Toxic alcohols

Alcohol: Ethanol

• Risk assessment
  • Dose estimated by standard drinks (10g ethanol)
    • 375mL can mid-strength 3.5%
    • 100mL glass of wine
    • 30mL shot of spirit
  • Co-ingestion of other CNS depressants increases risk of respiratory depression
  • Seizures can occur in intoxication and withdrawal

Alcohol: Ethanol

• Toxic mechanism
  • Augmentation of GABA-A receptor + Glycine, NMDA, 5-HT3, adenosine and L-type Ca channel effects
  • Direct dose-dependent cardiovascular depression and impairs gluconeogenesis (hypoglycaemia in children and cirrhotics)
• Toxicokinetics
  • Absorption – Rapid
  • Distribution – Total body water 0.6L/kg
  • Metabolism
    • Oxidised by cytosolic and microsomal ADH to acetaldehyde, which in turn is metabolised by acetaldehyde dehydrogenase to acetate
    • Both cytosolic steps involve NAD to NADH reduction
    • Above serum ethanol 4mmol/L zero order kinetics apply (constant amount of ethanol metabolised per unit time – 4mmol/L/hr
    • Production of NADH pushses pyruvate to lactate (raised lactate) with less pyruvate available for gluconeogenesis and fatty acid oxidation (hypoglycaemia)

Alcohol: Ethanol

Alcohol: Ethanol

• Investigations
  • Screening ECG, BSL, paracetamol
  • Serum ethanol
    • Assists risk assessment in patients with CNS depression but cannot assume ethanol is the only cause
    • Whole blood ethanol (used for legal driving limits) levels are 10% lower than serum ethanol
• Management
  • Resuscitation and supportive care
    • ABC
    • Thiamine 200mg IV or PO TDS if potential thiamine deficiency
    • Monitor for urinary retention and place IDC if necessary
  • Decontamination
    • Activated charcoal does not bind ethanol
  • Enhanced elimination
    • Haemodialysis effective but rarely indicated
  • Antidotes – None available

Alcohol: Ethanol

• Disposition
  • Discharge once clinically well, ambulatory, eating, drinking, passing urine and cooperative
  • Counsel before discharge
  • Anticipate alcohol withdrawal during observation phase in alcohol dependence
• Pitfalls
  • Failure to regard ethanol intoxication as potentially life threatening
  • Failure to detect and manage other intoxications or medical conditions e.g. subdurals
  • Discharge of intoxicated patients before they are competent

Alcohol: Ethylene glycol

• Deliberate self-poisoning is usually lethal without timely intervention
• Found in antifreeze, coolant and radiator/brake fluid
• Risk assessment
  • >1mL/kg (1g/kg) is potentially lethal
  • Assume all deliberate poisonings are potentially lethal
  • Co-ingestion of ethanol complicates risk assessment
  • Dermal and inhalational exposure do not pose risk
  • Minor ingestions in children (taste/lick) do not require hospital assessment unless symptoms develop

Alcohol: Ethylene glycol

• Toxic mechanism
  • Toxic effect on CNS like ethanol
  • More important toxic effects are due to metabolites with severe raised anion gap metabolic acidosis due to accumulation of glycolic acid and lactate (increased NADH and decreased conversion of lactate to pyruvate – like ethanol)
  • Calcium oxalate crystals form in renal tubules, myocardium, muscles and brain
  • Hypocalcaemia follows
  • Acute oliguric renal failure occurs due to nephrotoxic glycolic acid and calcium oxalate

Alcohol: Ethylene glycol

• Toxicokinetics
  • Absorption – Rapid
  • Distribution – Total body water 0.6L/kg with rapid CNS penetration
  • Metabolism 
    • Sequential by ADH and acetaldehyde dehydrogenase to glycoaldehyde and glycolic acid, which in turn is converted to glyoxylic acid and oxalic acid
  • Elimination 
    • Half-life 3-9 hours
    • Ethanol in serum concentration of 11-22mmol/L competitively inhibits ADH preventing metabolism of ethylene glycol to glycoaldehyde with subsequent increase in elimination half-life to 14-17 hours, as ethylene glycol then has to be excreted solely by the kidney

