEEN A. DELANEY Optimal metabolic and physiologic function requires a consistent fluid volume with a stable composition. Pathologic alterations in fluid or electrolyte concentrations result from changes in absorption, elimination, regulatory mechanisms, or transcellular shifts between fluid compartments. These alterations occur with diseases affecting gastrointestinal, renal, and skeletal functions and exposure to environmental elements, medications, or toxins. In this chapter the pathophysiology, clinical presentations, differential diagnoses, and management of body fluid volume and electrolyte disorders are discussed with a focus on disorders associated with drugs and toxins.

WATER AND SODIUM
Regulation of Fluid and Electrolyte Pools Water accounts for 60 per cent of body weight, with two thirds of total body water (TBW) in the intracellular fluid (ICF) space and one third in the extracellular fluid (ECF) space. The ECF is divided into intravascular (25 per cent) and interstitial (75 per cent) compartments. Most solutes, including electrolytes, do not cross cellular membranes, but free movement of water allows different compartments to remain in osmotic * equilibrium. Sodium salts are the primary extracellular osmoles within the ECF, whereas potassium salts comprise most of the ICF osmoles. Water volume and sodium concentration are interdependent, and changes in the TBW reflect changes in serum sodium concentration. Changes in the intravascular sodium concentration alter the osmolarity of other compartments by affecting the movement of water between them. Both the adrenal and the pituitary glands contribute to the regulation of blood volume and serum osmolarity. Hypothalamic receptors stimulate thirst after very small increases in osmolarity.[51] The pituitary neurohypophysis releases antidiuretic hormone (ADH) in response to increased plasma osmolarity or decreased blood volume or blood pressure. ADH stimulates absorption of free water at the distal renal tubule. Decreases in renal perfusion lead to release of renin by the renal juxtaglomerular apparatus, which converts angiotensinogen to angiotensin I. Pulmonary angiotensin-converting enzymes change angiotensin I to angiotensin II, which stimulates release of aldosterone from the adrenal cortex. Aldosterone is also released in response to hyperkalemia. It causes sodium reabsorption and potassium secretion in the renal cortical collecting tubules and acts on epithelial cells in the colon and the sweat and salivary glands to increase sodium conservation in those tissues. Disorders of ADH regulation result in impairment of sodium and water balance. The syndrome of inappropriate secretion of ADH (SIADH) occurs when ADH is released despite normal or hypo-osmolarity. This condition is characterized by hyponatremia and an inability to dilute urine to an osmolality less than 100 mOsm/kg water. Patients characteristically gain 4 to 5 L of water before stabilizing. Diabetes insipidus occurs when ADH deficiency impairs renal water conservation, resulting in hypernatremia if water intake is restricted. Diabetes insipidus is termed neurogenic if it results from inappropriate osmolality sensing or ADH

release. Nephrogenic diabetes insipidus is a result of insensitivity of the renal collecting tubule to ADH.
* An osmole is a unit measure for the total number of particles in a solution. Concentrations of osmoles are called osmolarity when expressed as osmoles per liter of solution and osmolality when expressed as osmoles per kilogram of water. The differences between the two concentration terms are small when referring to solutions of the human body; thus, osmolarity is used more commonly because body fluids are more easily expressed in liters. Osmosis is the diffusion of water from a compartment of lower osmolarity to one of higher osmolarity.

Differential Diagnosis of Toxin-Induced Fluid Deficits Fluid deficits can result from agents that (1) cause vomiting or diarrhea; (2) injure tissue with resultant third spacing (caustic agents); or (3) increase urination, sweating, or respiratory rate. Toxins that precipitate vomiting include acetaminophen, anticholinesterases, aspirin, caffeine, carbon monoxide, cardiac glycosides, colchicine, disulfiram/ethanol interactions, ipecac abuse, iron, metals, mushrooms, nicotine, and theophylline. Diarrhea is associated with ingestion of anticholinesterases, cathartics, colchicine, iron, lithium, metals, mushrooms, nicotine, phosphorus, and podophyllin. Anticholinesterases, diuretics, and lithium increase urination. Diaphoresis can result from cocaine or other sympathomimetic agents, disulfiram/ethanol interactions, anticholinesterases, phencyclidine, theophylline, and salicylates. Insensible pulmonary losses are increased by agents that enhance respiratory drive by causing metabolic acidosis (e.g., cyanide, glycols, iron, toluene, salicylates, toxic alcohols, metformin) or respiratory alkalosis (e.g., sympathomimetics, salicylates). Clinical Assessment of Hydration The heart rate, blood pressure, orthostatic vital signs, mental status, urine output, mucosal moistness, and the temperature, color, moistness, and turgor of the skin provide clinical information about the state of hydration. Drugs and toxins that alter these findings make a clinical determination of volume status more difficult. Numerous medications affect the pulse, respiratory rate, and blood pressure. Vasodilators, a- and ßadrenergic receptor antagonists, central a-adrenergic receptor agonists, cyclic antidepressants, and phenothiazines cause postural hypotension. Anticholinesterase medications increase urinary frequency, and diuretics increase urinary output. Anticholinergic agents result in urinary retention that may not be appreciated unless a Foley catheter is placed. Anticholinergic agents cause the skin to be warm, flushed, and dry whereas sympathomimetics, such as cocaine and theophylline, make the skin cool and damp regardless of the state of hydration. When present, laboratory indicators of volume depletion such as elevation of the hematocrit, serum bicarbonate, and blood urea nitrogen are helpful in assessing the volume status of poisoned patients. Hyponatremia Pathophysiology Acute hyponatremia causes cerebral edema because water moves across the blood-brain barrier into relatively hyperosmolar neurons. Compensatory mechanisms reduce the osmotic gradient by moving sodium, potassium, and chloride from the neurons and cerebral interstitium into the cerebrospinal fluid. Persistent hyponatremia results in the loss of other neuronal osmoles, particularly amino acids, further decreasing the osmotic gradient.[73] Clinical Presentation

The symptoms of hyponatremia are primarily neurologic and include headache, dizziness, anorexia, nausea, mental status alteration, irritability, myoclonus, tremors, seizures, and coma. Musculoskeletal symptoms such as weakness, abdominal pain, and muscle cramping also occur. [99] The severity of symptoms correlates with the magnitude of hyponatremia and, most importantly, with its rate of development. Significant hyponatremia that develops slowly may cause minimal symptoms. Differential Diagnosis True hyponatremia, defined as a plasma osmolality less than 280 mOsm/kg, is often classified according to the ECF volume status. Hypovolemic hyponatremia results from gastrointestinal, skin, and renal losses of water and sodium. Euvolemic hyponatremia is usually due to SIADH with various pulmonary conditions, central nervous system (CNS) infections, and tumors.[86] Certain drugs and toxins (discussed later) have also been associated with the development of SIADH. Dilutional hyponatremia with increased ECF results from renal failure, cirrhosis, nephrotic syndrome, and congestive heart failure. Hyponatremia Associated with Drugs and Toxins The synthesis and activity of aldosterone are affected by angiotensin-converting enzyme inhibitors and potassium-sparing diuretics. Thiazide and loop diuretics commonly cause a mild, insignificant hyponatremia. Profound hyponatremia due to diuretics is a rare, idiosyncratic reaction.[70] Ethanol-induced hyperlipidemia may result in a pseudohyponatremia. [27] Many medications may cause SIADH, including cyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, phenothiazines, butyrophenones, and sulfonylureas ( Table 10–1 ). [44][86] Chlorpropamide has been shown to increase ADH activity, whereas the mechanism by which tolbutamide, another sulfonylurea, produces SIADH is less clear. Acetaminophen and the biguanide antihyperglycemics, phenformin and metformin, also accentuate ADH activity but have not been associated with hyponatremia.[60]

Table 10-1 -- Agents That Decrease Serum Sodium Levels: Hyponatremia SIADH-Associated Agents Non–SIADH-Associated Agents Increased Antidiuretic Hormone Secretion Inhibits Angiotensin I–Converting Enzyme Barbiturates Carbamazepine Clofibrate Morphine Nicotine Oxcarbazepine Vincristine Increased Antidiuretic Hormone Activity Biguanides Captopril Inhibits Aldosterone (Renal Tubular Cells) Potassium-sparing diuretics Increased Gastrointestinal Loss Colchicine Other or Unknown Mechanism Silver nitrate * Lithium † Thiazide or loop diuretics

SIADH-Associated Agents Metformin Phenformin Cyclophosphamide Paracetamol Sulfonylureas ADH-like Desmopressin Oxytocin Other or Unknown Mechanism Psychotropics Tricyclic antidepressants (amitriptyline) Nontricyclic antidepressants Fluoxetine Tranylcypromine MAO inhibitors Butyrophenones Phenothiazines Thioridazine Thiothixene Clonidine Diazoxide

Non–SIADH-Associated Agents Glycine (transurethral prostatectomy syndrome) Licorice (glycyrrhiznic acid) Nonsteroidal anti-inflammatory drugs Arginine

Data from references 11 , 14 , 20 , 34 , 41 , 44 , 60 , 86 and 94 .
* Rare now that silver nitrate is not used in burn wound dressings; occurred owing to osmotic redistribution of sodium from the wound into the hypotonic silver nitrate in the dressing. † Rare. Lithium is usually associated with diabetes insipidus.

Management Hyponatremia is most life-threatening when the sodium drops abruptly to levels below 120 mEq/L over a 24hour period. When the time course cannot be deduced from the clinical setting, the presence of severe neurologic symptoms implies an acute development of hyponatremia. These patients require aggressive treatment to avoid the neurologic sequelae of acute hyponatremia.[79] In patients who have significant neurologic symptoms the serum sodium should be rapidly corrected to 120 to 125 mEq/L at a rate of 1 mEq/L/hr or less using hypertonic (3 per cent) sodium chloride or isotonic saline with a concomitant diuretic.[19][89] Hypertonic saline should be stopped once the serum sodium concentration reaches this level.

Most patients who present in an outpatient setting will have chronic hyponatremia. The extent of cerebral adaptation to hyponatremia, which correlates with the duration of hyponatremia, must be considered before treatment is instituted because replacement of neuronal osmoles, depleted by the compensatory response to hyponatremia, occurs slowly. The absence of severe neurologic symptoms implies a slow onset of hyponatremia. Rapid administration of saline will make the extracellular fluids relatively hyperosmotic, causing neuronal dehydration as water exits the neurons. Excessively rapid correction of chronic hyponatremia has been associated with the neurologically devastating syndrome referred to as central pontine myelinolysis. More recently this has been termed osmotic demyelination syndrome because it has been demonstrated to also occur outside the pons.[89] Asymptomatic or mildly hyponatremic patients who are euvolemic or hypervolemic are best managed with water restriction. Infusion of isotonic saline solutions is appropriate for mildly symptomatic patients with hypovolemic hyponatremia. These patients should be corrected no faster than 12 mEq/L/d.[88] Hypernatremia Pathophysiology Hypernatremia causes water to move from cells out to the relatively hyperosmotic ECF, resulting in cellular dehydration. The brain slowly adapts to this extracellular fluid shift by increasing its intracellular content of amino acids (so-called idiogenic osmoles), which draw water back into the cells and restore their volume. Clinical Presentation Symptom severity is related to the degree of hypernatremia and its rate of onset. CNS symptoms are most prominent and include irritability, delirium, lethargy, and coma. Neuromotor symptoms include weakness, tremor, rigidity, and increased deep tendon reflexes. A normal mental status can be maintained up to serum sodium levels of 170 mEq/L if the onset is slow enough to allow compensation to occur. Small blood vessels may tear during cerebral contraction causing subdural and subarachnoid hemorrhages. Seizures also result from focal intracerebral bleeding.[99] Profound hypotension is unusual even when significant dehydration is present because the intravascular volume is restored by the movement of intracellular fluid into the ECF. Despite preservation of the circulatory volume, most patients are clinically dehydrated and the skin turgor is decreased. Whereas diabetes insipidus may be associated with significant hypernatremia if the patient does not have access to water, polyuria and polydipsia are the only symptoms when the patient can drink freely. Differential Diagnosis The most common cause of hypernatremia is a decrease in TBW due to reduced intake or increased loss of fluids. Common causes include diarrhea, vomiting, hyperpyrexia, and excessive sweating. Various agents can cause hypernatremia by (1) increasing the sodium load, (2) increasing free water losses by impairing ADH release or response, or (3) increasing obligatory loss of free water in the kidneys or gastrointestinal tract through osmotic effects ( Table 10–2 ).[5][14] Excessive use of hypertonic povidone-iodine solutions on wounds can cause extracorporeal diffusion of water.[14] Oral salt exposures can cause significant elevations of serum sodium despite ingestion of seemingly small amounts of salt. The ingestion of one level tablespoon of salt (250 mEq sodium) by a 3-year-old child with 10 L of TBW could potentially increase the serum sodium by 25 mEq/L. [8][58] Most salt poisonings are unintentional, occurring when infant formula is

inadvertently prepared with salt instead of sugar, or following the use of salt as an emetic.[58]

Table 10-2 -- Agents That Increase Serum Sodium Levels: Hypernatremia Diabetes Insipidus–Associated Agents Non–Diabetes-Insipidus–Associated Agents Nephrogenic Amphotericin B Colchicine Demeclocycline Foscarnet Gentamicin Lithium Lobenzarit Mesalazine Methoxyflurane Propoxyphene Rifampin Streptozotocin Decreased Central ADH Secretion Phenytoin Ethanol Increased Sodium Load Antacids (backing soda) Sodium exchange resins Tablet salt Fleet Phospho-soda Increased Urinary Excretion Glycerin Isosorbide Mannitol Urea Increased Gastrointestinal Loss Lactulose Sorbitol Other or Unknown Mechanism Cholestyramine Povidone-iodine topical

Data from references 5 , 11 , 14 , 23 , 30 , 40 , 41 , 56 , 58 , 63 , 68 , 76 , 84 and 87 .

Diabetes insipidus is diagnosed by the demonstration of hypotonic urine in the setting of a concentrated serum osmo-lality. Neurogenic diabetes insipidus may result from tumors, infections, and granulomatous diseases, or various toxins (see Table 10–2 ) that affect the CNS. Ethanol is a well-recognized inhibitor of ADH release; however, it has not been associated with clinically significant diabetes insipidus.[14] Nephrogenic diabetes insipidus results when the kidney does not appropriately respond to ADH. It may result from both toxicologic (see Table 10–2 ) and nontoxicologic causes. [11] Therapeutic levels of lithium commonly cause polyuria with small elevations of the serum sodium concentration; however, the incidence of nephrogenic diabetes insipidus during therapy with lithium is unclear.[11] Management The management of hypernatremia depends on the underlying etiology and the patient’s state of hydration. If hypernatremia is due to a sodium gain, volume expansion will be present and the administration of a diuretic is appropriate. Most cases occur in patients with extracellular fluid loss who are hypovolemic.[54] These patients should receive volume replacement with normal saline, which is relatively hypotonic, until vital sign abnormalities are corrected.[54] Patients whose hypernatremia has developed over more than 2 to 3 days will have formed intracellular idiogenic osmoles so that rapid correction of hypernatremia may cause

cerebral edema, seizures, or other neurologic sequelae. Acute cases of hypernatremia can be corrected over 48 hours, whereas chronic cases require at least 72 hours of cautious correction. Therapy for diabetes insipidus depends on its cause. Neurogenic diabetes insipidus requires replacement of ADH with aqueous vasopressin or desmopressin (DDAVP), a modified vasopressin that has a longer therapeutic half-life. Other agents that increase the release of endogenous ADH include chlorpropamide, clofibrate, and carbamazepine.[11] Nephrogenic diabetes insipidus does not respond to exogenous ADH. Thiazide diuretics, which paradoxically decrease the urine output in patients with diabetes insipidus, are the mainstay of treatment of nephrogenic diabetes insipidus. They work by causing mild volume depletion, which results in enhanced proximal tubular resorption of filtrate and decreased delivery of water to the distal tubule. Nonsteroidal anti-inflammatory agents also reduce polyuria by inhibiting the renal synthesis of prostaglandins, enhancing the response to ADH.[11]

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POTASSIUM
Regulation Potassium homeostasis is maintained primarily by renal regulation with some contribution from gastrointestinal absorption and losses and intracellular and extracellular shifts. Renal potassium regulation is affected by plasma potassium concentration, aldosterone levels, and the rate of delivery of free water to the distal collecting tubules. Both increased plasma potassium and increased aldosterone stimulate sodiumpotassium (Na+,K+) pumps in the tubular cells of the distal tubule and collecting tubules. This increases the intracellular potassium concentration and results in increased passive diffusion of potassium into the tubules. Elevated plasma potassium also stimulates aldosterone secretion by the adrenal cortex. Increased flow of water in the collecting tubules dilutes the luminal potassium. This increases passive potassium diffusion from the tubular cells into the lumen.[38] The electrical gradient created by sodium reabsorption in the distal tubule is offset by co-transport of accompanying anions of sodium, usually chloride. However, if sodium presents to the distal tubule with anions that are not able to enter tubular cells, then the potential difference between the distal tubule and the tubular cells becomes more negative. Impermeable anions include bicarbonate, sulfate, and penicillins.[5] The increased negative gradient causes the potassium to move from the cell into the tubular lumen, also resulting in increased potassium losses. Hypokalemia Pathophysiology Although the ECF contains less than 2 per cent of total body potassium, small changes in serum potassium have significant effects on cellular function.[5] Potassium affects many enzymatic processes including glycogenesis and mitochondrial oxidative metabolism. It also affects osmotic pressure and acid-base balance.[15] Hypokalemia decreases the resting membrane potential of electrically active cells, inhibiting the generation of action potentials and decreasing neuromotor, cardiac, and gastrointestinal activity. Clinical Presentation Hypokalemia commonly causes muscular weakness that primarily affects the lower extremities and proximal muscle groups. Severe potassium deficiency results in death due to respiratory paralysis. Impaired gastrointestinal motility results in abdominal distention, cramping, nausea, and vomiting. Electrocardiographic (EKG) changes include the development of U waves, lengthening of the PR and QRS intervals, T wave flattening, ST segment depression, bradydysrhythmias, heart blocks, atrioventricular dissociation, and ventricular tachycardia. Cardiac contractility and vasomotor tone are depressed. Mental status impairment is rare. Hypokalemia promotes the intracellular movement of hydrogen ions that results in serum alkalosis with intracellular acidosis. Profound hypokalemia results in the kidney excreting hydrogen ions despite the presence of alkalosis in an attempt to maintain serum potassium levels. This paradoxical aciduria reflects the severity of the hypokalemia. The kidney cannot correct the alkalosis until the potassium is replenished.[99] Differential Diagnosis

Hypokalemia results from intracellular movement of potassium and from renal and enteric fluid losses. Diarrhea leads to significant losses of potassium due to its high concentration in diarrheal fluids. Although gastric secretions contain minimal amounts of potassium, hypokalemia occurs in vomiting patients because of intracellular shift of potassium associated with the vomiting-induced metabolic alkalosis.[5] Renal losses in the setting of primary or secondary hyperaldosteronism can be significant. Profound hypokalemia resulting in paralysis is seen in the familial disorder “periodic hypokalemic paralysis.” This is associated with rapid intracellular shifts of potassium. Many pharmacologic agents are associated with hypokalemia ( Table 10–3 ). Diuretic therapy is the most common cause of hypokalemia.[49] Potassium losses are not usually large, and total body stores are not affected.[40][70] Thiazide diuretics are more often implicated in the development of hypokalemia than are loop diuretics.[70] Hypokalemia is common in alcoholics and is attributed to decreased potassium intake, increased intracellular shifts from ß-adrenergic receptor stimulation, respiratory alkalosis, hyperinsulinemia due to hypophosphatemia, diarrhea, and inappropriate kaliuresis due to hypomagnesemia.[27] Sympathomimetic agents cause an intracellular shift of potassium that is not usually significant unless it results from overdose.[5][40] Intracellular shift of potassium is also associated with the inhalation of toluene.[91] In some cases the chronic abuse of toluene has been associated with profound hypokalemia, resulting in paralysis. This has been attributed to renal potassium losses in the setting of a toluene-induced renal tubular acidosis.[91] Salicylates cause hypokalemia through respiratory alkalosis and other unclear mechanisms.[32] Patients with geophagia develop hypokalemia when potassium is bound to certain types of clay.[36] The glycyrrhizic acid in licorice has been proposed to cause hypokalemia by binding and stimulating aldosterone receptors.[40] Carbenoxolone, used for the treatment of peptic ulcers in Europe, has significant mineralocorticoid activity and has been associated with hypokalemia.[74] Very high doses of hydrocortisone have caused hypokalemia.[69]

Table 10-3 -- Agents That Affect Serum Potassium Hyperkalemia Increased Potassium Load Salt substitutes Saltpeter (K+NO 3) Potassium supplements Penicillins (potassium salts)

Hypokalemia

Increased Urinary Excretion (Nonreabsorbable Anions) Bicarbonate Carbenicillin Penicillin G Sulfates

Decreased Urinary Excretion (Inhibits Aldosterone) Increased Urinary Excretion (Tubular Damage) Heparin Potassium-sparing diuretics * Angiotensin-converting enzyme inhibitors Decreased Urinary Excretion (Other/Unclear) Heparin Nonsteroidal anti-inflammatory drugs Cyclosporins Gentamicin Tetracycline (outdated) Amphotericin B Increased Urinary Excretion (Aldosterone-like) Licorice (glycyrrhizic acid) Glucocorticoids Carbenoxolone

Hyperkalemia Transcellular Shift Out of Cells Alpha-adrenergic agonists Arginine Beta2-adrenergic blockers Cardiac glycosides Glucagon Fluoride Succinylcholine Cyclophosphamide Fluoride Rhabdomyolysis-Inducing Agents Terlipressin

Hypokalemia

Increased Urinary Excretion (Other) Diuretics (except potassium sparers) Methylxanthines Caffeine Increased Gastrointestinal Loss Cathartics Colchicine Laxatives (phosphate enemas) Sodium polystyrene sulfate Trancellular Shift into Cells Chloroquine Dextrose Sympathomimetics Theophylline Beta-adrenergic agonists Insulin Toluene Other, Unknown, or Mixed Mechanisms Barium (soluble salts) Clay (geophasia) Ethanol Methyl mercury Salicylates

Data from references 5 , 14 , 18 , 30 , 36 , 40 , 41 , 45 , 61 , 68 , 92 , 93 and 96 .
* Amiloride and triamterene also decrease potassium excretion by a mechanism independent of aldosterone.

Management Treatment of symptomatic hypokalemia consists of an intravenous infusion of 10 to 20 mEq of potassium chloride in 50 to 100 mL of dextrose 5 per cent in water or normal saline per hour. The rate should not exceed 40 mEq/hr, unless the hypokalemia is life-threatening. Patients with renal impairment must be observed carefully during potassium administration. Cardiac monitoring is advisable when potassium is administered faster than 40 mEq/hr or the patient has renal impairment. Oral therapy is safer in asymptomatic patients. Hypokalemia may be resistant to potassium repletion if hypomagnesemia is

concurrently present.[53] Hyperkalemia Pathophysiology Hyperkalemia results from increased intake, decreased urinary excretion in the setting of acute renal failure or hypoaldosteronism, or shift from the intracellular to the extracellular space. Extensive tissue injury is associated with significant release of intracellular potassium. Toxins may result in hyperkalemia from all of these mechanisms (see Table 10–3 ). Severe hyperkalemia as a direct consequence of acute poisoning is infrequent and occurs primarily with inhibition of sodium-potassium adenosine triphosphatase (Na+,K+ATPase) activity.[13] The rate of rise of the serum potassium level is an important determinant of its clinical effects. Patients who are chronically hyperkalemic may tolerate very high potassium levels without serious sequelae. Clinical Presentation The primary clinical effects of potassium toxicity are reflected in characteristic EKG abnormalities. Acute elevations of potassium to levels around 6 mEq/L result in a more positive resting membrane potential, and cell activation occurs more readily. The rate of repolarization also increases, resulting in narrow, peaked T waves and shortened QT intervals. As the potassium level approaches 7 mEq/L, conduction delays result in PR interval and QRS complex widening. ST segments become depressed and P waves lose amplitude, widen, and are eventually lost. Above 8 mEq/L a confluence of the widening QRS complex with the T wave occurs, resulting in a sine-wave appearance of the EKG tracing. This progresses to ventricular fibrillation or cardiac standstill as levels rise above 10 to 12 mEq/L. The presence of concomitant hypocalcemia, hyponatremia, acidemia, and the rate of change of the potassium levels cause variations in the relationship between these EKG changes and the specific serum potassium levels. [73][99] The primary neuromuscular effect of hyperkalemia, seen at potassium levels greater than 8 mEq/L, is weakness that typically affects the lower extremities first. Ascending paralysis has also been reported, although this is more classically associated with hypokalemia.[73] Patients who became toxic after ingestions of potassium salts commonly complain of abdominal pain, nausea and vomiting, and occasional gastrointestinal bleeding.[13] Differential Diagnosis Hyperkalemia can result from increased potassium intake, transcellular shifts in the setting of diabetic ketoacidosis, tissue destruction (rhabdomyolysis, crush injury, burns), and decreased mineralocorticoid effects. Dangerous hyperkalemia most commonly results from acute renal failure and oliguria. Medicationinduced hyperkalemia (see Table 10–3 ) is generally mild and clinically significant only in association with renal failure. Beta-adrenergic receptor antagonists commonly cause small elevations of serum potassium. Aldosterone resistance or decreased renin-angiotensin system activity are associated with potassiumsparing diuretics, heparin, and angiotensin-converting enzyme inhibitors.[40][68] Nonsteroidal antiinflammatory agents inhibit renal prostaglandin synthesis, which in turn inhibits prostaglandin-mediated secretion of renin. This can result in hyperkalemia associated with hyporeninemic hypoaldosteronism or a type 4 renal tubular acidosis.[40][68] Large potassium loads from potassium-containing salt substitutes and saltpeter (KNO3) have been associated with significant hyperkalemia.[14][87] Potassium-sparing diuretics

increase potassium and magnesium levels by decreasing their renal clearances.[70] Inhibition of cell membrane Na+,K+-ATPase pumps by cardiac glycosides, primarily digoxin and digitalis, is of particular importance. Therapeutic doses of digitalis cause insignificant elevations in serum potassium; however, acute intoxication results in hyperkalemia, which correlates with mortality.[7][81] Drugs that are associated with significant rhabdomyolysis are also associated with hyperkalemia. Management The urgency of treatment is determined by the severity of EKG changes. Calcium directly antagonizes the cardiac effects of hyperkalemia and is indicated if significant EKG changes (QRS widening, heart block, or ventricular dysrhythmia) are present.[28][83] Ten milliliters of 10 per cent calcium gluconate (0.5–1.0 mL/kg) should be given over 2 to 3 minutes and may be repeated every 5 minutes as long as the EKG manifestations persist. The antagonistic effects of calcium start within minutes and last 30 minutes. Calcium is contraindicated in the treatment of hyperkalemia related to digoxin toxicity.[53] Various agents lower potassium acutely by promoting its redistribution into the intracellular space. Nebulized albuterol decreases serum potassium 0.5 to 1.5 mEq/L within 30 minutes, with effects lasting 4 to 6 hours.[4] One ampule (44 mEq) of sodium bicarbonate in adults (1.0–2.0 mEq/kg in children) works within 30 minutes with a duration of 2 hours. Dextrose (25 g in an adult or 1.0 g/kg in a child) plus insulin (10 units of regular insulin in an adult or 0.1 U/kg in a child) also work within 30 minutes with a 2-hour duration of effect.[28][53][83] Orally or rectally administered cation exchange resins, such as sodium polystyrene sulfate (Kayexalate), decrease potassium levels by binding it before elimination from the body. The oral dose is 15 to 20 g mixed in 30 to 100 mL of a 20 to 70 per cent sorbitol solution to prevent constipation. Rectal administration as an enema is also effective. Fifty to 60 g is given in 200 mL of tap water and retained at least 30 minutes, but preferably for 2 to 3 hours. The recommended pediatric oral or rectal dose is 1.0 g/kg.[83] Sodium polystyrene sulfate releases sodium in exchange for potassium and may precipitate sodium-induced fluid retention and heart failure.[53][73] It is important to emphasize the appropriate treatment for hyperkalemia in the setting of cardiac glycoside overdose is the use of antidotal treatment for digoxin poisoning (see Chapter 44 ). The primary cardiotoxic effects in this situation are related to digoxin toxicity, not to hyperkalemia, which is just a marker of digoxin effects on the Na+,K+-ATPase pump.

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CALCIUM
Regulation Ninety-nine per cent of the body’s calcium is in bone, with 1 per cent in equilibrium between inactive protein bound and active ionized states. The ionized form mediates the physiologic effects of calcium. Levels of physiologically active ionized calcium are regulated by vitamin D and parathyroid hormone (PTH). Vitamin D comes from dietary sources or ultraviolet-mediated skin conversion of 7-dehydrocholesterol to cholecalciferol, which is converted by liver microsomal enzymes to 25-hydroxycholecalciferol, which is then converted in the kidneys to the active form, 1,25-dihydrocholecalciferol (Calcitriol). Prolactin, parathyroid hormone, estrogens, and hypophosphatemia stimulate the final step in the production of 1,25dihydrocholecalciferol. Epinephrine, dopamine, and decreases in levels of ionized calcium increase PTH release. PTH raises serum calcium by increasing calcitriol production and, in combination with calcitriol, increasing osteoclastic activity and intestinal and renal reabsorption of calcium. Calcitonin, which lowers serum calcium by decreasing bone osteoclastic activity, is increased primarily by hypercalcemia.[2] Standard laboratory measurements of calcium reflect the total of bound and ionized calcium, which varies directly with the serum albumin concentration. Despite wide variations in total calcium levels that reflect varying serum albumin concentrations, levels of ionized calcium remain constant in the patient whose calcium regulatory mechanisms are functioning normally. [10][100] An estimate of the normalized serum calcium is given by the following formula: Corrected calcium = Serum calcium (mg/dL) + 8[4 – Serum albumin (g/dL)] Whenever physiologically significant abnormalities in the serum calcium are suspected the ionized calcium should be measured directly. Hypocalcemia Pathophysiology Calcium is critical to neurotransmitter function within the central and autonomic nervous systems, neuromuscular junctions, and adrenal medulla. It is required for depolarization of nerves and muscle cells and for secretion of many hormones, including adrenocorticotropic hormone, adrenal corticosteroids, ADH, and insulin.[99] Hypocalcemia makes membranes more permeable to sodium, resulting in hyperexcitability. Clinical Presentation The symptoms of hypocalcemia are primarily neurologic and correlate with its level and rate of development. Paresthesias and numbness of the hands, extremities, and face typically occur first and progress to fasciculations, muscle cramps, carpopedal spasm, tetany, and seizures.[99] Chvostek’s or Trousseau’s signs may be elicited in patients with minimal hypocalcemic symptoms. Although rare, laryngeal spasm with

dyspnea is the most common cause of death due to hypocalcemia.[99] Cardiac contractility is decreased, and heart failure can occur. EKG changes include prolonged ST segments and Q-Tc intervals and inverted terminal T waves.[99] Hypocalcemia manifests in infancy with hyperirritability, twitching, tremors, seizures, vomiting, and spells of apnea.[57] Differential Diagnosis Hypocalcemia may result from hypoparathyroidism, pseudohypoparathyroidism, renal failure, short bowel syndrome, pancreatitis, vitamin D deficiency, and hypomagnesemic or hyperphosphatemic states. Hyperventilation results in symptoms of tetany due to stimulation of increased protein binding of calcium by respiratory alkalosis. Many agents can cause hypocalcemia ( Table 10–4 ). Phosphate complexes with calcium to produce hypocalcemia. Hypocalcemia has been associated with phosphate-containing enema solutions, ingestions, parenteral infusions, and white phosphorus burns. [14][55] Patients who ingest and metabolize ethylene glycol may develop hypocalcemia secondary to complexation of the oxalate metabolite with calcium. Fluoride ions rapidly complex with calcium, and lethal hypocalcemia has occurred in patients burned with hydrofluoric acid.[45] Induction of the microsomal electron transport system by ethanol, phenytoin, phenobarbital, or other agents increases the metabolism of vitamin D to an inactive form, resulting in hypocalcemia.[14] Colchicine and mithramycin inhibit bone resorption[61] whereas cadmium causes renal tubular defects and calcium wasting.[77] A decrease in ionized serum calcium attributed to the binding of calcium by foscarnet has been reported in patients treated for cytomegalovirus retinitis with this agent.[37]

Table 10-4 -- Agents That Affect Serum Calcium Hypercalcemia Aluminum Androgens Antacids (calcium-containing) Hypocalcemia Increased Phosphate Load Enemas Oral agents

Beta-adrenergic receptor agonists White phosphorous burns Foscarnet * Lithium Potassium Tamoxifen Thiazide diuretics Vitamin A Vitamin D Increased Urinary Excretion Aminoglycosides Bicarbonate Cadmium Loop diuretics Calcium Complexes Formed Citrate Oxalate (ethylene glycol) Fluoride Microsomal Oxidizing System Induction Phenobarbital

Hypercalcemia Phenytoin

Hypocalcemia

Inhibition of Bone Resorption Calcitonin Cisplatin Colchicine Mithramycin Other or Unknown Mechanism Ethanol Foscarnet * Ibuprofen † Toluene Data from references 1 , 14 , 26 , 41 , 52 , 61 , 62 , 85 , 96 and 100 .
* Foscarnet is associated with both hypercalcemia[33] and hypocalcemia.[37] † Both increased and very decreased magnesium levels associated with suppression of parathormone.

Management Clinically suspected hypocalcemia should be confirmed by measurement of the ionized calcium. If patients have significant symptoms (seizures, hypotension, dysrhythmias, or tetany), empirical management should be initiated before the return of the ionized calcium. Calcium is available either as a 10-mL ampule of 10 per cent calcium gluconate (93 mg of elemental calcium) or as a 10-mL ampule of 10 per cent calcium chloride (360 mg of elemental calcium). An initial dose of 100 to 300 mg of elemental calcium will increase the serum ionized calcium for 1 to 2 hours. If symptoms continue, doses should be repeated or an infusion at a rate of 0.5 to 2.0 mg/kg/hr can be initiated.[71] Children should receive 0.5 to 1.0 mL/kg of 10 per cent calcium gluconate.[57] Patients with hypomagnesemia may fail to respond to calcium supplementation until magnesium is also replaced. Calcium chloride has significant tissue toxicity and should only be infused through a well-secured, large-bore intravenous line. Calcium should not be added to bicarbonate-containing parenteral solutions because they can precipitate as calcium salts.[53] Asymptomatic patients should receive oral calcium supplements. Management should also focus on correcting the underlying cause of the hypocalcemia. Hypercalcemia Pathophysiology Hypercalcemia inhibits neuronal activation and excitability by decreasing membrane permeability to sodium. Neurotransmitter release is also decreased. Heart contractility is increased and ventricular systole is shortened, reflecting calcium’s role in cardiac excitation-contraction. Dysrhythmias may result from the shortened refractory period and slowed conduction. The most consistent EKG changes are Q-Tc interval

shortening with increased PR intervals, widening of the QRS complex, and T wave flattening. The most common renal effect is loss of concentrating ability. Electrolyte absorption in the proximal tubule and water permeability in the distal tubule are also decreased.[25][99] Clinical Presentation CNS depression is a prominent symptom with fatigue and weakness that may progress to delirium, lethargy, or coma. Cardiac dysrhythmias may occur, particularly atrioventricular blocks. An osmotic diuresis results in polyuria with loss of electrolytes and dehydration. Other symptoms include constipation, nausea and vomiting, and abdominal pain.[99] Differential Diagnosis Primary hyperparathyroidism is the most common cause of hypercalcemia. The most severe cases of hypercalcemia result from malignancies metastatic to bone or from tumors with ectopic parathormone activity. Other causes include immobilization, hyperthyroidism, Addison’s disease, milk-alkali syndrome, and multiple endocrine adenomas. Toxin-related causes are infrequent and typically due to inappropriate use of calcium or vitamin D supplements (see Table 10–4 ).[14] Oral calcium, often taken in the form of antacids, can cause mild elevations.[14] Hypervitaminosis A or D[24] or aluminum-containing antacids[85] increase osteoclastic bone absorption. Dietary potassium supplementation increases calcium retention by suppressing calcitriol synthesis.[52] Beta-adrenergic receptor agonists increase PTH secretion.[26] Unlike loop diuretics, thiazides increase renal tubular calcium reabsorption.[70] Lithium causes hypercalcemia in patients with primary hyperparathyroidism but not in normal individuals.[14] Management Hypercalcemia should be confirmed with evaluation of the ionized calcium. Volume replacement and saline diuresis are the mainstays of initial therapy. Intravenous normal saline at 2.5 to 4.0 L/d, depending on the patient’s volume status, can lower total calcium levels by 1.5 to 4.0 mg/dL/d.[10] Loop diuretics enhance the calciuric effect of diuresis. Various agents specifically inhibit bone resorption. The biphosphonates, etidronate (7.5 mg/kg intravenously over 4 hours daily for 3 to 7 days) and pamidronate (15–45 mg daily for up to 6 days) are safe and effective. They begin to decrease calcium within 2 days of the onset of dosing. The antitumor agent mithramycin (25 µg/kg IV over 3 to 6 hours), a potent inhibitor of RNA synthesis in osteoclasts begins to work within 12 hours and has maximal reduction in 48 to 72 hours. Unfortunately, it is associated with hepatotoxicity, nephrotoxicity, and thrombocytopenia and is contraindicated in patients with these disorders.[10][17] Calcitonin (4–8 units/kg intramuscularly every 6 to 12 hours) begins to inhibit bone resorption within hours of its administration but is the least effective.[10] Glucocorticoids are helpful when hypercalcemia is due to hematologic cancers but not other causes.[10] Mild hypercalcemia (less than 12 mg/dL) usually responds to saline diuresis alone. Severe or persistent symptoms despite diuresis indicate a need for additional therapy of moderate elevations of 12 to 14 mg/dL. Regardless of symptoms, all patients with levels greater than 14 mg/dL require the prevention of bone resorption. Patients with life-threatening symptoms should be treated with calcitonin plus mithramycin, if not contraindicated, or a biphosphonate. The ultimate management of hypercalcemia requires correction of the

underlying etiology.

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MAGNESIUM
Regulation Magnesium is the second most abundant intracellular cation and is the only cation not under direct hormonal control. Most magnesium is not readily exchangeable. Bone and skeletal muscle are the major reservoirs, containing 60 per cent and 20 per cent of the total magnesium, respectively. Only 1 to 2 per cent of the total body magnesium is in the ECF, and one third of that is protein bound.[62][64] Gastrointestinal absorption is unregulated, whereas magnesium’s homeostasis is well maintained by its renal elimination.[62] Patients with normal renal function may vary their daily magnesium excretion from more than 400 mEq/d in those with hypermagnesemia to less than 1 mEq/d in those with deficiencies.[29] Proximal tubular magnesium reabsorption is increased by PTH and decreased by volume expansion, osmotic diuresis, hypercalcemia, and various medications.[62] Hypomagnesemia Pathophysiology Magnesium is a cofactor in most cellular metabolic and energy-related reactions that involve phosphorus, including membrane-bound ATPase. It is required for glycolysis and oxidative phosphorylation.[97] Hypomagnesemia results in widespread membrane instability and has diverse neuromuscular and cardiovascular effects. Clinical Presentation Central nervous system and neuromuscular manifestations of hypomagnesemia include hyperexcitability, seizures, irritability, disorientation, psychotic behavior, ataxia, and athetoid movements. It is unclear whether these symptoms attributable to hypomagnesemia are due to the magnesium or to the commonly associated hypocalcemia or hypokalemia.[65] Cardiovascular effects include congestive heart failure and both supraventricular and ventricular dysrhythmias. EKG changes include ST segment depression, PR interval prolongation, and QRS complex widening. Differential Diagnosis Alcoholism is the most common cause of hypomagnesemia in the United States.[65] Diarrheal diseases, hyperaldosteronism, and renal disorders may also cause hypomagnesemia. Many medications are associated with hypomagnesemia ( Table 10–5 ). Diuretics are classically associated with hypomagnesemia[62][65][70]; however, one review suggests that the data supporting this are poor.[21] Potassium-sparing diuretics protect against diuretic-induced magnesium deficiency.[65]

Table 10-5 -- Agents That Affect Serum Magnesium

Hypermagnesemia Antacids (magnesium-containing)

Hypomagnesemia Increased Urinary Excretion

Cathartics (magnesium-containing) Aminoglycosides Epsom salt Lithium Amphotericin Calcium Cisplatin Diuretics (loop, thiazide, osmotic) Ethanol Growth hormone Thyroid hormone Increased Gastrointestinal Loss Colchicine Laxatives Transcellular Shift into Cells Cardiac glycosides Insulin Other or Unknown Mechanism DDT Fluoride poisoning Ibuprofen Data from references 1 , 2 , 41 , 45 , 61 and 64 . Management Because serum magnesium levels correlate poorly with total body magnesium, some recommend the administration of magnesium salts to high-risk patients (alcoholics, patients on loop diuretics) even in the absence of serum hypomagnesemia. [65] Oral supplementation is adequate for mild (serum level > 1 mEq/L), asymptomatic hypomagnesemia. Gastrointestinal absorption is slow and inappropriate for significant depletions. Oral therapy may be complicated by diarrhea. Symptomatic patients or those with serum levels below 1 mEq/L likely have significant total body depletions of 1 to 2 mEq/kg of body weight.[29] These patients are best replenished with parenteral magnesium. However, even patients with significant deficits lose most parenterally administered magnesium in the urine. One gram of salt is equivalent to 4 mmol (8 mEq) of magnesium. Serum magnesium equilibrates slowly with intracellular magnesium, and replacement of the total body deficit requires at least 3 to 4 days of therapy. Routine parenteral replacement recommendations vary from 0.5 to 1 mmol/kg (approximately 10 g of magnesium sulfate for a 70-kg adult) over the first 24 hours[65] to 4 to 6 g of a 10 to 20 per cent solution over 3 hours repeated every 6 to 12 hours.[29][31] Magnesium-deficient patients with malignant dysrhythmias, digoxin toxicity, seizures, or tetany should be treated more emergently with 2 to 3 g (10–15 ml of a 20 percent solution) of magnesium sulfate intravenously over 1 minute. This is followed by a continuous infusion of 2 per cent magnesium sulfate (1 g

in 500 mL of dextrose 5 per cent in water) at 100 mL per hour for 5 hours.[65] Parenteral therapy in children is done with 25 to 50 mg/kg of magnesium sulfate diluted in 25 to 100 mL of normal saline over 20 to 30 minutes. In more emergent situations, the same amount may be provided by direct intravenous bolus.[75] Serum magnesium should be checked daily. Close monitoring is required in patients with renal impairment, and the amount of magnesium administered should be decreased in these patients.[29][31] Parenteral infusions of magnesium may be complicated by hypocalcemia, hypotension, or respiratory depression due to hypermagnesemia.[53] Hypermagnesemia Pathophysiology and Clinical Presentation Hypermagnesemia causes neuromuscular suppression manifested as decreased deep tendon reflexes and weakness that can progress to paralysis and respiratory failure. Lethargy is common. Hypotension may result from decreased vascular tone. Cardioinhibitory actions include bradydysrhythmias, atrial fibrillation, and heart blocks. EKG changes include increased PR intervals, QRS complex widening, and conduction delays.[16][65] Death may result from respiratory depression, severe hypotension, or cardiac arrest secondary to loss of impulse formation and conduction.[65] Differential Diagnosis Because the kidneys have a profound capacity to excrete magnesium, the most common cause of hypermagnesemia is renal insufficiency.[62][65] However, patients with normal renal function have developed profound hypermagnesemia after the acute ingestion of massive magnesium loads.[64][65] Other causes of hypermagnesemia include hypothyroidism, milk-alkali syndrome, adrenal insufficiency, tumor lysis, rhabdomyolysis, and hyperparathyroidism. Various medications can cause hypermagnesemia (see Table 10–5 ). Magnesium is available in many overthe-counter products, including antacids and laxatives. Most severe cases involving massive gastrointestinal exposures result from the administration of magnesium sulfate or magnesium citrate as cathartics.[65] Significant oral exposures have also resulted from ingestion of Epsom salts (magnesium sulfate).[64] Inadvertent administration has also occurred when ampules of magnesium were mistaken for other therapeutic agents, such as glucose.[39] Vitamin D supplementation in a patient with renal insufficiency has resulted in hypermagnesemia. [82] . Management The first step is to ensure that patients receive no further magnesium. This may be all that is required if there are no life-threatening signs and the patient has normal renal function. Saline infusions and loop diuretics promote diuresis. Because calcium will also be diuresed and hypocalcemia may exacerbate the signs and symptoms of hypermagnesemia, calcium levels should be monitored during therapy. Severely symptomatic patients, particularly those with cardiac dysrhythmias or neuromuscular manifestations, should receive calcium intravenously to antagonize the effects of hypermagnesemia. Calcium chloride or gluconate should

be administered at a rate of 100 to 200 mg of elemental calcium every 3 to 5 minutes until the cardiovascular or neuromuscular instability has been improved.[65] Dialysis should be considered in patients with renal insufficiency or who do not respond to the just mentioned therapy.[53][65] Dialysis has been used in severely hypermagnesemic patients who have normal renal function.[43]

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PHOSPHATE
Regulation Phosphate is the major intracellular anion, and serum levels may not reflect the total body stores. Homeostasis is primarily under the direct hormonal influence of PTH, which increases phosphate excretion within the proximal renal tubules. Gastrointestinal absorption is relatively unregulated. Transcellular shifts can be significant, with insulin, glucose, and alkalosis all driving phosphate intracellularly to promote glycolysis.[62] Phosphate homeostasis is closely related to that of various cations. Bone resorption, induced by hypophosphatemia, also releases calcium. Magnesium or calcium inhibition of PTH release results in phosphate retention. Renal tubular reabsorption is inhibited by hypokalemia. [95] Hypophosphatemia Pathophysiology Phosphorus is found in all nucleic acids, phospholipids, and nucleotides. The chemical energy required for cellular metabolism is stored in phosphorylated adenine (adenosine triphosphate [ATP]) and guanine (guanosine triphosphate [GTP]) nucleosides. Phosphorus also serves as a cofactor in numerous enzymatic processes, regulates glycolysis, and is required for the mitochondrial electron transport system.[48] Red blood cell ATP and 2,3-diphosphoglycerate (2,3-DPG) combine with hemoglobin to decrease its binding of oxygen. Because phosphate is required for ATP and 2,3-DPG production, hypophosphatemia results in impaired oxygen delivery. Depletion of ATP in white blood cells results in decreased leukocyte motility, chemotaxis, and bacterial killing. Most effects of hypophosphatemia reflect the inability of cells to regenerate ATP when inorganic phosphate falls too low.[66] Clinical Presentation The most common effects of hypophosphatemia are neuromuscular and hematologic. Symptoms include weakness, tremors, paresthesias, decreased deep tendon reflexes, altered mental status, and hyperventilation. Depletion of red and white blood cells and platelets results in impaired oxygen delivery, tissue hypoxia, an increased incidence of infections, and bleeding. Rhabdomyolysis due to hypophosphatemia is seen in starvation and in alcoholics after a few days of carbohydrate loading, which may occur with hospitalization.[12][50][66] Differential Diagnosis Hypophosphatemia is associated with decreased oral intake of phosphate, increased urinary excretion (vitamin D deficiency, renal tubular disorders), and alkalosis. Alcoholism is the most common cause because of poor oral intake and malnutrition. Medications can cause hypophosphatemia through multiple mechanisms ( Table 10–6 ). Antacids bind phosphate and prevent its absorption, and symptoms can develop in as little as 2 weeks.[78] Paracetamol, even without liver failure, is associated with hypophosphatemia.[42]

Table 10-6 -- Agents That Affect Serum Phosphate Hyperphosphatemia Hypophosphatemia Increased Phosphate Load Increased Gastrointestinal Loss Enemas Oral agents White phosphorous burns Antacids (aluminum, magnesium, calcium) Colchicine Iron Increased Urinary Excretion Androgens Bicarbonate salts Diuretics Estrogens Glucagon Hypomagnesemia Steroids (chronic) Transcellular Shift into Cells Alkalosis Glucose Insulin Salicylates Toluene Theophylline Other or Unknown Mechanism Arginine Ethanol (chronic, withdrawal) Paracetamol Data from references 12 , 22 , 34 , 41 , 55 , 61 , 62 , 66 , 72 , 78 and 96 . Management As with any predominantly intracellular ion, determining the magnitude of deficiency is difficult and treatment is empirical. Asymptomatic patients or those with mild hypophosphatemia (>1 mg/dL) may be managed with oral supplements such as skim milk (1 g/L) or a phosphate salt (up to 1.3 g/dL).[12][66][90] Those with serum levels less than 1 mg/dL should receive 2.5 mg/kg of intravenous potassium phosphate or sodium phosphate, diluted in 1 L, over 6 to 12 hours. Symptomatic patients should receive 5.0 mg/kg.[35][90] Parenteral administration should be discontinued when the serum phosphate concentration exceeds 2 mg/dL.[12][90] Phosphate administration, particularly parenterally, can worsen hypocalcemia or

hypomagnesemia, and these cations also need to be monitored closely.[12][35][66] Hyperphosphatemia Pathophysiology and Clinical Presentation Symptoms of hyperphosphatemia are primarily due to resultant hypocalcemia. Symptoms reflect hyperexcitability and are mostly neurologic, including muscle cramps, paresthesias, tetany, and seizures.[12][66] EKG changes include Q-T c prolongation.[46][66] Metabolic acidosis occurs frequently.[46] Calcium-phosphate extraskeletal precipitation may occur if the solubility product for phosphate and calcium is greater than 58 mg/dL.[66] Differential Diagnosis Hyperphosphatemia is associated with renal failure, hypoparathyroidism, pseudohypoparathyroidism, and tumor lysis after chemotherapy. Dangerous hyperphosphatemia is rare but can result from the administration of oral, parenteral, or rectal phosphate preparations. Phosphate enemas have been associated with both serious morbidity and death, primarily in children.[22][55][72] Management Mild hyperphosphatemia does not require treatment except for the treatment of the underlying cause. Antacids containing divalent cations including aluminum, calcium, or magnesium are effective intestinal phosphate binders and are the mainstay for preventing hyperphosphatemia of renal failure. Each of these binders can result in their own complications, and their use requires appropriate attention.[12][66] Assuming normal renal function, severe acute hyperphosphatemia may be managed with intravenous saline administration coupled with diuretic therapy.[12] Glucose and insulin administration induce a transcellular shift with a decrease in plasma phosphate concentration. [12] Hemodialysis may rarely be required if the hyperphosphatemia has been refractory to standard therapy in the setting of renal failure.[12][66] Intravenous calcium administration may be cautiously considered in patients with severe symptoms such as tetany or seizures.[12] However, calcium administration may be complicated by extraskeletal precipitation of calcium phosphate.

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EFFECTS OF DECONTAMINATION TECHNIQUES AND ANTIDOTES ON FLUID AND ELECTROLYTE BALANCE
Gastrointestinal Decontamination Gastric decontamination with syrup of ipecac or lavage generally does not alter fluid or electrolyte levels, even when using water to facilitate the procedure.[67] However, overzealous lavage with water has resulted in water intoxication with associated hyponatremia, particularly in children.[6] Hypernatremia due to lavage with large quantities of normal saline has been described. Isotonic polyethylene glycol solutions have been used for gastrointestinal surgery preparation and for whole-bowel irrigation decontamination. Doses of up to 1 L/hr do not alter volume status or electrolyte levels.[9][39] Cathartics A single dose of a magnesium cathartic is safe, but multiple doses can cause hypermagnesemia.[80] Magnesium absorption is increased when intestinal motility is decreased.[80] Caution must be exercised when using magnesium in adults with renal insufficiency or in small children whose immature renal function may make them more prone to hypermagnesemia. [59] The hypertonic intestinal load with the cathartic sorbitol causes movement of free water from the body into the intestinal tract, resulting in diarrheal volumes as large as 4 to 5 L within 12 to 24 hours. Sorbitol caused severe hypernatremic dehydration in a child after a single excessive dose and in an adult after multiple doses.[3] When multiple doses of charcoal are used, a cathartic should only be given with the first dose. It is of concern that in a recent study it was found that charcoal was available only in combination with sorbitol in 16 per cent of the hospitals surveyed.[98] Antidotes Some antidotes can cause electrolyte alterations. Dextrose, particularly when accompanied by insulin, causes potassium to shift intracellularly and hypokalemia may ensue.[53] Euglycemic hyperinsulin therapy (constant infusion of 4 U/min) plus a 20 per cent dextrose solution to maintain euglycemia has been used to reverse verapamil toxicity in an animal model. Hypokalemia may result from this therapy.[47] Digoxin-specific antibody fragments can cause hypokalemia by reactivating the Na +,K+ pump.[7] Alkalinization with sodium bicarbonate or induced hyperglycemia can cause hypokalemia by shifting potassium intracellularly. Calcium is used to manage severe hyperkalemia or hypermagnesemia, calcium channel blocker overdose, fluoride poisoning, and hypocalcemia resulting from ethylene glycol or fluoride poisoning. Overzealous calcium administration may cause hypercalcemia. SUMMARY Fluid and electrolyte abnormalities may result from exposure to various medications and toxins. Fortunately,

the clinical significance of these abnormalities is usually minimal. Some toxins may make hydration assessment difficult by altering clinical findings and vital signs. Many medications induce the syndrome of inappropriate ADH, resulting in hyponatremia. Hyponatremia or hypernatremia induced by pharmacologic agents are often chronic, necessitating slow correction to avoid problems due to rapid fluid shifts. Hypermagnesemia occurs infrequently unless renal insufficiency is present. Alcoholism is the most common cause of both hypomagnesemia and hypophosphatemia because of poor nutrition and increased diuresis. The management of poisoned patients, particularly children, can cause problems. Inappropriate use of either magnesium products or sorbitol for gastrointestinal decontamination has resulted in electrolyte-related, deleterious outcomes, particularly in children. Antidotes can affect electrolytes, including hypokalemia resulting from either dextrose or digoxin specific antibody fragments.

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REFERENCES
1. Al-Harbi NN, Domrongkitchaiporn S, Lirenman DS: Hypocalcemia and hypomagnesemia after ibuprofen overdose. Ann Pharmacother 1997; 31:432-434. 2. Agus ZS, Wasserstein A, Goldfarb S: Disorders of calcium and magnesium homeostasis. Am J Med 1982; 72:473-488. 3. Allerton JP, Strom JA: Hypernatremia due to repeated doses of charcoal-sorbitol. Am J Kidney Dis 1991; 17:581-584. 4. Allon M, Dunlay R, Copkney C: Nebulized albuterol for acute hyperkalemia in patients on hemodialysis. Ann Intern Med 1989; 110:426-429. 5. Alpern RJ, Saxton CR, Seldin DW: Clinical interpretation of laboratory values. In: Tannen R, Kokko JP, ed. Fluid and Electrolytes, Philadelphia: WB Saunders; 1990:3-58. 6. American Academy of Clinical Toxicology, European Association of Poison Centres and Clinical Toxicologists: Position statement: Gastric lavage. Clin Toxicol 1997; 35:711-719. 7. Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific fab antibody fragments. Circulation 1990; 81:1744-1752. 8. Barer J, Hill LL, Hill RM, Martinez WM: Fatal poisoning from salt used as an emetic. Am J Dis Child 1973; 125:889-890. 9. Beck DE, Harford FJ, DiPalma JA, et al: Bowel cleansing with polyethylene glycol electrolyte lavage solution. South Med J 1985; 78:1414-1416. 10. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 1992; 326:1196-1203. 11. Blevins LS, Wand GS: Diabetes insipidus. Crit Care Med 1992; 20:69-79. 12. Bourke E, Yanagawa N: Assessment of hyperphosphatemia and hypophosphatemia. Clin Lab Med 1993; 13:183-207. 13. Bradberry SM, Vale JA: Disturbances of potassium homeostasis in poisoning. Clin Toxicol 1995; 33:295-310. 14. Brass EP, Thompson WL: Drug-induced electrolyte abnormalities. Drugs 1982; 24:207-228. 15. Brown RS: Potassium homeostasis and clinical implications. Am J Med 1984; 77(5A):3. 16. Chipperfield B: Magnesium and the heart. Am Heart J 1972; 93:679. 17. Chisholm MA, Mulloy AL, Taylor AT: Acute management of cancer-related hypercalcemia. Ann Pharmacother 1996; 30:507-513. 18. Clemessy J, Favier C, Borron SW, et al: Hypokalaemia related to acute chloroquine ingestion.

Lancet 1995; 346:877-880. 19. Cluitmans FHM, Meinders AE: Management of severe hyponatremia: Rapid or slow correction?. Am J Med 1990; 88:161-166. 20. Connelly DM: Silver nitrate: Ideal burn wound therapy?. NY State J Med 1970; 70:1642-1644. 21. Davies DL, Fraser R: Do diuretics cause magnesium deficiency?. Br J Clin Pharmacol 1993; 36:1-10. 22. Davis RF, Eichner JM, Bleyer WA, et al: Hypocalcemia, hyperphosphatemia, and dehydration following a single hypertonic phosphate enema. J Pediatr 1977; 90:484-485. 23. Delaney V, dePertuz Y, Nixon D: Indomethacin in streptozocin-induced nephrogenic diabetes insipidus. Am J Kidney Dis 1987; 9:79-83. 24. DiPalma JR, Ritchie DM: Vitamin toxicity. Annu Rev Pharmacol Toxicol 1977; 17:133-148. 25. Douglas PS, Carmichael KA, Palevsky PM: Extreme hypercalcemia and electrocardiographic changes. Am J Cardiol 1984; 54:674. 26. Eisenbud E, LoBue CC: Hypocalcemia after therapeutic use of magnesium sulfate. Arch Intern Med 1976; 136:688-691. 27. Elisaf M, Merkouropoulos M, Tsianos EV, et al: Acid-base and electrolyte abnormalities in alcoholic patients. Miner Electrolyte Metab 1994; 20:274-281. 28. Ettinger PO, Regan TJ, Oldewurtel HA: Hyperkalemia, cardiac conduction, and the electrocardiogram: A review. Am Heart J 1974; 88:360-371. 29. Flink EB: Therapy of magnesium deficiency. Ann NY Acad Sci 1969; 162:901-905. 30. Forman J, Baluarte HJ, Gruskin AB: Hypokalemia after hypertonic phosphate enemas. J Pediatr 1979; 94:149-151. 31. Foy A: Magnesium the neglected cation. Med J Aust 1980; 1:305-306. 32. Gabow PA: How to avoid overlooking salicylate intoxication. J Crit Care 1986; 1:77-85. 33. Gayet S, Ville E, Durand JM, et al: Foscarnet-induced hypercalcaemia in AIDS [letter]. AIDS 1997; 11:1068-1070. 34. Gerard JM, Luisiri A: A fatal overdose of arginine hydrochloride. Clin Toxicol 1997; 35:621-625. 35. Goldsmith RS: Multiple effects of phosphate therapy. N Engl J Med 1970; 282:927. 36. Gonzalez JJ, Owens W, Ungaro PC, et al: Clay ingestion: A rare cause of hypokalemia. Ann Intern Med 1982; 97:65-66. 37. Guillaume MP, Karmali R, Bergmann P, Cogan E: Unusual prolonged hypocalcemia due to foscarnet in a patient. Clin Infect Dis 1997; 25:932-933. 38. Guyton AC, Hall JE: Textbook of Medical Physiology, 9th ed. Philadelphia, WB Saunders, 1996.

