Toxic Alcohols: Methanol & Ethylene Glycol Poisoning — Viva

Q1: Mechanism and recognition (3 min)

Examiner: A chronic alcoholic presents 14 hours after drinking illicit alcohol with blurred 'snowstorm' vision, a severe high anion-gap metabolic acidosis and an elevated osmolal gap. Walk me through the mechanism and why this is methanol.^[1]

Expected answer:

• Toxic alcohols have relatively low toxicity until metabolised by hepatic alcohol dehydrogenase (ADH). Methanol -> formaldehyde -> formic acid (formate), the toxin.^[1]
• Formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality; the acidosis is caused directly or indirectly by formic acid production.^[1]
• Formate inhibits cytochrome oxidase and is the prime cause of ocular toxicity; acidosis increases toxicity further by enabling greater cellular diffusion of formic acid. Visual impairment ranges from blurred vision and altered visual fields to complete blindness.^[1]
• The dual laboratory signature — high anion gap (from formate) + elevated osmolal gap (from unmetabolised parent methanol) — plus visual symptoms localises it to methanol.^[1]
• Formate clearance is folate-dependent (10-formyl tetrahydrofolate synthetase) — the rationale for intravenous folinic acid.^[1]

Follow-up: Why is the osmolal gap elevated here? The unmetabolised parent methanol is a small osmotically active molecule that raises measured plasma osmolality without contributing to the anion gap.

Q2: The dual gap and its time-course (3 min)

Examiner: How do the anion gap and osmolal gap change over time, and what is the diagnostic trap?^[5]

Expected answer:

• The two gaps are inversely related over time.
• Early (before metabolism): the parent alcohol is osmotically active -> osmolal gap HIGH, anion gap near-normal.
• As ADH converts parent to organic acids, the anions accumulate -> anion gap RISES (consuming bicarbonate), while the osmotically active parent is depleted -> osmolal gap FALLS.
• The trap: late in the course a single measurement can show a NORMAL osmolal gap with a HIGH anion gap — this does NOT exclude toxic alcohol poisoning. A normal osmolal gap never excludes the diagnosis in a clinically suspicious case.^[5]

Follow-up — reproduce the calculations:

• Anion gap = [Na+] - ([Cl-] + [HCO3-]); normal 8-12 mmol/L (mainly negatively charged albumin).^[6]
• Osmolal gap = Measured osmolality - Calculated osmolality; Calculated = (1.86 x sodium + glucose + urea)/0.93 (all mmol/L). The reference value lacks consensus: at most 5 mOsm/kg has been proposed for healthy subjects; 20 mOsm/kg or more remains the practical suspicion threshold.^[5]

Q3: Management ladder (3 min)

Examiner: How do you manage suspected methanol poisoning, with doses?^[2]

Expected answer — stepwise:

1. ABCDE, IV fluids, oxygen, continuous monitoring.
2. BLOCK ADH immediately — do NOT wait for levels. Fomepizole 15 mg/kg load (IV or oral), then 10 mg/kg every 12 h until concentrations are under 30 mg/dL. During haemodialysis: 1 mg/kg/h continuous infusion. Fomepizole is first-line (no need to monitor fomepizole concentrations; fewer adverse effects than ethanol).^[2]
3. Sodium bicarbonate IV for ophthalmologic abnormalities or significant acidosis.^[1]
4. Cofactor: intravenous FOLINIC ACID (leucovorin) to enhance formate metabolism; continue folic/folinic acid during extracorporeal treatment.^[1][3]
5. Haemodialysis for EXTRIP severe methanol features — new vision deficits, pH of 7.15 or lower, anion gap over 24 mmol/L, coma or seizures.^[3]
6. Continue antidotes during extracorporeal treatment; stop ECTR when methanol is under 200 mg/L with clinical improvement.^[3]

Follow-up — when fomepizole is unavailable (ethanol): Ethanol is the traditional antidote but has never been studied prospectively and is not FDA-approved for ethylene glycol. It has complex dosing, difficulty maintaining therapeutic concentrations, a heavier monitoring burden and more adverse effects. Antidote dosing must be adjusted during extracorporeal treatment. Do not quote unsourced gram-per-kilogram loading numbers.^[2]