Alcohol: Ethylene glycol

• Clinical features
  • Initial features within 1-2 hours: Like ethanol intoxication
  • Over 4-12 hours: Dyspnoea, tachypnoea, tachycardia, HTN, reduced LOC, seizures, coma, death
  • Flank pain and oliguria suggest oliguric renal failure
  • Late cranial neuropathies seen 5-20 days later (CN II, V, VII, VIII, IX, X, XII)

Alcohol: Ethylene glycol

• Investigations
  • Screening ECG, BSL, paracetamol
  • Chem20/VBG/serum osmolality
    • Elevated osmolar gap, anion gap acidosis and raised lactate are surrogate markers
    • Anion gap acidosis with elevated lactate +- osmolar gap with hypocalcaemia and rising creatinine are pathognomic of ethylene glycol toxicity
    • Elevated lactate must be interpreted with caution as some labs do not differentiate between lactate and glycolate
  • Serum ethanol – To determine if co-ingestant and to titrate therapy
  • Serum ethylene glycol if available
  • Urine microscopy – Calcium oxalate crystals are pathognomonic but absence does not rule out EG toxicity

Alcohol: Ethylene glycol

• Management
  • Resus, supportive care
    • Intubation without hyperventilation can cause acute decompensation
    • Consider bolus IV sodium bicarb 1-2mmol/kg pending dialysis
    • Treat seizures with benzos
    • Detect and correct hypoglycaemia, hyperkalaemia and hypomagnesaemia
    • ONLY correct hypocalcaemia if prolonged QT or refractory seizures
    • Fluid balance
  • Decontamination – Not indicated
  • Enhanced elimination
    • Haemodialysis reduces elimination half-life to 2.5-3.5 hours
    • Lactate-free dialysates with added bicarbonate may assist correction of acidaemia

Alcohol: Ethylene glycol

• Indications for haemodialysis
  • History of large EG ingestion with osmolar gap >10
  • Acidaemia with pH <7.30
  • Acute renal failure
  • Ethylene glycol level >8mmol/L if available
• End-points for haemodialysis
  • Correction of acidosis
  • Osmolar gap <10
  • Ethylene glycol <3.2mmol/L
• Antidotes
  • Ethanol and fomepizole used as temporising measures while awaiting haemodialysis

Alcohol: Ethylene glycol

• Disposition
  • Children or adults well after suspected unintentional ingestion with bicarb >20 at 4 or more hours after ingestion can be discharged
  • If acute renal failure ensues, dialysis may be required for several weeks but full recovery usually occurs
  • Follow-up of severe intoxications must exclude development of cranial neuropathies
• Handy tips
  • Co-ingestion of ethanol delays presentation of clinical features
  • Plan for transfer to haemodialysis facility as soon as provisional diagnosis of EG toxicity made
• Pitfalls
  • Absence of symptoms DOES NOT exclude significant ingestion
  • Normal osmolar gap (<10) does not exclude significant intoxication (even small amounts can be significant + metabolites cause greatest harm)
  • False reliance on normal serum bicarb to exclude significant ingestion when ADH blocked by ethanol

Alcohol: Isopropyl alcohol (isopropanol)

• Risk assessment
  • CNS intoxication identical to ethanol but more potent
  • Marked GI irritation and ketosis without direct acidosis
  • 1mL/kg of 70% solution can cause inebriation and >4mL/kg can cause coma and respiratory depression
  • Co-ingestion of other respiratory depressants increases the risk of respiratory depression
  • Children: Taste or lick does not require hospital evaluation unless symptomatic. >3mL associated with CNS depression. Significant toxicity possible from using rubbing alcohol on skin as an antipyretic measure
• Found in hand sanitisers, disinfectants, solvents, glass cleaner and perfumes