39. Hoffman RS, Smilkstein MJ, Rubenstein F: An “amp” by any other name: The hazards of intravenous magnesium dosing. JAMA 1989; 261:557. 40. Howes LG: Which drugs affect potassium?. Drug Safety 1995; 12:240-244. 41. Janson CL, Marx JA: Fluid and electrolyte balance. In: Rosen P, Barkin RM, ed. Emergency Medicine Concepts and Clinical Practice, St. Louis: Mosby–Year Book; 1992:2132-2175. 42. Jones AF, Harvey JM, Vale JA: Hypophosphataemia and phosphaturia in paracetamol poisoning. Lancet 1989; 2:608-609. 43. Jones J, Heiselman D, Dougherty J, et al: Cathartic-induced magnesium toxicity during overdose management. Ann Emerg Med 1986; 15:1214-1218. 44. Kazal LA, Hall DL, Miller LG, et al: Fluoxetine-induced SIADH: A geriatric occurrence?. J Fam Pract 1993; 36:341-343. 45. Kirkpatrick JJR, Enion DS, Burd DAR: Hydrofluoric acid burns: A review. Burns 1995; 21:483-493. 46. Kirschbaum B: The acidosis of exogenous phosphate intoxication. Arch Intern Med 1998; 158:405408. 47. Kline JA, Tomaszewski CA, Schroeder JD, et al: Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharm Exp Ther 1993; 267:744-767. 48. Knochel JP: The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977; 137:203-220. 49. Knochel JP: Diuretic-induced hypokalemia. Am J Med 1984; 77:11. 50. Knochel JP: Interactions of drugs with alcohol. Ann NY Acad Sci Med 1975; 242:272. 51. Leaf A: The clinical and physiologic significance of the serum sodium concentration. N Engl J Med 1962; 267:24. 52. Lemann J, Pleuss JA, Gray RW: Potassium causes calcium retention in healthy adults. J Nutr 1993; 123:1623-1626. 53. Lindeman RD, Papper S: Therapy of fluid and electrolyte disorders. Ann Intern Med 1975; 82:64-70. 54. Marsden PA, Halperin ML: Pathophysiological approach to patients presenting with hypernatremia. Am J Nephrol 1985; 5:229-235. 55. Martin RR, Lisehora GR, Braxton M, et al: Fatal poisoning from sodium phosphate enema. JAMA 1987; 257:2190-2192. 56. Masson A: Mesalazine associated nephrogenic diabetes insipidus presenting as a weight loss. Gut 1992; 33:563-564. 57. Mizrahi A, London RD, Gribetz D: Neonatal hypocalcemia—its causes and treatment. N Engl J Med 1968; 278:1163-1165.

58. Moder EG, Hurley DL: Fatal hypernatremia from exogenous salt intake: Report of a case and review of the literature. Mayo Clin Proc 1990; 65:1587-1594. 59. Mofenson HC, Caraccio RR: Magnesium intoxication in a neonate from oral magnesium hydroxide laxative. J Toxicol Clin Toxicol 1991; 29:215-222. 60. Moses AM, Miller M: Drug-induced dilutional hyponatremia. N Engl J Med 1974; 291:1234-1239. 61. Murray SS, Kramlinger KG, McMichan JC, et al: Acute toxicity after excessive ingestion of colchicine. Mayo Clin Proc 1983; 58:528-532. 62. Narins RG, Jones ER, Stom MC, et al: Diagnostic strategies in disorders of fluid, electrolyte and acidbase homeostasis. Am J Med 1982; 72:496-518. 63. Navarro JF, Quereda C, Quereda C, et al: Nephrogenic diabetes insipidus and renal tubular acidosis secondary to foscarnet therapy. Am J Kidney Dis 1996; 27:431-434. 64. Nordt SP, Williams SR, Turchen S, et al: Hypermagnesemia following an acute ingestion of epsom salts in a patient with normal renal function. Clin Toxicol 1996; 34:735-739. 65. Olinger ML: Disorders of calcium and magnesium metabolism. Emerg Med Clin North Am 1989; 7:795-822. 66. Peppers MP, Geheb M, Desai T: Hypophosphatemia and hyperphosphatemia. Crit Care Clin 1991; 7:201-214. 67. Peterson CD: Electrolyte depletion following emergency stomach evacuation. Am J Hosp Pharm 1979; 36:1366-1369. 68. Ponce SP, Jennings AE, Madias NE, et al: Drug-induced hyperkalemia. Medicine 1985; 64:357-370. 69. Ramsahoye BH, Davies SV, El-Gaylani N, et al: The mineralocorticoid effects of high dose hydrocortisone. BMJ 1995; 310:656-657. 70. Ramsay LE, Yeo WW, Jackson PR: Metabolic effects of diuretics. Cardiology 1994; 84(suppl 2):4856. 71. Reber PM, Heath HI: Hypocalcemic emergencies. Med Clin North Am 1995; 79:93-106. 72. Reedy JC, Zwiren GT: Enema-induced hypocalcemia and hyperphosphatemia leading to cardiac arrest during induction of anesthesia in an outpatient surgery center. Anesthesiology 1983; 59:578-579. 73. Rose BD: Clinical Physiology of Acid-Base and Electrolyte Disorders, 4th ed. New York, McGrawHill, 1994. 74. Royston A, Prout BJ: Carbenoxolone-induced hypokalaemia simulating Guillain-Barre(c) syndrome. BMJ 1976; 2:150-151. 75. Sacchetti A, Brilli R, Barkin RM: Fluid and electrolyte balance. In: Barkin RM, ed. Pediatric Emergency Medicine: Concepts and Clinical Practice, St. Louis: CV Mosby; 1997:166. 76. Sakane N, Yoshida T, Umekawa T, Miyazaki R: Nephrogenic diabetes insipidus induced by lobenzarit

disodium treatment in patients with rheumatoid arthritis. Intern Med 1996; 35:119-122. 77. Scott R, Haywood JK, Buddy K, et al: Whole body calcium deficit in cadmium-exposed workers with hypercalciuria. Urology 1980; 15:356. 78. Shields HM: Rapid fall of serum phosphorus secondary to antacid therapy. Gastroenterology 1978; 75:1137-1141. 79. Shires T, Williams J, Brown F: Acute change in extracellular fluids associated with major surgical procedures. Ann Surg 1961; 154:803-810. 80. Smilkstein MJ, Steedle D, Kulig KW, et al: Magnesium levels after magnesium-containing cathartics. J Toxicol Clin Toxicol 1988; 26:51-65. 81. Smith TW, Antman EM, Friedman PL, et al: Digitalis glycosides: Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 1984; 27:21-56. 82. Soreensen E, Tougaard L, Brochner-Mortensen J: Iatrogenic magnesium intoxication during 1-alphahydroxycholecalciferol treatment. BMJ 1976; 2:215. 83. Soriano J: Potassium homeostasis and its disturbances in children. Pediatr Nephrol 1995; 9:364-374. 84. Sotos JF, Cutler EA, Finkel MA, et al: Hypocalcemic coma following two pediatric phosphate enemas. Pediatrics 1977; 60:305-307. 85. Spencer H, Lender M: Adverse effects of aluminum-containing antacids on mineral metabolism. Gastroenterology 1979; 76:603-606. 86. Spigset O, Hedenmalm K: Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Safety 1995; 12:209-225. 87. Sporer KA, Mayer AP: Saltpeter ingestion. Am J Emerg Med 1991; 9:164-165. 88. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. Ann Intern Med 1987; 107:656-664. 89. Sterns RH, Riggs JE, Schochet SS: Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986; 314:1535-1542. 90. Stoff JS: Phosphate homeostasis and hypophosphatemia. Am J Med 1982; 72:495. 91. Streicher HZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults. Ann Intern Med 1981; 94:758-762. 92. Szylman P, Benzakin A, Szjnader Y, Taitelman U: Potassium-wasting nephropathy in an outbreak of chronic organic mercurial intoxication. Am J Nephrol 1995; 15:514-520. 93. Vamvakas S, Teschner M, Bahner U, Heidland A: Alcohol abuse: Potential role in electrolyte disturbances and kidney diseases. Clin Nephrol 1998; 49:205-213. 94. Van Amelsvoort T, Bakshi R, Devaux CB, et al: Hyponatremia associated with carbamazepine and oxcarbazepine therapy: A review. Epilepsia 1994; 35:181-188.

95. Vianna NJ: Severe hypophosphatemia due to hypokalemia. JAMA 1971; 215:1497. 96. Voigts A, Kaufman J, Christian E: Acidosis and other metabolic abnormalities associated with paint sniffing. S Med J 1983; 76:443-452. 97. Walker WC: The biochemistry of magnesium. Ann NY Acad Sci 1969; 162:717. 98. Wax PM, Yang RY, Hoffman RS, et al: Prevalence of sorbitol in multiple-dose activated charcoal regimens in emergency departments. Ann Emerg Med 1993; 22:1807-1812. 99. Weiner M, Epstein FH: Signs and symptoms of electrolyte disorders. Yale J Biol Med 1970; 43:76109. 100. Zaloga GP: Hypocalcemia in critically ill patients. Crit Care Med 1992; 20:251-262.

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Chapter 11 – Acid-Base Disturbances in the Poisoned Patient
KATHLEEN A. DELANEY Acid-base disturbances occur frequently in poisoned patients, both as a primary manifestation of the poisoning and as a secondary consequence of hypoxia, shock, or seizures. In the patient who is poisoned with an unknown substance, acid-base disturbances offer a clue to the nature of the toxin ( Table 11–1 ). Simple and familiar examples of acid-base disturbances in poisoned patients include the respiratory alkalosis associated with salicylate or theophylline toxicity or the respiratory acidosis commonly noted in serious opioid and sedative hypnotic overdoses. Mixed acid-base disturbances are also common, for example, the respiratory alkalosis and metabolic acidosis of salicylate poisoning or the metabolic and respiratory acidosis that might occur in a patient poisoned with propoxyphene who has had a seizure and has respiratory depression. Several serious poisonings discussed later are associated with a primary anion gap metabolic acidosis. In this chapter, a rational clinical approach is offered to the diagnosis of common pure and mixed acid-base disturbances and both the toxicologic and nontoxicologic differential diagnoses are reviewed.

Table 11-1 -- General Approach to Acid-Base Disturbances in the Poisoned Patient 1. Determine the pH and PCO2 from the arterial blood gas. 2. Calculate the anion gap from the serum electrolytes. 3. Classify the disturbance: a. Respiratory alkalosis (see Table 11–8 ) 1) Toxic: salicylates, sympathomimetic agents 2) Nontoxic: increased intercerebral pressure, liver failure, hypoxia, heart failure, sepsis b. Respiratory acidosis (see Table 11–7 ) 1) Toxic: a) Severe: barbiturates, ethanol, opioids, botulism, tetanus b) Mild to moderate: -hydroxybutyrate, cyclic antidepressants, benzodiazepines 2) Nontoxic: severe hypokalemia, Guillain-Barré syndrome, cervical cord injury, myasthenia gravis c. Metabolic alkalosis (see Table 11–6 ) 1) Toxic: chronic use of antacids, diuretics, licorice 2) Nontoxic: volume depletion (any cause), gastric outlet obstruction, Bartter’s syndrome, hyperaldosteronism, magnesium deficiency d. Anion-gap metabolic acidosis (see Table 11–4 ) 1) Toxic: chronic use of antacids, diuretics, licorice

a) Common: salicylates, carbon monoxide, paraldehyde, cyanide, isoniazid (+ seizures), iron, methanol, ethylene glycol, hydrogen sulfide b) Less common: phenformin, metformin, toluene, ibuprofen 2) Nontoxic: lactic acidosis (nontoxic causes), ketoacidosis, uremia e. Non–anion gap metabolic acidosis (see Table 11–5 ) 1) Toxic: chronic toluene exposure, acetazolamide 2) Nontoxic: bicarbonate wasting conditions such as renal tubular acidosis or diarrhea, ketonuria f. Mixed disorder 4. For an anion-gap metabolic acidosis, see Table 11–4 . a. Consider the clinical situation and likely causes of anion-gap acidosis. b. Measure lactate. b. Measure lactate. c. Measure ketones. d. Calculate the osmol gap. e. Assess the response to resuscitation.

CHARACTERIZATION OF THE ACID-BASE DISTURBANCE
The primary acid-base disturbances are metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. These are defined in Table 11–2 . Many combinations of these disturbances are possible, resulting in mixed disorders. The data provided by the serum electrolytes and an arterial blood gas analysis are used to identify and characterize the acid-base disturbance.

Table 11-2 -- Specific Acid-Base Disorders Condition pH Primary Change Metabolic acidosis Anion gap Nonanion gap Metabolic alkalosis >7.45 Increased bicarbonate <7.35 Decreased bicarbonate

Respiratory acidosis <7.35 Increased PCO2 Respiratory alkalosis >7.45 Decreased PCO2 Mixed disorders Any combination

The first step in the characterization of an acid-base disturbance is to be certain that the laboratory data are accurate. The clinical formula H+ = 24 × PCO2/HCO3– can be used to confirm the accuracy of acid-base data, which may be distorted by laboratory error and errors of timing.[27](See Table 11–3 for determination of the

H+ concentration represented by a given pH.) This formula is derived from the Henderson-Hasselbalch equation pH = pK + log (HCO3–)/(H2CO3), which is a mathematical description of the equilibrium equation for the bicarbonate buffer system:

Table 11-3 -- Chart to Determine [H+] pH [H+] 7.00 100 7.05 90 7.10 80 7.15 70 7.22 60 7.30 50 7.40 40 7.52 30 7.60 28 7.70 20 8.00 10

The Henderson-Hasselbalch (H-H) equation * describes the relationship between the three critical variables that determine the physiologic acid-base state: the pH (the negative log of the hydrogen ion concentration), the PCO2, and the serum HCO3-. It allows calculation of any of the three acid-base variables, given two of the three, and helps confirm that the measured components of the acid-base system are consistent with the laws of systems in equilibrium.[11][27]
* The true H-H equation is pH = pK + log (HCO 3–/H2CO3). The pK (the pH at which 50 per cent of the H2CO3 is dissociated) of carbonic acid is 6.1. The concentration of H2CO3 is given by multiplication of the P CO2 by a constant 0.03 mEq/L/mmHg, which relates the solubility of gaseous CO2 in liquid. Using these numbers and taking the antilog of both sides, the equation becomes H+ (nmol/L) 24 × P CO 2/HCO 3–.[27]

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USE OF THE HENDERSON-HASSELBALCH EQUATION IN THE CLINICAL SETTING
An 18-year-old woman presents with status epilepticus associated with cocaine injection. Her seizures are controlled after the administration of intravenous diazepam. The arterial blood gas analysis shows a pH of 7.30 and PCO2 of 30 mmHg. The serum HCO3- measured in the chemistry laboratory is 5 mEq/dL. These numbers do not seem “right,” so their accuracy is checked by the H-H equation, which gives a calculated HCO3- of 14 mEq/dL:

Because the laws of equilibrium demand that the H-H equation apply in all cases, the inconsistency between the measured HCO3- and the calculated HCO 3- suggests a laboratory error. Another explanation of this difference between the calculated and measured serum HCO3- is that the electrolytes were drawn early during placement of the intravenous line to control the seizures and the arterial blood gas sample was drawn later when some recovery from the lactic acidosis produced by the seizures had occurred. This “time discrepancy” between the serum electrolyte measurement and the arterial blood gas measurement is a common cause of error in acid-base data gathered in the clinical setting.

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METABOLIC ACIDOSIS
Metabolic acidosis is a marker of potentially serious underlying illness or poisoning. It is generally well tolerated and is rarely as important clinically as the process that caused the acidosis. The determination of the cause of the acidosis is of great concern to the physician because it dictates appropriate therapy. The following is a step-by-step approach to the diagnosis of the patient with metabolic acidosis. Step 1: Calculate the Anion Gap Metabolic acidosis is classified as “anion gap” and “non–anion gap” acidosis. The discussion of processes that change the anion gap without affecting the acid-base state is beyond the scope of this chapter (see references 12 , 17 , 27 for more detailed reading). A non–anion gap acidosis is most commonly caused by the loss of HCO3-, with compensatory retention of chloride to maintain electroneutrality. An anion gap acidosis is caused by the addition of an acid (AH) to the blood. An acid is a combination of a base or anion with a hydrogen ion, defined by the equation: AH = A- + H+. When endogenously generated organic acids (ketoacids, lactic acid) or exogenous acids (salicylates, formic acid from methanol, glycolic acid from ethylene glycol) are added to serum, they combine with HCO3-, releasing CO2 and H2O and adding an “unmeasured anion”:

The addition of an acid to blood leads to an increase in the number of “unmeasured anions,” creating an anion gap. The anion gap is given by the following formula (in mEq/L): Na+ - (Cl- + HCO3–). Because serum potassium is small and relatively constant, it is usually left out of the equation. The “normal” anion gap depends on values determined in the specific chemistry laboratory. Historically, the normal anion gap has been reported to be 12 mEq/L ± 4.[29][34] Because newer instruments measure higher chloride values, the “normal” anion gap in many laboratories is lower, in the range of 7 mEq/L ± 4.[42] The term anion gap is somewhat misleading, because the laws of electroneutrality dictate that the number of anions (negatively charged) and cations (positively charged) in a solution be equal. Anion gap refers to an increase in the normal amount of unmeasured anions. In normal plasma, the total of “unmeasured” anions (albumin + phosphate + sulfate + organic acids) is 23 mEq/L, whereas the total amount of “unmeasured” cations (potassium + magnesium + calcium) is 11 mEq/L. Total serum cations must equal total serum anions; therefore, unmeasured cations (UC) plus sodium equal unmeasured anions (UA) plus chloride and HCO3-, which can be transformed to Na+ - (Cl- + HCO3-) = UA - UC = the anion gap. In addition to the presence of metabolic acidosis, the anion gap is also increased by a decrease in unmeasured cations such as calcium and magnesium. [1][17][29] A significant decrease in serum albumin will decrease the anion gap by lowering the unmeasured anions. This may result in underestimation of the significance of a metabolic acidosis.[13]

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ASSESSMENT OF THE PATIENT WITH ANION GAP ACIDOSIS
Step 2: Consider the Common Causes of Anion Gap Metabolic Acidosis ( Table 11–4 ) The presence of an anion gap metabolic acidosis often suggests a serious underlying disorder, especially when the acidosis persists after resuscitation. Clearly, many poisoned patients will have a history of a toxic exposure, simplifying the physician’s diagnostic task. In other cases, there will be no history available and the broader differential diagnosis of the anion gap acidosis must be considered.

Table 11-4 -- Causes of Anion Gap Metabolic Acidosis Lactic acidosis: Non-toxic: sepsis, hypoxia, shock, tumors, thiamine deficiency, ischemia (especially bowel infarction) Toxic: iron, metformin, phenformin, paraldehyde, isoniazid (+ seizures), cyanide, carbon monoxide, sodium azide, hydrogen sulfide Mixed acidosis (partial lactate): methanol, ethylene glycol, salicylates, severe ketoacidosis, ibuprofen (rare) Ketoacidosis: alcoholic, starvation, diabetic Salicylism: includes lactate and ketoacidosis, as well as salicylic acid Toxic alcohols: methanol, ethylene glycol (predominantly toxic metabolites plus component of lactic acidosis) Uremia: accumulation of phosphoric and sulfuric acid metabolites Benzoic and hippuric acidemia: acute toluene poisoning (rarely detected due to rapid metabolism and renal clearance of metabolites) Ibuprofen: propionic acid and metabolites (presumed) A commonly used mnemonic: M U D P I L E S methanol, metformin uremia (creatinine >4 mg/dL, anion gap <25 mEq) diabetic ketoacidosis (also alcoholic, starvation) paraldehyde, phenformin iron, isoniazid, ibuprofen lactate (shock, seizures, sepsis, ischemia, carbon monoxide, HsS, cyanide) ethylene glycol salicylates, solvents

Common nontoxic causes of anion gap acidosis include lactic acidosis from sepsis, shock, hypoxia, and seizures. Uremia is associated with an anion gap acidosis due to uncleared sulfuric acid and phosphoric

acid moieties. The anion gap generally does not exceed 25 mEq/L in the uremic patient, and an anion gap acidosis is not seen until the creatinine rises above 4 to 6 mg/dL.[12][29] Ketoacidosis is a common cause of anion gap acidosis that may be severe. It develops as a consequence of the absence of insulin in the insulin-dependent diabetic patient or in the carbohydrate-depleted alcoholic patient. Mild ketoacidosis has also been observed in patients with salicylism and cyanide toxicity. The presence of a significant anion gap metabolic acidosis in a vomiting alcoholic patient frequently raises concerns about the possibility of a toxic alcohol ingestion. The demonstration of significant ketoacidosis suggests the alternate diagnosis of alcoholic ketoacidosis. Initially, ketones may not be measurable in these patient, making the diagnosis more difficult.[14][21][24] In addition, some lactic acid may be present in patients with severe ketoacidosis. Several common toxins cause metabolic acidosis as a primary manifestation of their toxicity. Methanol and ethylene glycol are broken down to acid metabolites, formic acid and glycolic acid, respectively. Lactic acidosis contributes part of the acidosis caused by these toxic alcohols.[8][15][20] Salicylates cause lactic acidosis due to uncoupling of oxidative phosphorylation and interfere with fatty acid metabolism, resulting in mild ketoacidosis.[12][16] In the setting of a severe overdose, iron is associated with a metabolic acidosis predominantly due to lactate.[30] Phenformin has been associated with lactic acidosis as an unpredictable response to therapeutic doses.[32][41] Metformin has also been associated with lactic acidosis in the setting of overdose and in chronic toxicity secondary to decreased renal clearance.[17a][39] Older articles cite paraldehyde as a cause of lactic acidosis. This agent is no longer used for the treatment of alcohol withdrawal and is currently of historical interest.[12] Toxins that lead to tissue anoxia such as carbon monoxide and methemoglobin producers, or toxins that shut down the electron transport system such as hydrogen sulfide, cyanide, sodium azide, and methanol, are associated with lactic acidosis, which may be profound.[4][6][9][40] Any toxin that causes shock, hypoxia, or seizures can also produce a lactic acidosis as a manifestation of these processes. Isoniazid causes a profound lactic acidosis, always in the setting of seizures.[7] Severe agitation precipitated by poisoning with stimulants such as phencyclidine or cocaine is also associated with lactic acidosis. Lactate produced by reversible conditions (agitation, seizures, hypotension, hypoxia) clears rapidly when the precipitating condition is treated. Metabolic acidosis caused by cellular toxins or by toxins that produce acid metabolites does not clear with treatment of shock or seizures.[28] Step 3: Measure the Serum Lactate In cases of acidosis when the serum lactate level is elevated, the contribution of lactate to the anion gap can be estimated by subtracting the measured lactic acid level (in millimoles per liter) from the anion gap. If the measured lactate does not account for the anion gap, the presence of another acid must be suspected. Step 4: Measure Urine and Serum Ketones Because the renal threshold for the clearance of ketones is very low, the presence of urine ketones is a sensitive indicator of the presence of serum ketones.[29] The nitroprusside reaction used in the ketone dipsticks or Acetest tabs detects only the presence of the serum ketones acetoacetate and acetone. Under conditions of poor tissue perfusion or when the NADH/NAD+ ratio is elevated, as in alcoholic ketoacidosis, a significant fraction of the serum ketones may be present as ß-hydroxybutyrate, the reduced form of acetoacetate. This accounts for the apparent paradoxical increase in serum ketones noted as patients with severe ketoacidosis improve with therapy, and occasionally for undetectable ketones despite the presence of severe ketoacidosis.[14][24][26]

Demonstrable ketonuria coupled with metabolic acidosis may also indicate salicylate toxicity. Small amounts of ketones may be demonstrated in as many as 41 per cent of salicylate poisoned patients, owing to the disruption of fatty acid metabolism. [16] Ketonuria may also theoretically be seen in cyanide poisoning owing to the disruption of fatty acid metabolism, but the severe lactic acidosis predominates (see Chapter 86 ). Step 5: Calculate the Osmol Gap The serum osmolarity is elevated in the presence of small, uncharged osmotically active molecules such as alcohols, glycols, sugars such as mannitol, and drug vehicles such as propylene glycol.[10][18] In the diagnosis of an unexplained anion gap acidosis, the demonstration of an osmol gap is occasionally useful (although not foolproof) in detecting the presence of a toxic alcohol. The osmol gap is the difference between the serum osmolality, measured by the technique of freezing point depression, and the serum osmolarity that is calculated from the major contributors to osmolarity: serum sodium, glucose, and blood urea nitrogen. (In blood, the osmolality, which is the number of particles or moles per kilogram of solution, is essentially equivalent to the osmolarity, which is the number of particles or moles per liter of solution). When detected, the blood ethanol level must also be included in the calculation. A large increase in the osmol gap suggests the presence of small osmotically active molecules such as propylene glycol, methanol, isopropyl alcohol, or ethylene glycol.[18] Of these, only methanol and ethylene glycol cause a significant and persistent acidosis, owing to their conversion to toxic acid metabolites. Propylene glycol is metabolized to lactate and may cause a transient increase in the anion gap. The following formula, used when the blood urea nitrogen, glucose, and ethanol levels are given in milligrams per deciliter, is a widely accepted means of calculating an approximate serum osmolarity.[18][25]

The normal osmol gap has been reported to be less than 10 mOsm.[10][12] However, a wide variation has been reported in normal populations. A recent determination of the “normal” osmolar gap in a pediatric emergency department population showed a range of -13.5 to +8.9 mOsm (95 per cent confidence intervals) when this formula was used.[25] A similar study in an adult emergency department demonstrated osmol gaps between -10 and + 14 mOsm (95 per cent confidence intervals).[19] A small increase in the osmol gap is seen in chronic renal failure (< 20 mOsm)[33] and significant lactic and ketoacidosis (< 15 mOsm).[10][31] Because of the wide range of the normal osmol gap in the healthy population, a “normal” osmol gap does not exclude a significant toxic alcohol or glycol poisoning. For example, a patient with a baseline osmol gap of -14 who has a calculated osmol gap of 10 mOsm could have an ethylene glycol level as high as 144 mg/dL.[19] In addition, it is important to note that the toxic metabolites of methanol and ethylene glycol do not raise the osmol gap, and the gap may not be significantly elevated even in clinically severe poisonings if a substantial amount of the alcohol has been metabolized.[15][35] Step 6: Assess the Response to Resuscitation Lactic acidosis due to shock, hypoxia, and seizures resolves quickly when these conditions are corrected. Spontaneous correction of a lactic acidosis generally occurs within 1 hour of the cessation of lactic acid production.[28] A persistent metabolic acidosis suggests the presence of acidosis due to a toxin, ketoacidosis, or an ongoing lactic acidosis. Toxic causes of ongoing lactic acidosis include methanol, salicylate, phenformin, metformin, iron, and inhibitors of oxygen transport such as cyanide. Nontoxic causes

of persistent lactic acidosis include bowel infarction and sepsis.[2] In cases of severe ketoacidosis in which ketones are initially negative owing to a predominance of ß-hydroxybutyrate, the urine dip test should become positive for ketones as resuscitation progresses.[12]

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NON–ANION GAP OR HYPERCHLOREMIC METABOLIC ACIDOSIS ( Table 11–5 )
The toxic differential of this disorder is limited. A common toxic cause of a hyperchloremic metabolic acidosis is the chronic abuse of toluene-containing substances (glue sniffing).[5][36][38] Although toluene exposure acutely causes an anion gap acidosis owing to its rapid metabolism to benzoic and hippuric acids, rapid renal excretion of the hippurate anion associated with retention of chloride leads to a hyperchloremic acidosis that simulates a renal tubular acidosis. [5] Acetazolamide, by inhibiting carbonic anhydrase, decreases renal acid clearance and results in a non–anion gap metabolic acidosis.[27] The chloridecontaining acids, such as ammonium chloride, hydrochloric acid, arginine, and lysine hydrochloride also cause a hyperchloremic acidosis when given in excessive amounts.[27] A hyperchloremic metabolic acidosis has been reported after inhalation of chlorine gas.[37] Cholestyramine, the chloride anion-exchange resin used to treat pruritus associated with excess production of bile acids, is also associated with a hyperchloremic metabolic acidosis when large amounts are used.

Table 11-5 -- Causes of Non–Anion Gap Hyperchloremic Metabolic Acidosis Renal tubular acidosis (renal losses of bicarbonate) Rapid infusion of saline (dilutional) Ketoacidosis (renal losses of ketoacids with retention of chloride) Gastrointestinal loss of bicarbonate Diarrhea Small bowel fluid losses Ureterosigmoidostomy Ileal-loop bladder Acetazolamide (inhibition of carbonic anhydrase) Chronic toluene use (renal losses of hippurate with retention of chloride) Cholestyramine Ammonium chloride

The most common nontoxic causes of hyperchloremic non–anion gap metabolic acidosis include two HCO3-wasting conditions: renal tubular acidosis and severe diarrhea. It also occurs in patients with ketoacidosis who lose large amounts of negatively charged ketones in the urine with subsequent chloride retention. This may result in a simple hyperchloremic metabolic acidosis, when HCO3- is generated as fast as it is titrated by production of ketoacids, or there may be a mixed acidosis, with both anion gap and hyperchloremic patterns.[1][2][12][29] Rapid increase in extracellular volume, such as occurs during volume resuscitation with normal saline, results in dilution of the serum HCO3- and a hyperchloremic metabolic acidosis.[29]

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SIMPLE METABOLIC ALKALOSIS ( Table 11–6 )
Metabolic alkalosis is usually not related to poisoning, although it may occur as an indirect consequence of poisoning with agents that cause fluid losses through mechanisms such as severe diaphoresis, persistent vomiting, or increased urine output. Excessive use of HCO3- in the treatment of dyspepsia, or abuse of diuretics for weight control, may result in significant alkalemia. A normovolemic patient without endocrine abnormality will rapidly excrete a HCO3- load and will not become alkalemic. The maintenance of a metabolic alkalosis requires two factors: 1. A source of HCO3-, either endogenous (loss of hydrogen ion and retention of HCO3- through vomiting or aldosterone-stimulation of renal tubules) or exogenous (NaHCO3, Ringer’s lactate, sodium citrate) and Table 11-6 -- Causes of Metabolic Alkalosis Toxic Licorice (chronic ingestion) Sodium bicarbonate (chronic use) Diuretics Antacids Penicillins Nontoxic Volume depletion Mineralocorticoid excess Gastric outlet obstruction Bartter’s syndrome Liddle’s syndrome Magnesium deficiency Severe potassium depletion

2.

A stimulus to the renal tubules to reabsorb HCO3- and secrete hydrogen ion. The latter stimulus is supplied most commonly by contraction of extracellular volume and secondary stimulation of aldosterone secretion. The most common causes of metabolic alkalosis are persistent vomiting and diuretic use.[11]

A rare cause of alkalemia is the presence of excess mineralocorticoid, as may be seen in an aldosteronesecreting tumor or Cushing’s syndrome. When the cause is in doubt, a random urinary chloride will help to

distinguish the patient with metabolic alkalosis due to volume depletion from the patient with mineralocorticoid excess. Metabolic alkalosis in the normovolemic patient with mineralocorticoid excess is associated with a urinary chloride concentration of more than 10 mEq/L. The volume-depleted patient will show a urinary chloride excretion of less than 10 mEq/L, unless a diuretic is still acting on the renal tubules.[11] Another rare cause of alkalemia is severe potassium depletion, in which hydrogen ion is secreted by the renal tubules in exchange for potassium (paradoxical aciduria). Excessive use of licorice has been associated with metabolic alkalosis, owing to the effects of glycyrrhizic acid, which are like a mineralocorticoid.

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RESPIRATORY ACIDOSIS ( Table 11–7 )
Respiratory acidosis is caused by depression of ventilation, leading to retention of CO2. In acute respiratory acidosis, the blood pH is decreased in proportion to the degree of CO2 retention. A familiar example of acute respiratory acidosis is the patient with a heroin overdose whose arterial blood gas is pH 7.20, PCO2 is 63 mmHg, and serum HCO3- level is 24 mEq/L. Table 11-7 -- Causes of Respiratory Acidosis Agents causing central nervous system sedation (opioids, sedative-hypnotics, barbiturates) Botulism Tetanus toxin Cervical cord injury Severe neuropathy or myopathy (Guillain-Barré syndrome, myasthenia gravis) Primary pulmonary disorders (restrictive, obstructive) Upper airway obstruction Severe hypokalemia

A useful rule of thumb in the patient with acute respiratory acidosis is given by the following: For each 10 mmHg increase in PCO2, the pH decreases by 0.08 mEq. Many toxins cause respiratory depression, resulting in respiratory acidosis. The most severe depression of respiration is seen in overdoses of opioids and barbiturates. The hypoxia associated with overdoses of these agents, and the hypotension associated with barbiturate toxicity, also result in concomitant lactic acidosis. Other sedative-hypnotic agents such as ethchlorvynol, methaqualone, chloral hydrate, and ethanol as well as isopropanol also cause significant respiratory acidosis after large ingestions. Milder respiratory depression is typically seen after large ingestions of benzodiazepines, gamma-hydroxybutyrate, and other sedative agents such as carbamazepine and neuroleptics. Respiratory impairment by botulinum or tetanus toxin may also result in acute respiratory acidosis. Respiratory acidosis may complicate and increase the severity of acidosis during salicylate toxicity or increase the cardiotoxicity of cyclic antidepressants. Chronic respiratory acidosis is associated with compensatory renal excretion of HCO3- so that the pH of the blood is normal (compensatory metabolic alkalosis). A familiar example of this is the patient with chronic obstructive pulmonary disease (COPD) whose arterial blood gas is pH 7.40, PCO2 is 60 mmHg, and serum HCO3- level is 36 mEq/dL. Chronic respiratory acidosis is a result of chronic impairment of ventilation in patients with COPD or neuromotor impairment of respiration and is not a consequence of acute poisoning.

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RESPIRATORY ALKALOSIS ( Table 11–8 )
In acute respiratory alkalosis, the pH of the blood is elevated in proportion to the degree of depression of PCO2. An example of acid-base values in a patient with acute respiratory alkalosis is pH, 7.70; PCO2, 20 mmHg; and serum HCO3- level, 24 mEq/L. Again, a useful rule of thumb for acute respiratory alkalosis is given by the following: For each 10 mmHg decrease in PCO2 the pH increases by 0.08. Several toxins and conditions secondary to poisoning are associated with respiratory alkalosis. Salicylates, strychnine, theophylline, and sympathomimetic agents cause central respiratory stimulation resulting in respiratory alkalosis. Hypoxia from aspiration or adult respiratory distress syndrome or increased intracranial pressure from hemorrhage or head injury may also lead to respiratory alkalosis in the intoxicated patient. Acute hepatic failure, meningitis, sepsis, shock, and acute cardiopulmonary conditions such as pulmonary embolism, asthma, tamponade, and pneumothorax may all cause respiratory alkalosis. A differential diagnosis of acute respiratory alkalosis is given in Table 11–8 .

Table 11-8 -- Causes of Respiratory Alkalosis Early sepsis Salicylism Sympathomimetics (e.g., theophylline, amphetamine, cocaine) Hepatic insufficiency Psychogenic Hypoxia Pericardial effusion/tamponade Heart failure Shock Increased intracranial pressure Meningoencephalitis

In chronic respiratory alkalosis, significant renal compensation leads to increased excretion of HCO3- so that the pH of the blood is normal (compensatory hyperchloremic metabolic acidosis). A familiar example is a long stretch of mild bronchospasm or hypoxia, resulting in a patient with pH, 7.42; PCO2, 20; and serum HCO3-, 12 mEq/dL.

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MIXED ACID-BASE DISORDERS
Several acid-base disturbances may occur simultaneously in the same patient. Although sometimes challenging, the diagnoses of these processes can be accomplished with some thought and clinical understanding. The following examples review the most common and clinically relevant mixed acid-base disturbances. Patient with Metabolic Acidosis and Respiratory Alkalosis The rule in metabolic acidosis ( Table 11–9 ) is that the compensatory increase in the respiratory drive does not overcompensate for the decreased pH; that is, the pH only approaches and is never greater than normal unless there is a coexistent second acid-base disturbance such as a primary respiratory alkalosis. [3] Clinical settings in which one might see a respiratory alkalosis and anion gap metabolic acidosis include salicylate toxicity, theophylline toxicity associated with seizures, and sepsis or head injury with shock or seizures. Normal renal compensation for a primary respiratory alkalosis would have a respiratory alkalosis with non–anion gap metabolic acidosis. An example of this type of mixed disturbance would be a patient with a serum HCO3- level of 12 mEq/L with pH of 7.53 and PCO2 of 15 mmHg. Table 11-9 -- Clinical Rules of Thumb Regarding the “Pure Metabolic Acidosis” 1. Respiratory compensation never raises the pH to normal (>7.35)[3] 2. Experimental observation: PCO2 does not go lower than 10 mmHg[3][21] 3. Experimental observation: The PCO2 is approximately [1.5 × bicarbonate + 8 ± 2][3][11][21] 4. For a pure anion gap acidosis, the increase in the anion gap should equal the decrease in the bicarbonate. Patient with Metabolic Acidosis and Respiratory Acidosis The degree of respiratory compensation that is normally shown by patients with metabolic acidosis is given by Winter’s equation, which was derived from observation of patients with uncomplicated acute metabolic acidosis. The expected PCO2 is approximated by the expression: PCO2 = [1.5 × serum HCO3- + 8] ± 2. This equation is used primarily to detect relative hypoventilation. Patients whose P CO2 is higher than that predicted by this equation have a superimposed respiratory acidosis. Sometimes this finding simply provides a clue to a subtle second underlying disorder, and at other times the mixed disturbance is clinically serious and usually obvious. Consider the patient with a mixed overdose of salicylate and secobarbital with an arterial blood gas of pH 6.9 and P CO2 of 40 mmHg. Although the PCO2 is normal, the inappropriate degree of respiratory compensation for this metabolic acidosis is intuitively apparent, and most clinicians would intubate this patient without resorting to any calculation. In another case, Winter’s equation suggests an overlooked therapy. A patient took an overdose of propoxyphene and arrived having seizures with an arterial blood gas of pH 7.10, PCO2 of 30 mmHg, and serum HCO3- level of 9 mEq/L. Winter’s equation (1.5 × 9 + 8) predicts a PCO2 of 21 mmHg. Clearly, the respiratory compensation for the metabolic acidosis caused by the seizures is inadequate and is a reminder of the need to manage the respiratory depression caused by the opioid.

In addition to mixed overdoses, other common clinical settings in which a mixed respiratory acidosis and metabolic acidosis might occur include (1) barbiturate overdoses with hypotension or (2) seizures or primary ventilatory impairment and metabolic acidosis. Patient with a Mixed Metabolic Disturbance Mixed metabolic disturbances, especially the presence of an anion gap metabolic acidosis and a metabolic alkalosis, are quite common. The most familiar example is the patient with diabetic ketoacidosis and persistent vomiting. The vomiting causes loss of hydrogen ion, and a potentially significant metabolic alkalosis may develop; however, the ongoing production of ketoacids neutralizes the HCO3-. The result may be a normal or near-normal serum HCO3- with a large anion gap representing the metabolic acidosis. The best way to analyze this condition is to recognize that for a simple anion gap metabolic acidosis the magnitude of the increase in the anion gap should approximate the decrease in the serum HCO3- (of course, we can only approximate the baseline “normal” anion gap). With a superimposed metabolic alkalosis, the magnitude of increase in the anion gap is greater than the magnitude of the decrease in serum HCO3-; that is, the change in the anion gap (delta AG) is greater than the change in the serum HCO3- (delta BC). Situations in which HCO3- is relatively increased, indicating a superimposed metabolic alkalosis, include the vomiting patient with anion gap metabolic acidosis and the patient with anion gap metabolic acidosis who has been treated with NaHCO3.[12][17][27] A very significant metabolic alkalosis, such as that seen in patients with gastric outlet obstruction, may result in an anion gap in the range of 18 to 20 mEq/L. This is due to the effect of alkalemia in increasing negative charges on serum proteins and may cause some confusion in the assessment of these patients.[17][23] When the delta BC is greater than the delta AG, an anion gap metabolic acidosis and a hyperchloremic non–anion gap metabolic acidosis are present. This “brain teaser” is either clinically obvious or not particularly significant. It might occur in a patient with a renal tubular acidosis who develops a superimposed anion gap metabolic acidosis or in a patient with massive diarrhea who develops hypovolemic shock. It also commonly occurs in the patient with diabetic ketoacidosis when large amounts of ketones are excreted in the urine.[17][27] Diagnosis of Mixed Acid-Base Disorders Definitions and Normal Values

Serum HCO3- = 24 mEq/L Arterial blood gases: pH =7.40, PCO2 = 40 mmHg Anion gap = 7 ± 4 mEq/L Delta BC = change in serum HCO3Delta AG = approximated change in anion gap

Case 1 An 80-year-old man has been confused and complaining of shortness of breath for 1 week. He also has a hearing problem and has seen three otolaryngologists in the past month. Chest radiograph suggests noncardiogenic pulmonary edema. The following were determined: Na+, 140 mEq/L; K+, 3.0 mEq/L; Cl-, 108 mEq/L; HCO3–, 12 mEq/L; glucose, 120 mg/dl; pH, 7.53; PCO2, 15 mmHg; and PO 2, 70 mmHg. Serum salicylate level is 70 mg/dL. 1. 2. 3. Calculate the anion gap: 140 - (108 + 12) = 20 mEq/L Calculate the delta BC: 24(normal) – 12 = 12 mEq/L Approximate the delta AG: 20 - 7 = 13 mEq/L (close enough!)

Diagnoses

Respiratory alkalosis (salicylate toxicity with central nervous system stimulatory effect and hypoxia secondary to pulmonary edema) Anion gap acidosis (salicylism) Case 2 A 23-year-old man complained of weakness. He had a history of chronic solvent abuse. The following were determined: pH, 7.17; PCO2, 35 mmHg; PO 2, 110 mmHg; Na+, 149 mEq/L; K+, 1.0 mEq/L; Cl-, 129 mEq/L; and HCO3-, 10 mEq/L. 1. 2. Calculate the anion gap: 149 - (129 + 10) = 10 mEq/L (normal) Calculate the expected PCO2 (Winter’s equation): [1.5 × HCO 3-] + 8 = 23 ± 2 mmHg

Diagnoses

Non–anion gap metabolic acidosis (chronic toluene abuse) Respiratory acidosis (hypokalemic myopathy, also due to toluene) Case 3 A 45-year-old alcoholic man has been vomiting for 3 days. His blood pressure is 100/70 mmHg, and his pulse is 110 beats per minute. The physician just gave him 30 mg of diazepam for tremulousness. The following were determined: pH, 7.29; PCO2, 43 mmHg; Na+, 145 mEq/L; K+, 3.0 mEq/L; Cl-, 96 mEq/L; and HCO3-, 19 mEq/L. Serum ketones are positive at 1:2.

1. 2. 3. 4.

Calculate the anion gap: 145 - (96 + 19) = 30 mEq/L Calculate the delta BC: 24 (normal) – 19 = 5 mEq/L Calculate the expected PCO2 (Winter’s equation): 1.5 × 19 + 8 = 36.5 ± 2 mmHg Approximate the delta AG: 30 - 7 = 23 mEq/L

Diagnoses

Metabolic alkalosis (vomiting, delta AG > delta BC) Anion gap metabolic acidosis (likely alcoholic ketoacidosis, given the clinical picture) Respiratory acidosis (mild and relative, possibly due to diazepam) Case 4 A 22-year-old woman took an overdose of propoxyphene. She arrived actively seizing in the emergency department. The following laboratory studies were obtained on arrival: pH, 7.10; PCO2, 30 mmHg; Na+, 140 mEq/L; K+, 3.4 mEq/L; Cl-, 106 mEq/L; HCO3-, 9 mEq/L. 1. 2. 3. 4. Calculate the anion gap: 140 - (106 + 9) = 25 mEq/L Calculate the expected PCO2: = [1.5 × 9] + 8 = 21.5 ± 2 mmHg Calculate the delta BC: 24 - 9 = 15 mEq/L Calculate the delta AG: 25 - 7 = 18 mEq/L

Diagnoses

Anion gap metabolic acidosis (probably lactic acidosis from seizures) Acute respiratory acidosis (opioid toxicity) Case 5 A 27-year-old woman with a past history of significant iron overdose and subsequent pyloric stricture has been vomiting for 2 weeks. On admission her pulse is 140 beats per minute and her blood pressure is 60 mmHg by palpation. Also she had pH, 7.40; PCO2, 40 mmHg; PO 2, 300 mmHg on a 50 per cent mask; Na+, 150 mEq/L; K+, 2.6 mEq/L; Cl-, 86 mEq/L; HCO3-, 24 mEq/L; blood urea nitrogen, 80 mg/dL; creatinine, 3.0 mg/dL.

1. 2. 3.

Calculate the anion gap: 150 - (86 + 24) = 40 mEq/L Calculate the delta BC: 0 Calculate the delta AG: 40 - 7 = 33 mEq/L

Diagnoses

Anion gap metabolic acidosis (hypotension with shock, delta AG > delta BC) Metabolic alkalosis (gastric outlet obstruction, vomiting) Case 6 Mr. Jones is a 22-year-old man with polyuria and polydipsia for 1 week and intractable vomiting for 4 days. Today he is critically ill, with a temperature of 104°F. The following were also determined: Na +, 150 mEq/L; Cl-, 100 mEq/L; HCO3-, 20 mEq/L; K+, 3.8 mEq/L; blood urea nitrogen, 50 mg/dL; creatinine, 1.8 mg/dL; glucose, 650 mg/dL; serum ketones, +1:8; pH, 7.50; PCO2, 26 mmHg; and PO 2, 100 mmHg. 1. 2. 3. Calculate the anion gap: 150 - (100 + 20) = 30 mEq/L Calculate the delta BC: 24 - 20 = 4 mEq Approximate the delta AG: 30 - 7 = 23 mEq

Diagnoses

Anion gap metabolic acidosis (diabetic ketoacidosis) Concurrent metabolic alkalosis (vomiting) Respiratory alkalosis (sepsis?)

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REFERENCES
1. Adrogue HJ, Wilson H, Boyd AE, et al: Plasma acid-base patterns in diabetic ketoacidosis. N Engl J Med 1982; 307:1603-1610. 2. Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J Med 1998; 338:26-34. 3. Albert MD, Dell RB, Winters RW: Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann Intern Med 1967; 66:32. 4. Albertson TE, Reed S, Siefkin A: A case of fatal sodium azide ingestion. Clin Toxicol 1986; 24:339-351. 5. Batlle DC, Sabatina S, Kurtzman NA: On the mechanism of toluene-induced renal tubular acidosis. Nephron 1988; 49:210-218. 6. Baud FJ, Barriot P, Toffis V, et al: Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991; 325:1761-1766. 7. Blanchard PD, Yao JDC, McAlpine DE, Hurt RD: Isoniazid overdose in the Cambodian population of Olmsted County, Minnesota. JAMA 1986; 256:3131-3133. 8. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of ethylene glycol poisoning: Methylpyrazole Toxic Alcohols Study Group. N Engl J Med 1999; 340:832-838. 9. Buehler JH, Berns AS, Webster JR, et al: Lactic acidosis from carboxyhemoglobinemia after smoke inhalation. Ann Intern Med 1975; 82:803. 10. Dorwart WV, Chalmers L: Comparison of methods for calculating serum osmolality from chemical concentrations and the prognostic value of such calculation. Clin Chem 1975; 21:190-194. 11. Dubose Jr TD: Acidosis and alkalosis. In: Fauci A, Braunwald E, Isselbacher KJ, et al ed. Harrison’s Principles of Internal Medicine, New York: McGraw-Hill; 1998:277-286. 12. Emmett M, Narins RG: Clinical use of the anion gap. Medicine 1977; 56:38-54. 13. Figge J, Jabor A, Kazda A, Fenci V: Anion gap and hypoalbuminemia. Crit Care Med 1998; 26:18071810. 14. Fulop M, Hoberman HD: Alcoholic ketosis. Diabetes 1975; 25:785. 15. Gabow PA, Clay K, Sullivan JB, Lepoff R: Organic acids in ethylene glycol intoxication. Ann Intern Med 1986; 105:16-20. 16. Gabow PA, Anderson RJ, Potts DE, Schrier RW: Acid-base disturbances in the salicylate-intoxicated adult. Arch Intern Med 1978; 138:1481-1484. 17. Gabow PA: Disorders associated with an altered anion gap. Kidney Int 1985; 27:472-483.

17a. Gan SC, Barr J, Arieff AI, Pearl RG: Biguanide-associated lactic acidosis: Case report and review of the literature. Arch Intern Med 1992; 152:2333-2336. 18. Gennari FJ: Serum osmolity: Uses and limitations. N Engl J Med 1984; 310:102-105. 19. Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR: Osmol gaps revisited: Normal values and limitations. Clin Toxicol 1993; 31:81-93. 20. Jacobsen D, Webb R, Collins TD, McMartin KE: Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol 1988; 3:418-423. 21. Levy LJ, Duya J, Girgis M, et al: Ketoacidosis associated with alcoholism in nondiabetic subjects. Ann Intern Med 1973; 78:213. 23. Madias NE, Ayus JC, Adrogue HJ: Increased anion gap in metabolic alkalosis: The role of plasma protein equivalency. N Engl J Med 1979; 300:1421-1423. 24. Marliss EB, Ohman JL, Aoki TT, et al: Altered redox state obscuring ketoacidosis in diabetic patients with lactic acidosis. N Engl J Med 1970; 283:978. 25. McQuillen KK, Anderson AC: Osmol gaps in the pediatric population. Acad Emerg Med 1999; 6:27-30. 26. Miller PD, Heinig RE, Waterhouse C: Treatment of alcoholic acidosis. Arch Intern Med 1978; 138:67. 27. Narins RG, Emmett M: Simple and mixed acid-base disorders: A practical approach. Medicine 1980; 59:161-187. 28. Oh MS, Uribarri J, Carroll HJ: Electrolyte case vignette: A case of unusual organic acidosis. Am J Kidney Dis 1988; 11:80-82. 29. Oh MS, Carroll HJ: The anion gap. N Engl J Med 1977; 287:814-817. 30. Robotham JL, Lietman MD: Acute iron poisoning: A review. Am J Dis Child 1980; 134:875-879. 31. Schelling JR, Howard RL, Winter SD, Linas SL: Increased osmol gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 1990; 113:580-582. 32. Searle GL, Siperstein MD: Lactic acidosis associated with phenformin therapy: Evidence that inhibited lactate oxidation is the causative factor. Diabetes 1975; 24:741-745. 33. Sklar AH, Linas SL: The osmolal gap in renal failure. Ann Intern Med 1983; 98:481-482. 34. Smithline N, Gardner Jr KD: Gaps—anionic and osmol. JAMA 1976; 236:1594-1597. 35. Steinhart B: Severe ethylene glycol intoxication with normal osmol gap—“a chilling thought.”. J Emerg Med 1990; 8:583-585. 36. Streicher JZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults. Ann Intern Med 1981; 94:758-762. 37. Szerlip HM, Singer I: Hyperchloremic metabolic acidosis after chlorine inhalation. Am J Med 1984; 77:581-582.

38. Taher SM, Anderson RJ, McCarthy R, et al: Renal tubular acidosis associated with toluene sniffing. N Engl J Med 1974; 290:765-768. 39. Teale KF, Devine A, Stewart H, Harper NJ: The management of metformin overdose. Anaesthesia 1998; 53:698-701. 40. Vogel SN: Lactic acidosis in acute cyanide poisoning. In: Ballantyne B, ed. Clinical and Experimental Toxicology of Cyanide, Bristol, England: Wright; 1987. 41. Williams RH, Palmer JP: Farewell to phenformin for treating diabetes mellitus. Ann Intern Med 1975; 83:567-568. 42. Winter SD, Pearson R, Gabow PA, et al: The fall of the serum anion gap. Arch Intern Med 1990; 150:311-313.

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Uncited reference Levinsky NG: Acidosis and alkalosis. In: Wilson JD, Braunwald E, Isselbacher KJ, ed. Harrison’s Principles of Internal Medicine, New York: McGraw-Hill; 1991:289-295.

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Chapter 12 – Special Considerations in the Pregnant Patient
KATHLEEN SHILALUKEY GIDEON KOREN

Acute or chronic exposure to potential hazards, whether drug, chemical, or irradiation, can have major adverse effects on the outcome of pregnancy.[41 ] Although it is standard practice that the mother’s welfare determines her need for drug therapy, many factors, including cultural norms, may affect this decision as well.[2 ] [3 ] [4 ] [5 ] [6 ] [7 ] [8 ] [9 ] [10 ] [11 ] [12 ] [13 ] [14 ] [15 ] [16 ] [17 ] [18 ] [19 ] [20 ] [21 ] [22 ] [23 ] [24 ] [25 ] [26 ] [27 ] [28 ] [29
] [30 ] [31 ] [32 ] [33 ] [34 ] [35 ] [36 ] [37 ] [38 ] [39 ] [40 ] [41 ] [42 ] [43 ] [44 ] [45 ] [46 ] [47 ] [48 ] [49 ] [50 ] [51 ] [52 ] [53 ] [54 ] [55 ] [56

Quite often, a pregnant woman may willfully consume massive doses of harmful drugs or chemicals with the intention of committing suicide or inducing an abortion, therefore precipitating an acute toxicologic emergency.
] [57 ] [58 ] [59 ] [60 ] [61 ] [62 ] [63 ] [64 ] [65 ] [66 ] [67 ]

In prescribing medication to pregnant women, the benefits of therapy must outweigh the risks. Apart from direct cost, adverse effects and their economic costs must be considered. In order to provide optimal care and avoid potential problems, it is vital to have a thorough knowledge of the drug in question. Drug information varies in quality, usefulness, validity, and credibility. Drug information as it relates to pregnancy often suffers from a paucity of data and conflicting reports owing to the ethical limitations on the conduct of such research. To acquire accurate drug information, a combination of literature reviews and consultation with health professionals and drug information centers is necessary. Communication with the manufacturers of the drugs concerned is also helpful. Conventional methods of acquiring authoritative knowledge on drug use in pregnancy have ranged from case reports (extremely useful when a small number of cases of adverse effects producing consistent malformations arise from a rare drug) to epidemiologic studies conducted prospectively or retrospectively. The impact of meta-analysis (the statistical combination of research from independent studies as a method of summarizing the literature either for observational studies or for controlled clinical trials) has been important in minimizing bias and using reliable studies. The creation of teratogen information services in North America and Europe during the past decade has increased information on issues concerning drug administration in pregnancy and decreased unjustified fears after exposure to nonteratogens. This has also been shown to reduce unjustified elective abortions that may occur owing to misinformation on drugs used in pregnancy. The past decade has experienced the introduction of new techniques to evaluate fetal exposure to drugs, including the detection of chemicals in neonatal hair and meconium. Furthermore, new in vitro methods such as the placental perfusion model help elicit new information on drug and chemical transport into the fetal compartment that cannot be studied in pregnancy owing to obvious ethical limitations. This chapter addresses characteristics of acute and chronic toxicologic exposures in pregnancy. The figures and tables review the management of a poisoned pregnant woman and the adverse effects to the neonate for commonly used drugs and those most harmful during pregnancy. General management principles for the poisoned mother and the management of selected toxins are alluded to, highlighting special considerations for selected drugs ( Figs. 12–1 and 12–2 ; Tables 12–1 and 12–2 ).

Figure 12-1 The management of poisoning in a pregnant patient.

Figure 12-2 Pharmacokinetic variables affected by physiologic changes in pregnancy.

Table 12-1 -- Clinical Implications of Drug Consumption and Exposure in Pregnancy Anticonvulsants[7 ] [11 ] [18 ] [26 ] [38 ] Drug concentration levels fall because of extracellular fluid with increased Vd; decreased plasma protein binding, with more free drug for biotransformation; folate supplementation, which increases liver metabolism of phenytoin; increased GFR, which results in faster clearance rates of drugs eliminated by the kidney Seizure frequency is increased in 45%, unchanged in 50%, and decreased in 5% Phenytoin: fetal hydantoin syndrome (see Fig. 12–1: characteristic facial alterations, hypoplastic distal phalanges and nails), microcephaly, mental retardation, neuroblastoma, cardiac defects, sevenfold increased risk for global IQ =84 Declining total antiepileptic serum concentrations with increasing free levels may result in toxicity; hence blood levels should be checked regularly. As polytherapy increases teratogenic risk, monotherapy should be used wherever possible (e.g., carbamazepine as a first-line drug for grand mal seizures). 4 mg/day of folate decreases the risk of NTD. Level II ultrasound † and maternal a-feto-proteins or amniocentesis useful to rule out NTDs. * Carbamazepine

Primidone: phenytoin-like abnormalities * Phenytoin

Carbamazepine: increased risk for NTD—estimated risk of 1% * Ethosuximide

Valproic acid: estimated risk of 1–2% for NTD * Phenobarbital

Ethosuximide: fetal hemorrhage * Valproic acid

* Primidone

Relative risk of teratogenicity: Risk unknown; however, 5–10% conform to a typical syndrome

Antipsychotics/antidepressants[29 ]

* Lithium carbonate Drug concentration levels fall due to pregnancy-induced increase in GFR Patients experience more depression spells Probable higher risk for Ebstein’s anomaly, spina bifida, VSD, mitral atresia, neonatal withdrawal symptoms, neonatal jaundice, rapid breathing, cyanosis, bradycardia, urinary retention, GI bleeding, diabetes insipidus, shock, hyperthyroidism 0.1% of pregnant women use lithium. Lithium crosses the placenta, with concentrations being similar on maternal and fetal sides. Women needing lithium therapy should continue the drug and undergo ultrasound and echocardiogram follow-up at 18 weeks as higher doses are used owing to increased clearance rates. However, after birth, GFR returns to prepregnancy levels, warranting reduction in dose administered. Careful follow-up of

renal and thyroid function tests indicated in neonate. Lithium is not a major teratogen, as reported in earlier studies. Lithium has a narrow toxic-therapeutic range; hence the drop in concentration may result in suboptimal therapy

Cyclics (amitriptyline, desipramine)

Desipramine, the major metabolite of imipramine, is also associated with withdrawal signs (e.g., cyanosis, tachycardia, diaphoresis, weight loss) Caregivers should be advised of patients on cyclics. Relative risk of teratogenicity: Initial cases of bilateral amelia not shown to be associated with teratogenicity in cyclics in subsequent studies

Desipramine inhibits sperm motility in vitro. Fluoxetine[54 ]

A prospective collaborative study did not show increased risk of major malformation despite earlier studies implicating fluoxetine in increased prematurity and increased stillbirths and miscarriages Women treated simultaneously with CAs and fluoxetine have higher rates of miscarriages; hence it is not wise to prescribe these drugs concurrently. Anticoagulants[25 ]

Hydroxycoumarins cause fetal warfarin syndrome: characteristic facial alterations, CNS and skeletal malformations, mental retardation, optic nerve atrophy The use of heparin in the first trimester should be encouraged, as it does not cross the placenta. * Hydroxycoumarins (see Fig. 12–2 )

Critical time of exposure is 6–12 weeks gestation, associated with defective ossification of bone, resulting in nasal hypoplasia and chondrodysplasia punctata; second and third trimester exposure produces optic nerve atrophy, microcephaly, mental retardation Women on anticoagulants should be followed up in a high-risk perinatal unit. Relative risk of teratogenicity: 16% of exposed fetuses have malformations, 3% hemorrhages, 8% stillbirths

Increase in stillbirths, preterm delivery, and death Risks of coumadin increase toward term and delivery; discontinue its use at 36 weeks to minimize effects. Heparin[69 ]

Although subcutaneous heparin does not cross the placenta, dose-related bone demineralization causing osteoporosis in the mother may arise.

