Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Fomepizole for the Treatment of Methanol Poisoning.

Brent J, McMartin K, Phillips S, Aaron C, Kulig K.

N Engl J Med 2001;344:424-9. [abstract; full-text for subscribers]

Reviewed by Dan Mackey MD, Mercy Hospital, Springfield, MA

Review posted June 23, 2001

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I. What is being studied?:

The study objective:

The efficacy and safety of an alcohol dehydrogenase inhibitor, fomepizole, in the setting of acute methanol intoxication.

The study design:

Non-randomized, uncontrolled, multicenter prospective observational study.

The patients included:

Patients > 12yrs of age in whom there was a documented serum methanol level > 20mg/dl or a strong suspicion of methanol ingestion. In the latter case patients had to also meet 2 of the following 3 criteria: arterial pH < 7.3, serum HCO3 < 20mm/L, or serum osmolality gap > 10mOsm/kg.

The patients excluded:

Patients were excluded for pyrazole allergies, pregnancy, and if treatment with ethanol was begun prior to consideration for the study (even though this exclusion was not followed because 7 of 11 patients had alcohol levels).

The interventions compared:

The study was not designed to compare fomepizole treatment with any other regimen. The authors administered fomepizole to 11 consecutive patients who met entry criteria for the study. Glucose, electrolytes and fluids were administered as clinically necessary along with supplemental folate, and supplemental oxygen (as needed to maintain oxygen saturation > 90%). An IV loading dose of 15 mg/kg was administered followed by a bolus of 10 mg/kg every 12 hours. After the 4th dose the dosage was increased again to 15 mg/kg "to counteract the induction of fomepizole metabolism." Treatment with fomepizole was continued until serum methanol concentration was below 20 mg/dl. Hemodialysis was employed if the patient was acidotic, had certain visual symptomatology, or if the serum methanol concentration failed to decrease by at least 10 mg/dl per 24 hour period.

The outcomes evaluated:

Death, residual illness or disability and visual acuity were the clinical outcomes. Also assessed was inhibition of formic acid production, resolution of metabolic acidosis and maintenance of a plasma fomepizole concentration of more than 0.8 mcg/ml.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

This study was not controlled.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. Of the initial 15 subjects enrolled in the trial, four were not included in the overall analysis because their initial serum formic acid level was < 20mg/dl. All 15 subjects were included in the adverse effects analysis.

No. One patient who had abnormal visual acuity results on hospital day 3, did not have follow-up visual acuity testing because he was transferred to a psychiatric facility.

Were patients analyzed in the groups to which they were randomized?

N/A

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No. The study was not blinded.

4. Was the group homogeneous at the start of the trial?

No. There was wide variability in the timing of starting treatment with fomepizole, and a broad range in initial methanol levels.

5. Aside from the experimental intervention, was the group treated consistently?

No. Three patients had significant alcohol levels and 7 received hemodialysis. The hemodialysis patients received a median of one fomepizole treatment vs. a median of 4 doses in the patients who did not have hemodialysis.

III. What were the results?

1. How large was the treatment effect?

Since this was an observational study and not a controlled trial, there was no calculated "treatment effect."

The authors concluded that "in response to fomepizole, plama formic acid levels fell and metabolic abnormalities resolved in all patients." They present data on formic acid and methanol levels over time in 5 patients who underwent hemodialysis and 3 patients who did not. Hemodialysis clearly removed methanol efficiently, but it demonstrates the lack of effect of dialysis on formic acid concentrations. Since the hemodialysis patients only received a median of one dose of fomepizole it is difficult to discern the drug's effect. In the non-dialyzed patients, since the formic acid concentration decreased over time with very little methanol elimination, fomepizole's efficacy in blocking formic acid production is demonstrated.

The authors report that nine of the eleven patients included in the final analysis survived. The demise of the other two patients was attributed to pre-admission anoxic brain injury secondary to being comatose with severe acidosis and very high formic acid levels from significant methanol poisoning and were unlikely to have their outcome altered by the drug therapy

Their visual acuity outcome data demonstrated that seven of the eleven patients had transient visual deficits, but none suffered permanent visual loss. (They excluded the two patients who did not survive, and the other two patients presumably suffered no adverse effects on visual acuity). No attempt was made to compare these results with historical controls or any other treatment modality. However, it is generally accepted that risk of toxicity is greatest when serum methanol levels reach or exceed 20 mg/dl.