Alcohol: Isopropyl alcohol

• Toxic mechanism
  • Central augmentation of GABA-A receptors
  • Production of acetone and severe ketosis may contribute to CNS depression
  • Dose-dependent cardiovascular depression
  • Severe anion gap acidosis IS NOT a feature (unlike the other toxic alcohols)
• Toxicokinetics
  • Absorption – Rapid
  • Distribution – Total body water 0.6L/kg
  • Metabolism
    • Metabolised by hepatic alcohol dehydrogenase to acetone
  • Excretion
    • 40% excreted unchanged by lungs and kidneys
    • Acetone excreted unchanged by lungs and kidneys
    • Elimination half-life 16 hours

Alcohol: Isopropyl alcohol

• Duration of inebriation usually longer than ethanol ingestion
• Acetone breath may indicate ketosis
• Investigations
  • Screening ECG, BSL, paracetamol
  • Chem20, serum osmolality, serum acetone, VBG
    • Raised osmolar gap in absence of raised anion gap metabolic acidosis is suggestive of isopropyl alcohol intoxication (although also seen with ethylene glycol and methanol intoxication presenting early or with ethanol co-ingestion)
    • Serum acetone raised and qualitative ketones positive
  • Urinalysis for ketones

Alcohol: Isopropyl alcohol

• Resus and supportive care
  • Thiamine 200mg IV/PO TDS acts as a cofactor in metabolism to acetone
  • +-IDC
• Decontamination – Not indicated
• Enhanced elimination – HD highly effective but rarely indicated
• No antidotes
  • Ethanol not indicated as while ADH metabolises isopropyl alcohol to acetone, a good outcome is expected with supportive care

Alcohol: Methanol

• Often in setting of home-made distilled spirits (moonshine) or adulterated commercial products (esp. in developing world)
• Deliberate self-poisoning is usually lethal without appropriate intervention
• Also found in carburettor cleaning fluid, solvents, fuel additive, dyes, stains, racing car fuel
• Risk assessment
  • >0.5mL/kg of 100% methanol is potentially lethal
  • Ingestion of less than a mouthful is benign
  • Co-ingestion of ethanol complicates risk assessment
  • Dermal or inhalational exposure is very unlikely to lead to intoxication
  • Children: Taste or lick do not need hospital unless symptomatic. >0.25mL/kg can theoretically cause toxicity

Alcohol: Methanol

• Toxic mechanism
  • Production and accumulation of formic acid leads to severe raised anion gap metabolic acidosis and direct cellular toxicity through inhibition of cytochrome oxidase
  • Retinal injury and oedema lead to blindness
  • Subcortical white matter haemorrhages and putamenal oedema classic
  • Late hyperlactataemia due to inhibition of cellular oxidative metabolism
• Toxicokinetics
  • Absorption – Rapid peak levels in 30-60min
  • Distribution – Rapid across total body water (0.7L/kg)
  • Metabolism
    • By ADH to formaldehyde and then by aldehyde dehydrogenase (ALDH) to formic acid
  • Elimination
    • Half-life 24 hours
    • Ethanol at serum concentration 22mmol/L competitely inhibits ADH so that methanol cannot be metabolised to formic acid increasing half-life to 48 hours and methanol is eliminated by kidney and pulmonary routes unchanged

Alcohol: Methanol

• Clinical features
  • Similar to ethanol
  • Following latent period of 12-24 hours get headache, dizziness, vertigo, dyspnoea, blurred vision and photophobia
  • Severe intoxication leads to tachypnoea, drowsiness and blindness
  • Progressive to coma and seizures heralds cerebral oedema
  • Papilloedema with progressive demyelination and 1/3 suffer irreversible visual complications
  • Those who recover from serious CNS toxicity often show extrapyramidal movement disorders

Alcohol: Methanol

• Investigations
  • Screening ECG, BSL, paracetamol
  • Chem20, VBG, serum osmolality
  • Raised AG acidosis, raised lactate and osmolar gap are surrogate markers
  • Serum ethanol – to identify and titrate for treatment
  • Serum methanol if available
  • Brain CT – Characteristic ischaemia or haemorrhagic injury to basal ganglia in patients with permanent neurological sequelae

