ANALYTIC REVIEWS Antidote Use in the Critically Ill Poisoned Patient David P. Betten, MD* Rais B. Vohra, MD† Matthew D. Cook, DO† Michael J. Matteucci, MD†‡ Richard F. Clark, MD† of these treatments have long since fallen out of The proper use of antidotes in the intensive care setting when combined with appropriate general supportive care favor because they were found to offer little or no may reduce the morbidity and mortality associated with benefit and in many cases produce significant detri- severe poisonings. The more commonly used antidotes mental effects. Strychnine, cocaine, and other stim- that may be encountered in the intensive care unit ulants, for example, were commonly used in the (N-acetylcysteine, ethanol, fomepizole, physostigmine, 1920s and 1930s for barbiturate overdoses. Their naloxone, flumazenil, sodium bicarbonate, octreotide, pyridoxine, cyanide antidote kit, pralidoxime, atropine, inherent toxicity and the low mortality rate associ- digoxin immune Fab, glucagon, calcium gluconate and ated with barbiturate poisonings treated with sup- chloride, deferoxamine, phytonadione, botulism anti- portive care alone led to their eventual dismissal [1]. toxin, methylene blue, and Crotaline snake antivenom) Antidotes commonly used today, when adminis- are reviewed. Proper indications for their use and knowl- tered in conjunction with aggressive supportive edge of the possible adverse effects accompanying antido- tal therapy will allow the physician to appropriately care, are often able to decrease the severity and manage the severely poisoned patient. duration of symptoms while possessing safety pro- files more benign than their predecessors. In certain Key words: antidote, poisoning, overdose circumstances, when used promptly and appropri- ately, their use may be life saving. The infrequent presentation of individuals The use of antidotes for poisonings has been requiring particular antidotes and the relatively high explored for thousands of years. The vast majority cost of antidotes has resulted in many hospitals car- rying inadequate quantities of some of the more From *Department of Emergency Medicine, Sparrow Health commonly used antidotes [2,3]. Antidote stocking System, Michigan State University College of Human Medicine, guidelines were recently established by a multidis- Lansing, Michigan, †University of California, San Diego, California Poison Control System, San Diego, California, and ‡Department of ciplinary panel of 12 health care professionals. Emergency Medicine, Naval Medical Center, San Diego, California. Sixteen antidotes were unanimously identified by the consensus panel for stocking (Table 1) [4]. Received Sep 30, 2005, and in revised form Feb 24, 2006. Accepted for publication Mar 1, 2006. Hospitals not possessing these antidotes should at the minimum have pre-identified neighboring Address correspondence to David P. Betten, MD, Department health care centers that will readily be able to trans- of Emergency Medicine, Sparrow Health System, Michigan State University College of Human Medicine, 1215 E. Michigan Ave, port these antidotes on an emergency basis. Lansing, MI 48912-1811, or e-mail: [email protected]. The following is a brief review of some of the more commonly used antidotes that may be used in Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF. Antidote use in the critically ill poisoned patient. J Intensive Care Med. the intensive care setting. Given the complexity of 2006;21:255-277. management of severely poisoned patients and subtleties in the use of many antidotes, further con- This review was co-written by LCDR Michael J. Matteucci, MC, USN, while a Fellow at UCSD Medical Center training in Medical sultation with a medical toxicologist or poison cen- Toxicology. The views expressed in the article are those of the ter (national poison center hot line: 1-800-222-1222) authors and do not reflect the official policy or position of the should be considered. The management of acute Department of the Navy, Department of Defense, nor the US and chronic heavy metal poisonings (arsenic, lead, Government. mercury, etc) is not addressed, and the reader is DOI: 10.1177/0885066606290386 referred to several excellent reviews pertaining to Copyright © 2006 Sage Publications 255 Betten et al Table 1. Consensus Stocking Guidelines of 20 Commonly Encountered Antidotes for Hospitals That Accept Emergency Admissions as Determined by an Expert Multidisciplinary Panel [4] Consensus Not Reached Not Recommended Recommended for Stocking for Routine Stocking for Routine Stocking N-acetylcysteine Flumazenil Black widow antivenin Crotalid snake antivenin Physostigmine Ethylenediamine tetraacetic acid Calcium gluconate/chloride Sodium bicarbonate Cyanide antidote kit Deferoxamine Digoxin