Finally the authors report success in obtaining fomepizole levels above 0.8 mcg in 152 out of 155 blood samples with their dosing strategy (but it is unclear if they were peak or trough levels).

2. How precise was the estimate of the treatment effect?

The major problem with this study is the presence of two significant confounding variables: ethanol and hemodialysis. First, regarding ethanol, the authors failed to explain why, despite the exclusion criteria, three patients were admitted to the study after receiving therapeutic doses of ethanol at referring institutions. . Ethanol is a competitive inhibitor of alcohol dehydrogenase, whereas fomepizole is a non-competitive inhibitor. Therefore, fomepizole's effects should start take effect once it is administered after ethanol. It should maintain the ethanol level however.

A total of seven of the eleven patients, in fact, had detectable levels of ethanol upon initiation of treatment with fomepizole. The authors offered lack of correlation (p = 0.96) between the initial formic acid and ethanol levels as evidence that ethanol had no therapeutic effect on the metabolism of methanol to formic acid. However, the lack of correlation between the two levels is unhelpful since the dosage of methanol ingested was either unknown or unreported. For example, if two subjects ingested differing toxic doses of methanol, but were exposed to the same doses of ethanol, the measured formic acid levels would be different implying a lack of correlation between ethanol and formic acid levels at that given point in time. Additionally, varying time intervals between methanol ingestion and the measurement of the serum levels could also affect the correlation between the two levels; a longer interval between ingestion and serum evaluation theoretically allows for more metabolism to formic acid, etc.

Furthermore, it is unknown whether the four patients excluded from the final analysis due to low serum methanol levels also had detectable levels of ethanol. Regardless, the study was statistically underpowered to address such relationships The second confounding variable, hemodialysis, removes methanol and is useful in addressing severe acidosis. More patients than not (7 of 11) were influenced by this modality which precludes any determination of the efficacy of fomepizole in the absence of hemodialysis.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Currently the answer is no for several reasons: (1) There is limited data on fomepizole in children. (2) There are no conclusive data from this study to argue the efficacy of fomepizole in the absence of hemodialysis and/or ethanol. (3) Fomepizole is not available in the community hospital where my practice is located. The timing of fomepizole treatment was about 24 hours in 4 cases and unknown in 3 others. Therefore, in severe poisoning, transferring to an institution with fomepizole may be beneficial. One can still use ethanol until reaching a site with the drug.

2. Were all clinically important outcomes considered?

The two most important outcomes of visual impairment and death were considered. Other clinical outcomes which could have been incorporated include pancreatitis, basal ganglia infarcts, cardiac dysrhythmias, and seizures. Additionally, the effects of the timing from ingestion to initiating fomepizole treatment would be extremely interesting to determine if this drug should be available at all institutions or only tertiary care centers.

3. Are the likely treatment benefits worth the potential harms and costs?

The cost and availability of fomepizole were not commented upon. If (1) the safety of fomepizole in children, and (2) the efficacy of fomepizole as either an alternative to ethanol or as an adjunct to hemodialysis could be established, its ease of administration and apparent consistency in achieving therapeutic serum concentrations could make potential use of this medicine quite attractive pending the results of more definitive studies. Unfortunately (or fortunately!), methanol poisoning is sufficiently rare and a prospective trial comparing ethanol with fomepizole is unlikely to be feasible. This may be one intervention where biochemical evidence and anecdotal experience may be sufficient to consider this agent when faced with this relatively rare but life-threatening condition.

References

1. Tintinali, et al. Emergency Medicine: A Comprehensive Study. Fifth Ed. New York; McGraw-Hill, 2000:1103-08.
2. Fleisher, G., Ludwig, S. Textbook of Pediatric Emergency Medicine. Fourth Ed Philadelphia: Lippincott Williams & Wilkins, 2000: 897-902.

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