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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 Stephen W. Borron, MD, MS E. Martin Caravati, MD, MPH Daniel J. Cobaugh, PharmD Steven C. Curry, MD Jay L. Falk, MD Lewis Goldfrank, MD Susan E. Gorman, PharmD, MS Stephen Groft, PharmD Kennon Heard, MD Ken Miller, MD, PhD Kent R. Olson, MD Gerald O’Malley, DO Donna Seger, MD Steven A. Seifert, MD Marco L. A. Sivilotti, MSc, MD Tammi Schaeffer, DO Anthony J. Tomassoni, MD, MS Robert Wise, MD Gregory M. Bogdan, PhD Mohammed Alhelail, MD Jennie Buchanan, MD Jason Hoppe, DO Eric Lavonas, MD Sara Mlynarchek, MPH Dong-Haur Phua, MD Sean Rhyee, MD, MPH Shawn Varney, MD Amy Zosel, MD For the Antidote Summit Authorship Group
From the Rocky Mountain Poison & Drug Center - Denver Health, Denver, CO (Dart, Heard, Schaeffer, Bogdan, Alhelail, Buchanan, Hoppe, Lavonas, Mlynarchek, Phua, Rhyee, Varney, Zosel); Department of Surgery, University of Texas Health Sciences Center, San Antonio, TX (Borron); Division of Emergency Medicine, Utah Poison Control Center, University of Utah Health Sciences Center, Salt Lake City, UT (Caravati); ASHP Research and Education Foundation, Bethesda, MD (Cobaugh); Department of Medical Toxicology and Banner Poison Control Center, Banner Good Samaritan Medical Center, Phoenix, AZ (Curry); Department of Emergency Medicine, Orlando Regional Medical Center, University of Florida, Orlando, FL (Falk); New York City Poison Center; New York University School of Medicine, New York, NY (Goldfrank); Division of Strategic National Stockpile, Centers for Disease Control and Prevention, Atlanta, GA (Gorman); Office of Rare Diseases Research, Bethesda, MD (Groft); Division of Emergency Medicine, School of Medicine (Dart, Heard, Lavonas, Schaeffer) and Department of Pharmaceutical Sciences, School of Pharmacy (Bogdan), University of Colorado Denver, Aurora, CO; Orange County Fire Authority and Orange County Health Care Agency Emergency Medical Services, Irvine, CA, and National Association of EMS Physicians, Lenexa, KS, (Miller); University of California, San Francisco, and San Francisco Division, California Poison Control System, San Francisco, CA (Olson); Division of Research, Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, PA (O’Malley); Tennessee Poison Center, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Seger); University of New Mexico School of Medicine & Medical Director, New Mexico Poison and Drug Information Center, Albuquerque, NM (Seifert); Department of Emergency Medicine and Department of Pharmacology & Toxicology, Queen’s University, Ontario, Canada (Sivilotti); Yale University School of Medicine, Department of Surgery, Section of Emergency Medicine, and Yale-New Haven Center for Emergency Preparedness and Disaster Response, New Haven, CT (Tomassoni); Division of Standards and Survey Methods, The Joint Commission, Oakbrook Terrace, IL (Wise).
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.]
0196-0644/$-see front matter Copyright © 2009 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2009.01.023
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INTRODUCTION Antidotes are a critical component in the care of poisoned patients. Antidotes such as digoxin immune Fab can be lifesaving; however, an antidote must be available at the appropriate time to be effective. For some poisons, the antidote must be available immediately. The administration of cyanide antidote can resuscitate a patient only if the antidote is administered before irreversible injury develops. For other antidotes, there is time to procure the drug from the pharmacy or from another hospital. The use of a specific antidote was reported by US poison centers approximately 80,000 times in 2006.1 Unfortunately, important antidotes often are not stocked at all or are stocked in an insufficient amount. Insufficient stocking of a diverse group of antidotes has been documented repeatedly in many countries, including the United States and Canada.2-9 Although national recommendations of an expert panel were published in 2000, reports of inadequate stocking persist.10,11 The causes of this serious problem are unknown but are likely related in part to limited awareness, infrequent use, interruptions in supply, and allocation of limited hospital pharmacy resources. Previous studies have found that larger hospitals are more likely than smaller or rural hospitals to stock antidotes adequately.4,7 Perceived cost of antidotes based on purchase price, as well as pharmacist and physician unfamiliarity with poisons and their antidotes, may also contribute.4,12 Changes in the types of antidotes available may also play a role. In recent years, new antidotes have become available and others have been discontinued. The Joint Commission (TJC) sets standards for accreditation of hospitals in the United States but does not explicitly address antidote stocking. TJC standard MM.2.10 states simply that medications available for dispensing or administration be selected, listed, and procured according to criteria. Standard MM.2.30 states that emergency medications or supplies, if any, be consistently available, controlled, and secured.13 Individual state governments also regulate hospitals, although their attention in terms of antidotes has primarily been focused on mass casualty and terrorist events. However, California recently sanctioned a hospital for violating a regulation requiring “. . .availability of prescribed medications 24 hours a day.”14 In that case, digoxin Fab was not available immediately for a patient with cardiac glycoside toxicity. Although published documentation of insufficient antidote stocking is common, scholarly research and analysis of the phenomenon are almost nonexistent. Often, the efficacy of an antidote is well studied, but few studies address the number of patients or the period in which patients must be treated. Given the approval of new antidotes, the changes in availability of antidotes, a changing regulatory environment, and the continued lack of antidote stocking, the objective of this evidence-based consensus process was to develop recommendations for the stocking of antidotes at hospitals that provide emergency care. To produce useful and clinically Volume , . : September
Antidote Stocking Guidelines relevant guidelines despite an evidence base that is incomplete, we combined a structured analysis of the existing literature with an expert consensus panel.
MATERIALS AND METHODS Overview Recommendations for antidote stocking were created in 2 phases similar to the development of American College of Emergency Physicians (ACEP) clinical policies. First, standardized evidence-based summaries of the medical literature were generated for each antidote. Each summary was then independently reviewed and revised by a primary reviewer from the expert panel. The reviewer presented the summary and the recommendation to the full panel, and an iterative process was used to reach consensus. The panel was instructed to address specifically the needs of hospitals that provide emergency care in the United States. Stocking of antidotes for mass casualty events was not addressed by the panel. Details about administration of each antidote were not addressed by the panel. Phase 1 Relevant medical literature was obtained by nonmedical staff with extensive experience in searching and retrieving medical literature. Evidence-based summaries of the medical literature for each antidote were created by a group of emergency physicians and clinical toxicologists not involved in the consensus process. For each antidote, a standardized summary of 5 to 20 pages was created for subsequent assessment by the primary reviewer. Publications used to create the summary were identified with 3 methods: (1) searches for each antidote and its indications, using the National Library of Medicine’s PubMed database (http://www.pubmed.gov); limited to “human” and “English” for article types “clinical trials,” “reviews,” or “case reports”; (2) review of chapter bibliographies for each antidote in 2 textbooks of toxicology15,16; and (3) review of bibliographies of selected articles from the previous 2 methods for additional citations. Each article was classified according to its methodology, using the clinical guideline model of the ACEP (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) and then summarized with a standardized form.17 Phase 2 Each literature summary developed in phase 1 was provided to 1 expert panel member serving as the primary reviewer for that antidote. The expert panel was a diverse group of 19 professionals representing various perspectives (Table 1). The principal investigator served as the nonvoting chairperson and selected individuals for the panel according to evidence of Annals of Emergency Medicine 387
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Table 1. Profile of antidote panel members. Discipline or Specialty Clinical pharmacology Critical care medicine Clinical pharmacy Disaster preparedness/response Emergency medicine Emergency medical services Hospital pharmacy Internal medicine Clinical toxicology Pediatrics Poison center administration Public health Regulatory medicine or hospital accreditation
No. of Participants 3 3 2 6 11 4 1 2 15 2 9 1 4
Categories were self-selected by panel participants. Total is greater than 19 because of multiple designations of some individuals.
