A Winter’s Tale: Ethylene Glycol

Katherine Earl, DVM, discusses ethylene glycol toxicity in dogs and cats including clinical signs, treatment options, and monitoring these patients in the hospital.

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Given the recent overall trend for a drier but very cold winter season, ethylene glycol as an intoxication may become more prevalent in our metro area. Ethylene glycol can be found in numerous car fluids (motor fluid, brake fluid, etc.), photographic developing mediums, paints, wood thinners and most prominent in our minds – antifreeze - which is 95% ethylene glycol. Pets gain access to antifreeze in the classic puddle left over from servicing a car or leaking from a radiator. The minimum lethal dose is very small: roughly 4.4 ml/kg in dogs and 1.5 ml/kg in cats which translates to roughly one tablespoon for a 10 pound dog and one teaspoon for a 7 pound cat.

Once ingested, ethylene glycol is rapidly absorbed from the gastrointestinal tract and converted to glycoaldehyde via alcohol dehydrogenase (ADH) in the liver. Further metabolites are produced with the key one being glycolic acid which is metabolized to glyoxylic acid and finally to oxalic acid. Oxalic acid circulates and binds with calcium to form calcium oxalate monohydrate crystals which are internalized by renal tubule cells and result in cell death and by extension renal failure.

Clinical signs associated with antifreeze ingestion can be divided into two stages: (1) ethylene glycol associated and (2) metabolite associated which follow in sequence. In stage 1 the ingestion of ethylene glycol itself acts as a central nervous system depressant in addition to causing gastric irritation. Physical manifestations of this stage include vomiting, depression, ataxia, and – in dogs – polyuria/polydipsia initially due to the osmotic diuresis. The onset of clinical signs is roughly 30 minutes post ingestion with signs persisting up to 12 hours after ingestion. Dogs after this time point may appear to “recover,” while cats do not recover and remain neurologically depressed.

Stage 2 occurs roughly 36 to 72 hours post ingestion in dogs (12 to 24 hours post ingestion in cats) and is manifested by a marked metabolic acidosis and renal failure. Clinical signs are similar to those in stage 1 but with different underlying etiologies: vomiting due to uremia secondary to renal failure, obtundation/depression due to level of acidosis. For both dogs and cats within 72 to 96 hours of ingestion, anuric renal failure develops carrying a grave prognosis.

Diagnosis of ethylene glycol intoxication initially is largely based on clinical suspicion given presentation and history. Early changes in a routine minimum database that may support the diagnosis are attributed to the presence of the metabolites of ethylene glycol that result in a metabolic acidosis. Within 1 hour of significant ingestion, decreased bicarbonate concentration may be appreciated and an increased anion gap is seen by 3 hours post ingestion and may remain increased for up to 48 hours post ingestion.

Later in the clinical course azotemia becomes apparent – between 24 to 48 hours post ingestion in dogs and only ~ 12 hours post ingestion in cats. Two other biochemical changes that may be noted at this stage are: hypocalcemia and hyperglycemia (in roughly 50% of affected animals). Hypocalcemia is attributed to the formation of calcium oxalate crystals. Hyperglycemia may be associated with both the effects of increased circulating insulin antagonists such as epinephrine and the inhibition of glucose metabolism by aldehydes produced in ethylene glycol breakdown.

Confirming a diagnosis of ethylene glycol consists of documenting ethylene glycol serum concentrations. Several bedside test kits have been developed that typically detect greater than or equal to 50 mg/dl. Serum concentrations peak up to 6 hours post ingestion and are no longer detectable at 48 to 72 hours post ingestion due to metabolism of the parent compound. Unfortunately the toxic dose for cats can be below the detectable level and results can be confounded by concurrent administration of other compounds such as ethanol. The gold standard for ethylene glycol detection is gas chromatography which – while not available readily in house – is an analysis that can be performed under STAT conditions at a human laboratory.

If neither of the above modalities is available, calculation of serum osmolality can provide strong supportive evidence as it increases within 1 hour of ingestion and in parallel with ethylene glycol serum concentrations. Serum osmolality can be calculated from the following equation:

2 (Na + K) + glucose/18 + BUN/2.8

Normal serum osmolality ranges from 280 to 310 mOsm/kg with a normal osmolal gap of < 10 mOsm/kg. The value for the osmolal gap can be multiplied by a factor of 5 to obtain a close approximation to the serum concentration of ethylene glycol. In addition some formulations of antifreeze have sodium fluorescein present within it that can be detected via Wood’s lamp on the pet’s fur, mouth, paws and in the urine where it is excreted up to 6 hours post ingestion.

One of the most key principles of treatment for ethylene glycol intoxication is to start antidotal therapy prior to confirmation of ingestion and not delay treatment if a high index of suspicion exists. Treatment predominantly centers on preventing metabolism of ethylene glycol while increasing its excretion. Since ethylene glycol is so rapidly absorbed, it is no longer recommended to induce emesis/perform gastric lavage unless within 2 hours of known ingestion. Activated charcoal is not recommended as it does not adsorb ethylene glycol readily and when administered with sorbitol, it may confound potential confirmatory tests.

There are predominantly two possible treatments for ethylene glycol ingestion – administration of ethanol (intravenous or orally) or administration of fomepizole (4-Methyl H-pyrozole). The former works by providing a competitive substrate for ADH as ethanol has significantly greater affinity for ADH than ethylene glycol. Ethanol may be given intravenously every 4 hours (given its short half-life) or as a CRI. The preferred protocol here at DoveLewis is the latter with an initial 1.3 ml/kg bolus of 30% ethanol followed by a CRI of 0.42 ml/kg/hour for 48 hours. Complications of ethanol treatment include considerable CNS depression, polyuria, and metabolic acidosis. Oral ethanol administration has even more complications as the oral route increases gastric irritation and may result in increased emesis and significant dehydration.

Fomepizole acts as a direct inhibitor of ADH and therefore has fewer side effects compared to ethanol. The predominant limiting factor of fomepizole administration is cost. The canine protocol consists of an initial 20 mg/kg bolus followed by 15 mg/kg administered at 12 and 24 hours post and ending with 5 mg/kg at 36 hours post or until ethylene glycol serum levels are nil. Cats can receive treatment with fomepizole at a higher dose protocol: initial 125 mg/kg bolus followed by 31.3 mg/kg doses at 12, 24 and 36 hours post.  Coupled with either ethanol or fomepizole administration, supportive care including intravenous fluids and serial monitoring is recommended.

If the pet presents past the point where ADH inhibition would be useful, but prior to detectable azotemia, continuous renal replacement therapy or dialysis can be used to remove the metabolites of ethylene glycol before renal failure occurs. If the pet is already azotemic on presentation, treatment should be directed at managing anuric/oliguric renal failure either with hemodialysis/peritoneal dialysis or aggressive medical management (diuresis, furosemide, and mannitol).  Animals that survive this stage may take up to a year to regain renal function and – in some cases – may remain in chronic renal failure.

Prognosis for ethylene glycol toxicity when treated early is good to excellent: studies have demonstrated positive outcome when fomepizole can be administered within 5 hours to dogs and within 3 hours to cats. Once azotemia has developed, prognosis becomes grave. In times of changing weather and freezing rain, it is important to keep ethylene glycol toxicity on the differential list as missing it can be literally a matter of life or death.

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Justine Lee's picture

Hmm. Stage 2 is typically 12-24 hours in dogs and is a very nebulous stage as it's ill defined. I would call 36-72 hours Stage 3, IMO. (dogs)

Stephanie  Cowan 's picture

How useful is urinalysis in terms of appreciating renal dysfunction in these cases?