Unit conversion table: Table 1 in Alcohols.
Methanol (wood alcohol, wood spirits) is used in industry, in window cleaning products (particularly as a windshield-washing fluid), as a fuel, and in paint thinners. It cannot be discerned by taste and smell from ethanol, which results in poisonings of persons consuming counterfeit alcohol products (containing methanol instead of ethanol). Methanol is rapidly absorbed from the gastrointestinal tract, distributed to the body water, and is not protein bound. Maximum blood levels are observed within 30 to 60 minutes from ingestion. Toxic methanol levels have also been reported after significant dermal exposure and concentrated inhalation. Methanol is metabolized by alcohol dehydrogenase about 10 times slower than ethanol. About 2% to 5% is excreted unchanged by the kidneys and 10% to 15% through the breath.
Mechanism of toxicity: Methanol is a central nervous system (CNS) depressant that produces an inebriation similar to that of ethanol. Methanol is metabolized by alcohol dehydrogenase to formaldehyde, which is then converted to formic acid by aldehyde dehydrogenase. In methanol poisoning, severe metabolic acidosis develops secondary to formic acid accumulation as well as lactate production due to inhibition of mitochondrial cytochrome c oxidase by formic acid. Formic acid accumulates in the optic nerve and can cause irreversible blindness from damage to the retina and optic nerve.
Toxic dose: The toxic dose depends on whether methanol was ingested alone or together with ethanol; in the former case, its toxicity is reduced. The consumption of as little as 10 mL of pure methanol may result in permanent loss of vision and as little as 30 mL may be lethal. Typically, the lethal oral dose of pure methanol is in the range of 30 to 240 mL (20-150 g), with the median lethal dose being 100 mL (about 1-2 mL/kg). At the bedside, a toxic volume of methanol can be calculated (in mL) as (15 x patient’s weight in kg) divided by the % methanol in the ingested fluid. For example, a toxic amount for a 100 kg patient who ingested a 50% methanol solution would be (15 x 100)/50 = 30 mL.
1. Symptoms of early poisoning: Initially, before methanol is metabolized, it causes CNS depression and intoxication symptoms similar to those of ethanol. It may also cause gastritis.
2. Symptoms of late poisoning: After a latent period of 18 to 24 hours, the metabolites of methanol accumulate and cause an anion gap metabolic acidosis. Visual disturbances, blindness, coma, and acute kidney injury with myoglobinuria may result. Patients describe visual disturbances as blurred vision, haze, or a “snowfield.” Fundoscopic examination of these patients may reveal hyperemia of the optic disc or retinal edema. An afferent pupillary defect is a bad sign. Patients may have tachycardia, tachypnea, and altered mental status from advanced acidosis. With massive methanol overdoses, pulmonary edema and cardiovascular collapse may occur. Acute hemorrhagic pancreatitis is not uncommon in patients with methanol overdose. Some long-term survivors of methanol poisoning report parkinsonism-like extrapyramidal symptoms.
Clinical diagnosis of methanol intoxication is suggested by the history, symptoms (particularly visual changes), ocular physical examination, and an anion gap metabolic acidosis in the presence of an osmolar gap.
1. Specific testing for serum methanol, although not widely available, is helpful as methanol levels >6.25 mmol/L (about 20 mg/dL) are considered toxic; levels >12.5 mmol/L (40 mg/dL) are very serious. Optic nerve damage correlates with levels >20 mmol/L and usually occurs at levels >30 mmol/L (100 mg/dL). Levels >150 mg/dL are potentially lethal. If available, serum formate concentrations better reflect the degree of toxicity, since a low or normal methanol level may reflect nearly complete conversion to formic acid.
2. Other suggested investigations include measurement of levels of electrolytes (with anion gap calculation), blood glucose, blood urea nitrogen, creatinine, serum osmolarity (and osmolar gap calculation [see Formulas in Alcohols]), arterial blood gas, lactate level, ethanol level, and lipase (if pancreatitis is suspected). A large anion gap not accounted for by lactate may be a clue to a potential toxic alcohol ingestion. High beta-hydroxybutyrate levels may suggest alcoholic ketoacidosis as the cause or contributor to the anion gap.
1. Decontamination: There are no known methods of decontamination. Activated charcoal does not adsorb methanol but may be worthwhile if coingestion of other drugs or toxins is suspected. If ingestion of a large volume occurred within 20 to 30 minutes of presentation, aspiration of gastric contents may be performed.
