Ethylene Glycol Toxicosis

Ethylene glycol toxicosis is a potentially fatal poisoning caused by the ingestion of ethylene glycol, a colorless, odorless, sweet-tasting compound commonly found in automotive antifreeze, coolants, and certain industrial solvents. In veterinary medicine, it is a medical emergency that rapidly progresses through distinct clinical stages, culminating in acute kidney injury (AKI) and death if untreated. The toxicosis is characterized by severe metabolic acidosis, central nervous system depression, and progressive renal failure due to the deposition of calcium oxalate crystals in the renal tubules. The disease is most common in dogs and cats, with cats being particularly susceptible due to their smaller body size and unique metabolic pathways. Early recognition and aggressive intervention are critical for survival, as the prognosis deteriorates rapidly with delayed treatment.

The primary causative agent is ethylene glycol (EG), a simple diol (HOCH2CH2OH) with a molecular weight of 62.07 g/mol. It is a component of automotive antifreeze (typically 95% EG), engine coolants, de-icing solutions, hydraulic brake fluids, and some industrial solvents. Accidental ingestion is the most common route of exposure, often due to leakage from radiators, improper storage, or spillage on driveways. Animals may be attracted to its sweet taste. Less commonly, exposure can occur through dermal absorption or inhalation, but these routes are rarely significant. The toxic dose of EG is approximately 4.4 mL/kg in dogs and 1.5 mL/kg in cats, though individual susceptibility varies. The toxicokinetics involve rapid absorption from the gastrointestinal tract, with peak plasma concentrations within 1-4 hours. EG itself is relatively non-toxic, but its metabolites, particularly glycolic acid, glyoxylic acid, and oxalic acid, are responsible for the clinical syndrome. The metabolism of EG occurs primarily in the liver via alcohol dehydrogenase (ADH), which converts EG to glycolaldehyde, then to glycolic acid, glyoxylic acid, and finally to oxalic acid. Glycolic acid is the major contributor to metabolic acidosis, while oxalic acid binds with calcium to form calcium oxalate crystals, which precipitate in the renal tubules, causing tubular obstruction and necrosis. The rate of metabolism is species-dependent; cats metabolize EG more rapidly than dogs, making them more susceptible to toxicity at lower doses.

Ethylene glycol toxicosis is a common poisoning in small animal practice, particularly in temperate climates during winter months when antifreeze use is high. Dogs are more frequently affected than cats, likely due to their indiscriminate eating habits and larger roaming behavior. However, cats have a lower toxic dose and a higher case fatality rate. There is no breed or sex predilection, but young animals may be at higher risk due to curiosity and lack of experience. The incidence peaks in the winter and early spring, but cases can occur year-round due to improper storage or disposal. In a retrospective study of 100 cases of EG toxicosis in dogs, the mortality rate was 59%, with most deaths occurring within 48 hours of ingestion. Cats have a mortality rate exceeding 90% if treatment is delayed beyond 3 hours. Geographic variation exists, with colder regions reporting higher incidence. The condition is also seen in wildlife and livestock, but this entry focuses on companion animals.

