Toxic alcohols: methanol and ethylene glycol poisoning

• Methanol and ethylene glycol (EG) are both small, water-soluble alcohols that are harmless while unchanged but become lethal after they are metabolised by alcohol dehydrogenase (ADH) to toxic acids. ^[1][2]
• The diagnosis is often clinical, supported by a high anion gap and a high osmolar gap; the definitive test is the measured serum concentration, which may take hours.
• Methanol produces visual failure from formic acid; ethylene glycol produces renal failure from glycolic and oxalic acids.
• The first-line antidote is fomepizole, which blocks ADH. Ethanol is the cheaper, universally available alternative, with complex dosing and central nervous system effects.
• Severe or worsening cases need haemodialysis, which clears both the parent alcohol and its acid metabolites. Guidelines from EXTRIP and others set different concentration and pH cut-offs, and they should be applied together with clinical judgement.

By the end of this page you should be able to:

1. Explain why unmetabolised methanol and ethylene glycol are relatively benign, and how ADH converts them to the acids that cause disease.
2. Interpret an anion gap and an osmolar gap, and name the thresholds that trigger antidote therapy and dialysis.
3. Recognise the clinical picture of methanol poisoning and that of ethylene glycol poisoning, and distinguish each from the other and from diabetic or alcoholic ketoacidosis.
4. Set out the management of a suspected ingestion: ADH blockade with fomepizole or ethanol, bicarbonate, dialysis endpoints, and supportive care.
5. List the EXTRIP indications for extracorporeal treatment for each alcohol.
6. Adjust fomepizole and ethanol dosing during haemodialysis, and know when antidote therapy can be stopped.
7. Describe the renal complication of methanol and the risk factors that make it more likely.

• Methanol (CH3OH) is present in windscreen washer fluid, industrial solvents, some antifreezes, carburettor cleaners, copy machine fluid, perfumes and several fuels. ^[1]
• Ethylene glycol (C2H6O2) is the principal component of most motor antifreezes and coolants, and a solvent in some industrial processes. It tastes sweet, which is why accidental ingestion is common. ^[2]
• Both are well absorbed from the gut within minutes, both distribute in total body water, and neither is protein bound. Their toxicity is delayed until ADH converts them to acid. ^{[3] [8]}

Ingestions are usually either accidental, most often in children exploring a sweet-tasting liquid or in an adult mistaking antifreeze for a drink, or deliberate, in self-harm or in the pursuit of intoxication when ethanol is unavailable. ^[2] Industrial and domestic exposures can also follow inhalation or skin absorption, although these are rare. ^[3] Methanol has caused mass poisonings when illegally manufactured spirits were contaminated with it; these outbreaks occur in places where alcohol regulation is weak and clinical recognition may be delayed. ^{[1] [8]} There is no reliable global incidence figure in the sources used here, and case fatality depends far more on the speed of treatment than on the setting.

• Route. Oral ingestion is by far the commonest route; rare cases follow inhalation or dermal absorption. ^[3]
• Underlying conditions. A history of alcohol use disorder, depression, homelessness, or poor access to medical care raises the risk of both self-harm and delayed presentation. ^{[1] [8]}
• Risk factors for kidney injury in methanol poisoning (a cohort of 603 hospitalised patients, of whom 135 developed acute kidney injury at admission) include anaemia, hypertension, volume depletion, sepsis, rhabdomyolysis and acute pancreatitis. ^[8] Sepsis carried the largest odds ratio. ^[8]
• Pre-existing chronic kidney disease increases the risk of methanol-related osmotic nephrosis, because clearance of both the alcohol and formate is reduced. ^[8]
• Children have been poisoned by small volumes of antifreeze; the lethal dose given in the product label is approximately 1.4 mL/kg for ethylene glycol and 1-2 mL/kg for methanol. ^[7]

Methanol is absorbed rapidly: absorption is essentially complete within 30 to 60 minutes, and peak blood concentrations occur within that window. ^{[1] [8]} It distributes throughout total body water and is not protein bound. ^[3] Once absorbed, hepatic ADH oxidises it to formaldehyde, which has a half-life of only one to two minutes before aldehyde dehydrogenase converts it to formic acid. ^{[3] [8]}

