All animals are susceptible to ethylene glycol (EG) toxicity, but it is most common in dogs and cats. Most intoxications are associated with ingestion of antifreeze, which is typically 95% EG. These 95% commercial antifreeze preparations are diluted ~50% with water when used in vehicle cooling systems. The widespread availability of antifreeze, its sweet taste and small minimum lethal dose, and the lack of public awareness of the toxicity (ie, improper storage and disposal) contribute to the frequency of this intoxication. In addition, antifreeze may be ingested by way of intentional poisoning or because it is the only available liquid in cold weather. Other sources of EG include some heat-exchange fluids used in solar collectors and ice-rink freezing equipment and some brake and transmission fluids. Cutaneous absorption from topical products that contain EG has been reported to cause toxicity in cats.
EG intoxication occurs most commonly in temperate and cold climates, because antifreeze is used both to decrease the freezing point and to increase the boiling point of radiator fluid. In colder climates, the incidence of EG intoxications is seasonal, with most cases occurring in the fall, winter, and early spring, when antifreeze is added to radiator fluid or when cooling systems are flushed.
The minimum lethal dose of undiluted EG is 1.4 mL/kg body wt in cats, 4.4 mL/kg in dogs, 7–8 mL/kg in poultry, and 2–10 mL/kg in cattle. Younger animals may be more susceptible.
EG is rapidly absorbed from the GI tract; in dogs, blood concentrations of EG peak within 3 hr of ingestion. Approximately 50% of ingested EG is excreted unchanged by the kidneys; however, a series of oxidation reactions in the liver and kidneys metabolize the remaining EG. Toxic metabolites of EG cause severe metabolic acidosis and renal tubular epithelial damage.
The first of two rate-limiting biotransformation steps is the production of glycoaldehyde from EG by the enzyme alcohol dehydrogenase. Glycolaldehyde is then rapidly metabolized to glycolic acid. The oxidation of glycolic acid to glyoxylic acid is the second rate-limiting step, which allows glycolic acid to accumulate, resulting in acidosis and nephrotoxicosis. Glyoxylic acid is rapidly metabolized to formic acid, carbon dioxide, glycine, serine, and oxalate. Oxalate is not further metabolized and is cytotoxic to the renal tubular epithelium and exacerbates the metabolic acidosis. Glycolic acid and oxalate are the metabolites thought to be most responsible for acute tubular necrosis associated with EG ingestion. Oxalate also combines with calcium to form a soluble complex that is excreted via glomerular filtration. Calcium oxalate crystals form within the lumina of tubules as water is reabsorbed from the glomerular filtrate and the pH decreases (smaller numbers of calcium oxalate crystals may also be observed in the adventitia of blood vessel walls throughout the body).
Clinical signs are dose- and time-dependent and can be divided into those caused by unmetabolized EG and those caused by its toxic metabolites. The onset of clinical signs is almost immediate and resembles alcohol (ethanol) intoxication. Dogs and cats exhibit vomiting due to GI irritation, polydipsia and polyuria, and neurologic signs (CNS depression, stupor, ataxia, knuckling, decreased withdrawal and righting reflexes). Polydipsia occurs due to osmotic stimulation of the thirst center, and polyuria occurs due to an osmotic diuresis and decreased production and release of antidiuretic hormone. As CNS depression increases in severity, dogs and cats drink less; however, the osmotic diuresis continues and results in dehydration. Dogs may appear to transiently recover from these CNS signs ~12 hr after ingestion.
Oliguric acute renal failure usually develops between 12 and 24 hr in cats and between 36 and 72 hr in dogs. Signs include lethargy, anorexia, dehydration, vomiting, diarrhea, oral ulcers, salivation, tachypnea, and possibly seizures or coma. The kidneys are often swollen and painful on abdominal palpation.
Pigs ingesting EG are usually depressed, weak, and reluctant to move; knuckling, posterior ataxia, trembling, collapse, abdominal distention, pulmonary edema, and muffled heart sounds are common sequelae. Poultry may become drowsy, ataxic, dyspneic, and recumbent; torticollis, ruffled feathers, and watery droppings are also seen. Cattle may become depressed, tachypneic, and ataxic, and develop paraparesis or recumbency. Epistaxis and hemoglobinuria have also been seen in cattle that have ingested large doses of EG.
Renal tubular epithelial necrosis with calcium oxalate crystals in the tubular lumina is the characteristic finding of EG intoxication. Calcium oxalate crystals appear birefringent when viewed with polarized light. Pulmonary edema and hemorrhagic gastroenteritis are common secondary findings in dogs and cats. Pigs and cattle often develop renal and perirenal edema. Pigs may also have pulmonary edema with tan fluid in the pleural and peritoneal cavities. Poultry usually do not develop gross lesions.