Q4: Haemodialysis indications and the ethylene glycol comparison (2 min)

Examiner: When do you dialyse, and how does ethylene glycol differ?^[3]

Expected answer — dialysis indications (EXTRIP):

• Methanol: coma, seizures, new vision deficits, pH of 7.15 or lower, persistent acidosis, anion gap over 24 mmol/L, concentration thresholds by antidote, impaired kidney function.^[3]
• Ethylene glycol: recommend for coma, seizures or AKI, glycolate over 12 mmol/L or anion gap over 27 mmol/L; suggest at glycolate 8-12 or anion gap 23-27. An absolute EG concentration above 50 mg/dL should no longer be used as an independent haemodialysis criterion in patients treated with fomepizole.^[4][7]

Ethylene glycol differences: metabolised by ADH to glycolate and oxalate. These toxic metabolites cause metabolic acidosis, renal failure, hypocalcaemia and aciduria; calcium oxalate contributes to acute tubular necrosis. Urinary calcium oxalate crystals are the bedside signature.^[4][11]

Q5: Pitfalls and special scenarios (2 min)

Expected answer:

• Co-ingested ethanol is itself the traditional ADH-blocking antidote and alters the time-course — still give fomepizole; monitor.^[2]
• Normal osmolal gap late does not exclude toxic alcohol; the reference value lacks consensus.^[5]
• Point-of-care lactate assay can misread glycolate and glyoxylic acid as L-lactate — a falsely elevated lactate paradoxically supports ethylene glycol.^[8]
• Isopropanol causes an increased osmolal gap, ketonemia and ketonuria WITHOUT metabolic acidosis, plus a fruity/sweet breath and CNS depression — NOT a toxic-alcohol-duo member; management is supportive; haemodialysis only for severe life-threatening poisoning.^[9]
• Propylene glycol — iatrogenic ICU cause of anion gap + osmolal gap, classically continuous lorazepam infusion; also phenytoin and phenobarbital; treat by withdrawing the source.^[10]
• Children: fomepizole is efficacious and safe; not recommended during pregnancy (Megarbane).^[2]

References11ShowHide

1. [1]Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning J Toxicol Clin Toxicol, 2002.PMID 12216995
2. [2]Mégarbane B Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole Open Access Emerg Med, 2010.PMID 27147840
3. [3]Roberts DM, Yates C, Megarbane B, et al Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement Crit Care Med, 2015.PMID 25493973
4. [4]Ghannoum M, Gosselin S, Hoffman RS, et al Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup Crit Care, 2023.PMID 36765419
5. [5]Skaaland H, Larstorp ACK, Lindberg M, Jacobsen D Reference values for osmolal gap in healthy subjects and in medical inpatients Scand J Clin Lab Invest, 2020.PMID 31809199
6. [6]Seifter JL Anion-gap metabolic acidemia: case-based analyses Eur J Clin Nutr, 2020.PMID 32873962
7. [7]Sivilotti ML, Burns MJ, McMartin KE, Brent J Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. For the Methylpyrazole for Toxic Alcohols Study Group Ann Emerg Med, 2000.PMID 10918102
8. [8]Tintu A, Rouwet E, Russcher H Interference of ethylene glycol with (L)-lactate measurement is assay-dependent Ann Clin Biochem, 2013.PMID 23129723
9. [9]Slaughter RJ, Mason RW, Beasley DM, Vale JA, Schep LJ Isopropanol poisoning Clin Toxicol (Phila), 2014.PMID 24815348
10. [10]Pillai U, Hothi JC, Bhat ZY Severe propylene glycol toxicity secondary to use of anti-epileptics Am J Ther, 2014.PMID 22926232
11. [11]Taira S, Tamayose S, Kikumura T, Nishihira M Clinical manifestations and renal pathology of ethylene glycol CEN Case Rep, 2025.PMID 39134788