Ethylene glycol is a sweet tasting, colourless, odourless compound that is used as an antifreeze, and is a constituent of brake fluids, engine coolants and some solvents. It has properties similar to ethanol but is converted by alcohol dehydrogenase to toxic metabolites that cause a severe metabolic acidosis and renal toxicity. The commonly quoted minimum lethal dose is 1-1.5 mL/kg (as little as 100 mLin an adult), but there are reports of individuals surviving much larger ingestions and clinical outcome depends to a large degree on the time between exposure and the institution of definitive management. Treatment with ethanol or fomepizole and haemodialysis may be lifesaving.
Ethylene glycol is a gastric irritant. Central nervous system (CNS) depression results from ethylene glycol and the CNS effects of a number of metabolites including glycolic acid. Ethylene glycol has a relatively short half-life, and so in cases of prolonged coma it is most likely the secondary metabolic disturbances and cerebral oedema causing the on-going CNS depression.
Renal toxicity in the form of acute tubular necrosis results from deposition of calcium oxalate crystals in the proximal tubules of the kidney. However it is unlikely that this is the only mechanism of renal toxicity. Other proposed mechanisms include a direct cytotoxic effect of ethylene glycol itself. Calcium oxalate crystals can be seen in the urine, but their absence does not exclude ethylene glycol toxicity.
Myocardial dysfunction may occur following deposition of calcium oxalate crystals in myocardial cells. Secondary insults include the deleterious effects of hypocalcaemia on the cardiac conduction system, and the negative inotropy produced by metabolic disturbances and acidosis.
Ethylene glycol itself is essentially non-toxic in terms of metabolic and acid-base disturbances. The metabolic acidosis results primarily from the accumulation of glycolic acid. Lactic acid contributes to a lesser degree via the promotion of lactic acid formation due to reduced NAD/NADH ratios.
Conversion of glycolate to glyoxylate is the rate limiting step in ethylene glycol metabolism. The reaction is saturable and therefore glycolate accumulates and dissociates to glycolic acid. Evidence suggests that the amount of oxalate produced is relatively small and that this does not contribute significantly to the anion gap metabolic acidosis. Hypocalcaemia secondary to calcium-oxalate chelation can theoretically occur.
Ethylene glycol is rapidly absorbed from the gastrointestinal tract with peak concentrations occurring within 1-3 hours. Ethylene glycol is not efficiently absorbed via the skin or respiratory system.
Ethylene glycol has high water and lipid solubility and a volume of distribution similar to body water (0.6 L/kg).
Some ethylene glycol (approximately 20%) is excreted unchanged in the urine however the major pathway is metabolism by alcohol dehydrogenase to glycoaldehyde from which aldehyde dehydrogenase forms glyocolate. Further metabolism to nontoxic substances requires pyridoxine, thiamine and magnesium.
Ethylene glycol's half-life in overdose is about 3 hours, but can range up to 8.6 hours. In the presence of an antidote the half-life increases (17-18 hours with ethanol, up to 20 hours with 4-methylpyrazole [fomepizole]).
The initial effects of ethylene glycol resemble those of alcohol with CNS depression, ataxia, nausea and vomiting. Subsequent CNS effects may be secondary to the acidosis or to the activity of the metabolites and include coma and convulsions. Patients may appear “drunk”, but do not have the characteristic smell associated with ethanol intoxication. In very severe poisoning there may be deposition of calcium oxalate crystals in the brain causing seizures and potentially permanent injury.
With the development of acidosis, tachycardia, tachypnoea and hypertension may occur however more severe toxicity is manifested by hypotension and cardiogenic shock.
Acute tubular necrosis leading to oliguria and renal failure may occur. Calcium oxalate crystals may be seen in the urine and the renal damage may be permanent.
The major features seen are a severe acidosis with a raised anion gap. The osmolal gap may be only mildly elevated in clinically significant poisoning (i.e. still be within the normal range). A concentration of 50 mg/dL produces a rise in the osmolal gap of only 10 mmol/kg. Some of the metabolites may also contribute to the osmolal gap. The relationship between anion and osmolar gaps and the clinical course has been characterised for methanol.
The patients should have their electrolytes (including calcium and magnesium) measured.