previous antidote research, professional experience with the acquisition and use of antidotes, or their potential role in the provision of antidotes (eg, TJC). This approach was necessary because there is no formal body or compendium that evaluates candidate antidotes or their appropriate stocking. The primary reviewers assessed and revised the literature summary produced in phase 1 for each assigned antidote, using their knowledge and experience. The primary reviewer could add articles to the summary. Each primary reviewer then formed a provisional recommendation about the antidote and presented the revised literature summary and the recommendation to the entire panel. The panel’s deliberations occurred on March 6 to 7, 2008. The evidence-based analysis was formulated to provide information to the panel about the fundamental questions involved in the selection of each antidote: 1. Is the antidote effective? 2. Do the medical benefits of its use outweigh its risks? If the consensus was affirmative for the first 2 questions, the panel addressed 3 additional questions: 3. Is time an important factor in its use? a. Does the antidote need to be available immediately on patient arrival in the emergency department (ED)? b. Does the antidote need to be available for administration 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 weighing 100 kg? An iterative process was used to reach consensus on stocking of each antidote. After presentation of an antidote by the primary reviewer and discussion by the entire panel, a vote was taken to determine consensus. An antidote was recommended for stocking if the panel consensus was affirmative for the first 2 questions. The additional questions were addressed to assist hospitals in determining where an antidote should be stocked and in what quantity. For all questions, consensus was defined as agreement of at least 75% of eligible panel members, provided there was no strong disagreement vote. Each member 388 Annals of Emergency Medicine
could vote in one of 3 ways: agreement, disagreement, or strong disagreement. If 1 or more panel members expressed strong disagreement, the discussion was continued and another vote taken. If agreement could not be reached, the decision was listed as “consensus not reached.” The panel’s estimate of the antidote amount needed per patient was based on clinical considerations: dose, duration of therapy (8 or 24 hours), use of extracorporeal elimination such as hemodialysis, and other factors. The panel chose to consider one 100-kg patient as the basis for calculating the amount of antidote to stock. This weight was chosen by using recent data from the National Health and Nutrition Examination Survey.18 This weight falls between the 75th and 85th percentile for men and approximates the 90th percentile for women. 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 purchasing agreements that allow them to purchase at a price below average wholesale price. When a partial unit would be needed to complete the dosing, the number of units (eg, vials) of the drug was rounded to the next full unit. For example, the calculation of acetylcysteine based on weight usually results in a partial vial; therefore, cost of purchasing was estimated by rounding up to the next full vial. Competing interests were managed proactively and transparently. Each panel member completed a competing interest form for each antidote, disclosing any financial interest or stock ownership or financial support (research grants, consulting agreements) from each antidote manufacturer or marketer for the preceding 10 years. Any relationship (ie, funding for a clinical trial, a single consultation with the company, or any level of equity holding in the company) was considered a competing interest. No participant reported equity holdings in a company. Six participants reported funding for clinical research and 6 reported previous consulting agreements with an antidote manufacturer. The panel was informed of all competing interests for each antidote as it was considered. Each panel member with a competing interest was allowed to participate in discussion but was excluded from voting on the antidote involved.
RESULTS There were 1,446 articles retrieved and reviewed; 583 articles were used to develop the literature summaries and provisional recommendations. Class I evidence was occasionally available, typically to show the efficacy of the drug. Class II evidence was more commonly available but again focused on efficacy. Class III evidence was plentiful but extremely variable. A few class III studies were rigorously performed medical record reviews, but most were case reports or chart reviews without an appropriate description of methods. Virtually no articles explicitly addressed the questions of the appropriate time for availability and number of patients a facility should be prepared to treat. Volume , . : September
Dart et al Overall, the panel recommended consideration of 24 antidotes for stocking in hospitals that accept emergency patients, counting only 1 antidote when alternatives were available (eg, fomepizole or ethanol for treatment of toxic alcohols). The panel recommended that 12 of these antidotes be immediately available for administration on patient arrival (Table 2). Antidotes for opioid, cardiac glycoside, cyanide poisoning, or other conditions may be lifesaving if administered before irreversible injury has occurred. In most hospitals, this period requires that the antidote be stocked in the ED. Another 9 antidotes were recommended for availability within 1 hour of the decision to use the antidote (Table 2), allowing the antidote 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 stocked, but they are not necessarily needed within 1 hour of ordering. Consensus was not reached for Prussian blue. Finally, 2 antidotes, both antitoxins for botulism, were not recommended for stocking. For some conditions, more than 1 antidote can effectively treat a poisoning or overdose. The panel identified 3 instances in which more than 1 effective antidote was available: ethanol or fomepizole for treatment of toxic alcohol exposure, antivenin Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) or antivenin (Crotalidae) polyvalent for treatment of crotaline snakebite, and the conventional cyanide antidote kit (sodium nitrite and sodium thiosulfate) or hydroxocobalamin for cyanide toxicity. In these cases, the panel designated a preferred agent, although either agent was recognized as acceptable in meeting the need for stocking. The preference was determined in the same manner as the decision to recommend stocking of an antidote: by group debate reaching consensus without a vote of strong disagreement. Fomepizole was preferred over ethanol for several reasons: simplicity of use, lack of need for compounding in pharmacy, reduction in medication errors, potential to avoid hemodialysis, and anticipated safety in children. The use of ethanol is further complicated by the lack of a commercially available 10% solution in the United States, requiring compounding of a 10% solution from a 95% solution of ethanol.19 Hydroxocobalamin was preferred over the conventional cyanide antidote kit because of its wider indications, ease of use, and anticipated safety in widespread use. FabAV was preferred over antivenin (Crotalidae) polyvalent because of improved safety profile and the fact that production of the Wyeth antivenom has been discontinued. Supplies of the Wyeth antivenom were available but difficult to obtain at the time of the panel’s assessment. The panel recommended the amount of antidote needed to treat a 100-kg patient for either 8 hours or 24 hours (Table 3). In most cases, the amount of antidote recommended for stocking did not match the package label precisely because of changes in clinical practice since the label content was approved by the Food and Drug Administration and because some Volume , . : September
Antidote Stocking Guidelines antidotes, such as octreotide and others, are not labeled for their use as an antidote. The panel observed that many considerations can affect the decision to stock an antidote, as well as the amount of an antidote that should be stocked. A rigid recommendation for all hospitals is difficult to justify and may lead to insufficient stocking. For example, a hospital in an area endemic for crotaline snakes (rattlesnakes, copperhead snakes, water moccasins) should stock antivenom, but the amount recommended for 1 patient may be insufficient if 2 bites could require treatment simultaneously. To address these situations, the panel recommended that hospitals perform a hazard vulnerability assessment for each antidote (Tables 3, 4).
LIMITATIONS Little class 1 and 2 evidence was available for most antidotes; therefore, many of the panel’s recommendations are based on expert analysis and experience. The process attempted to compensate for individual bias by using a large diversified panel, by presenting structured summaries of medical information, and by prohibiting voting by members with a competing interest. This approach helped to constrain undocumented or unsubstantiated opinion of panel members in 2 ways. First, the published medical evidence was reviewed and this supported the expectation that the reviewer’s conclusions would be evidence based within the limits of available information. Second, the other panel members (who reviewed the evidence simultaneously) acted as a counterbalance against unsubstantiated individual positions of the reviewer. The panel was chosen by the nonvoting chairman according to documented clinical and research expertise, which may have resulted in an unintended bias toward academia. This possibility was counterbalanced by the voting rules that allowed a single objection to reject a recommendation. Several exotic antidotes and antidotes not readily available in North America were not considered. The panel was also asked not to anticipate singular and rare events, such as terrorist acts or mass casualty incidents. It was not possible to assess the full cost-benefit relationship because information about the value of benefit is not available. The intended audience of the recommendations was an individual hospital providing emergency care, rather than larger regions, states, or national organizations, given the different needs and resources of such entities.