* Alkylating agents[7 ] (busulfan, chlorambucil, cyclophosphamide, methlorethamine) Depends on condition: Acute leukemias have increased spontaneous abortions, premature births, and stillbirths; also have increased maternal bleeding and infections if mother’s peripheral blood counts are suppressed by chemotherapy. Cytotoxic drugs exert effects predominantly on rapidly dividing cells, affecting fetal development and causing abortion or teratogenicity if given in first trimester Chemotherapy required for acute leukemia has to be commenced once the diagnosis has been made. However, therapeutic abortions may be recommended if the diagnosis was made in the first half of pregnancy and poor maternal prognosis and the effects of multidrug chemotherapy on the fetus have been considered. To initiate breast cancer treatment in the presence of metastases, termination of pregnancy would be necessary. Chemotherapy exposure of the female fetus causes concern, as mutations/chromosomal aberrations produced in female ovules could cause embryo pathology to manifest in subsequent generations. Relative risk of teratogenicity: Breast cancer, cervical cancer, Hodgkin’s disease, and ovarian cancer are disease states that do not affect pregnancy outcomes. However, metastasis to the fetus has been reported with melanoma. Effects on development include microphthalmia, hypoplastic ovaries, cloudy corneas, agenesis of kidneys, cardiac effects, digit malformations Level II ultrasound * will detect visible malformations. Primary lesions warrant prompt surgical intervention once diagnosed. Case report data suggest 10–15% of cases were malformed by different drugs; this may be an overinflated number

* Antimetabolite agents (aminopterin azauridine, cytarabine, 5-fluorouracil, 6-mercaptopurine, methotrexate)[7 ]

Cytotoxic drugs with folic acid antagonism (e.g., methotrexate) have greatest risk, especially when administered in first trimester. Malformations include hydrocephalus, meningoencephalocele, anencephaly, malformed skull, cerebral hypoplasia, growth retardation, extremity and finger malformation. Aminopterin syndrome: cranial dystosis, hydrocephalus, hypertelorism, anomalies of external ear, micrognathia, posterior cleft palate. Relative risk of teratogenicity: Case report data suggest 7–75% of cases were malformed; this may be an overinflated number

Antimicrobials

Causes yellow, gray-brown, or brown staining of deciduous teeth and enamel destruction. Critical time of exposure from 16 weeks of gestation. Exposure before 14 weeks of gestation associated with no risk. * Tetracycline[9 ]

Relative risk of teratogenicity: Problems arise in 50% of fetuses exposed to tetracycline; oxytetracycline causes problems in 12.5% of cases

* Thalidomide[46 ]

Causes limb phocomelia/amelia, hypoplasia, congenital heart and renal defects, abducens paralysis, deafness Thalidomide is effective against leprosy and is in current use. Two reliable birth control methods advocated when it is prescribed to fertile females. Relative risk of teratogenicity: A 20% risk when exposure occurs between 34 and 50 days of gestation

Anesthetic gases[17 ] (thiopental, nitrous oxide, enflurane, halothane)

Not shown to cause untoward embryonic/fetal effects; case reports of increased miscarriages, but methodologic problems, especially response bias, preclude definite conclusions Most epidemiologic studies do not suggest congenital anomalies are increased by occupational exposure to volatile anesthetics. Workplace standards for nitrous oxide: TLV-TWA, 50 ppm. Decreased fertility among female dental assistants exposed to unscavenged nitrous oxide. Benzodiazepines[10 ] (diazepam, oxazepam, chlordiazepoxide) Contrasting kinetics of BDZ attributed to different routes of elimination; increased Vd lowers major demethylation metabolite of diazepam (i.e., nordiazepam); also increased half-life BDZ implicated in earlier studies to risk of both cleft lip and cleft palate, but these findings refuted by other researchers. Also reported are abnormal growth and neurodevelopment and slow gross motor development normalizing at 18 months. Fine motor functions impaired when BDZ is given at higher doses in Sweden; hence these effects not seen in studies in North America, where lower BDZ doses are prescribed. Used near term, BDZ may decrease respiratory rate and cause neonatal withdrawal and hypotonia. Detectable pharmacologic activity in neonate up to 10 days. Relative risk of teratogenicity: Initial studies reporting an increased risk of cleft palate refuted; initial studies associated chlordiazepoxide with increased congenital heart disease, but even with positive association, no homogeneous pattern of malformation detected

Cannabinoids[6 ]

Marijuana not associated with congenital abnormalities in humans, but neonates have dose-related increased

tremors, increased startle reflexes, and altered visual responsiveness There is a nearly fivefold increase of maternal blood CO Hb and threefold increase in inhaled tar with smoking marijuana compared with tobacco cigarettes. Cigarette smoking[1 ] [28 ] [45 ] [63 ] Fetal concentrations of carboxyhemoglobin higher than maternal levels due to higher affinity of fetal hemoglobin for CO. CO decreases oxygen carried to cells, impairs cytochrome enzymes. Increased high risk for LBW, prematurity, spontaneous abortions, perinatal mortality, sudden infant death; increased abnormal neurobehavioral development Nicotine and cotinine determination in fetal hair can now be done. There is good correlation between maternal and neonatal concentrations of nicotine/cotinine. Contains nicotine, hydrogen cyanide, benzopyrene, among many substances; CO is an unhealthy by-product of smoking

Cocaine[23 ]

Causes fetal intracranial hemorrhage, PROM, abruptio placentae, LBW, meconium staining, SIDS, fetal distress. Recreational use of cocaine is increasing in reproductive-age women. In American inner cities, use is as high as 40%.

Genitourinary malformation increased with cocaine use. Adverse reproductive effects associated with pregnancy exposure to cocaine are increased in polydrug abusers. Fetal ultrasound of abdomen and head indicated to rule out malformations and intracranial hemorrhage. Maternal urine, primarily, and maternal and neonate hair samples are useful in determining cocaine abuse by detecting cocaine and metabolite benzoylecgonine on a minimum of 8 hair strands. (Neonatal hair grows in last 3–4 months of pregnancy.)

Babies exposed to cocaine, alcohol, and marijuana have poor language skills.

Children with first trimester cocaine exposure revealed lower Bayley scores and lower scores on verbal comprehension and expressive language. * Ethanol[8 ] [30 ] [31 ]

FAS (prenatal and postnatal growth retardation), CNS dysfunction, facial dysmorphology ± short palpebral fissures, flat maxillary area FAS (see Fig. 12–4) arises in pregnant women drinking at least six standard drinks/day in the first trimester (1 standard drink = 12 oz beer = 5 oz glass of wine = 1.5 oz liquor = 15 g [0.5 oz] absolute ethanol). Relative risk for teratogenicity: Ethanol >2 g/kg/d over the first trimester results in two-to threefold increased risk for congenital malformations (~10%)

Long-term problems: attention deficits, MR, spontaneous abortions, abruptio placentae, premature placental separation, stillbirths, LBW, congenital malformation Calculate intake of ethanol. If mother is ethanol dependent, refer to addiction center. Level II ultrasound * detects visible malformations.

Use of diazepam helpful.

Disulfiram contraindicated in pregnant/planning women, because it is associated with spontaneous abortions, clubfoot, and other limb reductions. * Ionizing radiation[5 ] (X-rays, gamma rays, radionuclides) Long wavelength electromagnetic waves (radar, FM radio waves, diathermy, microwaves), sound waves, ultrasound

Ionized radiation has two effects: Despite increased concern about effects of ionizing radiation on health and reproduction, medical use of X-rays is growing. No medical justification for terminating pregnancy if radiation exposure = 10 rads.

(1) Deterministic effects: soft tissue function loss at a few hundred millisieverts The roentgen (R) international unit amount of X-radiation that produces 1 electrostatic unit of charge in 1 cm3 air under standard conditions: 1 rad = ionizing radiation equal to 100 ergs/g tissue; 100 rad = 1 Gy (Gray) = 1 joule/kg.

(2) Stochastic effects: Random modification of genetic structure resulting from ionizing radiation still permits proliferation; 2–4 weeks of gestation appear to be the time period for radiation-induced multiple malformations to arise The rem (roentgen-equivalent man) causes the same biologic effect as 1 R of X/gamma ray: 100 rem = 1 sv (sievert).

Microcephaly is the most common adverse outcome of high-dose radiation in pregnancy ± MR The RBE is a relationship between the absorbed energy (in rad/Gy) and the effectiveness of that energy in causing damage (a correction factor for predicting the biologic effectiveness of absorbed radiation).

Perinatal deaths and LBW as high as 30% in irradiated Wilm’s

Childhood cancer survivors given abdominal or gonadal irradiation have increased miscarriages as adults

Leukemic children receiving CNS radiation have decreased fertility as adults, indicating that doses of 18–24 Gy to brain may cause hypothalamic/pituitary injury Organic solvents[40 ] [70 ]

Aliphatic hydrocarbons associated with spontaneous abortions Adequate epidemiologic studies difficult to conduct and interpret. Also opposite results on aliphatic hydrocarbons. Methylene chloride is converted in vivo to CO. Radionuclides[68 ]

Fetal thyroid has higher affinity for iodides compared with the mother; the lowest dose reported to destroy the fetal thyroid in a fractionated manner was 12.2 mCi. Iodine as I125 used to label minute hormonal doses in vitro and in vivo. I123 used for uptake studies, while I131 binds protein.

Sodium pertechnetate for thyroid imaging delivers lower radiation than iodide, as it has a shorter half-life.

Inorganic radioactive potassium, cesium, thallium, selenium, chromium, iron, and strontium cross the placenta readily. Sterilents/disinfectants

Probably higher rate of spontaneous abortions Conflicting studies; exposure in pregnancy best avoided. Ethylene oxide

* Systemic retinoids[37 ] (isotretinoin, etretinate) (see Fig. 12–3

Causes spontaneous abortions; microcephalus; hydrocephalus; defects of cranium, face, ears, heart, limbs, liver. Cognitive defects without dysmorphology occur. Women treated with this medication should be on two reliable birth control methods. Ultrasound can pick up malformations if late diagnosis is made. Relative risk of teratogenicity: for isotretinoin ~38%; 80% of malformations observed are CNS

See Table 12–2 for list of abbreviations.

Drug

Effect of Pregnancy on Drug

Effect of Pregnancy on Disease Condition

Effect of Drug on Fetus

Practical Points

† A detailed ultrasound performed between 16 and 18 weeks gestation to detect any visible malformations. * Proven human teratogen

Table 12-2 -- Impact of Pregnancy on the Management of Common Drugs and Chemicals Acetaminophen[20 ] Transplacental NAC transfer insignificant in humans. Most common drug ingested in pregnancy after nutritional supplementation. Use NAC in pregnant woman if clinically indicated. Acetaminophen toxicity initially can be silent, or mimic morning sickness in pregnancy. In acetaminophen toxicity, the fetus may not survive or may be spared hepatotoxicity even when the mother develops it. Fetus most vulnerable to acetaminophen hepatotoxicity in the third trimester. Fetal livers have cytochrome P450 and glutathione. Can metabolize via sulfation but lack glucuronidation metabolism. * Carbon monoxide[22 ] [41 ] (CO) More aggressive oxygen and hyperbaric therapy than nonpregnant patients Mild or moderate CO exposure has caused stillbirth, as fetal CO levels rise and fall more slowly than maternal levels. CO levels as low as 15% have caused stillbirths. Digitalis[39 ] [48 ] [64 ] [66 ] (digitoxin) Fetal cardiac monitoring helpful. Digitalis poisoning in pregnancy at 7 months gestation reported nearly four decades ago. Poisoning was fatal for fetus following spontaneous labor. Autopsy consistent with prolonged intrauterine anoxia. Purified digoxin-specific antibodies (Digibind) used in life-threatening conditions. Safety and efficacy in a fetus unknown. Both digoxin and digitoxin cross the placenta in first trimester, making fetus vulnerable to cardiovascular dysfunction (e.g., bradycardia). Data on transplacental passage of Fab antibody lacking. Iron[4 ] [14 ] [21 ] [34 ] [49 ] [59 ] [61 ] [71 ] [72 ] [73 ] Standard life support measures, good supportive therapy. Following deferoxamine administration, skeletal anomalies and ossification delays observed in animal offspring at more than three times the maximal dose administered to humans. These abnormalities have not been shown conclusively to occur in humans. However, the metaplasia and dysplasia observed in children receiving deferoxamine may show possible bony changes not observed in the small cohort published to date. Exchange transfusion in newborn. Iron has been used by pregnant women to commit either suicide or abortion. Use of iron chelators (e.g., deferoxamine) as clinically indicated. Despite proven animal teratogenicity, the 10 case reports, including a large study, suggest that the benefit outweighs the risk of deferoxamine use in

pregnancy. Deferoxamine does not cross the placenta well. Lead[2 ] [3 ] [15 ] [16 ] [24 ] [27 ] [33 ] [35 ] [51 ] [58 ] [75 ] Maternal cord blood screening studies, as well as several case reports, demonstrate that lead freely crosses the placenta. Lead crosses the placenta as early as 12–14 weeks, probably by both passive diffusion and active transport. Only five case reports of lead toxicity with pregnancy in the literature. Lead toxicity ranged from clinical toxicity to no evidence of clinical toxicity in pregnancy. Dimercaprol given intramuscularly causes adverse effects; poor drug of choice in pregnancy. Spontaneous abortion, infertility, microcephaly, prematurity, stillbirth, and fetal death can occur. Nearly 20% of exposures experience PROM and increased HT at delivery, increased learning disabilities, increased minor anomalies, hemangiomas, hydrocele, undescended testes, chromosomal aberrations (gaps, breaks, fragments). Dimercaptosuccinic acid, structurally similar to dimercaprol, given orally seems the best choice; no reported data during pregnancy. Pregnancy-induced changes in calcium regulation induce lead mobilization from bones, increased lead bioavailability to maternal and fetal compartments. Iron deficiencies enhance susceptibility to lead toxicity. Unlikely that EDTA enters the fetus, as reported in a single case. Valid use of chelators based on maternal symptoms and toxicity. Chelators should not be used in asymptomatic pregnant women. Prolonged use of chelators affects essential trace element transport to the fetus. Also, chelators can mobilize maternal bone lead, potentially increasing fetal exposure. Organophosphorous pesticides[52 ] [74 ] Appropriate life support, GI decontamination, meticulous respiratory care, administration of atropine and pralidoxime. Pesticide-related agricultural occupational exposure can cause thousands of cases through contaminated food (e.g., aldicarb-contaminated watermelon). Monitor fetus; consider delivery if distress documented. Carbamates do not effectively cross to the CNS. Removal from exposure until cholinesterase returns to 75% of baseline in mild toxicity. Trans-GI epithelial passage has occurred with organophosphates, making transplacental transfer plausible. Mecarbam found in higher concentration in the fetus. Neonatal plasma and RBC cholinesterase ranged from 50%–70% of adult values; hence increased fetal sensitivity to pesticides is expected. TLV-TWA, 0.1 mg/m3 for parathion. Salicylates[43 ] Unlike acetaminophen, the parent drug rather than metabolite produces toxicity and places fetus at risk. Fewer than 10 cases of salicylate toxicity in pregnancy reported. Salicylates cross the placenta and attain higher levels in the fetus than in the mother. Salicylate toxicity in the newborn includes hyperpnea, hypertonia, irritability, poor appetite, malnourishment. Postmortem findings reveal tentorial and cerebral hemorrhage. BDZ, benzodiazepines; CA, cyclic antidepressant; CNS, central nervous system; CO, carbon monoxide; COHb, carboxyhemoglobin; EDTA, ethylenediaminetetraacetic acid; FAS, fetal alcohol syndrome; GFR, glomular filtration rate; GI, gastrointestinal; HT, hypertension; LBW, low birth weight; MR, mental retardation; NAC, N -

acetylcysteine; NTD, neural tube defect; PROM, premature rupture of membranes; RBC, red blood cell; RBE, relative biologic effectiveness; SIDS, sudden infant death syndrome; TLV-TWA, the time-weighted average concentration for a normal 8-hour workday; a 40-hour workweek to which nearly all workers may be repeatedly exposed, day after day without adverse effect; Vd, volume of distribution; VSD, ventricular septal defect. Drug Management Comments
* Proven human teratogen.

GENERAL CONSIDERATIONS

Gastrointestinal decontamination with activated charcoal is a mainstay of treatment but is ineffective in overdoses of iron, lithium, acetone, borates, caustics, alcohols, hydrocarbons, and metals. Management for specific toxins is discussed in appropriate chapters in this book.

Successful outcome of the maternal-fetal unit is dependent on appropriate and adequate management of the mother.

Proven effective medications or antidotes should not be withheld, especially in overdose conditions, owing to fear of adverse effects on the fetus.

The fetus is most vulnerable to teratogenicity during the first trimester. However, knowledge about medications used in pregnancy and whether they have any teratogenic or other adverse effects on the fetus at any time is necessary.

Multidisciplinary teamwork among the clinician, obstetrician, perinatologist, and toxicologist can optimize patient management.

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REFERENCES
1. Abel EL: Smoking and pregnancy. J Psychoactive Drugs 1984; 16:327. 2. Angell NF, Lavery JP: The relationship of blood lead levels to obstetric outcome. Am J Obstet Gynecol 1982; 142:40. 3. Baghurst PA, Robertson EF, Oldfield RK, et al: Lead in the placenta, membranes and umbilical cord in relation to pregnancy outcome in a lead-smelter community. Environ Health Perspect 1991; 90:315. 4. Blanc P, Hryhorczuk D, Danel I: Deferoxamine treatment of acute iron intoxication in pregnancy. Obstet Gynecol 1984; 64:125. 5. Book SA, Goldman M: Thyroidal radioiodine exposure to the fetus. Health Phys 1975; 29:874. 6. Buchanan CK: Helpful sources of information. In: Turner DJ, Finnell RH, Chernoff GF, et al ed. Peace of Mind During Pregnancy, New York: Facts on File; 1988:356-360. 7. In: Cherry SH, Berkowitz RL, Kase NG, ed. Medical, Surgical and Gynaecological Complications of Pregnancy, 3rd ed. Baltimore: Williams & Wilkins; 1985. 8. Clarren SK, Smith DW: The fetal alcohol syndrome. N Engl J Med 1978; 298:1063. 9. Cohlan SQ: Tetracycline staining of the teeth. Teratology 1977; 15:127. 10. Czeizel A: Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reprod Toxicol 1988; 1:183. 11. Dansky L, Andermann F, Sherwin AL, et al: Maternal epilepsy and congenital malformations: Correlation with maternal plasma anticonvulsant levels during pregnancy. In Janz D, Bossi L, Dain M (eds): Epilepsy, Pregnancy and the Child. New York, Raven Press, p 251. 12. Davidson JM, Hytten FE: Glomerular filtration during and after pregnancy. J Obstet Gynecol 1974; 81:588. 13. Dettli L: Elimination kinetics and drug dosage in renal insufficiency patients. Triangle 1975; 14:116. 14. Dugdale AE, Powell LW: Acute iron poisoning: Its effects and treatment. Med J Aust 1964; 2:990. 15. Ellenhorn MJ: Toxic exposure in pregnancy. In: Ellenhorn MJ, Barceloux DG, ed. Medical Toxicology, 1st ed. New York: Elsevier; 1988:132-152. 16. Foreman H, Trüjillo TT: The metabolism of C-14-labeled ethylene diaminetetra-acetic acid in human beings. J Lab Clin Med 1954; 43:566. 17. Friedman JM: Teratogen update: Anesthetic agents. Teratology 1988; 37:69. 18. Gaily E, Kantola-Sorsa E, Granstrom MZ: Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol 1990; 32:403.

19. Gershanik JJ, Brooks GG, Little JA: Blood lead values in pregnant women and their offspring. Am J Obstet Gynecol 1974; 119:508. 20. Goldfrank LR, Howland MA, Weisman RS, et al: Acetaminophen. In: Goldfrank LR, et al ed. Goldfrank’s Toxicologic Emergencies, 4th ed. East Norwalk, CT: Appleton and Lange; 1990:251-260. 21. Goldfrank LR, Kulberg AG, Kirstein RH: Iron. In: Goldfrank LR, et al ed. Goldfrank’s Toxicologic Emergencies, 4th ed. East Norwalk, CT: Appleton and Lange; 1990:277-288. 22. Gossel AT, Bricker JD: Carbon monoxide, cyanides, and sulfides. In: Gossel AT, Bricker JD, ed. Principles of Clinical Toxicology, 1st ed. New York: Raven Press; 1984:84104. 23. Graham K, Koren G, Klein J, et al: Determination of gestational cocaine exposure by hair analysis. JAMA 1989; 262:3328. 24. Graziano JH, Siris ES, La Iancono N, et al: 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985; 37:431. 25. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68:122. 26. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 1974; 87:285. 27. Hu H: Knowledge of diagnosis and reproductive history among survivors of childhood plumbism. Am J Public Health 1991; 81:1070. 28. Ishiyama J, Nagai T, Toshida S: Detection of basic drugs (methamphetamines, antidepressants and nicotine) from human hair. J Forensic Sci 1983; 28:380. 29. Jacobson SJ, Jones K, Johnson K, et al: Prospective multicentre study in pregnancy outcome after lithium exposure during first trimester. Lancet 1992; 339:530. 30. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999. 31. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1:1267. 32. Kerr MG: Cardiovascular dynamics in pregnancy and labour. Br Med Bull 1968; 24:19. 33. Kimmel CA: Critical periods of exposure and developmental effects of lead. In: Kacew S, Reasor MJ, ed. Toxicology and the Newborn, New York: Elsevier; 1984:217-236. 34. Koren G, Bologa M, Pastuszak A: The way women perceive teratogenic risk: The decision to terminate pregnancy. In: Koren G, ed. Maternal-Fetal Toxicology, 1st ed. New York: Marcel Dekker; 1990:373-381. 35. Koren G, Cheng M, Klein J, et al: Lead exposure in mothers and infants in Toronto, 1989. Can Med Assoc J 1990; 142:1241. 36. Kyriakou D, Papanicalaou C, Gyparaki M, et-al.: Absence of desferrioxamine teratogenicity in a thalassemic patient [abstract]. Second International Conference on Thalassemia and the

Haemoglobinopathies, Herakleion (Crete), Greece, October 21–24, 1987, p 106. 37. Lammer EJ, Chen DJ, Hoar RM, et al: Retinoic acid embryopathy. N Engl J Med 1985; 313:837. 38. Lander CM, Edwards VE, Eadie MJ, et al: Plasma anticonvulsant concentrations during pregnancy. Neurology (Minneapolis) 1977; 27:128. 39. Lewander WJ, Gaudreault P, Einhorn A, et al: Acute pediatric digoxin ingestion—a ten-year experience. Am J Dis Child 1986; 140:770. 40. Lindbohm ML, Taskinen H, Sallmen M, et al: Spontaneous abortions among women exposed to organic solvents. Am J Ind Med 1990; 17:449. 41. Longo LD: The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1977; 129:69. 42. Luxford AME, Kellaway GSM: Pharmacokinetics of digoxin in pregnancy. Eur J Clin Pharmacol 1983; 25:117. 43. Lynd PA, Andreasen AC, Wyatt RJ: Intrauterine salicylate intoxication in a newborn. Clin Pediatr (Phila) 1976; 15:912. 44. Martin K: Successful pregnancy in ß-thalassemia major. Aust Paediatr J 1983; 19:182. 45. Martin TR, Bracken ME: Association of low birth-weight with passive smoke exposure in pregnancy. Am J Epidemiol 1986; 124:633. 46. Newman CGH: Clinical aspects of thalidomide embryopathy—a continuing preoccupation. Teratology 1985; 32:133. 47. Nimmo WS, Wilson JE, Prescott LF: Narcotics analgesics and delayed gastric emptying during labour. Lancet 1975; 1:890. 48. Okita GT, Plotz EJ, Dans ME: Placental radioactive digitoxin in pregnant women and its fetal distribution. Circ Res 1956; 4:376. 49. Olenmark M, Biber B, Dottori O, et al: Fatal iron intoxication in late pregnancy. Clin Toxicol 1987; 25:347. 50. Palmisano PA, Polhik RB: Fetal pharmacology. Pediatr Clin North Am 1972; 19:3. 51. Palmisano PA, Sneed RC, Cassady G: Untaxed whisky and fetal lead exposure. J Pediatr 1969; 75:869. 52. Papadopoulou-Tsoukali H, Njau S: Mother-fetus postmortem toxicologic analysis in a fatal overdose with mecarbam. Forensic Sci Int 1987; 35:249. 53. Parry E, Shields R, Turnbull AC: Transit time in the small intestine in pregnancy. J Obstet Gynaecol Br Com 1970; 77:900. 54. Pastuszak AL, Schick-Boschetto B, Zuber C, et al: Pregnancy outcome following first trimester exposure to fluoxetine (Prozac). JAMA 1993; 269:2246.

55. Perez V, Gorodisch S, Casavilla F, et al: Ultra structure of human liver at the end of normal pregnancy. Am J Obstet Gynecol 1971; 110:428. 56. Philipson A: Pharmacokinetics of antibiotics in pregnancy and labour. Clin Pharmacokinet 1979; 4:297. 57. Pirani BBK, Campbell DM, MacGillivray I: Plasma volume in normal first pregnancy. J Obstet Gynaecol Br Com 1973; 80:884. 58. Rabinowitz M, Bellinger E, Leviton A, et al: Pregnancy hypertension, blood pressure during labour, and blood lead levels. Hypertension 1987; 10:447. 59. Rayburn WF, Donn SM, Wulf ME: Iron overdose during pregnancy: Successful therapy with deferoxamine. Am J Obstet Gynecol 1983; 147:717. 60. Reboud P, Groulade J, Groslambert P, et al: The influence of normal pregnancy and the post partum state on plasma proteins and lipids. Am J Obstet Gynecol 1963; 86:820. 61. Richards R, Brooks SEH: Ferrous sulphate poisoning in pregnancy (with afibrinogenaemia as a complication). West Indian Med J 1966; 15:134. 62. Rowland AS, Baird DD, Weinberg CR, et al: Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992; 327:993. 63. Rush D, Callahan KR: Exposure to passive cigarette smoking and child development. Ann N Y Acad Sci 1989; 562:74. 64. Saarikoski S: Placental transfer and fetal uptake of H-digoxin in humans. Br J Obstet Gynaecol 1976; 83:879. 65. Schou M, Amdisen A, Steenstrap DR: Lithium and pregnancy. II. Hazards to women given lithium during pregnancy and delivery. BMJ 1973; 2:137. 66. Sherman Jr JL, Locke RV: Transplacental neonate digitalis intoxication. Am J Cardiol 1960; 6:834. 67. Shilalukey K, Robieux I, Spino M, et al: Are current pediatric dose recommendations for intravenous theophylline appropriate?. J Asthma 1993; 30:109. 68. Smith EM, Warner GG: Estimates of radiation dose to embryo from nuclear medicine procedures. J Nucl Med 1979; 17:836. 69. Swiet de M, Dorrington Ward P, Fidler J, et al: Prolonged heparin therapy in pregnancy causes bone demineralization. Br J Obstet Gynaecol 1983; 90:1129. 70. Taskinen H, Anttila A, Lindbohm ML, et al: Spontaneous abortions and congenital malformations among the wives of men occupationally exposed to organic solvents. Scand J Work Environ Health 1989; 15:346. 71. Thomas RM, Skalioka AE: Successful pregnancy in transfusion dependent thalassemia. Arch Dis Child 1980; 55:572. 72. Turk J, Aks S, Ampuero F, et al: Successful therapy of iron intoxication in pregnancy with intravenous

deferoxamine and whole bowel irrigation. Vet Hum Toxicol 1993; 35:441. 73. Van Amyde KJ, Tenenbein M: Whole bowel irrigation during pregnancy. Am J Obstet Gynecol 1989; 160:646. 74. Weis OF, Muller FO, Lyell H, et al: Materno-fetal cholinesterase inhibitor poisoning. Anesth Analg 1983; 62:233. 75. Zelterlund B, Winberg J, Lundgren G, et al: Lead in umbilical cord blood correlated with the blood lead of the mother in areas of low, medium or high atmospheric pollution. Acta Paediatr Scand 1977; 66:169.

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Chapter 13 – Poison Centers
JERROLD B. LEIKIN EDWARD P. KRENZELOK In the first half of this century, poison information was nearly nonexistent, and at best viewed as an esoteric field of medicine. It was placed haphazardly in health science curricula, essentially not taught in medical schools, and generally not regarded as a specific or separate discipline. Because formal poison control services did not exist, serious morbidity and mortality from childhood poisoning developed into a significant problem for both parents and physicians, accounting for up to half of all accidents in the home and a tragic number of fatalities. However, since 1953, when the first poison information hot line opened in Chicago, poison control centers have emerged as important health care providers firmly established in our nation’s health care system.[3][5][23] As poison control centers began to flourish, the American Association of Poison Centers (AAPCC) was subsequently created in 1958 for the purpose of developing educational programs for health care providers along with the general public, addressing the needs of its members and, most importantly, standardizing the operation of poison control centers.[3] Criteria for AAPCC designation as a regional poison control center include a geographically defined region (with a population base of 1 million to 10 million), continuous 24-hour free availability to the general public and to health care providers, written protocols, qualified certified specialists in poison information, medical direction, regional data collections, and educational programs ( Table 13–1 ).[12]

Table 13-1 -- American Association of Poison Control Centers Criteria for Regional Poison Center Certification • The center must maintain comprehensive reference sources on poisonings. • The center must serve a geographic area with a population base of optimally less than 10 million people. • The center must operate 24 hours a day/365 days per year and be readily accessible by telephone. • The center must participate in AAPCC’s national data collection system, the Toxic Exposure Surveillance System (TESS). • The center must be staffed at all times by licensed pharmacists, nurses, and/or physicians who attained additional training in clinical toxicology. • The center must utilize and maintain protocols, follow-up guidelines, and quality assurance strategies that provide consistent approaches in the evaluation and treatment of the poisoned patient. • The center must have a medical director and a managing director, and these directors must have specific qualifications. • The center must have an ongoing quality-improvement program. • The center must provide education for the public and for health care professionals.

Rapid growth in the poison control system followed during the 1960s and 1970s. By 1978, there were 661 poison centers operating in the United States and its territories.[23] This tremendous evolution of poison

centers and the poison prevention movement, in conjunction with such legislation as the Poison Prevention Packaging Act of 1970, led to a marked decline in pediatric deaths from poisoning during this time period.[25] For example, pediatric deaths from salicylate overdose declined by more than 80% from the 1960s to the 1980s. In the 1980s and 1990s there was a precipitous decline in the number of poison control centers, from 104 in 1991 to 75 in 1997 in the United States (in 2000 51 were certified by the AAPCC). An updated list can be ). [19] A obtained from the AAPCC; telephone: 202-362-7217 or the AAPCC website, www.AAPCC.org poison center certified by the AAPCC has an average human exposure call volume of 38,191 and employs an average of 10.9 specialists in poison information.[10][19] These specialists in poison information are most often nurses or pharmacists who have received extensive training in clinical toxicology. The AAPCC offers an annual certification examination for specialists as a means to standardize poison treatment and attain quality assurance. Poison centers respond to an average 8.8 human exposures per 1000 population served.[19] In 1997, American poison centers reporting to the AAPCC Toxic Exposure Surveillance System (TESS) responded to 2,192,088 human exposures.[19] In addition to human exposure calls, poison centers manage some cases involving animal exposures and supply information on poisons, poison prevention, drugs and drug identification, teratogenicity, and occupational, medical, and environmental concerns. The administrative structure of a regional poison control center varies. Each center must have a managing director and a medical director; in some centers a single individual fulfills both requirements. About half of the AAPCC-certified poison centers have a managing director certified by the American Board of Applied Toxicology (ABAT). Similarly, the medical director in an AAPCC-certified regional poison control center is usually certified in medical toxicology, either by the now-defunct American Board of Medical Toxicology or the special American Board of Medical Specialties (ABMS) certification in medical toxicology. The ABMS examination is sponsored by the American Boards of Emergency Medicine, Preventive Medicine, and Pediatrics and is administered as a sub-board by the American Board of Emergency Medicine. Additionally, most poison centers maintain a list of nonphysician consultants, which may include botanists, mycologists, zoologists, entomologists, and herpetologists. In the United States, poison centers are information units and do not provide direct treatment. Therefore, they do not stock antidotes. However, the centers should be aware of the location of important antidotes that are stocked inadequately by most hospitals. [6][7][8][11][14][16][22][24][27] Although the Joint Commission on Accreditation of Health Care Organizations (JCAHO) does not address the specific criteria regarding antidote storage and availability, guidelines have been developed by the American Academy of Clinical Toxicology (AACT) regarding antidote availability. [1][9][15] Suggested minimum stock quantities of antidotes are listed in Table 13–2 .[4]

Table 13-2 -- Uses and Suggested Minimum Stock Quantities for 25 Selected Antidotes Antidote Suggested Minimum Stock Quantity N-Acetylcysteine (Mucomyst) Amyl nitrite, sodium nitrite, sodium thiosulfate (cyanide antidote kit) Antivenin polyvalent (Crotalidae)—equine origin 600 mL in 10- or 30-mL vials of 20% solution Three antidote kits 10 vials (Note: 30 vials or more may be needed in serious cases)

Antidote Atropine sulfate Black widow spider antivenin (Latrodectus mactans antivenin) Calcium disodium EDTA (Versenate) Calcium gluconate, calcium chloride Deferoxamine mesylate (Desferal) Digoxin immune Fab (Digibind) Dimercaprol (BAL in Oil) Ethanol Flumazenil (Romazicon) Folinic acid (Leucovorin), folic acid Fomepizole (Antizol) Glucagon Hyperbaric oxygen (HBO) Methylene blue Naloxone (Narcan)
D-Penicillamine

Suggested Minimum Stock Quantity Five vials, 20 mL/vial (0.4 mg/mL) and twenty 10 mL (0.1 mg/mL) ampules. Total: 60 mg 1 vial Two 5-mL ampules, 200 mg/mL 10% calcium gluconate: Five 10-mL vials 10% calcium chloride: Five 10-mL vials Twelve 500 mg vials 20 vials Ten 3-mL (100 mg/mL) ampules 8 L of 10% EtOH in D5W and 1 pint 95% ethanol Twenty 5-mL vials or ten 10-mL vials. Each has 0.1 mg/mL. Total: 10 mg Folinic acid: six 50-mg vials Folic acid: six 50-mg vials 1.5 g/vial, four vials Fifty 1-mg vials (may offer only 5–10 hours of treatment in serious cases). A 10-mg/10-mL vial is no longer available from the manufacturer. Post the location and phone number of nearest HBO chamber. Ten 10-mL (10 mg/mL) ampules Naloxone: fifty 1-mL ampules (0.4 mg/mL) Bottle of 100 capsules: 125 mg or 250 mg/capsule Ten 2-mL (1 mg/mL) ampules Two 0.5-mL ampules (2 mg/mL) and two 5-mL ampules (10 mg/mL)

(Cuprimine)

Physostigmine salicylate (Antilirium) Phytonadione, vitamin K1 (AquaMEPHYTON, Mephyton)

Pralidoxime chloride, 2 PAM (Protopam) 1 g/kit, five kits Pyridoxine hydrochloride, vitaminB6 Sodium bicarbonate Succimer (Chemet) Twenty-five 10-mL (1 g) vials or eight 30-mL (3 g) vials Twenty-five 20-mEq vials Bottle of 100 capsules; 100 mg/capsule

Modified from Burda AM: Poison antidotes: Issues of inadequate stocking with review of uses of 24 common antidotal agents. J Pharm Pract 1997; 10:235–248.

The cost-effectiveness of poison centers has been evaluated in several studies. With about 72.5% of reported toxic exposures being treated at home, poison control centers truly represent the nation’s first

successful attempt at home health care services.[19] An economic analysis performed for the Department of Health and Human Services found that every $1 spent on poison control services resulted in $7 of medical savings. Compared with various cost-saving preventive health measures for children receiving Medicaid, only childhood immunizations afforded more cost savings ( Fig. 13–1 ).[20] A second analysis compared 1992 data on incidence, medical spending, and payment sources for poisoning in jurisdictions both with and without poison center service.[21] Poison centers reduced the number of patients who received outpatient medical treatment for poisoning by 24 per cent and the number of people hospitalized by 12 per cent. Each call from the public into a poison center saves an estimated $175 in other medical spending.[2][13][17][18][20][21][26] Because the average call costs about $28 to a poison center (including indirect costs), the dollar savings results in almost $6.50 saved in medical care payments for every dollar spent on poison center services ( Table 13–3 ). This amounts to a reduction of an estimated $355 million nationally in medical spending (all dollar figures are calculated in 1992 dollars and do not account for the dollar value of life and functional capacity saved).[21] Furthermore, individuals, private insurance companies, and the federal government benefit the most, based on cost-savings analysis. [18][21] Increasing regional poison center coverage to the entire U.S. population would result in significant cost savings ( Table 13–4 ). In spite of these obvious financial benefits, poison centers continue to struggle for survival. However, government agencies are aware of these benefits and the potential dilemma facing the nation if more poison centers close.

Figure 13-1 Selected Cost-Saving Preventive Health Measures. (From Miller TR: Government Financial Options to Preserve and Expand Poison Control Centers: A Report to Congress.)

Table 13-3 -- Annual Poisonings and Resultant Medical Spending During the Year of Injury (United States, 1991–1992), by Medical Treatment

Cases Fatal Hospitalized Other medically treated Poison control consultations Poison control center only Total M, million. 13,000 * 285,000 1,090,000 —† 1,820,000 3,208,000

Mean$/Case 11,700 8,700 245 28 28 925

$/Year 155 M 2,475 M 265 M 15 M 50 M 2,960 M

Data from 1991 US Vital Statistics, 1992 National Hospital Discharge Survey, 1987 National Medical Expenditure Survey, and 1992 Annual Report of the American Association of Poison Control Centers, adjusted for nonreporting centers. From Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A benefit-cost analysis. Ann Emerg Med 1997; 20:239–245.
* Exact count is 13,232. † There were 600,000 consultations, which are included as cases under “Other medically treated,” but for which costs are shown separately.

Table 13-4 -- Predicted Annual Incidence and First-Year Medical Care Spending for Poisonings with No Coverage and with Complete Coverage (United States, 1992), by Medical Treatment No Poison Centers Center for All Cases Fatal Hospitalized Other medically treated Poison control consultations Poison control center only Total M, million. Data from 1991 US Vital Statistics and original computations. All estimates were computed before rounding. From Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A benefit-cost analysis. Ann Emerg Med 1997; 20:239–245.
* The estimated 700,000 consultations are included as cases under “Other medically treated,” although the related costs are shown separately. † Rounded number.

$/Year * 155 M 2,810 M 350 M 0M 0M 3,315 M

Cases 13,000 † 280,000 † 1,030,000 —* 2,115,000 3,440,000

$/Year 155 M 2420 M 250 M 20 M 60 M 2905 M

13,000 † 325,000 1,440,000 0 0 1,790,000

Poison centers are essential to the future of the field of clinical toxicology ( Table 13–5 ). In addition to

providing outpatient assessment of exposures or sophisticated toxicology expertise to health care personnel, poison centers serve as a training site for students, residents, pharmacists, physicians, and medical toxicology fellows. Fellowship-trained physicians are certified in medical toxicology through the medical toxicology sub-board administered by the American Board of Emergency Medicine. Pharmacists and other qualified individuals in related specialties can be certified in toxicology by the ABAT. Medical Review Officer (MRO) training and certification for Department of Transportation drug analysis can be obtained through the American College of Occupational and Environmental Medicine. As the focal point for these activities, the poison center is critical to the training of all aspiring clinical toxicologists and provides a venue to practice the specialty.

Table 13-5 -- Summary of Health and Economic Benefits of a Regional Poison Control Center • Reduction of unnecessary emergency department visits and inappropriate use of medical resources • Decreased burden on a region’s emergency medical transportation system • Reduction in adverse effects resulting from the use of outdated, hazardous first aid procedures in the home • A reduction in the time required to diagnose and establish definitive care for the poisoned victim • Minimizing public health effects of community exposure to toxic materials • Early detection and elimination of unusually hazardous commercial products through regulatory notification, recall, repackaging, reformulation, or product discontinuation • Improved care of poisoning victims, decreasing disabilities, and costly long-term medical care • Reduced incidence of unintentional poisoning in the home and workplace • Enhanced management of drug-addicted patients by providing recommendations, referrals, and assistance • Reduced exposure to potential toxins during pregnancy • Improved patient care by educating physicians, nurses, paramedics, and other health care professionals in poison management and medical toxicology Modified from Litovitz T, Kearney TE, Holm K, et al: Poison Control Centers: Is there an antidote for budget cuts? Am J Emerg Med 1994; 12:585–599.

REFERENCES
1. American Academy of Clinical Toxicology: Facility assessment guidelines for regional toxicology treatment centers. J Toxicol Clin Toxicol 1993; 31:211-217. 2. Bindl L, Ruchardt J, Pfeiffer A, et al: Effect of a German poison control center on health care cost reductions in harmless exposure cases. Vet Hum Toxicol 1997; 39:48-50. 3. Botticelli JT, Pierpaoli PG: Louis Gdalman, pioneer in hospital pharmacy poison information services. Am J Hosp Pharm 1992; 49:1445-1450. 4. Burda AM: Poison antidotes: Issues of inadequate stocking with review of uses of 24 common antidotal agents. J Pharm Pract 1997; 10:235-248. 5. Burda AM, Burda NM: The nation’s first poison control center: Taking a stand against accidental childhood poisoning in Chicago. Vet Hum Toxicol 1997; 39:115-119.

6. Chyka PA, Conner HG: Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp Pharm 1994; 51:1346-1348. 7. Dart RC, Stark Y: Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA 1996; 276:1508-1510. 8. Davis NM: Insufficient stocking of poisoning antidotes. Hosp Pharm 1997; 32:1078-1103. 9. de Garbino JP, Haines JA, Jacobsen D, et al: Evaluation of antidotes: Activities of the International Programme on Chemical Safety. J Toxicol Clin Toxicol 1997; 35:333-343. 10. Felberg L, Litovitz TL, Morgan J: State of the nation’s poison centers: 1995 American Association of Poison Control Centers survey of U. S. poison centers. Vet Hum Toxicol 1996; 38:445-453. 11. Freeman G: Is your pharmacy sufficiently stocked? Lack of key supplies is a liability risk. Healthcare Risk Manage 1997; 19:1-12. 12. Geller RJ, Fisher III JG, Leeper JD, et al: American poison control centers: Still the same?. Ann Emerg Med 1988; 17:599-603. 13. Harrison DL, Draugalis J, Slack MK, et al: Cost effectiveness of regional poison control centers. Arch Intern Med 1996; 156:2601-2608. 14. Howland MA, Weisman R, Sauter D, et al: Non-availability of poison antidotes. N Engl J Med 1986; 314:927-928. 15. Joint Commission on Accreditation of Healthcare Organizations : 1994 Accreditation Manual for Hospitals, Oakbrook Terrance, IL: JCAHO; 1994:162. 16. Kanatani MS, Kearney TE, Levin RH, et al: Treatment of toxicologic emergencies—antidote preparedness: An evaluation of Bay Area hospital pharmacies and its impact on emergency planning. Vet Hum Toxicol 1992; 34:319. 17. Kelly NR, Ellis MD, Kirkland RT, et al: Effectiveness of a poison center: Impact on medical facility visits. Vet Hum Toxicol 1997; 39:44-48. 18. Litovitz T, Kearney TE, Holm K, et al: Poison control centers: Is there an antidote for budget cuts?. Am J Emerg Med 1994; 12:585-599. 19. Litovitz TL, Klein-Schwartz W, Dyer KS, et al: 1967 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998; 16:443-497. 20. Miller TR: Government Financial Options to Preserve and Expand Poison Control Centers: A Report to Congress. 21. Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A benefit-cost analysis. Ann Emerg Med 1997; 29:239-245. 22. Parker DP, Dart RC, McNally JJ: Critical deficiencies in the treatment of toxicologic emergencies: Antidote stocking in Arizona hospitals. Vet Hum Toxicol 1990; 32:376. 23. Scherz RG, Robertson WO: The history of poison control centers in the United States. J Toxicol Clin

Toxicol 1978; 12:291-296. 24. Spoeke DG: Guide to the acquisition, storage, and use of antidotes. Am J Hosp Pharm 1981; 38:498506. 25. US Consumer Product Safety Commission. Poison prevention packaging: A text for pharmacists and physicians. Washington, DC, 1993; pp 5–7. 26. Williams RM: Are poison control centers cost-effective?. Ann Emerg Med 1997; 29:246-247. 27. Woolf AD, Chrisanthus K: On site availability of selected antidotes: Results of a survey of Massachusetts hospitals. Am J Emerg Med 1997; 15:62-66.

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Chapter 14 – Managing Patients with Hazardous Chemical Contamination
MARK KIRK The odds are high that man and chemicals will come together. Hundreds of thousands of chemicals are manufactured, then transported by rail, waterway, highway or pipeline and ultimately stored for use in the community, workplace, or home. Chemicals are helpful when used and properly contained but can be hazardous if misused or accidentally released. Hazardous materials are not dangerous if appropriately contained but can injure life and damage the environment following uncontrolled release from their containers.[18] For example, chlorine is not harmful until its transport container ruptures and it escapes into the environment. Patients harmed by hazardous chemicals require special handling and treatment. Emergency care providers, prehospital or hospital-based, must assess the situation before treating victims of hazardous chemical accidents; otherwise, the would-be rescuer may become a victim.[1][31][51][59][60][77] In an unprepared emergency department (ED), one contaminated patient may disrupt departmental operations, overwhelm staff, deplete supplies, and create a disaster. A hazardous chemical release producing hundreds to thousands of victims is the most extreme hazardous material (Haz-Mat) situation a community can face. Prehospital resources and hospitals were overwhelmed in Bhopal, India, when methyl isocyanate was accidentally released, and in Japan when sarin, a nerve agent, was deliberately released into the Tokyo subway system.[49][52][60]

RECOGNIZING PATIENTS WITH CHEMICAL CONTAMINATION
Rapidly recognizing hazardous chemical contamination is most important for effective management. Contamination may go unrecognized because multiple traumatic injuries, sudden unconsciousness, or unexplained cardiac arrest of victims may distract health care workers. In patients ingesting toxic substances, off-gassing of vapors from the GI tract or vomitus may harm health care workers.[1] The true risk to these workers is difficult to estimate because no procedure or instrument is available to rapidly detect chemical contamination on patients. Therefore, prehospital and ED personnel must be alert for high-risk situations. Table 14–1 lists situations in which hazardous chemical contamination is likely.

Table 14-1 -- Indications of Possible Chemical Contamination Site of incident Industrial Chemical manufacturing plant Hazardous waste site Pipeline Transportation accidents

Train derailment Tanker truck Plane (crop duster) Barges and cargo ships Agricultural Farm accidents Type of incident Fire Explosion Ruptured tank Spill Structural collapse Terrorism Clandestine laboratories Findings at the incident Vapor clouds Dead animals, insects, or fish Several people with similar complaints Rescue from enclosed spaces Chemical odors Patient findings Unexplained unconsciousness in otherwise healthy person Unexplained cardiac arrest in otherwise healthy person Strong odors on clothes, skin, or breath Unidentified liquids or particulates on skin or clothing Chemical burns Irritation of the eyes, mucous membranes, or skin Methemoglobinemia Overdoses of cleaning or agricultural chemicals

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MANAGEMENT STEPS FOR CHEMICALLY CONTAMINATED PATIENTS
Confusion, panic, a major rescue response, and many seriously ill victims were pictured by the media after the release of sarin in the Tokyo subway system in 1995.[59][60] Effectively dealing with chemically contaminated patients requires an organized approach in order to minimize chaos. This approach includes management of (1) information, (2) resources, and (3) medical therapies for specific patient problems. Information Management Toxin identification must be a priority in the emergency response and must be communicated to hospitals prior to transporting patients. Notification is essential even if a toxin is only suspected and not confirmed.[7] When chemical identification or the hazards of exposure are uncertain, the treatment team must assume the patient is contaminated by a highly toxic chemical. Information must also be as accurate and reliable as possible in order to minimize confusion and fear and optimally guide critical decisions for patient care, ED operations, and mass casualty response. In general, information gathered by on-scene professionals is more reliable than hearsay from an injured victim or a news broadcast. Reliable facts help physicians make decisions that are best for the patient and ED operations. Reacting to a worst-case scenario removes staff from their work areas, disrupts emergency department operations, and delays specialized or life-saving medical care. In many cases, a less extensive response may be safe and effective. For example, a patient with carbon monoxide poisoning is not a contamination risk. To treat such patients, the staff does not need protective equipment and the patient does not require decontamination procedures. Accurate, specific information can guide actions and keep safety a priority. Decisions made in the early stages of an incident are very important because mistakes tend to be magnified manyfold as the response progresses.[76] Thoughtful decisions and advanced preparation, based on reliable and accurate information, can mean the difference between effectively handling a situation and turning the hospital into a disaster zone. The following specific questions will help guide information management. What is the risk involved? Is the hospital at direct risk from the Haz-Mat incident?[7] For example, a plume of toxic gas can enter the ventilation system from a nearby incident. In these situations, actions such as sheltering in place or evacuation may be necessary to protect the staff and patients from harm. If the hospital is not at risk, advanced preparation for victims should include an estimation of the magnitude of an incident and the resources available to handle it. Mass casualty plans and specialized resources should be activated as soon as the need is recognized.

Specific information to obtain includes (1) the expected numbers and categories of victims, both critical/ambulatory and contaminated/uncontaminated, and (2) the circumstances surrounding the incident, such as explosion, fire, or building collapse, to guide mobilization of specialty resources (e.g., hyperbaric oxygen, trauma surgery, radiation expertise). What is the suspected chemical? Accurate identification of chemical(s) involved can be difficult. Aids to identification are listed in Tables 14–2 and 14–3 . By law, identification placards must be used for the transportation and storage of hazardous chemicals. Shipping papers, Material Safety Data Sheets (MSDS), and inventory lists may be helpful. In some cases, recognizing a specific toxic syndrome can assist with chemical identification. A regional poison center can be extremely helpful in identifying chemical names from placards, chemical code numbers, or symptoms.

Table 14-2 -- Information Resources for Chemical Identification Container labels Placards/markings Department of Transportation (DOT) placard categories Explosive Flammable Oxidizer Poisonous Radioactive Corrosive National Fire Protection Association (NFPA) Classification System United Nations (UN) Hazard Class Numbers Bills of lading, shipping papers Material Safety Data Sheets Plant supervisors/company representatives/company chemists Fire department incident commander On-scene chemical detection Regional poison center/medical toxicologist Specific toxic syndromes Odors (see Table 14–3 )

Table 14-3 -- Odors Related to Chemical Identification

Odor Sharp, pungent Fishy Garlic or fishy Ammonia Aniline

Toxin

Arsine, phosphine Benzene Toluene

Sweet, ether-like

Xylene Ethylene oxide Methylene chloride Trichloroethylene

Pungent

Chlorine Formaldehyde

Sharp, choking Bitter almond Rotten egg Musty or fruity Irritating, sharp Garlic or solvent odor Sweet, acrid

Hydrochloric acid Chlorine Hydrogen cyanide Hydrogen sulfide Methyl bromide Nitrogen oxides Organophosphate pesticides Phenol

Musty or new-mown hay Phosgene Fruity and pungent Toluene diisocyanate

At the scene of an incident, a wide range of instruments and detection devices can be used to detect the presence and approximate concentrations of chemicals. However, a specific chemical detected on the scene may not be the cause of a patient’s problems. The observed symptoms and physical findings in exposed victims must be consistent with those expected from the identified toxin. Once the chemical is identified, specific chemical characteristics, toxic effects, and specific therapies can be found by using any of several resources ( Table 14–4 ). Additional information that will help with decision making can be found by answering the following questions.

Table 14-4 -- Information Resources for Health Risk Information * Material Safety Data Sheets Computer data bases

Poisindex/Tomes (Micromedex) Hazardous Substance Data Bank (HSDB) Chemical Hazard Response Information System (CHRIS) Toxicology Data Network (TOXNET) National Library of Medicine (Medline) Internet Connections (Examples) ATSDR Web Site: http://www.atsdr.cdc.gov/atsdrhome.html CDC Home Page: http://www.cdc.gov.ezproxy.med.nyu.edu/ EPA Home Page: http://www.epa.gov/ TOXIKON: Medical Toxicology Online: http://toxikon.er.uic.edu/ Vermont SIRI MSDS Collection: http://hazard.com/msds Reference Texts Agency for Toxic Substance and Disease Registry (U.S. Department of Health and Human Services). Managing Hazardous Materials Incidents, Volume 3. Medical Management Guidelines for Acute Chemical Exposures. 1994. Agency for Toxic Substance and Disease Registry. (U.S. Department of Health and Human Services.) Managing Hazardous Materials Incidents, Volume 2. Hospital Emergency Departments, 1991. Sullivan JB, Krieger GR: Hazardous Materials Toxicology: Clinical Principles of Environmental Health. Baltimore, Williams & Wilkins, 1992. Borack J, Callan M, Abbott W: Hazardous Materials Exposure: Emergency Response and Patient Care. Englewood Cliffs, NJ, Prentice-Hall, 1991 1996 North American Emergency Response Guidebook: A Guidebook for First Responders during the Initial Phase of a Hazardous Materials/Dangerous Goods Incident. Washington, DC, U.S. Department of Transportation, 1996. Klaassen CD: Casarett and Doull’s Toxicology: The Basic Science of Poisons. 5th ed. New York, McGraw-Hill, 1995. Rom WN: Environmental and Occupational Medicine. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1998. Agencies with Telephone Hotlines Regional poison centers County and state health departments Agency for Toxic Substances and Disease Registry (ATSDR) 1-404-639-0615 Chemical Transportation Emergency Center (CHEMTREC) 1-800-424-9300 (toll free in the United States and Canada) Environmental Protection Agency (EPA)—contact regional office Centers for Disease Control and Prevention (CDC) 1-404-639-2888

National Response Center and Terrorist Hotline 1-800-424-8802 Radiation Emergency Assistance Center/Training site (REAC/TS) 1-865-576-1005 (ask for REAC/TS) Other Industrial plant representative (chemist or toxicologist)
* Do not rely on a single reference source for information. Attempt to verify information from two additional reference sources. This is not an all-inclusive list of references but has been selected as a representative list for use in an emergency department. Most regional poison centers will have many of these references available.

Does this chemical pose a risk of secondary contamination? Primary contamination is the direct contact of a chemical on a patient. Secondary contamination occurs when chemical contamination is passed onto rescue personnel, health care workers, or equipment. Hazardous materials pose a risk of secondary contamination only if they are both toxic and likely to be carried on the skin, clothing, or hair of a patient in quantities large enough to harm staff[1] ( Table 14–5 ). In most cases, emergency treatment does not need to be delayed for special decontamination procedures if victims have been decontaminated at the scene or have been exposed to chemicals posing a low likelihood of secondary contamination.[1]

Table 14-5 -- Secondary Contamination Risks Materials that pose serious risk of secondary contamination Highly toxic liquids Highly toxic solids Highly toxic finely divided solids Vapors that condense to a liquid state on clothing and skin Ingested substances that can form toxic gases (off-gassing) Vomitus from ingested toxic substances Radioactive liquids and dusts Certain biologic agents Materials that pose little risk of secondary contamination Gases Vapors (unless condensed to liquid on clothing or skin) Substances with no serious toxicity Source: Adapted from Agency for Toxic Substances and Disease Registry (ATSDR, U.S. Department of Health and Human Services). Managing Hazardous Materials Incidents, Volume 3. Medical Management Guidelines for Acute Chemical Exposures. 1994. What is the dose?

The dose is the total amount of chemical absorbed by the patient during an exposure. A patient’s dose may be estimated from various information available from the patient, incident commander, emergency medical services (EMS) personnel, or chemical information. The dose of any substance depends mostly on the concentration of the chemical and the duration of the exposure. Other factors include the route of exposure, absorption characteristics of the chemical (e.g., lipid-soluble chemicals tend to be more readily absorbed by the skin) and the site of the exposure (e.g., enclosed space versus outdoors). Additionally, warning properties of some chemicals can be clues to the extent of exposure. A warning property is the concentration at which a chemical’s odor can be detected or irritant symptoms occur. However, some toxins have a detectable odor or cause irritant symptoms only after exposure to extremely high concentrations that may cause other serious toxic effects. For example, phosgene produces serious toxic effects at concentrations near the odor threshold. Hydrogen sulfide will cause olfactory nerve paralysis as air concentrations rise to lethal levels. It is important not to rely on detection of odors alone in order to estimate the potential exposure. What is the clinical significance of the estimated dose? Data from on-scene air measurements may be available to estimate the magnitude of the exposure. The Occupational Safety and Health Administration (OSHA) has developed guidelines for workplace exposures. Acute toxicity levels, such as immediately dangerous to life and health (IDLH) and short-term exposure limit (STEL), apply to occupational exposures and are less useful for acute environmental exposures.[5][80] Nevertheless, they can be used as estimates of a clinically significant dose ( Table 14–6 ).