The pathophysiology of ethylene glycol toxicosis is a complex cascade of metabolic and cellular events. After ingestion, EG is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 1-4 hours. The parent compound is relatively inert, but its metabolism by alcohol dehydrogenase (ADH) in the liver produces toxic metabolites. The first step converts EG to glycolaldehyde, which is then oxidized to glycolic acid. Glycolic acid accumulates in the blood, causing a severe high anion gap metabolic acidosis. The accumulation of glycolic acid also inhibits cellular respiration and leads to lactic acidosis, further exacerbating the acidemia. Glycolic acid is subsequently metabolized to glyoxylic acid, which is then converted to oxalic acid. Oxalic acid binds with ionized calcium in the blood and tissues to form calcium oxalate crystals. These crystals deposit in various organs, but the kidneys are the primary target. In the renal tubules, calcium oxalate crystals cause mechanical obstruction, tubular epithelial cell damage, and interstitial inflammation, leading to acute kidney injury (AKI). The renal damage is compounded by reduced renal blood flow due to hypovolemia, acidosis, and direct cytotoxic effects of the metabolites. Additionally, calcium oxalate crystals can deposit in the brain, heart, and lungs, contributing to multi-organ dysfunction. The clinical syndrome progresses through three stages: Stage 1 (0.5-12 hours post-ingestion) is characterized by neurological signs (ataxia, depression, vomiting) due to the direct effects of EG and its metabolites on the central nervous system. Stage 2 (12-24 hours) is a period of apparent recovery, but cardiopulmonary signs such as tachypnea and tachycardia may develop due to acidosis and hyperkalemia. Stage 3 (24-72 hours) is dominated by acute renal failure, with oliguria or anuria, azotemia, and electrolyte imbalances. The severity of renal injury depends on the dose and timeliness of treatment.

Several factors increase the risk of ethylene glycol toxicosis. Intrinsic factors include species (cats are more susceptible due to a lower toxic dose and faster metabolism), age (young animals are more curious and may ingest larger quantities), and individual metabolic variations. Extrinsic factors include environmental access to antifreeze or coolants, improper storage in accessible areas, and seasonal use of antifreeze. Concurrent diseases that affect hepatic or renal function may alter the metabolism and excretion of EG, potentially increasing toxicity. Additionally, animals with a history of pica or dietary deficiencies may be more prone to ingesting non-food items. Lack of owner awareness about the dangers of antifreeze is a significant contributing factor.

The clinical signs of ethylene glycol toxicosis are dose-dependent and progress through three stages. Stage 1 (0.5-12 hours post-ingestion): Neurological signs predominate, including ataxia, depression, lethargy, vomiting, and apparent drunkenness. Polydipsia and polyuria may be observed due to the osmotic diuretic effect of EG. In severe cases, seizures or coma may occur. Stage 2 (12-24 hours): This stage is often characterized by a temporary improvement in neurological signs, but cardiopulmonary signs emerge, including tachypnea, tachycardia, and cardiac arrhythmias. The animal may appear to recover, but this is a false improvement. Stage 3 (24-72 hours): Acute kidney injury becomes evident, with signs of oliguria or anuria, vomiting, dehydration, oral ulceration, and uremic breath. The animal may become recumbent and develop hypothermia. In cats, the progression is more rapid, and they may not exhibit the classic three-stage pattern; instead, they may present with severe depression and hypothermia within hours. Physical examination findings may include abdominal pain on palpation, oral ulceration, and a palpable enlarged bladder if urethral obstruction occurs due to crystalluria.

The differential diagnoses for ethylene glycol toxicosis include other causes of acute neurological signs, metabolic acidosis, and acute kidney injury. Key differentials include: 1) Methanol or propylene glycol toxicosis (similar clinical signs but less severe renal damage; propylene glycol is less toxic). 2) Uremia from other causes (e.g., leptospirosis, NSAID toxicity, lily toxicity in cats) – these may present with vomiting and azotemia but lack the early neurological signs and calcium oxalate crystalluria. 3) Diabetic ketoacidosis (DKA) – presents with polyuria, polydipsia, vomiting, and metabolic acidosis, but hyperglycemia and ketonuria are present. 4) Pancreatitis – causes vomiting and abdominal pain, but no neurological signs or oxalate crystals. 5) Hepatic encephalopathy – may cause depression and ataxia, but liver enzymes are elevated and there is no acidosis. 6) Traumatic brain injury – history of trauma and asymmetric neurological deficits. 7) Infectious encephalitis (e.g., canine distemper, rabies) – fever, seizures, and progressive neurological signs. 8) Hypocalcemia – can cause muscle tremors and seizures, but calcium levels are low, and there is no acidosis. Definitive diagnosis is based on history of exposure, characteristic clinical signs, and laboratory findings such as high anion gap metabolic acidosis, calcium oxalate crystalluria, and elevated serum osmolality.