These electrolytes should be repeated regularly in confirmed cases of ethylene glycol poisoning as late deterioration may occur.
Metabolism of ethylene glycol and the formation of glycolic and lactic acids produces a raised anion gap metabolic acidosis. It is important to remember that patients who present early following ethylene glycol ingestion, prior to significant ethylene glycol metabolism, may have normal acid-base status and a normal anion gap. This situation signifies a good prognosis, as long as the diagnosis is made and appropriate treatment instituted to prevent the formation of toxic metabolites. Patients who present late following significant ethylene glycol ingestion are likely to have an established raised anion-gap metabolic acidosis.
There are many pitfalls in using the osmolal gap to make the diagnosis of significant ethylene glycol exposure. An ethanol concentration is required to calculate a meaningful osmolal gap in ethylene glycol poisoning. Ethanol will contribute to any osmolal gap. A significantly raised osmolal gap is useful in providing evidence to confirm a significant ethylene glycol exposure, but a normal osmolal gap is not reassuring and does not exclude the diagnosis for a number of reasons:
1. Many patients will have a negative resting osmolal gap. A toxic exposure of ethylene glycol may not raise the osmolal gap above the commonly quoted normal upper limit of +10 mOsmol/kg H20.
2. Patients who present late after significant ethylene glycol exposure following metabolism of the parent molecule will have a minimal increase in the osmolal gap (as ethylene glycol is the primary contributor to the increased measured osmolality). In this case the osmolal gap is likely to be normal, but there will be a significantly raised anion-gap metabolic acidosis.
A quantitative serum concentration of ethylene glycol may be useful to indicate the need for haemodialysis. Availability of serum ethylene glycol concentrations is often an issue in suspected cases of ingestion, and often the diagnosis has to be made on the basis of history and collaborative biochemical evidence. A peak ethylene glycol concentration of > 50 mg/dL is associated with severe toxicity. A peak of less than 20 mg/dL is not associated with severe toxicity, but this concentration is only reassuring in a clinically well patient without a metabolic acidosis (a low ethylene glycol concentration may be measured in late presenters following metabolism of the parent molecule).
See the following for lethal concentrations of alcohols and their corresponding osmolal gaps.
Molecular Weight: 46
Potentially Lethal Concentration (mg/dL): 350
Corresponding Osmolal Gap (Osmol/kg H2O): 75
Substance: Ethylene glycol
Molecular Weight: 62
Potentially Lethal Concentration (mg/dL): 200
Corresponding Osmolal Gap (Osmol/kg H2O): 35
Osmolal gap=(Ethanol [mg/dL])/3.7 – 0.35 or, in SI units:
Osmolal gap (Osmol/kg)=1.25 (Ethanol [mmol/L]) – 0.35
(from Purssell et al)
Monohydrate and dihydrate crystals form after a latent period of 4-8 hours, however calcium oxalate crystals in the urine are seen in less than 50% of cases of significant ethylene glycol poisoning. In addition the finding of urinary calcium oxalate crystals is not specific for ethylene glycol exposure. Therefore the absence of calcium oxalate crystals within the urine does not exclude the diagnosis of ethylene glycol poisoning.
Ethylene glycol is one of a number of drugs that can lead to an unconscious patient with a metabolic acidosis. Hypocalcaemia and a raised anion gap make the diagnosis more likely. A normal osmolal gap does not exclude significant ethylene glycol poisoning but a raised osmolal gap is very suggestive of poisoning with ethylene glycol, methanol or other toxic alcohols and ethers.
There are a number of derivatives of ethylene glycol such as the monomethyl, ethyl and butyl ethers. These may be converted to methanol or ethylene glycol and would be expected to cause similar toxicity. However clinical experience with these products is very limited. Diethylene glycol appears to have similar toxicity to ethylene glycol however larger compounds, triethylene glycol, polyethylene glycol appear to have much poorer absorption and are generally excreted unchanged by the kidney.
A dose of over 1 mL/kg body weight may cause significant toxicity or death.
The following clinical signs are associated with a poor prognosis and are an indication for intensive care admission and usually haemodialysis.
Initial management should be directed at stabilising airway, breathing and circulation. Treatment is then directed at limiting or preventing acidosis, renal failure and coma.