Table 14-6 -- Terms Used to Estimate Exposure to Hazardous Materials PEL: Permissible exposure level (OSHA). An 8-hour time-weighted average (TWA) of chemical concentration in air that cannot be exceeded. Also known as the threshold limit value (TLV-TWA) by the American Congress of Governmental Industrial Hygienists (ACGIH). Ceiling limit: A chemical’s airborne concentration that can never be exceeded. IDLH: Immediately dangerous to life and health. A chemical’s concentration that poses immediate threat to life, or causes irreversible or delayed effects, or compromises ability to escape the environment. STEL: Short-term exposure level. A 15-minute TWA that should not be exceeded at any time during the work day. What are the anticipated toxic effects of the chemical? Table 14–4 illustrates the variety of available resources containing information on human toxic effects of chemicals and treatment. The reliability of hazard information varies among the many resources. For example, Material Safety Data Sheets (MSDS) are a good source for chemical identification, but information regarding human health effects is often incomplete or inaccurate.[10][32][37][40][48] Inert ingredients listed on the MSDS may actually be toxic to humans at certain levels, but they are inert when the products are used as intended. Regional poison centers and medical toxicologists are often the most reliable resources for upto-date human health risk information and specific treatment recommendations.[13][58] Despite published research, the human health risks of many chemicals remain uncertain. Potential toxic effects should be anticipated from those chemicals with little or no documented toxicity.

Is there a specific treatment or antidote? Early recognition of the need for specific therapies and antidotes allows time to accumulate amounts sufficient for the anticipated needs. In addition, it allows time to become familiar with special administration procedures and potential adverse effects. Are there delayed or long-term effects? Identifying those toxins with slow onset of toxic effects allows appropriate medical observation of exposed patients. Injury to the liver, kidney, or bone marrow may not be evident for several days. Serious effects such as dermal sensitization, asthma, cancer, or risks to unborn children are not a major concern in the acute phases of an emergency response, but appropriate follow-up must be assured. Far more uncertainty exists regarding long-term effects than risks from acute exposures. Additionally, community resources such as the local health department and primary health care providers should be utilized for follow-up and monitoring of long-term effects. Resource Management Resources are defined as the facilities, medical and specialized equipment, supplies, pharmaceuticals, and personnel required for management of a hazardous material incident. Facility Any facility, including a hospital receiving casualties, must have management plans and procedures in place prior to an incident. These plans must provide for the decontamination and care of contaminated patients while minimizing the risk of secondary contamination of staff and other patients. A confinement area for potentially contaminated patients (“hot zone”) should be established. This area should be clearly marked and contain decontamination and resuscitation equipment. Entry to and exit from this area should be carefully controlled, and it should be the only access into the hospital. Contaminated patients are taken to the “hot zone,” where decontamination and resuscitation procedures are performed. Also, anyone with suspected chemical exposure should be denied hospital entry and instead moved into this area for decontamination or verification of a nontoxic exposure. For many EDs, outside decontamination is the most practical option.[19] Inside the hospital, decontamination can occur in specially designed facilities equipped with separate ventilation systems that provide adequate air flow.[26] Ideally, “clean” patients from the hot zone are delivered to a patient treatment area. Staff in the hot zone should be limited in order to avoid unnecessary personnel exposure. Equipment, Supplies, and Antidotes Necessary specialized equipment and supplies are listed in Table 14–7 . In addition, standard resuscitation equipment and medical supplies should be available in the hot zone. Lifesaving procedures must be performed in this area until decontamination is complete. Use older or disposable equipment and supplies in the hot zone, because they are likely to be contaminated. Antidotes and other needed pharmaceuticals may not be available in sufficient quantities in the ED.[21][82] For example, a large number of organophosphatepoisoned patients will quickly deplete the atropine and pralidoxime stores of most hospitals.[21][82] Once the toxic chemical has been identified or a specific toxic syndrome recognized, appropriate amounts of the

antidotes can be acquired. The hospital pharmacy or a regional poison center can assist in locating antidotes at other hospitals or local pharmaceutical warehouses.

Table 14-7 -- Recommended Equipment and Supplies Stretcher with plastic tub or foldable rubber tubs for top of stretcher (several manufacturers) Warm water source Hose with shower head Mild soap Soft-bristled brushes Plastic garbage bags Wading pool for containing water run-off Clean dry clothing for decontaminated patients Privacy barrier Disposable medical equipment and supplies Portable suction with disposable collection bags Oxygen source Optional decontamination equipment Portable outdoor showers Dedicated decontamination rooms with separate ventilation and method of containing water run-off Personnel protective equipment (PPE) Chemical-resistant clothing Chemical-resistant suits (e.g., Tyvek or Saranex) with built-in hood and boots Rubber aprons Chemical-resistant gloves (e.g., butyl rubber) taped at the sleeve Splash-protective eyewear Respiratory protection (requires specific training, fit testing, and record keeping) Self-contained breathing apparatus Supplied air respirators Air-purifying respirators Personnel All personnel involved in the care of Haz-Mat victims must avoid self-contamination.[68] Personnel directly working with victims must put on adequate protective equipment prior to caring for patients; the level of protection must be adequate for the toxicity of the chemical(s). Training in the use of specialized personal

protective equipment is essential, because improper use may result in injury.[3] Contaminating vapors or fumes may harm hospital staff, especially if respiratory protective equipment is not worn and the work area is not ventilated to the outside. Surgical masks do not protect from toxic gases, vapors, or fumes. Patients with noticeable chemical odors or exposure to chemicals with the potential to release toxic vapors or fumes should remain outside the ED until properly decontaminated. The absence of an odor does not reliably exclude a toxic chemical, because some highly toxic chemicals are odorless. Recommended protective equipment for decontamination and resuscitation team members is listed in Table 14–7 .[3][15] No consensus exists for the minimal level of protection required for hospital decontamination, especially with regard to respiratory protection. Selecting the appropriate protective equipment depends on the specific toxin identified. For example, a patient contaminated with a strong corrosive such as hydrofluoric acid should be handled with splash-protective equipment, including chemical-resistant clothing, gloves, and eye protection. In addition, ED personnel require full respiratory protection when caring for a patient contaminated with a highly toxic chemical that continues to produce fumes or vapors, such as sodium azide. Resource Management for Mass Casualty Incidents A disaster is defined as a situation that overwhelms available resources. Management of equipment, supplies, personnel, and specific antidotes is necessary to maximize good outcomes for the greatest number of potential survivors. The hospital’s mass casualty incident coordinator must assess available resources and forecast future needs. Maintaining specialized supplies may be a problem. For example, the decontamination procedure requires special supplies that are not stockpiled in most emergency departments. Security officers are essential to secure a perimeter and control access to the hot zone and other hospital entrances. A single hospital entrance for patients must be established to prevent contamination of areas outside the hot zone. Traffic control around the hospital may be problematic because of the use of outside areas to hold patients prior to decontamination. Others, such as reporters, volunteers, and family, must be kept out of the hot zone. Patient Management Chemically contaminated patients require special handling and treatment. Emergency care providers must first protect their personal safety and create a safe environment prior to patient assessment or even lifesaving interventions. Visualizing the contaminated patient as someone engulfed in flames may help. Extinguishing the “flames” terminates further injury to the patient but, just as important, protects emergency care providers from getting burned. Triage Triage is the sorting of patients, based on the likelihood of survival given the resources available.[38][76] The duty to one person is abandoned in favor of saving many.[23][53][76] The initial triage decision focuses on treating life-threatening problems in potentially salvageable patients while assessing the urgency for decontamination. Assessment of vital signs may be unreliable because of impaired vision and dexterity of

staff in full protective gear.[39] Doing the best for the most may require using resources to decontaminate less seriously ill patients (even asymptomatic patients) over those more critically ill. Decontamination at the scene decreases the likelihood of “load and go” transport. In turn, this may result in delayed transport of critically ill patients. Conversely, improperly trained prehospital care providers or an overwhelmed EMS system may transport patients prematurely to the hospital prior to adequate decontamination, thus risking secondary contamination of personnel.[47] Patients may also arrive by private vehicle, with no prior decontamination performed.[60] A mechanism for triaging those patients must be in place. Decontamination The objectives of decontamination are to prevent spread of contamination and to terminate the patient’s toxin exposure. Data regarding decontamination are limited, but fundamental principles can be found in military chemical battlefield studies and radiation accident protocols.[46][62][68] Decontamination should occur as close to the site of exposure as possible to limit the spread of toxic agents and to decrease the time to initial treatment.[16] In a Haz-Mat incident, decontamination is best performed in the prehospital setting. The need and urgency for decontamination procedures are determined by chemical toxicity and the potential for secondary contamination, with urgency further influenced by patient condition ( Fig. 14–1 ). An asymptomatic patient exposed to a highly toxic chemical needs decontamination before any medical treatment, while decontamination procedures must occur simultaneously with lifesaving treatment for a critically ill patient. Contaminated patients may bypass the EMS system and walk into the ED. Therefore, hospitals should be prepared to decontaminate patients arriving by transport independent of the EMS system.

Figure 14-1 Determining the need for decontamination.

Toxic chemicals cause injury when inhaled or absorbed through the skin, open wounds, or mucous membranes. Airborne toxins account for most exposures in Haz-Mat incidents, and removal from the source may be sufficient to prevent further exposure.[77] However, toxic fumes may contain aerosolized chemicals or vapors that can condense on skin or clothing.[28] Continued chemical contact with the skin may worsen toxicity through direct skin injury or systemic absorption. Some toxins, such as caustics and solvents, directly damage the structural integrity of the skin, yet other toxins (e.g., pesticides, hydrogen fluoride, and methemoglobin inducers) penetrate tissues, enter the circulation, and cause systemic toxic effects.[36][57][70][74] Skin irritation, burns, or deposits of liquid and solid materials on skin and clothing are clues to the presence of hazardous materials requiring decontamination. Copious water irrigation within minutes of exposure, and definitely within the first hour, following a chemical burn is crucial in reducing direct corrosive effects (incidence of full thickness burns) and systemic toxic effects.[20][29][33][44][54] Using a universal substances decontamination protocol that is not specific for any chemical will reduce confusion and avoid delays.[19][43] Basic principles for decontamination of radiation exposures can be adapted for chemical decontamination [43][46]( Table 14–8 ). Contaminated clothing is a source of primary and secondary contamination, can enhance toxin absorption by acting as an occlusive dressing, and should be removed expeditiously.[79] Copious water irrigation will dilute a chemical and decrease its duration of contact with a patient’s skin. Occasionally detergents, dilute bleach, corn meal, or specific neutralizing agents may

be recommended, but water irrigation should never be delayed to search for these additional agents. Avoid hot water, strong detergents, vigorous scrubbing, or stiff brushes; skin abrasion or vasodilation may enhance toxin absorption. Associated ocular injuries are common with chemical burns, and eye irrigation may be needed.[11][56][65]

Table 14-8 -- Decontamination Procedures Establish hot zone Set up decontamination equipment Put on personal protective equipment Remove all of patient’s clothing Handle clothing as hazardous waste (Place in plastic bag) Immediately remove any obvious contamination Wash or wipe away liquid material Brush away solid or particulate material Prioritize decontamination 1. Obvious contamination sites 2. Contaminated wounds 3. Eyes (remove contact lenses) 4. Mucous membranes 5. Skin 6. Hair Use copious low-pressure water irrigation Do not delay water irrigation searching for specialized decontamination solutions or neutralizing agents Use mild soap Gentle washing Contain water run-off * Decontaminate all equipment and personnel prior to leaving hot zone
* Containment may be unnecessary because concentrations of chemicals in water run-off from a contaminated patient arriving at the hospital are relatively low compared to primary spills. Most cases do not require special containment (exceptions include elemental mercury and radioisotopes) but should be contained when in doubt. Local regulations should be understood before deciding not to contain water run-off.

Unfortunately, the effectiveness of decontamination must be judged without the benefit of objective criteria. Studies suggest that copious water irrigation and soap cleansing are highly effective in removing many chemical contaminants.[11][12][33][43][45][79] The skin’s stratum corneum is the protective barrier against penetration of many chemicals. Soap and water cleansing may mechanically remove the upper layers of the stratum corneum where many chemicals are deposited.[78] Unfortunately, toxins with high lipid solubility, such as pesticides, can penetrate the skin rapidly and may be incompletely removed by washing.[27][29][79] In

these cases, delayed systemic effects can occur despite decontamination. Immediate Stabilization After decontamination, treatment of victims exposed to hazardous materials primarily involves symptomatic and supportive care. In many cases, decontamination can occur simultaneously with lifesaving interventions. A rapid primary and secondary survey of the patient will guide therapeutic decisions. Early endotracheal intubation is recommended in the presence of upper airway edema, central nervous system depression, hypoxia, hypoventilation, or excessive bronchial secretions. Administering supplemental oxygen is important because many hazardous materials can produce hypoxia. Hypotension should be treated initially and cautiously with crystalloid fluids, because many toxins have the potential to cause the adult respiratory distress syndrome. Vasopressors and inotropes may be required after the intravascular volume status has been optimized. A secondary survey should identify systemic toxic effects, coexisting trauma, or other medical illnesses. Obtaining past medical history may be helpful because toxic effects may be exaggerated by underlying medical conditions or exacerbation of pre-existing illnesses, such as asthma or cardiac disease. Identifying a toxic syndrome can guide subsequent medical therapy or antidote administration, even if the specific toxin is unknown. Specific antidotes exist for a limited number of chemical exposures. Table 14–9 lists those antidotes most often needed.

Table 14-9 -- Examples of Antidotes for Hazardous Material Exposures Antidote Toxin Cyanide antidote kit Oxygen/hyperbaric oxygen Methylene blue Atropine/pralidoxime Calcium Cyanide Carbon monoxide Methemoglobin inducers Organophosphates/carbamates Hydrofluoric acid

Chelators (BAL, DMSA, EDTA) Metals (lead, mercury, arsenic)

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MEDICAL PROBLEMS ENCOUNTERED WITH CHEMICAL CONTAMINATION
Patients from Haz-Mat incidents can present with (1) contamination without apparent injury, (2) associated trauma, (3) chemical burns, (4) irritant gas symptoms, (5) a variety of systemic toxic syndromes, or (6) psychological harm ( Table 14–10 ).

Table 14-10 -- Hazardous Material Toxic Syndromes Toxic Syndrome Chemical burns Common Signs and Symptoms Painful, burning skin Examples Acid or alkaline corrosives, hydrofluoric acid, phenol, hydrocarbon solvents such as degreasers or defatters

Mucous membrane irritation Systemic toxic effects Mucous membrane irritation Irritant gas syndrome Coughing, dyspnea Acute bronchospasm Pulmonary edema, noncardiogenic Mucous membrane irritation Acute solvent syndrome Headache, lightheadedness, dizziness, nausea Chest tightness, dyspnea, lethargy, confusion, coma, dysrhythmias Cyanosis unresponsive to oxygen therapy Methemoglobinemia Headache, lightheadedness, dizziness, nausea, chest tightness, dyspnea, dysrhythmias Pinpoint pupils and eye pain Dyspnea, chest tightness, acute bronchospasm, pulmonary edema Nerve agents: sarin, soman, tabun, VX, organophosphate, carbamate insecticides Aniline, nitrogen oxides, amyl nitrite, chlorates, dinitrophenol Xylene, toluene, benzene, isocyanates, methyl bromide, methylene chloride Aliphatic hydrocarbons Ammonia, chlorine, isocyanates, acrolein, sulfur dioxide, hydrogen chloride

Acetylcholinesterase

Toxic Syndrome Acetylcholinesterase poisoning

Common Signs and Symptoms Headache, lightheadedness, muscle weakness, coma, seizures Tachycardia or bradycardia, diaphoresis, salivation, lacrimation, vomiting, diarrhea, abdominal cramps Early or low-level exposure: nausea, vomiting, headache, dizziness Coma, seizures, syncope

Examples

Cyanide, hydrogen sulfide, azides, phosphine, carbon monoxide

Metabolic poisoning

Cardiac dysrhythmias, hypotension Metabolic acidosis “Knocked down”—cardiac arrest Pulmonary edema, noncardiogenic Arsine, chlorine, ethylene oxide, methyl bromide, nitrogen oxides, phosgene, phosphine Carbon tetrachloride, 2-nitropropane Cadmium

Delayed toxic effects

Hepatic injury Renal injury Hemolysis (arsine)

Psychogenic illness

Headache, faintness, dizziness, nausea, chest Often indistinguishable from many tightness, weakness, extremity numbness, dyspnea or hyperventilation, mucous serious toxic exposures membrane irritation

Contamination Without Apparent Injury Frequently, patients exposed to toxic chemicals will have no medical problems, and decontamination is the only treatment necessary. Most often, no further risk of harm is present. However, some toxins, such as pesticides, have the potential to reach the systemic circulation or cause delayed onset of toxicity despite adequate decontamination. With such exposures, a prolonged period of observation is necessary even if the patient appears relatively asymptomatic at the time of evaluation. Associated Trauma Haz-Mat accidents are frequently associated with fire, explosion, structural collapse, or transportation accidents, and the likelihood of associated trauma is high. Traumatic injuries may be so apparent and seem so urgent that appropriate precautions are not taken for the concomitant chemical contamination. In addition, toxic effects may be overlooked. Conversely, the treatment team may focus on chemical contamination problems at the expense of recognizing traumatic injuries. Bandages, trauma dressings, splints, and cervical immobilization devices applied in the field may be sources of secondary contamination. Open wounds are especially problematic. They can absorb a chemical directly into the systemic circulation and thus deserve priority in the decontamination process.

Chemical Burns Chemicals harm skin by producing an inflammatory reaction, necrosis, or desiccation. Corrosives such as hydrochloric acid or sodium hydroxide cause coagulation or liquefaction necrosis. Hydrocarbons act as defatting agents to the skin, and vesicants such as mustard agents damage cellular DNA. After removing chemicals from the skin by copious water irrigation, most burns are treated similarly to thermal burns. Few antidotes or specific therapies are required for toxins causing chemical burns. Complications of chemical burns result from the loss of the skin’s protective barrier. This lost barrier allows chemical absorption into the systemic circulation, intravascular fluid losses, and microorganism invasion. Systemic toxic effects after dermal absorption include metabolic, electrolyte, hepatic, renal, or hematologic abnormalities. For example, hydrofluoric acid burns can be associated with profound hypocalcemia and rapid hemodynamic compromise.[74] Inhalation Injury Acute pulmonary injury can occur along any part of the respiratory tract. Toxins induce inflammatory and irritant reactions that cause mucosal edema. The loose tissue of the upper airway is vulnerable to massive edema. For example, edema from corrosive injury due to ammonia can occlude the upper airway. In addition to edema, cellular debris, secretions, and bronchospasm cause bronchiolar obstruction. Ventilation may be difficult owing to intense toxin-induced bronchoconstriction and should be treated with ß-adrenergic agonist bronchodilators and frequent suctioning. Inhalants with low water solubility have poor warning properties that allow significant concentrations to reach the alveoli. Phosgene and nitrogen oxides are examples of inhalants that produce delayed onset of pulmonary edema. Lifesaving treatment must focus on a patent airway and adequate ventilation. Early endotracheal intubation is crucial in the critically ill patient. Succinylcholine for rapid sequence intubation should be used cautiously in patients poisoned with acetylcholinesterase inhibitors because neuromuscular blockade can be prolonged. In these cases a short-acting, nondepolarizing neuroparalytic such as vecuronium may be preferable. Parenchymal injury is best managed with oxygen, positive end-expiratory pressure, and avoidance of overhydration. Insufficient data exist to support a beneficial effect of glucocorticosteroids on either upper airway or alveolar injury. Their use may increase the risk of bacterial pneumonia, and they should not be used in this setting.[55] Systemic Effects Many organ systems are vulnerable to the systemic effects of toxins. Serious central nervous system effects such as seizures, delirium, or coma can occur. The comatose patient often requires only supportive care, but for the actively seizing patient, benzodiazepines should be titrated to seizure termination. Less serious complaints of headache, dizziness, nausea, and vomiting are common manifestations of many poisons. Several toxins such as cyanide, acrylonitriles and hydrogen sulfide interfere with cellular use of oxygen and produce metabolic acidosis. Hemolysis from arsine gas and methemoglobinemia from aniline and nitrites are examples of toxins affecting the hematologic system. Delayed effects such as hepatic injury, acute renal failure, aplastic anemia, or cancer may ultimately develop. Systemic manifestations of acetylcholinesterase inhibitors such as pesticides and nerve agents are probably most important to recognize. Identifying the signs and symptoms of excess acetylcholine will make the diagnosis, alert the need for rescuer protection

and guide antidote therapy. Psychologic Harm When there has been a large chemical accident, television coverage may show dramatic images of black billowing clouds of smoke, firefighters dressed in “moonsuits,” and neighborhood evacuations. Along with the drama, facts about the incident are often conflicting or unknown. These images and information problems may provoke anxiety and fear among emergency responders, victims, nearby residents, and even the entire community. The public is aware of the dangers of toxic chemicals and may perceive exposures to even small amounts of chemicals as harmful. The public’s opinion of risk is often based on trust and fear rather than the critical analysis of scientific evidence. [72] Acute anxiety reactions and the syndrome of mass psychogenic illness are common in chemical accidents. [9][34][67] In the attempt to “do the best for the most,” health care workers must learn to respond to these reactions. Psychogenic-induced symptoms seem very real to the victims and may mimic those produced by a toxic exposure. Headaches, faintness, dizziness, nausea, chest tightness, difficulty in breathing (hyperventilation), irritation of the eyes, nose, or throat, weakness and extremity numbness are the most frequent complaints.[9] Differentiating true toxicity from a powerful emotional reaction can be extremely difficult. A large number of people with emotional reactions can overwhelm the entire emergency response system and hinder timely treatment of those with true toxic emergencies. Patients must be triaged as toxic emergencies whenever symptoms are indistinguishable from true toxic effects. The psychological syndrome is most effectively treated when it is rapidly recognized. Disbanding a group of patients can diminish symptoms that are exacerbated by the sight and sound of other victims. To alleviate fears, emphasize the certainties of the incident but never downplay or minimize the patient’s concerns. Informing the media and public about an incident is important. A credible spokesperson should provide timely information to the public during an emergency to minimize emotional responses that can occur if insufficient information is given. [8][63][72] Accurate and timely information will prevent rumors and can alleviate many fears associated with a toxic exposure.[71] Special Risks to Rescue Personnel Recent data indicate that first responders account for many of the victims from Haz-Mat incidents.[35] Depending on ambient temperature and the physical condition of the rescuer, life-threatening heat illness can develop quickly when personnel are in fully encapsulated protective equipment.[17][41] Traumatic injuries may occur during rescue operations. Accidental disruption of the protective suit or respirator malfunction may lead to serious contamination. Psychologic stress may play a role in rescuer illnesses.[30][69][71] Aftermath All patients need a definitive disposition. Those discharged from the hospital need specific reasons to return for re-evaluation and instructions on expected continued effects, potential long-term effects, and the need for

medical follow-up. Many companies have prearranged follow-up for workplace accidents. ED clean-up involves disposal of contaminated clothing, equipment, supplies, and water run-off. An industrial hygienist or an agency such as the health department should certify the entire facility, especially the hot zone area, as ready to resume normal operations. Prior contractual arrangements with hazardous waste disposal companies and appropriate agencies will speed these processes. Additionally, all involved prehospital and hospital personnel should attend a critical incident stress debriefing that also addresses concerns about health risks from exposure.[8][24][25][73] The debriefing should review lessons learned from the incident and suggestions for revising the response plan. Community concerns must be addressed. Questions will arise about contamination of air, soil, food, pets, livestock, and drinking water. If unanswered, these questions may influence the number of patients seeking medical attention hours to days following an incident. In addition, community critical incident stress debriefing is crucial because post-traumatic stress disorder is prevalent following all types of disasters.[14][69][71] The health department, regional poison center and Environmental Protection Agency can assist in dealing with many of these concerns.

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DEVELOPING THE HAZ-MAT RESPONSE PLAN
Recommendations The plan should be as simple as possible.[7] Table 14–11 lists issues to address in a response plan.[6] The task of providing the best care for patients should be reconciled with the burdens of complying with regulations. The objective is to develop a workable plan with the intent to use it.[22] Define the roles and priorities and outline the most important tasks within the hospital. Determine resources needed and resources already available. Departments must solve problems together, in advance, during nonurgent conditions. A spirit of cooperation and trust, along with a clear mission, will lead to more effective decision making under urgent conditions.

Table 14-11 -- A Guide to Haz-Mat Preplanning in the Emergency Department Initial Notification How is hospital notified of transport of chemically contaminated patients? Who notifies hospital? What information is given to hospital regarding chemically contaminated patient? Is there a process for verification of the notification? The Plan Where is the written plan stored? Is there a specific hazardous material plan? Is there a specific plan for radiation contamination? Is there a separate mass casualty plan? Who is authorized to implement the plan? Are there specific criteria for activating the plan? Does the plan include a call list for notification? Does the plan include a list of information resources? Safety Issue Does the hospital have evacuation contingency plans? Leadership Does the plan: Define who is in charge of the incident? Define the chain of command for reporting and decision making? Information Management

Does the plan: Assign a person to be responsible for obtaining additional information regarding the alleged toxin, expected number of patients? Assign a person to be responsible for obtaining information (toxic effects, specific treatments and antidotes, long-term health effects) about alleged chemical exposure? Assign a person to list all patients and track them through the hospital? Assign a person responsible for media and public information? Resource Management Equipment Where is the equipment stored? Is a person assigned to maintain equipment on a routine basis? Does the stored equipment include: Decontamination equipment and supplies Tape barricades Soap Soft brushes Shower nozzle Containment vessels for water run-off Containment vessels for contaminated clothing Personnel Does the plan define specific staff duties? Does the plan assign a person to assess health of staff involved in incident? Does the plan assign a person to assess the health of ambulance crews transporting patients? Is personnel protective equipment available? Patient Management Is there an assigned person to oversee patient flow? Routine ED patients Asymptomatic walk-in patients with contamination Transfer of decontaminated patients into patient care areas Transfer of patients to wards, ICU, hyperbaric oxygen Transfer of patients to specialized care facilities (burn center, trauma center, pediatric ICU, hyperbaric facility) Is there an assigned person to perform follow-up evaluations on patients? How is documentation handled? Does the plan have a designated area for potentially contaminated dead victims?

Does the plan have a mechanism for removing the contaminated dead? Do patients have specific follow-up instructions? Do patients need a follow-up appointment? Wrap-Up Does the plan have specific criteria for “all clear”? Are all staff decontaminated prior to leaving the hot zone? Are there provisions for debriefing the staff? Potential long-term health risks Critical incident stress debriefing Is there an industrial hygienist to determine that the facility (specifically the hot zone) is safe for use? Is there a prearranged agency for facility clean-up? Is there a prearranged agency to dispose of containment vessels with water run-off and contaminated clothing and supplies? Is there provision for critiquing the plan? Is there a mechanism for feedback to all participants? Is there a provision for revising the plan?

Information resources must be part of the plan because misinformation is a major pitfall in all Haz-Mat incidents.[7] A regional poison center should be effectively integrated into the response plan as an information management resource.[13][40][58][64][75] The poison center can assist in chemical identification and provide information on the number of patients, toxicity data, and specific decontamination and treatment recommendations to the scene and to local hospitals. Additionally, the poison center can provide toxicologic information to the media and public to ensure accurate information regarding the toxicity of chemicals. After the incident, the poison center can assist public health agencies in long-term care and follow-up of patients.[40][81] An effective plan must undergo continual quality improvement by periodic practice, unscheduled testing, and revision.[3][50] Detailed guidelines for prehospital and ED planning can be found in several publications.[3][4][6][42][45][61] Pitfalls Inertia is the biggest obstacle to having a workable Haz-Mat plan in an emergency department. Other obstacles include some common misconceptions:

1. 2.

Misconception: It will never happen here. At many hospitals, enthusiasm for planning is generated only following an accident in the community.[7] Unfortunately, even this interest quickly dissipates. Misconception: We already have a disaster plan. The typical hospital “disaster” plan is a document intended to meet certification requirements. Often the plan is written for a plane crash, but planners assume it is adaptable to any situation, ranging from a chemical exposure to a tornado. Misconception: The plan must be complex in order to be safe and compliant. Recommendations for Haz-Mat planning are frequently too complex. Some authorities recommend elaborate equipment, complicated protocols, and the highest level of personal protective equipment for every situation. These recommendations derive from military battlefield principles, fire services protocols, hazardous waste site protocols, and governmental regulations for hazardous chemicals. In reality, the hospital deals with low levels of contamination compared to those encountered at the site of the spill.[66] Chemical residue on clothing poses the greatest contamination risk for hospitals, and this risk is significantly decreased once the clothing is removed. Therefore, clothing removal and a thorough shower will suffice for most. Rarely will high-level personal protective equipment, multistep decontamination procedures, and containment of water run-off be necessary. A complex response is costly, time-consuming (both for training and patient care), and usually unnecessary. Keeping the plan simple and flexible will facilitate appropriate hospital response.

3.

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REFERENCES
1. Abrams J, El-Mallakh RS, Meyer R: Suicidal sodium azide ingestion. Ann Emerg Med 1987; 16:1378. 3. Agency for Toxic Substances and Disease Registry : Managing Hazardous Materials Incidents. Washington, D.C., U.S. Department of Health and Human Services, 1991. 4. Aghababian RV: Hospital disaster planning. Top Emerg Med 1986; 7:46. 5. Alexeeff GV, Lipsett MJ, Kizer KW: Problems associated with the use of immediately dangerous to life and health (IDLH) values for estimating the hazard of accidental chemical releases. Am Ind Hyg Assoc J 1989; 50:598. 6. Auf der Heide E: Community medical disaster planning and evaluation guide, Dallas, American College of Emergency Physicians, 1995. 7. Auf der Heide E: Disaster planning, part II: Disaster problems, issues, and challenges identified in the research literature. Emerg Med Clin North Am 1996; 14:453. 8. Bertazzi PA: Industrial disasters and epidemiology. Scand J Work Environ Health 1989; 15:85. 9. Boxer PA: Occupational mass psychogenic illness. J Occup Med 1985; 27:867. 10. Bresnitz EA, Rest KM, Miller N: Clinical industrial toxicology: An approach to information retrieval. Ann Intern Med 1985; 103:967. 11. Bromberg BE: Hydrotherapy of chemical burns. Plast Reconstr Surg 1965; 35:85. 12. Bunner BL, Wannemacher RW, Broski FH: Cutaneous absorption and decontamination of (3H)T-2 toxin in the rat model. J Toxicol Environ Health 1989; 26:413. 13. Burgess JL, Keifer MC, Barnhart S, et al: Hazardous materials exposure information service: Development, analysis, and medical implications. Ann Emerg Med 1997; 29:248. 14. Burkle FM: Acute-phase mental health consequences of disasters: Implications for triage and emergency medical services. Ann Emerg Med 1996; 28:119. 15. California Emergency Medical Services Authority, Toxics Epidemiology Program: Hazardous materials medical management protocols. California Emergency Medical Services and the Toxics Epidemiology Program, Los Angeles County Department of Health Services, 1989. 16. Cancio LC: Chemical casualty decontamination by medical platoons in the 82nd Airborne Division. Milit Med 1993; 158:1. 17. Carter BJ, Cammermeyer M: Emergence of real casualties during simulated chemical warfare training under high heat conditions. Milit Med 1985; 150:657. 18. Charan NB, Lakshminarayan S, Meyers G, et al: Effects of accidental chlorine inhalation on pulmonary

function. West J Med 1985; 143:333. 19. Cox RD: Decontamination and management of hazardous materials exposure victims in the emergency department. Ann Emerg Med 1994; 23:761. 20. Curreri PW, Asch MJ, Pruitt BA: The treatment of chemical burns: Specialized diagnostic, therapeutic, and prognostic considerations. J Trauma 1970; 10:634. 21. Dart RC, Stark Y, Fulton B, et al: Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA 1996; 276:1508. 22. DeAtley C: Hazardous materials exposure mandates integrated patient care. Occup Health Saf 1991; March 40. 23. Doyle CJ: Mass casualty incident: Integration with prehospital care. EMS/Prehosp Care 1990; 8:163. 24. Durham TW, McCammon SL, Allison EJ: The psychological impact of disaster on rescue personnel. Ann Emerg Med 1985; 14:664. 25. Edwards JG: Psychiatric aspects of civilian disasters. Br Med J 1976; 1:944. 26. El Sanadi N, Grove C, Takacs M, et al: A hospital-based, hazardous materials decontamination and treatment unit: Utilization patterns over a nine-month period. Prehosp Disaster Med 1993; 8:337. 27. Feldman RJ, Maibach HI: Percutaneous penetration of some pesticides and herbicides in man. Toxicol Appl Pharmacol 1974; 28:126. 28. Fiserova-Bergerova V, Pierce JT, Droz PO: Dermal absorption potential of industrial chemicals: Criteria for skin notation. Am J Ind Med 1990; 17:617. 29. Fredriksson T: Percutaneous absorption of parathion and paraoxon: IV. Decontamination of human skin from parathion. Arch Environ Health 1961; 3:185. 30. Fullerton CS, Ursano RJ: Behavioral and psychological responses to chemical and biological warfare. Milit Med 1990; 155:54. 31. Gough AR, Markus K: Hazardous materials protections in ED practice: Laws and logistics. J Emerg Nurs 1989; 15:477. 32. Greenberg MI, Cone DC, Roberts JR: Material Safety Data Sheet: A useful resource for the emergency physician. Ann Emerg Med 1996; 27:347. 33. Gruber RP, Laub DR, Vistnes LM: The effect of hydrotherapy on the clinical course and pH of experimental cutaneous chemical burns. Plast Reconstr Surg 1975; 55:200. 34. Hall EM, Johnson JV: A case study of stress and mass psychogenic illness in industrial workers. J Occup Med 1989; 31:243. 35. Hall HI, Haugh GS, Price-Green PA, et al: Risk factors for hazardous substance releases that result in injuries and evacuations: Data from 9 states. Am J Public Health 1996; 86:855. 36. Harris JC, Rumack BH, Peterson RG: Methemoglobinemia resulting from absorption of nitrates.

JAMA 1979; 242:2869. 37. Himmelstein JS, Frumkin H: The right to know about toxic exposures: Implications for physicians. N Engl J Med 1985; 312:687. 38. Hodson PB: Assessment of casualties in a chemical environment. JR Army Med Corps 1985; 131:116. 39. King JM, Frelin AJ: Impact of the chemical protective ensemble on the performance of basic medical tasks. Milit Med 1984; 149:196. 40. Koehler GA, Van Ness C: The emergency medical response to the Cantara hazardous materials incident. Prehosp Disaster Med 1993; 8:359. 41. Kolka MA, Cadarette BS: Heat exchange after cholinolytic and oxime therapy in protective clothing. Milit Med 1990; 155:390. 42. Lanese TR, Slattery J: Preparing for a hazardous materials incident. Firehouse 1991; 12:74. 43. Lavoie FW, Coomes T, Cisek JE, et al: Emergency department external decontamination for hazardous chemical exposure. Vet Hum Toxicol 1992; 34:61. 44. Leonard LG, Scheulen JJ, Munster AM: Chemical burns: Effect of prompt first aid. J Trauma 1993; 22:420. 45. Leonard RB: Community planning for hazardous materials disasters. Top Emerg Med 1986; 7:55. 46. Leonard RB, Ricks RC: Emergency department radiation accident protocol. Ann Emerg Med 1980; 9:462. 47. Leonard RB, Teitelman U: Manmade Disasters. Crit Care Clin 1991; 7:293. 48. Lerman SE, Kipen HM: Material Safety Data Sheets: Caveat emptor. Arch Intern Med 1990; 150:981. 49. Lorin HG, Kulling PE: The Bhopal tragedy—What has Swedish disaster medicine planning learned from it?. J Emerg Med 1986; 4:311. 50. Merchant JA: Preparing for disaster. Am J Public Health 1986; 76:233. 51. Merrit NL, Anderson MJ: Malathion overdose: When one patient creates a department hazard. J Emerg Nurs 1989; 15:463. 52. Misra NP, Pathak R, Gaur JJBS, et al: Clinical profile of gas leak victims in acute phase after Bhopal episode. Indian J. Med Res 1987; 86(suppl):11. 53. Mitchell GW: The triage process. Top Emerg Med 1986; 7:34. 54. Moran KD, O’Reilly T, Munster AM: Chemical burns: A ten-year experience. Am Surg 1987; 11:652. 55. Moylan JA, Chan C: Inhalation injury—An increasing problem. Ann Surg 1977; 188:34. 56. Mozingo DW, Smith AA, McManus WF, et al: Chemical burns. J Trauma 1988; 28:642.

57. Mullett T, Zoeller T, Bingham MD, et al: Fatal hydrofluoric acid cutaneous exposure with refractory ventricular fibrillation. J Burn Care Rehabil 1987; 8:216. 58. Nantel AJ: The role of the clinical toxicologist in chemical and environmental accidents. Clin Toxicol 1995; 33:603. 59. Ohbu S, Yamashina A, Takasu N, et al: Sarin poisoning on Tokyo subway. South Med J 1997; 90:587. 60. Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996; 28:129. 61. Plante DM, Walker JS: EMS Response at a hazardous material incident: Some basic guidelines. J Emerg Med 1989; 7:55. 62. Saenger EL: Radiation accidents. Ann Emerg Med 1986; 15:1061. 63. Sandman P: Explaining environmental risks—Some notes on environmental risks communication. U.S. Environmental Protection Agency, 1986; Nov. 64. Savelkousl TJF, Leenhouts HP, Sangster B: The role of poison control centers in radiation accidents. Clin Toxicol 1989; 27:305. 65. Sawhney CP, Kaushish R: Acid and alkali burns: considerations in management. Burns 1989; 15:132. 66. Schultz M, Cisek J, Wabeke R: Simulated exposure of hospital personnel to solvent vapors and respirable dust during decontamination of chemically exposed patients. Ann Emerg Med 1995; 26:324. 67. Selden BS: Adolescent epidemic hysteria presenting as a mass casualty, toxic exposure incident. Ann Emerg Med 1989; 18:892. 68. Sidell FR: What to do in case of an unthinkable chemical warfare attack or accident. Postgrad Med 1990; 88:70. 69. Silverman JJ, Hart RP, Garrettson LK, et al: Posttraumatic stress disorder from pentaborane intoxication. JAMA 1985; 254:2603. 70. Simpson LA, Cruse CW: Gasoline immersion injury. Plast Reconstr Surg 1981; 67:54. 71. Singer TJ: An introduction to disaster: Some considerations of a psychological nature. Aviat Space Environ Med 1982; 53:245. 72. Slovic P: Perception of risk. Science 1987; 236:280. 73. Summers GM, Cowan ML: Mental health issues related to the development of a National Disaster Response System. Milit Med 1991; 156:30. 74. Tepperman PB: Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn. J Occup Med 1980; 22:691. 75. Vicas IM: Poison center participation in a municipal chemical disaster exercise (abstract). Prehospital and Disaster Medicine 1993; 8:S98.

76. Waeckerle JF: Disaster planning and response. N Engl J Med 1991; 324:815. 77. Walter FG, Dedolph R, Kallsen GW, et al: Hazardous materials incidents: A one-year retrospective review in central California. Prehosp Disaster Med 1992; 7:151. 78. Weber LW, Zesch A, Rozman K: Decontamination of human skin exposed to 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in vitro. Arch Environ Health 1992; 47:302. 79. Wester RC, Maibach HI: In vivo percutaneous absorption and decontamination of pesticides in humans. J Toxicol Environ Health 1985; 16:25. 80. Wiener RK, Shaver DK: The applications of toxicologic parameters in emergency response planning. Toxicol Lett 1989; 49:361. 81. Wing JS, Sanderson LM, Brender JD, et al: Acute health effects in a community after a release of hydrofluoric acid. Arch Environ Health 1991; 46:155. 82. Woolf AD, Chrisanthus K: On-site availability of selected antidotes: Results of a survey of Massachusetts hospitals. Am J Emerg Med 1997; 15:62.

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Uncited reference Agency for Toxic Substances and Disease Registry : Managing Hazardous Materials Incidents. Washington, D.C., U.S. Department of Health and Human Services, 1994.

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Chapter 15 – Drug Testing in the Workplace
SCOTT D. PHILLIPS Substance abuse costs the citizens of the United States in excess of $200 billion annually in time lost and overtime for replacement workers.[12][36] Drug testing of workers has resulted from the high prevalence of abuse and the economic consequences and has rapidly expanded over the past 10 years to cover millions of workers in the United States. This includes most of the Fortune 500 companies. Increased testing has led to a dramatic decrease in the number of workers testing positive ( Fig. 15–1 ). Surveys suggest workers in certain job categories are more prone to abuse alcohol and other drugs. The U.S. Department of Health and Human Services (DHHS) found that construction workers are the most frequent substance abusers ( Figs. 15–2 and 15–3 ). Workers in public trust areas, including teachers, police officers, and child-care workers, report the lowest rate of substance abuse.[16]

Figure 15-1 Quest Diagnostics, Incorporated, Drug Testing Index. www.questdiagnostics.com

.

Figure 15-2 Percentage of workers reporting use of illegal drugs. (CW, Construction workers; CS, construction supervisors; FP, food preparation; WW, waiters and waitresses; HL, helpers and laborers; WDAA, writers, designers, artists, and athletes.)[16]

Figure 15-3 Percentage of workers reporting heavy use of ethanol. (AC, All construction; CL, construction laborers; HL, helpers and laborers; AM, auto mechanics; FP, food preparation; TD, drivers of light trucks.)[16]

Statistics of abuse are difficult to tabulate. Estimates are drawn using severaltechniques, including survey methods, collateral rates linked to other illnesses. Drug Abuse Warning Network (DAWN), rosters registers, prescription audits local studies, urine testing results treatment programs.[6][7][8][13][22][23][25][26][28][29][30][37][42][44][46][48][50][54][57][58] Each method has its own bias, and all are estimates. Regardless of the source cited, the estimates of adults in the United States who abuse alcohol and illicit drugs range from 10 to 40 per cent. The absolute number of workers tested is difficult to calculate but is in excess of 30 million. These include employees in sensitive positions at all agencies of the United States government; National Collegiate Athletic Association, Olympic, and certain professional athletes; and workers at businesses throughout the United States who undergo testing at the discretion of their companies. Athletic drug testing is a complex area not covered in this chapter. Since 1993 the prevalence of self-reports of illicit drug and alcohol abuse has decreased from 8.4 to 6 per cent in the combined U.S.

workforce ( Table 15–1 ).

Table 15-1 -- Prevalence Rates of Self-Reported Use of Illicit Drugs Testing Category 1996 1995 1994 1993 Safety-sensitive transportation workforce 3.6% 3.4% 3.5% 2.8% General workforce Combined U.S. workforce 6.4% 7.5% 8.6% 9.8% 5.8% 6.7% 7.5% 8.4%

From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.

DEPARTMENT OF TRANSPORTATION BACKGROUND AND TESTING
The U.S. Department of Transportation (DOT) anti-drug rules apply to agencies involved in the transportation industry. These include the Federal Aviation Administration, Federal Highway Administration, Federal Railroad Administration, Federal Transit Authority, Research and Special Projects Administration, and U.S. Coast Guard. Each may have specific requirements, and the reader is referred to the federal regulations for appropriate information. Only certain drugs are to be tested under DOT regulations: amphetamines, cocaine, marijuana, phencyclidine (PCP), and opiates. Other allowable tests include 6-acetylmorphine (heroin metabolite) and amphetamine isomers (D-isomer, illegal, vs. L-isomer, legal). They are known as the “NIDA-5.” Recently this list has expanded to include ethanol breath testing. The Drug-Free Workplace Act of 1988 requires contractors and recipients of federal grants to certify that they provide a drug-free work site. Requirements and penalties for noncompliance are specified. In 1990 the federal government extended urine drug testing to small trucking companies to address a national problem. The DOT workplace drug testing program, which began in 1988, mandates employers to implement testing programs for employees in safety-sensitive positions. The DOT put forth 49 CFR part 40, a rule establishing procedures for urine drug testing. These were modeled after the Mandatory Guidelines for Federal Workplace Testing Programs issued by the DHHS in April 1988.[14] The procedures, which were outlined in part 40, were amended in 1994 in response to an earlier 1994 amendment by DHHS and also to include requirements of the Omnibus Transportation Employee Testing Act of 1991.[15] The major changes dealt with volume collections for “shy bladder” patients, split specimens, and screening and confirmation levels for marijuana (discussed later under Laboratory Testing). The volume of urine currently required is 30 mL for a single collection and 45 mL for a split-specimen collection. With the 1994 amendment, when a donor reports that he or she is unable to provide a specimen, the procedure under DOT testing calls for the donor to be provided with up to 40 ounces of fluids over a 3-hour time period to produce a specimen that meets the volume requirement. If a specimen still cannot be provided, the collector reports this to the employer as a shy bladder and the donor is referred to an employee-designated physician for a shy bladder evaluation.

A split specimen is a single urine collection divided into two containers, or specimens. If the primary specimen tests positive, the donor may elect to have the secondary specimen tested. As of August 1994, split specimen collections, processing, and reporting are mandatory for employees in the aviation, railroad, and motor carrier industries. As of January 1995, split specimens are required for transit system and intrastate commercial drivers.

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REASONS FOR TESTING
Many reasons exist to test subjects for potential drug abuse.[40] In 1989, a blinded longitudinal study of 5465 job applicants conducted by the Office of Selection and Evaluation of the U.S. Postal Service sought to determine abuse patterns. Drug-test results in these applicants were compared with rates of absenteeism, turnover, injuries, and accidents while on the job. After an average of 1.3 years on the job, employees who had tested positive for any of the illicit drugs had an absenteeism rate 59.3 per cent higher than those testing negative. The positive group also had a 47 per cent higher rate of involuntary turnover. No relationship exists between positive drug-test results and rates of accident occurrence.[43] However, another study[51] found a significant increase in workplace injuries. This study screened 2537 employees and followed each for an average of 2 years. The authors found that marijuana-positive urine specimens predicted increased turnover, accidents, injuries, disciplinary actions, and absenteeism. These risks appeared to decrease during the second year of employment. For those who tested positive for cocaine, increased rates of turnover, accidents, injuries, disciplinary actions, and absenteeism occurred at levels that did not change from the first to the second year. These studies suggest it is beneficial to test employees who work in safety-sensitive areas to decrease the rates of injury and turnover. Nonetheless, the national debate continues as to the social and legal rights of those tested. A discussion of that debate is far beyond the scope of this chapter. Several categories of testing are prevalent ( Table 15–2 ). Pre-employment screening is the most common reason for testing and encompasses the majority of individuals tested. Random testing, or testing performed on a random basis after employment, is the second leading category and is a major deterrent to drug abuse. According to 49 CFR 382.305, randomization can be done with a “scientifically valid method” such as a random number table or a computer-generated random number list. Although this method detects many abusers, Dupont and associates[18] suggest that random urine drug tests in the workplace are most effective in identifying frequent users of illicit drugs. Their study found that 50 per cent of positive test results are from everyday users and less than 7 per cent of positive results occur in infrequent users of illicit drugs. Other categories of testing include postaccident, reasonable suspicion of abuse, rehabilitation, and those for persons on parole or probation. The percentage of positive results is shown in Tables 15–3 and 15–4 .

Table 15-2 -- Categories of Drug Testing by Percentage Category Percentage of Tests Pre-employment Random Post-accident Rehabilitation Probation and parole Suspicious activity 5 90 5

Table 15-3 -- Positive Drug Test Results by Testing Category, for Safety-Sensitive Transportation Workforce Testing Reason 1996 * 1995 1994 1993 Pre-employment 4.3% Periodic Random Post-accident For cause Return to duty 1.6% 2.9% 3.3% 4.1% 4.1% 3.4% 1.7% 1.7% 1.5% 3.0% 2.7% 2.4% 6.0% 3.4% 3.3%

11.0% 10.8% 9.5% 9.9% 3.8% 3.7% 2.8% 2.3%

From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.
* More than 968,000 tests in 1996.

Table 15-4 -- Positive Results by Drug Category for Safety-Sensitive Transportation Workers, as a Percentage of all Tests Drug Category 1996 1995 1994 1993 Marijuana Cocaine 3.4 1.2 3.7 1.4 3.5 1.8 0.8 0.5 3.4 2.4 1.1 0.8

Benzodiazepines 0.38 0.5 Opiates Barbiturates 0.46 0.5

0.19 0.26 0.33 0.38

From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.

.

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REASONS FOR NOT TESTING
Reasons also exist for not testing individuals, such as the concern over social and legal rights (e.g., invasion of privacy) previously mentioned.[17] Other reasons include the inability of a urine test to determine the degree of impairment while at work. As a result of a positive test, one may face job termination, discharge from the military, denial of employment, or parole violation. Although all DOT-regulated testing programs require mandatory referral of an employee to the company’s employee assistance program (EAP), at least for the first positive test result, non–DOT-regulated businesses may not use EAP services. The initial concern over test accuracy has been effectively eliminated with the use of the gas chromatography/mass spectrometry (GC/MS) confirmation test.

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SPECIMENS TESTED
Several body substances are potential sources for testing for drugs of abuse. Urine is the most common specimen of choice, but blood, hair, sweat, and breath testing occur in non-DOT testing. Each has advantages and disadvantages for testing. Urine testing is the “gold standard” for most drug testing programs. The substance is readily available, specimen collection is noninvasive, and urine is easily manipulated by laboratory personnel. The disadvantages are few but include a lack of correlation of test results with impairment or time of drug use. Also, metabolites rather than the parent drugs are usually measured. Sweat testing is done by applying an adhesive tamper-proof patch to the skin for 1 week to collect a sample. This patch is assayed for the NIDA-5 agents. Application and specimen collection are easy. The tamperproof adhesive limits intentional adulteration or early removal. Once the patch is removed, it cannot be reapplied. It also provides for detection of drugs over a longer period of time. Because of its interesting advantages, sweat testing may replace urine testing in the future. Blood tests correlate better with recent use, and parent drug concentrations can be measured. A major drawback of using this substance for testing is the invasive technique necessary for specimen collection, which requires a certain level of technical expertise as well as stirring the privacy rights issue. Also, all of the complications of venipuncture apply to this method. Hair test results have traditionally been difficult to interpret because of environmental contamination. The advantages of testing hair include its ease in collection and that it provides information about drug use over a longer period of time than urine. Breath testing is only useful for volatile compounds such as ethanol. Because of this, breath testing is quite useful to indicate impairment.

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COLLECTION AND HANDLING
Collectors are required to obtain samples and determine if certain forms of adulteration have occurred. In certain circumstances, witnessed collections may be compulsory. Breath alcohol technicians are trained to collect breath samples and interpret the results. The site collector ensures that the specimen is from the correct individual. This is done by using photo identification (ID) or, if photo ID is unavailable, by using the employer representative as a source. If there is no photo ID or employer representative, this is documented on the collection and control form. The collector then requests two forms of non–photo ID bearing the employee’s signature and then proceeds with the collection. When the donor signs the certification statement on the custody and control form, the collector compares the signature with that on the non–photo ID. If the signatures appear consistent, the specimen is processed. If not, the collector notes “signature identification is unconfirmed” on the custody and control form. The collector ensures there are no chemicals such as toilet bowel cleaners, soaps, and so on in the donor room. A coloring agent can be added to the water in the toilet. The sink faucet can be temporarily rendered nonfunctional by mechanical alteration or by taping the nozzle with tamper-proof security tape, which tears with attempted removal. After the donation, the collector ensures that the specimen has not been tampered with by measuring the temperature, observing the color, and looking for any foreign material in the urine. The temperature of the collection must be within 90°F to 100°F, measured within 4 minutes of donation. The specimen is sealed with tamper-resistant tape and initialed on the bottle label and dated by the collector and initialed by the donor. The label is also dated as a further check. Each bottle has a unique ID number. During specimen collection, the donor is usually allowed to urinate in private. Direct observation of urination may be required if the donor appears intoxicated, is suspected of specimen adulteration, has previously submitted an adulterated or tampered specimen, or has abused drugs. Split-specimen collection requires the use of the same seven-page custody and control form and a collection kit containing two sealable specimen bottles. The donated specimen is subdivided in the presence of the donor. The collector may collect the specimen either in a common collection container or in a specimen container. In the former, 30 mL of the sample is poured into the primary specimen bottle (specimen “A”) and at least 15 mL into the secondary specimen bottle (specimen “B”) for the split. In the latter method, the collector pours at least 15 mL into the secondary bottle (specimen “B”) for the split, making sure that a minimum of 30 mL is maintained in the primary bottle (specimen “A”). Both portions of the split sample are sent to the initial laboratory. Chain of custody forms are maintained for both portions. The initial drug testing is performed on the primary bottle. The secondary bottle is stored for several days at the discretion of the laboratory unless the primary sample is positive, in which case it is kept for at least 60 days. Specimen “A” is kept frozen for a minimum of 1 year. If specimen “A” is positive, the donor may request within 72 hours to have the split (“B”) analyzed. If requested, the medical review officer (MRO)

makes this request in writing to the laboratory. The initial laboratory then sends the “B” bottle to another laboratory. Only the metabolite that was found in bottle “A” will be assayed. This assay is done at the limits of detection (LOD) by GC/MS, rather than the original cutoff values. If positive at any level above the LOD, the split is positive and reported to the MRO.

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TRANSPORTATION
Allowable modes of transporting specimens include the U.S. Postal Service, overnight carriers, or laboratory couriers.

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CHAIN OF CUSTODY
The “chain of custody” requires that each individual directly handling the specimen must sign the seven-part custody and control form. When the sample is received from the donor, he or she will sign it over to the collector. The collector signs the form out to the laboratory, where it is then signed that the specimen was received in good condition. In 1994 a DOT amendment clarified the chain of custody during transit. Now there is no requirement for couriers or other shipping personnel to document their participation on the chain of custody form if they do not directly handle the specimen. Previously, positive tests were invalidated because the couriers did not enter their names and dates on the chain of custody form.

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LABORATORY TESTING
Each laboratory that performs DOT testing must be certified under the Substance Abuse and Mental Health Services Administration (SAMHSA, formerly NIDA–National Institute for Drug Abuse). For a laboratory to be SAMHSA certified, the director must have a doctorate or be board certified in toxicology. A list of currently certified laboratories can be obtained from SAMHSA and can also be found in the Federal Register (updated monthly). Laboratories are required to review the chain of custody form, inspect the specimen, and analyze it for illicit drugs. Laboratories are also authorized to screen for adulterants, typically by measuring creatinine, specific gravity, pH, and nitrite concentration. Testing for illicit drugs is a two-step process. The first step is a “screening enzyme immunossay” method. Positive samples are sent for the second-step “confirmation” test by GC/MS.[52] For a specimen to be considered positive, the analyte must be present above the cutoff levels in both the screening and the GC/MS assays. Specimens testing negative at screening are eliminated from further analysis. Initial Screening In DOT screening, the initial screening procedure uses an immunoassay that meets the requirements of the Food and Drug Administration for commercial distribution. This is typically an enzyme immunoassay test, such as the enzyme-mediated immunoassay test, EMIT. It is a relatively fast and cost-effective screening tool employed by many testing and hospital laboratories. The test is based on the amount of the drug analyte present being proportional to changes in spectrophotometric absorbance initiated by an enzymesubstrate reaction. 1. 2. An antibody to a known drug analyte is added to an aliquot of the test urine. If the analyte is present, it will bind to the antibody. A known amount of the analyte already attached to an enzyme, such as glucose-6 phosphate dehydrogenase (G6PD), is then added. The analyte, if initially present in the urine, and the analyteenzyme complex compete for binding to the antibody. The amount of analyte-enzyme complex left unbound is directly proportional to the amount of analyte initially present in the urine. The unbound analyte-enzyme complex is active. An enzyme substrate, such as nucleotide adenine dehydrogenase (NAD), is then added. The unbound, active G6PD reduces NAD to NADH. A spectrophotometer reads the solution absorbance at 340 nm. The absorbance increases proportionately to the increase in NADH concentration.

3. 4.

A pitfall in this method involves antibody interaction with nontested drug analytes. This may occur with impure antibodies or with nontested drug analytes that are structurally similar or isomers of tested drug analytes ( Table 15–5 ).

Table 15-5 -- Drugs That May Interfere with EMIT Screening Immunoassay

Amiodarone Ciprofloxacin Griseofulvin Mefenamic acid Metronidazole Salicyluric acid Sulindac Sulfasalazine Tolmetin sodium

The DOT has set specific, positive cutoff levels of the analytes for screening and confirmation ( Table 15–6 ). The marijuana cutoff limit has changed since the program began. With the 1994 amendment, the reportable positive, or cutoff, level for tetrahydrocannabinol (THC) was reduced from 100 ng/mL to 50 ng/mL. Amphetamine remains positive at 1000 ng/mL, morphine and cocaine at 300 ng/mL, and PCP at 25 ng/mL. A 1997 amendment (became effective December 1998) increased the cutoff of screening and confirmation levels of opiates (see Table 15–6 ).

Table 15-6 -- Laboratory Analytes, and Detection Levels and Times Drug Level (ng/mL) Drug Target Analyte Screening Confirmation Amphetamine Amphetamines Barbiturates Benzodiazepines Cannabinoids Cocaine Opiates and metabolites Phencyclidine Ethanol Methamphetamine Secobarbital Oxazepam Delta-9 THC-acid Benzoylecgonine Morphine Codeine 6-Acetylmorphine Phencyclidine Ethanol 25 25 0.04% (40 mg/dL) * * 50 300 2000 1000 500 500 + =200 amphetamine * * 15 150 2000 2000 10 †

Common Detection Times

=24 hours 18–29 hours 5–6 hours 1 day–3 weeks 2–3 days 1–3 days

Hours =3 days Hours

* Non-DOT testing may have variable cutoff levels. † When morphine concentration exceeds 2000 ng/mL.

Other screening techniques include radioimmunoassay (RIA), fluorescence polarization immunoassay (FPIA), cloned enzyme donor immunoassay (CEDIA), and kinetic interaction of microparticles in solution (KIMS). The latter two are more recent techniques, and CEDIA may be done in smaller laboratories, whereas KIMS is performed in larger laboratories. Confirmatory Testing If the screening test is positive, it is subjected to a more specific analytical method. Under DOT guidelines, GC/MS is the gold standard. In GC, the extracted specimen is vaporized by heat at the injection port and carried through a column by a steady flow of a heated gas. This specimen can terminate in a detector or be combined with a mass spectrometer that bombards the specimen with an electron beam, causing fracturing of molecular bonds. The fracturing pattern is specific for an analyte and results in “molecular fingerprinting,” which is compared with a known standard. The combined result of the GC/MS is a more sensitive and specific measurement of drugs of abuse. After abuse, the time period that an analyte can be detected will vary, depending on the duration and quantity of abuse of substances and on the particular analyte (see Table 15–6 ). Selected ion monitoring (SIM) is a newer method that may be used in the future. Confirmation analyte levels are presented in Table 15–6 . For confirmation of methamphetamine, both methamphetamine and amphetamine are measured. The test is considered positive if a methamphetamine level at or above 500 ng/mL is found in association with an amphetamine level of at least 200 ng/mL. Non-DOT Testing Non-DOT tests are not required to follow the previously presented techniques. They may be single or split collections, performed on or off site, and may or may not be followed by GC/MS confirmation. An example of on-site testing is the triage panel for drugs of abuse. In non-DOT testing, barbiturates and benzodiazepines are frequently added to the traditional NIDA-5. Secobarbital is the analyte of detection for barbiturates. Many benzodiazepines are metabolized to oxazepam, which is an excellent target analyte to measure.

