Ethylene glycol inebriation

This is a potentially life-threatening ingestion of ethylene glycol

Ethylene glycol can cause life-threatening toxicity if more than 1mL/kg is ingested. Ingestion of anymore than a mouthful requires hospital assessment. A taste or lick in a child is benign.

This is how the body handles ethylene gylcol (ADME):

• Absorption: Absorption from the gastrointestinal tract is rapid with peak concentrations occurring at 1-4 hours.
• Distribution: Ethylene glycol is distributed to total body water with rapid CNS penetration. It is not protein bound.
• Metabolism: Ethylene glycol is metabolised in the liver. It is first converted by alcohol dehydrogenase to glycoaldehyde, which is then metabolised to glycolic acid by aldehyde dehydrogenase. Glycolic acid is further metabolised to glyoxylic acid and oxalic acid.
• Elimination: Ethylene glycol has an elimination half-life of about 3 hours.

The toxic effects, other than the early state of alcohol intoxication, are mediated by ethylene glycol’s metabolites.

Initially there is a high osmolar gap due to the presence of ethylene glycol in the circulation. As it is metabolised the osmolar gap starts to normalise, but a HAGMA (high anion-gap metabolic acidosis) develops due to the formation of glycolic acid and its metabolites, as well as hyperlactemia (increased NADH suppresses the conversion of lactate to pyruvate).

Oxalic acid complexes with calcium, leading to crystal formation in the renal tubules, myocardium, muscles and brain. Hypocalcemia and renal failure (due to the nephrotoxic effects of calcium oxalate and glycolic acid) ensue.

As with the child in the case, the patient initially appears drunk following the ingestion of a significant amount of ethylene glycol. This state of alcohol intoxication occurs within 1-2 hours and is characterized by euphoria, nystagmus, drowsiness, nausea and vomiting. The patient has a high osmolar gap.

Over the next 4-12 hours the alcohol is metabolized into its toxic metabolites. As the high osmolar gap resolves, HAGMA (high anion gap metabolic acidosis) and hypocalcemia occur, with clinical manifestations that include dyspnoea, tachypnea, tachycardia, hypertension, shock, coma, tetany, seizures and death. Renal failure is heralded by flank pain and oliguria.

In survivors, late-occurring cranial neuropathies may also occur about 5-20 days post-ingestion.

No — at least not a useful one!

Alcohols are rapidly absorbed by the gastrointestinal tract. Furthermore, they do not bind to activated charcoal.

Useful investigations can include:

• Blood gas: HAGMA (may not be present early in the clinical course or if ethanol is coingested with ethylene glycol)
• Serum osmolarity: calculate an osmolar gap (gap may be normal in late toxicity, due to the metabolism of ethylene glycol) — see Q7.
• Ca and UEC: hypocalcemia and evidence of renal impairment is highly suggestive of ethylene glycol toxicity
• Ethanol levels: check for coingestion (primarily in the adult patient) and to guide further management.
• Serum ethylene glycol levels: not usually readily available, may take days for a result to be obtained
• serum beta-hydroxybutyrate levels: may be required to rule out alcoholic ketoacidosis in some settings
• urinalysis: oxalic acid crystals are pathognomonic for ethylene glycol poisoning, and para-aminohippuric crystals may also be also seen. Urine flourescence under a Wood’s lamp may also be detected if the radiator coolant contained fluorescein

Osmolar gap = (measured serum osmolality) — (calculated osmolarity)

A normal osmolar gap is <10.

Calculated osmolarity = 2 x [Na] + [glucose] + [urea] + [EtOH]

Note that all concentrations used in the above calculations are in mmol/L.

Yes — he may well need definitive treatment is not available at a peripheral center.

Hemodialysis (or hemofiltration)

Indications for hemodialysis include:

• ethylene glycol level > 8 mmol/L (50 mg/dL)
• acidosis < pH 7.25
• acute renal failure
• osmolar gap >10 and history of large ethylene glycol ingestion

The endpoints for discontinuing hemodialysis are:

• ethylene glycol level < 3.2 mmol/L (20 mg/dL)
• normal osmolar gap <10
• correction of acidosis

The evidence base for these indications and cutoffs is largely anecdotal. Interestingly there is a recent report by Buchanan et al (2010) of a patient with an ethylene glycol level 700 mg/dL who was treated with fomepizole alone, and did not require hemodialysis.