Formic acid is where the damage begins. It accumulates because the enzyme that clears it, 10-formyltetrahydrofolate dehydrogenase, depends on tetrahydrofolate and is easily saturated in humans. ^[3] The half-life of formic acid can therefore stretch to as much as 20 hours. ^[8] Formic acid is a strong acid, so it drives the metabolic acidosis; it also inhibits mitochondrial cytochrome c oxidase, blocking oxidative phosphorylation and producing tissue hypoxia. ^{[3] [8]} The undissociated acid is about three times more potent as an inhibitor of cytochrome oxidase than the formate anion. ^[8]

Tissues that are mitochondria-rich and energy-hungry, such as the optic nerve, retina and basal ganglia, suffer first. That is the origin of the blindness, and sometimes of Parkinsonian findings, in severe cases. ^{[3] [8]}

A useful bedside translation: 50 mg/dL of methanol raises the osmolar gap by about 17 mOsm/kg H2O. ^[8] This lets you back-calculate roughly what the blood concentration was before metabolism began.

Ethylene glycol is metabolised by the same enzyme, ADH, through a longer chain: glycolaldehyde, glycolate, glyoxylate and oxalate. ^[7] Glycolate is the main driver of the metabolic acidosis; oxalate precipitates with calcium as calcium oxalate crystals in renal tubules and elsewhere, producing the nephrotoxicity and hypocalcaemia. ^{[6] [7]} Like formic acid, glycolate and oxalate distribute in body water, are not protein bound, and are efficiently removed by dialysis. ^{[5] [6]}

The parent alcohol is, by itself, relatively non-toxic. ^[7] This is why a patient can look reasonably well for the first 6 to 12 hours after ingestion, then deteriorate as the acid metabolites accumulate. ^{[3] [6]}

Both alcohols share the same biphasic pattern on laboratory testing, and understanding it is the key to reading the bloods:

• Early, while unmetabolised alcohol is still present: the parent compound is an osmotically active particle that does not appear in the standard calculated osmolality formula, so the osmolar gap rises while the anion gap is often still normal.
• Late, as metabolites accumulate: the osmolar gap falls as the parent is converted, and the anion gap rises because the acids dissociate into hydrogen and their anions (glycolate, oxalate, formate).

By the time a patient is acidotic with a raised anion gap, a large fraction of the original alcohol has already been converted to toxic acid. ^{[5] [8]}

Ethylene glycol produces acute tubular injury through calcium oxalate crystal deposition, and has been associated clinically with flank pain, haematuria, oliguria and acute kidney injury progressing to anuria. ^[6] In one human autopsy/series context it is the renal damage that drives long-term morbidity.

Methanol is not traditionally regarded as a kidney-targeted poison, yet acute kidney injury is common in severe intoxication. Histology in biopsied cases has shown an osmotic nephrosis-like change: proximal tubular cells develop pinocytotic vacuoles and hydropic swelling without glomerular involvement. ^[8] Formic acid and the accompanying oxidative stress damage proximal tubular cells, and secondary injury from rhabdomyolysis, haemolysis, or hypotension adds to it. ^[8]

The AACT position statement (2002 edition) notes a latent period of roughly 12 to 24 hours, depending in part on the dose, before an uncompensated metabolic acidosis develops and visual function is impaired. ^[3] Early features are non-specific: nausea, vomiting, abdominal pain, mild central nervous system depression and tachypnoea from the accumulating acidosis. ^[3]

Visual symptoms are the hallmark and may be the presenting complaint: blurred vision, visual field defects, photophobia, and in severe cases complete blindness. ^{[3] [7]} Patients may also describe "snowfield" vision. Fundoscopy in methanol poisoning may show optic disc hyperaemia or papillitis. Neurological deterioration can progress to coma and seizures. ^{[1] [8]}

Early features resemble alcoholic intoxication but without the smell of ethanol: inebriation, ataxia, nausea, vomiting and abdominal pain. ^{[2] [6]} Tachycardia and hypertension are common, and hypocalcaemia may produce tetany or QT prolongation. As glycolate and oxalate accumulate over 12 to 24 hours, the patient develops a severe metabolic acidosis, renal colic and flank pain, haematuria, oliguria, then acute kidney injury. The EXTRIP workgroup (2023 edition) recognises neurotoxicity, metabolic acidemia, acute kidney injury and death as the major consequences. ^[6] Calcium oxalate crystals may be seen on urinalysis, though their absence does not exclude poisoning. ^[7]

Other causes of a high anion gap acidosis (mnemonic: MUDPILES or CAT MUDPILES) must be considered, along with the other toxic alcohols.

