Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care

TOXICOLOGY/CONCEPTS Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care

Richard C. Dart, MD, PhD From the Rocky Mountain Poison & Drug Center - Denver Health, Denver, CO (Dart, Heard, Schaeffer, Stephen W. Borron, MD, MS Bogdan, Alhelail, Buchanan, Hoppe, Lavonas, Mlynarchek, Phua, Rhyee, Varney, Zosel); Department of E. Martin Caravati, MD, MPH Surgery, University of Texas Health Sciences Center, San Antonio, TX (Borron); Division of Emergency Daniel J. Cobaugh, PharmD Medicine, Utah Poison Control Center, University of Utah Health Sciences Center, Salt Lake City, UT Steven C. Curry, MD (Caravati); ASHP Research and Education Foundation, Bethesda, MD (Cobaugh); Department of Jay L. Falk, MD Medical Toxicology and Banner Poison Control Center, Banner Good Samaritan Medical Center, Lewis Goldfrank, MD Phoenix, AZ (Curry); Department of Emergency Medicine, Orlando Regional Medical Center, University of Susan E. Gorman, PharmD, MS Florida, Orlando, FL (Falk); New York City Poison Center; New York University School of Medicine, New Stephen Groft, PharmD York, NY (Goldfrank); Division of Strategic National Stockpile, Centers for Disease Control and Kennon Heard, MD Prevention, Atlanta, GA (Gorman); Ofﬁce of Rare Diseases Research, Bethesda, MD (Groft); Division of Ken Miller, MD, PhD Emergency Medicine, School of Medicine (Dart, Heard, Lavonas, Schaeffer) and Department of Kent R. Olson, MD Pharmaceutical Sciences, School of Pharmacy (Bogdan), University of Colorado Denver, Aurora, CO; Gerald O’Malley, DO Orange County Fire Authority and Orange County Health Care Agency Emergency Medical Services, Donna Seger, MD Irvine, CA, and National Association of EMS Physicians, Lenexa, KS, (Miller); University of California, Steven A. Seifert, MD San Francisco, and San Francisco Division, California Poison Control System, San Francisco, CA Marco L. A. Sivilotti, MSc, MD (Olson); Division of Research, Department of Emergency Medicine, Albert Einstein Medical Center, Tammi Schaeffer, DO Philadelphia, PA (O’Malley); Tennessee Poison Center, Division of Clinical Pharmacology, Department of Anthony J. Tomassoni, MD, MS Medicine, Vanderbilt University Medical Center, Nashville, TN (Seger); University of New Mexico School Robert Wise, MD of Medicine & Medical Director, New Mexico Poison and Drug Information Center, Albuquerque, NM Gregory M. Bogdan, PhD (Seifert); Department of Emergency Medicine and Department of Pharmacology & Toxicology, Queen’s Mohammed Alhelail, MD University, Ontario, Canada (Sivilotti); Yale University School of Medicine, Department of Surgery, Jennie Buchanan, MD Section of Emergency Medicine, and Yale-New Haven Center for Emergency Preparedness and Disaster Jason Hoppe, DO Response, New Haven, CT (Tomassoni); Division of Standards and Survey Methods, The Joint Eric Lavonas, MD Commission, Oakbrook Terrace, IL (Wise). Sara Mlynarchek, MPH Dong-Haur Phua, MD Sean Rhyee, MD, MPH Shawn Varney, MD Amy Zosel, MD For the Antidote Summit Authorship Group

Study objective: We developed recommendations for antidote stocking at hospitals that provide emergency care. Methods: An expert panel representing diverse perspectives (clinical pharmacology, clinical toxicology, critical care medicine, clinical pharmacy, emergency medicine, internal medicine, pediatrics, poison centers, pulmonary medicine, and hospital accreditation) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for the quantity of an antidote that should be stocked and the acceptable period for delivery of each antidote. Results: The panel recommended consideration of 24 antidotes for stocking. The panel recommended that 12 of the antidotes be available for immediate administration on patient arrival. In most hospitals, this period requires that the antidote be stocked in the emergency department. Another 9 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel identiﬁed additional antidotes that should be stocked by the hospital but are not usually needed within the ﬁrst hour of treatment. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine the need for antidote stocking in that hospital. Conclusion: The antidote expert recommendations provide a tool to be used in creating practices for appropriate and adequate antidote stocking in hospitals that provide emergency care. [Ann Emerg Med. 2009;54:386-394.]