DISCUSSION The antidote expert panel recommended consideration of 24 antidotes for emergency stocking by facilities that provide emergency care. The recommendations are intended to be interpreted in the context of the potential clinical uses created by the catchment area served by a hospital; special needs for mass casualty events are not addressed in these recommendations. Insufficient stocking of antidotes needed on an emergency basis has been documented repeatedly in the United States and other Annals of Emergency Medicine 389
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Table 2. Antidote recommendations for stocking at facilities that accept emergency patients. Recommendation
Antidote
Poisoning Indication(s)
Should Be Stocked
Available Within 60 Minutes
Immediately Available*
Class of † Evidence
Acetylcysteine
Acetaminophen
Yes
Yes
No
Antivenin (Crotalidae) polyvalent, Wyeth, OR Crotalidae Polyvalent Immune ‡ Fab, ovine Antivenin (Latrodectus mactans) Antivenin (Micrurus fulvius)
North American crotaline snake envenomation North American crotaline snake envenomation Black widow spider envenomation Eastern and Texas coral snake envenomation Organophosphorus and N-methyl carbamate insecticides Botulism Infant botulism
Yes
Yes
No
I (IV) II (oral) III
Yes
Yes
No
II
Yes Yes
No Yes
No No
III III
Yes
Yes
Yes
III
No No
NA NA
NA NA
III I
Fluoride, calcium channel blocking agent
Yes
Yes
Yes
III
Yes Yes Yes
Yes No No
Yes No No
III II III
Yes Yes Yes Yes
Yes Yes Yes Yes
Yes Yes No Yes
III II II II
Yes
Yes
No
II
Yes
Yes
No
III
Yes
Yes
No
II
Yes Yes
Yes Yes
Yes Yes
III III
Yes Yes Yes
Yes Yes Yes
Yes Yes No
II I II
Yes Yes Yes
Yes Yes Yes
Yes No NC
II III II
Yes
Yes
Yes
III
NC Yes
NC Yes
NC Yes
II II
Atropine sulfate Botulism antitoxin, equine (A, B) Botulism immune globulin (BabyBIG) § Calcium chloride §
Calcium gluconate Calcium disodium EDTA Calcium trisodium pentetate (Calcium DTPA) Cyanide Antidote Kit OR ‡ Hydroxocobalamin hydrochloride Deferoxamine mesylate Digoxin Immune Fab Dimercaprol §
Ethanol OR ‡
Fomepizole
Flumazenil § Glucagon hydrochloride Methylene blue Naloxone hydrochloride § Octreotide acetate Physostigmine salicylate Potassium iodide Pralidoxime chloride Pyridoxine hydrochloride Prussian blue § Sodium bicarbonate
Lead Internal contamination with plutonium, americium, or curium Cyanide poisoning Cyanide poisoning Acute iron poisoning Cardiac glycosides/steroid toxicity Heavy metal toxicity (arsenic, mercury, lead) Methanol, or ethylene glycol poisoning Methanol, or ethylene glycol poisoning Benzodiazepine toxicity -Blocker, calcium channel blocker Methemoglobinemia Opioid and opiate drugs Sulfonylurea-induced hypoglycemia Anticholinergic syndrome Thyroid radioiodine protection Organophosphorus insecticide poisoning Isoniazid, hydrazine and derivatives Thallium/radiocesium Sodium channel blocking drugs, 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 welldesigned 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 Antidote
8 h*
Acetylcysteine
28 g
Antivenin (Crotalidae) polyvalent
24 h*
Drug AWP for 8 Hours, $
56 g
IV: 800.30 PO: 214.20 30 Vials 30 Vials 36,705
Crotalidae Polyvalent Immune Fab, ovine
12 Vials 18 Vials 18,858
Antivenin (Latrodectus mactans) Antivenin (Micrurus fulvius)
1 Vial
1 Vial
5 Vials
10 Vials 8,568.00
Atropine sulfate Botulism antitoxin, equine (A, B) Botulism immune globulin (BabyBIG) Calcium chloride
45 mg NA
165 mg 140.62 NA NA
NA
NA
NA
10 g
10 g
15.00
Calcium gluconate
30 g
30 g
26.70
Calcium disodium EDTA 0.75 g Calcium DTPA 1g Cyanide antidote kit 1 kit
2.25 g 1g 1 kit
58.03 70.00 274.56
Hydroxocobalamin hydrochloride
10 g
10 g
812.50
Deferoxamine mesylate Digoxin Immune Fab Dimercaprol Ethanol
12 g 15 Vials 500 mg 180 g
36 g 15 Vials 1.5 g 360 g
417.18 600.00 197.74 76.56
Fomepizole
1.5 g
4.5 g
1,364.85
Flumazenil
6 mg
12 mg
41.26
Glucagon hydrochloride Methylene blue Naloxone hydrochloride Octreotide acetate Physostigmine salicylate Potassium iodide Pralidoxime chloride Pyridoxine hydrochloride Prussian blue Sodium bicarbonate
90 mg 400 mg 20 mg 75 g 4 mg 130 mg 7g 8g NA 63 g
250 mg 600 mg 40 mg 225 g 4 mg 130 mg 18 g 24 g NA 84 g
7,875.00 40.72 131.50 24.08 9.72 12.10 758.66 899.20 NA 13.95
31.10
Notes and Considerations for Hazard Vulnerability Assessment (HVA) Note: This recommendation applies to stocking of either oral or intravenous products Note: Administer intravenously for hepatic failure Note: Product has been discontinued by manufacturer; some supplies remain HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) Note: Less common acute and delayed antivenom reactions, faster mixing, use in equine serum hypersensitivity HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) HVA: Geographic/endemic areas (Table 4) Note: Product has been discontinued by manufacturer; some supplies remaining. Antivenoms from Mexico or Costa Rica are likely effective. Contact regional poison center to locate antivenom sources. HVA: Geographic/endemic areas (Table 4) Note: Contact your state health department to assist with procurement from the Centers for Disease Control and Prevention Information from Infant Botulism Treatment and Prevention Program, Telephone: 510231-7600, http://www.infantbotulism.org/physician/obtain.php Note: do not administer subcutaneously. Should be administered by central venous IV route, if possible Note: May be given by IV, SQ routes Both calcium gluconate and calcium chloride should be available HVA: receiving hospital for research laboratory (Table 4) 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 Note: Can be used safely in patients with smoke inhalation. Red color of drug causes laboratory test interference, red discoloration of skin and urine HVA: Industry, history, local conditions, community planning, facility service area (Table 4)
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 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 Note: Primary use is for iatrogenic oversedation. Risks may outweigh benefits in patients with mixed/unknown overdose, chronic benzodiazepine use, seizure disorders, head injury
HVA: Industry, history, endemic conditions, community planning, facility service area (Table 4)
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 represent 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 used as therapeutic agents
Agents that are widely available should generally have the antidote stocked because important geographic differences are not anticipated
Characteristics of hospital catchment area
Industries, practices, activities, and indigenous fauna indicate potential need for antidote
Referral patterns
Many hospitals accept referrals from remote areas. These should be included in risk assessment Some modes of suicide or abuse become locally prevalent without a specific industry being present Depending on characteristics of area, more than 1 victim of a poisoning may be anticipated
Acetaminophen Anticholinergic agents Benzodiazepines Dapsone Digoxin Iron Isoniazid Lidocaine Opioid analgesics Sulfonylurea hypoglycemic agents Industries generating or using cyanide, heavy metals, hydrogen fluoride, organophosphorus chemicals, radionuclides, thallium Chemical transportation routes Indigenous fauna and flora (snakes, spiders, plants) Agricultural practices (organophosphate insecticides, cyanide baits, mining) Transfers to urban hospital from agricultural areas Referral from mining region
History or experience of use Anticipated volume of use
Anticipated time to restocking or resupply of antidote
Time to restocking varies greatly among hospitals
countries.2-9 However, it is difficult for hospitals to address this situation because widely accepted guidelines for antidote stocking have not emerged, although certain regional guidelines have been promulgated.11,20-22 National guidelines are difficult to produce because of the heterogeneity of hospital organization and management, as well as the diversity of service area. The expert panel therefore concluded that a mechanism allowing customization of stocking for each hospital should be used. To allow customized application of these guidelines, the panel developed the concept of an antidote hazard vulnerability assessment, an adaptation of the Hazard Vulnerability Assessment required in the United States for accreditation of hospitals by TJC. As defined by TJC, a Hazard Vulnerability Assessment is the identification of potential emergencies and the direct and indirect effects these emergencies may have on the hospital’s operations and the demand for its services.23 This process is already required of hospitals that are accredited by TJC and provides a useful framework to assess contingencies presented by poisoned patients. All hospitals should perform an antidote hazard vulnerability analysis. Myriad variables such as size, administrative structure, specialty, and local characteristics may affect institutional antidote needs. The hazard analysis 392 Annals of Emergency Medicine
Popularity of cyanide or other specific agents as a suicide agent Amateur snake keepers in area Residential or commercial fires (older buildings, lack of fire alarms, etc) Multiple casualty incidents (eg, smoke inhalation involving treatment with cyanide antidotes) Indigenous crotaline snakebite in areas with frequent occurrences such as the southeastern or southwestern United States Hospitals that stabilize and refer patients to other institutions should stock for the anticipated period 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
approach holds promise in facilitating the appropriate assessment of antidote stocking needs. The hazard assessment concept requires a hospital to formally analyze the need for an antidote and the amount of each antidote needed for their facility. Prioritization of risks is based on available objective data (hospital services and utilization, demographic information, local industrial uses, availability of antidote at neighboring facilities, and chemical transportation routes, among other factors) that require interaction with appropriate businesses and manufacturers, as well as local, state, and federal agencies. Table 4 provides potential variables that should be considered in this hazard assessment. A hospital should use the hazard assessment process to determine the treatment period for which antidote stocking should occur. Some hospitals may exist in an environment making stabilization and referral of a patient simple and rapid. Other hospitals may be subject to serious transportation difficulties and extreme weather conditions. The process of hazard assessment should include all stakeholders: for example, pharmacy, emergency medicine, clinical toxicology, ICU, risk management, nursing, pharmacy and therapeutic committee, hospital preparedness committee, and hospital administration. Volume , . : September
Dart et al The regional poison center is an important resource to include in the assessment process. Some hospitals may forgo stocking of some antidotes, optimistically concluding that antidotes can be obtained quickly from neighboring facilities in case of urgent need. However, the experience of the expert panel indicates that delays are often encountered during the transfer of antidotes from one hospital to another, even between neighboring hospitals or hospitals under the same management, thereby compromising patient care. Delays can arise from the lack of a dedicated system to facilitate transfer, the infrequent and unplanned nature of these requests, and difficulties prioritizing the delivery of a medication to another facility over urgent internal hospital orders. Infrequently used antidotes may be difficult to find during an emergency, even within the same facility.22 To address this issue, some facilities have created charts listing antidotes and their location within that hospital, some facilities have created a special area in the pharmacy specifically for the stocking of antidotes, whereas other facilities have created a poisoning cart similar to a cardiac arrest cart.22 It is recommended that each facility ensure that the place and the amount of each antidote stocked are known and accessible to appropriate hospital personnel within the period designated by the antidote expert panel. These recommendations are not intended to create a standard of care. The recommendations are specifically created for consideration by hospitals in preparing for clinical demands in their facility. Furthermore, antidote use will change as medical practice evolves and the characteristics of poisoning and overdose change. In addition, each hospital is faced with unique social, political, and geographic challenges that may alter the recommended amount of antidote to stock. The cost of a specific antidote is considered an important factor in hospital pharmacy purchasing decisions. Although the purchase price of some antidotes can appear expensive, the overall effect on the pharmacy expense budget is smaller than it may appear because they are infrequently used and can at times be returned on expiration if unopened.12 According to average wholesale price, the maximum total cost of all antidotes recommended by the panel to treat the minimum number of patients would be approximately $70,000 to stock antidotes for an 8-hour treatment period and $90,000 for a 24-hour period. The primary components of this cost are rattlesnake antivenom, digoxin Fab, and glucagon. Finally, many institutions actually stock more of an antidote than is appropriate.11 Strategies to minimize costs include reducing inappropriate use and wasteful overstocking, regional stock rotation, and sharing multivial packs between facilities. The stocking of antidotes has remained a persistent concern for at least 25 years. The use of the recommendations of the consensus panel, combined with a hospital antidote hazard vulnerability assessment, will allow a hospital to prepare appropriately for the treatment of poisoned patients. Volume , . : September
Antidote Stocking Guidelines Supervising editors: Lewis S. Nelson, MD; Michael L. Callaham, MD Dr. Nelson and Dr. Callaham were the supervising editors on this article. Dr. Dart did not participate in the editorial review or decision to publish this article. Panel decisions: Panelists without a conflict of interest were eligible to vote on any issue. Panelists with conflicts were prohibited from voting on the drugs involved in the competing interest. The chair was nonvoting and disclosed that Denver Health’s Rocky Mountain Poison and Drug Center is a nonprofit governmental facility that provides poison and drug information, and research and consulting services to various entities under contract. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Complete disclosures can be found in Appendix E1, available online at http://www.annemergmed.com. Publication dates: Received for publication July 4, 2008. Revisions received September 2, 2008, and January 10, 2009. Accepted for publication January 16, 2009. Available online May 5, 2009. Presented at XXVIII International Congress of the European Association of Poisons Centres and Clinical Toxicologists, May 2008, Seville, Spain. Reprints not available from the authors. Address for correspondence: Richard C. Dart, MD, PhD, 777 Bannock Street, Mailcode 0180, Denver, CO 80204; E-mail: [email protected].