Patients should have IV access with generous IV fluids. Patients with established clinically significant poisoning should be managed in a critical care setting. Patients with a significant ethylene glycol ingestion who present early without an established metabolic acidosis may potentially be managed in a ward environment if fomepizole is used as an antidote. Acidosis (pH<7.3) should be corrected with bicarbonate. Hypocalcaemia should be corrected with intravenous calcium if clinically significant. Unnecessary correction of hypocalcaemia may lead to further calcium oxalate formation and tissue deposition. Seizures should be treated with benzodiazepines.
Ethylene glycol is very rapidly absorbed and is not well adsorbed to charcoal. In most patients therefore GIT decontamination will not be helpful.
Traditionally ethanol has been the mainstay of treatment however if available fomepizole should be first line treatment.
Ethanol has a higher affinity for alcohol dehydrogenase than ethylene glycol and competitively inhibits the metabolism of it to more toxic metabolites. Thus, it is most useful prior to the conversion of ethylene glycol to toxic metabolites and has little role in patients with low ethylene glycol concentrations and a marked acidosis. Ethanol is indicated for significant ethylene glycol ingestion (> 1 mL/kg or ethylene glycol concentration > 20 mg/dL). Ethanol should be given orally or intravenously if the oral route is not tolerated. A blood ethanol of 100 mg/dL (0.1 g/dL (%), 21.7 mmol/L) is required to maximally inhibit alcohol dehydrogenase.
Loading dose = Cp (target concentration) * Vd (volume of distribution)
= 1 g/L * 0.6 * body weight (kg)
= 0.6 g * body weight
Thus for a 60 to 70 kg adult the loading dose is 36 - 42 g of ethanol.
This is equivalent to:
The dose required to maintain this concentration is 5 - 10 g/hour (depending on whether the enzymes in the patient have been induced by chronic alcohol consumption). This rate should be doubled during dialysis. Ethanol concentrations should be monitored frequently and the rate adjusted accordingly.
This is an alcohol dehydrogenase inhibitor that is not generally available in some countries but is an alternative to ethanol therapy that is efficacious and safer to use than ethanol. It has a much longer half-life and dosing calculations are much easier than for alcohol. It is, however, a great deal more expensive than ethanol.
The product literature recommends a loading dose of 15 mg/kg given as 30 minute infusion followed by 10 mg/kg every 12 hours until ethylene glycol concentrations are low. Patients who have renal impairment will have prolonged EG elimination and will require longer duration of treatment with fomepizole. Fomepizole is dialysable and so the frequency of administration should increase to 4th hourly during dialysis. A 'standard' course in Australia is likely to cost in the order of $AUS6000- 8000.
Thiamine 100 mg QID and pyridoxine 50 mg QID should be considered in patients with significant poisoning. These increase the metabolism of glyoxylate to nontoxic metabolites. However there is no clinical evidence to support the effectiveness of these co-factors in otherwise healthy patients. They should be administered to patients who may be deficient in these co-factors, particularly alcoholics (magnesium should also be provided to these patients).
Treatment of specific complications such as seizures, cardiogenic shock is the same as for any patient. However, the primary aim should be to rapidly correct electrolyte and acid-base disturbances and to remove the toxic metabolites and prevent further formation of toxic metabolites with ethanol and haemodialysis.
Ethylene glycol and its metabolites including glycolate are cleared by haemodialysis. Haemodialysis also effectively corrects acid-base disturbances. Although haemoperfusion does remove ethylene glycol, clearance rates are significantly lower than haemodialysis and therefore this technique does not provide clinically significant removal of ethylene glycol or its metabolites.
The haemodialysis may also be used to correct the acidosis by using a bicarbonate dialysate. Haemodialysis should continue until the ethylene glycol concentration is < 20 mg/dL and the acidosis is largely corrected. Haemodialysis removes ethanol and the ethanol dose or infusion rate should be approximately doubled during dialysis. Fomepizole administration should be increased to 4th hourly.
It is possible the onset of toxicity may occur late, particularly in patients who have coingested alcohol and therebyinhibited the formation of toxic metabolites for a period of time. However if patients appear clinically well and have normalrenal function / acid-base status and have no measured ethylene glycol then they require no further treatment.Patients may be left with permanent renal damage and brain damage due to calcium oxalate crystal deposition.
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