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INTRODUCTION relevant guidelines despite an evidence base that is incomplete, Antidotes are a critical component in the care of poisoned we combined a structured analysis of the existing literature with patients. Antidotes such as digoxin immune Fab can be an expert consensus panel. lifesaving; however, an antidote must be available at the appropriate time to be effective. For some poisons, the antidote MATERIALS AND METHODS must be available immediately. The administration of cyanide Overview antidote can resuscitate a patient only if the antidote is Recommendations for antidote stocking were created in 2 administered before irreversible injury develops. For other phases similar to the development of American College of antidotes, there is time to procure the drug from the pharmacy Emergency Physicians (ACEP) clinical policies. First, or from another hospital. The use of a specific antidote was standardized evidence-based summaries of the medical literature reported by US poison centers approximately 80,000 times in were generated for each antidote. Each summary was then 2006.1 Unfortunately, important antidotes often are not independently reviewed and revised by a primary reviewer from stocked at all or are stocked in an insufficient amount. the expert panel. The reviewer presented the summary and the Insufficient stocking of a diverse group of antidotes has been recommendation to the full panel, and an iterative process was documented repeatedly in many countries, including the United used to reach consensus. The panel was instructed to address States and Canada.2-9 specifically the needs of hospitals that provide emergency care in Although national recommendations of an expert panel were the United States. Stocking of antidotes for mass casualty events published in 2000, reports of inadequate stocking persist.10,11 was not addressed by the panel. Details about administration of The causes of this serious problem are unknown but are likely each antidote were not addressed by the panel. related in part to limited awareness, infrequent use, interruptions in supply, and allocation of limited hospital Phase 1 pharmacy resources. Previous studies have found that larger Relevant medical literature was obtained by nonmedical staff hospitals are more likely than smaller or rural hospitals to stock with extensive experience in searching and retrieving medical 4,7 antidotes adequately. Perceived cost of antidotes based on literature. Evidence-based summaries of the medical literature purchase price, as well as pharmacist and physician unfamiliarity for each antidote were created by a group of emergency 4,12 with poisons and their antidotes, may also contribute. physicians and clinical toxicologists not involved in the Changes in the types of antidotes available may also play a role. consensus process. For each antidote, a standardized summary In recent years, new antidotes have become available and others of 5 to 20 pages was created for subsequent assessment by the have been discontinued. primary reviewer. Publications used to create the summary were The Joint Commission (TJC) sets standards for accreditation identified with 3 methods: (1) searches for each antidote and its of hospitals in the United States but does not explicitly address indications, using the National Library of Medicine’s PubMed antidote stocking. TJC standard MM.2.10 states simply that database (http://www.pubmed.gov); limited to “human” and medications available for dispensing or administration be “English” for article types “clinical trials,” “reviews,” or “case selected, listed, and procured according to criteria. Standard reports”; (2) review of chapter bibliographies for each antidote MM.2.30 states that emergency medications or supplies, if any, in 2 textbooks of toxicology15,16; and (3) review of be consistently available, controlled, and secured.13 Individual bibliographies of selected articles from the previous 2 methods state governments also regulate hospitals, although their for additional citations. Each article was classified according to attention in terms of antidotes has primarily been focused on its methodology, using the clinical guideline model of the mass casualty and terrorist events. However, California recently ACEP (class I: good-quality randomized and blinded clinical sanctioned a hospital for violating a regulation requiring trials and good-quality systematic reviews of good-quality “. . .availability of prescribed medications 24 hours a day.”14 In randomized trials; class II: prospective, nonrandomized, or that case, digoxin Fab was not available immediately for a nonblinded clinical trials, cohort, or well-designed case-control patient with cardiac glycoside toxicity. studies, good-quality observational or volunteer studies; class Although published documentation of insufficient antidote III: retrospective case series, case studies, relevant expert stocking is common, scholarly research and analysis of the opinions, or animal studies) and then summarized with a 17 phenomenon are almost nonexistent. Often, the efficacy of an standardized form. antidote is well studied, but few studies address the number of patients or the period in which patients must be treated. Given Phase 2 the approval of new antidotes, the changes in availability of Each literature summary developed in phase 1 was provided antidotes, a changing regulatory environment, and the to 1 expert panel member serving as the primary reviewer for continued lack of antidote stocking, the objective of this that antidote. The expert panel was a diverse group of 19 evidence-based consensus process was to develop professionals representing various perspectives (Table 1). The recommendations for the stocking of antidotes at hospitals that principal investigator served as the nonvoting chairperson and provide emergency care. To produce useful and clinically selected individuals for the panel according to evidence of