Alcohol: Methanol

• Management
  • Resuscitation
    • Maintain hyperventilation
    • Systemic acidosis enhances formic acid inhibition of cytochrome oxidase. If pH <7.30, administer bicarb in 50mmol aliquots targeting above 7.30
    • Treat seizures with benzos
    • Folic/Folinic acid 50mg IV q6h until poisoning definitively treated (cofactor in metabolism of formic acid)
  • Decontamination – Not indicated
  • Enhanced elimination
    • HD is definitive – removes methanol and formic acid and corrects acidosis
    • Lactate-free dialysate with added bicarb may help correct acidaemia

Alcohol: Methanol

• Indications for HD
  • Any patient that fulfills criteria for ADH blockade
  • Acidaemia pH <7.3
  • Visual symptoms
  • Renal failure
  • Deterioration in vital signs or electrolytes despite supportive care
  • Methanol >16mmol/L
• End-points for HD
  • Correction of acidosis
  • Osmolar gap <10
  • Methanol <6

Alcohol: Methanol

• EXTRIP
• Recommend IHD
  • Severe methanol poisoning
    • Coma
    • Seizures
    • New vision deficit
    • pH <7.15
    • Persistent metabolic acidosis despite support and antidotes
    • AG >24
• Serum methanol 
  • >700mg/L in context of fomepizole therapy
  • >600mg/L in context of ethanol therapy
  • >500mg/L in absence of ADH blockade
• In context of impaired kidney function

Alcohol: Methanol

• EXTRIP
  • IHD is preferred method
  • ADH inhibitors should be continued throughout IHD
  • Folic acid should be continued
  • Cease IHD when methanol <200mg/L and clinical improvement observed

Alcohol: methanol

• Antidotes
  • Ethanol and fomepizole while awaiting HD
• Disposition
  • Children and adults who are well with bicarb >20 after 8 hours of observation can be discharged
• Handy tips
  • Methylated spirits in Australia does not contain methanol
  • Co-ingestion of ethanol delays the onset of clinical features
  • Plan for t/f to haemodialysis facility as soon as provisional diagnosis made
  • Serum bicarbonate provides a surrogate marker for formic acid production
• Pitfalls
  • Absence of raised osmolar gap does NOT rule out intoxication
  • Absence of symptoms does not exclude significant ingestion
  • If HAGMA + Lactic acidosis check calcium – If hypocalcaemia maybe more likely ethylene glycol

Other toxic alcohols

• Assume all intentional ingestions as lethal
• Initially present as ethanol intoxication with progressive lactic acidosis and coma, shock, seizures and renal failure
• Onset of toxicity may be delayed up to 48 hours following ingestion of glycol ethers (EGBE, EGME) and diethyl glycol
• Rapid IV delivery of propylene glycol (as diluent of diazepam/phenytoin) is associated with sudden cardiovascular collapse – direct toxic effect

Other toxic alcohols

• Investigations
  • Screening ECG, BSL, paracetamol
  • Chem20, VBG, osmolality
  • Serum ethanol

Other toxic alcohols

• Management
  • Resuscitation
    • Maintain hyperventilation
    • Bicarb pending haemodialysis if pH <7.0
    • Treat seizures with benzos
  • GI decontamination not indicated
  • Enhanced elimination
    • Haemodialysis highly effective
    • Indications 
      • Serum pH <7.3
      • Serum bicarb <20
      • Osmolar gap >10
      • Worsening severe lactic acidosis despite supportive therapy
      • Deteriorating vital signs despite supportive care

Other toxic alcohols

• Antidotes
  • Ethanol and fomepizole can be used in glycol ether intoxication prior to HD as for ethylene glycol poisoning
    • Unclear if beneficial for other toxic alcohols
• Disposition
  • Adults and children: If clinically well with venous bicarb >20 after 8 hours observation can be discharged
• Handy tips
  • Serum bicarb and arterial pH are the chief surrogate markers of toxic alcohol production
• Pitfalls
  • Absence of symptoms does NOT exclude significant ingestion
  • Normal osmolar gap <10 does not exclude significant intoxication
  • Failure to recognise the potential for delay in development of toxicity in glycol ether and diethylene glycol ingestions

Last Updated on October 14, 2020 by Andrew Crofton