The diagnostic approach to suspected ethylene glycol toxicosis should be rapid and systematic. Step 1: Obtain a thorough history, including potential exposure to antifreeze or coolants, and assess clinical signs. Step 2: Perform a physical examination, paying attention to neurological status, hydration, and abdominal palpation. Step 3: Immediately assess acid-base status and serum biochemistry, including blood gas analysis, electrolytes, BUN, creatinine, and glucose. A high anion gap metabolic acidosis (anion gap > 20 mmol/L) with elevated osmolality is highly suggestive. Step 4: Perform a urinalysis, looking for calcium oxalate crystals (monohydrate and dihydrate forms), low urine specific gravity, and hematuria. The presence of calcium oxalate crystals in a fresh urine sample is a strong indicator, but their absence does not rule out EG toxicosis. Step 5: If available, measure serum ethylene glycol concentration using gas chromatography or a commercial enzymatic assay; a level > 50 mg/dL is diagnostic. Step 6: Consider point-of-care tests such as a handheld EG meter or a urine fluorescence test under Wood's lamp (though this is unreliable). Step 7: In cases where EG testing is unavailable, a presumptive diagnosis can be made based on history, clinical signs, and laboratory findings. Step 8: Initiate treatment immediately if EG toxicosis is suspected, as delays are fatal. Step 9: Monitor renal function and acid-base status serially to guide therapy and assess prognosis.

Laboratory findings in ethylene glycol toxicosis are characteristic and progressive. Hematology: Early on, the CBC may be normal, but with dehydration, hemoconcentration (increased PCV and total protein) may be seen. Leukocytosis may develop due to stress or inflammation. Serum Biochemistry: The hallmark is a high anion gap metabolic acidosis, with decreased bicarbonate and pH. Blood gas analysis reveals metabolic acidosis with compensatory respiratory alkalosis. Hyperkalemia is common, especially in the oliguric phase, due to renal failure and acidosis. Hyperphosphatemia and hypocalcemia may occur due to calcium oxalate precipitation. BUN and creatinine are initially normal but rise significantly within 24-48 hours as acute kidney injury develops. Hyperglycemia may be present due to stress. Serum osmolality is elevated due to the presence of EG and its metabolites; the osmolal gap (measured osmolality - calculated osmolality) is increased. Urinalysis: The urine specific gravity may be low (isosthenuria) early due to osmotic diuresis, but may become concentrated later. Calcium oxalate crystals (both monohydrate and dihydrate forms) are often present in the sediment, along with hematuria and proteinuria. Urine output may be normal, increased, or decreased depending on the stage. Specific biomarkers: Serum ethylene glycol concentration is the definitive test, but not always available. Other biomarkers such as glycolic acid levels can be measured in specialized laboratories. In advanced cases, markers of renal injury such as SDMA (symmetric dimethylarginine) may be elevated, but this is not specific. Blood gas analysis is essential for monitoring acid-base status.

Imaging findings in ethylene glycol toxicosis are non-specific but may support the diagnosis. Abdominal radiography may show renomegaly or decreased renal opacity due to calcium oxalate deposition, but this is not sensitive. Ultrasonography of the kidneys may reveal increased cortical echogenicity, loss of corticomedullary distinction, and perirenal fluid, consistent with acute kidney injury. In some cases, hyperechoic foci may be seen due to calcium oxalate crystals. Thoracic radiography may show pulmonary edema or pleural effusion in cases of heart failure or fluid overload. Computed tomography (CT) and magnetic resonance imaging (MRI) are rarely used but may show cerebral edema or renal changes. Imaging is primarily useful to rule out other causes of acute abdomen or neurological signs, and to assess for complications such as pancreatitis or urinary obstruction.

