Elsevier

Annals of Emergency Medicine

Volume 53, Issue 4, April 2009, Pages 439-450.e10
Annals of Emergency Medicine

Toxicology/original research
Adverse Drug Events Associated With the Antidotes for Methanol and Ethylene Glycol Poisoning: A Comparison of Ethanol and Fomepizole

Presented at the North American Congress of Clinical Toxicology, October 2007, New Orleans, LA.
https://doi.org/10.1016/j.annemergmed.2008.05.008Get rights and content

Study objective

We investigate adverse drug events associated with antidotes ethanol and fomepizole in methanol or ethylene glycol poisonings. An “adverse drug event” is harm associated with normal or incorrect drug use. We describe type, frequency, severity, seriousness, and onset time of adverse drug events and test the hypothesis that fomepizole results in fewer adverse drug events than ethanol.

Methods

This cohort study included patients aged 13 years or older, hospitalized between 1996 and 2005 for methanol or ethylene glycol poisoning (identified by International Classification of Diseases, Ninth Revision or 10th Revision codes) and treated with at least 1 dose of ethanol or fomepizole. Two abstractors separately reviewed each chart, identifying new clinical events during antidote treatment. Three toxicologists determined, by consensus, which events were adverse drug events. The primary outcome was at least 1 adverse drug event, expressed as adverse drug event rate per person-day of antidote treatment. Association between time to first adverse drug event and antidote type was modeled by Cox regression, adjusted for confounders.

Results

Two hundred twenty-three charts were reviewed and 172 analyzed. Toxicologists identified at least 1 adverse drug event in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. Central nervous system symptoms accounted for most adverse drug events (48% ethanol-treated, 2% fomepizole-treated). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated (coma, cardiovascular). Serious (life-threatening) adverse drug events occurred in 11 of 130 (8%) ethanol-treated (respiratory depression, hypotension) and 1 of 42 (2%) fomepizole-treated (hypotension, bradycardia) cases. Median adverse drug event onset was within 3 hours after the start of either antidote. Ethanol and fomepizole adverse drug event rates were 0.93 and 0.13 adverse drug events per treatment-day, respectively. Adjusted hazard ratio was 0.16 (95% confidence interval 0.06, 0.40).

Conclusion

Given observational study limitations, results suggest lower occurrence of adverse drug events with fomepizole than ethanol.

Introduction

Ingestion of methanol and ethylene glycol can result in severe morbidity or death.1 Treatment includes antidote administration (ethanol or fomepizole) with or without hemodialysis, intravenous sodium bicarbonate, and vitamin therapy.2, 3 The American Association of Poison Control Centers' National Database reports that in 2006, fomepizole was administered to 1,485 patients and ethanol to 318 patients in the United States.4

No published studies compare the safety of ethanol and fomepizole in poisoned patients. Since its US market launch 10 years ago, some authors have recommended fomepizole as the preferred antidote for toxic alcohol poisoning on the grounds that is easier to administer and has fewer adverse effects than ethanol.5, 6 The high acquisition cost of fomepizole, approximately US $1000 per gram, is a deterrent to use and ethanol may be preferentially prescribed despite fomepizole availability.7, 8

The purpose of this study was to investigate the incidence of fomepizole and ethanol-related adverse drug events in the setting of methanol and ethylene glycol poisoning, evaluate the time of adverse drug event onset after antidote initiation, and test the hypothesis that fomepizole is less likely to result in an adverse drug event than ethanol. The term “adverse drug event” includes both the harmful effects associated with normal clinical use of a drug (adverse drug reactions) and harm resulting from incorrect usage (medication errors).9 Study objectives were to describe the type, frequency, severity, seriousness, and onset time of adverse drug events attributed to ethanol and fomepizole and estimate the risk of experiencing an antidote-related adverse drug event in fomepizole versus ethanol-treated patients, using the outcome of the adjusted hazard ratio for any adverse drug event.

Section snippets

Study Design and Setting

We conducted a cohort study in antidote-treated patients hospitalized for suspected methanol or ethylene glycol poisoning. Subjects were classified by antidote exposure and observed for the outcome of an antidote-related adverse drug event.10 The sample was drawn from 10 hospitals in British Columbia, Canada. Hospitals included 2 university-affiliated referral centers (>350 beds), 4 nonteaching regional hospitals (200 to 350 beds), and 4 community hospitals (100 to 200 beds). Referral and

Characteristics of Study Subjects

The study included 174 cases of suspected methanol and ethylene glycol poisoning, 2 of which were excluded from adverse drug event analysis. The Figure outlines inclusions, exclusions, and case classification. All hospitals contributed both ethanol- and fomepizole-treated cases. Each referral and regional facility admitted 2 to 3 cases per year, whereas community hospitals averaged 1 case per year.

Table 1 summarizes baseline case characteristics and Table 2 summarizes antidote and other

Limitations

Study limitations include the use of hospital chart data, which are susceptible to misclassification (eg, incorrect documentation of symptom onset times) and missing information (which could underestimate event frequency). Chart abstracters and reviewers were not blinded to the study hypothesis, which may have biased the evaluation of adverse drug events. Cases were selected by searching hospital admission records and therefore did not include patients treated in the ED without admission. Our

Discussion

Ethanol has been used as an antidote since the 1940s.24 Acute toxicity of ethanol as a recreational drug is well documented and includes central nervous system depression, cardiovascular effects, and hypoglycemia, but there is limited information about the adverse effects of ethanol when it is used as an antidote.3, 25, 26 Anecdotal reports describe respiratory arrest and aggressive behavior attributed to ethanol antidote.27, 28 Roy et al29 found minimal evidence of ethanol toxicity in 60

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    Supervising editor: E. Martin Caravati, MD, MPH

    Author contributions: KJL, ARL, BGS, RAP, and DED conceived and designed the study. KJL and JLB performed data collection. RAP, CRD, GDE, and JRK acted as expert reviewers. BGS was the senior statistician. KJL analyzed the data. KJL drafted the article, and all authors contributed substantially to its revision. KJL takes responsibility for the paper as a whole.

    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. KJL was supported by a training fellowship from the Michael Smith Foundation for Health Research (MSFHR). ARL is supported by MSFHR Senior Scholar and Canadian Institutes of Health Research New Investigator awards. BGS was supported by the Canada Research Chair Program.

    Publication dates: Available online July 18, 2008.

    Earn CME Credit: Continuing Medical Education is available for this article at: www.ACEP-EMedHome.com.

    Reprints not available from the authors.

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