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SPECIMEN INTEGRITY
Specimen integrity may be breached intentionally or nonintentionally during, or before, the collection process. Adulterants may be added directly to the sample, or various substances may be ingested to alter a test result. The toilet water in the collection room is typically colored with a colorant agent, so addition of this will alter the color of the sample. Dilution of the sample with forced oral intake of water is common, and the specimen’s creatinine and specific gravity may be measured to determine if the sample has been diluted (specific gravity less than 1.003, creatinine less than 20 mg/dL). Certain teas allegedly alter test results. Goldenseal tea can mask opiates on thin-layer chromatography screening. However, these substances do not interfere with GC/MS verification. A variety of substances have been substituted for urine as a specimen. Artificial urine is available on the street or by mail-order catalogue for substitution into the specimen container. Recently, the soft drink Mountain Dew has been found as a substitute in drug testing. It caused a false positive result for ethanol in a non-DOT urine test sample.[24] The substitutes may be preheated or stored in a body bag to maintain temperature. Other adulteration methods include the addition of substances that alter the pH or the ionic strength of a sample, which may inhibit antibody binding or interfere with the method of detection. Glutaraldehyde interferes with the rate of the enzyme reaction, which may result in a negative test for any of the DOT-tested drugs. However, glutaraldehyde is usually detected during routine laboratory evaluation. Table 15–7 lists some of the more common adulterants reported. When a specimen enters a laboratory and appears to have been adulterated, it is sent to a special area for further evaluation ( Table 15–8 ).

Table 15-7 -- Common Adulterants of Urine Drug Testing Alkylepoxysulfonate Apple juice Ammonia Bleach Detergent Drano (sodium hydroxide) Glutaraldehyde Goldenseal tea Lime-A-Way MJ Super Clean 13 Mountain Dew Nitrites Peroxide Pyridine (pyridium chlorochromate)

Saline Saliva Salt (sodium chloride) Soap Sodium bicarbonate Soft drinks Vanish Vinegar Visine Water

Table 15-8 -- Common Adulteration Checks Done by Laboratories on Urine Specimens Temperature Smell Appearance (precipitate at bottom or bubbles) pH Creatinine Specific gravity Electrolytes Nitrites

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REPORTING
Results and records must be maintained under strict confidentiality by all involved. The laboratory must keep the records in storage. If the specimen tests negative on initial screening, it is a negative result. If the specimen tests positive by screening assay and negative by the GC/MS confirmation screen, it is a negative test. If both the screening and confirmation tests are positive, the test is reported to the MRO as being positive.

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MEDICAL REVIEW OFFICER
Under DOT guidelines the MRO must interpret positive results, review the custody and control form for reported negative results, and manage problems arising from dilute and possibly adulterated specimens. By definition, an MRO is a licensed physician with training and experience in the diagnosis and treatment of substance abuse. In Florida and Oklahoma he or she must be certified by either the Medical Review Officers Certification Council (MROCC) or the American Association of Medical Review Officers (AAMRO), which are the currently available certifying bodies. As of this writing, no other states currently require certification, although this may change. MROs act as liaisons between the laboratory and employer and between the employer and donor. The MRO, or a designated representative, contacts the donor and conducts an interview to determine if there is an alternate medical explanation for the positive test result. The donor must provide documentation, such as prescriptions, use of cocaine during a recent nasal procedure, and so on. The MRO must then determine if the use was medically legitimate. Although the test is positive, it can be deemed negative by the MRO. It is worth noting that there is no medical indication for PCP or heroin. Finally, the MRO must be involved when split specimen testing is requested. The DOT does not mandate a formal role for MROs in alcohol testing. MROs are also not required in non-DOT testing, but they are strongly encouraged in this litigious field. A list of free Internet information sources for the MRO is given in Table 15–9 .

Table 15-9 -- Internet Sources of Free Drug Testing Information Direct Contact and Modem Services Federal Highway Administration (FHWA) Modem download 800-337-3492 Department of Transportation Fax on Demand 800-225-3784 (http://www.dot.gov Medical Review Officers Certification Council 847-228-7476 (http://www.mrocc.com Internet Addresses * American Medical Association (http://www.ama-assn.org.ezproxy.med.nyu.edu Canadian Centre on Substance Abuse (http://www.ccsa.ca ) ) ) ) )

National Clearinghouse for Alcohol and Drug Information (http://www.health.org/workpl.htm GPO Gate (http://gpo.ucop.edu/search/default.html ) )

Institute for a Drug Free Workplace (http://www.drugfreeworkplace.org:80/catalog.html Join Together (http://www.jointogether.org/news/jto/LatestNews.qry ) )

Medical Review Officers Certification Council (http://www,mrocc.com/index.htm U.S. Navy Statistical Models (http://nprdc.navy.mil:80/nprdc/drug-mod.htm U.S. Department of Labor–Substance Abuse Information Database (http://www.dol.gov/dol/asp/public/programs/drugs/said.htm ) )

National Association of Collection Sites (

) ) )

SAMHSA Media Services (http://www.samhsa.gov/media.htm

Department of Labor drug testing information (http://www.dol.gov/dol/asp/public/programs/drugs/facts.htm Substance Abuse and Mental Health Services Administration (SAMHSA) (http://www.samhsa.gov
* Other sources may be found by using Internet search engines.

)

The certified MRO has completed a course and a certifying examination of the interpretation of drug testing. Most will have some familiarity with substance abuse, others may not. Those involved with this field are strongly encouraged to become certified and gain experience in this field. Many MROs will have assistants initially contact the worker with a positive test for initial information such as prescription drug use. However, under DOT guidelines the MRO must give the worker an opportunity to discuss the test result with him or her. Any discussion of positive test results must be done by the MRO—this cannot be delegated.

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POST-TESTING EVALUATION AND TREATMENT
The U.S. DOT requires covered employers to use substance abuse professionals (SAPs) to evaluate safetysensitive employees who test positive for drugs or ethanol. SAPs are not required to be physicians. They must, however, have one of the following qualifications: • • A licensed physician with an MD or DO degree with knowledge of, and clinical experience in, the diagnosis and treatment of ethanol and disorders related to substance abuse A licensed or certified psychologist, social worker, or certified employee assistance professional (CEAP) with knowledge of, and clinical experience in, the diagnosis and treatment of disorders related to ethanol and controlled substances A counselor certified by the National Association of Alcohol and Drug Abuse Counselors

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SPECIFIC PROBLEMS WITH ANALYSIS
In non-DOT testing, nonsteroidal anti-inflammatory drugs have been associated with false positive immunoassays for benzodiazepines. They do not result in false-positive GC/MS results. Oxaprozin (Daypro), etodolac (Lodine), naproxen sodium (Anaprox), fenoprofen calcium (Nalfon), and tolmetin sodium (Tolectin) have been reported to cross react with the immunoassay antibodies. These false positive results do not occur with thin-layer chromatography screening or GC/MS confirmation. Ibuprofen and naproxen (Naprosyn) have not been shown to cross react on GC/MS.[31][47][49] However, some substances can produce “true” positives on GC/MS; careful MRO interpretation of these findings is required ( Table 15–10 ).

Table 15-10 -- Substances Causing Positives on GC/MS Confirmation Testing Test Substance Vicks Nasal Inhaler * Selegiline * Amphetamines Diet pills from other countries: Chlorbenzorex (Asenlix) Fenproperex Benzodiazepines “Black pearls” (Asian product) Cocaine Coca leaf teas (Health Inca Tea) Dronabinol (Marinol) Marijuana Hemp-containing foods: Seedy Sweeties Cranberry Coconut Hemp Bar Opiates Poppy seeds

* Chiral separation of isomers required.

Cocaine Several cocaine metabolites cross react with the immunoassay for cocaine. These include benzoylecgonine, cocaine, cocaethylene, ecgonine methyl ester, and ecgonine. There is no cross-reactivity with any of the “caine” analgesics, such as lidocaine, benzocaine, or procaine. Health Inca Tea contains cocaine, and drinking one cup can produce a positive drug test.[21] However, the only legitimate reason for a positive drug test for cocaine would be from a documented medical procedure in which the use of cocaine can be verified, for example in otolaryngologic surgery or after topical application of tetracaine-epinephrine-cocaine (TAC) before laceration repair. Passive inhalation is not a valid reason for a positive test. [4] Phencyclidine

Phencyclidine (PCP) immunoassays will react with both PCP and certain metabolites and analogs. The parent compound PCP is easily confirmed with GC/MS. Diphenhydramine and dextromethorphan may cause false positive fluorescence polarization immunoassay for PCP with levels up to 37 ng/mL.[35] High doses of thioridazine but not chlorpromazine have been reported to cause false-positive results by EMIT.[56] There are no medical indications for PCP. Opiates Knowing the metabolism of opiates in drug testing is essential for interpretation of positive opiate test results. Figure 15–4 shows that heroin and codeine are both metabolized to morphine and that morphine is not metabolized to codeine. In the metabolism of heroin to morphine the intermediate 6-acetylmorphine (6AM) is formed. The presence of 6-AM is indicative of heroin abuse, because morphine or codeine metabolism will not produce this intermediate substance. However, the half-life of heroin is very short, being completely converted to 6-AM within 10 to 15 minutes. The half-life of 6-AM is 0.6 hour, and the total morphine half-life is 7.9 hours. The finding of 6-AM in the urine indicates that either heroin or 6-AM was selfadministered within 24 hours of the collection.[11] As shown in Figure 15–4 , the presence of 6-AM is not due to the metabolism of either codeine or morphine.

Perhaps more confusing is the consumption of poppy seeds found in a variety of salad dressings and baked goods. The seeds contain varying amounts of morphine and codeine. They may or may not produce an opiate-positive urine, both on screening and GC/MS confirmation.[4][19] Because of this, MROs do not confirm a positive urine unless there is also clinical evidence of opiate abuse. An exception to this requirement is the finding of 6-AM, which arises solely from heroin metabolism.

Figure 15-4 Metabolic profile for heroin, codeine, and morphine.

Perhaps more confusing is the consumption of poppy seeds found in a variety of salad dressings and baked goods. The seeds contain varying amounts of morphine and codeine. They may or may not produce an opiate-positive urine, both on screening and GC/MS confirmation.[4][19] Because of this, MROs do not confirm a positive urine unless there is also clinical evidence of opiate abuse. An exception to this requirement is the finding of 6-AM, which arises solely from heroin metabolism. In testing, certain findings may distinguish opiate from poppy seed ingestion: 1. 2. 3. 4. A morphine-codeine ratio of 2 to 3:1 usually rules out poppy seed, and a ratio less than 2 favors codeine ingestion. Morphine levels greater than 2000 ng/mL without codeine or over 5000 ng/mL with measured codeine usually rule out poppy seeds as a source. Poppy seeds rarely result in urine positive results more than 24 to 36 hours after ingestion. Very high levels of morphine (> 10,000) with little or no codeine invariably indicate heroin or morphine use. In the last instance the laboratory must be able to detect codeine at a lower limit of 25 ng/mL.[20] The MRO must request codeine testing at this level; and, under DOT rules, this request must be written. However, these guidelines do not negate the MRO requirement to find clinical evidence of opiate abuse before reporting an opiate-positive urine sample.

Legislation effective December 1, 1998, increased opiate screening and confirmation levels dramatically. This is an effort to minimize false positive tests for poppy seeds and help with spousal use of codeine products. Other opioids do not cross react with current immunoassays for opiates. These substances include dihydrocodeine, oxycodone, hydrocodone, oxymorphone, hydromorphone, propoxyphene, methadone, meperidine, and fentanyl. Marijuana Cannabinoids are generally not detected in the urine after passive inhalation unless massive exposure has occurred. Experiments have shown that, to develop a positive urine test for THC secondary to sidestream marijuana smoke, the donor must have been in almost unrealistic circumstances. Passive inhalation of marijuana smoke is not an alternative medical reason for a positive test, which should be reported as a positive test by the MRO.[9][10][34][39][41][45] The only legitimate explanation for a positive THC acid test is from the prescribed use of dronabinol (Marinol). Dronabinol is approved by the Food and Drug Administration for use as an antiemetic in chemotherapy and as an appetite stimulant in patients with the acquired immunodeficiency syndrome (AIDS). Failure to exclude this as a possible explanation may result in litigation against the MRO. Clouding the issue, certain consumable products have been formulated with hemp products, including hemp seeds, hemp oil, and cheeses. Consumption of these products has been offered as an alternative

explanation for a THC-positive urine test. News of this has spread through newspapers, discussion groups, and over the Internet. Products include Seedy Sweeties (Hungry Bear Hemp Foods, Eugene, OR), and the Cranberry Coconut Hemp Bar (G&S, Steamboat Springs, CO). A more complicated issue involves state initiatives passed in California and Arizona in November 1996. In those states, medically recommended or prescribed marijuana became permissible. The DOT promptly responded by stating that marijuana or hemp ingestion is not a reason to overturn a THC-positive test.[1] Any individual in a safety-sensitive position assumes the responsibility for his or her positive test. The federal government considers the prescription of Schedule I drugs a violation of the law, subject to penalties. Arizona has now introduced recent legislation to ban the use of substances that the Drug Enforcement Agency regulates as Schedule I. Amphetamines Over-the-counter drugs are the most common cause of an amphetamine immunoassay positive urine sample.[5] More recent immunoassay tests are specific for amphetamine and methamphetamines. Previously, high concentrations of over-the-counter ephedrine and pseudoephedrine could, under very specific GC conditions, produce methamphetamine within the instrument. This resulted in a confirmed positive test for methamphetamine. Because methamphetamine is metabolized in vivo to amphetamine, methamphetamine levels at or above 500 ng/mL are not reported as positive unless amphetamine is also detected in concentrations at or above 200 ng/mL. False positive tests have been reported with the use of drugs containing the L-isomers of methamphetamine or amphetamine. Pharmacologically the D-isomer produces stimulation of the central nervous system whereas the D-isomer produces peripheral effects. Vicks Nasal Inhalers contain L-methamphetamine (desoxyephedrine) as the active ingredient. This noncontrolled substance is less than one tenth as potent as the illicit D-methamphetamine. Most laboratories will routinely perform chiral separation of the isomers; others will do so on request. Vicks Nasal Inhalers on chiral separation will show mainly L-isomer, with very small amounts of the D-form. Illicit methamphetamine has both L and D forms. The DHHS advises MROs that chiral identification of L-methamphetamine of greater than 80 per cent is consistent with the use of Vicks Nasal Inhalers.[3] Selegiline (Eldepryl), a drug used in the treatment of parkinsonism and depression, is metabolized to L-amphetamine and L-methamphetamine. Levels up to 720 ng/mL of amphetamine and greater than 2000 ng/mL of methamphetamine have been reported with selegiline use.[38] By requesting chiral separation, the pattern of the stereoisomers will allow one to differentiate selegiline from illicit methamphetamine use. Diet pills available in other countries can produce true positive urine tests. A Mexican diet aid, Asenlix, contains chlorbenzorex. Chlorbenzorex is metabolized in vivo to amphetamine and methamphetamine,[55] and ingestion can result in measurable urinary amphetamine. Fenproperex, another diet aid, is also metabolized to amphetamine and methamphetamine. The following may cross react with the amphetamine screening immunoassay: amphetamine/methamphetamine isomers, benzphetamine, ephedrine and pseudoephedrine, 3,4methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4methylenedioxyethamphetamine (MDEA), phenmetrazine, phentermine, phenylpropanolamine, and propylhexedrine. SUMMARY

Workplace drug testing has changed dramatically over the past decade with millions of workers in both the government and private sector now being tested. Drug testing is done in accordance with DOT standards, or as determined by the private employer. The current DOT program has evolved into a very well-organized and reproducible service. Skills and specific education or certification are necessary for the MRO physician to deal with this challenging area effectively. The decision to undertake a drug-detection program must be outcome based. Most employees testing positive require intervention by an SAP and counseling. The optimal program structure involves an integrated approach by the employer, employee, laboratory, MRO, and SAP. An organized, integrated testing program reduces the likelihood of falsely accusing a worker of illicit drug or ethanol use.

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REFERENCES
1. Anonymous: Federal response to state marijuana initiatives, and hemp-containing food products. MRO Update 1997; January:1–5. 3. Autry JH: Technical Advisory to All HHS/NIDA Certified Laboratories, Rockville, MD, Department of Health and Human Services, March 11, 1991. 4. Baselt RC, Yoshikawa DM, Chang JY: Passive inhalation of cocaine [letter]. Clin Chem 1991; 37:21602161. 5. Baselt RC: Urine drug screening by immunoassay: Interpretation of results. In: Baselt RC, ed. Advances in Analytical Toxicology, vol 1. Foster City, CA: Bimedial; 1984:81-123. 6. Bonito AJ, Nurco D: Validity of addict self-report in social research. Int J Addict 1976; 11:719-724. 7. Calahan D: American Drinking Practices, New Brunswick, CT, Rutgers Center of Alcohol Studies, 1969. 8. Community Epidemiology Work Group: Epidemiologic trends in drug abuse: Proceedings, December 1989. Rockville, MD, National Institute on Drug Abuse, 1990. 9. Cone EJ, Johnson RE, Darwin WD, et al: Passive inhalation of marijuana smoke: Urinalysis and room air levels of delta-9-tetrahydrocannabinol. J Anal Toxicol 1987; 11:890. 10. Cone EJ, Johnson RE: Contact highs and urinary cannabinoids excretion after passive exposure to marijuana smoke. Clin Pharmacol Ther 1986; 40:247-256. 11. Cone EJ, Welch P, Mitchell JM, Paul BD: Forensic drug testing for opiates: I.. Detection of 6acetylmorphine in urine as an indication of recent heroin exposure: Drug and assay considerations and detection times. J Anal Toxicol 1991; 15:1-7. 12. D’Aquila RT, Williams AB: Epidemic human immunodeficiency virus (HIV) among intravenous drug users (IVDU). Yale J Biol Med 1987; 60:545-567. 13. Dai B: Opium Addiction in Chicago, Shanghai, Commercial Press, 1970. Reprinted Montclair, NJ: Patterson Smith, 1970. 14. Department of Health and Human Services: Mandatory Guidelines for Federal Workplace Testing Programs. U.S. Department of Health and Human Services (DHHS) 1988. 15. Department of Health and Human Services: Omnibus Transportation Employee Testing Act of 1991. U.S. Department of Health and Human Services, 1991. 16. Department of Health and Human Services. Drug Use Among U.S. Workers: Prevalence and Trends by Occupation and Industry Categories, Washington, DC, U.S. Dept of Health and Human Services, Substance Abuse and Mental Health Services (SAMHSA), 1996. 17. Drug testing: What’s at stake? Industrial Chemical News 1986; April:61.

18. Dupont RL, Griffin DW, Siskin BR, et al: Random drug test at work: The probability of identifying frequent and infrequent users of illicit drugs. J Addictive Dis 1995; 14:1-17. 19. Elsohly HN, Elsohly MA, Stanford DF: Poppy seed ingestion and opiates urinalysis: A closer look. J Anal Toxicol 1990; 14:308-310. 20. Elsohly MA, Jones AB: Morphine and codeine in biological fluids: Approaches to source differentiation. Forens Sci Rev 1989; 1:13-21. 21. Elsohly MA, Stanford DF, Elsohly HN: Coca tea and urinalysis for cocaine metabolites [letter]. J Anal Toxicol 1986; 10:256. 22. Feldman HW, Agar MH, Beschner G: Angel dust: An ethnographic study of PCP users, Lexington, MA, Lexington Books, 1979. 23. Feldman HW, Aldrich MR: The role of ethnography in substance abuse research and public policy: Historical precedent and future prospects. In: Lambert EY, ed. The Collection and Interpretation of Data From Hidden Populations, Rockville, MD: National Institute on Drug Abuse; 1990:12-30. 24. Goldberger BA: Unsuspected ethanol ingestion through soft drinks and flavored beverages [letter}. J Anal Toxicol 1996; 20:332. 25. Greenwood JA: Estimating the number of narcotic addicts, Washington, DC, U.S. Department of Justice, 1971. Document SCID-TR-3. 26. Harris LS (ed): Proceedings of the 47th annual scientific meeting of the Committee on Problems of Drug Dependence. Rockville, MD, National Institute on Drug Abuse, 1987; 14:283–289. 28. Hubbard RL, Marsden ME, Rachal JV, et al: Drug abuse treatment: A national study of effectiveness, Chapel Hill, NC, University of North Carolina Press, 1989. 29. Hughes PH, Jaffe JH: The heroin copping area: A location for epidemiologic study and intervention activity. Arch Gen Psychiatry 1971; 24:394-400. 30. Hunt LG: Incidence and prevalence of drug use and abuse. In: Dupont RI, Goldstein A, O’Donnell J, ed. Handbook on Drug Abuse, Rockville: National Institute on Drug Abuse; 1979:395-403. 31. Jelic-Ivanovic Z, Majkic-Singh N, Spastic S, et al: Interference by analgesics and antirheumatic drugs in 25 common laboratory assays. J Clin Chem Biochem 1985; 23:287-292. 34. Law B, Mason PA, Moffat AC, et al: Passive inhalation of marijuana smoke: Urinalysis and room air levels of delta THC. Clin Pharmacol Ther 1983; 34:36-41. 35. Levine BS, Smith ML: Effects of diphenhydramine on immunoassay of phencyclidine in urine. Clin Chem 1990; 36:1258. 36. In: Lierman TL, ed. Building a Healthy America, New York: Mary Ann Liebert; 1987. 37. Lindesmith AR: Opiate Addiction, Bloomington, IL, Principia Press, 1947. 38. Meeker JE, Reynolds PC: Postmortem tissue methamphetamine concentrations following selegiline

administration. J Anal Toxicol 1990; 14:330-331. 39. Moreland J, Bugge A, Skuterund B, et al: Cannabinoids in blood and urine after passive inhalation of cannabis smoke. J Forens Sci 1985; 30:997-1002. 40. Morgan JP: The “scientific” justification for urine drug testing. Kansas Law Rev 1988; 36:683-697. 41. Mule SJ, Lomax P, Gross SJ: Active and realistic passive marijuana exposure tested by three immunoassays and GC/MS in urine. J Anal Toxicol 1988; 12:113-116. 42. National Institute on Drug Abuse: Data from the Client Oriented Data Acquisition Process (CODAP), Rockville, MD, National Institute on Drug Abuse, 1983. 43. Normand J, Salyards SD, Mahoney JJ: An evaluation of preemployment drug testing. J Appl Psychol 1990; 75:629-639. 44. Pazzaglini M: Street drug use in Delaware. Del Med J 1987; 159:729-732. 45. Perez-Reyes M, DiGuiseppi S, Mason AP, et al: Passive inhalation of marijuana smoke and urinary excretion of cannabinoids. Clin Pharmacol Ther 1983; 34:36-41. 46. Person Jr PH: Indicators of drug abuse—DAWN. In: Richards LR, Blevens LB, ed. The Epidemiology of Drug Abuse: Current Issues, Rockville, MD: National Institute on Drug Abuse; 1977:135-137. 47. Pulini M: False-positive benzodiazepine urine test due to oxaprozin. JAMA 1995; 273:1905. 48. Ramos R: Chicano intravenous drug users. In: Lambert EY, ed. The Collection and Interpretation of Data from Hidden Populations, Rockville, MD: National Institute on Drug Abuse; 1990:128-145. 49. Raphan H: In reply: False-positive benzodiazepine urine test due to oxaprozin. JAMA 1995; 273:1905. 50. Regier D, Meyers JK, Kramer M, et al: The NIMH epidemiologic catchment area program. Arch Gen Psychiatry 1984; 41:934-958. 51. Ryan J, Zwerling C, Jones M: The effectiveness of preemployment drug screening in prediction of employment outcome. J Occup Med 1992; 34:1057-1063. 52. Schwartz RH, Hawks RL: Laboratory detection of marijuana use. JAMA 1985; 254:788-792. 54. Snow M: Maturing out of narcotic addiction in New York City. Int J Addict 1974; 18:917-933. 55. Tarver JA: Amphetamine-positive drug screens from use of clobenzorex hydrochlorate [letter]. J Anal Toxicol 1994; 18:183. 56. Walberg CB, Gupta RC: Quantitation of phencyclidine in urine by enzyme immunoassay. J Anal Toxicol 1982; 6:97-99. 57. Wesson DR, Camber S: Phenylpropanolamine mentions in the Drug Abuse Warning Network: Numbers plus interactions. In: Morgan JP, Kagan DV, Brody JS, ed. Phenylpropanolamine Risks, Benefits, Controversies, New York: Praeger; 1985:362-370. 58. Winick C: Some aspects of careers of chronic heroin users. In: Josephson E, Carroll EE, ed. Drug use:

Epidemiological and Sociological Approaches, New York: John Wiley; 1974:105-124.

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Uncited references Anthony JC, Ritter CJ, Von Korff MR, et al: Descriptive epidemiology of adult cocaine use in four U.S. communities. NIDA Res Monogr 1986; 67:283. Hayes LW, Krasselt WG, Mueggler PA: Concentrations of morphine and codeine in serum and urine after ingestion of poppy seeds. Clin Chem 1987; 33:806-808. Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beechman data shows, Collegeville, PA, SmithKline Beechman Clinical Laboratories, 1996. Johnston LD, O’Malley PM, Bachman JG: Drug Use, Drinking and Smoking National Survey Results from High School, College and Young Adult Populations 1975–1988, Rockville, MD, National Institute on Drug Abuse, 1989. Siddiqi M, McKay CA: Letter to the editor: Passive inhalation of marijuana. MRO Update 1996; July/August:8–9.

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Section II – APPROACH TO THE POISONED PATIENT WITH

Chapter 16 – Central Nervous System Depression
KATHLEEN A. DELANEY PAUL KOLECKI

Essentials • • • • • • • Treat shock and respiratory failure Treat hypoglycemia Consider administration of thiamine Consider administration of naloxone Consider an acute neurosurgical emergency Consider acute bacterial meningitis Proceed with a thoughtful diagnostic approach directed by the history and physical examination

INTRODUCTION
Stupor, defined as a state of unresponsiveness from which the patient may be only briefly aroused by vigorous stimulation, and coma, a deeper state from which the patient cannot be aroused, are manifestations of central nervous system (CNS) depression.[30] Causes of CNS depression range from acute life-threatening toxic, metabolic, infectious, or neurosurgical emergencies that require immediate diagnosis and treatment, to less immediately life-threatening processes that require a thoughtful diagnostic approach ( Table 16–1 ). This chapter discusses the toxic differential diagnosis of the patient with stupor or coma, as well as nontoxic considerations. It emphasizes clinical decision making based on the history, the physical examination, and the readily obtainable laboratory assessments.

Table 16-1 -- Life-Threatening Causes of Coma That Require Immediate Diagnosis and Treatment Condition Signs Shock or respiratory failure Hypoglycemia Acute bacterial meningitis Cerebral mass lesion Vital signs, pulse oximetry Low reading on CBG (capillary blood glucose) test Fever, nuchal rigidity, petechiae, purpura, rapid deterioration Hyperventilation, focality, fixed pupils, posturing, absent doll’s eyes

Condition Vertebrobasilar artery thrombosis Severe thiamine deficiency Cyanide poisoning

Signs Hyperventilation, fixed pupils, absent doll’s eyes, posturing Absent or abnormal doll’s eyes, reactive pupils, history of ataxia, diplopia, history of alcohol abuse or nutritional depletion Severe acidosis, rapid deterioration

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INITIAL MANAGEMENT
Basics The initial management of all patients with coma is the same. The degree of airway management depends on the judgment of the physician at the bedside as to adequacy of the airway, respirations, oxygenation, and likely cause of coma. Options range from immediate intubation to observation in a well-staffed area. Management of the airway is followed by hemodynamic resuscitation. The temperature should always be measured to detect severe hyperthermia or hypothermia, which may be the cause of the coma (see Chapter 27 ). The patient should be completely undressed and examined for signs of trauma. Continuous monitoring of the blood pressure, pulse, respiratory rate, cardiac rhythm, and oxygen saturation is initiated. Coma Cocktail Reconsidered: Naloxone, Glucose, Thiamine, Flumazenil ( Table 16–2 ) Bedside measurement of serum glucose level and treatment of hypoglycemia are essential. Dextrose should be administered empirically to the comatose patient when reliable blood glucose testing is not available. Although studies have shown that increased serum blood glucose level is associated with more extensive ischemic infarction and poorer outcome in brain-injured patients,[42] it seems rational that the risk of worsening already severe brain injury is less than the failure to prevent severe injury from the completely reversible condition of hypoglycemia. Although thiamine deficiency is a very rare cause of coma, thiamine should be routinely administered to any nutritionally depleted or alcoholic adult with altered mental status. Even when thiamine deficiency is not the cause of coma, the administration of glucose to the thiaminedepleted patient has been shown to precipitate Wernicke encephalopathy.[41][43] The major indication for the administration of naloxone in a patient with suspected overdose is respiratory depression (respiratory rate <12).[16] Although the side effects of naloxone are minimal in the patient who is intolerant of opioids, it may precipitate severe withdrawal with vomiting and aspiration in the opioid-tolerant patient who is comatose from another cause, such as a sedative hypnotic, head injury, or hypoxia. It is prudent to begin treatment of the patient with suspected opioid dependence with an initial dose of 0.1 mg of naloxone, rather than the 0.4 to 2 mg that is commonly recommended.[17]

Table 16-2 -- Empirical Therapies in the Patient with Coma Treatment Indication Dose Hypertonic dextrose Demonstrated or suspected hypoglycemia

Complications

Adult: 1–2 ampules of D50W Possible exacerbation of ischemic (25 g); repeat prn brain injury Ped: bolus 0.5–1 g/kg/dose D25W, repeat prn

Naloxone

Respiratory depression

Adult: opiate dependence: 0.1 mg IV; 0.4–2.0 mg/dose Ped: Neonate: 0.01–0.03 mg/kg/dose

Acute opioid withdrawal, aspiration

Treatment

Indication

Dose Child: 0.4–2.0 mg/dose

Complications

Thiamine Nutritional depletion Alcoholism

Suspected Wernicke encephalopathy Ped: 10–25 mg/day IV/IM

Adult: 100 mg IV

None

Flumazenil

Respiratory depression due Adult: 0.2 mg over 30 sec q to benzodiazepine 1 min to total of 5 mg Ped: 0.01 mg/kg q 1 min to total of 1 mg

Seizures due to benzodiazepine withdrawal or effect of a coingestant

D25W, 25% dextrose in water; D50W, 50% dextrose in water; Ped, pediatric.

Flumazenil is a specific benzodiazepine antagonist that rapidly reverses coma associated with benzodiazepine overdose. Unfortunately, it can precipitate seizures resulting from benzodiazepine withdrawal in tolerant long-term users and has been associated with seizures when the epileptic effects of coingestants, such as cyclic antidepressants, are unmasked. It has a limited role in most overdoses because of these dangerous side effects. It is useful in the pure pediatric ingestion. It may be used cautiously in the adult without known long-term benzodiazepine use or without coingestion of an epileptogenic toxin, who has respiratory depression and is deemed likely to require intubation. If uncertainty exists regarding the risk of seizures, intubation and supportive care may be the better option.[19][23][38] Dire emergencies requiring very rapid diagnosis are listed in Table 16–1 . These include impending brain herniation from a mass lesion, basilar artery thrombosis, bacterial meningitis, hypoglycemia, and severe thiamine deficiency. Cyanide is the only toxin associated with coma as a primary manifestation that requires immediate intervention to prevent death after the initiation of supportive care (see Chapter 86 ). Further management, including decontamination, computed tomographic scanning of the head, lumbar puncture, and other antidotes and antibiotics, depends on the differential diagnosis generated by the history, physical examination, and laboratory assessment described in the Differential Diagnosis and Clinical Evaluation sections.

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PATHOPHYSIOLOGY
The Neuroanatomy of Consciousness The following discussion is drawn from the unequaled clinical work of Plum and Posner.[30] CNS depression occurs secondary to one of two anatomically distinct neurologic processes. The first is global injury to, or functional impairment of, the cerebral cortex.[30] A myriad of toxic and metabolic disturbances depress global brain function leading to stupor and coma ( Tables 16–3 and 16–4 ).

Table 16-3 -- Classes of Drugs/Toxins That Cause Central Nervous System Depression Class Anticholinergic Agents Antihistamines Belladonna alkaloids Group Examples Diphenhydramine, chlorpheniramine Hyoscyamine, scopolamine Carbamazepine Anticonvulsants Phenobarbital Phenytoin Valproate Cyclic antidepressants Amitriptyline Imipramine Antidepressants Selective serotonin reuptake inhibitors Fluoxetine Sertraline Nonselective serotonin reuptake inhibitors Cholinergics Insecticides War agents Hypoglycemics Sulfonylureas Venlafaxine Malathion Sarin Glyburide Glipizide Gamma-hydroxybutyrate (GHB) and related compounds Ibuprofen (rare, in large overdoses) Miscellaneous Isoniazid Lead

Class

Group Lithium

Examples

Phencyclidine (PCP) Butyrophenones Phenothiazines Neuroleptic Agents Dibenzodiazepines Haloperidol Chlorpromazine Mesoridazine Thioridazine Clozapine Olanzapine Opioids Alcohols Sedative-hypnotics Barbiturates Benzodiazepines Miscellaneous Sympathomimetics Toxic gases Meperidine, fentanyl, heroin, methadone, morphine Ethanol, ethylene glycol, methanol isopropanol Secobarbital, phenobarbital Diazepam, lorazepam Ethchlorvinyl meprobamate Amphetamines, cocaine Carbon monoxide, cyanide, hydrogen sulfide

Table 16-4 -- Nontoxic Causes of Stupor and Coma Class Hematologic disorders Infectious emergencies Metabolic disorders detected by simple laboratory assessment Metabolic disorders suspected on physical examination Neurologic disorders Neurosurgical emergencies Vasculitis CVA, cerebrovascular accident. Examples Hyperviscosity syndrome, thrombotic thrombocytopenic purpura Bacterial meningitis, meningoencephalitis Hypernatremia, hyponatremia, hypercalcemia, uremia, hyperglycemia, hypoglycemia Hepatic encephalopathy, uremia, myxedema, hypertensive encephalopathy Basilar artery thrombosis, brainstem CVA, subclinical status epilepticus, prolonged postictal state Subdural and epidural hematoma, subarachnoid hemorrhage, intracerebral hemorrhage, brain abscess, brain tumor, subdural empyema Lupus, endocarditis

The second anatomical basis for CNS depression is compression of the brainstem reticular activating system, which is the cause of stupor and coma in patients with focal brainstem injury or expanding CNS

mass lesions. Injury to the reticular activation system, which begins in the proximal brainstem (thalamus) and descends through the midbrain and pons to the medulla, leads to depression of consciousness. In the patient with an expanding supratentorial mass lesion, such as a hematoma, tumor, or abscess, or with massive cerebral edema secondary to a toxin such as ethylene glycol, or acetaminophen-induced hepatotoxicity,[24][26] characteristic neurologic changes occur in a rostral-to-caudal pattern as the mass effect traverses these areas of the brainstem. Pressure on the thalamus results in stupor and an increase in the respiratory rate manifested as hyperventilation or Cheyne-Stokes respiration. As the pressure effect reaches the midbrain, deep coma ensues, with continuing hyperventilation and fixation of the pupils in midposition. Decorticate responses may be present. Compression of the pons is associated with loss of the oculocephalic, or “doll’s eye” reflex and decerebrate or decorticate posturing. Finally, compression of the medulla leads to apnea and motor flaccidity. Discrete injury to the brainstem, such as occurs with cerebellar or pontine hemorrhage or infarct, also causes coma as a result of impairment of the reticular activating system. Neurologic signs are related to the injured area. For example, isolated injury to the pons is associated with posturing or rigidity, followed by quadriplegia and loss of the doll’s eye reflex. Unlike the patient with descending mass effect, the pupils are pinpoint as a result of selective injury to ascending sympathetic fibers and sparing of the anatomically higher parasympathetic functions of the midbrain.[30] In contrast to the patient with structural brain injury, a toxic-metabolic cause of coma produces patchy neurologic impairment. For example, the patient with a barbiturate overdose may have motor flaccidity and apnea, indicative of medullary dysfunction, but sparing of midbrain-mediated pupillary function.[30] Drug Effects on the Central Nervous System Many classes of drugs produce CNS depression when taken in excess. Examples of the more common classes include the sedative-hypnotics, opioids, and anticholinergics. Specific biochemical mechanisms of neuronal impairment have been elucidated for some of these classes of drugs. Agents with sedative-hypnotic properties produce CNS depression by enhancing the effects of gammaaminobutyric acid (GABA), an important CNS inhibitory neurotransmitter. The binding of GABA to specific GABAA receptors opens nearby chloride channels, resulting in an influx of negatively charged chloride ions into the neuron. The resultant cell hyperpolarization prevents membrane excitation and generation of an action potential. Sedative-hypnotics bind to the GABAA receptor complex at specific or nonspecific sites, depending on the agent. Benzodiazepines are one class of sedative agents that have well-defined, specific binding sites. These agents act indirectly by enhancing the response of chloride channels to binding of GABA to the GABAA receptor. They do not stimulate GABA receptors directly. In addition to causing CNS depression through similar facilitation of normal inhibitory mechanisms, other sedative agents such as ethanol and barbiturates depress membrane function by less well-defined membrane effects.[9][36][44] Opioids produce their desired analgesic effects by stimulating mu (Mu1 and Mu2), kappa, and delta receptors in the CNS. Opioids are used primarily for their analgesic effects in clinical practice and recreationally for their ability to produce euphoria. The analgesic effects of opioids are attributed to stimulation of delta, kappa, and Mu1 receptors. The characteristic pupillary constriction seen in opioid poisoning occurs through Mu2,- and kappa receptor–mediated stimulation of the parasympathetic pupillary enervation. After overdose, opioids produce significant CNS and respiratory depression. Respiratory depression is mediated predominantly by the Mu2 receptors.[39]

Scopolamine is a classic example of an anticholinergic agent with significant central effects. It produces confusion, agitation, hallucinations, and coma by interacting with central muscarinic receptors. Atropine, a drug with similar antimuscarinic properties, has very little CNS effect compared with scopolamine. The central muscarinic receptors are poorly defined. However, it is believed that the CNS effects of different agents are related to their ability to penetrate the CNS rather than to their affinity for different receptors. The usual clinical course is one of CNS stimulation (slight disorientation, agitation, hallucinations), followed by more significant dose-dependent CNS depression. Anticholinergic agents produce other characteristic clinical effects by blocking peripheral muscarinic receptors, resulting in dry flushed skin and mucous membranes, tachycardia, urinary retention, mydriasis, and decreased gastrointestinal motility.[7] Sympathomimetic agents such as cocaine have been associated with CNS depression.[6] Initially, these patients present with significant anxiety and agitation, followed by stupor. They assume normal sleeping postures, may be aroused to full orientation with vigorous stimulation, and then immediately fall back into a stuporous sleep. This common complication of cocaine bingeing has been attributed to depletion of neurotransmitters. Many metabolic disturbances cause stupor and coma through less well-defined mechanisms (see Table 16–4 ).

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DIFFERENTIAL DIAGNOSIS
The differential diagnosis of CNS depression resulting from toxins and other causes is extensive (see Tables 16–3 and 16–4 ). The appropriate direction for diagnosis and management is given by the history and physical examination, which are discussed in detail in the following section on clinical evaluation. The laboratory also provides useful information. Toxic Causes Poisoning, either inadvertent or intentional, is a common cause of mental status depression. In addition to the sedative hypnotics, anticholinergics, and opioids with well-defined mechanisms mentioned earlier, many agents cause CNS depression. An extensive list of toxins that may cause coma is found in Table 16–3 . As noted earlier, of all poisonings that cause coma secondary to direct impairment of brain function, cyanide poisoning requires the most urgent intervention. Nontoxic Causes Associated With Drug Use Mass lesions causing CNS depression are also common causes of coma, and their presence must be rapidly detected to prevent irreversible brain injury. Head injury can occur in patients who abuse agents that produce sedation or altered judgment, such as opioids and phencyclidine, so that a patient whose mental state depression is actually due to brain injury may have a history of possible overdose. Subdural and epidural hematomas are traumatic neurosurgical emergencies, and they may be historically and clinically occult in the drug-using patient. Subarachnoid hemorrhage and hemorrhagic cerebrovascular accidents occur as a consequence of cocaine use and can occur after suicidal ingestion of long-acting anticoagulant rodenticides.[19][45] These CNS emergencies progress rapidly in previously neurologically normal patients. A slower onset of neurologic depression occurs in patients with other mass lesions, especially those due to tumors and abscesses. These patients may have a history of headaches or altered behavior that preceded the onset of coma. Fatal frontal lobe abscess has been reported after sinus infections in patients who abuse intranasal cocaine.[34] Mass lesions due to acquired immunodeficiency virus–related toxoplamosis and CNS lymphoma, or brain abscesses due to endocarditis, occur in intravenous drug users. A history of analgesic drug ingestion for headache may lead the clinician to attribute mental status depression to the ingested analgesic, distracting from a search for the cause of the headache. Mental state depression due to acute bacterial meningitis is a diagnostic emergency. Vaculitis caused by thrombocytopenic purpura, endocarditis, or lupus may lead to coma. Cerebral vasculitis has also been reported in association with cocaine abuse.[10][18][25][27][33] Many metabolic disturbances lead to coma. Severe hypothyroidism,[28] hypercalcemia,[4][29] hyperglycemia,[2] hypoglycemia,[1] hypernatremia,[15] hyponatremia,[3][15] and uremia[22] are familiar causes of coma. These frequently occur in patients with suspected or known predisposing medical illness and premonitory symptoms. Hypoxic encephalopathy characteristically follows resuscitation from a period of

apnea or prolonged severe hypoxia. The initiating event is often related to a toxin. In some cases, neurologic recovery is followed by recurrence of coma.[31] Hypertensive encephalopathy is rarely a cause of coma. It is seen in patients with severe or acute elevations of blood pressure, often in patients with known hypertension and in association with papilledema and diastolic blood pressures above 130 mm Hg. [8] Hypertensive patients are predisposed to uremia and to CNS hemorrhage. Hepatic encephalopathy is associated with coma, most often in patients with clinical signs of liver injury and elevation of the prothrombin time and serum ammonia level.[15][40] Patients with liver failure have coagulation disturbances that predispose them to CNS hemorrhage, even in the absence of a history of trauma, so this possibility should always be considered. Seizures cause depression of mental status that often resolves rapidly, aiding in the diagnosis. Stupor (not coma) rarely is caused by partial complex or nonconvulsive status epilepticus, in which characteristic motor movements that suggest seizure activity are absent.[11][12][13] Although acute thiamine deficiency is rarely a cause of coma, it does occur as a near-terminal condition.[41]

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CLINICAL EVALUATION
Clues in the History Information from the family and the scene gives valuable clues to a toxicologic diagnosis. A history of suicidal intention, or history of recreational drug use, witnessed ingestion, empty bottles from the scene, or drug paraphernalia support the likelihood of poisoning as the cause of mental status depression. Determining the available medications or toxicants and the types of medical conditions in family members assists in identifying specific agents that might have been ingested. Sometimes, a history can be elicited of premonitory signs and symptoms occurring in poisoned patients before their progression to coma. These may also be observed in the clinical setting. For example, patients with anticholinergic poisoning may present with a distinctive mumbling, fragmented speech pattern, in which they speak clearly, then trail off into unintelligible words. As delirium progresses, these patients exhibit a “picking” behavior. Children with diphenoxylate-atropine poisoning may initially be hyperactive and babbling incoherently because of an atropine-induced anticholinergic syndrome. Further absorption of the drug can lead to opioid-induced coma. This type of deterioration is common in many progressive toxic or disease processes in which agitated delirium progresses to coma. The circumstances under which the patient was found also provide clues to the diagnosis. If the patient was found in a closed space the possibility of carbon monoxide poisoning should be considered. A comatose patient brought from a gym or a party may have ingested gamma-hydroxybutyrate. The very characteristic dramatic emergence after a period of observation, with rapid return to a normal mental status, confirms this diagnosis. Patients found on the street or at the bottom of a flight of stairs should be carefully assessed for the possibility of a traumatic brain injury. Previous medical illnesses should be carefully explored. A history of complaints before the onset of CNS depression, such as headache, fever, and abnormal behavior is very important, as is witnessed seizure activity. The Physical Examination The physical examination provides valuable information that directs the management and evaluation of the unconscious patient ( Tables 16–5 and 16–6 ). When a toxin is suspected, the examination should reveal findings that would be expected with the suspected toxin ( Table 16–7 ). For example, a patient who is comatose after the suspected ingestion of an opioid should have some sign of opioid intoxication, such as miosis, respiratory depression, and CNS depression, that improves after the administration of naloxone. Conversely, these findings in the absence of a history of opioid exposure suggest the diagnosis of opioid intoxication. A patient suspected of being comatose because of intoxication with ethanol has mild respiratory depression and hypotension, in addition to the characteristic odor of ethanol. These patients should improve steadily with observation. Patients poisoned with anticholinergics typically have some antimuscarinic signs, such as mydriasis, tachycardia, dry flushed skin and mucous membranes, ileus, myoclonus, and bladder distention. Cholinergic agents induce the opposite findings: miosis, diarrhea, salivation, and bronchorrhea. Characteristic odors, such as those of cyanide (bitter almonds) and insecticides (garlic), may be present and should be noted. Barbiturate-like drugs cause respiratory depression and hypotension, whereas benzodiazepine poisoning causes much less respiratory and hemodynamic depression, despite significant CNS depression. As a general rule, for all patients poisoned with sedative hypnotic drugs, pupillary reactivity

is preserved.

Table 16-5 -- The Coma Exam: Pertinent Positives and Negatives HEENT: trauma, hemotympaneum, icterus, pallor, odors (ketones? hydrocarbons? uremia? fetor hepaticus?) NECK: thyroid, carotid pulses, rigidity? CHEST: signs of pneumonia or aspiration HEART: murmurs (endocarditis?) ABDOMEN: ascites, character of bowel sounds, bladder distention EXTREMITIES: cyanosis, petechiae, purpura, splinter hemorrhages, track marks, edema SKIN: petechiae, purpura, uremic frost, color, moisture, bullous lesions (“barb blisters”)

Table 16-6 -- Neurologic Examination Finding Suggests Finding Toxic-Metabolic Hypoventilation Respiration Respiratory acidosis Metabolic acidosis Pupils Reactive Structural Hyperventilation Cheyne-Stokes Respiratory alkalosis Fixed Asymmetric Flaccidity Motor Asterixis Myoclonus Rigidity Reflexes Doll’s eye reflex Clonus, depressed Present Clonus, Babinski’s Absent Skew deviation Reactive pupils Fixed pupils Posturing Asymmetry

Highly predictive coma combinations Normal or decreased tone Posturing Respiratory acidosis Respiratory alkalosis

Table 16-7 -- Common Findings with Drugs Causing CNS Depression

Anticholinergics Opioids Cyclic antidepressants Sympathomimetics Neuroleptic agents Cholinergics Lithium Anticonvulsants

Decreased GI motility, dry flushed skin, hyperthermia, mydriasis, tachycardia, urinary retention, myoclonus Respiratory depression, miosis, hyporeflexia, hypothermia Anticholinergic toxidrome, dysrhythmias, hypotension, seizures Diaphoresis, hypertension, hyperthermia, mydriasis, seizures, tachycardia Rigidity, miosis (variable with phenothiazines), hypotension, anticholinergic signs Miosis, bronchorrhea, salivation, emesis, diarrhea, diaphoresis, fasciculations, muscle weakness Clonus, tremor, myoclonus, ataxia, seizures Nystagmus, ataxia, seizures Gastritis, nystagmus, familiar odor

Alcohols

Fruity breath odor, ketones (isopropanol) Metabolic acidosis (methanol/ethylene glycol)

Barbiturates Benzodiazepines

Hypotension, “barb blisters,” hypoventilation Normotensive, minimal respiratory depression when used as single agent Bitter almond odor (cyanide)

Toxic gases

Rotten egg odor (hydrogen sulfide) Metabolic acidosis: cyanide, hydrogen sulfide

Gamma-hydroxybutyrate (GHB) and related substances

Minimal respiratory depression, normal blood pressure, rapid emergence, nystagmus, no amnesia

CNS, central nervous system; GI, gastrointestinal.

Less specific signs suggest exposure to certain toxins. Deep Kussmaul respirations due to metabolic acidosis are associated with severe salicylism or ingestion of a toxic alcohol. Clonus and tremors are associated with lithium or monoamine oxidase inhibitors. Clonus with neuromotor rigidity suggests the neuroleptic malignant syndrome or a serotonin syndrome. Cerebral edema can occur with toxicity caused by salicylates, ethylene glycol, and methanol, and it can occur with hepatic failure caused, for example, by acetaminophen. Careful examination should be made for signs of infection that suggest meningitis or other CNS infection. Fever or nuchal rigidity, which may be absent in the early stages of bacterial meningitis, should always be assessed. Purpura or petechiae in the comatose patient suggest CNS infection with meningococci or the possibility of thrombotic thrombocytopenic purpura.[25][27] Heart murmur, track marks, Roth spots, or splinter hemorrhages indicate the possibility of endocarditis, with associated meningitis, embolic stroke, or brain abscess as a cause of coma. [10][33]

Certain metabolic disorders have characteristic physical signs that suggest the diagnosis ( Table 16–8 ). These disorders may be toxin induced. Signs of liver injury include icterus, spider angiomata, and a flapping tremor. Blood present in the stool may be the precipitating cause of hepatic encephalopathy in patients with hepatic failure caused by many toxins (see Chapter 21 ). Uremic patients have a dry, “frosty” appearance, may be hypertensive and tachypneic due to metabolic acidosis, and have an odor that suggests ammonia. Additionally, these patients have tremor, asterixis, increased motor tone, and seizures. [22] Patients with diabetic ketoacidosis appear dehydrated, have deep Kussmaul respirations, and the sweet odor of ketosis, which is not detectable by all examiners. A history of polyuria may be obtained. Diabetes mellitus has been produced by ingestion of Vacor (N-3-pyridylmethyl-N'-p-nitrophenyl urea). The families of patients with hypercalcemia may give a history of excessive ingestion of vitamins (hypervitaminosis A or D) or antacids; use of androgens, glucocorticoids, or thiazide diuretics; or a history of malignancy, bone pain, polyuria, or constipation. These patients also appear dehydrated with decreased skin turgor. Severe hypernatremia is associated with toxins that produce diabetes insipidus, such as lithium, with use of osmotic laxatives, such as sorbitol, lactulose, and glycerol; with excessive intake of sodium salts; or with inadequate access to water, such as a poorly tended nursing home patient or a homebound elderly person. Myxedema coma is suggested by diffuse, nonpitting edema; alopecia; loss of the lateral eyebrows; and very characteristic “hung up” reflexes. Hypothermia and hypoventilation are common. The family may give a history of loss of energy and constipation. Hypothyroidism can occur in patients taking lithium, although myxedema would be unlikely to occur,[21] and the diagnosis is also supported by a history of treatment for thyroid disorders or a surgical scar that suggests thyroid surgery.[28] It is important to consider this diagnosis because routine laboratory assessment does not give clues beyond the history and physical examination. Severe thiamine deficiency is characterized by ataxia and ophthalmoplegia. The finding of ophthalmoplegia, manifest as paralysis of the normal oculomotor, or doll’s eye, reflex in association with sparing of the pupillary response, should prompt consideration of severe thiamine deficiency as a cause of coma.[41]

Table 16-8 -- Findings Associated with Common Metabolic Causes of Stupor and Coma Condition Finding Laboratory Hypoglycemia, mild hyponatremia, mild hyperkalemia, mild metabolic acidosis Elevated prothrombin time, ammonia, bilirubin Calcium >14 mg/dL Glucose >800 mg/dL Sodium >160 mEq/dL Hypocalcemia Tetany, hyperreflexia Coma is unusual unless seizures occur Hyponatremia Myxedema Seizures, delirium, coma, myoclonus, asterixis Dough edema, “hung-up” reflexes, mild hypothermia, mild hypercarbia Sodium <120 mEq/dL Elevated TSH Ionized Ca2 + <2 mg/dL Adrenal Hypotension, tachycardia, stupor, fever insufficiency, severe Hepatic encephalopathy Hypercalcemia Hyperosmolar states Icterus, asterixis, spider angiomata, ascites Tenting, polyuria, dehydration, constipation Tenting, dehydration

Condition

Finding

Laboratory Metabolic acidosis

Thiamine deficiency Diplopia, ataxia, confusion coma, (severe) ophthalmoplegia, hypotension Uremia

Pallor, seizures, tremor, hyperventilation, Elevated BUN and creatinine, anemia, odor of uremia, asterixis, myoclonus, metabolic acidosis, hypocalcemia, “frost” hyperphosphatemia

BUN, blood urea nitrogen; TSH, thyroid-stimulating hormone. Findings That Suggest a Structural Cause of Coma A careful examination should be made for signs of trauma. The neurologic exam provides critical clues to the more urgent neurosurgical diagnoses. The presence of papilledema is a big clue. However, papilledema develops in patients who have had an expanding mass lesion for a period of time and is not seen in those with acute mass effects due to trauma. Patients with a rapidly increasing intracranial pressure do lose spontaneous venous pulsations, which is a less specific sign. Mass lesions cause other characteristic findings that speak against the diagnosis of a toxin and give clues to the need for emergent computed tomographic scanning. Focality, although it may occur transiently in certain kinds of encephalopathy and in the postical and posthypoglycemic states, strongly suggests the presence of a mass lesion. This includes the characteristic finding of the “blown pupil,” caused by third nerve compression from uncal herniation. These neurologic signs of mass effect are straightforward and are not discussed further. Many patients with traumatic brain injury have no history or physical signs of trauma. Diagnostic errors occur when clinicians fail to appreciate subtle signs of increased intracranial pressure in patients who do not have discernible focality and are mistakenly thought to be poisoned. A very early and characteristic sign of increased intracranial pressure is an elevation of the respiratory rate that results in respiratory alkalosis. This may also be accompanied by an elevation of the blood pressure. As the mass effect progresses, the pupils become fixed, usually in midposition. This presentation contrasts with the patient with CNS depression resulting from a sedative hypnotic agent, where coma is often associated with some degree of respiratory depression and pupils are spared. The comatose patient with an increased respiratory drive that is not due to metabolic acidosis should be suspected of having brain injury as the cause of coma. Other causes of a primary respiratory alkalosis include sepsis, hepatic failure, salicylism, theophylline poisoning, and cardiopulmonary disorders, such as hypoxia, pulmonary embolism, and tamponade ( Table 16–9 ). Cardiopulmonary disorders do not cause coma except in the setting of profound hypoxia or shock, although pulmonary aspiration can occur in patients with coma of other causes. Progression to fixed pupils confirms the presence of a mass lesion. Unlike the patient with severe anticholinergic poisoning who has widely dilated, fixed pupils in the setting of other peripheral anticholinergic signs, these patients with progressive brainstem compression have small or midposition pupils associated with hyperventilation.

Table 16-9 -- Causes of Hyperventilation

Increased intracerebral pressure Focal brainstem injury Metabolic acidosis of any cause Cardiopulmonary disorders Meningoencephalitis Sepsis Hepatic failure Toxins: e.g., salicylates, theophylline, dinitrophenol

A rare cause of coma that is a diagnostic emergency because it is treatable if it is recognized is an acute basilar artery thrombosis.[5] These patients often have underlying cerebrovascular disease that has resulted in previous symptoms of vertigo, diplopia, dysarthria, or drop attacks.[20] Neurologic findings in these cases suggest brainstem injury, which may be incomplete or asymmetric. The sudden onset of coma with fixed small or midposition pupils, impairment of doll’s eye reflex, hyperventilation, and posturing are clues to this diagnosis.[20][30] A final useful aspect of the clinical evaluation of a patient with CNS depression is the period of observation that follows the initial evaluation. Patients with seizures or mild intoxications with agents such as gammahydroxybutyrate and ethanol improve with observation. Patients with expanding CNS mass lesions, untreated meningitis, or severe poisoning deteriorate. Failure to improve or evidence of deterioration in a patient believed initially to have a minor problem should prompt timely reassessment.

