Fomepizole for Methanol Poisoning
Abstract & Commentary
Source: Brent J, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001;344:424-429.
Methanol poisoning may result in metabolic acidosis, blindness, and death. Fomepizole is a potent inhibitor of alcohol dehydrogenase. The investigators provide data on 11 consecutive patients who presented with methanol poisoning and were treated with fomepizole. Measured outcomes included the preservation of visual acuity, the resolution of metabolic acidosis, the inhibition of formic acid production, the achievement of therapeutic plasma concentrations of fomepizole with the dosing regimen, residual illness or disability, and death.
Patients were eligible for inclusion in the study if they had a serum methanol concentration of greater than 20 mg/dL or if there was a history or a strong suspicion of methanol ingestion. In addition, patients had to present with at least two of the following three findings: an arterial pH of less than 7.3, a serum bicarbonate concentration of less than 20 mmol/L, or a serum osmolality gap (determined by the freezing-point depression method) of greater than 10 mOsm/kg H2O.
Patients were treated with fomepizole until the serum methanol concentration was less than 20 mg/dL. Patients underwent hemodialysis after the administration of the loading dose of fomepizole for any of the following reasons: an initial arterial pH of less than 7.1; a decrease in either the arterial pH of more than 0.05 units or a serum bicarbonate concentration of greater than 5 mmol/L, despite bicarbonate supplementation; an arterial pH that could not be maintained at 7.3 or higher; a serum methanol concentration of greater than 50 mg/dL (15.6 mmol/L); any of a predetermined set of visual symptoms and signs; or a serum methanol concentration that declined at a rate of less than 10 mg/dL (3.1 mmol/L) per 24 hours.
Plasma formic acid concentrations were detectable in eight patients and correlated with the initial arterial pH values. In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients.
Of the 11 patients enrolled in the study, 9 survived. Seven patients initially had visual abnormalities, but at the end of the trial no surviving patient had any detectable visual deficits related to methanol poisoning. Fomepizole had few adverse effects. The two patients who died had anoxic brain injury that was present at the time of enrollment. During treatment, methanol had an elimination half-life of 54 hours.
Commentary by Richard J. Hamilton, MD, FAAEM, ABMT
This paper serves as a useful guide to the biochemistry of methanol poisoning, as well as to the use of fomepizole. Acidosis and poor outcome do correspond to formic acid levels—especially at levels greater than 20 mmol/L. Fomepizole is well-tolerated, reverses acidosis, and appears to prevent the development of permanent ocular injury.
However, fomepizole for methanol poisoning and fomepizole for ethylene glycol poisoning have one important difference—unmetabolized ethylene glycol is cleared by the kidneys and methanol must be exhaled from the lungs. A number of case reports show that ethylene glycol levels will fall fairly rapidly when fome-pizole is instituted. Patients without acidosis, with normal renal function, and ethylene glycol levels of 25- 50 mg/dL (sufficient to produce acidosis and injury without treatment) will improve with sufficient speed when fomepizole is used without hemodialysis. This is because the elimination half-life of ethylene glycol is 16-19 hours when fomepizole is used without hemodialysis.1,2
Note that in this study the elimination half-life for methanol, when fomepizole was used without hemodialysis, was 54 hours. In contrast to ethylene glycol, a methanol level between 25 and 50 mg/dL (sufficient to produce acidosis and injury without treatment) will require as much as three days of fomepizole therapy without hemodialysis. Clearly then, all patients with elevated methanol levels will need hemodialysis unless levels are trivially elevated and hemodialysis would complicate management (e.g., a child with a methanol level of 30 mg/dL without acidosis).
Fomepizole is an excellent antidote and certainly simplifies the approach to toxic alcohol ingestion. This study helps define its clinical application.
References
1. Sivilotti ML, et al. Toxicokinetics of ethylene glycol during fomepizole therapy: Implications for management. Ann Emerg Med 2000;36:114-125.
2. Borron SW, et al. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 1999;354:831.
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