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Table 1. Profile of antidote panel members. could vote in one of 3 ways: agreement, disagreement, or strong Discipline or Specialty No. of Participants disagreement. If 1 or more panel members expressed strong Clinical pharmacology 3 disagreement, the discussion was continued and another vote Critical care medicine 3 taken. If agreement could not be reached, the decision was listed Clinical pharmacy 2 as “consensus not reached.” Disaster preparedness/response 6 The panel’s estimate of the antidote amount needed per Emergency medicine 11 patient was based on clinical considerations: dose, duration of Emergency medical services 4 Hospital pharmacy 1 therapy (8 or 24 hours), use of extracorporeal elimination such Internal medicine 2 as hemodialysis, and other factors. The panel chose to consider Clinical toxicology 15 one 100-kg patient as the basis for calculating the amount of Pediatrics 2 antidote to stock. This weight was chosen by using recent data Poison center administration 9 from the National Health and Nutrition Examination Survey.18 Public health 1 Regulatory medicine or hospital accreditation 4 This weight falls between the 75th and 85th percentile for men and approximates the 90th percentile for women. Categories were self-selected by panel participants. Total is greater than 19 because of multiple designations of some individuals. The acquisition cost of each antidote was estimated by multiplying the average wholesale price by the amount of drug recommended by the panel. The average wholesale price is the estimated retail cost of a drug. In reality, most institutions have previous antidote research, professional experience with the purchasing agreements that allow them to purchase at a price acquisition and use of antidotes, or their potential role in the below average wholesale price. When a partial unit would be provision of antidotes (eg, TJC). This approach was necessary needed to complete the dosing, the number of units (eg, vials) because there is no formal body or compendium that evaluates of the drug was rounded to the next full unit. For example, the candidate antidotes or their appropriate stocking. calculation of acetylcysteine based on weight usually results in a The primary reviewers assessed and revised the literature partial vial; therefore, cost of purchasing was estimated by summary produced in phase 1 for each assigned antidote, using rounding up to the next full vial. their knowledge and experience. The primary reviewer could Competing interests were managed proactively and add articles to the summary. Each primary reviewer then formed transparently. Each panel member completed a competing a provisional recommendation about the antidote and presented interest form for each antidote, disclosing any financial interest the revised literature summary and the recommendation to the or stock ownership or financial support (research grants, entire panel. The panel’s deliberations occurred on March 6 to consulting agreements) from each antidote manufacturer or 7, 2008. The evidence-based analysis was formulated to provide marketer for the preceding 10 years. Any relationship (ie, information to the panel about the fundamental questions funding for a clinical trial, a single consultation with the involved in the selection of each antidote: company, or any level of equity holding in the company) was 1. Is the antidote effective? considered a competing interest. No participant reported equity 2. Do the medical benefits of its use outweigh its risks? holdings in a company. Six participants reported funding for If the consensus was affirmative for the first 2 questions, clinical research and 6 reported previous consulting agreements the panel addressed 3 additional questions: with an antidote manufacturer. The panel was informed of all 3. Is time an important factor in its use? competing interests for each antidote as it was considered. Each a. Does the antidote need to be available immediately on panel member with a competing interest was allowed to patient arrival in the emergency department (ED)? participate in discussion but was excluded from voting on the b. Does the antidote need to be available for administration antidote involved. within 60 minutes of the decision to use? 4. How many patients should a facility prepare for? 5. What amount of the antidote is needed to treat 1 patient RESULTS weighing 100 kg? There were 1,446 articles retrieved and reviewed; 583 articles An iterative process was used to reach consensus on stocking were used to develop the literature summaries and provisional of each antidote. After presentation of an antidote by the recommendations. Class I evidence was occasionally available, primary reviewer and discussion by the entire panel, a vote was typically to show the efficacy of the drug. Class II evidence was taken to determine consensus. An antidote was recommended more commonly available but again focused on efficacy. Class for stocking if the panel consensus was affirmative for the first 2 III evidence was plentiful but extremely variable. A few class III questions. The additional questions were addressed to assist studies were rigorously performed medical record reviews, but hospitals in determining where an antidote should be stocked most were case reports or chart reviews without an appropriate and in what quantity. For all questions, consensus was defined description of methods. Virtually no articles explicitly addressed as agreement of at least 75% of eligible panel members, the questions of the appropriate time for availability and provided there was no strong disagreement vote. Each member number of patients a facility should be prepared to treat.