• Serum methanol and ethylene glycol concentrations are the definitive investigations. Many hospitals send them away and results are delayed; treatment must start on clinical grounds. ^{[1] [7]}
• Arterial blood gas: arterial pH, bicarbonate, lactate. An arterial pH below 7.3 is one of the triggers for ADH blockade in the criteria quoted in Nogueira and colleagues' review. ^[8]
• Anion gap = sodium - (chloride + bicarbonate). It is normal early and rises late. ^{[5] [8]}
• Serum osmolality is measured and the osmolar gap calculated: measured osmolality minus calculated osmolality. A gap above 10 mOsm/L (with compatible history, or above 20 mOsm/L as the sole laboratory clue) is one of the quoted triggers for antidote therapy. ^[8] EXTRIP effectively treats the osmolar gap as a surrogate for the missing concentration: in the ethylene glycol workgroup's recommendations, an osmolar gap above 50 mOsm was one of the triggers for dialysis when the concentration was unknown. ^[6]
• Renal function (creatinine, urea), electrolytes including calcium in EG, glucose, ketones, and liver function tests. ^[7]
• Formate concentration is measured in some centres and correlates with severity. ^[3]
• Urinalysis: calcium oxalate crystals support EG. ^[7]
• Fundoscopy and visual acuity in methanol, both at presentation and during recovery. ^{[3] [7]}

There are no formal clinical scores validated for either poisoning, but the same measurements serve to stage severity. A raised concentration alone is not enough; the metabolic acidosis tells you how much of the parent has already become acid and therefore how sick the patient is. ^{[5] [8]}

The antidote is not withheld for a laboratory result: it is started on suspicion. The Antizol label reproduces the standard rule. ^[7]

• Begin ADH blockade immediately if there is any suspicion of ingestion (history, or anion gap acidosis, raised osmolar gap, visual symptoms, oxalate crystals) or a measured methanol or ethylene glycol concentration above 20 mg/dL. ^[7]
• The Nogueira review quotes, from Kraut and Kurtz 2008, broader triggers: a plasma concentration above 20 mg/dL; a recent ingestion with an osmolar gap above 10 mOsm/L; or strong clinical suspicion with supportive laboratory findings (arterial pH below 7.3, bicarbonate below 20 mEq/L, or osmolar gap above 20 mOsm/L). ^[8]
• Haemodialysis should be considered in addition to the antidote if the concentration is 50 mg/dL or more, or if there is significant or worsening metabolic acidosis, or renal failure. ^[7]

For methanol the EXTRIP workgroup (2015 edition) gives more granular indications. ^[5] For ethylene glycol the workgroup (2023 edition) gives a separate list. ^[6] Both are set out in the management section.

1. Airway, breathing and circulation. Intubate if the Glasgow Coma Scale falls, seizures are imminent, or the airway is unprotected. ^[8]
2. Fluids and perfusion. Hypotension and low mean arterial pressure predict renal injury and death; give intravenous crystalloid and add vasopressors such as norepinephrine when needed. ^[8]
3. Bicarbonate. Intravenous sodium bicarbonate is vital for a significant acidosis. It improves myocardial function and peripheral vascular responsiveness, and by shifting the balance toward the dissociated anion it limits tissue penetration of the undissociated acid and may increase urinary excretion of formate. It is generally given when arterial pH is below 7.3, as a bolus of 1 to 2 mEq/kg followed by an infusion to a target pH above 7.3. More aggressive correction is often justified when pH is below 7.1 to 7.2. ^[8] In severe acidosis, haemodialysis is the most effective way to deliver buffer. ^[8]
4. Electrolytes. Potassium and calcium (especially in EG) need close monitoring; oxygen and ECG monitoring are standard. ^[7]
5. Decontamination. Gastric lavage or activated charcoal is generally ineffective more than 30 to 60 minutes after ingestion, because both alcohols are absorbed quickly. ^[8]
6. Do not delay antidote therapy for any investigation. ^{[7] [8]}

Blocking ADH stops the production of formic acid (methanol) and of glycolate and oxalate (EG). There are two agents.