Fomepizole (4-methylpyruvate) is competitive antagonist that prevents ethylene glycol from being converted into its toxic metabolites by alcohol dehydrogenase. It is widely used in North America but is not currently available in Australia.

Ethanol also competes with toxic alcohols for conversion by alcohol dehydrogenase. Administration of ethanol can buy time until the patient is able to be dialysed. In the presence of ethanol or fomepizole, ethylene glycol is renally eliminated with a half life of about 17 hours.

Ethanol may be administered orally or IV — I personally prefer oral administration if possible 😉

Enteric administration of ethanol (oral or via nasogastric tube):

• Loading dose (unless the patient is already drunk on ethanol!): 1.8 mL/kg of 43% ethanol, or 4 x 30 mL shots of vodka in a 70kg adult.
• Maintenance: 0.2-0.4 mL/kg/h of 43% ethanol, or 40 mL shot each hour.

Intravenous administration of ethanol (make 10% ethanol by adding 100 mL of 100% ethanol to 900 mL of 5% dextrose in water):

• Loading dose (unless the patient is already drunk on ethanol!): 8 mL/kg of 10% ethanol.
• Maintenance: 1-2 mL/kg/h of 10% ethanol.

Supportive care and monitoring:

• The patient is kept in a monitored area
• The patient’s mental state closely observed
• Blood or breath ethanol levels can be checked every 2 hours to maintain blood ethanol concentrations of 100-150 mg/dL or 22-33 mmol/L
• Reduce rate of ethanol administration if blood ethanol concentration exceeds 150 mg/dL (33 mmol/L)
• The infusion is continued until haemodialysis is commenced

It may seem hard to believe, but there actually are some downsides to administering ethanol to patients:

• the patient will get even more drunk…
• hypoglycemia may occur, especially in children
• enteric administration may be complicated by gastritis and absorption may be less reliable
• intravenous ethanol needs to be pharmaceutical grade (not always readily available) and can cause local phlebitis

Other serious or life-threatening complications of ethylene glycol toxicity may require urgent management.

These include:

• Progressive coma or respiratory failure —
  Intubation and ventilation may be required. A 1 mmol/kg bolus of NaHCO3 prior to intubation may help prevent decompensation due to worsening acidosis. For the same reason the patient should be hyperventilated following intubation.
• Seizures —
  control with IV benzodiazepines, and intubate and ventilate as required (see above).
• Hypocalemia —
  correct if there are refractory seizures or prolonged QT only – otherwise calcium administration may contribute to further calcium oxalate crystal formation.
• Hypoglycemia, hyperkalemia and hypomagnesemia —
  correct as needed.

Some experts also advocate cofactor therapy with pyridoxine, folate and thiamine to promote the metabolism of glyoxylic acid to nontoxic metabolites.

Ethylene glycol is found in:

• Radiator coolants and antifreeze in concentrations 20-98%
• De-icing solutions
• Solvents
• Brake fluids

• Barceloux DG, et al (1999). American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee. Journal of Toxicology – Clinical Toxicology, 37 (5), 537-60 PMID: 10497633
• Brent J, McMartin K, Phillips SP et al.  Fomepizole for the treatment of ethylene glycol poisoning.  New England Journal of Medicine 1999; 340:832-838. PMID: 10080845
• Buchanan JA, et al. Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone-A Viable Therapeutic Option. J Med Toxicol. 2010 Apr 27. [Epub ahead of print] PMID: 20422336.
• Caravati EM, et al (2005). Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management. Clinical toxicology (Philadelphia, Pa.), 43 (5), 327-45 PMID: 16235508
• Lepik KJ, et al (2009). Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Annals of Emergnecy Medicine , 53 (4), 439-2147483647 PMID: 18639955
• Mégarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med. 2005 Feb;31(2):189-95. Epub 2004 Dec 31. PMID: 15627163
• Sivilotti ML. Ethanol: tastes great! Fomepizole: less filling! Ann Emerg Med. 2009 Apr;53(4):451-3. Epub 2008 Nov 4. PubMed PMID: 18986732.