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Overall, the panel recommended consideration of 24 antidotes, such as octreotide and others, are not labeled for their antidotes for stocking in hospitals that accept emergency use as an antidote. patients, counting only 1 antidote when alternatives were The panel observed that many considerations can affect the available (eg, fomepizole or ethanol for treatment of toxic decision to stock an antidote, as well as the amount of an alcohols). The panel recommended that 12 of these antidotes be antidote that should be stocked. A rigid recommendation for all immediately available for administration on patient arrival hospitals is difficult to justify and may lead to insufficient (Table 2). Antidotes for opioid, cardiac glycoside, cyanide stocking. For example, a hospital in an area endemic for poisoning, or other conditions may be lifesaving if administered crotaline snakes (rattlesnakes, copperhead snakes, water before irreversible injury has occurred. In most hospitals, this moccasins) should stock antivenom, but the amount period requires that the antidote be stocked in the ED. Another recommended for 1 patient may be insufficient if 2 bites could 9 antidotes were recommended for availability within 1 hour of require treatment simultaneously. To address these situations, the decision to use the antidote (Table 2), allowing the antidote the panel recommended that hospitals perform a hazard vulnerability assessment for each antidote (Tables 3, 4). to be stocked in the pharmacy, providing the hospital has an efficient mechanism for prompt delivery of medications to the ED. The panel recommended that 3 additional antidotes be LIMITATIONS stocked, but they are not necessarily needed within 1 hour of Little class 1 and 2 evidence was available for most antidotes; ordering. Consensus was not reached for Prussian blue. Finally, therefore, many of the panel’s recommendations are based on 2 antidotes, both antitoxins for botulism, were not expert analysis and experience. The process attempted to recommended for stocking. compensate for individual bias by using a large diversified panel, For some conditions, more than 1 antidote can effectively by presenting structured summaries of medical information, and treat a poisoning or overdose. The panel identified 3 instances by prohibiting voting by members with a competing interest. in which more than 1 effective antidote was available: ethanol or This approach helped to constrain undocumented or fomepizole for treatment of toxic alcohol exposure, antivenin unsubstantiated opinion of panel members in 2 ways. First, the Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) or published medical evidence was reviewed and this supported the expectation that the reviewer’s conclusions would be evidence antivenin (Crotalidae) polyvalent for treatment of crotaline based within the limits of available information. Second, the snakebite, and the conventional cyanide antidote kit (sodium other panel members (who reviewed the evidence nitrite and sodium thiosulfate) or hydroxocobalamin for cyanide simultaneously) acted as a counterbalance against toxicity. In these cases, the panel designated a preferred agent, unsubstantiated individual positions of the reviewer. although either agent was recognized as acceptable in meeting The panel was chosen by the nonvoting chairman according the need for stocking. The preference was determined in the to documented clinical and research expertise, which may have same manner as the decision to recommend stocking of an resulted in an unintended bias toward academia. This possibility antidote: by group debate reaching consensus without a vote of was counterbalanced by the voting rules that allowed a single strong disagreement. Fomepizole was preferred over ethanol for objection to reject a recommendation. Several exotic antidotes several reasons: simplicity of use, lack of need for compounding and antidotes not readily available in North America were not in pharmacy, reduction in medication errors, potential to avoid considered. The panel was also asked not to anticipate singular hemodialysis, and anticipated safety in children. The use of and rare events, such as terrorist acts or mass casualty incidents. ethanol is further complicated by the lack of a commercially It was not possible to assess the full cost-benefit relationship available 10% solution in the United States, requiring because information about the value of benefit is not available. compounding of a 10% solution from a 95% solution of The intended audience of the recommendations was an ethanol.19 Hydroxocobalamin was preferred over the individual hospital providing emergency care, rather than larger conventional cyanide antidote kit because of its wider regions, states, or national organizations, given the different indications, ease of use, and anticipated safety in widespread needs and resources of such entities. use. FabAV was preferred over antivenin (Crotalidae) polyvalent because of improved safety profile and the fact that production DISCUSSION of the Wyeth antivenom has been discontinued. Supplies of the The antidote expert panel recommended consideration of Wyeth antivenom were available but difficult to obtain at the 24 antidotes for emergency stocking by facilities that provide time of the panel’s assessment. emergency care. The recommendations are intended to be The panel recommended the amount of antidote needed to interpreted in the context of the potential clinical uses created treat a 100-kg patient for either 8 hours or 24 hours (Table 3). by the catchment area served by a hospital; special needs for In most cases, the amount of antidote recommended for mass casualty events are not addressed in these stocking did not match the package label precisely because of recommendations. changes in clinical practice since the label content was approved Insufficient stocking of antidotes needed on an emergency basis by the Food and Drug Administration and because some has been documented repeatedly in the United States and other

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Table 2. Antidote recommendations for stocking at facilities that accept emergency patients. Recommendation Available Should Be Within 60 Immediately Class of † Antidote Poisoning Indication(s) Stocked Minutes Available* Evidence Acetylcysteine Acetaminophen Yes Yes No I (IV) II (oral) Antivenin (Crotalidae) polyvalent, North American crotaline snake Yes Yes No III Wyeth, OR envenomation Crotalidae Polyvalent Immune North American crotaline snake Yes Yes No II ‡ Fab, ovine envenomation Antivenin (Latrodectus mactans) Black widow spider envenomation Yes No No III Antivenin (Micrurus fulvius) Eastern and Texas coral snake Yes Yes No III envenomation Atropine sulfate Organophosphorus and N-methyl Yes Yes Yes III carbamate insecticides Botulism antitoxin, equine (A, B) Botulism No NA NA III Botulism immune globulin Infant botulism No NA NA I (BabyBIG) § Calcium chloride Fluoride, calcium channel Yes Yes Yes III blocking agent § Calcium gluconate Yes Yes Yes III Calcium disodium EDTA Lead Yes No No II Calcium trisodium pentetate Internal contamination with Yes No No III (Calcium DTPA) plutonium, americium, or curium Cyanide Antidote Kit OR Cyanide poisoning Yes Yes Yes III ‡ Hydroxocobalamin hydrochloride Cyanide poisoning Yes Yes Yes II Deferoxamine mesylate Acute iron poisoning Yes Yes No II Digoxin Immune Fab Cardiac glycosides/steroid Yes Yes Yes II toxicity Dimercaprol Heavy metal toxicity (arsenic, Yes Yes No II mercury, lead) § Ethanol OR Methanol, or ethylene glycol Yes Yes No III poisoning ‡ Fomepizole Methanol, or ethylene glycol Yes Yes No II poisoning Flumazenil Benzodiazepine toxicity Yes Yes Yes III § Glucagon hydrochloride ␤-Blocker, calcium channel Yes Yes Yes III blocker Methylene blue Methemoglobinemia Yes Yes Yes II Naloxone hydrochloride Opioid and opiate drugs Yes Yes Yes I § Octreotide acetate Sulfonylurea-induced Yes Yes No II hypoglycemia Physostigmine salicylate Anticholinergic syndrome Yes Yes Yes II Potassium iodide Thyroid radioiodine protection Yes Yes No III Pralidoxime chloride Organophosphorus insecticide Yes Yes NC II poisoning Pyridoxine hydrochloride Isoniazid, hydrazine and Yes Yes Yes III derivatives Prussian blue Thallium/radiocesium NC NC NC II § Sodium bicarbonate Sodium channel blocking drugs, Yes Yes Yes II urine or serum alkalization

