Management of Methanol and Glycol Poisoning

Methanol Methanol is found in antifreeze solutions and windscreen-washing fluid, and is widely used as a solvent. Ingestion of as little as 10 mL of pure methanol has caused permanent blindness, and 30 mL is potentially fatal. Methanol itself is of low toxicity but produces toxic metabolites, the most important of which is formate. There is a direct correlation between the formate concentration and toxicity. The acidosis observed is caused directly or indirectly by formate production. Formate has also been shown to inhibit cytochrome oxidase. It is the principal cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formate into cells. Methanol causes mild and transient inebriation, nausea, vomiting, abdominal pain and mild central nervous system depression. This is followed by a latent period of 12–24 h, after which uncompensated metabolic acidosis develops (mortality increases with the severity and duration of the acidosis), coma supervenes, and visual function becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. Hyperglycaemia and pancreatitis may ensue. Patients who survive may suffer permanent neurological sequelae, including blindness, and parkinsonian-like features, such as rigidity and hypokinesis. Respiratory arrest, coma and severe metabolic acidosis are strong predictors of poor outcome. Supportive measures should be employed, and metabolic acidosis should be treated conventionally. If presentation is early after exposure, the priority is to inhibit methanol metabolism using either intravenous fomepizole or ethanol. Fomepizole requires less monitoring, but is more expensive than ethanol. After a loading dose of fomepizole 15 mg/kg over 30 min, four 12-hourly doses of 10 mg/kg should be given, followed by 15 mg/kg 12-hourly until the methanol concentration is not detectable. As fomepizole is dialyzable, if haemodialysis is employed, fomepizole should be given 6 h after the first dose and every 4 h thereafter. Alternatively, an infusion of fomepizole 1.0–1.5 mg/kg/hr can be given during dialysis. If fomepizole is unavailable, a loading dose of intravenous ethanol 50 g for an adult (50 mL of absolute ethanol in 1 L 5% glucose, that is a 5% ethanol solution) should be given, followed by an intravenous infusion of ethanol, 10–12 g/h (most easily given as 1 L 5% ethanol solution over 4–5 h), to achieve a blood ethanol concentration of approximately 1000 mg/L. Ethanol administration should be continued until methanol is undetectable in the blood. If haemodialysis is used, higher ethanol doses (17–22 g/h) must be given, as ethanol is readily dialyzable. Ideally, plasma methanol and alcohol concentrations should be measured frequently until recovery. Haemodialysis will enhance the elimination of methanol and formate and will correct severe metabolic abnormalities. Haemodialysis should be employed, particularly if presentation is late and marked metabolic acidosis is present. In addition, folinic acid 30 mg intravenously 6-hourly should be given to enhance formate metabolism. Ethylene glycol Ethylene glycol is most commonly used as an antifreeze. It may be drunk accidentally by children or intentionally by adults, sometimes as a substitute for ethanol. A lethal dose is of the order of 100 mL by ingestion. Ethylene glycol is oxidized by alcohol dehydrogenase to glycoaldehyde. Aldehyde dehydrogenase rapidly converts glycoaldehyde to glycolate. The conversion of glycolate to glyoxylate is slow. A small proportion of glyoxylate is metabolized to oxalate. Calcium ions chelate oxalate to form insoluble calcium oxalate monohydrate crystals; these may be seen in the urine. Ethylene glycol’s toxicity depends predominantly on its metabolites, though the initial mild inebriation is due to ethylene glycol itself. Central nervous system symptoms occur 6–12 h after ingestion and coincide with the peak production of glycolaldehyde; aldehydes inhibit many aspects of cellular metabolism. Glycolate is largely responsible for the marked acidosis seen in severe cases; lactate concentrations are generally not very high. Lactate is produced as a result of the large amount of the reduced form of nicotinamide adenine dinucleotide (NADH) formed by the oxidation of ethylene glycol and by inhibition of the tricarboxylic acid cycle by the condensation products of glyoxylate. Calcium oxalate monohydrate crystals are the cause of cerebral oedema and kidney failure. After a brief period of inebriation due to ethylene glycol itself, metabolic acidosis develops, followed by tachypnoea, coma, seizures, hypertension, the appearance of pulmonary infiltrates and oliguric kidney failure. If untreated, death from multi-organ failure usually occurs 24 to 36 h after ingestion. Calcium oxalate monohydrate crystalluria is diagnostic, and hypocalcaemia is frequent as a result of its formation. Severe acidosis, hyperkalaemia, seizures and coma carry a poor prognosis, and serum glycolate concentrations ≥770 mg/L are associated with a poor outcome. Supportive measures to combat cardiorespiratory depression should be employed, and metabolic acidosis, hypocalcaemia and kidney failure should be treated conventionally. If the patient presents early after ingestion, the priority is to inhibit metabolism using either intravenous fomepizole or ethanol (see above). Haemodialysis removes ethylene glycol, glycolaldehyde and glycolate but not oxalate, and will also correct acid–base disturbances. Haemodialysis should be employed, particularly if presentation is late and marked metabolic acidosis is present. Dialysis should be continued until the glycol and glycolate are no longer detectable in the blood. Diethylene glycol Diethylene glycol is used as a coolant, a building block in organic synthesis, and a solvent. It can also be found in some hydraulic and brake fluids. Many cases have resulted from the use of diethylene glycol in the production of medicines. Diethylene glycol is metabolized by alcohol dehydrogenase to 2-hydroxyethoxyacetaldehyde and by aldehyde dehydrogenase to 2-hydroxyethoxyacetate and diglycolic acid. Metabolic acidosis is primarily due to 2-hydroxyethoxyacetate, but lactate also plays a part in severe poisoning. Diglycolic acid is responsible for the development of kidney failure (proximal tubular necrosis) and hepatic damage. Nausea and vomiting, headache, abdominal pain, coma, seizures, metabolic acidosis and acute kidney failure have been reported most commonly. Pancreatitis and hepatitis have been observed, together with cranial neuropathies and demyelinating peripheral neuropathy. Management is identical to that for ethylene glycol, with the use of fomepizole or ethanol to prevent metabolism of diethylene glycol and haemodialysis to remove the glycol. It is not known whether 2-hydroxyethoxyacetate or diglycolic acid is removed by haemodialysis.