REFERENCES 1. Bronstein AC, Spyker DA, Cantilena LR, et al. 2006 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol. 2007;45:815-917. 2. Howland MA, Weisman R, Sauter D, et al. Nonavailability of poison antidotes. N Engl J Med. 1986;314:927-928. 3. Chyka PA, Conner HG. Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp Pharm. 1994;51:1346-1348. 4. Dart RC, Stark Y, Fulton B, et al. Insufficient stocking of poisoning antidotes in hospital emergency departments. JAMA. 1996;276: 1508-1510. 5. Nogue S, Soy D, Munne P, et al. Antidotes: availability, use and cost in hospital and extra-hospital emergency services of Catalonia (Spain). Arch Toxicol. 1997;19:299-304. 6. Ong HC, Yang C-C, Deng J-F. Inadequate stocking of antidotes in Taiwan: is it a serious problem? Clin Toxicol. 2000;38:21-28. 7. Juurlink DN, McGuigan MA, Paton TW, et al. Availability of antidotes at acute care hospitals in Ontario. CMAJ. 2001;165: 27-30. 8. Gorman SK, Zed PJ, Purssell RA, et al. Antidote stocking in British Columbia hospitals. CJEM. 2003;5:12-17. 9. Hruby K. Dostupnost antidote v nemocnicnich lekarnach ceske republiky. Ces Slov Farm. 2003;52:231-240. 10. Dart RC, Goldfrank LR, Chyka PA, et al. Combined evidence-based literature analysis and consensus guidelines for stocking of
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11.
12.
13.
14.
15. 16. 17.
emergency antidotes in the United States. Ann Emerg Med. 2000;36:126-132. Bailey B, Bussieres J-F, Dumont M. Availability of antidotes in Quebec hospitals before and after dissemination of guidelines. Am J Health Syst Pharm. 2003;60:2345-2349. Sivilotti MLA, Eisen JS, Lee JS, et al. Can emergency departments not afford to carry essential antidotes? CJEM. 2002; 4:23-33. Joint Commission on Accreditation of Healthcare Organizations. Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2007:111. California Department of Public Health. Hospital administration penalties by county. Available at: http://www.cdph.ca.gov/certlic/ facilities/Documents/HospitalAdministrativePenalties-2567FormsLNC/2567OliveViewUCLAMedical-Sylmar-EventE-EW2J11.pdf. Accessed May 22, 2008. Flomenbaum NE, ed. Goldfrank’s Toxicological Emergencies. 8th ed. New York, NY: McGraw-Hill; 2006. Dart RC et al. Medical Toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. Wolf SJ, Heard K, Sloan EP, et al. Clinical policy: critical issues in the management of patients presenting to the emergency
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18.
19.
20. 21.
22.
23.
department with acetaminophen overdose. Ann Emerg Med. 2007;50:292-313. McDowell MA, Fryar CD, Hirsch R, et al. Anthropometric Reference Data for Children and Adults: US Population, 19992002. Advance Data From Vital And Health Statistics; No. 361. Hyattsville, MD: National Center for Health Statistics; 2005. Berberet BR, Burda BR, Lodolce AE. Unavailability of 10% alcohol in 5% dextrose injection. Am J Health Syst Pharm. 2005;62: 2344-2345. Berndt E. Posted list of emergency drugs and antidotes. Am J Hosp Pharm. 1994;51:2602. Pettit HE, McKinney PE, Achusim LE, et al. Toxicology cart for stocking sufficient supplies of poisoning antidotes. Am J Health Syst Pharm. 1999;56:2537-2539. Ontario Poison Centre guidelines for stocking of emergency antidotes. Available at: http://www.ontariopoisoncentre.com/ ontariopoisoncentre/custom/antidotes2006.pdf. Accessed May 4, 2008. The Joint Commission on Accreditation of Healthcare Organization. 2009 Hospital Accreditation Standards. Oakbrook, IL: The Joint Commission; 2008. Available at: http://www.jointcommission.org/ NR/rdonlyres/F42AF828-7248-48C0-B4E6-BA18E719A87C/0/06_ hap_accred_stds.pdf. Accessed May 6, 2008.
Volume , . : September
Appendix E1. Disclosures. Funding for this research was provided by 8 pharmaceutical companies (Fougera, Dey, Protherics, Rare Disease Therapeutics, Heyl, Cumberland Pharmaceuticals, Heyltex, and Jazz Pharma-
Panelist Borron
Organization
Financial Interests
ceuticals) to the Denver Health and Hospital Authority. The sponsors had no input into the design, definitions, panel proceedings, analysis of the results, or drafting of the article. Dr. Heard received support from NIH Grant (1K08DA020573-01).
Clinical Grants
Consulting
Potential Antidote Interests
University of Texas Health Sciences Center at San Antonio Utah Poison Control Center American Society of HealthSystem Pharmacists Research & Education Foundation Banner Good Samaritan Medical Center
None
EMD Pharmaceuticals, Dey LP (Hydroxocobalamin)
Merck KGA (Hydroxocobalamin)
Hydroxocobalamin
None None
None None
None None
None None
None
None
Crotaline Immune Fab
Rocky Mountain Poison & Drug Center-Denver Health Orlando Regional Healthcare System New York University School of Medicine Centers for Disease Control & Prevention Office of Rare Disease at National institutes of Health Rocky Mountain Poison & Drug Center-Denver Health
None
See Note Below
Fougera (CroFab Unrestricted Education Grant for Toxicology Fellowship, Lectures-No Honoraria) See Note Below
None
None
None
Not Applicable - Non-Voting Chair of Panel None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
NAC (IV), Crotaline Immune Fab, DigiFab, BWS AV
Orange County Fire Authority/ Orange County Healthcare Agency California Poison Control System Albert Einstein Medical Center Rocky Mountain Poison & Drug Center-Denver Health
None
Fougera (CroFab Registry), Cumberland (NAC Registry), RDT (BWS Investigator), Protherics (DigiFab Investigator) None
None
None
None
None
None
None
None
None
None
None
None
None
BWS AV, DigiFab
Seger Seifert
Tennessee Poison Center University of New Mexico/ New Mexico Poison & Drug Information Center
None None
None Poisindex Editorial Board
None Crotaline Immune Fab
Sivilotti
Queen’s University
None
None
NAC (IV)
Tomassoni Wise
Yale New Haven Health Joint Commission
None None
RDT (BWS Co-Investigator), Protherics (DigiFab Retro Study) None Protherics (Investigator CroFab), RDT (Investigator Anavip), HRSA (Strategic AV System Grant) Cumberland (Unrestricted research grant) None None
None None
None None
Caravati Cobaugh
Curry
Dart Falk Goldfrank Gorman Groft
Heard
Miller
Olson O’Malley Schaeffer
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.