IV, Intravenous; NA, do not apply because panel did not recommend stocking; EDTA, ethylene diamine tetraacetic acid; DTPA, diethylene triamine pentaacetic acid; NC, panel could not reach consensus. Cyanide antidote kit: conventional kit composed of amyl nitrite, sodium nitrite, and sodium thiosulfate. Class of evidence: Class I: good-quality randomized and blinded clinical trials and good-quality systematic reviews of good-quality randomized trials; class II: prospective, nonrandomized, or nonblinded clinical trials, cohort or well- designed case-control studies, good-quality observational or volunteer studies; class III: retrospective case series, case studies, relevant expert opinions, or animal studies.16 *In most hospitals, immediately availability means that the antidote should be stocked in the ED. †Class of evidence was deﬁned as the highest level of evidence observed. ‡Preferred agent. §Indication listed in package label does not include its antidotal use.

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Table 3. Amount of antidote typically needed to treat 1 patient weighing 100-kg. Stocking Recommendation Drug AWP for Notes and Considerations for Hazard Vulnerability Antidote 8h* 24h* 8 Hours, $ Assessment (HVA) Acetylcysteine 28 g 56 g IV: 800.30 Note: This recommendation applies to stocking of either oral or intravenous products PO: 214.20 Note: Administer intravenously for hepatic failure Antivenin (Crotalidae) 30 Vials 30 Vials 36,705 Note: Product has been discontinued by manufacturer; some supplies remain polyvalent HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) Crotalidae Polyvalent 12 Vials 18 Vials 18,858 Note: Less common acute and delayed antivenom reactions, faster mixing, use in Immune Fab, ovine equine serum hypersensitivity HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) Antivenin (Latrodectus 1 Vial 1 Vial 31.10 HVA: Geographic/endemic areas (Table 4) mactans) Antivenin (Micrurus 5 Vials 10 Vials 8,568.00 Note: Product has been discontinued by manufacturer; some supplies remaining. fulvius) Antivenoms from Mexico or Costa Rica are likely effective. Contact regional poison center to locate antivenom sources. HVA: Geographic/endemic areas (Table 4) Atropine sulfate 45 mg 165 mg 140.62 Botulism antitoxin, NA NA NA Note: Contact your state health department to assist with procurement from the equine (A, B) Centers for Disease Control and Prevention Botulism immune NA NA NA Information from Infant Botulism Treatment and Prevention Program, Telephone: 510- globulin (BabyBIG) 231-7600, http://www.infantbotulism.org/physician/obtain.php Calcium chloride 10 g 10 g 15.00 Note: do not administer subcutaneously. Should be administered by central venous IV route, if possible Calcium gluconate 30 g 30 g 26.70 Note: May be given by IV, SQ routes Both calcium gluconate and calcium chloride should be available Calcium disodium EDTA 0.75 g 2.25 g 58.03 Calcium DTPA 1 g 1 g 70.00 HVA: receiving hospital for research laboratory (Table 4) Cyanide antidote kit 1 kit 1 kit 274.56 HVA: Industry, history, local conditions, community planning, facility service area (Table 4) Note: Nitrites cause methemoglobinemia and can impair oxygen delivery; should not be used in smoke inhalation patients with carbon monoxide poisoning; sodium thiosulfate may be used but evidence limited, and may cause hypotension Hydroxocobalamin 10 g 10 g 812.50 Note: Can be used safely in patients with smoke inhalation. Red color of drug causes hydrochloride laboratory test interference, red discoloration of skin and urine HVA: Industry, history, local conditions, community planning, facility service area (Table 4) Deferoxamine mesylate 12 g 36 g 417.18 Digoxin Immune Fab 15 Vials 15 Vials 600.00 Dimercaprol 500 mg 1.5 g 197.74 Ethanol 180 g 360 g 76.56 Note: Ethanol is an effective antidote. It is only available as 95% concentration and requires compounding at use. Loading dose, maintenance infusion, and frequent dose adjustments required. Medication errors are common Fomepizole 1.5 g 4.5 g 1,364.85 Note: Fomepizole preferred for simplicity of use, lack of need for compounding in pharmacy, reduction in medication errors, potential for avoiding hemodialysis in selected patients, and anticipated safety in children Flumazenil 6 mg 12 mg 41.26 Note: Primary use is for iatrogenic oversedation. Risks may outweigh beneﬁts in patients with mixed/unknown overdose, chronic benzodiazepine use, seizure disorders, head injury Glucagon hydrochloride 90 mg 250 mg 7,875.00 Methylene blue 400 mg 600 mg 40.72 Naloxone hydrochloride 20 mg 40 mg 131.50 Octreotide acetate 75 ␮g 225 ␮g 24.08 Physostigmine salicylate 4 mg 4 mg 9.72 Potassium iodide 130 mg 130 mg 12.10 Pralidoxime chloride 7 g 18 g 758.66 Pyridoxine hydrochloride 8 g 24 g 899.20 HVA: Industry, history, endemic conditions, community planning, facility service area (Table 4) Prussian blue NA NA NA Sodium bicarbonate 63 g 84 g 13.95

AWP, Average wholesale price. Cyanide antidote kit: conventional kit composed of amyl nitrite, sodium nitrite, and sodium thiosulfate. AWP is an estimate produced by commercial vendors to repre- sent the average price at which wholesalers sell drugs to physicians, pharmacies, and other purchasers. These minimum stocking recommendations are made to apply to all hospitals; any facilities with a Hazard Vulnerability Assessment indicating greater or lesser need should stock appropriately. *Facilities should plan for a minimum of 8 hours unless they have mechanisms for more rapid resupply or transfer already in place. Facilities should plan for 24 hours if they will maintain patients for longer periods or will provide deﬁnitive care. Caution: 24-hour amount may not be sufﬁcient for the entire treatment course.