immune Fab Dimercaprol Atropine Ethanol Fomepizole Glucagon Methylene blue Naloxone Pralidoxime Pyridoxine appropriate indications for treatment and methods sulfate that promotes acetaminophen metabolism of administration of common chelation agents [5-9]. through the nontoxic sulfation pathway. (2) NAC directly converts NAPQI to nontoxic cysteine and mercaptate conjugates. (3) NAC reduces NAPQI back Acetaminophen Poisoning to acetaminophen, where it may be further elimi- nated by other nontoxic routes. In the setting of pro- Acetaminophen misuse is responsible for more hos- gressive hepatic failure, NAC may offer further pitalizations following overdose than any other benefit as a result of its nonspecific antioxidant common pharmaceutical agent. Although aceta- effects and free radical scavenging properties in addi- minophen possesses an outstanding safety profile at tion to NAC-mediated improvement in microvascular therapeutic doses, a rapid course of progressive perfusion [12,13]. hepatic failure leading to death may occur following When administered early (<8 hours) after acute large overdoses when treatment is delayed. It has ingestion, NAC is almost completely effective in been estimated that 450 deaths annually and nearly preventing significant hepatotoxicity. The benefit of 40% of all cases of acute liver failure in the United this antidote is lessened beyond 8 hours following States are secondary to the inappropriate use of overdose as glutathione stores become further acetaminophen [10,11]. Toxicity occurs as a result of depleted [14]. Treatment should be initiated imme- acetaminophen’s metabolism via cytochrome p450 diately for any suspected toxic acetaminophen inges- to N-acetyl-p-benzoquinoneimine (NAPQI). At thera- tion beyond 8 hours. Current US Food and Drug peutic doses of acetaminophen, NAPQI is detoxified Administration (FDA)–approved treatment options by glutathione to nontoxic conjugates; however, include either oral or intravenous NAC. Oral NAC is with excess dosing and exhaustion of glutathione administered as a 140 mg/kg loading dose followed reserves, NAPQI accumulates, initiating a cascade of by 70 mg/kg every 4 hours for an additional 17 events capable of producing hepatocyte damage and doses for any patient with a toxic ingestion as plot- fulminant hepatic failure. ted on the Rumack-Matthew nomogram. Should signs of progressive hepatic damage be present after this 72-hour period, treatment with NAC may N-acetylcysteine still be of some benefit and should be continued until a definitive clinical and laboratory improve- N-acetylcysteine (NAC) prevents NAPQI-induced ment is noted. Success has been demonstrated with hepatoxicity through several mechanisms: (1) NAC a shortened treatment duration of oral NAC in functions as a glutathione (GSH) precursor that may several studies when administered to appropriate increase GSH availability as well as provide inorganic candidates [15-17]. Early NAC discontinuation 256 Journal of Intensive Care Medicine 21(5); 2006 Antidote Use should be considered only after a minimum of at N-acetylcysteine given orally is often poorly tol- least 20 hours of oral NAC administration when no erated due to its “rotten egg” sulfur smell. High-dose further acetaminophen is detectable in the serum antiemetics may be needed to prevent emesis. Any and hepatic transaminases and prothrombin times NAC dose vomited within 1 hour from ingestion are normal. should be readministered. If vomiting is present and Intravenous NAC has been used throughout persistent beyond 8 hours following acetaminophen Europe, Canada, Australia, and portions of the United ingestion, intravenous NAC should be strongly con- States for more than 2 decades with success demon- sidered. Intravenous NAC has been used effectively strated in treatment durations of 20 to 48 hours [18- and relatively safely throughout the world for more 20]. Intravenous NAC recently gained FDA approval than 20 years [19]. Anaphylactoid reactions with in the United States for patients treated within 8 to 10 intravenous NAC may occur as a dose- and rate- hours following an acute toxic acetaminophen inges- related effect; however, these reactions are generally tion. It is administered as a 140-mg/kg loading dose minor (pruritis, vomiting) and usually respond to over 15 minutes followed by a 50-mg/kg infusion antihistamines and a slowing of the NAC infusion over 4 hours, concluding with a 16-hour infusion of rate [20,24]. Major adverse effects and death follow- 100 mg/kg. When intravenous NAC is initiated ing intravenous NAC administration are exceedingly beyond 8 to 10 hours postingestion, it should be con- rare and are most commonly related to rapid intra- tinued beyond the 20-hour infusion if needed until venous loading in