Fomepizole is the preferred first-line antidote. It binds ADH 500 to 1000 times more tightly than ethanol does, so complete inhibition occurs at low blood concentrations, and it has a favourable side-effect profile (headache, nausea, dizziness), predictable pharmacokinetics, no sedation, and no effect on the osmolar gap, which means the gap can still be used to follow clearance if concentrations are not available. ^{[3] [4] [8]} The AACT methanol guideline (2002 edition) concluded that, although both are effective, fomepizole is the preferred antidote for methanol poisoning. ^[3] The AACT ethylene glycol guideline (1999 edition) noted fomepizole's advantages (validated efficacy, predictable kinetics, ease of administration, fewer adverse effects) against ethanol's advantages (experience and cost). ^[4] The trade-off is cost and availability. ^{[3] [4] [8] [2]}

Dosing from the Antizol label, which applies to both alcohols: ^[7]

• Loading dose 15 mg/kg intravenously, given as a slow infusion over 30 minutes.
• Then 10 mg/kg every 12 hours for four doses.
• Then 15 mg/kg every 12 hours until the alcohol is undetectable or below 20 mg/dL and the patient is asymptomatic with a normal pH.
• All doses are diluted in at least 100 mL of 0.9% sodium chloride or 5% dextrose and infused over 30 minutes. The solution solidifies below 25 degrees Celsius and should be liquefied by warming; this does not affect safety or potency. ^[7]
• The drug is dialyzable, so the interval is shortened to every 4 hours during haemodialysis, with a structured rule for dosing at the start, during and at the end of the session (see below).

Ethanol is the alternative when fomepizole is unavailable. It is a competitive substrate for ADH with roughly 10 to 20 times the affinity of methanol, and a serum concentration of about 100 mg/dL (22 mmol/L) saturates the enzyme and halts metabolite production. ^[8] It is cheap and universally available, but it sedates (confusing the neurological assessment), needs frequent blood-level monitoring, raises serum osmolality (obscuring the osmolar gap), can cause hypoglycaemia, and is cleared faster during haemodialysis. ^{[3] [8]}

Dosing from Nogueira and colleagues' 2026 review: ^[8]

• Intravenous: a 10% ethanol solution. Loading 0.6 to 0.8 g/kg over 30 to 60 minutes, then a maintenance infusion of 66 to 154 mg/kg/hour, adjusted for age, chronic alcohol use and measured levels. During haemodialysis the infusion rate should be raised two- to three-fold. ^[8]
• Oral or nasogastric (when no intravenous access is available): loading 0.8 g/kg, then 0.1 to 0.2 g/kg/hour, with frequent monitoring of the serum level to keep it near 100 mg/dL and to avoid toxicity. ^[8]

Cofactors. The AACT methanol guideline (2002 edition) recommends intravenous folinic acid to enhance formic acid metabolism, and this is continued through dialysis. ^{[3] [5]} Folic acid is also used in many protocols. EXTRIP's methanol consensus states that ADH blockers and folic or folinic acid should be continued during extracorporeal treatment. ^[5]

Indications differ between the two alcohols on paper, but in practice most teams dialyse for the same clinical reasons. ^{[5] [6] [7]} The conditions and thresholds the sources give are:

• Antizol label (applies to both). Haemodialysis should be considered in addition to the antidote for renal failure, significant or worsening metabolic acidosis, or a measured methanol or ethylene glycol concentration of 50 mg/dL or more. Dialyse to correct the metabolic abnormalities and to lower the concentration below 50 mg/dL. ^[7]
• EXTRIP methanol (2015 edition). Recommend dialysis for severe poisoning with any of: coma, seizures, new visual deficits, metabolic acidosis with blood pH 7.15 or lower, persistent metabolic acidosis despite supportive care and antidotes, or a serum anion gap above 24 mmol/L. Concentration thresholds: above 700 mg/L (21.8 mmol/L) on fomepizole; above 600 mg/L (18.7 mmol/L) on ethanol; above 500 mg/L (15.6 mmol/L) with no ADH blocker. Dialysis may also be indicated on the osmolar or osmol gap if no concentration is available, or in impaired renal function. ^{[5] [8]}
• EXTRIP ethylene glycol (2023 edition). Suggest dialysis when fomepizole is used and the concentration is above 50 mmol/L or the osmolar gap is above 50; recommend dialysis when ethanol is used and either of those thresholds is crossed; recommend when glycolate is above 12 mmol/L or the anion gap is above 27 mmol/L; suggest when glycolate is 8 to 12 mmol/L or the anion gap is 23 to 27 mmol/L; and recommend with severe features (coma, seizures or acute kidney injury). Mortality in the whole ethylene glycol cohort of 446 patients was 18.7%; in the subgroup with glycolate 12 mmol/L or less (or anion gap 28 mmol/L or less) it was only 3.6%, and in that subgroup dialysis did not improve outcomes. ^[6]
• Note that the wording differs ("suggest" versus "recommend") and so do the cut-offs. Guidelines differ in where they put the threshold because the evidence is sparse; clinical judgement and local availability matter. ^{[5] [6] [7]}

The preferred modality is intermittent haemodialysis for both alcohols; if it is not available, continuous renal replacement therapy is recommended over peritoneal or other methods. ^{[5] [6]}

When to stop dialysis.

• Methanol: when the concentration is below 200 mg/L (6.2 mmol/L) and there is clinical improvement. ^[5]
• Ethylene glycol: when the anion gap is below 18 mmol/L, or (suggested) when the concentration is below 4 mmol/L. ^[6]

When to stop the antidote. When the alcohol is undetectable or below 20 mg/dL and the patient is asymptomatic with a normal pH. ^[7]

For fomepizole, the Antizol label gives a precise table. ^[7]

• At the start of dialysis: do not give a dose if one was given less than 6 hours ago; give the next scheduled dose if it was given 6 hours ago or more. ^[7]
• During dialysis: give a dose every 4 hours.
• When dialysis ends: if it has been less than 1 hour since the last dose, give no dose at the end; 1 to 3 hours, give half the next scheduled dose; more than 3 hours, give the full next scheduled dose. ^[7]
• Off dialysis: give the next scheduled dose 12 hours after the last dose given. ^[7]

Ethanol is removed rapidly during dialysis as well, and the infusion rate must be raised two- to three-fold to stay near the target of 100 mg/dL. ^[8]

• Pregnancy. The Antizol label classifies fomepizole as pregnancy category C: animal reproduction studies have not been done and fetal risk is unknown. It should be given when clearly needed. ^[7]
• Children. Safety and effectiveness in paediatric patients have not been established on the Antizol label, although paediatric case series have used the same dosing per kilogram under close supervision. ^[7]
• Older adults. Safety and effectiveness in geriatric patients have not been established; renal function should be monitored. ^[7]
• Impaired renal function. Metabolites are renally cleared and dose intervals may need adjustment; dialysis is used where indicated. ^[7]
• Patients on chronic dialysis are effectively receiving the treatment that clears methanol and formate, but antidote adjustment is still required. ^[7]

• Where fomepizole is unavailable or unaffordable, ethanol is the pragmatic antidote. Its advantages are low cost and ready availability; its cost is the need for intensive monitoring that may only be safe in an intensive care unit. ^{[3] [8] [1]}
• The osmolar gap can guide treatment when no concentration is available; when neither the gap nor the concentration can be measured, treat on clinical suspicion and severe acidosis. ^{[5] [8]}
• Haemodialysis may not be available. Early antidote therapy, aggressive bicarbonate and correction of hypovolaemia are then the main interventions, with referral for dialysis as soon as possible. ^[8]
• A long-term solution to outbreak management is regionally coordinated poison centre advice and pre-positioned ethanol stocks. ^[8]