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Table 4. Hazard vulnerability assessment for emergency antidotes. Factor Principle Example Pharmaceutical products Agents that are widely available should Acetaminophen used as therapeutic generally have the antidote stocked Anticholinergic agents agents because important geographic Benzodiazepines differences are not anticipated Dapsone Digoxin Iron Isoniazid Lidocaine Opioid analgesics Sulfonylurea hypoglycemic agents Characteristics of Industries, practices, activities, and Industries generating or using cyanide, heavy metals, hydrogen fluoride, hospital catchment indigenous fauna indicate potential organophosphorus chemicals, radionuclides, thallium area need for antidote Chemical transportation routes Indigenous fauna and flora (snakes, spiders, plants) Agricultural practices (organophosphate insecticides, cyanide baits, mining) Referral patterns Many hospitals accept referrals from Transfers to urban hospital from agricultural areas remote areas. These should be Referral from mining region included in risk assessment History or experience of Some modes of suicide or abuse Popularity of cyanide or other specific agents as a suicide agent use become locally prevalent without a Amateur snake keepers in area specific industry being present Residential or commercial fires (older buildings, lack of fire alarms, etc) Anticipated volume of Depending on characteristics of area, Multiple casualty incidents (eg, smoke inhalation involving treatment use more than 1 victim of a poisoning with cyanide antidotes) may be anticipated Indigenous crotaline snakebite in areas with frequent occurrences such as the southeastern or southwestern United States Anticipated time to Time to restocking varies greatly Hospitals that stabilize and refer patients to other institutions should restocking or resupply among hospitals stock for the anticipated period of antidote Hospitals that provide tertiary or definitive treatment should stock for anticipated duration of illness or until restocking from another hospital or distributor can occur Time to restocking varies by antidote. Some may have prolonged periods before restocking can occur

countries.2-9 However, it is difficult for hospitals to address this approach holds promise in facilitating the appropriate situation because widely accepted guidelines for antidote stocking assessment of antidote stocking needs. have not emerged, although certain regional guidelines have been The hazard assessment concept requires a hospital to promulgated.11,20-22 National guidelines are difficult to produce formally analyze the need for an antidote and the amount of because of the heterogeneity of hospital organization and each antidote needed for their facility. Prioritization of risks is management, as well as the diversity of service area. The expert based on available objective data (hospital services and panel therefore concluded that a mechanism allowing utilization, demographic information, local industrial uses, customization of stocking for each hospital should be used. availability of antidote at neighboring facilities, and chemical To allow customized application of these guidelines, the transportation routes, among other factors) that require panel developed the concept of an antidote hazard vulnerability interaction with appropriate businesses and manufacturers, as assessment, an adaptation of the Hazard Vulnerability well as local, state, and federal agencies. Table 4 provides Assessment required in the United States for accreditation of potential variables that should be considered in this hazard hospitals by TJC. As defined by TJC, a Hazard Vulnerability assessment. A hospital should use the hazard assessment process Assessment is the identification of potential emergencies and the to determine the treatment period for which antidote stocking direct and indirect effects these emergencies may have on the should occur. Some hospitals may exist in an environment hospital’s operations and the demand for its services.23 This making stabilization and referral of a patient simple and rapid. process is already required of hospitals that are accredited by Other hospitals may be subject to serious transportation TJC and provides a useful framework to assess contingencies difficulties and extreme weather conditions. The process of presented by poisoned patients. All hospitals should perform an hazard assessment should include all stakeholders: for example, antidote hazard vulnerability analysis. Myriad variables such as pharmacy, emergency medicine, clinical toxicology, ICU, risk size, administrative structure, specialty, and local characteristics management, nursing, pharmacy and therapeutic committee, may affect institutional antidote needs. The hazard analysis hospital preparedness committee, and hospital administration.