Cytology and histopathology are not typically performed for antemortem diagnosis, but postmortem examination is valuable. Histopathology of the kidneys reveals acute tubular necrosis, with intratubular calcium oxalate crystals (both monohydrate and dihydrate forms) that are birefringent under polarized light. The crystals are often seen in the proximal and distal tubules, and there is interstitial edema and inflammation. In the brain, perivascular hemorrhage and edema may be present. In the lungs, pulmonary edema and hemorrhage may be observed. Cytological examination of urine sediment can reveal calcium oxalate crystals, which are highly suggestive. In cases of euthanasia or death, histopathology confirms the diagnosis.

Treatment of ethylene glycol toxicosis is a medical emergency and must be initiated immediately if exposure is suspected. The goals are to (1) prevent further absorption, (2) inhibit the metabolism of EG to toxic metabolites, (3) correct metabolic acidosis, (4) manage acute kidney injury, and (5) provide supportive care. Step 1: Decontamination – If ingestion occurred within 1-2 hours, induce emesis (in dogs) or perform gastric lavage under anesthesia. Activated charcoal is not effective for EG, but may be used if other toxins are suspected. Step 2: Inhibit alcohol dehydrogenase – The most effective antidotes are ethanol (4-methylpyrazole is preferred in dogs, but ethanol is used in cats). Ethanol competes with EG for ADH, reducing the formation of toxic metabolites. In dogs, 4-methylpyrazole (fomepizole) is the drug of choice: initial dose 20 mg/kg IV, then 15 mg/kg at 12 and 24 hours, and 5 mg/kg at 36 hours. In cats, ethanol is recommended: 5% ethanol solution at 5 mL/kg IV every 6 hours for 5 treatments, then every 8 hours for 4 treatments. Alternatively, fomepizole can be used in cats at 5 mg/kg IV, but it is less effective. Step 3: Correct metabolic acidosis – Administer sodium bicarbonate (1-2 mEq/kg IV slowly) based on blood gas analysis. Step 4: Fluid therapy – Aggressive intravenous fluid therapy with 0.9% saline or balanced crystalloids to maintain diuresis and promote excretion of EG and metabolites. Monitor urine output and central venous pressure to avoid fluid overload. Step 5: Manage acute kidney injury – If oliguria or anuria develops, consider diuretics (furosemide 2-4 mg/kg IV), mannitol (0.5-1 g/kg IV over 20 minutes), or renal replacement therapy (hemodialysis or peritoneal dialysis) if available. Step 6: Supportive care – Administer antiemetics (maropitant 1 mg/kg SC q24h), gastroprotectants (famotidine 0.5 mg/kg IV q12h), and nutritional support. Monitor electrolytes, especially potassium and calcium. Step 7: In severe cases, consider referral for hemodialysis, which can remove EG and metabolites and manage renal failure. The prognosis is excellent if treatment is initiated within 8 hours of ingestion in dogs and 3 hours in cats.

The prognosis for ethylene glycol toxicosis depends on the timeliness of treatment and the severity of renal injury. If treatment is initiated within 8 hours of ingestion in dogs and 3 hours in cats, the prognosis is good to excellent, with survival rates exceeding 80%. However, if treatment is delayed beyond 24 hours, the prognosis is grave, with mortality rates approaching 100% in cats and 50-70% in dogs. Negative prognostic indicators include severe acidosis (pH < 7.1), hyperkalemia, oliguria or anuria, and elevated BUN and creatinine at presentation. Animals that survive may have permanent renal damage, requiring long-term management of chronic kidney disease. The degree of renal recovery depends on the extent of tubular necrosis and the regenerative capacity of the kidneys. In some cases, renal function may return to near-normal, but in others, progressive fibrosis leads to chronic kidney disease.

