Methanol toxicity

Background

• Found in antifreeze, windshield washer fluid, solvents
• Colorless, volatile liquid with distinctive “alcohol” odor
• Methanol slowly metabolized to formaldehyde by alcohol dehydrogenase
• Formaldehyde then quickly metabolized to formic acid by aldehyde dehydrogenase
• Very toxic formic acid slowly metabolized, which translates to two clinical features:
  • Latency and delay in onset of symptoms
  • Prolonged symptoms due to accumulation of formic acid
• Parent compound causes only mild inebriation; metabolite (formic acid) causes toxicity both directly and indirectly
  • Binds to cytochrome oxidase > blockade of oxidative phosphorylation > lactic acidosis
  • In itself causes anion gap metabolic acidosis
• Most exposures from ingestion; may be systemically absorbed after inhalation or dermal exposure but rarely causes significant clinical toxicity

Pharmacology

• Peak serum concentration 30-60 minutes, elimination half-life 12-20 hours
• Permanent blindness reported at as little as 0.1 mL/kg (6-10 mL in adults)
• Lethal dose = 1-2 mL/kg
• Metabolite (eg. formic acid) causes toxicity, but does NOT cause osmolal gap

Clinical Features

Symptoms begin 12-24hr after ingestion (may occur even later if ETOH is co-ingested as EtOH competes with alcohol dehydrogenase and has greater affinity for the enzyme than methanol)

CNS depression

• Confusion, ataxia, depressed mental status, seizure
  • Less inebriating than ethanol or ethylene glycol
• Visual disturbances (50% of patients)
  • Development may precede or parallel that of other clinical symptoms
  • Cloudy or blurry vision ("stepping out into a snowstorm")

Anion-gap acidosis

• May be severe (bicarb < 5, pH < 7)
• Compensatory tachypnea

Cardiovascular

• Tachycardia
• Hypotension→ can progress to shock

Respiratory

• Tachypnea
• shortness of breath (compensating for metabolic acidosis) → may progress to respiratory depression and/or failure

GI

• Abdominal pain
• nausea and vomiting
• Anorexia
• Pancreatitis and gastritis
• Transaminitis (mild and transient)

Differential Diagnosis

Sedative/hypnotic toxicity

• Absinthe
• Barbiturates
• Benzodiazepines
  • Flunitrazepam (Rohypnol)
• Chloral hydrate
• Gamma hydroxybutyrate (GHB)
• Baclofen toxicity
• Opioids
  • Lomotil toxicity
  • Loperamide toxicity
• Toxic alcohols
  • Ethanol
  • Ethylene glycol
  • Isopropyl alcohol
  • Methanol
• Xylazine toxicity

Evaluation

Chemistry

• Anion gap acidosis

Serum Osm

• Osm gap (measured - calculated)
  • Calculated serum osm = 2Na + BUN/2.8 + glucose/18 + ethanol/4.6
  • Normal is < 10
  • Note: Cannot rule out toxic ingestion with a "normal" osmol gap
  • Only parent alcohol is osmotically active
  • Delayed presentation may mean that much of it is already metabolized

Toxic alcohol levels

Methanol

• <20mg/dL - asymptomatic
• >20mg/dL - CNS symptoms may appear
• >50mg/dL - ocular problems
• >150-200mg/dL - risk of fatality

Other labs

• Ethanol level
• VBG

Toxic Alcohols Anion/Osmolar Gaps

Osmolar gap	Metabolic acidosis	Osmolar gap	Anion gap	Ketones	Ca Oxolate stones	Reduced vision	Management
Ethanol	+	+	+ (if ketoacidosis)	+	-		Mainly supportive
Ethylene glycol	+	+	+	-	+	-	Fomepizole, Thiamine, Pyridoxine, +/- Dialysis
Methanol	+	+ (early on, then disappears)	+	-	-	+	Fomepizole or ethanol, Folinic acid, +/- Dialysis
Isopropyl alcohol	-	+	-	+	-	+	Mainly supportive
Propylene gylcol	+	+ (initially)	+ (converted to lactate)	-	-	-

Management

ADH enzyme blockade

Both fomepizole and ethanol have greater affinity for ADH than methanol. Providing IV alcohol is not commonly used but a possible treatment option

Fomepizole

• Dosing: 15mg/kg IV over 30min; follow by 10mg/kg q12hr until level <20 or acidosis resolves
• Indications:
  • Methanol level >20mg/dL (=6.24 mmmol/L)
  • Suspected significant methanol ingestion with ETOH level <100mg/dL
  • Coma or altered mental status in patient with unclear history and osm gap >10
  • Coma or altered mental status in patient with unclear history and unexplained met acidosis and ETOH level <100

Ethanol

• Dosing
  • IV: load 800mg/kg; then give 100mg/kg/hr
  • Oral: 3-4 1-oz "shots" of 80-proof liquor); then give 1-2 "shots" per hour
• BAL of 100-150 completely saturates alcohol dehydrogenase
• Disadvantages: makes patients inebriated thus requiring close monitoring for CNS and respiratory depression, individual metabolic variations make dosing complicated, frequent serum level monitoring and dosage adjustments are required, administration of the 10% IV ethanol solution requires central venous access

Correction of metabolic acidosis

Profound acidemia is corrected with sodium bicarbonate

• Bicarbonate 1-2mEq/kg IV bolus to attain pH = 7.45-7.50
• Follow by infusion of 150mEq/L in D5 at 1.5-2x maintenance fluid rate
• Monitor for worsening hypocalcemia

Dialysis

Indications:

1. Refractory metabolic acidosis (pH <7.25) with AG >30
2. Renal insufficiency
3. Visual symptoms
4. Deteriorating vital signs despite aggressive supportive care
5. Electrolyte abnormalities refractory to conventional therapy
6. Methanol level >50mg/dL (controversial)

Enchanced formic acid metabolism

1. Folinic acid 50mg IV q4hr
   • May facilitate breakdown of formic acid into carbon dioxide and water

Disposition

• Consult toxicologist and/or poison control

See Also

• Ethylene Glycol Toxicity
• Toxic Alcohols
• In-Training Exam Review