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The regional poison center is an important resource to include Supervising editors: Lewis S. Nelson, MD; Michael L. Callaham, MD in the assessment process. Some hospitals may forgo stocking of some antidotes, Dr. Nelson and Dr. Callaham were the supervising editors on this article. Dr. Dart did not participate in the editorial review optimistically concluding that antidotes can be obtained quickly or decision to publish this article. from neighboring facilities in case of urgent need. However, the experience of the expert panel indicates that delays are often Panel decisions: Panelists without a conflict of interest were encountered during the transfer of antidotes from one hospital eligible to vote on any issue. Panelists with conflicts were prohibited from voting on the drugs involved in the competing to another, even between neighboring hospitals or hospitals interest. The chair was nonvoting and disclosed that Denver under the same management, thereby compromising patient Health’s Rocky Mountain Poison and Drug Center is a care. Delays can arise from the lack of a dedicated system to nonprofit governmental facility that provides poison and drug facilitate transfer, the infrequent and unplanned nature of these information, and research and consulting services to various requests, and difficulties prioritizing the delivery of a medication entities under contract. to another facility over urgent internal hospital orders. Funding and support: By Annals policy, all authors are required Infrequently used antidotes may be difficult to find during an to disclose any and all commercial, financial, and other 22 emergency, even within the same facility. To address this relationships in any way related to the subject of this article, issue, some facilities have created charts listing antidotes and that might create any potential conflict of interest. See the their location within that hospital, some facilities have created a Manuscript Submission Agreement in this issue for examples special area in the pharmacy specifically for the stocking of of specific conflicts covered by this statement. Complete antidotes, whereas other facilities have created a poisoning cart disclosures can be found in Appendix E1, available online at http://www.annemergmed.com. similar to a cardiac arrest cart.22 It is recommended that each facility ensure that the place and the amount of each antidote Publication dates: Received for publication July 4, 2008. stocked are known and accessible to appropriate hospital Revisions received September 2, 2008, and January 10, personnel within the period designated by the antidote expert 2009. Accepted for publication January 16, 2009. Available online May 5, 2009. panel. These recommendations are not intended to create a Presented at XXVIII International Congress of the European standard of care. The recommendations are specifically created Association of Poisons Centres and Clinical Toxicologists, May for consideration by hospitals in preparing for clinical demands 2008, Seville, Spain. in their facility. Furthermore, antidote use will change as Reprints not available from the authors. medical practice evolves and the characteristics of poisoning and Address for correspondence: Richard C. Dart, MD, PhD, 777 overdose change. In addition, each hospital is faced with unique Bannock Street, Mailcode 0180, Denver, CO 80204; E-mail: social, political, and geographic challenges that may alter the [email protected]. recommended amount of antidote to stock. The cost of a specific antidote is considered an important factor in hospital pharmacy purchasing decisions. Although the REFERENCES 1. Bronstein AC, Spyker DA, Cantilena LR, et al. 2006 Annual report purchase price of some antidotes can appear expensive, the of the American Association of Poison Control Centers’ National overall effect on the pharmacy expense budget is smaller than it Poison Data System (NPDS). Clin Toxicol. 2007;45:815-917. may appear because they are infrequently used and can at times 2. Howland MA, Weisman R, Sauter D, et al. Nonavailability of be returned on expiration if unopened.12 According to average poison antidotes. N Engl J Med. 1986;314:927-928. 3. Chyka PA, Conner HG. Availability of antidotes in rural and urban wholesale price, the maximum total cost of all antidotes hospitals in Tennessee. Am J Hosp Pharm. 1994;51:1346-1348. recommended by the panel to treat the minimum number of 4. Dart RC, Stark Y, Fulton B, et al. Insufficient stocking of poisoning patients would be approximately $70,000 to stock antidotes for antidotes in hospital emergency departments. JAMA. 1996;276: an 8-hour treatment period and $90,000 for a 24-hour period. 1508-1510. 5. Nogue S, Soy D, Munne P, et al. Antidotes: availability, use and The primary components of this cost are rattlesnake antivenom, cost in hospital and extra-hospital emergency services of digoxin Fab, and glucagon. Finally, many institutions actually Catalonia (Spain). Arch Toxicol. 1997;19:299-304. stock more of an antidote than is appropriate.11 Strategies to 6. Ong HC, Yang C-C, Deng J-F. Inadequate stocking of antidotes in minimize costs include reducing inappropriate use and wasteful Taiwan: is it a serious problem? Clin Toxicol. 2000;38:21-28. 7. Juurlink DN, McGuigan MA, Paton TW, et al. Availability of overstocking, regional stock rotation, and sharing multivial antidotes at acute care hospitals in Ontario. CMAJ. 2001;165: packs between facilities. 27-30. The stocking of antidotes has remained a persistent concern 8. Gorman SK, Zed PJ, Purssell RA, et al. Antidote stocking in British for at least 25 years. The use of the recommendations of the Columbia hospitals. CJEM. 2003;5:12-17. 9. Hruby K. Dostupnost antidote v nemocnicnich lekarnach ceske consensus panel, combined with a hospital antidote hazard republiky. Ces Slov Farm. 2003;52:231-240. vulnerability assessment, will allow a hospital to prepare 10. Dart RC, Goldfrank LR, Chyka PA, et al. Combined evidence-based appropriately for the treatment of poisoned patients. literature analysis and consensus guidelines for stocking of