Volume , . : September
Annals of Emergency Medicine 394.e1
Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care Richard C. Dart, MD, PhD Stephen W. Borron, MD, MS E. Martin Caravati, MD, MPH Daniel J. Cobaugh, PharmD Steven C. Curry, MD Jay L. Falk, MD Lewis Goldfrank, MD Susan E. Gorman, PharmD, MS Stephen Groft, PharmD Kennon Heard, MD Ken Miller, MD, PhD Kent R. Olson, MD Gerald O’Malley, DO Donna Seger, MD Steven A. Seifert, MD Marco L. A. Sivilotti, MSc, MD Tammi Schaeffer, DO Anthony J. Tomassoni, MD, MS Robert Wise, MD Gregory M. Bogdan, PhD Mohammed Alhelail, MD Jennie Buchanan, MD Jason Hoppe, DO Eric Lavonas, MD Sara Mlynarchek, MPH Dong-Haur Phua, MD Sean Rhyee, MD, MPH Shawn Varney, MD Amy Zosel, MD For the Antidote Summit Authorship Group
From the Rocky Mountain Poison & Drug Center - Denver Health, Denver, CO (Dart, Heard, Schaeffer, Bogdan, Alhelail, Buchanan, Hoppe, Lavonas, Mlynarchek, Phua, Rhyee, Varney, Zosel); Department of Surgery, University of Texas Health Sciences Center, San Antonio, TX (Borron); Division of Emergency Medicine, Utah Poison Control Center, University of Utah Health Sciences Center, Salt Lake City, UT (Caravati); ASHP Research and Education Foundation, Bethesda, MD (Cobaugh); Department of Medical Toxicology and Banner Poison Control Center, Banner Good Samaritan Medical Center, Phoenix, AZ (Curry); Department of Emergency Medicine, Orlando Regional Medical Center, University of Florida, Orlando, FL (Falk); New York City Poison Center; New York University School of Medicine, New York, NY (Goldfrank); Division of Strategic National Stockpile, Centers for Disease Control and Prevention, Atlanta, GA (Gorman); Office of Rare Diseases Research, Bethesda, MD (Groft); Division of Emergency Medicine, School of Medicine (Dart, Heard, Lavonas, Schaeffer) and Department of Pharmaceutical Sciences, School of Pharmacy (Bogdan), University of Colorado Denver, Aurora, CO; Orange County Fire Authority and Orange County Health Care Agency Emergency Medical Services, Irvine, CA, and National Association of EMS Physicians, Lenexa, KS, (Miller); University of California, San Francisco, and San Francisco Division, California Poison Control System, San Francisco, CA (Olson); Division of Research, Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, PA (O’Malley); Tennessee Poison Center, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Seger); University of New Mexico School of Medicine & Medical Director, New Mexico Poison and Drug Information Center, Albuquerque, NM (Seifert); Department of Emergency Medicine and Department of Pharmacology & Toxicology, Queen’s University, Ontario, Canada (Sivilotti); Yale University School of Medicine, Department of Surgery, Section of Emergency Medicine, and Yale-New Haven Center for Emergency Preparedness and Disaster Response, New Haven, CT (Tomassoni); Division of Standards and Survey Methods, The Joint Commission, Oakbrook Terrace, IL (Wise).
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.]
0196-0644/$-see front matter Copyright © 2009 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2009.01.023
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INTRODUCTION Antidotes are a critical component in the care of poisoned patients. Antidotes such as digoxin immune Fab can be lifesaving; however, an antidote must be available at the appropriate time to be effective. For some poisons, the antidote must be available immediately. The administration of cyanide antidote can resuscitate a patient only if the antidote is administered before irreversible injury develops. For other antidotes, there is time to procure the drug from the pharmacy or from another hospital. The use of a specific antidote was reported by US poison centers approximately 80,000 times in 2006.1 Unfortunately, important antidotes often are not stocked at all or are stocked in an insufficient amount. Insufficient stocking of a diverse group of antidotes has been documented repeatedly in many countries, including the United States and Canada.2-9 Although national recommendations of an expert panel were published in 2000, reports of inadequate stocking persist.10,11 The causes of this serious problem are unknown but are likely related in part to limited awareness, infrequent use, interruptions in supply, and allocation of limited hospital pharmacy resources. Previous studies have found that larger hospitals are more likely than smaller or rural hospitals to stock antidotes adequately.4,7 Perceived cost of antidotes based on purchase price, as well as pharmacist and physician unfamiliarity with poisons and their antidotes, may also contribute.4,12 Changes in the types of antidotes available may also play a role. In recent years, new antidotes have become available and others have been discontinued. The Joint Commission (TJC) sets standards for accreditation of hospitals in the United States but does not explicitly address antidote stocking. TJC standard MM.2.10 states simply that medications available for dispensing or administration be selected, listed, and procured according to criteria. Standard MM.2.30 states that emergency medications or supplies, if any, be consistently available, controlled, and secured.13 Individual state governments also regulate hospitals, although their attention in terms of antidotes has primarily been focused on mass casualty and terrorist events. However, California recently sanctioned a hospital for violating a regulation requiring “. . .availability of prescribed medications 24 hours a day.”14 In that case, digoxin Fab was not available immediately for a patient with cardiac glycoside toxicity. Although published documentation of insufficient antidote stocking is common, scholarly research and analysis of the phenomenon are almost nonexistent. Often, the efficacy of an antidote is well studied, but few studies address the number of patients or the period in which patients must be treated. Given the approval of new antidotes, the changes in availability of antidotes, a changing regulatory environment, and the continued lack of antidote stocking, the objective of this evidence-based consensus process was to develop recommendations for the stocking of antidotes at hospitals that provide emergency care. To produce useful and clinically Volume , . : September
Antidote Stocking Guidelines relevant guidelines despite an evidence base that is incomplete, we combined a structured analysis of the existing literature with an expert consensus panel.
MATERIALS AND METHODS Overview Recommendations for antidote stocking were created in 2 phases similar to the development of American College of Emergency Physicians (ACEP) clinical policies. First, standardized evidence-based summaries of the medical literature were generated for each antidote. Each summary was then independently reviewed and revised by a primary reviewer from the expert panel. The reviewer presented the summary and the recommendation to the full panel, and an iterative process was used to reach consensus. The panel was instructed to address specifically the needs of hospitals that provide emergency care in the United States. Stocking of antidotes for mass casualty events was not addressed by the panel. Details about administration of each antidote were not addressed by the panel. Phase 1 Relevant medical literature was obtained by nonmedical staff with extensive experience in searching and retrieving medical literature. Evidence-based summaries of the medical literature for each antidote were created by a group of emergency physicians and clinical toxicologists not involved in the consensus process. For each antidote, a standardized summary of 5 to 20 pages was created for subsequent assessment by the primary reviewer. Publications used to create the summary were identified with 3 methods: (1) searches for each antidote and its indications, using the National Library of Medicine’s PubMed database (http://www.pubmed.gov); limited to “human” and “English” for article types “clinical trials,” “reviews,” or “case reports”; (2) review of chapter bibliographies for each antidote in 2 textbooks of toxicology15,16; and (3) review of bibliographies of selected articles from the previous 2 methods for additional citations. Each article was classified according to its methodology, using the clinical guideline model of the ACEP (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) and then summarized with a standardized form.17 Phase 2 Each literature summary developed in phase 1 was provided to 1 expert panel member serving as the primary reviewer for that antidote. The expert panel was a diverse group of 19 professionals representing various perspectives (Table 1). The principal investigator served as the nonvoting chairperson and selected individuals for the panel according to evidence of Annals of Emergency Medicine 387
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Table 1. Profile of antidote panel members. Discipline or Specialty Clinical pharmacology Critical care medicine Clinical pharmacy Disaster preparedness/response Emergency medicine Emergency medical services Hospital pharmacy Internal medicine Clinical toxicology Pediatrics Poison center administration Public health Regulatory medicine or hospital accreditation
No. of Participants 3 3 2 6 11 4 1 2 15 2 9 1 4
Categories were self-selected by panel participants. Total is greater than 19 because of multiple designations of some individuals.