Diagnosis is often difficult because the nonspecific multisystemic signs may appear similar to other types of CNS disease or trauma, gastroenteritis, pancreatitis, ketoacidotic diabetes mellitus, and acute renal failure due to renal ischemia or other nephrotoxicants. If ingestion of EG is not witnessed, diagnosis is usually based on a combination of history, physical examination, and laboratory data.
Within 3 hr of ingestion of toxic doses of EG, dogs and cats develop normochloremic metabolic acidosis with an increased anion gap, minimally concentrated or isosthenuric urine with an acidic pH, and marked serum hyperosmolality with an increased osmolal gap. Serum osmolality can be increased as much as 100 mOsm/kg above normal (280–310 mOsm/kg) within 3 hr of EG ingestion. The difference between measured and calculated (1.86 [Na+ + K+] + glucose/18 + BUN/2.8 + 9) osmolality is referred to as the osmolal gap. The gap is caused by the presence of osmotically active particles (eg, ethylene glycol) in the serum that are not factored into the above equation. Calcium oxalate crystalluria may be observed as early as 3 and 6 hr after ingestion in cats and dogs, respectively. Monohydrate calcium oxalate crystals (clear, 6-sided prisms) are more common than dihydrate calcium oxalate crystals (maltese cross or envelope-shaped). EG concentrations in serum and urine are detectable by 1–2 hr after ingestion. Commercial test kits can detect serum EG concentrations of ≥50 mg/dL. Some antifreeze preparations contain fluorescein, which appears bright yellow-green when viewed under a Wood’s lamp. Urine fluorescence has been used as a qualitative adjunctive test in suspected EG ingestions in people and may be of value in veterinary medicine. Hyperphosphatemia has been seen in dogs within 3 hr of ingestion of commercial antifreeze solutions that contain phosphate rust inhibitors. This hyperphosphatemia resolves before the onset of EG-induced acute renal failure and azotemia, then recurs when the animal becomes azotemic.
The prognosis varies inversely with the amount of time that elapses between ingestion and initiation of treatment. Treatment is aimed at decreasing absorption of ingested EG, increasing excretion of unmetabolized EG, preventing metabolism of EG, and correcting the metabolic acidosis that occurs with EG metabolism. Further absorption of EG is prevented by induction of emesis or gastric lavage (or both) within 1–2 hr of ingestion, although the rapidity of EG absorption from the GI tract suggests these procedures may not be beneficial. Vomiting should not be induced in a dog or cat exhibiting neurologic signs because of increased risk of aspiration. Activated charcoal is not likely to reduce absorption of EG from the GI tract. Once absorption has occurred, excretion of EG is increased by fluid therapy designed to correct dehydration and increase urine production. To prevent metabolism of EG, the activity of alcohol dehydrogenase is decreased by direct inactivation or by competitive inhibition. 4-Methylpyrazole (4-MP, fomepizole) effectively inactivates alcohol dehydrogenase in dogs without the adverse effects of ethanol and is the treatment of choice. The dose of 4-MP (5% solution [50 mg/mL]) is 20 mg/kg body wt, IV, initially, followed by 15 mg/kg, IV, at 12 and 24 hr, and 5 mg/kg, IV, at 36 hr. Commercial formulations of 4-MP are available. If 4-MP is not available, an ethanol regimen (5.5 mL of 20% ethanol/kg body wt, IV, every 4 hr for five treatments and then every 6 hr for four additional treatments) is recommended.
In cats, 4-MP is ineffective at the canine dosage, and either a higher, extra-label dosage (125 mg/kg initially, followed by 31.3 mg/kg at 12, 24, and 36 hr after the initial dose) or ethanol is used. The recommended dosage is 5 mL of 20% ethanol/kg body wt diluted in IV fluids and given as a drip over 6 hr for five treatments, and then over 8 hr for four more treatments.
The metabolic acidosis associated with metabolism of EG is corrected by administration of sodium bicarbonate. The formula 0.3 − (0.5 × kg body wt) × (24 − plasma bicarbonate) is used to determine the dose, in mEq of bicarbonate. One-half of this dose should be given IV slowly to prevent overdose, and plasma bicarbonate concentrations should be monitored every 4–6 hr. Additional doses of bicarbonate based on the above formula are frequently necessary. Monitoring urine pH may also be helpful, with a goal of maintaining the urine pH between 7.0 and 7.5.
In dogs and cats with azotemia or in oliguric acute renal failure, inhibition of alcohol dehydrogenase is of little benefit, because almost all of the EG has already been metabolized. The prognosis for these animals is guarded to poor. Treatment should include correction of fluid, electrolyte, and acid-base disorders and, if possible, induction of diuresis.