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guide.medlive.cn Antidote Stocking Guidelines Dart et al

emergency antidotes in the United States. Ann Emerg Med. department with acetaminophen overdose. Ann Emerg Med. 2000;36:126-132. 2007;50:292-313. 11. Bailey B, Bussieres J-F, Dumont M. Availability of antidotes in 18. McDowell MA, Fryar CD, Hirsch R, et al. Anthropometric Quebec hospitals before and after dissemination of guidelines. Reference Data for Children and Adults: US Population, 1999- Am J Health Syst Pharm. 2003;60:2345-2349. 2002. Advance Data From Vital And Health Statistics; No. 361. 12. Sivilotti MLA, Eisen JS, Lee JS, et al. Can emergency Hyattsville, MD: National Center for Health Statistics; 2005. departments not afford to carry essential antidotes? CJEM. 2002; 19. Berberet BR, Burda BR, Lodolce AE. Unavailability of 10% alcohol 4:23-33. in 5% dextrose injection. Am J Health Syst Pharm. 2005;62: 13. Joint Commission on Accreditation of Healthcare Organizations. 2344-2345. Comprehensive Accreditation Manual for Hospitals. Oakbrook 20. Berndt E. Posted list of emergency drugs and antidotes. Am J Terrace, IL: Joint Commission on Accreditation of Healthcare Hosp Pharm. 1994;51:2602. Organizations; 2007:111. 21. Pettit HE, McKinney PE, Achusim LE, et al. Toxicology cart for 14. California Department of Public Health. Hospital administration stocking sufﬁcient supplies of poisoning antidotes. Am J Health penalties by county. Available at: http://www.cdph.ca.gov/certlic/ Syst Pharm. 1999;56:2537-2539. facilities/Documents/HospitalAdministrativePenalties-2567Forms- 22. Ontario Poison Centre guidelines for stocking of emergency LNC/2567OliveViewUCLAMedical-Sylmar-EventE-EW2J11.pdf. antidotes. Available at: http://www.ontariopoisoncentre.com/ Accessed May 22, 2008. ontariopoisoncentre/custom/antidotes2006.pdf. Accessed May 15. Flomenbaum NE, ed. Goldfrank’s Toxicological Emergencies. 8th 4, 2008. ed. New York, NY: McGraw-Hill; 2006. 23. The Joint Commission on Accreditation of Healthcare Organization. 16. Dart RC et al. Medical Toxicology. 3rd ed. Philadelphia, PA: 2009 Hospital Accreditation Standards. Oakbrook, IL: The Joint Lippincott Williams & Wilkins; 2004. Commission; 2008. Available at: http://www.jointcommission.org/ 17. Wolf SJ, Heard K, Sloan EP, et al. Clinical policy: critical issues in NR/rdonlyres/F42AF828-7248-48C0-B4E6-BA18E719A87C/0/06_ the management of patients presenting to the emergency hap_accred_stds.pdf. Accessed May 6, 2008.

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guide.medlive.cn Appendix E1. Disclosures. ceuticals) to the Denver Health and Hospital Authority. The Funding for this research was provided by 8 pharmaceutical com- sponsors had no input into the design, deﬁnitions, panel proceed- panies (Fougera, Dey, Protherics, Rare Disease Therapeutics, ings, analysis of the results, or drafting of the article. Heyl, Cumberland Pharmaceuticals, Heyltex, and Jazz Pharma- Dr. Heard received support from NIH Grant (1K08DA020573-01).

Financial Potential Antidote Panelist Organization Interests Clinical Grants Consulting Interests

Borron University of Texas Health None EMD Pharmaceuticals, Dey LP Merck KGA (Hydroxocobalamin) Hydroxocobalamin Sciences Center at San (Hydroxocobalamin) Antonio Caravati Utah Poison Control Center None None None None Cobaugh American Society of Health- None None None None System Pharmacists Research & Education Foundation Curry Banner Good Samaritan None None Fougera (CroFab Unrestricted Crotaline Immune Fab Medical Center Education Grant for Toxicology Fellowship, Lectures-No Honoraria) Dart Rocky Mountain Poison & None See Note Below See Note Below Not Applicable - Non-Voting Drug Center-Denver Health Chair of Panel Falk Orlando Regional Healthcare None None None None System Goldfrank New York University School None None None None of Medicine Gorman Centers for Disease Control None None None None & Prevention Groft Ofﬁce of Rare Disease at None None None None National institutes of Health Heard Rocky Mountain Poison & None Fougera (CroFab Registry), None NAC (IV), Crotaline Immune Drug Center-Denver Health Cumberland (NAC Registry), Fab, DigiFab, BWS AV RDT (BWS Investigator), Protherics (DigiFab Investigator) Miller Orange County Fire Authority/ None None None None Orange County Healthcare Agency Olson California Poison Control None None None None System O’Malley Albert Einstein Medical None None None None Center Schaeffer Rocky Mountain Poison & None RDT (BWS Co-Investigator), None BWS AV, DigiFab Drug Center-Denver Health Protherics (DigiFab Retro Study) Seger Tennessee Poison Center None None None None Seifert University of New Mexico/ None Protherics (Investigator CroFab), Poisindex Editorial Board Crotaline Immune Fab New Mexico Poison & Drug RDT (Investigator Anavip), Information Center HRSA (Strategic AV System Grant) Sivilotti Queen’s University None Cumberland (Unrestricted None NAC (IV) research grant) Tomassoni Yale New Haven Health None None None None Wise Joint Commission None None None None

Note: Denver Health’s Rocky Mountain Poison & Drug Center is a non-proﬁt governmental facility that provides poison & drug information, research and consulting services to various entities under contract. Clients of the Rocky Mountain Poison & Drug Center include a variety of governmental, nongovernmental and commercial organizations. In addition to the sponsors of the Antidote Summit, these include Eli Lilly, Abbott Laboratories, Wyeth Pharmaceuticals, Roche Pharmaceuticals, and others.

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