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LABORATORY EVALUATION
A computed tomographic scan of the head should be performed immediately after resuscitation in any patient suspected of having a CNS mass lesion as a cause of coma. This includes the patient with a focal neurologic examination, fixed pupils (unless there is a clear history of anticholinergic exposure with a confirmatory toxidrome), papilledema, or unexplained respiratory alkalosis and coma. The electrocardiogram provides valuable information regarding the possible presence of certain toxins. The characteristic electrocardiographic changes associated with overdose of a cyclic antidepressant are helpful in assessing the patient with an anticholinergic syndrome. Minor conduction disturbances that suggest poisoning occur in patients poisoned with lithium, carbamazepine, and some of the neuroleptics. Characteristic QT prolongation occurs in patients poisoned with mesoridazine and thioridazine, sometimes leading to torsades de pointes tachycardia. The arterial blood gas provides valuable information regarding the differential diagnosis of coma. In the comatose patient, metabolic acidosis is seen in patients who are postictal or who have ketoacidosis, uremia, sepsis, or poisoning with a toxic alcohol, iron, cyanide, azide, salicylates, or a biguanide, such as metformin. Respiratory acidosis is seen in patients with sedative hypnotic or opioid overdose, as well as patients with spinal cord injury and other structural or intrinsic pulmonary disorders associated with hypoventilation. Respiratory alkalosis occurs in patients with increased intracranial pressure, sepsis, aspiration, hepatic failure, or poisoning with salicylates or theophylline (see Chapter 11 for a more extensive discussion of acidbase disturbances). Measurement of serum sodium, blood urea nitrogen, calcium, and glucose levels may give information regarding the primary cause of coma. Mild hypnonatremia and hyperkalemia suggest adrenal insufficiency. An elevated anion gap indicates certain toxins, as well as the possibility of acidosis from uremia, ketoacidosis, seizures, shock, or hypoxia. Toxic agents that can cause CNS depression and an anion gap metabolic acidosis include carbon monoxide, cyanide, azide, ethylene glycol, iron, isoniazid, methanol, paraldehyde, salicylate, and toluene. Poisoned patients with CNS depression can also be evaluated for an osmol gap, although a “negative” gap does not eliminate the toxic possibilities (see Chapter 11 ). Toxins that produce both CNS depression and an elevated osmol gap include ethanol, ethylene glycol, methanol, and isopropanol. A small increase in the osmol gap is seen in chronic renal failure (<20 mOsm) and significant lactic and ketoacidosis (<15 mOsm).[35][37] CNS depression and an anion gap metabolic acidosis accompanied by an osmol gap should immediately suggest poisoning with ethylene glycol or methanol ( Table 16–10 ). Peripheral metabolic acidosis per se does not cause alteration of mental status.[30]

Table 16-10 -- Differential Diagnosis of Central Nervous System Depression

Anion Gap Acidosis Toxins Carbon monoxide, cyanide, ethylene glycol, iron, ibuprofen (rare, large overdoses), isoniazid, metformin, methanol, paraldehyde, salicylate, and toluene Ketoacidosis: diabetic, alcoholic, starvation Metabolic causes Lactic acidosis: Shock, seizures, sepsis, severe adrenal insufficiency, severe thiamine deficiency, Uremia

Osmolar Gap Ethylene glycol, ethanol, methanol, isopropanol <15 mOsm

<20 mOsm

Thyroid-stimulating hormone should be measured in patients in whom myxedema coma is suspected. An acetaminophen level should be measured in all patients with suspected suicidal ingestion. Elevated creatinine phosphokinase levels indicate the possibility of rhabdomyolysis due to muscle compression or compartment syndrome in comatose patients. The demonstration of thrombocytopenia and hemolytic anemia on the complete blood count is most useful in the diagnosis of thrombotic thrombocytopenic purpura.[25][27] The white blood cell count is not sufficiently sensitive or specific to rule in or exclude infections as a cause of coma. A lumbar puncture is required when meningitis or menigoencephalitis is suspected on the basis of the history or examination. A toxicologic screen may give no information, may be helpful, or may mislead. A positive toxicologic screen for cocaine, opiates, or ethanol commonly occurs in patients with CNS injury or infection but may be an indicator of remote use and does not necessarily indicate clinical toxicity with the demonstrated drug. In addition, many intoxicants are not detected by routine laboratory screens. A quantitative level of an agent such as carbon monoxide (carboxyhemoglobin), lithium, phenobarbital, carbamazepine, theophylline, salicylate, or ethanol that is sufficiently high to cause coma in a patient suspected of poisoning with that agent is very helpful. The significance accorded to the results of a toxicologic screen should always be considered in the context of the history, the physical examination, and the patient’s clinical course. The electroencephalogram is a useful tool when partial complex or nonconvulsive status epilepticus is suspected as a cause of coma.[12][13] It is also useful to distinguish patients with psychogenic causes of coma.[30][32]

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DEFINITIVE TREATMENT
The definitive treatment of the comatose patient depends on the cause of the CNS depression. Excellent supportive care in an intensive care environment is essential in all cases. The importance of early detection of CNS mass lesions, basilar artery thrombosis, and bacterial infections has been emphasized. Most patients with CNS depression related to poisoning who arrive alive in the hospital do well with supportive care and decontamination with activated charcoal. Specific agents may require specific antidotal therapies or decontamination with whole-bowel irrigation or dialysis. The reader is referred to the specific chapter of that poison/toxin for more details concerning definitive treatment and to the chapters on decontamination and extracorporeal therapies (see Chapters 5 and 6 ).

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DISPOSITION/NEED FOR CONSULTANTS
Poisoned patients with CNS depression need to be medically treated until they return to their normal mental status. Patients with prolonged periods of CNS depression should be admitted to an intensive care unit. A Regional Poison Control Center is an invaluable tool in determining the cause of the CNS depression, in obtaining treatment recommendations, and in accessing the expertise of a medical toxicologist.

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REFERENCES
1. Agardh CD, Folbergrova J, Siesjo BK: Cerebral metabolic changes in profound insulin-induced hypoglycemia, and in the recovery period following glucose administration. J Neurochem 1978; 31:11351142. 2. Arieff AI, Carroll HJ: Nonketotic hyperosmolar coma with hyperglycemia: Clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine 1972; 51:73-94. 3. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine 1976; 55:121-129. 4. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 1992; 26:1196-1202. 5. Brandt T, von Kummer R, Muller-Kuppers M, et al: Thrombolytic therapy of acute basilar artery occlusion: Variables affecting recanalization and outcome. Stroke 1996; 27:875. 6. Brody SL, Slovis CM, Wrenn KD: Cocaine-related medical problems: Consecutive series of 233 patients. Am J Med 1990; 88:325-331. 7. Brown JH, Taylor P: Muscarinic receptor agonists and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al ed. Goodman & Gilman's The Pharmacologic Basis of Therapeutics, 9th ed. New York: McGraw-Hill; 1996:141-160. 8. Chester EM, Agamanolis DP, Banker BQ, Victor M: Hypertensive encephalopathy: A clinicopathologic study of 20 cases. Neurology 1978; 28:928-939. 9. Curry SC, Mills CM, Graeme KA: In: Neurotransmitters P., Goldfrank LR, Flomenbaum N, Lewin N, et al ed. Goldfrank's Toxicologic Emergencies, Stamford, CT: Appleton & Lange; 1998:137-171. 10. Delaney KA: Endocarditis in the emergency department. Ann Emerg Med 1991; 20:405-414. 11. Ellis JM, Lee SI: Acute prolonged confusion in later life as an ictal state. Epilepsia 1978; 19:119-128. 12. Engel Jr J, Ludwig GI, Retell M: Prolonged partial complex status epilepticus: EEG and behavioral observations. Neurology 1978; 28:363-369. 13. Fagan KJ, Lee SI: Prolonged confusion following convulsions due to generalized nonconvulsive status epilepticus. Neurology 1990; 40:1689. 15. Fried LF, Palevsky PM: Hyponatremia and hypernatremia. Med Clin North Am 1997; 81:585-609. 16. Hoffman JR, Schriger DL, Luo JS: The empiric use of naloxone in patients with altered mental status. Ann Emerg Med 1991; 20:256. 17. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness: Controversies in the use of the “coma cocktail”. JAMA 1995; 274:562-569.

18. Kaye BR, Fainstat M: Cerebral vasculitis associated with cocaine abuse. JAMA 1987; 258:2104-2105. 19. Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med 1992; 21:331336. 20. Kubik CS, Adams RD: Occlusion of the basilar artery: A clinical and pathological study. Brain 1946; 69:73-121. 21. Lazarus JH: The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid 1998; 8:909-913. 22. Locke S, Merrill JP, Tyler HR: Neurologic complications of acute uremia. Arch Intern Med 1961; 108:519-530. 23. Lopez A, Rebollo J: Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med 1990; 18:1480-1481. 24. Makin AJ, Wendon J, Williams R: A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993). Gastroenterology 1995; 109:1907-1916. 25. Moake JL: Haemolytic-uraemic syndrome: Basic science. Lancet 1994; 343:393-397. 26. Morgan B, Ford M, Follmer R. Ethylene glycol ingestion resulting in brainstem and midbrain dysfunction. J Toxicol Clin Toxicol, in press 27. Neild GH: Haemolytic-uraemic syndrome in practice. Lancet 1994; 343:398-401. 28. Newmark SR, Himathongkam T, Shane JM: Myxedema coma. JAMA 1974; 230:884-885. 29. Patten BM, Bilezikian JP, Mallette LE, et al: Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974; 80:182-193. 30. Plum F, Posner JB: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1982. 31. Plum F, Posner JB, Hain RF: Delayed neurological deterioration after anoxia. Arch Intern Med 1962; 110:18-25. 32. Pro JD, Wells CE: The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst 1977; 38:804-808. 33. Pruitt AA, Rubin RH, Karchmer AW, et al: Neurologic complications of bacterial endocarditis. Medicine 1978; 57:329-343. 34. Rao AN: Brain abscess: A complication of cocaine inhalation. NY State J Med 1988; 88(10):548-550. 35. Schelling JR, Howard RL, Winter SD, et al: Increased osmolal gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 1990; 113:580. 36. Sieghart W: Structure and pharmacology of gamma-amino butyric acid A receptor subtypes. Pharmacol Rev 1995; 47:181-234. 37. Sklar AH, Linas SL: The osmolal gap in renal failure. Ann Intern Med 1983; 98:481-482.

38. Spivey WH: Flumazenil and seizures: Analysis of 43 cases. Clin Ther 1992; 14:292-305. 39. Sporer KA: Acute heroin overdose. Ann Intern Med 1999; 130:584-590. 40. The brain in fulminant hepatic failure. Lancet 1991; 338(156):[Editorial] 41. Wallis WE, Willoughby E, Baker P: Coma in the Wernicke-Korsakoff syndrome. Lancet 1978; 2:400403. 42. Wass CT, Lanier WL: Glucose modulation of ischemic brain injury: Review and clinical recommendations. Mayo Clin Proc 1996; 71:801-812. 43. Watson AJS, Walker JF, Tomkin GH, et al: Acute Wernicke’s encephalopathy precipitated by glucose loading. Ir J Med Sci 1981; 150:301-303. 44. Whiting PJ, McKernan RM, Waffard KA: Structure and pharmacology of vertebrate GABAA receptor subtypes. Int Rev Neurobiol 1995; 38:95-138. 45. Wokak JC, Flann ES: Intracranial hemorrhage and cocaine use. Stroke 1987; 18:712-715.

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Uncited reference Feske SK: Coma and confusional states: Emergency diagnosis and management. Neurol Clin 1998; 16:238-256.

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Chapter 17 – Central Nervous System Agitation
LARISSA VELEZ-DAUBON KATHLEEN A. DELANEY

Essentials • • • Manage immediate life threats: airway, breathing, and circulation (ABCs) Assess core temperature and glucose level Control agitation with physical restraints, followed by chemical restraints ° Prevent injury to the patient and health care personnel ° Decrease complications, such as hyperthermia and rhabdomyolysis

• •

Examine for specific toxidromes that aid in the differential diagnosis of agitation Consider toxic, traumatic, infectious, structural, and metabolic causes before arriving at the diagnosis of psychiatric disturbances

INITIAL STABILIZATION AND TREATMENT
Life-threatening airway and hemodynamic compromise commonly causes agitation. Hypoxia and shock need to be diagnosed and treated immediately, followed by detection and treatment of hypoglycemia and hyperthermia. Diabetic patients whose disease is poorly controlled may have adrenergic and neuroglycopenic symptoms despite a “numerical euglycemia.” Such patients may have symptomatic hypoglycemia at plasma glucose levels that are considered to be in the normal range.[6] Also, the assessment of the hydration status of the agitated patient is important because dehydration is a common finding. An initial rhythm strip should be obtained to search for arrhythmias and QRS widening. The presence of agitation should not delay resuscitation and treatment. Studies note that agitation often interferes with and delays the delivery of medical care.[12] Malnourished or alcoholic patients should receive thiamine hydrochloride, 100 mg intravenously, during the initial treatment in order to prevent the occurrence of Wernicke encephalopathy. This therapy has been found to be safe and cost-effective in preventing delayed deterioration in function of the alcoholic patient. [29] To facilitate evaluation and treatment, initial management also includes physical restraint, quickly followed by chemical restraint. A combination of physical and chemical restraints has been found to be the safest and most effective approach to the management of agitation. Physical control of the patient prevents injury to the patient and to health care personnel, and chemical restraints prevent the development of complications associated with prolonged motor agitation. The most important of these complications are rhabdomyolysis and potentially lifethreatening hyperthermia. [11][15][49] The selection of agents for chemical restraint is discussed in Definitive

Treatment. After treatment of threats to life and adequate sedation, a detailed examination should focus on signs of injury, infection, endocrine disturbance, hepatic or renal failure, and neurologic deficits. Examination should include a search for common toxidromes, especially signs of anticholinergic or sympathomimetic poisoning, which commonly present with agitation. A thorough neurologic examination, including an examination of the mental status, is essential. When the history or physical examination suggests the possibility of a significant toxic ingestion, gastrointestinal decontamination with 1 g/kg of activated charcoal is indicated. Gastric lavage is generally contraindicated in the agitated patient because of the risk of complications, unless a recent lethal ingestion is suspected (see Chapter 5 ). Because of the risk of aspiration, induction of vomiting is also contraindicated in any patient with an altered mental status.

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DIFFERENTIAL DIAGNOSIS
In general, the causes of agitation can be divided into toxic, neurologic (structural), infectious, metabolic, and functional disorders. Toxins Toxic exposures that lead to agitation fall into four categories: (1) recreational exposure to illicit drugs, (2) inadvertent overdose or idiosyncratic response to pharmaceutical agents, (3) suicidal ingestion, and (4) exposures to environmental agents. Common recreational drugs that result in agitation include cocaine, amphetamines, phencyclidine, and the hallucinogens. Suicidal ingestion of many medications and drugs may initially present as delirium, followed by deeper states of depression of consciousness (see Chapter 16 ). This group includes agents with anticholinergic properties (e.g., the antihistamines, tricyclic antidepressants, and neuroleptics), lithium, monoamine oxidase inhibitors, and salicylates. Delirium may also result from combinations of therapeutic amounts of serotonergic agents, resulting in the serotonin syndrome (see Chapter 63 ). The elderly are particularly susceptible to central nervous system (CNS) effects of therapeutic drugs. Numerous agents have been associated with agitated delirium in the elderly, particularly because of polypharmacy and the elderly’s use of medications with anticholinergic properties.[14][37][44] Occupational, inadvertent, recreational, or suicidal exposure to many nonpharmaceutical agents must also be considered. These agents include carbon monoxide, pesticides, hydrocarbons, and certain mushrooms (see Table 17–1 for agents that can cause agitation).

Table 17-1 -- Toxic Causes of Agitated Delirium Anticholinergic agents Antihistamines: diphenhydramine, chlorpheniramine, pyrilamine Antipsychotics: phenothiazines, butyrophenones, thiothixenes Antispasmodics: orphenadrine, cyclobenzaprine Antidepressants: amitriptyline, nortriptyline Antiparkinsonians: benztropine, amantadine[22] Antiemetics: prochlorperazine Atropine, scopolamine Adrenergic agonists Cocaine Amphetamine and its derivatives (methamphetamine, MDMA) Phenylpropanolamine Ephedrine/pseudoephedrine Xanthines (caffeine, theophylline, aminophylline)

Phencyclidine (PCP) Hallucinogens LSD Mushrooms Aspirin Lithium Alcohol Carbon monoxide Monoamine oxidase inhibitors Steroids Valproate-induced hepatic encephalopathy Hydrocarbons Combinations of serotonergic agents (serotonin syndrome) SSRIs: paroxetine, sertraline Withdrawal syndromes Sedative-hypnotics Gamma hydroxybutyrate (GHB) Ethanol Opiates Amantadine[22] Unusual: propranolol,[38] ibuprofen[48] Environmental/occupational Long-term manganese exposure (“manganese madness”) Long-term organophosphate/carbamate exposure Long-term lead, mercury, arsenic, aluminum exposure LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; SSRI, selective serotonin reuptake inhibitor. Neurologic/Structural These patients may have evidence of trauma or focality on neurologic examination, although often they do not. The most commonly encountered lesions are frontal contusions, subdural hematomas, subarachnoid hemorrhages, and space-occupying lesions. Spontaneous cerebrovascular accidents are also associated with acute agitation.[42] Patients at special risk are those with history of alcoholism, chronic hypertension, or cocaine abuse; the elderly, and patients receiving anticoagulation. Patients with diffuse CNS injury may also present with agitated delirium that progresses to coma. A postictal state may also be a cause of agitation.

Infectious Delirium is a common complication of CNS infection. Physical signs of CNS infection include fever and meningeal irritation. Petechiae or purpura may also be noted, especially when Neisseria meningitidis is the etiologic organism. Risk factors for these infections include immunosuppression, intravenous drug use, sinusitis, and cerebrospinal fluid leaks. Many patients experience meningitis or meningoencephalitis without any predisposing risk factors. In addition, many patients with meningitis, particularly the elderly and children younger than 2 years, may not show the nuchal rigidity commonly associated with meningeal irritation. Metabolic Many metabolic abnormalities can result in agitation. The most commonly encountered abnormality is hypoglycemia, and the importance of an initial peripheral glucose evaluation cannot be overemphasized. Patients with hypernatremia, hyponatremia, hypercalcemia, hyperglycemia, or uremia may present with mild mental status alterations that progress to coma. Encephalopathy due to thrombotic thrombocytopenic purpura, hepatic failure, thyrotoxicosis, or severe hypertension may also present with extreme agitation (see Table 17–2 for a differential diagnosis of nontoxic causes of agitation).

Table 17-2 -- Nontoxic Causes of Agitation Neurologic/structural Frontal contusion Subarachnoid hemorrhage Subdural hematomas Space-occupying lesions Normal-pressure hydrocephalus Seizures/postictal states Cerebrovascular accidents Dementia (Alzheimer’s disease, multi-infarct, AIDS) Rare: Huntington disease[50] Infectious Meningitis Encephalitis Brain abscess Sepsis Metabolic Hypoglycemia/hyperglycemia Hyponatremia

Hypercalcemia (malignancy, hyperparathyroidism) Uremia (renal failure) Hypercarbia Hypoxemia (pulmonary embolism, pneumothorax, pulmonary edema, arrhythmias, MI) Hypothermia/hyperthermia Hepatic encephalopathy Vitamin deficiency (thiamine [Wernicke encephalopathy], folic acid, vitamin B 12, niacin [pellagra], pyridoxine) Porphyria Rare: Wilson disease Hypertensive encephalopathy Pheochromocytoma Thyrotoxicosis (thyroid storm)/hypothyroidism (“myxedema madness”) Functional Schizophrenia Personality disorder (antisocial, borderline) Psychogenic (anxiety) Bipolar disorder (mania) AIDS, acquired immunodeficiency syndrome; MI, myocardial infarction.

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CLINICAL EVALUATION
A thorough physical examination should note the presence or absence of evidence of head trauma, including an evaluation for hemotympanum and evidence of cerebrospinal fluid rhinorrhea. Pupil size, symmetry, and reactivity give important information. Small, poorly reactive pupils are commonly seen with the metabolic encephalopathies, whereas large pupils suggest adrenergic stimulation or cholinergic blockade. A single dilated and sluggish or fixed pupil in an awake patient suggests an expanding posterior communicating artery aneurysm.[24] Nystagmus is an important, although nonspecific, ocular finding that characterizes many toxic-metabolic encephalopathies and, occasionally, structural causes of agitation. The funduscopic examination, although difficult in these patients, can yield valuable information regarding chronic medical conditions, such as hypertension and diabetes mellitus. Other significant findings in the funduscopic examination are the subhyaloid hemorrhages associated with subarachnoid hemorrhage and papilledema seen in association with chronically increased intracranial pressure. The mouth should be examined for dehydration, signs of tongue biting, and abnormal odors, such as ketones, fetor hepaticus, uremia, and hydrocarbons. The presence of cyanosis or jaundice should be noted. Signs of meningeal irritation suggest meningitis or subarachnoid hemorrhage. The cardiopulmonary examination should note murmurs, which may suggest endocarditis or cerebral embolization, and signs of pulmonary congestion, infection, or bronchospasm. The character of the patient’s breathing gives important diagnostic clues. Hyperventilation in the agitated patient is associated with metabolic acidosis, anxiety, fever, and poisoning with salicylates, cyanide, carbon monoxide, and theophylline. It is also an early sign of increased intracranial pressure. The abdominal examination should include a careful assessment of bowel sounds and evidence of bladder distention. The clinician should carefully inspect the extremities for needle tracks and the skin for petechiae and purpura and should also note the presence or absence of moisture. Stigmata of chronic liver disease include spider angiomas, bitemporal atrophy, ascites, gynecomastia, testicular atrophy, asterixis, and caput medusae. Table 17–3 shows some specific findings associated with nontoxic causes of agitation.

Table 17-3 -- Findings in Selected Nontoxic Causes of Agitation Condition Vital Signs History Tachycardia, Palpitations, weight loss, hypertension (wide heat intolerance, frequent pulse pressure), bowel movements increased temperature Fever, tachycardia Headache

Clues in Examination Fine hair, lid lag, exophthalmos, stare, enlarged thyroid, proximal weakness, tremor, excessive sweating Nuchal rigidity, +/- altered mental status, petechiae, purpura

Thyrotoxicosis

Meningitis

Condition Hepatic encephalopathy

Vital Signs Tachypnea, tachycardia

History

Clues in Examination Spider angiomas, bitemporal atrophy, ascites, gynecomastia, testicular atrophy, icterus, asterixis, caput medusae Flame-shaped hemorrhage, AV nicking, cotton wool patches, disc blurring/papilledema Subhyaloid hemorrhage New murmur, needle tracks, Roth spots, Janeway lesions, splinter hemorrhages Hypoxemia, acidosis, leukocytosis, petechiae Ataxia, ophthalmoplegia

Ethanolism, hepatitis

Hypertensive encephalopathy Subarachnoid hemorrhage Endocarditis

Hypertension

Hypertension

Tachypnea

Sudden, unusual headache

Fever, tachycardia Fever (+/-), tachycardia, hypotension Normal (+/-), tachycardia

IVDA, fevers

Sepsis Wernicke encephalopathy

Immunocompromise

Ethanolism, malnutrition

AV, arteriovenous; IVDA, intravenous drug abuse. Neurologic Examination A complete neurologic examination should focus on evidence of impairment of both focal and global brain dysfunction. Focal abnormalities suggest a structural lesion and include asymmetry of cranial nerves, motor strength, and reflexes, as well as aphasia, agnosia, or apraxia. Impairment of orientation and fluctuating wakefulness suggest the global CNS impairment of delirium. Myoclonus, tremor, diffuse hyperreflexia, cogwheeling, and rigidity all are seen in patients with various causes of delirium. None of these findings should be present in the patient in whom a functional psychiatric disorder is considered. Mental Status Examination The mental status examination is described in Table 17–4 . The term delirium (also referred to as acute confusional state) refers to an acute cognitive impairment characterized by an attention deficit and a fluctuating level of consciousness.[36] The patient can also display disturbances in the sleep-wake cycle, disturbed psychomotor behavior, emotional disturbances, and impaired judgment.[17][40] Delirium is a readily reversible condition if a treatable cause is identified early. When it is not recognized and diagnosis and treatment are delayed, the mortality in patients with delirium is between 15 and 30 per cent.[46][55] It is one of the most common presentations of medical illness in the elderly.[40][45] In contrast to delirium, dementia is a chronic, gradual deterioration of the cognitive (intellectual) functions that is not associated with altered level of consciousness and does not have a fluctuating course. It is usually accompanied by impairment of the recent memory, even in its early stages.[51] The demented patient who presents with an abrupt deterioration in the baseline functioning should be evaluated for superimposed delirium.[53] Table 17–5 describes the differences between dementia and delirium.

Table 17-4 -- Mental Status Examination Appearance and behavior Level of consciousness: wakefulness, alert, follows commands Posture and motor behavior: restlessness, handwringing, singing Dress, grooming, and personal hygiene Facial expression: apathy, anger, elation Manner, affect, and relationship with other persons: appropriate, suspicious Speech and language Quantity, rate, volume, fluency Mood (sad, elated, indifferent, anxious) Thought process (flight of ideas, loose associations, incoherence) Thought content (compulsions, obsessions, phobias, hallucinations) Insight Judgment Memory (recent, remote) Attention (serial sevens, backward spelling) Mini-Mental State Examination can also be included

Table 17-5 -- Differentiating Between Dementia and Delirium Dementia Normal vital signs Normal/unremarkable physical examination Gradual/insidious onset Prior history usual Normal alertness Difficulty finding words, perseveration Disoriented, recent memory more affected than remote +/- Auditory hallucinations, delusions (often absent) Stable mood Fragmented sleep Delirium Abnormal vital signs frequent Multiple clues of organic illnesses Acute onset No prior psychiatric history Impaired/fluctuating alertness, confused Pressured speech Disoriented, immediate memory more affected than remote Visual or tactile hallucinations (poorly organized) Labile mood Altered sleep-wake cycle

Psychosis is defined as a disorder characterized primarily by well-organized hallucinations or delusions.

Normally, alertness and cognition are not impaired. The differences between agitated patients with an organic (delirium) and patients with a functional (psychiatric) disorder have been well described in the literature.[40][44] Delirium is characterized by global impairment of cognitive functions. Disorientation in some or all spheres (time, date, place, person) is always present, the extent and severity of which depend on the severity of the delirium. Wakefulness and orientation often fluctuate. The thoughts are disorganized and the mood is labile. Visual hallucinations are more common in delirium, in contrast to the predominantly auditory hallucinations of psychosis. Hallucinations are not frequently present in dementia. Functional (psychiatric) disorders can be differentiated from delirium by the preservation of cognitive functions in the first group. Orientation is intact, and delusions are very well organized. The mood is also constant. The most commonly encountered functional disorders causing agitation are schizophrenia, the personality disorders, and bipolar disorder. If asked, most of these patients give a history of a psychiatric illness. Although it is always true that disorientation and impairment of wakefulness imply delirium, apparently “functional” disorders are occasionally associated with organic disturbances, such as brain tumors and temporal lobe seizures. In this particular group of patients, the age of onset of symptoms may give clues to an organic cause.[34] Table 17–6 demonstrates the differences between an organic (delirium) and a functional (psychosis) cause of agitation. A screening study of 1140 patients demonstrated that the evaluation of four parameters identifies most patients with delirium. These are (1) disorientation, (2) abnormal vital signs, (3) clouded consciousness, and (4) age greater than 40 without prior psychiatric history.[21] Toxidromes Specific toxidromes that predominantly affect the vital signs, skin, pupils, and gastrointestinal tract characterize intoxication with certain agents. Table 17–7 summarizes familiar toxidromes seen in poisonings that present with agitation.

Table 17-7 -- Common Toxidromes Presenting with Agitation Name Vital Signs Physical Examination Mydriasis, bladder distention, ileus, myoclonus, anhidrosis (including axillae) Diaphoresis, tremor, mydriasis

Laboratory/Diagnostics QRS (>0.10 sec), suspect TCA; QT prolonged, suspect trifluoperazine (Stelazine) or thioridazine (Mellaril) Metabolic acidosis, hyperglycemia, hypokalemia, leukocytosis Complications: rhabdomyolysis (ARF), hyperthermia, myocardial ischemia

Anticholinergic

Tachycardia, fever

Tachycardia, fever, hypertension Sympathomimetic

Salicylates

Tachypnea/hyperpnea, fever

Hyperpnea

Increased anion gap, respiratory alkalosis/metabolic acidosis, ketonuria

Name

Vital Signs

Physical Examination Diaphoresis, diarrhea, tremor, hyperreflexia, rigidity, ataxia, nystagmus Chest pain, headache disorientation Miosis, hyperreflexia, nystagmus, ataxia

Laboratory/Diagnostics

Fever, tachycardia, Serotonin syndrome hypertension

Nonspecific

Carbon monoxide Phencyclidine (PCP) Lysergic acid diethylamide (LSD) Lithium Sedative-hypnotic withdrawal Opioid withdrawal

Tachycardia Tachycardia, hyperthermia Tachycardia Tachycardia Tachycardia, mild hypertension Mild tachycardia

Increased COHgb levels Complications: rhabdomyolysis (ARF), hyperthermia

Delusions, Complications: hyperthermia, hallucinations, paranoia, rhabdomyolysis (ARF) distorted perception Tremors, hyperreflexia Tremors, mydriasis, anxiety, seizures Diarrhea, vomiting, yawning, piloerection, needle tracks Prerenal azotemia Nonspecific

Nonspecific

ARF, acute renal failure; COHgb, carboxyhemoglobin; TCA, tricyclic antidepressant.

Adrenergic agonists include amphetamines and cocaine. Poisoning with these agents is associated with tachycardia, hypertension, tachypnea, and hyperthermia. The pupils are enlarged, the skin is flushed and diaphoretic, and gastrointestinal peristalsis is increased. Anticholinergics include atropine, antihistamines, some antipsychotics, antiemetics, and some anticonvulsants. Hallucinations, tachycardia, and hyperthermia are seen generally without significant alteration of the blood pressure or respiratory rate. The pupils are enlarged and may be unreactive. The skin is hot, dry, and flushed. This anhydrosis, combined with the increased muscle activity, is thermogenic and may result in significant hyperthermia. Gastrointestinal paralysis that results in ileus and urinary retention occur. Withdrawal from opioids, such as heroin, methadone, meperidine, hydrocodone, and oxycodone, causes characteristic symptoms, the severity of which is inversely related to the duration of the effects of the drug. Opioid withdrawal does not cause alteration of the mental status. Symptoms of withdrawal may be abrupt and severe after the administration of Table 17-6 -- Differentiating Between Delirium and Psychosis Delirium Abnormal vital signs frequent Acute onset

Psychosis

Normal vital signs; may have tachycardia History of prior similar episodes, recurrent

Delirium No prior psychiatric history Impaired/fluctuating alertness, confused Disoriented, immediate memory more affected than remote Visual or tactile hallucinations (poorly organized)

Psychosis History of psychiatric conditions, family history Alert, awake Oriented, no memory impairment Well-organized hallucinations, mainly auditory; delusions

the opioid antagonist naloxone or after acute abstinence from a short-acting opioid, such as heroin. These patients manifest hypertension and tachycardia with normal respiratory rate and temperature. They also have yawning, lacrimation, piloerection, dilated pupils, nausea, vomiting, and rhinorrhea. Increased gastrointestinal peristalsis results in diarrhea. This withdrawal syndrome, although extremely uncomfortable for the patient, is rarely life-threatening. Federal laws prohibit the treatment of opiate withdrawal by the administration of opiates in the emergency setting.[32] Physical signs of ethanol withdrawal include mydriasis, tremor, hypertension, tachycardia, tachypnea, hyperthermia, and diaphoresis. Seizures are common. This may lead to a severe delirium that is lifethreatening (see Chapter 70 ). The withdrawal syndrome associated with long-term use of other sedativehypnotics, such as benzodiazepines and barbiturates, is identical to ethanol withdrawal. The time course and severity are related inversely to the duration of action of the drug involved. These patients lack the physical findings suggestive of long-term alcohol abuse. Patients poisoned with phencyclidine often present with very extreme agitation. The severity of agitation leads to tachycardia, hypertension, diaphoresis, and fever. Pupils are small and reactive. Nystagmus is very prominent. Salicylates directly stimulate the respiratory center and cause uncoupling of oxidative phosphorylation. These patients may be agitated because of CNS impairment, with fever and marked hyperpnea. The respiratory rate is markedly increased both in frequency and in depth. The lithium-intoxicated patient can be a diagnostic challenge. Lithium ingestion should be suspected in all the patients with known bipolar disorder. The most important hallmarks of lithium toxicity are seizures, tremor, hyperreflexia, and altered mental status. The serotonin syndrome is an uncommon entity that can cause agitated delirium. The most common findings are tachycardia, hypertension, myoclonus, diaphoresis, and hyperthermia. In contrast to the neuroleptic malignant syndrome, the serotonin syndrome tends to be milder, it evolves more rapidly, and the duration of symptoms is shorter[9][41](see Chapter 63 ).

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LABORATORY AND DIAGNOSTIC STUDIES
Quantitative toxicologic studies are useful in the assessment of only a few specific agents, including carbon monoxide, lithium, salicylates, digoxin, ethanol, ethylene glycol, methanol, many antiseizure medications, and theophylline.[39] These quantitative tests can be selectively ordered, guided by the history, physical findings, and substances available to the patient. Acetaminophen should also be included in toxicologic screens because of our inability to predict toxicity. Qualitative drug screens give information about exposure, which may be useful in a number of scenarios: substance abusers who may need chemical dependency interventions, patients exposed to cocaine who present with chest pain or new-onset seizures, and critically ill patients with unexplained illnesses in whom unsuspected drugs are present.[33] In all other settings, routine urine drug screens rarely change the patient’s management or affect the patient’s outcome.[8][31][39] Two studies suggest a more selective use of the urine drug screen, using physical examination and toxidrome recognition to improve the probability of a positive test result.[31][43] Although drug screens may help guide therapy in some cases, they can also be misleading. For example, the head-injured ethanol abuser may be thought to be simply intoxicated, delaying the diagnosis and treatment for a head injury. Treatment should always be directed at the symptomatology, not at the laboratory results. Laboratory studies are most useful in the detection of end-organ damage and should address the most common and important complications in agitated patients, which include alterations of renal and hepatic function, acid-base disturbances, and rhabdomyolysis. Routine laboratory assessment of electrolytes and markers for muscle breakdown (e.g., creatinine, creatine kinase, myoglobin, and potassium) is indicated. An elevation of the white blood cell count is often a nonspecific finding in the agitated patient. Examination of the cerebrospinal fluid and cultures of the blood and cerebrospinal fluid are indicted if infection is suspected. If the neurologic examination is focal or suggests increased intracranial pressure or if trauma or subarachnoid hemorrhage is suspected, a head computed tomographic scan must be performed. In patients with signs of liver disease, tests of coagulation and ammonia levels are useful. A 12-lead electrocardiogram can identify dysrhythmias, evidence of sodium channel blockade associated with poisoning, and evidence of ischemia or infarction that may precipitate delirium in an elderly patient. The chest x-ray study can help in the diagnosis of pneumonia, congestive heart failure, and pneumothorax.

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DEFINITIVE TREATMENT
Most patients who present with agitation due to toxic exposures do well with supportive management alone.[8][31][39] As previously stated, it is imperative to gain control of the agitated patient. Many studies have addressed the issue of rapid tranquilization.[20] The goal of rapid tranquilization is to prevent injury, avoid complications, and allow for evaluation and treatment of the agitated patient. Table 17–8 provides a summary of the most commonly used agents to control agitation.

Table 17-8 -- Drugs Used to Control Agitation Drug Dose/Route/Frequency Onset/Duration Onset: 5–10 min Onset: 1–2 min Duration: 20–30 min 4 mg/IM, IV q 20 min Lorazepam 2.5–5 mg/IM, IV q 5 min Midazolam Onset (IM): 20 min Duration: 4–6 hr Onset: 1–2 min Duration: 20–30 min Loading dose: 2.0–2.5 mg/kg Propofol Infusion: 5.0–50 µg/kg/min Droperidol 2.5–10 mg IM or 1.25–2.5 mg IV q 30 min Duration: 4–8 min Onset: 5–10 min Dystonia, seizure, hyperthermia, orthostasis, akathisia, hypotension Onset: 40 sec Apnea, hypotension, negative inotropism, infections, allergies Apnea, sedation, confusion, ataxia Sedation, confusion, ataxia Side Effects Dystonia, seizure, hyperthermia, akathisia Sedation, confusion, ataxia Haloperidol 2.5–10 mg/IM q 30 min 5–10 mg/IV q 5–10 min Diazepam

The neuroleptics have been demonstrated to be effective in the control of agitation caused by psychosis in several studies.[4][12][23][25][35] Droperidol, an analog of haloperidol that lacks antipsychotic properties, has also been utilized to control agitation.[7][26][47][54] Several studies have suggested the use of combination therapy to treat the patient with psychotic agitation.[3][5] A multicenter, double-blind trial of 98 patients concluded that the combination of lorazepam and haloperidol produced faster control of agitation and had fewer side effects than either drug alone.[3] Side effects and lack of efficacy in treatment of specific disorders limit the use of neuroleptics in the patient in whom the diagnosis is unclear. In addition to their wellrecognized association with dystonic reactions, neuroleptics such as haloperidol decrease the threshold for seizures and impair the body’s ability to dissipate heat.[18][20] They have been associated with increased mortality when used as sole agents in the treatment of sedative hypnotic withdrawal.[27][52]

Benzodiazepines are fast acting and have few side effects.[19] Several authors argue for their use as firstline agents for the agitated psychotic patient.[3][20] Lorazepam and midazolam can be used both intramuscularly and intravenously and should be strongly considered if the patient does not have an intravenous line in place. They have a fast onset and no active metabolites.[30][56][57] Benzodiazepines decrease heat production by stopping excess motor activity and normalizing vital signs. Another desirable effect of the benzodiazepines is their ability to terminate and prevent seizures.[28] Benzodiazepines are the drugs of choice in the management of sedative hypnotic withdrawal.[21] Although the benzodiazepines are not completely cross-tolerant, they blunt the most important manifestations of ethanol withdrawal[16](see Chapter 75 ). They are also indicated in the management of agitation caused by cocaine toxicity.[11][28] Several animal studies of cocaine poisoning have demonstrated significant increases in morbidity when cocaine-poisoned animals are treated with neuroleptics as compared with benzodiazepines[10][18] (see Chapter 70 ). The use of propofol as a sedating agent has also been reported. Propofol is an oil emulsion with a rapid onset of action and a short half-life. It acts in the gamma-aminobutyric acid receptor, similar to the action of the benzodiazepines. The main side effect is hypotension. [13] For certain toxins, antidotes can be used for both diagnostic and therapeutic measures. The chapters dealing with each specific toxin give a detailed description of the different antidotes and the indications for their use.

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DISPOSITION AND NEED FOR CONSULTANTS
Poisoned patients whose mental status and vital signs do not normalize in the emergency department need to be admitted. If a toxin is apparent as the causal agent, the Poison Control Center should be contacted. Some hospitals also have a toxicology service that may offer specific management recommendations. In general, most patients require admission, with the exception of uncomplicated insulin-induced hypoglycemia, minor toxic exposures whose effects resolve quickly, and well-defined seizure disorders with postictal agitation that resolves in the emergency department. All patients with intentional ingestions should undergo a psychiatric evaluation before discharge is considered.[2]

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REFERENCES
2. American College of Emergency Physicians : Clinical policy for the initial approach to patients presenting with acute toxic ingestions or dermal or inhalation exposure. Ann Emerg Med 1999; 33:735-761. 3. Battaglia J, Moss S, Rush J, et al: Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997; 15:335-340. 4. Benforado JM, Houden D: The use of haloperidol to control agitation/violence during admission to an alcohol detoxification center. Curr Alcohol 1980; 7:331-338. 5. Bieniek SA, Ownby RL, Penalver A, et al: A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 1998; 18:57. 6. Boyle PJ, Schwartz NS, Shah SD, et al: Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988; 318:14871492. 7. Branney SW, Colwell CB, Aschbrenner JK, et al: Safety of droperidol for sedating out-of-control ED patients. Acad Emerg Med 1996; 3:527. 8. Brett A: Implications of discordance between clinical impression and toxicology analysis in drug overdose. Arch Intern Med 1988; 148:437-441. 9. Brown TM, Skop BP, Mareth TR: Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 1996; 30:527. 10. Catravas JD, Water IW, Walz MA, et al: Acute cocaine intoxication in the conscious dog: Pathophysiologic profile of acute lethality. Arch Int Pharmacodyn Ther 1978; 235:328-340. 11. Chan TC, Evans SD, Clark RF: Drug-induced hyperthermia. Crit Care Clin 1997; 13:785-808. 12. Clinton JE, Sterner S, Stelmachers Z, et al: Haloperidol for sedation of disruptive emergency patients. Ann Emerg Med 1987; 16:319-322. 13. Coomes TR, Smith SW: Successful use of propofol in refractory delirium tremens. Ann Emerg Med 1997; 30:825-828. 14. Cooper JW: Adverse drug reaction-related hospitalizations of nursing facility patients: A 4-year study. South Med J 1999; 92:485-490. 15. Curry SC, Chang D, Conner D: Drug-and toxin-induced rhabdomyolysis. Ann Emerg Med 1989; 18:1068-1084. 16. Delaney KA: Evaluation and management of psychiatric syndromes in the intensive care unit. Contemp Manag Crit Care 1991; 1:147-174. 17. Delaney KA, Goldfrank L: Delirium: Assessment and management in the ICU. Probl Crit

Care 1987; 1:78-93. 18. Derlet RW, Albertson TE, Rice P: The effect of haloperidol in cocaine and amphetamine intoxication. J Emerg Med 1989; 7:633-637. 19. Dietch JT, Jennings RK: Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry 1988; 49:184-188. 20. Dubin WR, Feld JA: Rapid tranquilization of the violent patient. Am J Emerg Med 1989; 7:313. 21. Dubin WR, Weiss KJ, Zeccaradi JA: Organic brain syndrome: The psychiatric impostor. JAMA 1983; 249:60-62. 22. Factor SA, Molho ES, Brown DL: Acute delirium after withdrawal of amantadine in Parkinson’s disease. Neurology 1998; 50:1456-1458. 23. Fernandez F, Holmes VF, Adams F, Kavanaugh JJ: Treatment of severe, refractory agitation with haloperidol drip. J Clin Psychiatry 1988; 49:239-241. 24. Feske SK: Coma and confusional states: Emergency diagnosis and management. Neurol Clin 1998; 16:237-256. 25. Garza-Treviño E, Hollister LE, Overall JE, Alexander WF: Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J Psychiatry 1989; 146:15981601. 26. Granacher RP, Ruth DD: Droperidol and acute agitation. Curr Ther Resp 1979; 25:361-365. 27. Greenblatt DJ, Gross PL, Harris J, et al: Fatal hyperthermia following haloperidol therapy of sedativehypnotic withdrawal. J Clin Psychiatry 1978; 39:63. 28. Hoffman RS: An effective strategy for managing cocaine-induced agitated delirium. J Crit Illness 1994; 9:134-149. 29. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness. JAMA 1995; 274:562569. 30. Kao LW, Moore GP: The violent patient: Clinical management, use of physical and chemical restraints, and medicolegal concerns. Emerg Med Pract 1999; 1:1-24. 31. Kellerman AL, Fihn SD, LoGerto JP, et al: Impact of drug screening in suspected overdose. Ann Emerg Med 1987; 16:1206-1216. 32. Khantzian EJ, McKenna GJ: Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med 1979; 90:361-372. 33. Kirk M, Pace S: Pearls, pitfalls, and updates in toxicology. Emerg Med Clin North Am 1997; 15:427449. 34. Larson EW, Richelson E: Organic causes of mania. Mayo Clin Proc 1998; 63:906-912. 35. Lenchan GP, Gastfriend DR, Stetler CJ: Use of haloperidol in the management of agitated or violent,

alcohol intoxicated patients in the emergency department: A pilot study. J Emerg Nurs 1985; 11:72-79. 36. Lipowski ZJ: Delirium (acute confusional states). JAMA 1987; 258:1789-1792. 37. Lipowski ZJ: Delirium in the elderly patient. N Engl J Med 1989; 320:578-582. 38. Love JN, Handler JA: Toxic psychosis: An unusual presentation of propranolol intoxication. Am J Emerg Med 1995; 13:536-537. 39. Mahoney JD, Gross PL, Stern TA, et al: Quantitative serum toxic screening in the management of suspected drug overdose. Am J Emerg Med 1990; 8:16-22. 40. Marsh CM: Psychiatric presentations of medical illnesses. Psychiatr Clin North Am 1997; 20:181-204. 41. Mills KC: Serotonin syndrome: A clinical update. Med Toxicol 1997; 13:763-783. 42. Mori , Yamadori A: Acute confusional state and acute agitated delirium: Occurrence after infarction in the right middle cerebral artery territory. Arch Neurol 1987; 44:1139-1143. 43. Nice A, Leikin JB: Maturen A, et al: Toxidrome recognition to improve efficiency of emergency urine drug screens. Ann Emerg Med 1988; 17:676. 44. O’Keefe KP: Sanson TG: Elderly patients with altered mental status. Emerg Med Clin North Am 1998; 16:701-716. 45. Purdie FR: Honigman B, Rosen P: Acute organic brain syndrome: A review of 100 cases. Ann Emerg Med 1981; 10:455-461. 46. Rabins PV, Folstein MF: Delirium and dementia: Diagnostic criteria and fatality rates. Br J Psychiatry 1982; 140:149-153. 47. Richards JR, Derlet RW, Duncan DR: Chemical restraint for the agitated patient in the emergency department: Lorazepam versus droperidol. J Emerg Med 1998; 16:567-573. 48. Ritter A, Eskin B: Ibuprofen overdose presenting with severe agitation and hypothermia. Am J Emerg Med 1998; 16:549-550. 49. Ruttenber AJ, Lawler-Heavner J, Yin M, et al: Fatal excited delirium following cocaine use: Epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci 1997; 42:25-31. 50. Tardiff K: Unusual diagnoses among violent patients. Psychiatr Clin North Am 1998; 21:567-576. 51. Thal L: Dementia update: Diagnosis and neuropsychiatric aspects. J Clin Psychiatry 1988; 49(Suppl):5-7. 52. Thomas DW, Freedman DX: Treatment of the alcohol withdrawal syndrome: Comparison of promazine and paraldehyde. JAMA 1964; 188:316. 53. Tueth MJ: Dementia: Diagnosis and emergency behavioral complications. J Emerg Med 1995; 13:519525.

54. Van Leevwen AMH, Molders J, Sterkmans P, et al: Droperidol in acutely agitated patients. J Nerv Ment Dis 1977; 164:280-283. 55. Weddington WW: The mortality of delirium: An underappreciated problem?. Psychosomatics 1982; 23:1232-1235. 56. Wyant M, Diamone BI, O’Neal E, et al: The use of midazolam in acutely agitated psychiatric patients. Psychopharmacol Bull 1990; 26:126. 57. Young GP: The agitated patient in the emergency department. Emerg Med Clin North Am 1987; 5:765.

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Uncited reference Alarcon RD, Franceschini JA: Hyperparathyroidism and paranoid psychosis: Case report and review of the literature. Br J Psychiatry 1984; 145:477-486.

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Chapter 18 – Seizures
TAREG A. BEY FRANK G. WALTER

Essentials of Initial Treatment • • • • • Assess the airway. Apply oxygen. Intubate if clinically indicated. Monitor. Ensure intravenous access. Exclude hypoglycemia. Initiate cooling for hyperthermia (=40°C). Control seizures (see Table 18–7 ). Table 18-7 -- Acute Seizure Treatment Intravenous Sedation Dosage * Sedation Elimination Onset Half-Life 0–5 min 43 hours

Antiepileptics Diazepam

Indications Seizures or withdrawal (first-line drug)

Contraindications

Inability to manage Adults: 5 mg hypoventilation over 1 min Children: 0.1–0.3 mg/kg

Lorazepam

Seizures or withdrawal (first-line drug)

Adults: 2 mg Inability to manage over 1 min † hypoventilation Children: 0.05–0.1 mg/kg Adults: 2.5 mg Inability to manage over 2 min hypoventilation Children: 0.05–0.2 mg/kg Shock

0–5 min

14 hours

0–2 min

2 hours

Midazolam

Seizures or withdrawal (first-line drug)

Adults and children: 20 mg/kg infusion at up to 50 Recurrent or prolonged Porphyria mg/min (in Phenobarbital seizures (second-line 5–10 min 99 hours adults or up to 1 drug) mg/kg/min for Inability to manage children, for status hypoventilation epilepticus)

Antiepileptics

Indications Isoniazid (INH) Monomethylhydrazinecontaining mushrooms (e.g., Gyromitra spp.) Hydrazine rocket fuel Theophylline ‡

Pyridoxine (vitamin B6)

Intravenous Sedation Elimination Sedation Onset Half-Life Contraindications Dosage * Dosage for seizures: 5 g vitamin B 6 empirically in adults or 70 mg/kg in None N/A 2–3 weeks children. Can give 1 g vitamin B6 for each 1 g of INH ingested, if ingested dose known.

Experimental data support the use of pyridoxine in theophylline-induced seizures.[36][88] However, this is not yet standard care.
* Sedation dosage does not equal the dosage to terminate a seizure and may be insufficient to control seizures (see Tables 18–5 and 18–6 ). † Lorazepam can also be administered by intramuscular injection until intravenous access is obtained. ‡ In therapy-refractory, theophylline-induced seizures, 5 g of IV pyridoxine can be added as a third-line drug.

Institute continuous electroencephalographic monitoring in paralyzed patients.

INTRODUCTION
A seizure is an episode of neurologic dysfunction caused by abnormal neuronal electrical discharges. The Latin word ictus, which literally means “attack,” is used synonymously with seizure. The term convulsion describes a motor seizure. Epilepsy and seizure disorder are synonymous terms describing chronic neurologic dysfunction characterized by recurrent, spontaneous seizures. Seizures are also classified as partial or generalized based on the extent of neuroanatomic involvement and as simple or complex based on their effects on awareness.[20] Complex seizures alter the level of consciousness, whereas simple seizures do not. Status epilepticus is defined as more than 30 minutes of continuous seizure activity, or two or more sequential seizures without full recovery of consciousness between attacks.[90] Seizures can be induced in any individual by electroconvulsive therapy, drugs, head trauma, withdrawal from sedative-hypnotics or alcohols, infections, or metabolic disturbances such as hyponatremia, hypocalcemia, or hypoglycemia ( Tables 18–1 , 18–2 , 18–3 ).[56][69][72][90] Seizures induced by drugs, toxins, or toxicants are complex and are associated with loss of consciousness and generalized tonic-clonic convulsions. Metabolic disorders such as hypoglycemia, uremia, and other hyperosmolar states may produce focal seizures in the absence of detectable focal brain lesions.[9][56] Focal seizures are especially common in hyperosmolar conditions, because of brain shrinkage that tears small bridging vessels, resulting in microscopic focal lesions.

Table 18-1 -- Important Causes of Seizures Toxic • Tricyclic and tetracyclic antidepressants (including carbamazepine) • Stimulants (cocaine, amphetamines) • Anticholinergics, including antihistamines • Organophosphates/carbamates • Theophylline • Isoniazid • Lithium • Salicylates • Sedative-hypnotic, barbiturate, and alcohol withdrawal; with opioid withdrawal in neonates only • Opioids (propoxyphene, meperidine) • Gamma-hydroxybutyrate • Metaldehyde • Camphor • Iron • 4-Aminopyridine • CO, cyanide, hydrogen sulfide, azides Metabolic • Glucose excess or deficiency • Hypoxia • Uremia • Inborn metabolic error (pyridoxine-dependent epilepsy) • Electrolyte imbalance (hyponatremia, hypernatremia, hypocalcemia) • Endocrinopathy (thyrotoxicosis) Infectious • Meningitis • Cerebral abscess • Cerebral cysticercosis • AIDS-related brain infections Structural • Infarct

• Hemorrhage • Head trauma • Tumor Others • Shock • Eclampsia

Table 18-2 -- Most Common Causes of Seizures Due to Drug Abuse and Overdose Drugs Antidepressants (e.g., tricyclics and tetracyclics) Cocaine and other stimulants Diphenhydramine and other antihistamines Theophylline Isoniazid Cardiodepressant antidysrhythmic agents (calcium channel blockers, mexiletine, procainamide) Other (e.g., sedative-hypnotic withdrawal, lithium) Total cases n 55 55 14 10 10 4 43 % 29 29 7 5 5 2 23

191 100

Modified from Olson KR, Kearney TE, Dyer JE, et al: Seizures associated with poisoning and drug overdose. Am J Emerg Med 1994; 12:392–395.

Table 18-3 -- Clinical Evaluation and Treatment of Patients with Seizures Specific Seizure Differential Physical Exam Diagnostic Likely Etiologies Studies Settings Diagnoses Clues Airports, ports, train stations, and customs offices Body packers with drug-filled condoms or packets Cocaine, amphetamines, intracranial hemorrhage, head trauma Sympathomimetic toxidromes Abdominal xrays, CT, toxicology screens

Definitive Treatment Benzodiazepines, barbiturates, whole bowel irrigation, rarely gastrotomy or enterotomy Benzodiazepines, O2, glucose if hypoglycemic, phenobarbital for continued seizures

Endoscopy suites, Benzodiazepine ICUs, and antagonism with recovery flumazenil rooms

Hypoxia and hypoglycemia

Sympathomimetic toxidromes

Pulse oximetry, bedside glucose check, toxicology screens ABG with cooximetry for CO

Carbon monoxide

Differential Likely Etiologies Diagnoses monoxide and/or cyanide, Firefighters airway and fire Smoke inhalation obstruction, victims simple asphyxia, and head trauma Other local anesthetic anaphylactic or anaphylactoid reactions with hypoxia and/or shock

Seizure Settings

Physical Exam Clues Smoke smell, soot, nasal and oral burns, signs of hypoxia without cyanosis

Specific Diagnostic Studies oximetry for CO and metHb; venous blood gas for elevated O2, CN level, lactate level; CT

Definitive Treatment 100% oxygen, endotracheal intubation, hyperbaric oxygen, sodium thiosulfate for CN

Local anesthesia

Lidocaine toxicity

Local anesthetic injection sites, Pulse oximetry, wounds, surgical incisions, cyanosis, lidocaine blood pallor, hives, levels diaphoresis, stridor, wheezing Signs of hypoxia without cyanosis, pesticide (garlic) odor, cholinergic toxidromes ABG with cooximetry for CO; cholinesterase levels

Benzodiazepines. Treat anaphylactic and anaphylactoid reactions, if present. Stop lidocaine. 100% oxygen, endotracheal intubation, hyperbaric oxygen, atropine, pralidoxime, chelators Endotracheal intubation, hyperventilation, glucose if hypoglycemic, benzodiazepines for seizure disorder or sympathomimetics, antidysrhythmics for dysrhythmias O2, glucose if hypoglycemic, antibiotics, benzodiazepines for withdrawal, airway management

Miniepidemics

Other on-the-job exposures, food Carbon monoxide, poisoning with organophosphates mushrooms or heavy metals

Motor vehicle accidents

Head trauma, myocardial ischemia

Hypoglycemia, seizure disorder, Signs of head cocaine, alcohol trauma withdrawal, cardiac dysrhythmia

Stat bedside glucose check, CT, ECG

Nursing homes

Elder abuse, pneumonia, Sepsis, hypoxia, urinary tract or drug intoxication or other infection, withdrawal hypoglycemia, seizure disorder, CVA

Fever, respiratory distress, signs of septic shock

Stat bedside glucose check, pulse oximetry, ABG, chest xray, cultures, drug levels

Drug intoxications Parties and and photic-evoked discos seizures

Drugs of abuse, Track marks and Toxicology stroboscopes, drug paraphernalia screens, CT head trauma

Benzodiazepines

Drugs of abuse, Drug packets Drug intoxications, alcohol stuffed in body

Seizure Settings

Prisons

Differential Likely Etiologies Drugs of abuse, Diagnoses Drug intoxications, alcohol body stuffers with withdrawal, drug-filled sedativecondoms or hypnotic packets withdrawal, head trauma Cerebral gas embolism, near drowning, contaminated air (e.g., CO)

Physical Exam Clues Drug packets stuffed in body cavities, track marks, sympathomimetic toxidromes, signs of head trauma Abnormal funduscopy, cutis marmorata

Specific Diagnostic Studies Abdominal xrays, CT, toxicology screens

Definitive Treatment Benzodiazepines, barbiturates, whole bowel irrigation, rarely gastrotomy or enterotomy

Scuba divers

Decompression sickness

Chest x-ray, ABG with cooximetry for CO, CT

Hyperbaric oxygen

CT, cranial computed axial tomography; CO, carbon monoxide; CN, cyanide; O2, oxygen; CVA, cerebrovascular accident; ABG, arterial blood gas; metHb, methemoglobin; ECG, electrocardiogram; UTI, urinary tract infection.

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PATHOPHYSIOLOGY
Epileptogenesis derives in part from imbalances between excitatory and inhibitory processes in selected brain regions. Glutamate is the major cerebral excitatory neurotransmitter.[33] It undergoes decarboxylation by the enzyme glutamic acid decarboxylase (GAD) to form gamma-aminobutyric acid (GABA), the major cerebral inhibitory neurotransmitter ( Fig. 18–1 ).[22][53][62] Both glutamate receptor agonists and GABA antagonists elicit local neuronal excitatory responses in animal models of seizures.[53][54][65]

Figure 18-1 Glutamic acid is decarboxylated by the enzyme glutamic acid decarboxylase (GAD) to -aminobuytric acid (GABA). The enzyme GAD requires the cofactor pyridoxal 5-phosphate (PLP), the active form of pyridoxine (vitamin B6). INH, for example, depletes pyridoxine, inhibits the formation of pyridoxal 5-phosphate and is metabolized to hydrazones that inhibit pyridoxine phosphokinase.

GABA inhibits neuronal conduction by opening membrane chloride channels, an effect mediated by binding to specific GABAA receptors ( Fig. 18–2 ). The resultant increased flow of chloride into the neuron lowers the membrane resting potential and decreases its excitability.[22][53][54][62] The benzodiazepine and barbiturate anticonvulsants potentiate the effects of GABA by binding at sites adjacent to GABAA receptors on the neurolemmal chloride ionophore macromolecular complex (see Fig. 18–2 ).[53][54][62]

Figure 18-2 Conceptual diagram of the GABA A receptor-chloride ionophore.

Adenosine, a precursor of the high-energy nucleotide adenosine triphosphate (ATP), is a neuromodulator that acts as an endogenous anticonvulsant by binding to specific presynaptic adenosine receptors and decreasing neurotransmitter release.[10][23][24][29][71] Status epilepticus increases cerebral metabolism, resulting in the increased production and accumulation of adenosine in the extracellular space, where it exerts a neuroinhibitory effect. Adenosine also causes cerebral vasodilation and increases cerebral blood flow to meet the higher metabolic demands of the brain during status epilepticus. In animal models, dipyridamole potentiates the protective neuroinhibitory effect of adenosine while methylxanthines such as theophylline antagonize it ( Fig. 18–3 ).[10][29]

Figure 18-3 Diagram of proposed mechanism of ictal-interictal cycling due to changes in the interictal adenosine concentration [ADO], which rises during electroencephalographic (EEG) local activity, causes cessation of ictal activity, and then falls during the interictal period. Dipyridamole prolongs the interictal phase by inhibiting reuptake of adenosine. Theophylline blocks access of adenosine to its receptors, allowing ictal activity to continue despite the continuous high concentration of adenosine. (The depicted changes of ADO are schematic and may not reflect actual trajectories.) (From Eldridge FL, Paydarfar D, Scott SC, et al: Role of endogenous adenosine in recurrent generalized seizures. Exp Neurol 1989; 103:179.)