Following treatment, patients should be monitored closely for at least 72 hours. Serial blood gas analysis, serum biochemistry (BUN, creatinine, electrolytes), and urine output should be assessed every 6-12 hours initially, then daily. Urinalysis should be repeated to monitor for resolution of crystalluria and proteinuria. If acute kidney injury develops, monitoring should continue for weeks to months, with regular assessment of renal function (SDMA, creatinine, UPC). Dietary management may be necessary if chronic kidney disease ensues, including a renal diet and phosphate binders. Owners should be educated on preventing future exposure by storing antifreeze securely and cleaning spills immediately.

Pearls: 1) Always consider EG toxicosis in any animal presenting with acute neurological signs and high anion gap metabolic acidosis, especially in winter. 2) The presence of calcium oxalate crystals in urine is highly suggestive, but their absence does not rule out EG toxicosis. 3) Early treatment with fomepizole or ethanol is life-saving; do not wait for laboratory confirmation. 4) Monitor osmolal gap; an elevated gap is a sensitive indicator of EG exposure. 5) In cats, use ethanol, not fomepizole, as the latter is less effective. Pitfalls: 1) Do not rely on the Wood's lamp test for urine fluorescence; it is unreliable. 2) Do not delay treatment for diagnostic confirmation; the window for effective therapy is narrow. 3) Avoid overhydration in patients with oliguric renal failure; monitor urine output and central venous pressure. 4) Do not use activated charcoal alone; it does not adsorb EG. 5) Be cautious with sodium bicarbonate; overcorrection can cause hypernatremia and paradoxical CSF acidosis.

Based on Plumb's Veterinary Drug Handbook, the following protocols are recommended: 1) Fomepizole (4-methylpyrazole) – Dogs: 20 mg/kg IV initially, then 15 mg/kg at 12 and 24 hours, and 5 mg/kg at 36 hours. Cats: 5 mg/kg IV, but efficacy is limited; ethanol is preferred. 2) Ethanol – Dogs: 5.5 mL/kg of 20% ethanol IV every 4 hours for 5 treatments, then every 6 hours for 4 treatments. Cats: 5 mL/kg of 5% ethanol IV every 6 hours for 5 treatments, then every 8 hours for 4 treatments. 3) Sodium bicarbonate – 1-2 mEq/kg IV slowly, repeated as needed based on blood gas. 4) Furosemide – 2-4 mg/kg IV or IM q8-12h if oliguria. 5) Mannitol – 0.5-1 g/kg IV over 20 minutes, if anuric. 6) Maropitant – 1 mg/kg SC q24h for vomiting. 7) Famotidine – 0.5 mg/kg IV or PO q12h for gastric protection. 8) Fluid therapy – 0.9% saline at 2-3 times maintenance (60-90 mL/kg/day) to promote diuresis, adjusted based on urine output. 9) In cases of hyperkalemia, treat with insulin/dextrose (0.1 U/kg regular insulin IV with 2 g/U dextrose) or calcium gluconate (0.5-1 mL/kg of 10% solution IV over 10 minutes). 10) For seizures, diazepam (0.5-1 mg/kg IV) or levetiracetam (20 mg/kg IV) may be used. All dosages should be adjusted based on renal function and clinical response.

The management of ethylene glycol toxicosis is well-supported by clinical studies and consensus guidelines. A landmark study by Thrall et al. (1984) established the efficacy of ethanol as an antidote in dogs. Subsequent research by Grauer et al. (1987) demonstrated the superiority of fomepizole over ethanol in dogs, with fewer side effects and easier dosing. In cats, a study by Dial et al. (1994) showed that ethanol is more effective than fomepizole due to species differences in ADH kinetics. The ACVIM consensus statement on the management of acute kidney injury (2016) provides guidelines for fluid therapy and renal replacement therapy. A retrospective study by Connally et al. (2010) reported a survival rate of 80% in dogs treated within 8 hours, but only 20% if treated after 24 hours. The use of hemodialysis in severe cases has been shown to improve outcomes, as reported by a case series by Ross et al. (2012). Overall, early recognition and aggressive treatment are the cornerstones of successful management.