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=Ethylene Glycol=

==OVERVIEW==

Ethylene glycol is a sweet tasting compound that is used as an antifreeze. It has properties similar to alcohol but is converted by alcohol dehydrogenase to toxic metabolites that cause a severe metabolic acidosis and renal toxicity. Treatment with alcohol or fomepizole and haemodialysis may be life saving.

==MECHANISM OF TOXIC EFFECTS==

The metabolic acidosis results from accumulation of acid metabolites of ethylene glycol and from promotion of lactic acid formation due to reduced NAD/NADH ratios. Oxalate metabolites cause renal toxicity and oxalate crystals may be seen in the urine.

===Ethylene glycol metabolism [[image:ethylene.gif align="center"]]===
==KINETICS IN OVERDOSE==

===Absorption===
Ethylene glycol is rapidly absorbed with peak concentrations occurring within 1-2 hours.

===Distribution===
Ethylene glycol has high water and lipid solubility and a volume of distribution similar to body water (0.6 L/kg).

===Metabolism - Elimination===
Some ethylene glycol is excreted unchanged in the urine however the major pathway is metabolism by alcohol dehydrogenase to
glycoaldehyde from which aldehyde dehydrogenase forms glyoxalate. Further metabolism to nontoxic substances requires pyridoxine, [[Thiamine|thiamine]] and [[Magnesium Treatment|magnesium]] .

==CLINICAL EFFECTS==

===Central nervous system effects===
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.

===Cardiac effects===
With the development of acidosis, [[Heart rates|tachycardia]], tachypnoea and hypertension may occur however more severe toxicity is manifested by hypotension and cardiogenic shock.

===Renal effects===
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.

===Metabolic effects===
The major features seen are a severe acidosis with a raised [[ANION GAP ACIDOSIS|anion gap]]. The [[Osmolal Gap|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.

==INVESTIGATIONS==

===Biochemistry===
The patients should have their electrolytes (including calcium, magnesium) measured.
These electrolytes should be repeated regularly in confirmed cases of ethylene glycol poisoning as late deterioration may
occur.

===Blood concentrations===
**Conversion factor**
* g/L x 16.1 = mmol/L
* mmol/L x 0.062 = g/L
A quantitative serum concentration of ethylene glycol may be useful to indicate the need for [[3.2.3.1.1 Haemodialysis|haemodialysis]].

==DIFFERENTIAL DIAGNOSIS==

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, [[2.2.5.2.5 Methanol|methanol]] or other toxic alcohols and
ethers .

==DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS==

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.

==DETERMINATION OF SEVERITY==

===Ingested dose===
A dose of over 1 mL/kg body weight may cause significant toxicity or death.

===Prognostic features===
The following clinical signs are associated with a poor prognosis and are an indication for intensive care admission and
usually haemodialysis.
* Coma
* [[Status Epilepticus and Treatment of Seizures|Seizures]]
* Renal failure
* Hypotension
* Ethylene glycol concentration > 50 mg/dL
* Calcium oxalate crystals in the urine
* Severe acidosis (pH < 7.1)
* Hyperkalaemia

==TREATMENT==

===Supportive===
Patients should have IV access with generous[[3.4.8 Fluid Resuscitation| IV fluids]]. Patients with clinically significant poisoning should be monitored in
intensive care. Acidosis should be corrected with bicarbonate. Hypocalcaemia should be corrected with intravenous calcium.

===GI Decontamination===
Ethylene glycol is very rapidly absorbed and is not well adsorbed to [[3.2.2.2.3 Activated charcoal|charcoal]]. In most patients therefore GIT decontamination will not be helpful.

===Antidotes===
Traditionally ethanol has been the mainstay of treatment however if available 4-Methyl pyrazole (fomepizole) should be first
line treatment.

**Ethanol**
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 intravenously or
orally if the intravenous preparation is not available. A blood alcohol of 100 mg/dL (0.1 g/dL (%), 21.7 mmol/L) is required
to maximally inhibit alcohol dehydrogenase.

**//Loading dose//**
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
* 4 standard drinks (4 * 30 mL of spirits)
>> or
* 360 to 420 mL of 10% ethanol IV

**//Maintenance dose//**
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 and the rate adjusted accordingly.

**4-Methyl pyrazole (fomepizole)**
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 $AUS8000.

**Vitamins**
Thiamine 100 mg QID and pyridoxine 50 mg QID should be given to patients with significant poisoning. These increase the
metabolism of glyoxalate to nontoxic metabolites.

===Treatment of specific complications===
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.

===Elimination enhancement===
Ethylene glycol and its metabolites are cleared by haemodialysis.

**Haemodialysis**
//Indications//
* renal failure
* severe metabolic acidosis (pH < 7.1)
* calcium oxalate crystals in the urine
* ethylene glycol concentration > 50 mg/dL

The haemodialysis may also be used to correct the acidosis by using a bicarbonate dialysate. Haemodialysis should continue
until the ethylene glycol is < 10 mg/dL and the acidosis is largely corrected. Haemodialysis removes ethanol and the ethanol
infusion rate should be approximately doubled during dialysis. Fomepizole administration should be increased to 4th hourly.

==LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP==

It is possible the onset of toxicity may occur late, particularly in patients who have coingested alcohol and thereby
inhibited the formation of toxic metabolites for a period of time. However if patients appear clinically well and have normal
renal function and have no measured ethylene glycol then they require no further treatment.
Patients may be left with permanent renal damage and brain damage.

==REFERENCES==

[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8814469&dopt=Abstract|Hylander B, Kjellstrand CM.]] Prognostic factors and treatment of severe ethylene glycol intoxication. Int Care Med 1996;22:546.
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10080845&dopt=Abstract|Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K. ]]Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med. 1999 Mar 18;340(11):832-8.
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10497633&dopt=Abstract|Barceloux DG, Krenzelok EP, Olson K, Watson W. ]]American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol. 1999;37(5):537-60.
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10918102|Sivilotti ML, Burns MJ, Mc Martin KE, Brent J]]. Toxicokinetics of ethylene glycol during fomepizole therapy: Implications for management. Ann Emerg Medicine 2000; 36(2): 114-125
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