previous antidote research, professional experience with the acquisition and use of antidotes, or their potential role in the provision of antidotes (eg, TJC). This approach was necessary because there is no formal body or compendium that evaluates candidate antidotes or their appropriate stocking. The primary reviewers assessed and revised the literature summary produced in phase 1 for each assigned antidote, using their knowledge and experience. The primary reviewer could add articles to the summary. Each primary reviewer then formed a provisional recommendation about the antidote and presented the revised literature summary and the recommendation to the entire panel. The panel’s deliberations occurred on March 6 to 7, 2008. The evidence-based analysis was formulated to provide information to the panel about the fundamental questions involved in the selection of each antidote: 1. Is the antidote effective? 2. Do the medical benefits of its use outweigh its risks? If the consensus was affirmative for the first 2 questions, the panel addressed 3 additional questions: 3. Is time an important factor in its use? a. Does the antidote need to be available immediately on patient arrival in the emergency department (ED)? b. Does the antidote need to be available for administration 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 weighing 100 kg? An iterative process was used to reach consensus on stocking of each antidote. After presentation of an antidote by the primary reviewer and discussion by the entire panel, a vote was taken to determine consensus. An antidote was recommended for stocking if the panel consensus was affirmative for the first 2 questions. The additional questions were addressed to assist hospitals in determining where an antidote should be stocked and in what quantity. For all questions, consensus was defined as agreement of at least 75% of eligible panel members, provided there was no strong disagreement vote. Each member 388 Annals of Emergency Medicine
could vote in one of 3 ways: agreement, disagreement, or strong disagreement. If 1 or more panel members expressed strong disagreement, the discussion was continued and another vote taken. If agreement could not be reached, the decision was listed as “consensus not reached.” The panel’s estimate of the antidote amount needed per patient was based on clinical considerations: dose, duration of therapy (8 or 24 hours), use of extracorporeal elimination such as hemodialysis, and other factors. The panel chose to consider one 100-kg patient as the basis for calculating the amount of antidote to stock. This weight was chosen by using recent data from the National Health and Nutrition Examination Survey.18 This weight falls between the 75th and 85th percentile for men and approximates the 90th percentile for women. 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 purchasing agreements that allow them to purchase at a price below average wholesale price. When a partial unit would be needed to complete the dosing, the number of units (eg, vials) of the drug was rounded to the next full unit. For example, the calculation of acetylcysteine based on weight usually results in a partial vial; therefore, cost of purchasing was estimated by rounding up to the next full vial. Competing interests were managed proactively and transparently. Each panel member completed a competing interest form for each antidote, disclosing any financial interest or stock ownership or financial support (research grants, consulting agreements) from each antidote manufacturer or marketer for the preceding 10 years. Any relationship (ie, funding for a clinical trial, a single consultation with the company, or any level of equity holding in the company) was considered a competing interest. No participant reported equity holdings in a company. Six participants reported funding for clinical research and 6 reported previous consulting agreements with an antidote manufacturer. The panel was informed of all competing interests for each antidote as it was considered. Each panel member with a competing interest was allowed to participate in discussion but was excluded from voting on the antidote involved.
RESULTS There were 1,446 articles retrieved and reviewed; 583 articles were used to develop the literature summaries and provisional recommendations. Class I evidence was occasionally available, typically to show the efficacy of the drug. Class II evidence was more commonly available but again focused on efficacy. Class III evidence was plentiful but extremely variable. A few class III studies were rigorously performed medical record reviews, but most were case reports or chart reviews without an appropriate description of methods. Virtually no articles explicitly addressed the questions of the appropriate time for availability and number of patients a facility should be prepared to treat. Volume , . : September
Dart et al Overall, the panel recommended consideration of 24 antidotes for stocking in hospitals that accept emergency patients, counting only 1 antidote when alternatives were available (eg, fomepizole or ethanol for treatment of toxic alcohols). The panel recommended that 12 of these antidotes be immediately available for administration on patient arrival (Table 2). Antidotes for opioid, cardiac glycoside, cyanide poisoning, or other conditions may be lifesaving if administered before irreversible injury has occurred. In most hospitals, this period requires that the antidote be stocked in the ED. Another 9 antidotes were recommended for availability within 1 hour of the decision to use the antidote (Table 2), allowing the antidote 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 stocked, but they are not necessarily needed within 1 hour of ordering. Consensus was not reached for Prussian blue. Finally, 2 antidotes, both antitoxins for botulism, were not recommended for stocking. For some conditions, more than 1 antidote can effectively treat a poisoning or overdose. The panel identified 3 instances in which more than 1 effective antidote was available: ethanol or fomepizole for treatment of toxic alcohol exposure, antivenin Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) or antivenin (Crotalidae) polyvalent for treatment of crotaline snakebite, and the conventional cyanide antidote kit (sodium nitrite and sodium thiosulfate) or hydroxocobalamin for cyanide toxicity. In these cases, the panel designated a preferred agent, although either agent was recognized as acceptable in meeting the need for stocking. The preference was determined in the same manner as the decision to recommend stocking of an antidote: by group debate reaching consensus without a vote of strong disagreement. Fomepizole was preferred over ethanol for several reasons: simplicity of use, lack of need for compounding in pharmacy, reduction in medication errors, potential to avoid hemodialysis, and anticipated safety in children. The use of ethanol is further complicated by the lack of a commercially available 10% solution in the United States, requiring compounding of a 10% solution from a 95% solution of ethanol.19 Hydroxocobalamin was preferred over the conventional cyanide antidote kit because of its wider indications, ease of use, and anticipated safety in widespread use. FabAV was preferred over antivenin (Crotalidae) polyvalent because of improved safety profile and the fact that production of the Wyeth antivenom has been discontinued. Supplies of the Wyeth antivenom were available but difficult to obtain at the time of the panel’s assessment. The panel recommended the amount of antidote needed to treat a 100-kg patient for either 8 hours or 24 hours (Table 3). In most cases, the amount of antidote recommended for stocking did not match the package label precisely because of changes in clinical practice since the label content was approved by the Food and Drug Administration and because some Volume , . : September
Antidote Stocking Guidelines antidotes, such as octreotide and others, are not labeled for their use as an antidote. The panel observed that many considerations can affect the decision to stock an antidote, as well as the amount of an antidote that should be stocked. A rigid recommendation for all hospitals is difficult to justify and may lead to insufficient stocking. For example, a hospital in an area endemic for crotaline snakes (rattlesnakes, copperhead snakes, water moccasins) should stock antivenom, but the amount recommended for 1 patient may be insufficient if 2 bites could require treatment simultaneously. To address these situations, the panel recommended that hospitals perform a hazard vulnerability assessment for each antidote (Tables 3, 4).
LIMITATIONS Little class 1 and 2 evidence was available for most antidotes; therefore, many of the panel’s recommendations are based on expert analysis and experience. The process attempted to compensate for individual bias by using a large diversified panel, by presenting structured summaries of medical information, and by prohibiting voting by members with a competing interest. This approach helped to constrain undocumented or unsubstantiated opinion of panel members in 2 ways. First, the published medical evidence was reviewed and this supported the expectation that the reviewer’s conclusions would be evidence based within the limits of available information. Second, the other panel members (who reviewed the evidence simultaneously) acted as a counterbalance against unsubstantiated individual positions of the reviewer. The panel was chosen by the nonvoting chairman according to documented clinical and research expertise, which may have resulted in an unintended bias toward academia. This possibility was counterbalanced by the voting rules that allowed a single objection to reject a recommendation. Several exotic antidotes and antidotes not readily available in North America were not considered. The panel was also asked not to anticipate singular and rare events, such as terrorist acts or mass casualty incidents. It was not possible to assess the full cost-benefit relationship because information about the value of benefit is not available. The intended audience of the recommendations was an individual hospital providing emergency care, rather than larger regions, states, or national organizations, given the different needs and resources of such entities.
DISCUSSION The antidote expert panel recommended consideration of 24 antidotes for emergency stocking by facilities that provide emergency care. The recommendations are intended to be interpreted in the context of the potential clinical uses created by the catchment area served by a hospital; special needs for mass casualty events are not addressed in these recommendations. Insufficient stocking of antidotes needed on an emergency basis has been documented repeatedly in the United States and other Annals of Emergency Medicine 389
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Table 2. Antidote recommendations for stocking at facilities that accept emergency patients. Recommendation
Antidote
Poisoning Indication(s)
Should Be Stocked
Available Within 60 Minutes
Immediately Available*
Class of † Evidence
Acetylcysteine
Acetaminophen
Yes
Yes
No
Antivenin (Crotalidae) polyvalent, Wyeth, OR Crotalidae Polyvalent Immune ‡ Fab, ovine Antivenin (Latrodectus mactans) Antivenin (Micrurus fulvius)
North American crotaline snake envenomation North American crotaline snake envenomation Black widow spider envenomation Eastern and Texas coral snake envenomation Organophosphorus and N-methyl carbamate insecticides Botulism Infant botulism
Yes
Yes
No
I (IV) II (oral) III
Yes
Yes
No
II
Yes Yes
No Yes
No No
III III
Yes
Yes
Yes
III
No No
NA NA
NA NA
III I
Fluoride, calcium channel blocking agent
Yes
Yes
Yes
III
Yes Yes Yes
Yes No No
Yes No No
III II III
Yes Yes Yes Yes
Yes Yes Yes Yes
Yes Yes No Yes
III II II II
Yes
Yes
No
II
Yes
Yes
No
III
Yes
Yes
No
II
Yes Yes
Yes Yes
Yes Yes
III III
Yes Yes Yes
Yes Yes Yes
Yes Yes No
II I II
Yes Yes Yes
Yes Yes Yes
Yes No NC
II III II
Yes
Yes
Yes
III
NC Yes
NC Yes
NC Yes
II II
Atropine sulfate Botulism antitoxin, equine (A, B) Botulism immune globulin (BabyBIG) § Calcium chloride §
Calcium gluconate Calcium disodium EDTA Calcium trisodium pentetate (Calcium DTPA) Cyanide Antidote Kit OR ‡ Hydroxocobalamin hydrochloride Deferoxamine mesylate Digoxin Immune Fab Dimercaprol §
Ethanol OR ‡
Fomepizole
Flumazenil § Glucagon hydrochloride Methylene blue Naloxone hydrochloride § Octreotide acetate Physostigmine salicylate Potassium iodide Pralidoxime chloride Pyridoxine hydrochloride Prussian blue § Sodium bicarbonate
Lead Internal contamination with plutonium, americium, or curium Cyanide poisoning Cyanide poisoning Acute iron poisoning Cardiac glycosides/steroid toxicity Heavy metal toxicity (arsenic, mercury, lead) Methanol, or ethylene glycol poisoning Methanol, or ethylene glycol poisoning Benzodiazepine toxicity -Blocker, calcium channel blocker Methemoglobinemia Opioid and opiate drugs Sulfonylurea-induced hypoglycemia Anticholinergic syndrome Thyroid radioiodine protection Organophosphorus insecticide poisoning Isoniazid, hydrazine and derivatives Thallium/radiocesium Sodium channel blocking drugs, 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 welldesigned 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.
