Methanol is present in a variety of substances found around the home and workplace, including paint solvents, gasoline additives, air or brake line antifreeze, canned-heat products, windshield washer fluid, and duplicating chemicals.
Pharmacokinetics and Pathophysiology
Methanol is rapidly absorbed following ingestion. Peak serum concentration can be reached as early as 30–90 minutes after ingestion. As with ethanol, methanol is primarily metabolized by hepatic alcohol dehydrogenase. The half-life of methanol may be as long as 24 hours, but in the presence of ethanol or fomepizole, it is longer. In one report of methanol poisoning in an infant, methanol metabolism demonstrated first-order elimination kinetics.6 Methanol itself is harmless; however, its main metabolite, formic acid, is extremely toxic. Fatalities have been reported after ingestion of as little as 15 mL of a 40% methanol solution, although 30 mL is generally considered a minimal lethal dose. Ingestion of only 10 mL can lead to blindness. Adults have survived ingestions of 500 mL.
The onset of symptoms following methanol ingestion varies from 1 to 72 hours. Patients may have the classic triad consisting of visual complaints, abdominal pain, and metabolic acidosis. Eye signs and symptoms are generally delayed and include blurring of vision, photophobia, constricted visual fields, snowfield vision, and hyperemia of the optic disk. Although the blindness is usually permanent, recovery has been reported.7
Patients typically complain of nausea and vomiting and can experience gastrointestinal bleeding and acute pancreatitis. Unlike other alcohols, these patients often lack the odor of ethanol on their breath and typically have a clear sensorium. Methanol toxicity should be suspected in patients with altered mental status and metabolic acidosis of unclear etiology, especially if they have complaints involving vision.8
Measurement of the serum methanol concentration is the key laboratory test. Other recommended studies include a complete blood cell count, serum electrolytes and blood glucose, lipase, blood urea nitrogen (BUN) and serum creatinine, a urinalysis, and an arterial blood gas. Classically, methanol-intoxicated patients develop an elevated anion gap metabolic acidosis, although this may not be present if the patient presents before a significant quantity of formic acid has been generated.9 The anion gap is calculated using the equation:
Another equation that assists in establishing the diagnosis is the presence of an elevated osmol gap, which is the difference between the measured and calculated serum osmolarities. An elevated osmol gap indicates the presence of an unmeasured osmotically active substance in the serum.
The formula for calculating serum osmolarity is: 2(NA) + glucose/18 + BUN/2.8.
Normally, the difference between the measured and calculated serum osmolalities is less than 10 mOsm (other toxicological causes of an elevated osmol gap include ethylene glycol, ethanol, and isopropanol poisoning, all of which are highly osmotically active compounds). Although the osmol gap is a useful indicator, cases of significant methanol and ethylene glycol overdoses have been reported with normal osmol gaps.
Generally, levels <20 mg/dL result in no effects. It is generally stated, but undocumented, that methanol levels <20 mg/dL are non-toxic and peak levels >50 mg/dL indicate serious toxicity. Ocular effects occur at levels >100 mg/dL, and fatalities have been reported in untreated victims with levels >150 mg/dL.10 One problem in interpreting levels is the time of ingestion versus the time of patient presentation and serum level assessment. Patients with low serum methanol concentrations may still be significantly poisoned and acidotic if they present late in their clinical course.
As for ethanol poisoning, gastric decontamination is not indicated in methanol poisoning chiefly because it is absorbed so quickly from the stomach. If a significant ingestion of methanol is likely, empiric treatment with the intravenous alcohol dehydrogenase inhibitor fomepizole is recommended11,12 even if laboratory tests are unavailable. Fomepizole binds hepatic alcohol dehydrogenase and prevents the metabolism of methanol to the toxic metabolite formic acid. Other indications for fomepizole therapy include serum methanol levels >20 mg/dL or acidemia (pH < 7.20). A fomepizole loading dose of 15 mg/kg should be administered, followed by doses 10 mg/kg every 12 hours for four doses until methanol levels are less than 20 mg/dL. Fomepizole is the only FDA-approved antidote for methanol poisoning.13 A recent investigation demonstrated that oral administration of fomepizole produced similar blood levels as an identical intravenous dose.14
If fomepizole is unavailable, ethanol may be administered to block alcohol dehydrogenase.15 To inhibit toxic metabolite formation, ethanol levels are maintained between 100 and 120 mg/dL. An intravenous solution of 10% ethanol in D5 W is optimal, with a loading dose of 0.6 g/kg. A simplified approximation of the loading dose is 1 mL/kg of 10% diluted absolute ethanol. Close monitoring of the ethanol level every 1–2 hours is necessary in order to adjust the maintenance infusion rate for each individual patient. If IV ethanol preparations are unavailable, oral ethanol therapy can be instituted. Since hypoglycemia is a complication of toxic ethanol levels in young children, serum glucose concentrations must be closely monitored.
Continued therapy with fomepizole or ethanol is recommended until methanol level falls below 20 mg/dL. Although there are no clinical outcome data confirming the superiority of either of these antidotes, there are significant disadvantages with ethanol therapy. These include difficulty in maintaining therapeutic concentrations, induced hypoglycemia, and CNS depression that may require endotracheal intubation, particularly in children. Unlike ethanol, fomepizole does not cause CNS depression and hypoglycemia. Particularly in children, minimal side effects make fomepizole the antidote of choice.
Additional therapies for methanol poisonings may include bicarbonate if the serum pH falls below 7.20. Folate, the active form of folic acid, is a coenzyme in the metabolic step converting the toxic metabolite formate to CO2 and H2O and can be administered to the methanol-poisoned patient. Up to 50 mg of folate can be given intravenously every 4 hours until the acidosis is corrected and methanol levels fall below 20 mg/dL.
Hemodialysis effectively removes methanol and formic acid. Indications for dialysis include visual impairment, metabolic acidosis not corrected with bicarbonate administration, renal failure, and methanol levels >50 mg/dL (with or without clinical signs or symptoms). It is important to note that fomepizole and ethanol are readily dialyzed, so the rate of IV administration may have to be increased during dialysis. For fomepizole, the recommendation is increasing the frequency of dosing to every 4 hours during hemodialysis.16
Any patient who is comatose and has abnormal vital signs, visual complaints, metabolic acidosis, or high methanol levels require admission to a pediatric intensive care unit. Asymptomatic patients without evidence of acidosis and with a methanol level <20 mg/dL may be discharged after observation in the emergency department.4