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SPECIFIC MECHANISMS OF INDUCED SEIZURES
Four major pathophysiologic mechanisms are associated with the biochemical induction of seizures: (1) impairment of GABA inhibition, (2) excess stimulation of glutamate receptors, (3) defects in systems that modulate excitatory and inhibitory functions, and (4) defects in neurolemmal ion channels. [31] Impairment of GABA Inhibition Substances that inhibit the GABAA receptor-chloride ionophore complex have the potential to cause seizures. These include cyclic antidepressants, ciprofloxacin, imipenem, penicillin, bicuculline, picrotoxin, and monamine oxidase inhibitors such as tranylcypromine.[22][54][55][62] Prolonged alcohol use appears to reduce GABA-mediated inhibition of brain cells by altering the density and sensitivity of GABA receptors.[32] The benzodiazepine antagonist flumazenil has been shown to precipitate seizures.[14][57][64] In U.S. premarketing trials, six seizures were observed in 446 overdose patients treated with flumazenil.[74] Four of these six patients had co-ingested large doses of cyclic antidepressants.[74] Flumazenil is believed to precipitate seizures when given in mixed benzodiazepine/cyclic antidepressant overdoses because flumazenil counteracts the anticonvulsant activity of the co-ingested benzodiazepines.[55][81] Substances or conditions that result in GABA deficiency also cause seizures. The synthesis of GABA by GAD requires pyridoxal 5-phosphate (PLP), an activated form of pyridoxine (vitamin B6) (see Fig. 18–1 ) that is formed from pyridoxine by the enzyme pyridoxine phosphokinase. Hydrazines such as isoniazid (INH) or monomethylhydrazine from the toxic mushroom Gyromitra esculenta inhibit GABA synthesis by blocking the synthesis of PLP by pyridoxine phosphokinase. They also directly bind and inactivate PLP and enhance its renal elimination.[40][80] Pyridoxine-dependent epilepsy is an autosomal recessive disease associated with significantly decreased GAD activity. It presents in infants as seizures unresponsive to standard therapy and is associated with high concentrations of glutamic acid and low concentrations of GABA in the cerebrospinal fluid (CSF). High doses of pyridoxine abolish the metabolic derangements and seizures.[7][37] GABA deficiency may also be caused by conditions that deplete precursors of GABA. Seizures are rare in diabetic ketoacidosis because of the availability of ketone bodies for energy metabolism.[22] However, patients with nonketotic hyperosmolar diabetic coma do not produce significant amounts of ketone bodies, an important source of energy for the brain.[22] This leads to increased cerebral utilization of amino acids such as GABA and its precursors for energy production via the GABA shunt and the Krebs cycle.[22] The GABA shunt links GABA metabolism to the Krebs cycle.[22] Under normal conditions, GABA a-oxoglutarate transaminase (GABA-T), the key enzyme in the GABA shunt, facilitates production of adequate GABA levels, when sufficient a-ketoglutarate is present.[22] When the concentration of a-ketoglutarate is low, GABA is converted to succinic semialdehyde, which subsequently enters the Kreb’s cycle as succinic acid, resulting in GABA depletion.[22][61] Excess Stimulation of Glutamate Receptors

Febrile seizures in children may be a consequence of increased glutamate production associated with the temperature-related increase in the brain’s metabolic rate. Studies in animals demonstrate that increased glutamate levels occur during hyperthermia and predispose to seizures.[65] Substances that stimulate glutamic acid receptors may also cause seizures. An example of this is domoic acid, a toxin associated with shellfish poisoning.[84] Defects in Systems That Modulate Excitatory and Inhibitory Functions: Adenosine Inhibition Toxic levels of theophylline and other methylxanthines block the inhibitory effect of adenosine, precipitating seizures that are continuous and refractory to therapy.[29][45] Theophylline also impairs the cerebral vasodilatory effect of adenosine, resulting in decreased cerebral blood flow and cerebral ischemia during seizures.[71] These effects of theophylline on the neuroregulatory role of adenosine contribute to the high morbidity and mortality associated with theophylline-induced seizures.[10][71] Mortality rates as high as 29 per cent have been reported in patients with theophylline overdoses who develop seizures.[45] Defects in Neurolemmal Ion Channels 4-Aminopyridine, a drug that has been used to treat multiple sclerosis, can cause seizures in overdose.[82][92] 4-Aminopyridine has potassium channel blocking properties and increases presynaptic calcium concentrations and presynaptic release of neurotransmitters.[82][92][94] Phenytoin and phenobarbital were both protective against 4-aminopyridine lethality in an animal study.[92] Stork and Hoffman described three patients with 4-aminopyridine intoxication whose drug-induced seizures were successfully treated with benzodiazepines, phenytoin, and supportive care.[82] One of these three patients also received phenobarbital. Further study is needed to determine the role of phenytoin in the treatment of seizures induced by 4-aminopyridine.

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DIFFERENTIAL DIAGNOSIS
Seizures may be caused by a variety of toxic, metabolic, infectious, or structural abnormalities (see Table 18–1 ).[2][9][32][52][56][69][76][86][90] Toxic causes are discussed here. Life-threatening causes that require immediate diagnosis and treatment such as central nervous system (CNS) infections, hypoglycemia, hyponatremia, and hypocalcemia should always be excluded. [90] The possibility of eclampsia is indicated by obvious late-term pregnancy or a history of recent pregnancy.[79] Occult head injury should be suspected, especially when status epilepticus occurs or the patient’s postictal mental status does not clear rapidly. Common causes that are not usually life-threatening include chronic epilepsy and alcohol withdrawal seizures. Toxic Seizures A retrospective poison center review of 191 seizures associated with drug abuse or overdose found the most common causes were due to cyclic antidepressants, cocaine and other stimulants, antihistamines, theophylline, INH, and antidysrhythmics.[68] Agents associated with toxic seizures in this study are listed in Table 18–2 . Seizures related to cocaine and other stimulants, ethanol and sedative-hypnotic withdrawal, and diphenhydramine tend to be brief and self-limited.[50][68] Although the majority of seizures associated with cyclic antidepressant overdose are also brief, 20 to 30 per cent were characterized as prolonged, repetitive, or status epilepticus.[30][68] Seizures associated with theophylline, antidysrhythmics, and INH poisoning commonly result in status epilepticus.[45][68][69] Patients with large ingestions of cocaine, especially body packers with leaking packets, may also have status epilepticus. Seizures associated with salicylate, lithium, carbon monoxide, cyanide, or hydrogen sulfide poisoning indicate life-threatening toxicity. Meperidine and propoxyphene are opioids classically associated with seizures.[12][78][93] Meperidine and propoxyphene are hepatically demethylated to proconvulsant metabolites, normeperidine and norpropoxyphene.[12][93] Recently, the abuse of gamma-hydroxybutyric acid (GHB) has become commonplace in bars and discos. It is also touted as an effective body building agent and may be abused by body building enthusiasts.[17] GHB was synthesized initially as a GABA agonist. When mixed with ethanol or taken in excess, it causes sedation and seizures, both of which are short lived.[17][27] No deaths have been reported.[16] GHB is metabolized to CO2 and H2O and cannot be measured with routine toxicology tests; therefore, the diagnosis is usually based on history.[16][17][27] The mechanism of its toxicity is unclear.[16] Seizures have also been described after ingestion of the molluscicide metaldehyde.[41][44][63] Metaldehyde also causes a profound metabolic acidosis. It is suspected that metaldehyde, a polymer of acetaldehyde, causes seizures through reduction of brain concentrations of GABA.[41]

Anaphylaxis and anaphylactoid reactions precipitated by allergies and adverse drug reactions can produce secondary seizures due to hypoperfusion and/or hypoxia. Hyperosmolar substances such as radiographic contrast media can also produce seizures.[50] The incidence of seizures due to adverse drug reactions in patients hospitalized for other conditions is low. [73] The Boston Collaborative Drug Surveillance Program reported 17 seizures in 12,617 inpatients (0.1 per cent).[73] Cocaine Users Cocaine commonly causes seizures as a manifestation of its toxic effects. Patients who use cocaine also have an increased incidence of vascular insults such as thrombotic and hemorrhagic strokes. Patients who use intravenous cocaine are at risk of infectious complications such as meningitis, brain abscess, and acquired immunodeficiency syndrome–related CNS infections. Cocaine users with status epilepticus may also have a large gastrointestinal load of cocaine due to body packing or body stuffing (see Chapter 75 ). Even patients with single, first-time seizures associated with cocaine use should have other underlying causes excluded because cocaine can lower seizure thresholds in individuals with undetected CNS lesions.[77] This was demonstrated by a report of two patients with first-time seizures after the use of crack cocaine who were shown to have previously unsuspected brain tumors on routine head computed tomography (CT).[77] Every patient with a first-time seizure should have a complete diagnostic evaluation regardless of the presumed or suspected cause. The Alcoholic Patient Alcohol withdrawal and sedative-hypnotic withdrawal are common causes of seizures; however, they rarely cause status epilepticus. [32][58] In one large series, only 3 per cent of patients with alcohol withdrawal developed status epilepticus.[86] In a study of 249 patients with status epilepticus and complete diagnostic workups, only 27 patients (11 per cent) had alcohol withdrawal as their only detectable etiology of status epilepticus.[2] Clearly, causes other than alcohol or sedative-hypnotic withdrawal must be carefully excluded in the alcoholic patient who develops status epilepticus or whose mental status does not normalize after a seizure. Occult head injury is a frequent problem in alcoholics, who often have unreported trauma.[58] Barbiturate withdrawal can also cause seizures but is less commonly noted, due to the decreased long-term use of these drugs. Metabolic Disturbances Hypoglycemia is associated with intentional or inadvertent overdoses of hypoglycemic drugs. In one study, 9 of 125 hypoglycemic diabetic patients (7 per cent) developed seizures. [56] Motor seizures occur in 20 to 25 per cent of patients with nonketotic hyperosmolar diabetic coma, 75 per cent of which are focal.[61] This high incidence of seizures is attributed to reduced availability of ketone bodies and the increased utilization of GABA and its precursors as cerebral energy sources. Seizures are rare in patients with diabetic ketoacidosis.[22] Other metabolic disorders such as hypoxia, hypocalcemia, hyponatremia, and hypernatremia also cause seizures.[9] Patients with chronic renal failure can have seizures secondary to uremia. Dialysis disequilibrium syndrome associated with very recent dialysis can also cause seizures.

Brain Injury Head trauma commonly leads to seizures.[52][69][90] The risk of traumatic seizures rises dramatically with low Glasgow Coma Scale scores and abnormal cranial CT findings.[52] Seizures can also be caused by spontaneous intracranial hemorrhages. Of 222 patients with supratentorial intracerebral hemorrhages, 27 patients (12 per cent) had seizures within 24 hours of their strokes and 6 patients (3 per cent) had a delayed onset of seizures, 2 to 4 months after their strokes. Intracerebral hemorrhages related to underlying vascular malformations or neoplastic lesions are associated with a much higher incidence of seizures.[89] Although seizures are more common with intracerebral hemorrhages, any cerebrovascular insult, including nonhemorrhagic infarction, embolic stroke, or subarachnoid hemorrhage can cause seizures.[28][89] Febrile Seizures Fever and high body temperatures predispose to seizures in children. [43][65] Two to 5 per cent of all febrile children between the ages of 3 months and 5 years manifest simple febrile seizures without underlying CNS pathology.[20] Although febrile seizures are common in this age group, the possibility of CNS infection should always be considered. In one study, 25 (13 per cent) of 187 pediatric patients with bacterial meningitis presented with seizures. Four of these 25 children had no other signs or symptoms of meningitis.[76]

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CLINICAL PRESENTATION
The events leading up to a seizure, the setting in which a seizure occurs, and the physical examination are important clues to the etiology of the seizure (see Table 18–3 ).[50][56][61][69][77][81][86] The prehospital history obtained from EMS personnel, the family, or other witnesses provides important information when caring for these patients. When the nature of the prehospital event is unclear, questions should focus on signs that indicate that a seizure occurred, such as loss of consciousness, tonic-clonic movements, urinary or fecal incontinence, tongue biting, or evidence of a postictal state. Other important historical clues include suicidal ideation, available medications, antecedent head trauma, headaches, fevers, or a prior history of seizures. Family, friends, law enforcement officers, and emergency medical services personnel can assist by searching the patient’s home, car, and personal belongings for medications, empty pill bottles, illicit drugs, drug paraphernalia, plants, mushrooms, and open or spilled chemical containers. The medical and medication histories of both the patient and family members are important. A family history of seizures, psychiatric disorders, asthma, or tuberculosis indicates the possibility of exposure to carbamazepine, cyclic antidepressants, lithium, theophylline, or INH. The routine use of antiepileptic medications indicates that the patient has epilepsy. A recent decrease in the dose or cessation of sedativehypnotic agents suggests the possibility of withdrawal seizures. In patients chronically on theophylline therapy, the recent addition of a macrolide or fluoroquinolone antibiotic, systemic antifungals such as ketoconazole, or cimetidine can result in decreased theophylline clearance and toxic theophylline blood levels.[1][18][45] The past medical history should include a review for antecedent depression, previous suicide threats or attempts, alcoholism, drug abuse, other psychiatric illnesses, epilepsy, head trauma, neurosurgery, stroke, diabetes, hypertension, recent pregnancy, renal insufficiency, dialysis, cancer, tuberculosis, and human immunodeficiency virus infection.[61][69] The physician should focus on vital signs, perform a complete neurologic examination, and consider signs of trauma, incontinence, and gingival hyperplasia and cutaneous signs of drug abuse. Recognition of familiar toxic syndromes (toxidromes) related to cholinergic, anticholinergic, or sympathomimetic toxicants in patients with seizures will help focus the differential diagnosis on likely causes of drug-induced seizures ( Table 18–4; see Table 18–3 ).

Table 18-4 -- Toxidromes of Toxicants That Can Cause Seizures Toxicants Toxidromes Other Helpful Signs and Diagnostic Tests Usually brief, self-limited seizures Track marks Formication Ecthyma Cocaine and amphetamines Sympathomimetic: aand ß-adrenergic

Toxicants

Toxidromes

Other Helpful Signs and Diagnostic Tests Drug paraphernalia Often brief, self-limited seizures, however, 20–30% are status epilepticus Prolonged QRS complex (>100 msec)

Cyclic antidepressants

Anticholinergic

Prominent R wave in aVR Rightward axis deviation of the terminal 40 msec of the QRS complex Hypotension Coma, convulsions, and cardiovascular collapse

Diphenhydramine, Datura species

Anticholinergic

Usually brief, self-limited seizures; uncommonly, status epilepticus Usually brief, self-limited seizures Signs of delirium tremens

Ethanol withdrawal and sedative-hypnotic drug withdrawal

Sympathomimetic: aand ß-adrenergic

Signs of alcoholic ketoacidosis such as emesis, dehydration, and ketotic breath Stigmata of alcoholic liver disease, such as ascites, asterixis, fetor hepaticus, palmar erythema, and spider angiomata Usually recurrent or continuous seizures (i.e., status epilepticus) refractory to benzodiazepines and barbiturates, but responsive to pyridoxine Profound lactic acidosis

Isoniazid

Status epilepticus

Organophosphates

Cholinergic: muscarinic and nicotinic

Pesticide (garlic) odor Usually recurrent or continuous seizures (i.e., status epilepticus) refractory to conventional doses of benzodiazepines and barbiturates, possibly responsive to pyridoxine Anion gap metabolic acidosis, hyperglycemia, and hypokalemia, in acute theophylline overdoses Profound lactic acidosis

Theophylline

Sympathomimetic: predominantly ßadrenergic

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LABORATORY EVALUATION
Specific laboratory studies should be determined by the clinical presentation.[46] Useful diagnostic tests can include measurement of electrolytes, calcium, magnesium, blood urea nitrogen, and glucose; pregnancy tests; measurement of arterial blood gases with co-oximeter determination of carboxyhemoglobin and methemoglobin levels; CSF examination; and qualitative or quantitative urine or serum drug levels, depending on the toxicants suspected. Pregnancy should be excluded in women with child-bearing potential.[79] Other useful studies can include cranial CT or magnetic resonance imaging (MRI), chest and abdominal radiography, electrocardiography (ECG), and electroencephalography (EEG) with neurology consultation. The First Seizure The evaluation of the patient with a first-time seizure is determined somewhat by the history and presentation. The healthy patient who has normal vital signs and no meningismus or headache and whose mental status returns rapidly to normal requires an expeditious intracranial imaging study (cranial CT or MRI) and an EEG at some point. A urine toxicologic analysis for drugs of abuse such as cocaine or amphetamine may provide valuable information. More complicated patients with first-time seizures require more extensive and more urgent diagnostic workups (see Tables 18–3 and 18–4 ). This includes patients with status epilepticus, a possible toxic ingestion, unexplained fever, persistent or severe postictal headache, a focal neurologic examination, evidence of increased neuromotor irritability such as clonus or myoclonus, a persistent postictal alteration of consciousness or confusion, or a history of significant antecedent illness, headaches, weight loss, or fevers. Measurements of oxygen saturation, glucose, electrolytes, calcium, magnesium, and blood urea nitrogen can be useful. The use of quantitative levels of toxicants or drugs known to precipitate seizures such as carbon monoxide, theophylline, lithium, and salicylates should be guided by the history and physical examination. A qualitative urine toxicology screen for drugs of abuse is particularly helpful in adolescents and young adults with unexplained seizures, and even in small children who may be exposed to their parents’ drugs of abuse through parental neglect. An ECG is helpful if cardiotoxic drugs such as cyclic antidepressants, antidysrhythmics, or neuroleptics are suspected. Abdominal radiography can be useful in patients suspected of being cocaine body packers. Chest radiography may show mass lesions in patients suspected of having malignant metastases to the brain. Emergent head CT scans or MRIs are indicated in the evaluation of patients with antecedent headache, head trauma, a persistently altered or declining mental status, or a new focal neurologic deficit.[3][28][69][77][90] Patients who have headache, altered mental status, unexplained fever, or immunosuppression require blood cultures and a lumbar puncture for CSF analysis, provided there is no suspicion of a focal lesion or increased intracranial pressure; in these cases, empirical antibiotic therapy is indicated before head CT scanning. A head CT scan, followed by lumbar puncture if the scan is normal, is indicated when the diagnosis of subarachnoid hemorrhage is suspected.

Patients with status epilepticus and/or hyperthermia require a dipstick urinalysis for myoglobin and measurement of serum electrolytes, creatinine, and creatine kinase to screen for suspected rhabdomyolysis. Neurology consultation and continuous bedside EEG monitoring are indicated in patients who have status epilepticus requiring neuromuscular paralysis. Patients With Epilepsy Studies in unselected groups of seizing patients who presented to emergency departments included high numbers of known epileptic patients on antiepileptic medications. These studies demonstrated that measurements of antiepileptic drug levels are very useful tests for determining seizure etiology.[28][46] Known epileptic patients who are on antiepileptic medications initially require only a stat bedside blood glucose determination and measurement of antiepileptic blood levels unless a complicating condition is suspected. Laboratory Abnormalities Due to Seizures Leukocytosis due to demargination commonly occurs in patients with seizures. Respiratory acidosis is common, especially during status epilepticus. Lactic acidosis is also common; indeed, its demonstration in the patient with an unclear prehospital history suggests the possibility of a seizure. Patients with status epilepticus may have profound lactic acidosis. Lactic acidosis resolves rapidly when motor activity is controlled. In patients whose acidosis does not resolve significantly within 1 hour of the cessation of generalized motor convulsions, the possibility of ketoacidosis, uremia, lactic acidosis from sepsis, or poisoning with toxic alcohols or glycols, salicylates, theophylline, iron, carbon monoxide, or cyanide should be considered (see Chapter 11 for a complete discussion of the evaluation of the patient with metabolic acidosis).

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MANAGEMENT
Resuscitation The management of patients with seizures is logical and systematic. Resuscitation requires the immediate identification and management of life threats such as airway obstruction, hypoxia, hypoglycemia, hyperthermia, and shock. The safest practice is to endotracheally intubate all actively seizing poisoned patients. Dronen and associates found a higher success rate and lower complication rate with orotracheal intubation after paralysis with succinylcholine than with blind nasotracheal intubation in poisoned patients.[25] Succinylcholine is contraindicated in patients with hyperkalemia. The use of succinylcholine requires a rapid but thoughtful risk/benefit analysis when there are significant risk factors for hyperkalemia such as prolonged status epilepticus, as indicated by a history or the presence of significant hyperthermia. The use of succinylcholine is also relatively contraindicated in patients who seize after poisoning with an organophosphate insecticide that inhibits serum cholinesterase, an enzyme required for the reversal of the drug effect of succinylcholine. Moderately short-acting, nondepolarizing agents such as vecuronium or atracurium can be used in patients with contraindications to succinylcholine. Because actively seizing patients may have significant lactic acidosis and hypercarbia, an increased ventilatory rate should initially be used in paralyzed patients to ensure adequate respiratory compensation for metabolic and respiratory acidoses.[83] Control of Seizures in Poisoned Patients Benzodiazepines Benzodiazepines are the initial drugs of choice to terminate seizures. Diazepam, lorazepam, and midazolam have been used successfully. All three drugs have similar mechanisms of action but different pharmacokinetics ( Tables 18–5 , 18–6 , 18–7 ).[6][19][26][34][38][49][51]

Table 18-5 -- Comparison of Intravenous Diazepam and Lorazepam in Treatment of Status Epilepticus Diazepam (n = 33) Lorazepam (n = 37) Dose = 10 mg, IV Rate = 10 mg/2 min First injection seizure control = 19 (58%) * Total seizures controlled = 25 (76%) * Dose = 4 mg, IV Rate = 4 mg/2 min First injection seizure control = 29 (78%) * Total seizures controlled = 33 (89%) *

Latency of action = 0–10 min (median = 2 min) * Latency of action = 0–15 min (median = 3 min) * Modified from Leppik IE, Derivan AT, Homan RW, et al: Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983; 249:1452–1454.
* Not statistically significantly different.

Table 18-6 -- Comparison of Intravenous and Rectal Lorazepam and Diazepam to Control Seizures Diazepam Intravenous Rectal Total Patients requiring multiple doses Patients requiring additional antiepileptic drugs Patients with subsequent respiratory depression Intravenous and rectal doses IV administration rate n = 34 n = 19 n = 53 n = 25 (47%) n = 17 (32%) n = 8 (15%) Lorazepam n = 27 n=6 n = 33 n = 8 (24%) n = 1 (3%) n = 1 (3%)

0.3–0.4 mg/kg 0.05–0.1 mg/kg 15–30 sec 15–30 sec 7–8 min later

Time when second dose of same drug given, if no termination of seizure 7–8 min later

Modified from Appleton R, Sweeney A, Choonara I, et al: Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol 1995; 37:682–688.

Studies comparing diazepam with lorazepam show that diazepam is more lipid soluble and enters the brain rapidly. However, its receptor binding is weaker and brain concentrations fall rapidly, resulting in a shorter duration of action than that of lorazepam.[72] One comparative study showed that diazepam distributed into the brain within 10 seconds and maintained EEG seizure control for 20 to 30 minutes whereas lorazepam distributed into the brain within 3 minutes and maintained EEG seizure control for up to 3 hours.[26] Clinical studies have had differing results. A comparison of intravenous and rectal lorazepam with intravenous and rectal diazepam in children with status epilepticus showed that lorazepam was superior (see Table 18–6 ).[6] A double-blind clinical study of patients with status epilepticus found both drugs to be equally efficacious (see Table 18–5 ).[51] Seizures refractory to diazepam or lorazepam have been successfully terminated with loading doses of midazolam ranging from 2.5 to 15 mg in adults, sometimes followed by continuous infusions ranging from 1 to 20 mg/hr (0.06–0.39 mg/kg/hr). [19][34][49] Barbiturates When intravenous benzodiazepines do not terminate a seizure, if seizures recur after the use of benzodiazepines, or if seizures occur after flumazenil administration, barbiturates are the next drugs of choice. INH, theophylline, and other methylxanthines produce status epilepticus more commonly than other epileptogenic toxicants. Patients with seizures induced by these toxicants will generally require loading with phenobarbital. There is little scientific information comparing the safety and efficacy of long-acting (phenobarbital), intermediate-acting (pentobarbital), and short-acting (thiopental) barbiturates in patients with status epilepticus. In spite of the lack of comparative data, phenobarbital has become the second-line drug of choice, owing to its longer duration of action (see Table 18–7 ). It is less lipid soluble than the benzodiazepines, and consequently the onset of therapeutic action is delayed up to 10 minutes.[72] The recommended dose of phenobarbital is 20 mg/kg of body weight, given at a rate of up to 50 mg/min in adults

or up to 1 mg/kg/min in children, for status epilepticus. Phenobarbital may produce severe soft tissue necrosis and should be given only intravenously. The treating physician should anticipate and be prepared to manage the development of respiratory failure and hypotension with the intravenous administration of phenobarbital. Phenytoin Although phenytoin is the second-line agent indicated in the treatment of most causes of status epilepticus, it is not usually useful in the management of drug-induced seizures. Phenytoin increased the frequency and duration of episodes of ventricular tachycardia in dogs poisoned with cyclic antidepressants and failed to prevent imipramine-induced seizures in a rat model.[8][15] It was ineffective in prophylaxis of fatal theophylline-induced seizures in mice; indeed, the LD50 for theophylline was lower for mice treated with phenytoin than for controls.[11] Phenobarbital significantly raised the theophylline LD 50 and provided significant prophylaxis for theophylline-induced seizures in this mouse model.[11] Findings from this animal study are compatible with a retrospective human study in which 21 of 22 patients with theophylline-induced seizures failed to respond to phenytoin treatment.[42] Phenytoin is also ineffective in INH-induced seizures.[11] These data emphasize not only that phenytoin is ineffective for certain drug-induced seizures but also that phenytoin may increase the morbidity and mortality of seizures in some cases. Seizures induced by 4-aminopyridine are an exception and have responded favorably in animal experimental studies and in case reports.[82][92][94] Pyridoxine Patients with seizures caused by known or suspected INH, hydrazine, or monomethylhydrazine (Gyromitra species) toxicity should receive intravenous pyridoxine in addition to benzodiazepines.[80] See Table 18–7 for pyridoxine dosing recommendations. Empirical administration of pyridoxine should also be considered in overdose patients with refractory status epilepticus because these cases may be due to unsuspected ingestions of INH. Preliminary observations suggest that pyridoxine may also be of benefit in the management of patients with refractory seizures due to theophylline or other methylxanthines. This requires further study.[36][88] Neuromuscular Paralysis When standard therapies fail to control status epilepticus, neuromuscular blockade and general anesthesia are recommended. Neuromuscular blockade prevents rhabdomyolysis, lactic acidosis, and hyperthermia due to excessive muscle activity, but it does not terminate seizures and does not protect against the brain injury associated with status epilepticus.[60][75] Irreversible brain damage is a well-recognized consequence of status epilepticus, even when the motor manifestations of seizures are controlled. The time required for brain injury to occur is unclear. A teenage girl who was in status epilepticus for 14 hours sustained permanent cognitive impairment despite neuromuscular blockade.[66] Baboons develop visible neuropathologic lesions after 82 minutes or more of convulsive status epilepticus.[59] Similar findings were noted when the animals were paralyzed, but the EEG manifestations of seizures continued.[60] Continuous EEG monitoring and aggressive therapy for electrical seizure activity is clearly indicated for patients who require neuromuscular paralysis for control of their convulsions. Hyperthermia

Status epilepticus may be associated with life-threatening hyperthermia due to increased muscular heat production. Normally, patients with core temperatures of 41°C (105°F) or higher are at high risk for lifethreatening organ injury; however, temperatures may rise rapidly, and treatment to prevent this should begin when the body temperature is less than 40°C (104°F). When benzodiazepines do not effectively control seizures, neuromuscular blockade is indicated to facilitate temperature control. Vecuronium is the drug of choice in this setting because rhabdomyolysis and hyperkalemia are often present, precluding the use of succinylcholine.[13] External cooling should be initiated at the same time as control of seizures. Although evaporative cooling is most efficacious, it is not always immediately available,[39][47][87][91] and packing in ice is also effective [21] (see Chapter 27 for a more extensive discussion). During cooling, we recommend continuous temperature monitoring with both a temperature-probe Foley catheter and a rectal thermistor. The patient should be cooled until the core temperature reaches 38.5°C to 39°C (101.3°F to 102.2°F).[39] Specific Toxicologic Treatments Gastrointestinal Decontamination Patients who have ingested epileptogenic toxicants can have the absorption of these toxicants altered. Syrup of ipecac is absolutely contraindicated because patients who are seizing or postictal are unable to protect their airways during emesis. Patients with ingestion of toxicants that can cause seizures can receive activated charcoal (AC). A 10:1, weight:weight ratio of AC to ingested drug is widely accepted as an optimal value for AC dosing.[4][67] Practically, the amount of toxicant ingested is usually unknown and the AC dosing is based on body weight, with 1 g/kg AC administered. AC has low binding avidity for lithium, iron, metals, alcohols, and glycols. Sorbitol may be used at the discretion of the attending physician. However, cathartics have not been proven to improve the clinical course of poisoned patients. Sorbitol also increases the risk of emesis and aspiration pneumonitis, and multiple doses of sorbitol have been associated with serious fluid and electrolyte abnormalities, bowel perforation, ventilatory failure due to distention from intraintestinal fermentation of sorbitol, and death.[5][70] Although orogastric lavage is not indicated in all patients who have ingested epileptogenic toxicants, it should be considered in patients who present within an hour of ingestion or have signs of serious clinical toxicity on presentation, especially when the ingestant is not bound to activated charcoal.[48] Antidotes Glucose Hypoglycemia should rapidly be excluded in every seizing patient and treated with intravenous D50W in adults and D25W in children, when demonstrated. The administration of thiamine is recommended in every adult patient who receives glucose. Flumazenil The administration of the benzodiazepine antagonist flumazenil is contraindicated in patients who have ingested potentially epileptogenic toxicants, even if benzodiazepines were co-ingested. It causes seizures in

mixed overdoses of benzodiazepines and epileptogenic toxicants and may also precipitate seizures in patients who chronically use benzodiazepines.[14][35][55][57][64][74][81] Its use will also render benzodiazepines relatively ineffective in treating seizures until the flumazenil receptor blockade has abated. Naloxone Naloxone is indicated for reversal of the apnea, hypotension, and mental status depression associated with opioid overdoses. It will not reverse seizures associated with normeperidine or norpropoxyphene toxicity.[12] Good experimental data indicate that naloxone is ineffective for meperidine-induced seizures and may actually exacerbate them. [12][85] Others The use of specific antidotes for carbon monoxide, organophosphate insecticides, cyanide, toxic alcohols and glycols, and iron poisoning depends on the clinical evidence that indicates poisoning with these substances. See specific chapters for further discussion of the diagnosis and treatment of poisoning with these agents. Disposition and Need for Consultants Most patients with drug-induced seizures require admission to the intensive care unit (ICU). An exception would be the insulin-dependent diabetic patient with inadvertent hypoglycemia or a stable patient with a seizure due to cocaine use. The patient with a seizure who is discharged home from the emergency department must have normal vital signs; a normal neurologic examination including a normal mental status; no other medical, surgical, or psychiatric conditions that would otherwise warrant hospitalization; appropriate follow-up; and availability of a safe environment with safe transportation. Consultation with a regional poison center and/or a medical toxicologist is indicated for patients with toxicant-induced seizures. Patients with toxicant-induced seizures who require neuromuscular paralysis and continuous EEG monitoring will require the consultation of a neurologist. . Pitfalls Pitfalls in the diagnosis and treatment of seizures are detailed in Table 18–8 .

Table 18-8 -- Pitfalls in Caring for Seizure Patients

• Not doing the primary survey and resuscitation (ABCDE) in a timely, systematic fashion. • Not performing specific toxicology therapy in a timely, systematic fashion. • Using a neuroparalytic drug whose duration of action exceeds the time it takes to load a seizing patient with 20 mg/kg of IV phenobarbital (i.e., 20–40 minutes). Longer neuromuscular blockade requires continuous EEG monitoring. • Failure to serially examine a seizure patient. A patient who does not wake up after a seizure does not necessarily have a “postictal state” but has status epilepticus or coma due to another serious pathologic process, until proven otherwise. • Not checking all seizure patients for hypoglycemia with stat bedside glucose determinations. • Giving glucose to adult patients without replenishing thiamine. • Not recognizing isoniazid-induced seizures and treating with pyridoxine. • Giving flumanzenil to unconscious seizure patients, to epileptic patients chronically taking benzodiazepines such as clonazepam, or to patients who have ingested potentially epileptogenic toxicants such as cyclic antidepressants. • Overlooking head injuries, spine injuries, other injuries, rhabdomyolysis, infection, and/or hyperthermia in seizing patients. • Overlooking treatable but life-threatening co-ingestants such as acetaminophen in patients with multiple-drug overdoses involving epileptogenic drugs.

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50. Kunisaki TA, Augenstein WL: Drug and toxin-induced seizures. Emerg Med Clin North Am 1994; 12:1027-1056. 51. Leppik IE, Derivan AT, Homan RW, et al: Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983; 249:1452-1454. 52. Lewis RJ, Yee L, Inkelis SH, et al: Clinical predictors of post-traumatic seizures in children with head trauma. Ann Emerg Med 1993; 22:1114-1118. 53. Lüddens H, Korpi ER, Seeburg PH: GABA A/benzodiazepine receptor heterogeneity: Neurophysiological implications. Neuropharmacology 1995; 34:245-254. 54. Macdonald RL, Olson RW: GABA A receptor channels. Annu Rev Neurosci 1994; 17:569-602. 55. Malatynska E, Knapp RJ, Ikeda M, et al: Antidepressants and seizure-interactions at the GABA-receptor chloride-ionophore complex. Life Sci 1988; 43:303-307. 56. Malouf R, Brust JCM: Hypoglycemia: Causes, neurological manifestions, and outcome. Ann Neurol 1985; 17:421-430. 57. Marchant B, Wray R, Leach A, et al: Flumazenil causing convulsions and ventricular tachycardia. BMJ 1989; 299:860. 58. McMicken DB, Freedland ES: Alcohol-related seizures. Emerg Med Clin North Am 1994; 12:10571079. 59. Meldrum BS, Brierley JB: Prolonged epileptic seizures in primates: Ischemic cell change and its relation to ictal physiological events. Arch Neurol 1973; 28:10-28. 60. Meldrum BS, Vigouroux RA, Brierley JB: Systemic factors and epileptic brain damage: Prolonged seizures in artificially paralyzed, ventilated baboons. Arch Neurol 1973; 29:82-87. 61. Messing RO, Simon RP: Seizures as a manifestion of systemic disease. Neurol Clin 1986; 4:563-584. 62. Mody I, De Koninck Y, Otis TS, et al: Bridging the cleft at GABA synapses in the brain. Trends Neurosci 1994; 17:517-525. 63. Moody JP, Inglis FG: Persistence of metaldehyde during acute molluscicide poisoning. Hum Exp Toxicol 1992; 11:361-362. 64. Mordel A, Winkler E, Almog S, et al: Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med 1992; 20:1733-1734. 65. Morimoto T, Nagao H, Yoshimatsu M, et al: Pathogenesis of glutamate in hyperthermia-induced seizures. Epilepsia 1993; 34:447-452. 66. Munn RI, Farrell K: Failure to recognize status epilepticus in a paralyzed patient. Can J Neurol Sci 1993; 20:234-236. 67. Olkkola K: Effect of charcoal-drug ratio on antidotal efficacy of oral activated charcoal. Br J Clin Pharmacol 1985; 19:767-773.

68. Olson KR, Kearney TE, Dyer JE, et al: Seizures associated with poisoning and drug overdose. Am J Emerg Med 1994; 12:392-395. 69. Pellegrino TR: An emergency department approach to first-time seizures. Emerg Med Clin North Am 1994; 12:925-939. 70. Phillips L, Nichols M, King W: A comparison of cathartics in pediatric ingestions [abstract]. Vet Hum Toxicol 1994; 36:377. 71. Pinard E, Riche D, Puiroud S, et al: Theophylline reduces cerebral hyperemia and enhances brain damage induced by seizures. Brain Res 1990; 511:303-309. 72. Ramsey RE: Treatment of status epilepticus. Epilepsia 1993; 34(suppl 1):S71-S81. 73. Report from Boston Collaborative Drug Surveillance Program. Drug-induced convulsions. Lancet 1972; 2:677-679. 74. Romazicon : Physicians' Desk Reference, 49th ed. Montvale, NJ: Medical Economics Data Production Co; 1995:2058-2060. 75. Rosenberg J, Pentel PR, Pond S, et al: Hyperthermia associated with drug intoxication [abstract]. Vet Hum Toxicol 1984; 26:413. 76. Rosenberg NM, Meert K, Marino D, et al: Seizures associated with meningitis. Pediatr Emerg Care 1992; 8:67-69. 77. Seaman M, Gushee D: Investigation of cocaine-related seizures showing unsuspected brain tumor. Ann Emerg Med 1990; 19:733-734. 78. Shochet RB, Murray GB: Neuropsychiatric toxicity of meperidine. J Intensive Care Med 1988; 3:246252. 79. Shuster EA: Seizures in pregnancy. Emerg Med Clin North Am 1994; 12:1013-1025. 80. Sievers ML, Herrier RN: Treatment of acute isoniazid toxicity. Am J Hosp Pharm 1975; 32:202-206. 81. Spivey WH: Flumazenil and seizures: Analysis of 43 cases. Clin Ther 1992; 14:292-305. 82. Stork CM, Hoffman RS: Characterization of 4-aminopyridine in overdose. J Toxicol Clin Toxicol 1994; 32:583-587. 83. Sutherland G, Park J, Proudfoot A: Ventilation and acid-base changes in deep coma due to barbiturate or TCA poisoning. Clin Toxicol 1977; 11:403-412. 84. Teitelbaum JS, Zatorre RJ, Carpenter S, et al: Neurologic sequela of domoic acid intoxication due to the ingestion of contaminated mussels. N Engl J Med 1990; 322:1781-1787. 85. Tortella FC, Cowan A, Adler MW: Studies on the excitatory and inhibitory influence of intracerebroventricularly injected opioids on seizure thresholds in rats. Neuropharmacol 1984; 23:749-754. 86. Victor M, Brausch G: The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 1967; 8:120.

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Ford: Clinical Toxicology, 1st ed.
Copyright © 2001 W. B. Saunders Company

Chapter 19 – Peripheral Neuropathy
ROBERT S. HOFFMAN

Essentials • • Obtain a thorough history, including specific aspects of occupation and hobbies that may involve chemicals associated with peripheral neuropathy. Define the neuropathy in terms of: a. Onset b. Location c. System(s) of involvement Motor Sensory Autonomic Mixed

• • • •

Exclude common medical causes for the neuropathy. Collect both subjective and objective data to support the presence of a disorder. Perform biologic monitoring to confirm the exposure, if possible. Remove the patient from the exposure and begin definitive therapy if available.

PHYSIOLOGY/PATHOPHYSIOLOGY
The peripheral nervous system is exquisitely sensitive to injury from diseases and toxins. As summarized in several excellent reviews, it is the basic structure and function of the peripheral nervous system that creates this vulnerability.[4][10][51] Transport of electrical impulses across vast distances by single cells is a highly energy-dependent process. These single cells are often greater than 200,000 times longer than most other cells in the body, and, despite being configured into very narrow cylinders, the volume of the axon is substantially greater than that of the cell body. Whereas most synthetic functions of the cell occur in the cell body, cellular substrate utilization occurs predominately along the axon. Cellular products must be transported down the axon by an active (energy-dependent) mechanism. Finally, electrical conduction requires precisely timed opening and closing of multiple ion channels, and active ion pumping is used to restore the resting potential. All of these functions are energy dependent, with glucose metabolism as the

primary and almost exclusive substrate. Thus, any systemic condition that interferes with either the supply or utilization of oxygen and glucose or with protein synthesis and transport has the ability to impair peripheral nerves. In addition, a variety of disorders and toxins can directly damage the peripheral nervous system through highly selective destruction of certain cellular components. A number of classification systems can be used to describe peripheral neuropathies. These systems relate to the number of cells affected, the anatomic distribution of the resulting deficit, the function of the nerve cell(s) involved, and the histologic site of injury. Because each classification system offers insight into the disease process, etiologic agents, and the prognosis, it is often customary to describe neuropathies using terms derived from multiple schemes. A thorough understanding of this terminology and its implications is essential for the clinician because it serves as the gateway to literature review, consultant referral, diagnosis, and prognosis. Thus, each of these classification systems is reviewed in some depth. Because this chapter emphasizes patient evaluation, the discussion of these classification systems will proceed in a fashion that best follows a patient’s chief complaint. Number of Cells Affected A peripheral neuropathy may be subclassified as either a mononeuropathy (involving a single nerve) or a polyneuropathy (involving multiple nerves). In general, because toxins produce systemic changes that are often metabolic, most toxin-related neuropathies are polyneuropathies.[10] Clearly, exceptions to this rule occur. Early presentations of progressive disorders and several unique toxins may manifest as isolated mononeuropathies, especially those affecting cranial nerves. When a patient presents with stable involvement of a single nerve, however, trauma and vascular insult are more likely diagnoses. Although the patient’s chief complaint may suggest a mononeuropathy, this diagnosis should not be entertained until a thorough evaluation has been completed. A comprehensive examination is essential to detect subtle abnormalities of which the patient might not even be aware. Once these less-prominent deficits are found, the diagnosis of a polyneuropathy will be more clear. Anatomic Distribution of the Affected Area The simplest description of the anatomic area affected by a neuropathy involves a single distinction between local and widespread involvement. Thus, a focal neuropathy is one that affects an isolated body part, whereas a diffuse neuropathy involves a wider anatomic distribution. Similar to mononeuropathies, focal neuropathies are less common in toxin-mediated injuries. Once again, however, because many patients will present early in the course of a disorder, it is essential to evaluate them for progressive or subtle dysfunction of other areas. Diffuse neuropathies can be further subclassified into symmetric or asymmetric types. As a general rule, toxin-induced diffuse neuropathies tend to be symmetric. Diffuse neuropathies often take on a characteristic progression. Because long nerve fibers tend to be more sensitive to injury, patients will often complain of symptoms that began in their hands or feet and subsequently moved more proximally, or ascend. Although this progression is common of many neuropathies and is therefore not useful to distinguish toxin-induced from non–toxin-induced causes, very few toxin-induced peripheral neuropathies occur in descending fashion. Classic examples of descending neuropathies would be those that result from botulism or diphtheria.[18][47] Thus, a typical complaint for a toxin-involved neuropathy would relate to symptoms that began in the fingers or toes of both extremities and progressed to involve the hands and/or feet in a relatively symmetric distribution.

Function of Cells Affected The peripheral nervous system is functionally subdivided into motor, sensory, and autonomic divisions. In addition, the cranial nerves can be considered as a separate division because of their ability to be affected by a unique subset of toxins. The functional divisions of the peripheral nervous system involved correlate quite well with the patient’s symptoms. Whereas diseases and toxins are often associated with injury to a specific subdivision of the peripheral nervous system, many neuropathies demonstrate involvement of multiple functional divisions. For the purposes of this discussion, diseases and toxins that typically involve one functional division of the peripheral nervous system are grouped by their primary involvement only. Those disorders that are usually mixed are listed as such. Motor The physiologic correlate of a motor neuropathy is loss of function. Patients will complain of symptoms that range from weakness to plegia or paralysis of the affected area. Toxins that directly compromise nervous tissue will usually cause symptoms that begin distally, because the longer nerve fibers supplying distal muscles are injured first and then move proximally. Lead poisoning is the classic example of a toxin-induced motor neuropathy. Isolated wristdrop or footdrop might be the only presenting neurologic complaint of a patient with significant lead poisoning. For unclear reasons, lead neuropathy tends to affect the upper limbs first in adults and the lower limbs first in children.[44] The cranial nerves of the eyes are under very rigid control. Subtle muscle weakness from peripheral neuropathy can produce diplopia, which is a very common finding in motor neuropathies resulting from impaired impulse or neurochemical transmission. Examples of toxin-induced neuropathy in which diplopia might be the earliest or sole presenting complaint would include botulism, diphtheria, and elapid envenomation.[18][22][47] In addition, an isolated lateral rectus (CN VI) palsy is considered the hallmark of Wernicke’s encephalopathy which is often ethanol-induced.[11] In all of these disorders, ophthalmologic findings may represent early manifestations of life-threatening illnesses. Therefore, clinicians must evaluate patients with ophthalmologic findings for other neurologic deficits and observe them for progression of disease. Alternatively, toxins that alter neuronal conduction through electrolyte changes (especially potassium and magnesium) will usually produce more diffuse and precipitous symptoms. Hypokalemia from tolueneinduced renal tubular acidosis or ingestion of soluble barium salts can present as widespread pure motor weakness that may mimic massive stroke, catatonia, or neuromuscular blockade.[40][50] Common causes of toxin-induced peripheral motor neuropathies are listed in Table 19–1 .

Table 19-1 -- Toxin-Induced Peripheral Neuropathies: Distribution by System Involved * Motor Sensory Sensory and Motor Autonomic Botulism Buckthorn Dapsone Acrylamide Cisplatin Colchicine Arsenic Carbon disulfide 2'3'-Dideoxycytidine (ddC) Acrylamide Alloxan Cisplatin

Cranial

Botulism (early) Carbon disulfide Diphtheria (early)

Motor Eastern diamondback rattlesnake (rare) Elapid venom Lead Mercury Mojave rattlesnake

Sensory Ethanol

Sensory and Motor Disulfiram

Autonomic Doxorubicin Ethanol

Cranial Elapid venom (early) Methanol

Metronidazole Hexacarbons Phenytoin Pyridoxine Taxol Thallium Vincristine Isoniazid Organophosphates

Streptozotocin Thallium Taxol Thallium Trichloroethylene

* Toxins that cause mixed sensory and motor findings when one type predominates are listed under that particular finding.

When diffuse muscle weakness develops from any cause, it is critical to assess and serially evaluate the muscles of respiration to determine the need for intubation and mechanical ventilation before the onset of respiratory failure. Although arterial blood gas analysis and pulse oximetry are fundamental tools for evaluating the respiratory status, it should be remembered that consequential impairment of respiratory function can occur long before any depression in oxygen saturation or elevation in the partial pressure of carbon dioxide can be detected. Consequentially, respiratory muscle function assessment is more important than assessment of gas exchange. Measurement of the negative inspiratory force is the most rapid, reproducible objective determinant of respiratory status, in lieu of formal pulmonary function testing. This test can be accomplished at the bedside with minimal technology or skill. Sensory Whereas sensory neuropathies can involve every sense including position, vibration, temperature, taste, smell, vision, or hearing, the most common complaint of patients with toxin-induced sensory neuropathies involve touch and two-point discrimination. Patients typically complain of numbness, tingling, and difficulty manipulating small objects. Classic sensory toxin-induced neuropathies are often described as involving a symmetric area of the hands or feet in what is know as a “stocking and glove” distribution. This finding of a nondermatomal distribution implies distal involvement of multiple nerves. A classic example of this type of neuropathy would result from acrylamide exposure that occurs in the tile or grouting industry.[20] Like other neuropathies, a stocking and glove distribution may represent the onset of a progressive disorder or the extent of a stable condition. Certain other toxins produce sensory neuropathies that take on very characteristic findings. Some of the metals and metalloids result in a painful sensory neuropathy. Of these, thallium is the most classic with its tendency to produce an early and rapidly accelerating, exquisitely painful, ascending sensory neuropathy.[28] Overexposure to pyridoxine (vitamin B6) results in loss of position sense and causes the patient to have a wide-based, ataxic gait.[45] Other causes of sensory neuropathy are found in Table 19–1 . Autonomic Autonomic neuropathies are distinctly uncommon when compared with other forms of peripheral neuropathy

and usually result from diabetes. As such, the diabetic neuropathy caused by toxins such as Vacor, alloxan, streptozotocin, and similar compounds could be classified as toxin-induced autonomic neuropathies.[27][32][52] Autonomic neuropathy has also been described with exposures to acrylamide,[46] cisplatin,[41] doxorubicin,[13] ethanol,[33] taxol,[21] and thallium,[28] as shown in Table 19–1 . Patients may experience alteration of sweating, heart rate, blood pressure, postural tone, ejaculation, and other functions normally controlled by the autonomic nervous system. Histologic Site of Injury Electrical impulses can be altered or inhibited at any point along the cell. Most impulses originate at the cell body and result from chemically mediated depolarization of the cell membrane. The impulse travels down the axon, which is sometimes sheathed in myelin, until it reaches the nerve terminal. When the nerve terminal is depolarized, ion fluxes allow for release of chemical mediators that affect other nerves or organ systems. The histologic classification scheme of peripheral neuropathies simply locates the area of the cell that has been injured. While this classification scheme sheds little or no light on the patient’s symptom complex, it offers significant information with regard to prognosis. The information necessary to categorize a patient’s illness into one of these subdivisions cannot be obtained from the history or physical examination. Rather, it requires sophisticated testing, biopsy, or more commonly a review of the literature once the toxin has been identified. Peripheral neuropathies are thereby subdivided into four types: 1. 2. 3. 4. Neuronopathies, which are disorders of the cell body Axonopathies, which are disorders of the axon Myelinopathies, which are disorders of the myelin sheath Transmission neuropathies, which are disorders that interfere with the release of neurotransmitters from the nerve terminal

Neuronopathy Although toxin-induced neuronopathies are relatively uncommon, they are the most severe. Damage to the cell body is often permanent. When healing does occur, however, recovery is slow and usually incomplete. The classic example of a toxin-induced neuronopathy resulted from excessive utilization of pyridoxine (vitamin B6). Megatherapy with doses of pyridoxine as large as 2 to 6 g/d was recommended either as part of a body-building regimen or for prevention of premenstrual syndrome. Schaumburg and colleagues described seven women who chronically consumed this water-soluble vitamin.[45] These patients developed sensory findings that consisted of numb feet, unsteady gait, numbness in the hands, and, later, perioral paresthesias. Ultimately, stocking-and-glove sensory deficits developed but motor strength was always preserved. Testing revealed predominant abnormalities of position and vibration sense, whereas other sensory findings such as alterations of temperature, pain, and touch were less affected. This syndrome has been unfortunately reproduced after massive acute overdose with pyridoxine. Albin and colleagues described two patients who received high-dose pyridoxine therapy for ingestion of Gyromitra mushrooms.[3] Both patients were given an excess of 100 g (2000 mg/kg) intravenously over a 3-day period and rapidly developed symptoms similar to the patients with chronic exposure described previously. A milder form of pyridoxine neuropathy has been described after chronic administration of smaller doses in humans.[38] In these later patients, symptoms continued to develop after discontinuation of therapy, but ultimately some recovery was achieved.[38] In both the chronically overdosed and massively acutely

overdosed patients, recovery was slower and often incomplete.[3][45] Rarely, other toxins such as doxorubicin[13] have been associated with peripheral neuronopathy ( Table 19–2 ).

Table 19-2 -- Toxin-Induced Peripheral Neuropathies: Distribution by Histologic Lesion * Neuronopathy Axonopathy Myelinopathy Transmission Doxorubicin Pyridoxine Acrylamide Arsenic Cisplatin Colchicine Dapsone 2'3'-Dideoxycytidine (ddC) Ethanol Hexacarbons Mercury Phenytoin Organophosphates Taxol Thallium Vacor Vincristine
* Toxins that cause mixed histologic findings when one type predominates are listed under that particular finding.

Amiodarone Buckthorn Diphtheria Lead

Black widow spider venom Botulism Elapid and crotalid venom Saxitoxin

Trichloroethylene Scorpion venom Tetrodotoxin

Axonopathy Axonopathy is the most common form of toxin-induced peripheral neuropathy. An axonopathy can be viewed as a chemical transection of the axon. The toxin may attach to and destroy a specific region of the axon. The distal portion of the axon that is no longer connected to the cell body subsequently dies, and loss of function results. Alternatively, the toxin may interfere with the transport of nutrients or other essential molecules down the axon. The axonal remnant located distally to the last region of successful transport subsequently dies. Even though the symptoms of axonopathies are often devastating, recovery is expected because axons of the peripheral nervous system have the ability to regenerate, unlike axons of the central nervous system. This process is often slow, but complete restoration of function is possible. Classic forms of toxin-induced axonopathy include hexacarbon, acrylamide, organophosphates, and thallium. Exposure through occupational use or recreational abuse of glues or solvents that contain 6-carbon straight-chained molecules (n-hexane, or methyl n-butyl ketone) results in a characteristic mixed sensory and motor peripheral neuropathy. Typical examples come from industries such as the shoe and leather industry. Abbritti described 122 Italian shoe workers who developed a toxic polyneuropathy as a result of exposure to n-hexane.[1] Exposed individuals developed dysesthesias followed by symmetric alterations of

touch, perception, and motor function. Diagnostic correlates included findings such as swelling of axons and accumulation of packed neurofilaments on light microscopy[42] and denervation on electromyography.[8] Patients typically continued to experience deterioration after removal from exposure but then recovered with time. The etiology of this disorder appears to be related to the metabolite 2,5-hexandione (2,5-HD), which has been demonstrated experimentally to produce lesions identical to those caused by n-hexane and methyl nbutyl ketone ( Fig. 19–1 ).[37] 2,5-HD has been demonstrated to inhibit phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase, which results in impairment of glycolysis.[43] Although this finding generated a hypothesis that impaired axonal transport and energy production were responsible for the hexacarbon axonopathy, the concentration of 2,5-HD required to achieve this effect was much greater than was obtained clinically. 2,5-HD has also been shown to form pyrrole, which interferes with the interactions between neurofilaments and other proteins; crosslink neurofilaments; decrease phosphorylation of neurofilaments; and reduce proteolysis of neurofilaments. Although the exact mechanism is unclear, the most plausible chain of events is described by Abou-Donia as follows.[2] n-Hexane’s metabolism to 2,5-HD decreases phosphorylation of neurofilaments, which destroys the normal cytoskeletal matrix. Neurofilament proteins are then transported down the axon where they accumulate, crosslink, and produce the giant axonal swelling that characterizes this neuropathy.

Figure 19-1 Metabolism of n-hexane.

The use of acrylamide as a polymerizing agent in the 1950s was followed rapidly by human reports and animal models of acrylamide neurotoxicity.[20][29] Early symptoms may involve skin irritation and generalized fatigue. Neurologic dysfunction is characterized by symmetric findings of a mixed sensory, motor, and autonomic dysfunction in the hands and feet. Patients may complain of numbness, weakness, and excessive sweating. Deep tendon reflexes and vibration sense are also diminished or absent early in the disease.

The exact mechanism of acrylamide toxicity has not been established, although theories suggest that events such as a reduction in metabolic energy or an interference with cytoskeletal proteins are responsible.[26] Histologic findings consist of a classic “dying back” axonopathy.[19] Like other toxin-induced neuropathies described here, symptoms may progress for several weeks even after the exposure has ceased. Then the recovery phase begins. The time period for recovery ranges from a few months to a few years, and both the duration and extent of recovery are largely dependent on the degree of toxicity. One of the more dramatic examples of axonopathy resulted from an episode that has come to be known as “Ginger-Jake paralysis.” In the United States in the 1930s, an alcoholic drink prepared from ginger was contaminated with triorthocresyl phosphate (TOCP). TOCP is an organophosphate compound that has weak cholinesterase inhibition. Some estimates suggest that as many as 20,000 people were affected, as was summarized by Le Quesne.[25] Gastrointestinal symptoms were minimal or absent. Motor neuropathy presented as symmetric distal weakness and wasting. Sensory findings were absent or unimpressive. Although recovery often occurred, some residual spastic paraplegia was not uncommon. Inhibition of a specific neuroprotective esterase is thought to be responsible for the neurotoxicity.[25] Thallium toxicity produces multiorgan failure that is typical of most metal poisonings. As part of this process, a characteristic ascending, largely sensory, rapidly progressive, and severely painful sensory neuropathy develops. Although motor and autonomic findings have been described, the sensory findings are so pronounced they tend to overshadow the other components, except in the most severe of cases. In fact, this sensory neuropathy is so characteristic that, when combined with the subsequent development of alopecia, it is almost diagnostic of thallium toxicity. Patients will often have a transient gastrointestinal syndrome that may involve nausea, vomiting, diarrhea, or constipation.[28][30] Shortly thereafter they will complain of pain in their feet that is so severe that it prevents walking. Over the course of a few days, these symptoms will progress and become associated with other organ involvement. Although similar findings may be seen in patients with arsenic poisoning, the progression of these findings in thallium toxicity is much more abrupt. Electrophysiologic studies in thallium-poisoned patients show changes consistent with classic axonopathy and subclinical involvement of multiple neurons.[16] Although animal studies of thallium toxicity have demonstrated a variety of findings, swelling of axonal mitochondria seems to be a fairly consistent finding. Again, the exact mechanism of thallium-induced neuropathy is unclear. Some authors attribute thallium’s effect to its similarity to potassium and suggest thallium may impair sodium-potassium adenosine triphosphatase.[6] Other toxin-induced axonopathies can be found in Table 19–2 . Myelinopathy Myelin functions to insulate nervous tissue and enhance conduction velocity. Disorders that destroy only myelin have the unique ability to impair neuronal conduction without altering neuron integrity. Thus, although the patient may have severe and life-threatening manifestations of nervous system dysfunction, rapid and complete recovery is expected once the disorder has completed its course. A classic myelinopathy is Guillain-Barré syndrome (GBS), and, like GBS, respiratory failure is the most severe manifestation of toxininduced peripheral demyelinating disorders. The classic example of toxin-induced myelinopathy is diphtheria.[10][18] Agents such as amiodarone,[39] buckthorn,[9] lead,[49] and trichloroethylene[17] may also produce demyelination, although reports are conflicting (see Table 19–2 ).

Diphtheria is an infectious disease caused by Corynebacterium diphtheriae and is characterized by fever, fatigue, headache, sore throat, and a gray or green membrane on the tonsils. Ten to twenty per cent of patients with diphtheria will develop neurologic symptoms, ranging from cranial nerve palsies to peripheral neuropathy and frank paralysis that may begin 4 to 8 weeks after the onset of infection. Diphtheria toxin has the unique ability to directly interfere with myelin synthesis.[18] Recovery is generally complete as long as other organ damage has not occurred. Transmission Neuropathy Unlike the previous categories of peripheral neuropathy, transmission neuropathy involves no damage to the neuronal cell body, axon, or surrounding myelin. Rather, with transmission neuropathy, the toxin directly impairs either the propagation of electrical impulses or the release of neurotransmitter molecules from the nerve terminus. Botulism, tetrodotoxin, saxitoxin, and envenomation by black widow spiders, elapids, some crotalids, certain scorpions, and other examples of transmission neuropathies are listed in Table 19–2 . In addition, electrolyte abnormalities such as severe hypokalemia and hypomagnesemia produce similar findings. Because these derangements involve specific areas of nervous tissue function, the general rule of thumb is that recovery is relatively rapid and nearly or entirely complete when compared with the disorders listed earlier that affect other anatomic locations. The mechanism of botulism toxicity has been well described.[47] The toxin binds irreversibly to the nerve terminal where it prevents the release of acetylcholine. Patients manifest symptoms of acetylcholine lack as a pure motor weakness that begins commonly with diplopia or difficulty swallowing and rapidly descends to produce a flaccid paralysis with respiratory failure. Other manifestations of acetylcholine deficiency include dilated pupils, dry mouth, and constipation. Administration of antitoxin before the onset of symptoms is completely protective but only halts the progression of findings once symptoms have begun. Because binding of toxin to the nervous tissue is irreversible, recovery does not occur until the nerve terminal regenerates, which may require several months. Tetrodotoxin is found in puffer fish (fugu), the blue-ringed octopus, and certain newts, toads, and salamanders. Tetrodotoxin directly binds to the exterior mouth of sodium channels, where it prevents sodium channel opening and impairs impulse conductance down the axon.[36] After a tetrodotoxin-contaminated meal, patients may complain of perioral paresthesias, weakness, and shortness of breath. These symptoms are often followed rapidly by cardiorespiratory arrest and death. With endotracheal intubation and supportive care, prompt recovery is expected. Saxitoxin has a similar mechanism of action.[36] The black widow spider (Latrodectus mactans) possesses a complex toxin that reversibly binds to gangliosides and glycoproteins of the synaptosomal membrane where it opens sodium channels.[5] The net result is continuous release of acetylcholine and norepinephrine. Patients experience spasm of large muscle groups with severe pain and autonomic findings such as tachycardia, hypertension, and so on.[7] Because this binding is reversible, administration of antitoxin results in a rapid and complete restoration of nerve function. Scorpion envenomation in the United States is rarely associated with fatality. Rather, a painful neuropathy develops. Venom of Centruroides species of scorpion binds to sodium channels and incompletely inactivates them during depolarization to prolong the action potential.[53] An additional action enhances membrane depolarization.[31] The net result is repetitive and prolonged firing of nerves resulting in enhanced

excitability and pain. Although an antivenin exists, toxicity is usually self-limited and relieved with conventional supportive care.