390 Annals of Emergency Medicine
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Antidote Stocking Guidelines
Table 3. Amount of antidote typically needed to treat 1 patient weighing 100-kg. Stocking Recommendation Antidote
8 h*
Acetylcysteine
28 g
Antivenin (Crotalidae) polyvalent
24 h*
Drug AWP for 8 Hours, $
56 g
IV: 800.30 PO: 214.20 30 Vials 30 Vials 36,705
Crotalidae Polyvalent Immune Fab, ovine
12 Vials 18 Vials 18,858
Antivenin (Latrodectus mactans) Antivenin (Micrurus fulvius)
1 Vial
1 Vial
5 Vials
10 Vials 8,568.00
Atropine sulfate Botulism antitoxin, equine (A, B) Botulism immune globulin (BabyBIG) Calcium chloride
45 mg NA
165 mg 140.62 NA NA
NA
NA
NA
10 g
10 g
15.00
Calcium gluconate
30 g
30 g
26.70
Calcium disodium EDTA 0.75 g Calcium DTPA 1g Cyanide antidote kit 1 kit
2.25 g 1g 1 kit
58.03 70.00 274.56
Hydroxocobalamin hydrochloride
10 g
10 g
812.50
Deferoxamine mesylate Digoxin Immune Fab Dimercaprol Ethanol
12 g 15 Vials 500 mg 180 g
36 g 15 Vials 1.5 g 360 g
417.18 600.00 197.74 76.56
Fomepizole
1.5 g
4.5 g
1,364.85
Flumazenil
6 mg
12 mg
41.26
Glucagon hydrochloride Methylene blue Naloxone hydrochloride Octreotide acetate Physostigmine salicylate Potassium iodide Pralidoxime chloride Pyridoxine hydrochloride Prussian blue Sodium bicarbonate
90 mg 400 mg 20 mg 75 g 4 mg 130 mg 7g 8g NA 63 g
250 mg 600 mg 40 mg 225 g 4 mg 130 mg 18 g 24 g NA 84 g
7,875.00 40.72 131.50 24.08 9.72 12.10 758.66 899.20 NA 13.95
31.10
Notes and Considerations for Hazard Vulnerability Assessment (HVA) Note: This recommendation applies to stocking of either oral or intravenous products Note: Administer intravenously for hepatic failure Note: Product has been discontinued by manufacturer; some supplies remain HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) Note: Less common acute and delayed antivenom reactions, faster mixing, use in equine serum hypersensitivity HVA: Geographic/endemic areas, history/experience with exotic bites, consider simultaneous bite victims (Table 4) HVA: Geographic/endemic areas (Table 4) Note: Product has been discontinued by manufacturer; some supplies remaining. Antivenoms from Mexico or Costa Rica are likely effective. Contact regional poison center to locate antivenom sources. HVA: Geographic/endemic areas (Table 4) Note: Contact your state health department to assist with procurement from the Centers for Disease Control and Prevention Information from Infant Botulism Treatment and Prevention Program, Telephone: 510231-7600, http://www.infantbotulism.org/physician/obtain.php Note: do not administer subcutaneously. Should be administered by central venous IV route, if possible Note: May be given by IV, SQ routes Both calcium gluconate and calcium chloride should be available HVA: receiving hospital for research laboratory (Table 4) 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 Note: Can be used safely in patients with smoke inhalation. Red color of drug causes laboratory test interference, red discoloration of skin and urine HVA: Industry, history, local conditions, community planning, facility service area (Table 4)
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 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 Note: Primary use is for iatrogenic oversedation. Risks may outweigh benefits in patients with mixed/unknown overdose, chronic benzodiazepine use, seizure disorders, head injury
HVA: Industry, history, endemic conditions, community planning, facility service area (Table 4)
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 represent 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 used as therapeutic agents
Agents that are widely available should generally have the antidote stocked because important geographic differences are not anticipated
Characteristics of hospital catchment area
Industries, practices, activities, and indigenous fauna indicate potential need for antidote
Referral patterns
Many hospitals accept referrals from remote areas. These should be included in risk assessment Some modes of suicide or abuse become locally prevalent without a specific industry being present Depending on characteristics of area, more than 1 victim of a poisoning may be anticipated
Acetaminophen Anticholinergic agents Benzodiazepines Dapsone Digoxin Iron Isoniazid Lidocaine Opioid analgesics Sulfonylurea hypoglycemic agents Industries generating or using cyanide, heavy metals, hydrogen fluoride, organophosphorus chemicals, radionuclides, thallium Chemical transportation routes Indigenous fauna and flora (snakes, spiders, plants) Agricultural practices (organophosphate insecticides, cyanide baits, mining) Transfers to urban hospital from agricultural areas Referral from mining region
History or experience of use Anticipated volume of use
Anticipated time to restocking or resupply of antidote
Time to restocking varies greatly among hospitals
countries.2-9 However, it is difficult for hospitals to address this situation because widely accepted guidelines for antidote stocking have not emerged, although certain regional guidelines have been promulgated.11,20-22 National guidelines are difficult to produce because of the heterogeneity of hospital organization and management, as well as the diversity of service area. The expert panel therefore concluded that a mechanism allowing customization of stocking for each hospital should be used. To allow customized application of these guidelines, the panel developed the concept of an antidote hazard vulnerability assessment, an adaptation of the Hazard Vulnerability Assessment required in the United States for accreditation of hospitals by TJC. As defined by TJC, a Hazard Vulnerability Assessment is the identification of potential emergencies and the direct and indirect effects these emergencies may have on the hospital’s operations and the demand for its services.23 This process is already required of hospitals that are accredited by TJC and provides a useful framework to assess contingencies presented by poisoned patients. All hospitals should perform an antidote hazard vulnerability analysis. Myriad variables such as size, administrative structure, specialty, and local characteristics may affect institutional antidote needs. The hazard analysis 392 Annals of Emergency Medicine
Popularity of cyanide or other specific agents as a suicide agent Amateur snake keepers in area Residential or commercial fires (older buildings, lack of fire alarms, etc) Multiple casualty incidents (eg, smoke inhalation involving treatment with cyanide antidotes) Indigenous crotaline snakebite in areas with frequent occurrences such as the southeastern or southwestern United States Hospitals that stabilize and refer patients to other institutions should stock for the anticipated period 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
approach holds promise in facilitating the appropriate assessment of antidote stocking needs. The hazard assessment concept requires a hospital to formally analyze the need for an antidote and the amount of each antidote needed for their facility. Prioritization of risks is based on available objective data (hospital services and utilization, demographic information, local industrial uses, availability of antidote at neighboring facilities, and chemical transportation routes, among other factors) that require interaction with appropriate businesses and manufacturers, as well as local, state, and federal agencies. Table 4 provides potential variables that should be considered in this hazard assessment. A hospital should use the hazard assessment process to determine the treatment period for which antidote stocking should occur. Some hospitals may exist in an environment making stabilization and referral of a patient simple and rapid. Other hospitals may be subject to serious transportation difficulties and extreme weather conditions. The process of hazard assessment should include all stakeholders: for example, pharmacy, emergency medicine, clinical toxicology, ICU, risk management, nursing, pharmacy and therapeutic committee, hospital preparedness committee, and hospital administration. Volume , . : September
Dart et al The regional poison center is an important resource to include in the assessment process. Some hospitals may forgo stocking of some antidotes, optimistically concluding that antidotes can be obtained quickly from neighboring facilities in case of urgent need. However, the experience of the expert panel indicates that delays are often encountered during the transfer of antidotes from one hospital to another, even between neighboring hospitals or hospitals under the same management, thereby compromising patient care. Delays can arise from the lack of a dedicated system to facilitate transfer, the infrequent and unplanned nature of these requests, and difficulties prioritizing the delivery of a medication to another facility over urgent internal hospital orders. Infrequently used antidotes may be difficult to find during an emergency, even within the same facility.22 To address this issue, some facilities have created charts listing antidotes and their location within that hospital, some facilities have created a special area in the pharmacy specifically for the stocking of antidotes, whereas other facilities have created a poisoning cart similar to a cardiac arrest cart.22 It is recommended that each facility ensure that the place and the amount of each antidote stocked are known and accessible to appropriate hospital personnel within the period designated by the antidote expert panel. These recommendations are not intended to create a standard of care. The recommendations are specifically created for consideration by hospitals in preparing for clinical demands in their facility. Furthermore, antidote use will change as medical practice evolves and the characteristics of poisoning and overdose change. In addition, each hospital is faced with unique social, political, and geographic challenges that may alter the recommended amount of antidote to stock. The cost of a specific antidote is considered an important factor in hospital pharmacy purchasing decisions. Although the purchase price of some antidotes can appear expensive, the overall effect on the pharmacy expense budget is smaller than it may appear because they are infrequently used and can at times be returned on expiration if unopened.12 According to average wholesale price, the maximum total cost of all antidotes recommended by the panel to treat the minimum number of patients would be approximately $70,000 to stock antidotes for an 8-hour treatment period and $90,000 for a 24-hour period. The primary components of this cost are rattlesnake antivenom, digoxin Fab, and glucagon. Finally, many institutions actually stock more of an antidote than is appropriate.11 Strategies to minimize costs include reducing inappropriate use and wasteful overstocking, regional stock rotation, and sharing multivial packs between facilities. The stocking of antidotes has remained a persistent concern for at least 25 years. The use of the recommendations of the consensus panel, combined with a hospital antidote hazard vulnerability assessment, will allow a hospital to prepare appropriately for the treatment of poisoned patients. Volume , . : September
Antidote Stocking Guidelines Supervising editors: Lewis S. Nelson, MD; Michael L. Callaham, MD Dr. Nelson and Dr. Callaham were the supervising editors on this article. Dr. Dart did not participate in the editorial review or decision to publish this article. Panel decisions: Panelists without a conflict of interest were eligible to vote on any issue. Panelists with conflicts were prohibited from voting on the drugs involved in the competing interest. The chair was nonvoting and disclosed that Denver Health’s Rocky Mountain Poison and Drug Center is a nonprofit governmental facility that provides poison and drug information, and research and consulting services to various entities under contract. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Complete disclosures can be found in Appendix E1, available online at http://www.annemergmed.com. Publication dates: Received for publication July 4, 2008. Revisions received September 2, 2008, and January 10, 2009. Accepted for publication January 16, 2009. Available online May 5, 2009. Presented at XXVIII International Congress of the European Association of Poisons Centres and Clinical Toxicologists, May 2008, Seville, Spain. Reprints not available from the authors. Address for correspondence: Richard C. Dart, MD, PhD, 777 Bannock Street, Mailcode 0180, Denver, CO 80204; E-mail: [email protected].