2. Antidotes and specific therapies:
1) By competitively inhibiting alcohol dehydrogenase and methanol metabolism, the amount of formaldehyde and formic acid produced can be limited. Therapy is indicated for patients with a methanol blood concentration >20 mg/dL (~6 mmol/L), and, when methanol levels are unavailable or delayed, should be used in patients with an anion gap metabolic acidosis and osmolar gap not accounted for by ethanol or a history of methanol ingestion with an osmolar gap >10 mOsm/L.
a) Ethanol: Administer as early as possible, orally in a conscious patient or intravenously in an unconscious patient, to a target blood ethanol level of at least 20 mmol/L (>100 mg/dL, ie, 1%) but <40 mmol/L (~200 mg/dL). When given orally, start with a loading dose of 1 mL of 95% ethanol/kg followed by a maintenance dose of 0.1 to 0.2 mL of 95% ethanol/kg/h. If pharmaceutical-grade ethanol is unavailable, commercial alcohol (typically 40% alcohol, 80 proof) can be given as a loading dose of 2 mL/kg and a maintenance dose of 0.2 to 0.4 mL/kg/h. The loading dose will need to be adjusted if the patient has coingested ethanol and the maintenance dose doubled during dialysis. Parenterally, ethanol is typically given as either a 5% or 10% solution of ethanol in 5% glucose (dextrose). The less concentrated solution is administered in a bolus at 15 mL/kg over 30 minutes followed by a maintenance dose of 2 to 4 mL/kg/h, and the higher concentration is given at half the bolus amount and half the maintenance rates. The maintenance rates will need to be doubled if the patient is on dialysis. Sometimes, ethanol is added to the dialysate.
b) Fomepizole (4-methylpyrazole, 4-MP) is a competitive inhibitor of alcohol dehydrogenase and an easier-to-use antidote than ethanol, associated with greater convenience but also a higher cost. It is loaded at a dose of 15 mg/kg (up to 1.5 g for patients >100 kg) diluted in at least 100 mL of normal saline or 5% glucose and administered IV over 30 minutes. This is followed by 10 mg/kg every 12 hours for 4 doses and then increased to 15 mg/kg every 12 hours until methanol levels are <6 mmol/L (20 mg/dL). Since fomepizole is dialyzed, the dosing frequency is increased to every 4 hours during dialysis.
Note that both ethanol and fomepizole are reasonable first-line agents for toxic alcohol poisoning. Despite the higher direct cost of fomepizole, we suggest its use due to ease of administration and likely less need for monitoring.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to lack of experimental head-to-head comparisons and only indirect data from observational studies. For discussion on ethanol vs fomepizole in toxic methanol poisoning, see Appendix 1 at the end of the chapter. Beatty L, Green R, Magee K, Zed P. A systematic review of ethanol and fomepizole use in toxic alcohol ingestions. Emerg Med Int. 2013;2013:638057. doi: 10.1155/2013/638057. Epub 2013 Jan 31. PubMed PMID: 23431453; PubMed Central PMCID: PMC3574646.
c) Folic or folinic acid (the latter preferred, especially in liver disease) can hasten the conversion of formate into carbon dioxide and water. A commonly suggested dose for either is 1 mg/kg (up to 50 mg) given IV every 4 hours.
d) If toxic alcohol levels are unavailable and the contents of the product ingested are unknown, we recommend treating for ethylene glycol toxicity as well (see Ethylene Glycol).
3. Accelerated elimination: Hemodialysis is very efficient at removing methanol and formate. Indications for dialysis include:
1) A methanol level >15 mmol/L (50 mg/dL) and/or an osmolar gap >10.
2) Visual symptoms.
3) Acute kidney injury or concomitant renal failure.
4) Suspected methanol ingestion with metabolic acidosis.
5) Ongoing metabolic acidosis not responding to bicarbonate therapy.
Typical dialysis endpoints are a methanol level <6 mmol/L (20 mg/dL) and normalization of anion and osmolar gaps.
4. Supportive care aims to maintain vital parameters and correct any disturbances.
1) Ensure airway patency. Intubate and assist ventilation if necessary.
2) Treat coma (glucose, thiamine) and seizures (benzodiazepines) if they occur.
3) In the presence of acidosis, toxic organic acids are protonated into uncharged molecules, making them easier to penetrate tissues (like the retina) and less likely to be excreted in the urine. Formate can be converted to formic acid (thus reducing retinal exposure) by treating metabolic acidosis (pH <7.3) with intravenous sodium bicarbonate dosed depending on results from ongoing blood gas measurement.
No head-to-head trials have been reported on the subject of whether ethanol or fomepizole is better for toxic methanol poisoning. In one systematic review, both ethanol and fomepizole have been safely used for methanol and ethylene glycol intoxication. Fomepizole is higher priced, but ethanol is more difficult to administer and requires greater staffing costs, frequent monitoring, and the need for a critical-care bed. Administration of fomepizole may negate the need for dialysis in patients without renal failure or profound acidosis but further research is needed. Both ethanol and fomepizole are reasonable first line agents for toxic alcohol poisoning, but fomepizole is easier to use.