• Methanol. Formic acid toxicity produces a severe metabolic acidosis, visual loss that can be permanent, neurological deterioration (coma, seizures) and death if untreated. ^{[3] [8]} Permanent disability is reported most often in outbreaks with delayed care. ^[8]
• Ethylene glycol. Glycolate-driven acidosis, calcium oxalate deposition, acute tubular necrosis and acute kidney injury, hypocalcaemia, neurological injury and death. ^{[6] [7]}
• Acute kidney injury in methanol intoxication is a marker of severity and is associated with increased hospital mortality, intensive care use, ventilation and dialysis. ^[8]
• Antidote adverse effects. Fomepizole can cause headache, nausea, dizziness, rash and eosinophilia. ^{[7] [8]} Ethanol causes central nervous system depression, hypoglycaemia, hepatic effects and osmolar elevation. ^{[3] [8]}
• Post-dialysis complications include intracerebral haemorrhage if systemic anticoagulation was used; EXTRIP specifically recommends avoiding systemic anticoagulation during dialysis for methanol because it may increase the risk or severity of intracerebral bleeding. ^[5]

Prognosis is determined by the peak acidosis, the time to effective treatment and the presence of visual or renal injury at presentation. ^[8] Blindness at presentation and a low Glasgow Coma Scale portend poor outcomes. ^[8] In the EXTRIP ethylene glycol data set of 446 patients, overall mortality was 18.7%, but only 3.6% in the subgroup with glycolate 12 mmol/L or less. ^[6] Rapid recognition and combined antidote-plus-dialysis therapy has reduced mortality in modern series. ^[8] Visual recovery in methanol depends on how early the formate is cleared; ophthalmological follow-up is advised. ^{[3] [8]}

There is no screening programme for these poisonings. Prevention is practical:

• Store antifreeze, washer fluid and industrial solvents in original, childproof containers out of reach of children. ^[2]
• Public health measures against counterfeit or contaminated alcohol in areas where outbreaks occur. ^{[1] [8]}
• Workplace training and personal protective equipment for solvent exposure. ^[1]

Acid-base disorders; Acute kidney injury; Antidotes and management of poisonings; Toxidromes and approach to poisoning; Carbon monoxide and cyanide poisoning; Salicylate, lithium and iron poisoning; Methaemoglobinaemia and arsenic poisoning; Sepsis; Shock.

• Methanol and ethylene glycol are metabolised by alcohol dehydrogenase to acids that cause the disease: formic acid (methanol) and glycolate/oxalate (ethylene glycol). ^{[1] [6] [7]}
• The disease is biphasic: an early osmolar gap as the parent alcohol circulates, then a late anion gap as the acids accumulate. ^{[5] [8]}
• Methanol targets the optic nerve and brain; ethylene glycol targets the kidney as calcium oxalate; both cause a life-threatening metabolic acidosis. ^{[3] [6] [7]}
• Serum concentrations are definitive but are usually delayed; treatment starts on suspicion. ^{[7] [8]}
• ADH blockade is first-line: fomepizole is preferred, ethanol is the low-cost alternative. ^{[3] [4] [8]}
• Fomepizole dosing is 15 mg/kg loading, then 10 mg/kg 12-hourly for four doses, then 15 mg/kg 12-hourly, infused over 30 minutes, with the frequency raised to every 4 hours during dialysis. ^{[7] [8] [4]}
• Ethanol dosing aims for a serum level near 100 mg/dL, with a loading of 0.6-0.8 g/kg and a maintenance of 66-154 mg/kg/hour intravenously, rising two- to three-fold during dialysis. ^[8]
• Folinic acid is given with methanol to assist formate clearance, and continued through dialysis. ^{[3] [5]}
• Haemodialysis removes both parent and metabolite; intermittent dialysis is the modality of choice. ^{[5] [6]}
• Dialysis triggers include concentration 50 mg/dL or more, severe or worsening acidosis, renal failure, visual or neurological deficits, and the EXTRIP thresholds. Stop dialysis at methanol below 200 mg/L with clinical improvement, or when the ethylene glycol anion gap is below 18 mmol/L. ^{[5] [6] [7] [8]}
• Stop the antidote when the alcohol is below 20 mg/dL, the patient is asymptomatic and the pH is normal. ^[7]
• Methanol and ethylene glycol are both lethal in small volumes: about 1-2 mL/kg and 1.4 mL/kg. ^[7]
• Risk factors for methanol-related kidney injury include anaemia, hypertension, volume depletion, sepsis, rhabdomyolysis and acute pancreatitis. ^[8]