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SPECIAL SITUATION: THE HUMAN IMMUNODEFICIENCY VIRUS–POSITIVE PATIENT
The human immunodeficiency virus (HIV) epidemic has created a unique problem for clinicians evaluating patients with peripheral neuropathy in that peripheral neuropathy is associated with both the disease and its treatment. Comi and colleagues studied 23 patients for the presence of peripheral neuropathy. All 12 patients with the acquired immunodeficiency syndrome (AIDS) and 7 of 11 patients with HIV infection offered symptoms suggestive of peripheral neuropathy.[14] Clinical or neurophysiologic evidence of peripheral neuropathy was demonstrated in 6 of the 11 HIV patients and 11 of the 12 AIDS patients. The most common finding was a distal sensory and motor neuropathy consistent with axonal degeneration. Other authors estimate a 35 to 40 per cent incidence of peripheral neuropathy (most commonly axonal degeneration) in AIDS patients. [48][54] Numerous trials are required to evaluate new antiviral agents. Zalcitabin (2',3'-dideoxycytidine [ddC]) is one of a number of dideoxynucleosides known to cause peripheral neuropathy. In one study, peripheral neuropathy was reported as the most common adverse effect of ddC treatment. [35] Dubinsky and coworkers confirmed that the ddC-induced neuropathy was of an axonal type.[15] Although 2',3'-didoxyinoside (ddI) is known for its ability to cause pancreatitis, Lambert and colleagues reported that a painful peripheral neuropathy developed in 8 of 37 ddI-treated patients.[23] Interestingly, when ddC and ddI are combined, additive or even synergistic toxicity to the peripheral nervous system results. [24] Similarly, early work with stavudine (d4T) suggests that peripheral neuropathy may also be its most common side effect, occurring in just under 20 per cent of treated patients.[34] Because the neuropathies associated with the disease and its treatment are similar, clinicians are often forced to choose between discontinuing therapy or treating through the disorder. The time course for developing neuropathy is quite variable,[23] so little correlation can be made between the onset of therapy and neuropathy.

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DIFFERENTIAL DIAGNOSIS
The differential diagnosis of peripheral neuropathy includes common and rare medical disorders, toxin exposures, mechanical injury, and a variety of other syndromes. Infectious causes are common. In fact, leprosy, which causes a demyelinating neuropathy, is believed to be the most common cause of peripheral neuropathy worldwide. This disorder is distinctly uncommon, however, in the United States, where GBS is the most common cause of a postinfectious acute demyelinating disorder. Patients typically present with ascending motor findings associated with a loss of deep tendon reflexes and minimal or no sensory complaints. Cranial nerves are rarely involved (Miller-Fisher variant), and the most worrisome finding is respiratory compromise. Other infectious causes include Bell’s palsy, which is now fairly commonly seen with Lyme disease; the painful neuropathy of herpes zoster; and the descending neuropathy of diphtheria. A variety of medical illnesses are also responsible for peripheral neuropathy, of which diabetes is clearly the most common cause. Many varied neurologic lesions have been described in patients with diabetes. The classic diabetic neuropathy, however, is often termed mononeuritis multiplex, which is characterized by the sudden loss of single peripheral nerves in an asymmetric distribution. Patients will often have loss of sensation or burning paresthesias of their feet as a primary finding. Other fairly common neuropathies have been described with uremia, vitamin B 12 deficiency, AIDS, and paraneoplastic syndromes. Trauma-related nerve injury is also a common cause of neuropathy. In this category, repetitive motion injuries such as carpal tunnel syndrome require specific attention when evaluating a patient with hand complaints. The carpal tunnel is also affected in hypothyroidism, acromegaly, and rheumatoid arthritis. Peripheral neuropathy can be associated with rare hereditary disorders, endocrine abnormalities, and exposures to drugs and toxins. Many of the more common etiologic causes for peripheral neuropathy can be found in Table 19–3 .

Table 19-3 -- Differential Diagnosis of Peripheral Neuropathy * Mechanical Medical Infectious Toxins Trauma Carpal tunnel Vitamin B12 deficiency Diabetes Hypothyroid Botulism Diphtheria Guillain-Barré syndrome Acrylamide Ethanol Elapid venom Hexacarbons Lead Organophosphates

Drugs Amiodarone Dapsone Isoniazid Phenytoin Pyridoxine Taxol

Multiple myeloma HIV and AIDS Paraneoplastic Uremia Leprosy Lyme disease

Mechanical

Medical

Infectious Thallium

Toxins

Drugs Vincristine (See other agents in Tables 19–1 and 19–2 )

(See other agents in Tables 19–1 and 19–2 )

* A complete differential diagnosis of peripheral neuropathy is very extensive; this table lists some of the more common causes.

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CLINICAL EVALUATION
As always, the evaluation begins with a thorough history and physical examination. The history should concentrate on the onset, duration, and progression of symptoms as well as hobbies, occupations, and environmental sources of toxins. A thorough occupational history is essential and must not focus only on a job title but rather on a description of the type of work, the workplace, and possible chemicals or agents used by coworkers. Additional inquiry should focus on a family history of inherited disorders listed in Table 19–3 , access to medications (including over-the-counter dietary supplements), and the use of alcohol and other substances of abuse. Physical examination must include a complete search for medical illness and a comprehensive neurologic assessment. All distributions of the nervous system should be evaluated, including those modalities rarely examined (temperature discrimination), and documented. Objective findings such as measurement of twopoint discrimination, responsiveness of deep tendon reflexes, and strength should be quantified and recorded for comparison with pre-existing medical records and future examinations.

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LABORATORY EVALUATION
Common Laboratory Tests The potential for overutilization of the laboratory can easily be appreciated if the clinician elects to immediately screen for all disorders associated with peripheral neuropathy. This pitfall can only be avoided by a rational step-wise approach that is guided by the history and physical examination and by a complete knowledge of the incidence of these disorders. General screening for diabetes and severe electrolyte disorders such hypokalemia, hypomagnesemia, and hypophosphatemia is a generally indicated first step. In addition, a complete blood cell count, urinalysis, erythrocyte sedimentation rate determination, and liver function studies can give excellent clues to the patient’s general level of health, as well as to many systemic diseases. Although chest radiography and electrocardiography have some potential to detect tumors and infiltrative diseases, the usefulness of these studies is questionable. Examination of the cerebrospinal fluid is a required next step in any patient in whom there is a consideration of GBS. Specialized Laboratory Studies Biologic monitoring should be obtained to confirm exposure whenever the history suggests the role of toxins that are known to be associated with peripheral neuropathy. The two major pitfalls of biologic monitoring, however, are an inability to obtain determinants of exposure to all substances and the lack of a strong correlation between exposure and neuropathy. Thus, although confirmation of exposure increases the likelihood of causation, it should never be considered sufficient grounds for establishing a diagnosis of toxinrelated peripheral neuropathy. This commonly occurs during an assessment for metal exposure. Improper containers, collection methods, and the presence of small amounts of metals in most patients have the potential to mislead clinicians who are not experienced in metal poisoning. Electrodiagnostic testing (EDT) should be ordered. The first role of EDT is to confirm the diagnosis of peripheral neuropathy by distinguishing between primary muscle and neurologic disorders. Subsequently, EDT can define the location and extent of the disorder (number and distribution of nerves involved). This helps exclude trauma, diabetes, and a few other disorders such as carpal tunnel syndrome from the extensive differential diagnosis list. A further characterization can be made between an axonopathy and a myelinopathy. Because most toxin-mediated disorders are axonopathies and many common medical disorders are myelinopathies, this distinction can prove most useful. Knowledge of the distribution, extent, and probable histology of the disorder allows the clinician to correlate the patient’s clinical findings to those reported in the literature. If such a correlation exists, it will solidify a claim of causation. Finally, EDT has the ability to characterize effects at the neuromuscular junction. Certain disorders such as botulism, EatonLambert syndrome, and myasthenia gravis have characteristic findings on EDT that are nearly diagnostic. A final diagnostic test is sural nerve biopsy. Biopsy is usually reserved for unclear cases where the histology may prove diagnostic. The sural nerve is typically selected for its accessibility and lack of debility after biopsy.

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DEFINITIVE TREATMENT
Even though antidotal therapy is available for some toxin-induced peripheral neuropathies such as assorted venoms, metals and metalloids, and botulism, the mainstay of treatment for most patients with toxin-induced peripheral neuropathy is removal from exposure. The clinician should not be discouraged if the patient’s condition continues to deteriorate for a period of several weeks after removal from exposure, because this is a commonly described event. Rather, the clinician should counsel the patient about the duration of illness, expected recovery phase, the extent of the recovery expected based on the histology of the injury, and the course of rehabilitation therapy that will be required.

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DISPOSITION/NEED FOR CONSULTANTS
Peripheral neuropathy is rarely a life-threatening disorder. The clinician should recognize those findings that might suggest the need for immediate intervention or hospitalization. • The patient is manifesting symptoms of an acute progressive motor neuropathy. It is essential to recognize rapidly progressive motor neuropathies because of their potential to result in ventilatory insufficiency. Although this most commonly occurs as a complication of GBS, its toxic correlate could be considered the patient with botulism or elapid envenomation who presents with diplopia as a sole finding. The peripheral neuropathy is a manifestation of exposure to a toxin with associated life-threatening manifestations that are not related to the neuropathy itself. A good example would be the ascending painful sensory neuropathy that might serve as an early marker for a severe case of thallium toxicity. There is a potential need to administer an antidote that has intrinsic toxicity. This would include most antivenins, botulism antitoxin, and the metal chelators. The diagnosis is unclear and may be related to a medical illness with consequential indications.

• •

In the absence of these indications, the majority of patients with peripheral neuropathy can be evaluated as outpatients. Appropriate diagnosis and care will often require a concerted effort between a toxicologist, an occupational medicine physician, and a neurologist.

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REFERENCES
1. Abbritti G, Siracusa A, Cianchetti C, et al: Shoe-makers’ polyneuropathy in Italy: The aetiological problem. Br J Indust Med 1976; 33:92-99. 2. Abou-Donia MB: Solvents. In: Abou-Donia MB, ed. Neurotoxicology, Boca Raton: CRC Press; 1992:395-421. 3. Albin RL, Albers JW, Greenberg HS, et al: Acute sensory neuropathy-neuronopathy from pyridoxine overdose. Neurology 1987; 37:1729-1732. 4. Anthony DC, Graham DG: Toxic responses of the nervous system. In: Amdur MO, Doull J, Klaassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons, fourth edition New York: McGraw Hill; 1991:407-429. 5. Baba A, Cooper JR: The action of black widow spider venom in synaptosomes. J Neurochem 1980; 34:1369-1379. 6. Bank WJ: Thallium. In: Spencer PS, Schaumburg HH, ed. Experimental and Clinical Neurotoxicology, Baltimore: William & Wilkins; 1980:570-577. 7. Binder LS: Acute arthropod envenomation: Incidence, clinical features and management. Med Toxicol Adverse Drug Exp 1989; 4:163-173. 8. Buiatti E, Cecchini S, Ronchi O, Dolara P, Bulgarelli G: Relationship between clinical and electromyographic findings and exposure to solvents, in shoe and leather workers. Br J Indust Med 1978; 35:168-173. 9. Calderone-Gonzalez R, Rizzi-Hernandez H: Buckthorn polyneuropathy. N Engl J Med 1967; 277:69-71. 10. Cavanagh JB: Peripheral neuropathy caused by chemical agents. CRC Crit Rev Toxicol 1973; 2:365417. 11. Charness ME, Simon RP, Greenberg DA: Ethanol and the nervous system. N Engl J Med 1989; 321:442-454. 13. Cho ES: Toxic effects of adriamycin on the ganglia of the peripheral nervous system: A neuropathological study. J Neuropathol Exp Neurol 1977; 36:907-915. 14. Comi G, Medaglini S, Nemni R, et al: Peripheral nervous system involvement in AIDS and HIV patients: A comparative neurophysiologic and morphologic study (abstract). Int Conf AIDS 1991; 7:212. 15. Dubinsky RM, Yarchoan R, Dalakas M, Broder S: Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2',3'-dideoxycytidine (ddC). Muscle Nerve 1989; 12:856-860. 16. Dumitru D, Kalantri A: Electrophysiologic investigation of thallium poisoning. Musc Nerv 1990; 13:433437.

17. Feldman RG, White RF, Currie JN, et al: Long-term follow-up after single toxic exposure to trichloroethylene. Am J Ind Med 1985; 8:119-126. 18. Fisher CM, Adams RD: Diphtheritic polyneuritis: A pathological study. J Neuropathol Exp Neurol 1956; 15:243-268. 19. Fullerton PM: Electrophysiological and histological observations on peripheral nerves in acrylamide poisoning in man. J Neurol Neurosurg Psychiatry 1969; 32:186-192. 20. Garland TO, Patterson MWH: Six cases of acrylamide poisoning. Br Med J 1976; 4:134-138. 21. Jerian SM, Sarosy GA, Link CJ, Fingert HJ, Reed E, Kohn EC: Incapacitating autonomic neuropathy precipitated by taxol. Gynecol Oncol 1993; 51:277-280. 22. Kitchens CS, Van Mierop LHS: Envenomation by the eastern coral snake (Micrurus fulvis fulvis). JAMA 1987; 258:1615-1618. 23. Lambert JS, Seidlin M, Reichman RC, et al: 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322:1333-1340. 24. LeLacheur SF, Simon GL: Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine. J Acquir Immune Defic Syndr 1991; 4:538-539. 25. Le Quesne PM: Neurotoxic substances. Mod Trends Neurol 1975; 6:83-97. 26. Le Quesne PM: Clinical and morphological findings in acrylamide toxicity. Neurotoxicology 1985; 6:1724. 27. LeWitt PA: The neurotoxicity of the rat poison vacor: A clinical study of 12 cases. N Engl J Med 1980; 302:73-77. 28. Lovejoy FH: Thallium. Clin Toxicol Rev 1982; 4:1-2. 29. McCollister DD, Oyen F, Rowe VK: Toxicology of acrylamide. Toxicol Appl Pharmacol 1964; 6:172181. 30. Meggs WJ, Hoffman RS, Shih RD, Weisman RS, Goldfrank LR: Thallium poisoning from maliciously contaminated food. J Toxicol Clin Toxicol 1994; 32:723-730. 31. Meves H, Rubly N, Watt DD: Effect of toxins isolated from the venom of the scorpion Centruroides sculpturatus on the Na currents of the node of Ranvier. Pflugers Arch 1982; 393:56-62. 32. Monckton G, Pehowich E: Autonomic neuropathy in the streptozotocin diabetic rat. Can J Neurol Sci 1980; 7:135-142. 33. Monforte R, Estruch R, Valls-Sole J, Nicolas J, Villalta J, Urbano-Marquez A: Autonomic and peripheral neuropathies in patients with chronic alcoholism: A dose-related toxic effect of alcohol. Arch Neurol 1995; 52:45-51. 34. Montaner JS, Rachlis A, Zala C, et al: The safety profile of stavudine (d4T) in advanced HIV infection: Experience from the Canadian expanded access program (EAP) (abstract). Nat Conf Hum Retroviruses Relat Infect 1995; 2:104.

35. Moyle G, Goll A, Snape S: Safety of zalcitabine (ddC) in zidovudine (ZDV) intolerant individuals: Results of the European expanded access study (abstract). Int Conf AIDS 1994; 1:210. 36. Narahashi T: Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes. Fed Proc 1972; 31:1117-1123. 37. O’Donoghue JL, Krasavage WJ, Terhaar CJ: Toxic effects of 2,5-hexandione. Toxicol Appl Pharmacol 1978; 45:269. 38. Parry GJ, Bredesen DE: Sensory neuropathy with low-dose pyridoxine. Neurology 1985; 35:14661468. 39. Pellissier JF, Pouget J, Cros D, et al: Peripheral neuropathy induced by amiodarone chlorohydrate. J Neurol Sci 1984; 63:251-266. 40. Phelan DM, Hagley SR, Guerin MD: Is hypokalemia the cause of paralysis in barium poisoning?. Brit Med J 1984; 289:662. 41. Rosenfeld CS, Broder LE: Cisplatin-induced autonomic neuropathy. Cancer Treat Rep 1984; 668:659660. 42. Rizzuto N, Terzian H, Galiazzo-Rizzuto S: Toxic polyneuropathies in Italy due to leather cement poisoning in shoe industries. J Neurological Sci 1977; 31:343-354. 43. Sabri MI, Moore CL, Spencer PS: Studies on the biochemical basis of distal axonopathies. I. Inhibition of glycolysis of neurotoxic hexacarbon compounds. J Neurochem 1979; 32:683-689. 44. Seto DSY, Freeman JM: Lead neuropathy in children. Am J Dis Child 1964; 107:337-342. 45. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome. N Engl J Med 1983; 309:445-448. 46. Schmidt RE, Plurad SB, Clark HB: Acrylamide-induced sympathetic autonomic neuropathy resulting in pineal denervation. Lab Invest 1987; 56:505-517. 47. Simpson LL: The origin, structure, and pharmacologic activity of botulinum toxin. Pharmacol Rev 1981; 33:155-185. 48. So YT, Holtzman DM, Abrams DI, Olney RK: Peripheral neuropathy associated with acquired immunodeficiency syndrome. Prevalence and clinical features from a population-based survey. Arch Neurol 1988; 45:945-948. 49. Sobue G, Pleasure D: Experimental lead neuropathy: Inorganic lead inhibits proliferation but not differentiation of Schwann Cells. Ann Neurol 1985; 17:462-468. 50. Taher SM, Anderson RJ, McCarthy R, et al: Renal tubular acidosis associated with toluene sniffing. N Engl J Med 1974; 290:765-768. 51. Thomas PK: The peripheral nervous system as a target for toxic substances. In: Spencer PS, Schaumburg HH, ed. Experimental and Clinical Neurotoxicology, Baltimore: William & Wilkins; 1980:35-47.

52. Vadlamudi RV, McNeill JH: Effect of alloxan- and streptozotocin-induced diabetes on isolated rat heart responsiveness to carbachol. J Pharmacol Exp Ther 1983; 225:410-415. 53. Wang GK, Strichartz GR: Purification and physiologic characterization of neurotoxins from venoms of the scorpions Centruroides sculpturatus and Leiurus quinquestratus. Molec Pharmacol 1983; 23:519-533. 54. Wiley CA: Neuromuscular diseases of AIDS. FASEB J 1989; 3:2503-2511.

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Uncited reference Cho ES: Toxic effects of adriamycin on the ganglia of the peripheral nervous system: A neuropathological study. J Neuropathol Exp Neurol 1977; 36:907-917.

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Chapter 20 – Cardiovascular Instability Caused by Drugs or Chemicals
JEFFREY BRENT

Essentials • • • For patients with cardiovascular instability secondary to poisoning, standard treatment is appropriate with a few notable exceptions. Cardiovascular instability associated with poisonings may present as hypotension or hypertension, dysrhythmias, conduction disturbances, or myocardial depression. Rapid identification of certain specific toxic syndromes can prompt appropriate antidotal therapy. These syndromes include those caused by cyclic antidepressants, digitalis glycosides, cocaine, calcium channel blockers, and ß-adrenergic receptor antagonists.

PATHOPHYSIOLOGY
Most major toxic syndromes have some component of cardiovascular effects. Frequently, the cardiovascular manifestations of toxins are secondary to metabolic, pulmonary, or neurologic effects of the particular toxin. The focus of this chapter is on primary, or direct, cardiovascular effects of specific toxic substances. Even limiting the chapter in this way does not protect us from the remaining prodigious group of cardiovascular manifestations that can be directly caused by toxic substances. In addition, a primary cardiovascular effect of a toxin is frequently followed by a series of secondary manifestations on the same organ system. For example, hypertension caused by excessive amounts of the a-adrenergic receptor agonist phenylpropanolamine (PPA) can cause reflex secondary bradycardia.[6] The toxic manifestations of specific substances can be broadly divided into classes that have the following general effects: (1) agents that affect blood pressure; (2) agents that cause cardiac dysrhythmias and conduction disturbances; and (3) agents that cause myocardial depression. Subcategories exist within each of these major classes of toxic effects. The most common ones are considered in this discussion. Drug-Induced Hypertension Like all cardiovascular effects of toxins, hypertension can be either primary or secondary. Secondary hypertension, for example, could result from sympathetic hyperactivity caused by cocaine use. A variety of agents can have a primary hypertensive effect on the cardiovascular system. These are listed in Table 20–1 along with the mechanism by which they provoke this effect.

Table 20-1 -- Drugs and Chemicals Directly Causing Hypertension

Agent a1-Adrenergic Receptor Agonists Examples: Clonidine * Epinephrine Ergotamines Metaraminol Methoxamine Naphazoline Norepinephrine Oxymetazoline Phenmetrazine Phenylephrine Phenylpropanolamine Pseudoephedrine Tetrahydrozoline Tyramine Yohimbine Sympathomimetic Agents Examples: Amphetamine Cocaine Diethylproprion Fenfluramine MDMA ‡ Mescaline Methamphetamine Methylphenidate Pemoline Phenmetrazine Other

Mechanism Directly stimulate a1-adrenergic receptors

Release of catecholamines †

Latrodectus (black widow spider) Venom Release of catecholamines † Bretylium Release of catecholamines

Agent Caffeine (early) Cathinone alkaloids

Mechanism Release of catecholamines Release of catecholamines † Direct a-adrenergic receptor agonist Decreased catecholamine degradation

Monoamine oxidase inhibitors Nicotine Organophosphates Phencyclidine Theophylline (early)

Prevent catecholamine degradation Release of catecholamines Release of catecholamines Release of catecholamines Release of catecholamines

* Acts centrally as an a 2-adrenergic receptor agonist but can also act peripherally on a1-adrenergic receptors. † Also some direct vasoconstrictor activity. ‡ 3,4-Methylenedioxyamphetamine (“Adam” or “Ecstasy”).

Patients with drug-induced hypertension will typically manifest both an elevated systolic and a diastolic blood pressure, since the mechanism is vasoconstriction. The effects on heart rate can be variable. As noted earlier, pure a-adrenergic receptor agonists such as PPA can cause reflex bradycardia.[6] Alternatively, agents that have ß-adrenergic receptor agonist qualities will frequently induce tachycardia from the direct effect on cardiac ß1 receptors. Cardiac output ranges from normal to increased in drug-related hypertension. Toxin-Induced Hypotension Like hypertension, the hypotension seen in association with toxic exposures can be either primary or indirect. Secondary hypotension may be due to depressed cardiac contractility, a hemodynamically significant cardiac dysrhythmia, intravascular fluid loss, or decreased sympathetic tone. The latter can be caused by sympatholytic agents such as barbiturates, opioids, central a2-adrenergic receptor agonists, benzodiazepines, or other sedative-hypnotic drugs. These agents tend to act by inhibiting sympathetic outflow from the locus ceruleus. Direct-acting hypotensive agents are vasodilators. Sildenafil, a cyclic guanosine monophosphate–specific type 5 phosphodiesterase inhibitor, can potentiate the hypotensive effect of nitroglycerin and other organic nitrates that are nitrous oxide donors. Table 20–2 lists agents that cause hypotension by vasodilation.

Table 20-2 -- Vasodilators Angiotensin effector drugs ACE inhibitors Angiotensin receptor II antagonists Adenosine * Buflomedil †

Calcium channel antagonists Examples: Amlodipine Bepridil Cinnarizine Diltiazem Felodipine Flunarizine † Isradipine Nicardipine Nifedipine Nimodipine Verapamil Diazoxide Flosequinan † Hydralazine Minoxidil Naftidofuryl † Nitrates/nitrites Nitroprusside Phenothiazines Phenoxybenzamine Phentolamine Phosphodiesterase inhibitors Examples: Amrinone † Caffeine Dipyramidole Enoximone † Imazodan † Milrinone Pentoxifylline Pimobendan †

Piroximone † Theophylline Prazosin Sildenafil—nitroglycerin and other organic nitrate interaction Terazosin Cyclic antidepressants
* Short acting. † Not available in the United States.

Toxin-induced hypotension is characterized by a decrease in systolic and/or diastolic blood pressure. Tachycardia may be present as a compensatory response unless there is an inhibition of cardiac sympathetic tone or cardiac conduction by some other process. Because patients with direct drug-induced hypotension usually have vasodilation, their skin is frequently warm to the touch. Because vasodilation generally causes a disproportionate drop in diastolic blood pressure, these patients will frequently have a wide pulse pressure. Cardiac index could be decreased, normal, or increased depending on the status of the other components of the cardiovascular system. Isolated vasodilation will in general tend to increase cardiac output. Toxin-Induced Cardiac Dysrhythmias The diversity of toxins that can cause cardiac dysrhythmias by any mechanism is prodigious. Like toxinrelated effects on blood pressure, rhythm manifestations may be either primary or secondary. The secondary, or indirect, cardiac dysrhythmias can result from many mechanisms, including hypoxia, electrolyte abnormalities, vasodilation, vasoconstriction, or effects on the nervous system. For example, although cocaine exerts some direct cardiac effects on vasoconstriction of the coronary vasculature[7] and sodium channel blockade,[5] most rhythm disturbances caused by cocaine are due to the drug’s effect on autonomic sympathetic activity.[1][2][5] The heightened sympathetic discharge from the locus ceruleus caused by cocaine is responsible for many of its cardioexcitatory effects, which are a major component of the cardiovascular manifestations of cocaine toxicity. Although a variety of agents can cause primary and secondary effects on cardiac rhythm, it is of therapeutic and diagnostic importance that several agents cause specific and characteristic dysrhythmias. Table 20–3 lists the typical, or common, agents that cause primary cardiac dysrhythmias.

Table 20-3 -- Drugs and Chemicals Causing Primary Cardiac Dysrhythmias Toxin Dysrhythmia(s) ß1-Adrenergic receptor antagonists Calcium channel antagonists Bradycardia Bradycardia Rapid ventricular rate in Wolff-Parkinson-White syndrome with atrial fibrillation

Toxin Carbamazepine Cardiac glycosides Examples: Bufatoxin Digitoxin Digoxin Dogbane Foxglove Lily of the valley Milkweed Oleander Ouabain Chloral hydrate Chloroquine Ciguatera toxin Cocaine Emetine Ethanol Halogenated hydrocarbons Hellebore Lithium Magnesium Potassium Propoxyphene (norpropoxyphene) Q-Tc interval–prolonging agents (see Table 20–4 ) Thioridazine/mesoridazine Cyclic antidepressants Type 1A and 1C antidysrhythmics Multiple

Dysrhythmia(s)

Supraventricular and ventricular tachydysrhythmias, ventricular fibrillation Ventricular tachycardia Bradycardia, heart block Ventricular dysrhythmias, conduction block Ventricular fibrillation Atrial fibrillation Ventricular fibrillation * Bradycardia Bradycardia, sinoatrial or atrioventricular block Bradydysrhythmias, heart block Sine wave, ventricular fibrillation asystole Ventricular tachydysrhythmias Torsades de pointes Ventricular tachydysrhythmias Wide complex supraventricular tachycardias Bradycardia, ventricular tachydysrhythmias

* Theorized to be due to sensitization of myocardium to catecholamines, although hypoxia has not been ruled out.

Among those agents that cause very specific effects on cardiac rhythm are digitalis glycosides, cyclic

antidepressants, and the variety of substances that directly increase the Q-Tc interval and thus predispose the development of torsades de pointes. There are two major ways in which toxins can directly induce cardiac dysrhythmias. They may either increase, or provoke, dysrhythmogenic impulses or they may cause abnormal conduction of action potentials through the heart. The aberrant production of arrhythmogenic action potentials can result from abnormal automaticity of areas of the heart that are usually devoid of rhythm generative impulses. Alternatively, triggering of afterdepolarizations may cause oscillations in cardiac tissue potentials. If these oscillations occur in the resting, or phase IV, stage, they may cause the threshold for triggering the opening of voltage-gated sodium channels to be exceeded. The result ( Fig. 20–1 ) is an action potential that may be propagated, resulting in a phase 0 upstroke and spread of the action potential from the provoking site. Triggered afterpotentials are a cause of the characteristic dysrhythmias seen in cardiac glycoside toxicity.[12]

Figure 20-1 Cardiac electrical potentials in a cell that has afterpotentials generated during phase 4. Should one of these afterpotentials reach the threshold level, an action potential would be generated.

Drugs and chemicals that cause abnormal conduction of impulses tend to be dysrhythmogenic. They may stimulate re-entrant dysrhythmias or cause abnormalities in the action potentials in the cardiac conduction tissue. For example, cardiac glycosides inhibit cardiac conduction through the atrioventricular node.[12] Cyclic antidepressants have a characteristic effect on cardiac conduction distal to the His-Purkinje system such that impulses are propagated through right-sided fibers in an abnormal fashion, giving rise to the characteristic terminal rightward QRS forces seen on the surface electrocardiogram (EKG).[10] Torsades de Pointes Tachycardia

A unique type of ventricular tachydysrhythmia associated with a prolongation of the Q-T c interval is torsades de pointes ( Fig. 20–2 ). This is a reciprocating ventricular tachycardia because of the sequential and regular decreasing and increasing magnitudes of the QRS complex on the EKG. This dysrhythmia is triggered by early afterdepolarizations and results in the axis of the QRS complex rotating in sequential 360-degree cycles around the baseline of the EKG.[3] Patients with either hereditary or acquired Q-Tc prolongations are at risk for developing torsades de pointes. Acquired Q-Tc prolongation is generally due either to metabolic abnormalities or to drugs that affect phase II or III of the action potential. A list of drugs that broaden the QT c interval and predispose to torsades de pointes is provided in Table 20–4 . Class 1A antidysrhythmic agents (quinidine, procainamide, and disopyramide) are the most typical causes of torsades de pointes. The class 1A agents, particularly quinidine, can cause torsades de pointes even at therapeutic doses and levels.

Figure 20-2 A 37-year-old female intubated and comatose from a thioridazine overdose who sustained perfusing torsades de pointes following sinus rhythm with a prolonged Q-Tc interval.

Table 20-4 -- Drugs and Chemicals That Increase the Q-Tc Interval Amantadine Arsenic Astemizole Bepridil Butyrophenones Chloral hydrate Chloroquine Cisapride Citalopram Emetine Fluoride (secondary to hypocalcemia) Fluoxetine Ketoconazole Erythromycin Mercury (organic)

Organophosphates Pentamidine Phenothiazines (particularly thioridazine, mesoridazine) Phosphorus Pimozide Scorpion venom Terfenadine Tetracyclic antidepressants Tricyclic antidepressants Vaughan-Williams Class IA antidysrhythmics Disopyramide Procainamide Quinidine (levels usually therapeutic or subtherapeutic) Vaughan-Williams Class IC antidysrhythmics Encainide Flecainide Lorcainide Moricizine Propafenone Vaughan-Williams Class III antiarrythmics Amiodarone Bretylium N-Acetylprocainamide Sotalol

Supratherapeutic levels of astemizole and terfenadine are also associated with torsades de pointes. These generally occur when these agents bioaccumulate, usually a consequence of the simultaneous administration of a second agent that competitively inhibits their metabolic degradation by the cytochrome P450 isoenzyme 3A4. Other agents metabolized by this isoenzyme include macrolide antibiotics (except azithromycin), the imidazole antifungals, human immunodeficiency virus protease inhibitors (indinavir, ritonavir, saquinavir, and nelfinavir), serotonin reuptake inhibitors (fluvoxamine, nefazodone, and sertraline), zileuton, cisapride, sparfloxacin, mibefradil, and grapefruit juice. Use of these agents is contraindicated with these antihistamines. Cyclic antidepressants bind to the activated sodium channel [9][13] and thus act pharmacodynamically like class 1A antidysrhythmic agents. However, they are an infrequent cause of torsades de pointes. The tendency of cyclic antidepressants to provoke torsades de pointes may be attenuated by their promotion of increased heart rates. Because the Q-Tc interval is rate dependent, the

relative tachycardia induced by cyclic antidepressants may modulate their effect on the Q-Tc interval. Chloroquine is related to quinidine and probably exerts a similar effect on the activated sodium channel. Toxicity from this agent, which is a growing problem in European countries, may be associated with torsades de pointes. Drug- or chemical-induced torsades de pointes is an imperfectly understood process. The prolongation of the Q-Tc interval seen on the surface EKG is a manifestation of the prolonged phase II of the action potential. Normally phase II is terminated by a rapid outward K+ current, which renders the intracellular environment negative, a process referred to as phase III rapid repolarization. During the prolonged phase II (plateau phase) the cell is vulnerable to new further depolarizations that can initiate torsades de pointes. Thus, any agent that delays phase III repolarization both lengthens the Q-Tc interval and predisposes to torsades de pointes.[15] Toxin-Induced Myocardial Depression Like other toxic cardiovascular manifestations, myocardial depression can be either primary or secondary. Most often, myocardial depression associated with a toxic exposure is secondary to toxin-induced hypoxia, metabolic abnormalities, or myocardial ischemia. However, several toxins such as cyclic antidepressants, scorpion venom, and calcium channel antagonists have a direct depressant effect on the myocardium. A primary manifestation includes a decrease in cardiac contractility, with resulting decreases in cardiac index, blood pressure, and ejection fraction. Pulmonary capillary wedge pressure will generally be elevated. Calcium channel antagonists tend to depress myocardial contractility by blocking phase 2 calcium influx into the myocardial cell and therefore inhibiting excitation-contraction coupling. Of these agents the phenylalkylamine class[14] (e.g., verapamil) has more of an effect on the myocardium and therefore depresses myocardial contractility more than the other classes. However, at higher doses all calcium channel antagonists can depress myocardial contractility. Cyclic antidepressants can directly depress myocardial function in addition to causing conduction disturbances and hypotension due to vasodilation. Scorpion venom delays the inactivation of voltage-sensitive gated Na2+ channels,[4][8][11] resulting in depressed myocardial function. Cardiac dysfunction is a major source of morbidity and mortality associated with scorpion envenomation in certain parts of the world. The effect of scorpion antivenin in preventing or treating this myocardial depression is unknown. Differential Diagnosis The differential diagnosis of patients presenting with cardiovascular instability caused by drugs or other chemical substances is an exercise based on the pathophysiologic principles reviewed herein. Once the clinician has classified the nature of the cardiovascular instability into one of the small number of categories reviewed here, both the differential diagnosis and treatment follow naturally from the pathophysiology already reviewed. Patients should be categorized by whether they are having abnormalities of blood pressure, cardiac contractility, or cardiac conduction or dysrhythmias. For any of these abnormalities the next question is whether these abnormalities are primary or secondary.

Blood pressure abnormalities may involve hypertension or hypotension, which may be primary or secondary. Primary causes of hypotension are restricted to agents that cause vasodilation. Common agents that cause primary hypotension are listed in Table 20–2 . Secondary hypotension generally will result ultimately from secondary vasodilation, depression of myocardial function, or volume depletion. Primary hypertension is generally caused by vasoconstricting agents (see Table 20–1 ). Secondary hypertension typically results from sympathomimetic effects due to peripheral neuronal effects of drugs such as amphetamines. Alternatively, secondary sympathomimetic effects may be caused by centrally acting substances. Agents that cause renal injury may produce hypertension secondary to the toxic effect on the kidney and activation of the renin-aldosterone system. Although drugs and chemicals may be associated with a diverse variety of cardiac dysrhythmias, Table 20–3 shows that certain chemical agents are associated with specific dysrhythmias. Similarly, sinus bradycardia or tachycardia may be due to either direct or indirect effects of chemical agents. The Q-T c interval comprises ventricular depolarization and repolarization. Any process affecting either of these two events will prolong this interval. The chemical agents and drugs listed in Table 20–4 prolong the Q-Tc interval. Other causes include bundle branch block, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, ischemia, complete heart block, acute central nervous system events, and genetically determined prolonged Q-Tc syndrome. Primary myocardial depression can be caused by agents listed in Table 20–5 . Alternatively, myocardial depression can be secondary to ischemia, hypoxia, metabolic abnormalities, or volume depletion. Other nontoxicologic and less common causes of myocardial depression include infectious, infiltrative, or inflammatory diseases of the myocardium.

Table 20-5 -- Agents That Cause Primary Myocardial Depression Arsenic ß1-Adrenergic receptor antagonists Calcium channel antagonists Ciguatera toxin Colchicine Cyanide Cyclic antidepressants Ethanol * Iron Magnesium Scorpion venom Syrup of ipecac * Tetrodotoxin †

Types IA and IC antidysrhythmics
* Cardiomyopathy associated with chronic abuse. † Found primarily in the puffer fish (“fugu”) and blue-ringed octopus.

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CLINICAL EVALUATION
The clinical evaluation of patients with cardiovascular instability related to chemicals or drugs should be based on the relevant pathophysiology discussed earlier. Determining whether the cardiovascular instability is due to vasoactive agents, myocardial depression, cardiac dysrhythmias, or conduction disturbances is the essential primary challenge. Once that has been accomplished, the next goal is to determine the cause. This is best accomplished by determining whether the cardiovascular instability is primary or secondary. The clinical evaluation should focus in a very specific fashion on which of the above factors are operative. This includes, at the minimum, a physical examination to assess the status of the circulation, a determination of blood pressure and heart rate, and an EKG. On physical examination vascular perfusion can be quickly assessed by an evaluation of mentation, capillary refill, and the color and temperature of the skin. Blood pressure determination allows for the diagnosis of hypertension or hypotension; intra-arterial pressure monitoring may be necessary in cases of severe hypotension or peripheral vasoconstriction. A reduced diastolic pressure coupled with a wide pulse pressure is a clue to the possibility of vasodilation. In ambiguous cases, direct measurements of the hemodynamic parameters may be made with the use of a flow-directed pulmonary artery balloon (Swan-Ganz) catheter.

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LABORATORY STUDIES AND INTERPRETATION
The EKG may provide clues that suggest non–drug-related causes of the instability, such as ischemia or infarction. Rhythm disturbances may also be detected. Specific clues on the EKG suggesting the presence of a direct toxic effect may be found by assessing the Q-Tc and QRS intervals and looking for specific dysrhythmias and other conduction disturbances. The Q-Tc interval is considered to be the longest Q-Tc interval in the limb leads. Causes of prolonged Q-Tc are listed in Table 20–4 . Cyclic antidepressants have a variety of effects on the electrocardiogram. Prominent among them is a delay in the propagation of impulses in the right ventricular fibers.[10] As a result, right ventricular depolarization and subsequent repolarization are delayed. Because of the prolonged conduction time through the right side of the heart, the EKG shows a rightward shift of the axes of the QRS complex and the Q-Tc interval.[10] This results in a rightward deviation of the QRS complex manifested by a terminal S wave in leads I and AVL and a prominent R' wave in lead aVR[10] (see Chapter 62 ). The presence of torsades de pointes on the EKG suggests one of the agents listed in Table 20–4 . The various intervals of the EKG can yield important clinical clues to the presence of toxic substances. Atrioventricular block is seen primarily in the presence of ß-adrenergic receptor antagonists, calcium channel antagonists, particularly of the benzothiazepine and phenylalkylamine varieties, and cardiac glycosides. The rhythm and conduction disturbances seen in association with the cardiac glycosides are uniquely a combination of conduction block and increased automaticity. Thus, a variety of complex dysrhythmias can occur with these agents. The atrioventricular block may be high grade and associated with a variety of excitatory rhythms, including atrial tachydysrhythmias, accelerated junctional tachydysrhythmias, and a variety of ventricular dysrhythmias manifested mostly by premature depolarizations. These last dysrhythmias give rise to bigeminy and trigeminy, ventricular tachycardia, and ventricular fibrillation. Chest radiography is useful in evaluating for congestive heart failure, noncardiogenic pulmonary edema, and other cardiopulmonary processes that may influence hemodynamics. Serum electrolyte determination can reveal potassium abnormalities as well as metabolic acidosis, manifested by a decreased serum bicarbonate concentration. Magnesium and calcium levels may be helpful particularly in patients with prolonged Q-Tc intervals or torsades de pointes. Serum drug levels may be helpful in evaluating for drug toxicity, but these levels must be interpreted in the context of the clinical history. Patients taking medications over a prolonged period of time without an acute increase in dose may show significant clinical toxicity despite relatively modest elevations in serum drug levels. In contrast, after an acute overdose serum levels may be markedly elevated without significant signs of toxicity. This latter scenario is true of most medications that follow multicompartment kinetics, where measured serum levels do not reflect the tissue levels responsible for toxicity.

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DEFINITIVE THERAPY
Once the etiology of the cardiovascular problem is ascertained, appropriate therapeutic maneuvers may be undertaken. In most cases, standard advanced life support therapies are appropriate (see Chapter 3 ). In certain cases in which cardiovascular instability is induced by particular toxic agents, specific antidotes or therapies may be indicated. These are listed in Table 20–6 .

Table 20-6 -- Specific Antidotes for Cardiotoxins Agent Arsenic Antidote(s) British antilewisite

ß1-Adrenergic receptor antagonists Glucagon Calcium channel antagonists Cardiac glycosides Cyanide Fluoride Lactrodectus venom Magnesium Potassium Scorpion venom Sodium channel blockers Cocaine Cyclic antidepressants Norpropoxyphene Thioridazine/mesoridazine Class 1A and 1C antidysrhythmics Calcium, glucagon Antidigitalis Fab fragments Nitrites, thiosulfate, hydroxycobalamine Calcium, magnesium Antivenin Calcium Calcium, NaHCO3, dextrose + insulin Antivenin Sodium bicarbonate

The treatment of drug- or chemical-induced torsades de pointes involves removal of the offending agent, enhancing phase III repolarization, and preventing afterpotential generation. Stimulation of rapid repolarization may be achieved by increasing heart rate, either with ß1-adrenergic receptor agonists such as isoproterenol or with overdrive ventricular pacing. Class IB antidysrhythmics, such as lidocaine or phenytoin, enhance repolarization and may also be effective. Suppression of afterpotentials can also be achieved with type IB drugs. Magnesium may be the single most effective treatment. The mechanism of magnesium’s effect is unknown, but it probably suppresses afterdepolarizations.[15] It does not stimulate rapid repolarization and has no effect on the phase II action potential duration or the Q-Tc interval on the EKG.

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DISPOSITION
Patients with mild cardiovascular manifestations due to toxins with known self-limited effects on the cardiovascular system may be observed until the abnormalities resolve. An example is a patient with a mild sympathomimetic syndrome related to exposure to a sympathomimetic agent such as cocaine. Once the initial toxidrome has cleared, the patient may be discharged provided there is no concern for delayed or recurrent toxicity. All patients with moderate to severe, or persistent signs of, cardiovascular instability, including significantly abnormal vital signs, should be admitted to a monitored unit for treatment and observation until the drug toxicity resolves. Intensive medical care commensurate to the severity of their toxicity should be provided. Some patients with initial cardiovascular instability can be placed in an appropriately monitored observation unit. This would be particularly pertinent in cases in which minor and self-limited instability is anticipated and nursing and monitoring capabilities are appropriate to the patient’s toxidrome. In addition, patients with initial cardiovascular toxicity who responded to treatment, with resolution of the toxic manifestations, may also be observed in an observation unit. For example, patients with cyclic antidepressant toxicity manifested solely by sinus tachycardia who are not thought at danger for toxicity progression can be observed until their vital signs normalize and then be discharged. In a few cases, as clinical judgment dictates, patients with mild vital sign abnormalities may be discharged. For example, a patient with persistent mild thyrotoxicosis from excessive thyroid hormone ingestion would be expected to manifest this state for a period of days, generally beginning many days after the initial overdose. Such patients may be observed on an outpatient basis once their clinical course suggests no acute worsening. In all cases of deliberate drug or chemical use, the patient’s psychiatric status must be evaluated for potential or ongoing suicidal thoughts.

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REFERENCES
1. Abrahams TP, Cuntapay M, Varner KJ: Sympathetic nerve responses elicited by cocaine in anesthetized and conscious rats, 59. Physiol Behav; 1996:109-115. 2. Branch CA, Knuepfer MM: Causes of differential cardiovascular sensitivity to cocaine: II. Sympathetic, metabolic and cardiac effects. J Pharm Exp Ther 1994; 271:1103-1113. 3. Dessertenne F: La tachycardie ventriculaire à deux foyers opposés variables [Ventricular tachycardia with 2 variable opposing foci]. Arch Mal Coeur Vaiss 1966; 59:263-272. 4. Dias-Kadambi BL, Combs KA, Drum CL, et al: The role of exposed tryptophan residues in the activity of the cardiotonic polypeptide anthopleurin B. J Biol Chem 1996; 271:23828-23835. 5. Kloner RA, Hale S, Alker K, et al: The effects of acute and chronic cocaine use on the heart. Circulation 1992; 85:407-419. 6. Lake CR, Gallant S, Masson E, et al: Adverse drug effects attributed to phenylpropanolamine: A review of 142 case reports. Am J Med 1990; 89:195-206. 7. Lange RA, Cigarroa RG, Yancy Jr CW, et al: Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989; 321:1557-1562. 8. Marcotte P, Chen LQ, Kallen RG, et al: Effects of Tityus serrulatus scorpion toxin gamma on voltagegated Na+ channels. Circ Res 1997; 80:363-369. 9. Muir WW, Strauch SM, Schaal SF: Effects of tricyclic antidepressant drugs on the electrophysiological properties of dog Purkinje fibers. J Cardiovasc Pharmacol 1982; 4:82-90. 10. Niemann JT, Bessen HA, Rothstein RJ, et al: Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity. Am J Cardiol 1986; 57:1154. 11. Rogers JC, Qu Y, Tanada TN, et al: Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3–S4 extracellular loop in domain IV of the Na+ channel alpha subunit. J Biol Chem 1996; 271:15950-15962. 12. Rosen M: The links between basic and clinical cardiac electrophysiology. Circulation 1988; 77:251263. 13. Sasyniuk BI, Jhamandas V: Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. J Pharmacol Exp Ther 1984; 231:387-394. 14. Taira N: Differences in cardiovascular profile among calcium antagonists. Am J Cardiol 1987; 59:24B29B. 15. Tan HL, Hou CJY, Lauer MR, et al: Electrophysiologic mechanism of the long QT interval syndromes and torsades de pointes. Ann Intern Med 1995; 122:701-714.

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Chapter 21 – Hepatic Failure
ANTHONY ANKER

Essentials • • • • • • Treat hypoglycemia and electrolyte abnormalities. Correct intravascular volume deficits. Treat encephalopathy if present. Correct coagulopathy. Consider specific therapies such as N-acetylcysteine and hyperbaric oxygen. Consider referral for liver transplantation.

INITIAL STABILIZATION/TREATMENT
Hepatic injury is a common sequela of exposure to toxic agents.[20][50] It may be a primary manifestation of poisoning or part of a toxin-induced multiple organ injury syndrome. The initial treatment of toxic liver injury should focus on (1) the interruption of ongoing exposure to the toxin; (2) the use of special antidotes such as N-acetylcysteine for acetaminophen poisoning; and (3) supportive care. In many cases the liver injury resolves with simple withdrawal of the offending toxin.[39] For the critically ill patient, supportive care in an intensive care unit setting is crucial. Treatment of fluid, electrolyte, and acid-base abnormalities is essential to maintain proper cardiovascular function. Patients may require glucose administration and replacement of coagulation factors. The treatment of hepatic encephalopathy requires the reduction of serum ammonia concentration by decreasing protein intake and administering lactulose. The mainstay of treatment of cerebral edema is hyperventilation and oxygen supplementation. It is also essential to maintain adequate cerebral perfusion while treating cerebral edema. Hemodialysis or intubation for respiratory support may be indicated when other organ systems are affected. Early consultation with a transplant center is indicated in critically ill patients with acute hepatic failure.

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ANATOMY AND PHYSIOLOGY RELATED TO TOXICITY
Ingested toxins are absorbed from the gastrointestinal tract in a lipid-soluble state and are transported directly to the liver through the portal system, exposing the liver to the highest concentrations of these agents. In addition, because of its central role in the detoxification of xenobiotics, the liver is especially susceptible to toxic injury by metabolites of the toxin. Reactive metabolites produced by the process of detoxification often cause hepatocellular injury at the site of their formation. The mechanisms by which some chemicals, pharmaceuticals, and environmental toxins cause injury to the liver are well defined, whereas those of others are not. The acinus is the functional unit of the liver ( Fig. 21–1 ). It consists of an hepatic arteriole, a portal venule, and a bile ductule. Blood flows from the portal triad through hepatic sinusoidal conduits into the central (terminal) hepatic venule.[38] This anatomic relationship helps to explain physiologic differences between the different zones of the acinus. Zone 1 cells, which are closer to the hepatic arteriole, portal venule, and bile ductule, receive blood with a higher oxygen concentration and higher concentration of xenobiotics. They are less metabolically active than zone 3 cells. The environment of the central hepatic venule (zone 3) is more hypoxic, and there is increased activity of cytochrome P-450 enzymes, as well as increased detoxification capacity by other mechanisms (see later). Zone 2 represents a transition area.[3]

Figure 21-1 Anatomy and functional zones of the acinus and associated toxins. The hepatic arterioles travel with the bile ductules and the portal venules in the portal system (PS). Blood from the terminal hepatic arterioles (THA) and terminal portal venules (TPV) enters the hepatic sinusoidal (HS) system and is collected in the central venule, otherwise known as the central (terminal) hepatic venule (CHV). Zone 1 lies closest to the hepatic artery and receives blood with the highest oxygen content but also with the highest concentration of hepatotoxins, which are often carried by the portal vein. Zone 3 is closest to the terminal hepatic venules and receives oxygen-poor blood, so this area is most sensitive to ischemic injury. Zone 3 also has the highest cytochrome P-450 MFO activity. Zone 2 is intermediate in all respects. (Adapted from Rappaport AM, Wanless IR: Physioanatomic considerations. In Schiff L, Schiff ER (eds): Diseases of the Liver, 7th ed. Philadelphia, JB Lippincott Company, 1993.)

Differences in local environment and metabolic activity explain some of the patterns of liver damage seen

with different toxins. Because of its proximity to the portal venule, zone 1 receives the highest concentration of xenobiotics so that agents directly toxic to the liver, such as iron and yellow phosphorus, cause more damage in this area. In contrast, agents such as acetaminophen and carbon tetrachloride that undergo biotransformation by the cytochrome P-450 system cause damage to zone 3. The cytochrome P-450 system is a gene superfamily with over 300 members, some of which exhibit a spectrum of catabolic functions and some react with more select xenobiotics.[11][34] The activity of the cytochrome P-450 enzymes can be enhanced (induced) in certain circumstances. Induction of certain cytochrome P-450 enzymes will speed the metabolism of some xenobiotics but not others. For example, phenobarbital therapy[7] and chronic ethanol ingestion[45] appear to induce the enzymes that are also responsible for acetaminophen metabolism.[34] Patients who chronically ingest these agents may be at higher risk of hepatotoxicity than the general population after an acetaminophen overdose and perhaps even after therapeutic doses. There may be a survival advantage that explains this capacity to induce the P-450 function. Previous exposure to xenobiotics at low concentrations can be protective when the individual is reexposed to larger doses or higher concentrations.[26] The biotransformation of xenobiotics by the P-450 system from lipid-soluble parent compounds to watersoluble metabolites allows elimination of the toxin in the urine.[34][44] The biotransformation of xenobiotics is mediated by phase I and phase II reactions. Phase I reactions are oxidation reactions that convert lipophilic xenobiotics to more chemically reactive molecules by adding or exposing a more reactive hydroxyl (-OH), sulfhydryl (-SH), amino (-NH2), aldehyde (-COH) or carboxyl (-COOH) group. Phase II reactions conjugate the product of the phase I reaction with another molecule that significantly increases the water solubility of the resultant compound and renders it chemically unreactive. Sometimes a highly reactive electrophile or free radical is formed during a phase I reaction. If the phase II conjugation reaction is impeded, these reactive intermediates may react directly with hepatocyte macromolecules, resulting in damage to the hepatocyte.[15] Phase II reactions are synthetic and require energy provided by the hydrolysis of high-energy phosphate compounds such as adenosine triphosphate. They also require electron-rich molecules (nucleophiles) such as glutathione, S-adenosyl methionine, and uridine diphosphate glucuronic acid. The most common metabolites are the glucuronidation or sulfation products. [34][44] Phase II reactions may also take place without a preceding phase I reaction.[34][44] The most important example of a phase I enzyme system is the microsomal cytochrome P-450 monooxygenase system, or mixed-function oxygenase system. Cytochrome P-450 enzymes are heme proteins located mainly in the endoplasmic reticulum. The cytochrome gets its name from its spectrophotometric characteristics. When reduced cytochrome P-450 (Fe2+) binds to carbon monoxide, its maximal absorption spectrum occurs at 450 nm. These enzymes mediate many different types of oxidation reactions.

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DIFFERENTIAL DIAGNOSIS BASED ON MECHANISM ( Table 21–1 )
Free Radical Formation The mechanism of hepatic injury caused by carbon tetrachloride (CCl4) has been extensively studied. CCl4 is oxidized by the cytochrome P-450 2E1 to the CCl3• free radical.[1] The CCl3• radical forms covalent bonds with lipid membranes, causing lipid peroxidation, or may spontaneously react with molecular oxygen, forming the even more reactive CCl3OO• free radical. Low oxygen tensions and high cytochrome P-450 2E1 activity favor CCl3• formation in zone 3, whereas higher oxygen tension favors the formation of the CCl3OO• radical in zone 1. Although the more reactive CCl3OO• radical would be predicted to cause greater injury to zone 1, this is not observed because glutathione reacts more rapidly with the CCl3OO• radical in zone 1 than with the CCl3• radical in zone 3.[9] Therefore, zone 3 is subjected to greater liver injury by CCl4. Hyperbaric oxygen has been shown to decrease liver injury in animals, possibly by increasing the formation of the CCl3OO• radical, which is more readily detoxified.[8] Table 21-1 -- Known Mechanisms of Hepatotoxicity Rights were not granted to include this data in electronic media. Please refer to the printed book. Adapted from Kaplowitz N, Aw TY, Simon FR, et al: Drug-induced hepatotoxicity. Ann Intern Med 1986; 104:826–839. Electrophile Formation Some xenobiotics undergo phase I biotransformation to a strong electron seeking (electrophilic) intermediate. Acetaminophen is oxidized to N-acetyl-p-benzoquinoneimine (NAPQI) by the cytochrome P450 system, then detoxified and made water soluble by a phase II reaction with glutathione. In the setting of acetaminophen overdose, the supply of glutathione is depleted and NAPQI reacts directly with cellular macromolecules, causing liver damage.[37] Because the cytochrome P-450 MFO is concentrated in zone 3, it is not surprising that most liver damage occurs in this area. Oxygen Radical Formation After enzymatic reduction in a phase I reaction, some agents can react directly with molecular oxygen to form a superoxide anion radical (O2–•). The parent compound is then regenerated. Each molecule of the xenobiotic generates multiple O2–• radicals, which can then react to form hydrogen peroxide (H2O2) and the highly reactive hydroxyl radical (OH•). This causes a severe oxidative stress on hepatocytes. Examples of these agents are nitrofurantoin, paraquat, and doxorubicin.[15] Iron ions may play a role in the formation of these reactive intermediates.[2] .

Idiosyncratic Isoniazid (INH) is the best studied example of an idiosyncratic drug reaction—an hepatotoxic response that is not dose related and does not have a clear mechanism. There are no animal models of INH toxicity and only human data are available. Fifteen to 20 per cent of patients who receive INH as a single agent for the treatment of tuberculosis develop elevated liver transaminase levels. Less than 1 per cent of patients develop hepatic necrosis, which is often associated with concomitant rifampin use, or chronic alcohol consumption, both of which induce the cytochrome P-450 system.[18] Pathologically, INH causes diffuse hepatic necrosis similar to viral hepatitis.[15] People who rapidly acetylate INH were once thought to be more susceptible to INH hepatotoxicity than were slow acetylators,[27] but on further investigation this enzyme attribute does not clearly increase the risk of toxicity from INH.[12] Steatosis Many agents cause steatosis, generally after chronic exposure to the agent. Common toxins associated with steatosis include ethanol, amiodarone, valproic acid, and tetracycline. The intracellular accumulation of fat results from failure of a variety of hepatic functions related to the metabolism of lipids and fatty acids. These include impairment of lipoprotein synthesis; decreased oxidation of fatty acids; increased production of triglycerides; decreased binding of triglycerides to lipoproteins; increased peripheral fat mobilization; increased uptake of circulating lipids; and decreased hepatic release of very-low-density lipoproteins. When cell injury or death occurs, this reflects underlying metabolic dysfunction and not the presence of fat per se. Most hepatotoxins that cause steatosis also cause other pathologic changes, such as necrosis, inflammation, or cirrhosis. Some, like valproic acid, may cause steatosis without other significant associated pathologic processes.[21][51] Steatosis that is reversible with abstinence is an early pathologic lesion in alcoholic liver disease. This is most likely related to the increased NADH/NAD+ ratio that occurs during the hepatic metabolism of ethanol, resulting in decreased oxidation of fatty acids and the promotion of fatty acid synthesis. Ethanol also increases the uptake of fatty acids into hepatocytes and decreases lipoprotein secretion.[22] Recently, steatosis has been reported in HIV-infected patients taking antiviral agents such as zidovudine, zalcitabine, and didanosine. During experimental treatment of hepatitis B infection the nucleoside analog fialuridine caused several deaths due to failure of hepatic function. Pathologic examinations showed marked intracellular accumulation of fat with minimal necrosis and minimal elevation of hepatocellular enzymes and bilirubin. The severe acidosis seen in these cases suggested that injury was localized to the mitochondria.[25] Steatosis with extensive hepatocellular necrosis was reported in a fatal case of Bacillus cereus food poisoning associated with high levels of the emetic toxin cereulide in the bile and liver.[23] Autoimmune Mechanisms Halothane and possibly other inhalational anesthetics cause autoimmune hepatitis that is severe and, fortunately, rare. This generally occurs on re-expos