Correspondence

Fomepizole for Toxic Alcohol Poisoning

N Engl J Med 2009; 361:1213-1214September 17, 2009

Article

To the Editor:

Brent (May 21 issue)1 discusses the osmolal gap in the management of ethylene glycol and methanol poisoning. Although a high anion gap is characteristic and an elevated osmolal gap is a useful indicator of toxic alcohols in blood, an understanding of their temporal relationship is essential to avoid mismanagement of these conditions. The development of osmolal and anion gaps varies as a function of time from ingestion. As metabolism progresses, increasing amounts of these alcohols are converted to their metabolites. The contribution of the parent compounds to the osmolal gap decreases, whereas the contribution of the metabolites to the anion gap increases. Therefore, early in the course of poisoning, an anion gap may be absent in the presence of an osmolal gap, and an anion gap may exist without an osmolal gap as metabolism progresses.2

Simultaneous ingestion of ethanol competitively inhibits metabolism of these alcohols and may result in a delay in the appearance of the anion gap. Ethanol is also osmotically active — 100 mg per deciliter of ethanol contributes 22 mOsm per kilogram of water to the osmolal gap.3 Therefore, the osmolal contribution of ethanol must be subtracted from the measured osmolality.

Habib Rehman, M.B., B.S.
Regina Qu'Appelle Health Region, Regina, SK, Canada
habib31@sasktel.net

3 References

1. 1

   Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009;360:2216-2223
   Full Text | Web of Science | Medline

2. 2

   Mycyk MB, Aks SE. A visual schematic for clarifying the temporal relationship between the anion and osmolal gaps in toxic alcohol poisoning. Am J Emerg Med 2003;21:333-335
   CrossRef | Web of Science | Medline

3. 3

   Eder AF, McGrath CM, Dowdy YG, et al. Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem 1998;44:168-177
   Web of Science | Medline

To the Editor:

As has been well explained by Brent, fomepizole has advantages over ethanol in ethylene glycol and methanol poisoning. However, fomepizole has an important interaction with ethanol. These antidotes should not be administered together because they inhibit each other's metabolism and could alter each other's pharmacokinetic profiles.1 Because ethanol has an erratic metabolism, this interaction could exacerbate its adverse effects, such as changes in mental status, hypoglycemia, and pancreatitis.2 On the other hand, fomepizole must be used cautiously if the patient has a reported allergy to pyrazolones (e.g., dipyrone and phenylbutazone), whose structures have similarities with that of fomepizole.

Omar González-Santiago, Ph.D.
Lourdes Garza-Ocañas, M.D.
Universidad Autonoma de Nuevo León, Monterrey, Mexico
omargs28@yahoo.com

2 References

1. 1

   Jacobsen D, Sebastian CS, Dies DF, et al. Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans. Alcohol Clin Exp Res 1996;20:804-809
   CrossRef | Web of Science | Medline

2. 2

   Hantson P, Wittebole X, Haufroid V. Ethanol therapy for methanol poisoning: duration and problems. Eur J Emerg Med 2002;9:278-279
   CrossRef | Medline

Author/Editor Response

The letters from Rehman and from González-Santiago and Garza-Ocañas contribute to the discourse concerning the nuances of the clinical use of fomepizole. Rehman points out that the osmolal gap dissipates as ethylene glycol or methanol is metabolized. The reason is that only the parent compound contributes to this gap. Electroneutrality requires the acidic metabolites of ethylene glycol and methanol (primarily glycolate and formate), which are ionized to negatively charged carboxyl groups at physiologic pHs, to have a counter cation. In plasma, on a probabilistic basis, this would be a sodium ion. The equation for calculating the osmolal gap includes, for serum osmolarity, a term that is two times the sodium concentration, accounting for both the sodium ion itself and, by virtue of the coefficient, the metabolite anion (Table 3 of the article). Thus, these metabolites, unlike the parent compounds, will not contribute to the calculated osmolarity and hence decrease the osmolal gap. This event is important because the disappearance of the osmolal gap is evidence of metabolism of the parent compound, after which there is no benefit to inhibiting alcohol dehydrogenase. Rehman also correctly observes that the contribution of ethanol must be factored into the calculation of the predicted osmolarity (also explained in Table 3 of the article).

González-Santiago and Garza-Ocañas speculate that the pharmacokinetic interaction between fomepizole and ethanol might exacerbate the potential adverse effects of the latter. When fomepizole is used, ethanol continues to be metabolized, but with a reduction in the clearance rate of approximately 40%.1 There have been a number of instances in which fomepizole was administered to patients with blood alcohol concentrations in the intoxication range with no reported adverse effect, including one instance in which the fomepizole nullified an adverse effect of ethanol on a patient's level of consciousness.2 I agree with González-Santiago and Garza-Ocañas that fomepizole should be used with caution if a patient is allergic to pyrazoles; however, no allergic reactions in patients with intolerance to this class of medications have been reported in the literature.

Jeffrey Brent, M.D., Ph.D.
University of Colorado, Denver, CO
jeffrey.brent@ucdenver.edu

2 References

1. 1

   Jacobsen D, Sebastian CS, Dies DF, et al. Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans. Alcohol Clin Exp Res 1996;20:804-809
   CrossRef | Web of Science | Medline

2. 2

   Boyer EW, Mejia M, Woolf A, Shannon M. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics 2001;107:172-173
   CrossRef | Web of Science | Medline