REFERENCES 1. Bronstein AC, Spyker DA, Cantilena LR, et al. 2006 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol. 2007;45:815-917. 2. Howland MA, Weisman R, Sauter D, et al. Nonavailability of poison antidotes. N Engl J Med. 1986;314:927-928. 3. Chyka PA, Conner HG. Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp Pharm. 1994;51:1346-1348. 4. Dart RC, Stark Y, Fulton B, et al. Insufficient stocking of poisoning antidotes in hospital emergency departments. JAMA. 1996;276: 1508-1510. 5. Nogue S, Soy D, Munne P, et al. Antidotes: availability, use and cost in hospital and extra-hospital emergency services of Catalonia (Spain). Arch Toxicol. 1997;19:299-304. 6. Ong HC, Yang C-C, Deng J-F. Inadequate stocking of antidotes in Taiwan: is it a serious problem? Clin Toxicol. 2000;38:21-28. 7. Juurlink DN, McGuigan MA, Paton TW, et al. Availability of antidotes at acute care hospitals in Ontario. CMAJ. 2001;165: 27-30. 8. Gorman SK, Zed PJ, Purssell RA, et al. Antidote stocking in British Columbia hospitals. CJEM. 2003;5:12-17. 9. Hruby K. Dostupnost antidote v nemocnicnich lekarnach ceske republiky. Ces Slov Farm. 2003;52:231-240. 10. Dart RC, Goldfrank LR, Chyka PA, et al. Combined evidence-based literature analysis and consensus guidelines for stocking of
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11.
12.
13.
14.
15. 16. 17.
emergency antidotes in the United States. Ann Emerg Med. 2000;36:126-132. Bailey B, Bussieres J-F, Dumont M. Availability of antidotes in Quebec hospitals before and after dissemination of guidelines. Am J Health Syst Pharm. 2003;60:2345-2349. Sivilotti MLA, Eisen JS, Lee JS, et al. Can emergency departments not afford to carry essential antidotes? CJEM. 2002; 4:23-33. Joint Commission on Accreditation of Healthcare Organizations. Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2007:111. California Department of Public Health. Hospital administration penalties by county. Available at: http://www.cdph.ca.gov/certlic/ facilities/Documents/HospitalAdministrativePenalties-2567FormsLNC/2567OliveViewUCLAMedical-Sylmar-EventE-EW2J11.pdf. Accessed May 22, 2008. Flomenbaum NE, ed. Goldfrank’s Toxicological Emergencies. 8th ed. New York, NY: McGraw-Hill; 2006. Dart RC et al. Medical Toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. Wolf SJ, Heard K, Sloan EP, et al. Clinical policy: critical issues in the management of patients presenting to the emergency
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18.
19.
20. 21.
22.
23.
department with acetaminophen overdose. Ann Emerg Med. 2007;50:292-313. McDowell MA, Fryar CD, Hirsch R, et al. Anthropometric Reference Data for Children and Adults: US Population, 19992002. Advance Data From Vital And Health Statistics; No. 361. Hyattsville, MD: National Center for Health Statistics; 2005. Berberet BR, Burda BR, Lodolce AE. Unavailability of 10% alcohol in 5% dextrose injection. Am J Health Syst Pharm. 2005;62: 2344-2345. Berndt E. Posted list of emergency drugs and antidotes. Am J Hosp Pharm. 1994;51:2602. Pettit HE, McKinney PE, Achusim LE, et al. Toxicology cart for stocking sufficient supplies of poisoning antidotes. Am J Health Syst Pharm. 1999;56:2537-2539. Ontario Poison Centre guidelines for stocking of emergency antidotes. Available at: http://www.ontariopoisoncentre.com/ ontariopoisoncentre/custom/antidotes2006.pdf. Accessed May 4, 2008. The Joint Commission on Accreditation of Healthcare Organization. 2009 Hospital Accreditation Standards. Oakbrook, IL: The Joint Commission; 2008. Available at: http://www.jointcommission.org/ NR/rdonlyres/F42AF828-7248-48C0-B4E6-BA18E719A87C/0/06_ hap_accred_stds.pdf. Accessed May 6, 2008.
Volume , . : September
Appendix E1. Disclosures. Funding for this research was provided by 8 pharmaceutical companies (Fougera, Dey, Protherics, Rare Disease Therapeutics, Heyl, Cumberland Pharmaceuticals, Heyltex, and Jazz Pharma-
Panelist Borron
Organization
Financial Interests
ceuticals) to the Denver Health and Hospital Authority. The sponsors had no input into the design, definitions, panel proceedings, analysis of the results, or drafting of the article. Dr. Heard received support from NIH Grant (1K08DA020573-01).
Clinical Grants
Consulting
Potential Antidote Interests
University of Texas Health Sciences Center at San Antonio Utah Poison Control Center American Society of HealthSystem Pharmacists Research & Education Foundation Banner Good Samaritan Medical Center
None
EMD Pharmaceuticals, Dey LP (Hydroxocobalamin)
Merck KGA (Hydroxocobalamin)
Hydroxocobalamin
None None
None None
None None
None None
None
None
Crotaline Immune Fab
Rocky Mountain Poison & Drug Center-Denver Health Orlando Regional Healthcare System New York University School of Medicine Centers for Disease Control & Prevention Office of Rare Disease at National institutes of Health Rocky Mountain Poison & Drug Center-Denver Health
None
See Note Below
Fougera (CroFab Unrestricted Education Grant for Toxicology Fellowship, Lectures-No Honoraria) See Note Below
None
None
None
Not Applicable - Non-Voting Chair of Panel None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
NAC (IV), Crotaline Immune Fab, DigiFab, BWS AV
Orange County Fire Authority/ Orange County Healthcare Agency California Poison Control System Albert Einstein Medical Center Rocky Mountain Poison & Drug Center-Denver Health
None
Fougera (CroFab Registry), Cumberland (NAC Registry), RDT (BWS Investigator), Protherics (DigiFab Investigator) None
None
None
None
None
None
None
None
None
None
None
None
None
BWS AV, DigiFab
Seger Seifert
Tennessee Poison Center University of New Mexico/ New Mexico Poison & Drug Information Center
None None
None Poisindex Editorial Board
None Crotaline Immune Fab
Sivilotti
Queen’s University
None
None
NAC (IV)
Tomassoni Wise
Yale New Haven Health Joint Commission
None None
RDT (BWS Co-Investigator), Protherics (DigiFab Retro Study) None Protherics (Investigator CroFab), RDT (Investigator Anavip), HRSA (Strategic AV System Grant) Cumberland (Unrestricted research grant) None None
None None
None None
Caravati Cobaugh
Curry
Dart Falk Goldfrank Gorman Groft
Heard
Miller
Olson O’Malley Schaeffer
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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